Document R2ByKOzGjykwJNBzNd7aN2awa

A CRIaTEeS BmeT ARI6-0257 TWO YEAR ORAL (DIET) TOXICITY / CARCINOGENICITY STUDY OF FLUOROCHEMICAL FM-3924 IN RATS (RIKER Experiment No. 0281CR0012) Conducted During April, 1981 - - May, 1983 tue 101 8 RIKER Laboratories, Inc. / 3M Company St. Paul, Minnesota 55144-1000 U.S.A. 01482 THO YEAR STUDY OOFRALFLU(ODRIOETC)HETMIOCXAILCITFYH/-C3A92R4CINIONGERNAITCSITY (RIKER Experiment No. 0281CR0012) TABLE OF CONTENTS PAGE(s) REPORT SUMMARY . . . . . . ovine. 1 INTRODUCTION . ove ett t tte. 4 MATEARNIDMAETLHOSDS . . . . ................... 5 RESULTS LL. Tl DISCUSSION . . oo iii iii. 20 CONCLUSIONS... . . o.oo... 2 PRINCIPALPERSONNELLIST . . . . oo vv ou uuu uuu... 26 SIGNATUREPAGE . +. viv ieee eee eee. . 2T REPORTTABLES . . . . ...................... 20112 TABLE 1 - AinnatlhyteicDailetAna.ly.si.s .of.F.M-.39.24............2 TABLE 2 - Summary Males"... of Mean Body LLL Weights UU - LLL TABLE 3 - Summary Females of. .Me.an.B.od.y .We.ig.ht.s .- ...........3 TABLE 4 - SPeurmmaKriylogorfaMmeaBnodyFeeWdeigChotnsu-mpMtailoens . . . ....... 33 TABLE 5 - SPeurmmaKriylogofraMmeaBnodyFeeWdeigChotnsu-mpFteimoanles . . . . ..... 35 TABLE 6 - CSuommnarsyuomf p-MteMainaloAebnssolu. te..F.ee.d ........... 37 TABLE 7 - Summary of Mean Absolute Consumption - Female . . Feed . . ............ 39 TABLE 8 - EInstMiimlaltiegdraMmesanpeFrM-K39i2l4ogrCaomnsuPmerptiDoany . . . . ..... 41 01483 TABLE OF CONTENTS - Continued PAGE(s) TABLE 9 -Mortality Data . .................. 43 TABLE 10 - Summary of Clinical Signs . ............ 45 TABLE 11 - Summary of Ophthalmologic Changes . . ....... 47 TABLE 12 - Mean and Individual Hemogram Values - Males . . .. 49 TABLE 13 - Mean and Individual Hemogram Values - Females . . . 61 TABLE 14 - Mean and Males... Individual Clinical LLL CT hemistrU y ValuesT - TABLE 15 - Mean and Females I. ndiv. idua. l C. lini. cal . Ch.em. ist0r. y . Va. lu0es.-0. . a TABLE16 -UrinalyVasliuess . ................ 9 TABLE 17 - WIenidgihvtisd,ualMeaOnrgOarngaWneigRhetl,atiavned APbesrocelnutteToMeaWnholOergaBnody OWeniegYheta,ran.d .OrgaLn Lto BL rain WeighL t Ratios AL t Lee TABLE 18 - WIenidgihvtisd,ualMeaOnrgaOnrgaWneigRhetl,atiavned APbesrocleuntteToMeaWnholOergaBnody TWweoighYte,arsand LOrLgaLn .toLBLraLin WL eightLRatL ios A. t .. 108 TABLE 19 - FSuimnmdairnygsof- MNeaojpolrasMtiiccrosLceospiiocns . . .........1ll TABLE 20 - FSuimnmdairnygsof- NMoanj-oNreoMpilcarsotsiccopiLcesions . . ....... 112 REPORTFIGURES . . . . . . . oo. ................I1316 FIGURE 1 - Mean Body Weights - Males . . ...........13 FIGURE 2 - Mean Body Weights - Females . . . ......... 114 FIGURE 3 - KMeialnogrFaeemdMeCaonnsuBmopdtyioWneigPhetr - Males . . ....... 115 FIGURE 4- KMeialnogrFaemedMeCaonnsuBmopdytioWneigPhetr - Females . . ...... 116 01484 TABLE OF CONTENTS - Continued APPENDIX... ITEAM ITEMB ITEM C - ITEM D - ITEM E ITEM F - ITEM G - ITEM H ITEIM ITEM J - Air Monitoring of Animal Rooms . . .... Diet Analytical Data Sheets ....... APcatcheopltoagbylePaRraanmgeesterfsor.C.li.nic.a"l. .. EPxattehronlaolgyCoRnepsourlttanbty DVre.terRionbaerryt GP.athGeoillo,gist Blostatistical Analyses Procedures . . . . BSoudmymaWreyigohftMeaandn BFoedeyd WJaerighWtesighatndDaItnadiv.id.ua.l VOOrep.thetrhSiatnleamprhoyesncOoppIh.itchBaiElsvmtanoleluroa,gtiisoEtnxtea. rnnd.alD. atC.ao.ns.Buylt. ant Copy of the Study Protocol with Amendments quality Assurance Unit Statement . . . . . ACnhaelmyicsaels AonfalFyMs-e3s924ofinFMD-i3e9t2 a.nd..St.a.bili. ty PAGE(s) 117-1597 .. us 125 y . . . . . 1a . . . . 509 . An. im"al513 sg . . . . 1581 1588 ss 01485 THO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FM-3924 IN RATS (RIKER Experiment No. 0281CR0012) REPORT SUMMARY and The purpose of oncogenicity this of study was FM-3524, to assess the potential chronic an industrial grade of toxicity MN-ethy! perfluorooctanesul fonanido ethanol, by Tats per sex per dose group for two mixing years. in the diet and feeding to 50 An interim termination and evaluation vas performed at one year only the control and high-dose groups. on 15 additional rats per sex from A divided total into of 460 Sprague-Dawley rats (230 of four groups. The rats were fed diets each sex) containing were equally either 0, 10, 30 or 100 ppm of FH-3924 for the duration of the study. In-life observations performed included: daily observations for during abnormal the course of the study clinical signs; periodic physical examinations; periodic recording consumption; ophthalmoscopic examinations; of body weight and clinical and feed pathology determMiancartoisoconpsicincplousdtimnogrtheemmateoxlaomgiyn,atciloinnsicawlerechepmeirsftorrymeadnd ounrinaalllysiasn.imals including those that died or were dosing. Selected organ weights terminated prior to were obtained from the all end of of scheduled the rats at scheduled selected necropsy at one year as well fron the control and all as from 15 rats/sex/group, FM-3924-treated groups, randonly at the termination each animal of the study. at necropsy, Selected tissue and preserved specimens were for future harvested from histopathologic evaluation. 211 of the Microscopic control and evaluation high-dose was performed on tissues rats, while a similar preserved evaluation from was performed animals. on a limited Tist of tissues obtained from the Tow- and mid-dose The consisted major of a dions-elirfeelatfeidndidnegcsreaassesdociraatteed ofwitmheanFMb-o3d9y24weaidgmhitnigsatirna,tioann - increase in feed consumption per kilogram of mean body weight, a slight 1. 001486 increase in the incidence of ataxia. A slight increase in the incidence of clonic convulsions was seen only in the high-dose male rats when compared to the control group. In the high-dose groups, male mortality values were slightly increased whereas female mortality was slightly decreased when compared to the corresponding control groups. FM-3924 related hematologic changes were seen in the mid- and high-dose female rats only and consisted of a decrease in red blood. cell counts, in hemoglobin concentration, and in hematocrit values: these changes were observed very early in the study, but did not progress into anemia by the end of the two year dosing period. There was an increased incidence of poikilocytosis, microcytosis, and polychromasia in the high- and mid-dose females at 24 months. The degree of morphological change was generally noted as slight. Increased liver weights and microscopic findings including hepatomegalocytosis and hepatocellular degeneration with and without necrosis, were the primary dose-related toxicologic findings observed in this study. The hepatomegalocytosis was considered to be the result of chronic hepatocellular metabolic stimulation by FM-3924. The severity and incidence of the liver findings were similar at both the one year and two year necropsies. The non-neoplastic findings observed in this study were believed to be related to hepatocellular effects and/or were associated with a mild exacerbation of anticipated geriatric endocrine changes in this strain of rat and not considered to be primary test article-related effects. Specific histopathology findings which had an equivocal relationship to treatment with FM-3924 include a dose-related decrease of chronic myocarditis and a statistically significant, dose-related increase in ovarian tubular hyperplasia in the female test article treated groups. Other findings were considered to be spontaneous in origin, and occurred either sporadically or at a generally similar incidence among all groups including controls. The no observed adverse effect level (NOAEL) feed concentration was Judged to be greater than 30 but less than 100 ppm of FM-3924 in the diet. Based on feed consumption data, these NOAEL concentrations corresponded to approximate average daily doses for both sexes of 1.5 and 5.0 milligrams per kilogram of body weight, respectively. C0148; 2. The overall incidence of hepatocellular adenomas and carcinomas was . Tow in both control and FM-3924-treated groups with only the high-dose female rats possibly having a tumor incidence outside historical control Timits. The majority of neoplasms were observed in endocrine or endocrine-sensitive organs which are typical neoplastic sites for older rats of this strain. The incidence of these neoplasms was similar among control and test article-treated groups, and did not demonstrate a unique tumor type. Based on tumor incidence, types of tumors, onset time appearance, malignancy patterns of tumors and the final mortality two years, FM-3924 was not considered to be carcinogenic in the the design and conditions of this study. of tumor values at rat under 601488 3 THO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHENICAL FM-3924 IN RATS INTRODUCTION This study was designed to evaluate the chronic toxicologic and carcinogenic potential of FM-3924, an industrial grade of N-ethyl perfluorooctanesulfonamido ethanol, in rats following oral administration in the diet for a period of two years. The study was sponsored by the Commercial Chemical Division of 3M Company and was performed by the Pathology and Toxicology Department of Riker Laboratories, Inc., 3H Company, St. Paul, Minnesota, U.S.A. The study and subsequent reporting was coordinated for the sponsor by the 3M Corporate Toxicology Services staff. The in-life or dosing portion of the study began on April 21, 1981, and was completed on May 18, 1983. A copy of the study protocol with amendments is contained in this report as Appendix Item H. The study was designed to evaluate two separate fluorochemicals, FM-3924 and FC-143, using a common set of control animals. This report will describe the results of the FM-3924 treatment while the results relating to the FC-143 study will be reported separately. The study was conducted in accordance with the Department's Standard Operating Procedures (ie., SOPs) and in compliance with the Food and Drug Administration's Good Laboratory Practice (GLP) regulations (21 CFR Part 58). Various phases of the study were inspected by the RIKER Quality Assurance Unit; their statement is presented in Appendix Item I of this report. The original signed protocol with amendments, list of study personnel, raw data, study specimens, and other pertinent study samples/documents will be maintained within the Pathology and Toxicology Department archives currently located at 3H Center in St. Paul, Minnesota. 01489 4 MATERIALS AND METHODS Test System: Four-hundred and sixty Sprague-Dawley rats [Cr] scoss 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 four groups. The control and high-dose groups each contained 65 males and 65 females, whereas the mid- and low-dose groups each 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 animals were housed in two separate rooms, one containing the control groups and one containing the FM-3924 treatment groups in order to prevent cross contamination by potential vaporization and/or sublimation of the test article. 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 Timits 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 animal 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 animal 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 libitum. Test Substance/Diet Preparation: FM-3924 (Lot No. 547) was analyzed by the Commercial Chemicals Divisions (CCD) 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. 318, 347 and 412 in Appendix ItemJ). G01499 5. The test substance was a straw-colored waxy solid which was solubilized in ethanol prior to mixing into the diet. The formula and procedures for preparing the test article/diet mixtures are contained in Appendix Item B. Prior to initiating compound administration to any aninals, the test substance/diet mixture was assayed. FM-3924 was found to be uniformly blended and stable for one week in the ground feed (see CCD Analytical Report No. 202 in Appendix Item J). Throughout the study, test article/diet mixtures were prepared fresh weekly and representative samples of each were collected and assayed 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 FM-3924 was generally within a few percent of that desired (Table 1). The rats received either FH-3924-treated or control (i.e., untreated) diets in glass jars 10.2 cm high x 8.9 cm in diameter. A 5.1 cm access hole was cut in the stainless steel 1id. On a weekly basis the diet jars were removed and replaced with clean jars containing fresh diet mixtures. Experimental Design: The study consisted of one control group and three treatment groups. The dosage levels and animal distribution are Tisted hereinafter. _--_m-- Treatment Groups Dosage Levels (ppm) Group Size & Aninal Nusbers Males Females (An. Nos.) (An. Nos.) 1 - Control 0 2 - High 100 3 - Mid 30 4 Low 10 65 (3516-3580) 65 (3696-3760) 50 (3761-3810) 50 (3811-3860) 65 (4576-4640) 65 (4756-4820) 50 (4821-4870) 50 (4871-4920) 01491 6. An interim 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 chemistry (plasma) 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 randomly 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 SGOT), alanine aminotransferase (ALT-formerly SGPT), and calcium. Urine tests included oH, 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 001492 7. 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 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 FM-3924 and/or FC-95 (a FM-3924 metabolite). At the scheduled one and two year - necropsies, samples of liver, blood, kidney, spleen, Tung and bone marrow (fe. from the femur) were saved from five rats/sex/group. After collection, all specimens were frozen by the RIKER Drug Metabolism Department. The results of these analyses will be reported separately. Postmortem Examinations: Gross postmortem examinations were performed on all rats which died or were terminated in extremis, on all rats terminated at the one year interim necropsy, and on all rats surviving to the end of the scheduled dosing period. 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 cranium were examinedin situ and following removal from the body. Organ weights (ie. wet tissue) termination from both the control and control and all FM-3924-treated groups were obtained at the interim high-dose groups, and from the 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: 601493 & Aorta Adrenals (2) Brain (3 Sections including frontal cortex and basal ganglia, parietal cortex and thalamus; cerebellum and pons) Eyes Gonads Ovaries (2) Testes/Epididymides (2) Heart Small Intestine (3 Sections) Large Intestine Kidneys (2 Sections) Liver (2 Sections) Lung (2 Sections) Lymph node (mesenteric) 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-embedded tissue sections from all tissues listed above, when available, and from all rats in the control (Group 1) and high-dose (Group 2) populations regardless of the cause of death. Microscopic examination of tissues from the middle- (Group 3) and low- (Group 4) dose 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). Biostatistical Methods: The means and standard deviations for body weights, feed consumption, absolute organ weight, relative organ weight-towhole 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 p = 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 p = 0.05 significance level. The C01494 9. results of Dunnett's test have been indicated by asterisks on the mean tables. If Bartlett's test was significant at p = 0.001, the data were ranked and 2 two-tailed Dunnett's test was performed on the ranks. These results have been indicated by the pound sign (#) on the mean tables. 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 p = 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 Chi-Square test was used. An asterisk on the summary tables indicates a significant difference between the controls and the treated group. Internal RIKER memoranda pertaining to these biostatistical procedures are presented within Appendix Item E. C61495 10. RESULTS In-Life Findings: Body weight gains were depressed in the FM-3924treated male rats compared to the control male animals for only the first month and a half of the study. There was an approximate 14% decrease in the high-dose body weights by study week six and this difference was maintained until the end of the study. Further, a 2-6% decrease occurred in the low- and mid-dose male groups throughout the study (see Table 2, Figure 1 and Appendix Item F). Body weight gains were also depressed in the FM-3924 dosed female rats compared to the control female animals. However, there were several differences between the sexes regarding this parameter. The onset for this change was slower, the effects were clearly dose dependent, the degree of difference from control values was greater, and the changes in body weight gain continued throughout the study for the female groups. The body weight differences compared to control values at the end of the study were -20.8%, -15.3% and -3.5% for the high-, mid- and low-dose groups, respectively (see Table 3, Figure 2 and Appendix Item A. Feed consumption, measured as daily mean consumption per kilogram of mean body weight, was generally increased in all of the FM-3924-treated male and female groups over control animals. While more pronounced in the treated males, feed consumption increased gradually during the two year test period when compared to control group feed intake. In the males, this change was most pronounced in the high-dose group where there was roughly a 15% increase noted with sporadic values going as high as 33% during the two year test period. In the females, the pattern was less consistentduring the first 94 weeks. There was an increase in feed consumption during the last 10 weeks of the study, particularly in the mid-dose group, but also in the high-dose females. During this specific period, feed consumption increased as much as 35% in the mid-dose animals (see Tables 4 & 5 and Figures 3 & 4). Actual feed consumption (without regard for body weight change) was decreased in the high-dose males, but increased in the mid- and low-dose male groups during the first year of the study. During the second year, all male dose groups tended to consume more feed than the comparable 01496 " control animals. In the female treated groups, only the low-dose group showed a very slight increase in feed consumption. During the second year, all of the female dose groups tended to consume less feed than the comparable controls with the exception of the mid-dose group which consumed considerably more feed than the controls during the last ten weeks of the study (see Tables 6 & 7 and Appendix Item F). Test substance concentration measured as parts per million in the diet was determined at three month intervals with duplicate analyses performed on two separate occasions when aberrant values were detected. The mean deviations from the target concentration of the high-, mid- and low-dose groups were +3.4%, -1.8% and +1.4%, respectively (Table 1). Actual test substance consumption was determined for every two week period for each sex and each experimental group, and expressed as milligrams per kilogram per day (mg/kg/day). The mean test substance consumption was approximately 4.5, 1.3, and 0.4 mg/kg/day for males, and 5.5, 1.6 and 0.5 mg/kg/day for females regarding the high-, mid- and low-dose groups, respectively. Mean test substance consumption values calculated at two week intervals for the entire study are presented in Table 8. Overall survival rates, particularly for the male rats, were not affected during the two year test period. At the end of the first year, 15 rats/sex from the control and high-dose groups were terminated to fulfill protocol requirements. Therefore, the final survival rates based on 50 rats/sex/group were 70%, 64%, 70% and 78% for males, and 50%, 68%, 51% and 44% for females regarding the control, high-, mid- and low-dose groups, respectively. A possible test substance effect may have slightly lowered the survival rate in the high-dose male group; however, the survival rate in the high-dose females was higher when compared to control rats (see Table 9). A summary of the most commonly observed clinical signs is contained in Table 10. The only clinical sign that occurred more frequently in FM-3924treated groups than control groups was in clonic convulsions, which occurred at a slightly higher incidence in high-dose males. In this case, ten animals were affected whereas clonic convulsions were seen only in three, three and four male rats in the control, mid- and low-dose groups, - respectively. There was a very slight increase in the incidence of ataxia C0149; 12. in both sexes of the treated groups; however, there also was a background incidence of this clinical finding in the controls. The FM-3924 treated population of rats 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 combined with occasional ocular manifestations observed in eight male and three female high-dose animals, four male and three female mid-dose animals, and five male and 13 female low-dose rats. The submandibular swelling resolved within 10 days, and the incidence of residual ocular changes was extremely Tow. The control population had comparable signs during the sixteenth month of the study. Thirteen males and 13 females demonstrated signs of this condition which persisted for about 16 days from the time of onset. One male and three femalesdeveloped ocular opacities during this period. The incidence of palpable tissue masses the study was not increased in any of the compared to the control rats (Table 10). during the in-life phase of FM-3924-treated groups when The results of the final ophthalmoscopic examinations were negative relative to any FM-3924 treatment-related effects. Changes which were observed included a random distribution of cataracts considered to be typical geriatric changes along with some cases of chronic uveitis and superficial keratitis which were also considered to be within normal limits for aging populations of rats (see Table 11 and Appendix Item G). Many of the rats which exhibited ocular lesions were those used to obtain blood samples via the retrobulbar venous plexus. The high-dose female red blood cell counts were decreased below control values throughout the two year study with statistically significant decreases observed at 6, 12 and 18 months (Table 13). In contrast, the female mid-dose erythrocyte counts were statistically increased at 3 and 6 months, but were not significantly different from control values during the last year of the study. There was an increased incidence of poikilocytosis, microcytosis and polychromasia in the high- and mid-dose females at 24 months. The degree of morphological change was generally noted as slight. Hemoglobin values were statistically decreased in the high-dose females from month 3 to month 24. Hematocrit values were - statistically decreased in the high-dose females at the 3 month interval. C01498 EN Changes seen in Teukocytic parameters did not suggest a meaningful test substance effect at any FM-3924 dose levels (Tables 12 & 13). Increased white blood cell counts were seen' in the male FM-3924 treated groups during the first three months of the study, but the increase was only statistically significant at the high-dose and still within an acceptable range for all groups. The increase in leukocytes was generally due to small increases in neutrophils and/or leukocytes. At six months, leukocyte counts were again slightly elevated in all male FM-3924 treated groups with elevated neutrophil counts in the mid-dose, decreased neutrophils in the low-dose, and significantly elevated lymphocyte counts in both the mid- and Tow-dose groups. The only change seen in the FM-3924 treated females was a nonspecific decrease in leukocytes as a result of a decrease in lymphocytes during the first three months . Clinical chemistry findings at three months included slight increases in serun alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP) and blood urea nitrogen (BUN) in all of the FM-3924-treated male groups. The treated female groups at this same time showed only a minor rise in BUN when compared to concurrent control values. From six months until the end of the study, the high-dose (and occasionally mid-dose) male ALT and AST values were increased above both the concurrent controls and the historical control values for the laboratory. AP values were also increased during this same time period, but rarely did these values exceed historical control limits. After six months, no meaningful changes were noted in the female groups (Tables 14 & 15). Urinalysis findings demonstrated a general, time related increase in incidence and severity of albumin and occult blood in all of the male and female control and treated groups. These findings were more pronounced in the males than in the females at the end of the study. Other than an occasional incident of slight ketonuria in both control and treated animals, there were no other remarkable urinalysis findings (Table 16). Postmortem Findings: The consulting Veterinary Pathologist's complete report is presented in Appendix Item D. The important gross pathology findings seen at the one year interim termination were limited to the high-dose male rats in which there was an increase in the incidence of - pale and/or tan livers. This change was considered to be most likely a 01499 1. compound related effect. There were no specific necropsy findings in the high-dose female animals suggestive of any alterations related to the administration of FM-3924. FM-3924 related gross findings seen in male and female high-dose rats which were either found dead, terminated in extremis, or terminated at the end of the study were also limited primarily to the liver. Thesefindings included an increased incidence of hepatic masses, nodules and raised lesions, mottled livers, and yellow or pale focal lesions. There were no gross findings suggestive of a test substance related effect seen in the Tow- and mid-dose animals necropsied at comparable periods of time. Those gross pathologic findings which were observed were not related to test article administration, and were typical of findings seen in aging rats of this strain. These findings included mammary masses, pituitary masses and foci, ulcers on the hind footpads, pale livers, and pale, pitted and enlarged kidneys. Organ weights presented as either absolute or relative values (ie. ratio of organ/body weight or organ/brain weight) are contained in Tables 17 and 18. At the one year interim sacrifice where the only groups examined were the high-dose and controls (n = 15/sex/group), the most obvious changes in absolute weights were a statistically significant decrease in body weight and an increase in liver weight for both male and female high-dose animals compared with their respective control values. Statistically significant decreases (p = <0.05) in heart and spleen weights were also noted for both the males and females of the high-dose group, and statistically significant decreases were seen in adrenal and pituitary weights in the high-dose males only. Relative weight comparisons confirmed the increased liver weight in both sexes of the high dose group and in addition showed a significant increase in kidney and brain weights. Other statistically significant altered relative values in the high-dose group included increased uterine and adrenal weights in the females, and increased testicular and decreased pituitary weights in the males. Organ weights were obtained from all four groups at the end of the study (n = 15/sex/group). Statistically significant decreased bodyweights and increased liver weights when compared to control values were seen only in the high-dose male and female animals. The only other significant - change was a decrease in spleen weights in the high- and mid-dose male 013500 "= rats. Statistically significant relative organ weight changes found in both males and females included increased liver weights in the high- and mid-dose groups, and increased kidney weights in the high-dose group; statistically significant increased spleen weights were noted only in high-dose males. Liver to brain weight ratios were increased in all of the FH-3924 treated groups, but only in the high-dose groups was the change statistically significant (p = <0.05). Uterine and testicle to brain weight ratios were slightly increased in the FH-3924 treated groups. Details of the histopathologic findings are contained in Appendix Item D and a sumary of the major neoplastic and non-neoplastic microscopic changes found after two years of continuous oral administration of FM-3924 are enumerated in Tables 19 and 20. Histopathologic evaluation of the tissues obtained from the animals necropsied at one year indicated the major FM-3924 effects were confined to the liver. Diffuse megalocytosis (ie. hypertrophy) and vacuolation of hepatocytes were the most common findings in essentially all of the male and female rats in the high-dose group. In addition, hepatocytic necrosis was found in 6/15 high-dose males, but was not seen in any of the high-dose females. The majority of neoplasms observed after two years of dosing with FM-3924 involved either the liver or one of several endocrine or endocrine-sensitive organs (see Table 19). Hepatocellular carcinomas were found in 6%, 4%, 2% and 2% of the male rats from the control, high-, midand low-dose groups, respectively. For the females, hepatocellular carcinomas and adenomas were found only in the high-dose group with incidence values of 6% and 8%, respectively. The organ with the largest incidence of tumors was the pituitary gland in which adenomas in the control animals were 35% for males and 72% for females. Sporadic increases in incidence for this neoplasm were noted primarily for the FM-3924 treated males; however, there did not appear to be any meaningful relationship of these to the dose administered. Mammary gland adenocarcinomas were present in both control and treated female rats at a level of 15%, 21%, 24% and 13% for the control, high-, mid- and low-dose groups, respectively. Similarly, fibroadenomas were seen in 22%, 13%, 33% and 36% of the female rats at the end of the study. - Mammary gland adenomas (7%) and carcinomas (2%) were observed only in the 01501 16. female controls. The incidence of uterine polyps, benign growths of the endometrium, was slightly increased in the mid- and low-dose females. Likewise, there were minor variations in the tumor incidence in the adrenal glands (ie. pheochromocytomas) and thyroids, both of which commonly exhibit spontaneous tumors in geriatric rats of this strain. Only the incidence of C-cell carcinomas of the thyroid in female rats appeared to show a minimal dose dependent increase with an incidence of 0%, 4%, 3% and 2% for the control, high-, mid- and low-dose groups, respectively. However, in contrast, the male control animals showed a greater incidence of C-cell carcinomas than any of the FM-3924 treated male groups (ie. 5%, 2%, 2% and 0%, respectively). Non-neoplastic histopathologic changes at the end of the study were found in the adrenal, heart, kidney, liver, lung, testes, ovary, thyroid, urinary bladder and uterus (see Table 20). As noted in the one year interim histopathologic evaluation, the liver was the primary target organ for FM-3924 related effects, and there was a remarkable consistency in the type of findings observed after the second full year of test article administration at the high-dose level. Megalocytosis and hepatocyte - vacuolation (both findings considered to be reversible biological events) were the major changes seen in both males and females treated with the highest doses of FM-3924. Megalocytosis was also found at an incidence exceeding 50% in the mid- and low-dose males, but was essentially absent from the corresponding female groups. Hepatocyte vacuolation was observed at an incidence less than control values in the mid- and low-dose maleand female groups. Hepatic cystoid degeneration, a condition characterized by areas of multilocular microcysts in the liver parenchyma, was seen at an incidence of 8%, 30%, 16% and 12% in males from the control, high-, mid- and low-dose groups, respectively, while only the high-dose females were affected at an incidence of 8%. Hepatocellular necrosis was found at an incidence of between 6-10% in the control animals of both sexes, but the high-dose males demonstrated an incidence rate for this lesion of 20%, with 0% and 4% in the mid- and low-dose groups, respectively. The incidence of liver necrosis for females was 8%, 12% and 10% for the high to low treatment groups. Hyperplastic nodules, a localized proliferation of hepatic - parenchymal cells, was observed essentially only in the high-dose group 01502 v with an incidence of 10% in the males and 18% in the females as compared to 0% and 2% in the control male and female rats, respectively. The only other hyperplastic nodule seen was found in a mid-dose male animal. There was a statistically significant and dose dependent increase in tubular hyperplasia of the ovarian stroma of female rats. Tubular hyperplasia is a diffuse, non-neoplastic increase in stromal tubular elements which is usually bilateral and associated with decreased or absent follicular development. The incidence of this change was 0%, 31%, 23% and 13% in the control, high-, mid- and low-dose groups, respectively. Cystic glands of the uterine endometrium were found at a higher incidence in the high-dose females (29%) when compared to the control animals (14%). The incidence of nodular hyperplasia of the adrenal cortex was significantly increased in the high-dose males. A statistically significant increased incidence of foamy macrophage accumulation in the lung of the high-dose male and female rats was considered a possible test article effect. The remaining major non-neoplastic lesions (Table 20) and other histopathologic findings (Appendix Item similar to, increased, or decreased essentially all of these findings are endemic diseases and/or geriatric changes changes presented hereinafter were not fraitnsd.ings, although their incidence varied D) had varying incidences either from control values; however, commonly associated with either found in this strain of rat. The considered test-article related from that observed in the control In the lung, the incidences of alveolar macrophages and vascular mineralization were increased above control levels while the incidence of interstitial pneumonia was essentially equal to or less than the control incidence at the end of the study. Likewise, the characteristic lesions of an endemic renal disease seen in old rats appeared to be somewhat diminished in the high-dose males and females. The incidences of adrenal gland changes, usually found in old rats, were inconsistent, being either higher or Tower than the control values. The incidence of nodular hyperplasia of the adrenal cortex was significantly increased in the high-dose males; the incidence of sinusoidal ectasia was increased in the mid- and high-dose males but decreased in the females of the same group; 01503 18. and the incidence of adrenal cortical vacuolation was decreased in the treated males but generally increased in the FM-3924 treated females. The incidence of chronic myocarditis was reduced in a dosedependent fashion in the female rats while being increased above the control incidence in the mid- and low-dose males. Polyarteritis, a spontaneous lesion in the testes of old male rats, was found in this study in more control animals than in any of the FM-3924-treated groups. However, the incidence of testicular vascular mineralization was increased in the highand low-dose animals. The incidence of epithelial hyperplasia of the urinary bladder was decreased in all of the FM-3924-treated female groups, while there was an equivocal increase in the incidence for the mid-dose male group only. Finally, the incidence of thyroid C-cell hyperplasia was moderately increased in both the male and female high- and mid-dosegroups. C01504 19. DISCUSSION The purpose of this study was to define any long term toxicity and to profile the potential oncogenicity of FM-3924, a perfluoroalkylsulfonamido alcohol used in a variety of industrial manufacturing processes. The results of the study included a series of biological events which when taken as separate findings may appear to confound test substance dose, sex and/or time relationships. However, considering an overview of all of these results, there appears to be a common pattern of test substance related effects which may be generalized as follows. The general well being of a rat exposed to the experimental conditions of a two 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 animal population. Body weights of the males decreased as early as the second week of the study. The females also showed a decrease, but the time of onset was delayed and the early body weight differences were not as pronounced as those seen in the males. This effect did not appear to be associated with decreased palatability of the diet due to the addition of test article since feed consumption based on weight of diet consumed versus body weight was actually increased. The possible effects that the apparent SOA viral infection might have had on body weight gains were considered, but discounted since the FM-3324 treated animals continued to show weekly increases in body weight despite the fact that the total gains were less than control gains. Since there was a dose and sex dependent change in this parameter, the decrease in body weight gain could be associated with a direct test article effect, possibly through varying degrees of altered hepatocellular metabolic activity as suggested by the microscopic hepatocellular changes observed in tissues obtained at both the one and two year necropsies. Regardless of this assumption, mortality rates were not obviously affected by the decreased body weight gains. The concentration of the test substance in the diet was maintained during the full two years of the study at 10, 30 and 100 ppm for the low-, mid- and high-dose groups, respectively. The average daily dosage of FH-3924 for the same time period and for both sexes combined was estimated to be about 0.5, 1.5 and 5.0 mg/kg/day, respectively. Both in-life and postmorten results confirmed the systemic absorption of the test substance 01505 2. and the 100 ppm dosage level appeared to adequately comply with the concept of a maxinun tolerated dose for a long term study in this particular strain of rat. The only clinical signs seen during the study which were suggestive of a possible test article effect were ataxia and sporadic convulsions. The incidence of convulsions was increased very slightly only in the high-dose males, while ataxia was seen more frequently in both males and females of the FM-3924 treated groups as compared to control animals. These clinical signs were also seen in the control population but at a lower incidence. There were no cellular lesions found in the central or peripheral nervous system at the end of the study which could support a treatment related effect. In the high-dose females there was an apparent decrease in hemoglobin; however, these values were within the normal ranges for this laboratory. There were no other meaningful compound-related effects on the hematologic parameters. Elevation of serum alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase activities, primarily in the FM-3924 treated male rats, suggested the presence of hepatocellular alterations. Most of the increases in enzyme activity were more pronounced in the earlier phases of the study, subsequently resolved in the mid- and low-dose males, and persisted in the high-dose group until the end of the study. The mean values in the mid- and low-dose groups from which these observations were derived were influenced commonly by only one or two animals with aberrant serum enzyme activities. However, there was no meaningful exacerbation of the Tiver changes even into the geriatric period of the rat's life span. These findings were substantiated by the organ weight and histopathologic comparisons obtained at the one and two year necropsies. Mean blood urea nitrogen values were elevated in the male FM-3924 treated groups at three months, but not thereafter. If there were alterations in kidney function at that time, they did not persist until the end of the study since there was a decrease in the incidence of chronic nephropathy in the FM-3924 treated males at two years when compared with control males. Changes in the quality or character of the urine specimens from both - control and FM-3924 treated rats demonstrated a change in several urinary 01506 21. dose groups. PtoarabmeetaesrssoctihaattedwerweitPhrotghreessPirvoegreosvserivetimdee.genTehreasteivfeindcihnagnsgesweroef ncaotnsuirdaelrleyd occurring chronic renal disease commonly found in rats of this strain. The primary test article effect occurred in the liver organ weight (both absolute and relative), as gross as findings at increased necropsy, and ashistopathologic alterations. year necropsy, These changes were observed at the one but showed remarkably little progression one year laterat the two year necropsy. equal incidences The high-dose males and females had essentially of hepatic findings, while the mid- and low-dose males were more markedly affected than were the females from the corresponding year.of Hepatomegalocytosis increased metabolic and hepatocellular vacuolation are characteristic lesions may activity in the rat. progress to cystoid It is recognized that these hepatocellular necrosis. degeneration and, The incidence of hepatic necrosis ultimately, was slightly increased only in the high-dose males. rat in this study Since the liver in the rarely repairs parenchymal more typical cellula cell loss with fibrosis or scar tissue, a study, the r reaction is hepatocellular incidence of hyperplastic hyperplasia. In this high-dose male and female animals nodules were (ie., 10% and 18%, increased only respectively) in the to the control groups (ie. 0% and 2%, respectively). compared It is important to note were that noproliferative seen in any hepatic lesions (fe. hyperplasia nor neoplasia) of the high-dose rats after receiving FM-3924 for one Primary liver neoplasms consisted ofhepatocellu observed in this study after two years lar adenomas and carcinomas. of these neoplasms was Tow, with carcin The overall incidence and FM-3924 treated groups as omas occurring in both the control follows: males 6%, females 0%, 6% o% and 0% for the control, high-, mid- 4%, and 2% and 2%; and Tow-dose groups, respectively. Benign hepatic any group except the neoplasms (ie. adenomas) were not found in high-dose females where an incidence of 8% was recorded. Considering the chronic liver stimulation noted high-dose male and female groups during their life span, the hepatic neoplasia appears to be within reasonable limits with in both the incidence of the possib exception of the high-dose female group. incidence le Combined malignant and benign values are within reasonable historical control limits for the GO01507 * high-dose males while the high-dose females appear to be slightly outside these Timits only because there were no liver tumors seen in the control group. Based on these findings, FM-3924 was not considered to be a hepatic carcinogen in the rat. Most of the neoplasms observed in this study originated from endocrine or endocrine-sensitive organs including the adrenal glands, mammary gland, pituitary, thyroid and uterus. These are common sites for spontaneous or naturally occurring oncogenesis in this strain of rat as evidenced by the specific tunor incidence in the control group (see Table 19). Deviations fron the control incidence for these neoplasms were neither numerically meaningful nor did they involve a unique tumor type not commonly seen in this strain of rat. The non-neoplastic findings reported from the histopathologic evaluation of all of the animals scheduled for the two year necropsy were mostly geriatric lesions typical for this strain of rat. The organs in which these lesions were found included adrenal glands, heart, kidneys, Tung, testes, ovaries, thyroid, urinary bladder and uterus. Specific deviations from the control incidence seen in FM-3924 treated groups were addressed in the results section of this report. However, the following changes were considered equivocal test article related effects. The incidence of nodular hyperplasia of the adrenal cortex was significantly increased (22%) in the high-dose males compared to the same finding in the controls (4%), while the high-dose female rats showed a much lower incidence (2%). Lung changes were also sporadic in occurrence with the incidences of the accunulation of alveolar macrophages increased in the high-dose males and females. The incidence of ovarian (stromal) tubular hyperplasia was increased in a statistically significant and dose dependent manner. The interpretation of this finding is uncertain, but a possible explanation is that it was secondary to the hepatic changes which may evoke endocrine related effects in older rats. Likewise, the increase in uterine cystic glands in the high-dose females could be a manifestation of this biological phenomenon. 01508 " CONCLUSIONS The pertinent findings after administering FM-3924 to rats in the diet at concentrations of 0, 10, 30 and 100 ppm for up to two years under the conditions of this study may be summarized as follows: 1. FM-3924 related hematologic changes were seen in the high-dose female rats only and consisted of a decrease in hemoglobin concentration, and in hematocrit values with some evidence of altered red blood cell morphology in blood smears obtained at the end of the study. While the decrease in hemogram values was observed very early in the study, it did not progress into anemia by the end of the two year dosing period. 2. Increased liver weights and microscopic findings including hepatomegalocytosis, which was considered to be the result of chronic hepatocellular metabolic stimulation by FM-3924, and hepatocellular degeneration with and without necrosis, were the primary dose-related toxicologic findings observed in this study. These liver changes were seen at the one year necropsy, but showed very Tittle evidence of progression during the study. 3. The non-neoplastic findings observed in this study were not considered to be primary test article related effects, but were believed to be related to hepatocellular effects and/or were associated with a mild exacerbation of anticipated geriatric endocrine lesions in this strain of rat. Specific histopathology findings which had an equivocal relationship to treatment with FM-3924 included a statistically significant, dose-related increase in ovarian tubular hyperplasia observed with the female rat groups. Other findings were considered to be spontaneous in origin, and occurred either sporadically or at a generally similar incidence among all groups including controls. 01509 ". 4. The no observed adverse effect level (NOAEL) feed concentration was judged to be greater than 30 but less than 100 ppm of FH-3924 in the diet. Based on feed consumption data, these NOAEL concentrations corresponded to approximate average daily doses for both sexes of 1.5 and 5.0 milligrams per kilogram of body weight, respectively. 5. The overall incidence of hepatocellular adenomas and carcinomas was Tow in both control and FM-3924 exposed groups with only the high-dose female rats possibly having a tumor incidence outside historical control limits. The majority of neoplasms observed originated from endocrine or endocrine-sensitive organs which are typical neoplastic sites for older rats of this strain. The incidence of these neoplasms was similar among control and treated groups, and did not demonstrate a unique tumor type. 6. Based on the incidence and types of neoplasms, time of onset of tumor appearance, malignancy patterns of tumors found at two years and the final mortality values, FM-3924 was not considered to be carcinogenic in the rat. 01510 25. PRINCRIIPKAELR PEEXRPSEORNINMEELNTINNOV.OL0V2E8D1CWRIOT0H12THE- TCHONODYUECATRANODRALREP(ODRIETTI)NG OF TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FC-143 IN RATS -- NAME 000 S.1. Bistner, D.V.H. M.T. Case, D.V.M., Ph.D. R.G. Geil, D.V.H. R.M. Hawkinson, Ph.D. J.D. Henderson, D.V.M., M.S. MK. Hopp, A.A.S. C.D. King, D.V.H., 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. J.R. Nelson, H.T. 6.C. Pecore S.L. Westmark, A.A.S. L.0. Wiseth -- POSITION/EUNCTION ExVteertnearlinaCroynsuOlpthatnhta;lmologist Manager, Safety Evaluation ExtVeertnearlinaCroynsuPlattahnotl/ogist Supervisor, Statistical Services ManMaegdeirc,ineLabanodratPoartyhoAlnoigmyal SenSitourdyLAasbsoirsattaonrty Technician/ ExtReerpnoarlt PCroenpsaurlattainotn/Draft SeCnliionricMaeldicPaalthoTleocghynoDleotgeirsmti/nations AdvRaenpcoerdt TSyepcirnegtary/ Advanced Biostatistician ToxRiecporleosgeyntaStpievceiaalnidst/PSrpoojencstor Coordinator HisStloidteechPnroelpoagraitsito/nMicroscope Supervisor, Laboratory Animal Care Laboratory Technician SeAnsisoirstLeadboWriatthoryStuTdeychnDiactaian/ 601511 2. SIGNATURE PAGE TWO YEAR ORALFLU(ODIREOTC)HETNIOCXAILCITFYH/-C3A92R4CINIONGERANTISCITY STUDY OF RIKER Experiment No. 0281CR0012 From the Pathology and Toxicology Department RIKER Laboratories, Inc./3M Company St. Paul, Minnesota U.S.A. Study Director: ( Horner] d= toler Leonard J. inski, B.A. Senior Toxicologist Date Report Reviewed By: wuo99, James L. Allen, Ph.D. Diplomate, A.B.T. Research Toxicologist 45% Date Report Approved we Hee J 2 Edward & Erickson, Ph.D. Laboratory Manager 5-48 Date Report Reviewed By: > Foe 4 tod Steve V. Elrod, Ph.D. Diplomate, A.B.T. Fo EY Date Manager, Pathology/Toxicology and Laboratory Animal Medicine G 01512 a abies Io Year OroaFlFl(udoierto)caTrohxetncPktHy-39-2O4nciongeRnatteeity Study (8 AAnbaolvyet/iBceallovADneasliyrseed oCofncmeun-t3r9a2t4i8on) Approxeiaaete Study Month o (mesa ' ` ' 10 " " 6 16 1 2 2 CRoeoporAtnaNluymtbiecrsa am 2 1 0 320 PY sar ser 26 202 294 cToOnOceDnItNrEate 100 GmheE 3E8 m cro eno -am can sao soo cro eos eam sem eso -no - tov +5. -en - - Sos un sam Sam foe cae - san - ais en enor Ges aor soo can sto sao soos sso ern -ao Ran von ano sem eo so mo Mean Deviation for the study + 2.08 4 3.4v Stee fea CInocnorrcreicat)vaClhueesstcaglisveDnivaitsitohnis (lceDv)el die to instrument malfunction; 2, PIhenircacoerndrtoeascgategevnaeldauerevsellogwivevarsenarcpecoaesnpsatilabyblzlyeedduLae1fatiettro, naevvadreitaetcitoonr this dosage iwnasanainlsyttailclaeld.procedure; level reamalyien (two 24 vEexscklsudiTnagtasf)r.om sean deviation the percentages nesr s 20 acceptable diate. 01513 2. Tabs 2 Ivo Year OOrFalFlu(oDrieotc)arbTeonxicFiHt-y3-0o2n4cotgnenRtaotisty Study Summary of Mean Body Weishts (g) + Difference from Control aes sdetaary McoenatnroWEr. M1e0a0npWpim. 8 DAff. 3M0eapnr we. \ Diff. m10espnrmae. bite. o: ` Stoelsss 340 teease es eteled Ie tdeers saa wsso ie tmeesss aoe ama ae :` 10 G39s00 Ger e3las 3a GCi3a Tals ddoewnse ase aa es ssesaas aenn oes en I2 ie G9e353 S08 dGnelas aia DTIiLa Ciao smees crLen deo le denen es ee: ar p2si SSSe5ll3a aGas2ll7eo hCTiioaa sssseasos aaolse ssaeesieon Taapsk i2 i sSesloo Sls admelo sol Laae Lie ssaaaind send aass aa ssaays oaas see ae 53% 5 S$o6l3e Seals asiisse son nLiid Lilo sseesnss sens zaaeo ssseeonenss Caaaese 35 GSSoealode sSs1ia0ss4 oLLiiizasa sseess es ai4s ae ssreeoe Caaee seas as u@" s61l2as 3s ssaisn sel CLoiizaao sseemse ees aauu i sseers iase ers ae p25H GGGeu5ll3i ssseealessr nnoaead eeennwee aasa4s eeewmsaasn Gaas 001514 2. Zable 3 (conciuded) Io Yaar OozfadFli(oDrieetc)arTbooxnicFiHt-y3-5o2nco1gaeRntascity Study Summary of Maan Bocy Weights (3) 2 & Difference from Control wae - nnn MHseotenukdy McMeoeananerWeWele..MeM1e0aa0npWWmeC.. \DDiifff.. MMe2e0aanpWraWee. sDDiiefs.. MM1ee0apanpmnmr..s ppairere.. 5s5e GGsoe0li3os msseeaalles wLtiaanase eeeansses eceeezro eeesmaag aasa as beeos eGGoaaedls ssseeeaaloss ClLiiiaass eeemdwso siuoeens eeeammsas aa as es 7 Ges0i8s etl 1sl0s eoiz lLsah ls eewiss esos otoe 7 aeisee ees oenn i 7|7% s1sosl7os3 sssewsllllz LLLiiinooo eeeswdtsss a22s74 eeeawaess aass as a7 6G6e37s.0l1is essomelas LLLo 1a0s5 eeeaderisse a00 los eeesamosss aa as aaa e60ss0i.5s see1z2d3 llSeasdl eeeawmdsa aer5se eeesmwass aaasn "5" 06860.0 e003 seee1ls7ls7s Ciioolss lia eeesdsssr eeso ces aesesse ers aass an 2a 100 @Ge7515l17s sssaalnzs a lLiaals eewmss eo 0sseens eesrna ems oao a T1o0d2 sGzlis0 sseene iSi1s4 eemmos ease eesspen aeae re-------- ree -- erer_et ee---- e C01515 30. amie 3 Ivo Year OorfalFis(oDrieotc)arTbooxnicFiHt-y3-9o2n4co1gnenRtactisty Study Summary of Mean Body Weights (g) + % Difference from Control roses SMteuad,y MceoanntrWoE. M1e0a0npWmE. DIff. M2e0apn mWE. Diff. M1e0apn mwe. spice. o2 118.32 1le8e7s evsoe 1tesns 1am7e m1sse oolee :. 020075 a22a06 seoos aavaea scaios aanmos ssoos 1.0 sZeess2 a a0. SSs 74 3ze2n0e aclaoe saeoss aow 112 2Te0s7 aasiien c13s6 6a4s4o 5s4a 2m0a4s aa3 iiss JSoolts szeelnss Cw12e0 mpa2e3 acasr ssoilae toile 2pS S30i1e saemaa nCalles msoeuas Csaalss oasmoe ooir a2 S72038 aaees CCeias 3320s Ssaedd a3wmn csoonu 23 33383073 smsiia lCleee adaens Csalss a3l2s7 lciog 33 sS3l0s7 aamsas cCleenr adasnse sssoa aswene aasa 55 3B3e505 0e0ns 1issa aalmse ssoo maesse 0s SS6a32 d0n6a3 G1e5na asad c0a8n 3selss otlos p"r SSeeos d3r1ss Ltiae a3es sseow aaelse ioteo so S3e9l3e3 daaains Liieeds admese ceeosimses ioise 2 Wet els Cielo ama ee eos td 0151 3. : Two Year OorfalFlu(oDrioetc)arTboonxicFiHt-y39-2O4ncoigneRnaictisty Study Summary of Mean Body Weights (9) + % Difference from Control remazes se-- er------------------------------ Stpuoey MceonatnroWle. M1e0a0npWpEa. u DIff. M3e0anpmWt. DAff. M1e0apnraWe. s pier. ssee se 4a1s4l1 33aa0l2s 1t9e3r 3s.e0. 6s.i3s a0ls es i.e oat ao daoinsse aottee ate sons 602 pt aallss 4311 s3i5l0o0 sis L_17i.4 L174 aaoisl.s0 ses aal7s 23 a42s3.e8 -0onwae aslo sour 6a 7 44a2l7si 335077 n10l1ss aam7a aciea a1 els Ciel amis Cis aamsies saorn asoce an i7n2 76 aalssi dmieleel ilselee aazsslis ailze assi2 34 lie sat cals aassss asaa ase so 70 82 asreless asdlo 37 693 ez 2200.053 219 asmaas sea oess se adesees 11a7 ser als a86: 88 4s2a0i7s 4911 m38l3s 3897 m20l0z8 21s aaless sellss assis -10.7 aasros otliso sero oid s202 94 ssio2lies 33899276 2223..24 aae1s 1127.4 50517 39901 L211 asl 130 eaeerea i5a0 ae ais s9e 100 S50006090 S012 0022ss 396.9 1a9l.s5 2008 seesliss 111210 43s. 131 aessass ris asa ie 101042 sSo2l0e0 4309271.38 2200..16 a4x.e.26 152..39 asseos aalues --e-- r ------------------------------ 601517 2. sie feo tens oxe1R (bet) Tog xtetty-oncogentetsy Study A rg RRR SARog R--i ------ jot Study et Control mah 100 ppm wee mee 30 ppm vor er10 ppm amen i}\ I oSeronm:a oaNr ORBlE oid omano om ":: oDBnEroOnOaEN eiOInWE I5ma3n oa otnh ooumegnonem iAiWn RBBIr1o0O8BZ)Ee uTimpm BoFoemromoonegm g Boem ohwnmea IxH2 u b w5i BBE gZ iunrgoReeSs lCiR aE ME gr ome BCeR i sis mr pee B*iy 2 BS0212O08@8%r minanm SF 8 im sgmetoroinunn Sy ip smgEed vie Born %%% BShaeEaM8r: ooInlymoBEZr3ao oti ma oBume ooowmed i*8 i" NSBs31O88E33noLonnamo@8Bnroo vnmmgm og ooormu Pr: WI Sm o2% im ome nue i3" oBR epoo o883DoNoMwmEs 8mnr31o oimmo omomr8 oononmm 601518 = Zable 4 (concinded vo Year OorfelFiu(oDrioetc)arbToonxscFiNt-y3-5o3n4coigneRnaitciety Study S(u5ssoafrydieoft cMeoannsuFmoeoddpCeronsduaym)pt+ion PDeixffKerielnocgeramfrBoondyConWterioglht zs svetay cMeoanntrWoe. M1e0a0nprWet. \ Diff. M2e0anppWme. \ DAff. e10anpmws. 3 pire. s5e se 0ee Je aalnds ewimzaa ao ams s3eees sess 3 evr 3m2a 4s6a0s ma sae e"a 33345 30 4wallde a asaalne 3sek as7s mle san swmrs ssieae sez ves e&s 7 3326535 3206 jweaz Saomae awn aslo a3eas Sss7 3a sme ssead ssaas ed rs 772 33d0 aatoss aerass s3ls wsaerlss ssoedr mwesnss 7 wir es Ba ses ser sas o7a Jsss 363 wales ee2w7e1s do wo saess tsoes 364 sos ammza rwioew ame ate aa oe 33.60 sae asaoe a wwe 4 wen dmlae sneess ml size wiee ztsee se ze 21 % S3e0s Jes Basas awlaes 407 es 3smso amsoas do esr ssese dnaoee doo aa s3e 100 3a3 37 aalues ewnnos als sa d3l4e sasae dos vse serao saosse a0 +s 1T0o2s 3308 4m00s isessa 3des mweaes sseee amreee C01519 3. Table 5 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Mean Food Consumption Per Kilogram of Body Weight (g Of diet consuned per day) + Difference from Control FEMALES stuey Hoek CMoenatnroWle. M1e0a0npWpem. % DIff. M3e0apnpWme. % DIff. M1e0apnpWme. Diff. 21 19087..80 19061..43 -- 25..43 19082..29 --03..68 19096..62 +-00..88 4 97.2 80.3 -17.8 8219 14.7 931-42 6 81.0 736-91 79.0 - 2.5 85.3 +53 i 7401 748 v0.9 723-204 78.2 +55 1102 7702..26 67701..90 -2.3 - 4.6 70.4 -3.0 67.0 - a6 81.7 w12.5 71.4 +17 14 64.2 64.0 -0.3 66.7 + 3.9 69.3 + 7.9 16 57.2 63.1 +103 643 +1204 639 +117 18 64.3 66.3 +3.1 65.8 + 2.3 67.0 +42 20 63.4 61 +11 66.2 +44 65.9 +39 22 58.6 61.9 +5.6 61.5 +5.0 61.2 +4 2 59.5 60.4 +15 60.6 + 1.9 58.5 - 1.7 2268 6517..70 5588..65 -+ 25..60 5557..94 + 90..7 5s76..70 -- e1.s8 30 59.7 57.2 - a2 535-10. 55.2 -7.s 32 58.4 58.1 - 0.5 55.4 -sa 56.4 - 3.2 3 52.9 53.1 +o. 495-64 50.5 - as 36 56.7 59.2 +a 56.5 - 0.4 58.9 +39 308 5586..48 6508..16 ++ 32..29 5557..66 -- 21..14 5597..02 ++o01..70 a 54.2 57.5 46.1 53.4 - 1s 56.3 +3. a 54.7 55.4 +13 530-301 534-2. a6 06..25 556316 ++18196 5552..35 +4182.34 5520..08 ++5a..77 50 51.4 6-3 50.8 - 1.2 51.6 + 0.4 52 83 53.2 +1001 98 +3 oa +23 G01520 35. : Ivo Year oOfralPlu(oDrioetc)arbToonxiFci-t3y5-2o4ncoigneRnaitcisty Study Sum(m3azoyf odfietMeacnonFsouomdedCpoenrsumdapyt)io+n PAeDriKfifelroegnrcaes offromBoCdeyntWreeisght rmues re ---------------------------------------- Mopstsuokdy MMCeeoanntrWoWel..MeM1e0aa0nnWpWpEem. \D\ IDfifff.. MM3ee0aanpWmWet..sDADifrfe.. MMe1e0asnhpWrwe.. sDpiifrfe.. s5e4 se S015 46 s5a327 ma23 sia aos 5oa0si0s +~34l0s sens ssoo eodaz ass a 20 6 a 06 4 ssiollos t1a2l6 oasis -eo 4e6s7 o-5s7 are ile ddeeno - aons arg uae 2686 aas0 41 esaslto wwiosi s27 ae ssoet osae wll ves ssaez SSalne uss Co 772 76 44s3 4.3 ssi3e2 vwaers as2 -o2 aas3o sveoe ass ose aseise -waaee ao uel 870 a2 s45r7 so asesso +ws ell aslo 23 waalz 1s7o0 al -3e saese sooilasa ae aa aa I 4l3s 3 aaslls vaelsi sols wl aseelss ++ 52 ae es saaes osine aa Sa 5520 4456.9 465 aseollza vwoallse sta ol ssasss e+es sta ase aasoss CLaanle des Sas 55 100 42648 415 581377 4w0esr sis ual sseaid 2s0a0v5e ses a3 aodas -analns sad sae 101082 4426s dasellss awailzls sstass assezs sdeoss vaeie _------ C01s21 36. mus v0 Tour GOrFesat(eDrieecsa)roToonxiePitay-ooncotgaenRtaectety Stay SuCmomraerayt/aonfysmeoansTBoiutttoCroennmcues:ptrioonn C=oAntbaeeortte wus sBtrwy cBonmtrwe m100eppmm vues m30epnrtee voir m10e5t5em. soe ::| 2EBasammaee Ioltovssy mzmyseo tsoEdss mRm2eoansIosnw .:: fdBserookwomsomsomTIsENdRomSde M sLusr mmoem MoLoahn i*5 wBoaoReBDs IoMwiys BRomnSe tnJeeydnonB Bsoona osul I22H0 WMMayooooBwBwer oIIoosaIimsEsonwo aooIt evraab Hworoooosd z5x 3 WFeICd HBEn IIIUnsA RR C s nd nS omosmnioan 5x3 MWMeoaianBsne DnIosiwee ammene n IIkieeonBmIDoIitoaam "55 W E oo e Ra Dome TItiRoaoEke sotaooo uanouooouam pr:2 aWioORoowEon myolIohntr noomEmsnEooMtNnimnb BEwonooinnd "52 BeweoiodmnBeoe I1IN3inoBEYBDEoonanoommlneoson:oama 001522 an. -_-- study MHoosek 54 s56 e: 60 62 64 6668 70 72 7a 76 7880 82 84 86 88 50 5542 9% 9 100 110082 _-- Table 6 (concluded. Two Year OorfalFlu(oDrieotc)arbToonxicFiMt-y3-9O2n4coigneRnaitcisty Study Su(mam/arrayt/doafy)Me&an 3 FDoiofdfeCroennscuemptfiroonm - Absolute Control wes MeCMoeanantWroWelt. MeM1ea0a0nnWpWptem. 24.2 24.2 26.0 23.8 21 23.8 2309 23.6 24.2 2006 2306 20.8 2231.066 2122..40 2106 21.7 2401 24.2 22.7 24.8 24.6 24.0 22430.52 22260.50 241 23.8 2402 21.3 23.7 23.6 24.6 25.2 2601 24.1 24.3 26.1 26.1 25.1 2.2 24.6 25.2 24.6 2.6 2.9 2231.373 22420.12 DDIIffff.. -o0s 1-o7 -o. -25 ves -+e139 "1s "1s +84 Se -+8325 +"000s +38 +68 +08 2S0130 -20 -2.4 +12 ++3243 MeM3e0aanpnWpmWee.. 8%DDiIffff. 25.2 252 a a1 225a2 ++4466 246 25.4 +17 +233 22220018 -+e5a6 240s 208 "3a a3 2506 2s +128 +36 223496 -+2650 223100 --o8008 27.2 25.4 "4s +76 2409 2506 +33 +62 a2s5e6 1+220 247 2s -20 +33 2205.02 e+7s7 Mm1ee0aanppWWmee.. 2a 200 2244069 248 25.2 2230.22 237 2a 2601 2500 2200029 224108 2509 25.7 2508 253 226a3 2506 2s 26 204 uaDiDiffff. +0. - os ++3330 +205 422.3 -+'7si.0 4ely +1209 +1500 +12 -+1723 -- o8.4 +903 +8 +70 +500 +-o a0 +16 +45 +1303 +1200 01523 38. Table 7 Two Year OorfalFlu(oDrioetc)arbToonxicFiNt-y3-9O2n4coignenRiactisty Study Summary of Mean Food Consumption - Absolute (s/rat/day) + % Difference from Control FEMALES Wseteukdy CMoenatnroWle. M1e00anpWptm. Diff. M3e0apnpmWt. A DIff. M1e0anppWme. u Diff. 1 13.5 14.0 +37 13s +30 139 + 3.0 `2 1270.040 1177..10 -+10667 11760.78 1-1322 1t9e0s6 --1320 6 19.3 16.5 Ses tes -e2 203 +5.2 5 19.0 17.8 -63 182 -42 2001 +58 10 1905 1.2 S118 1s -s6 213 +902 2 19.6 16.2 -17 1707 -87 193 - 1s 116 1168..76 1166..12 -E3E0 RE1]82 1+960 1189.67 "+1520.00 18 19.7 17.4 "7 1s -25 20.2 +205 20 19.8 17.3 -1256 19.8 +00 203 +205 22 18.7 16.9 -e6 18.7 Too 19.4 +307 2 19.3 16.8 -130 18.8 -2i6 sls - 20 2268 1280.076 1166..74 -"112.83 1188..00 --13276 1198032 -- 6208 30 20.2 16.2 -19.8 17.0 -158 1e.4 Ere 32 2072 16.8 -16.8 18.0 -105 1900 -sl 34 18.5 15.5 "16.2 16a "le 17.3 -6s 36 20.2 17.8 Sis 190 -ss 2007 +205 3"80 2210..28 181..47 -S113322 1te9l0e0 -e6ns5 2201.25 2+00.50 a 20.1 17.9 "10 18s -60 20.8 Tas a 20.8 17.4 -164 19.0 -87 2001 -3 a 1189..73 1177..22 -s0 19.1 -1009 2008 21 19 +57 2001 +302 +az 50 2005 16.1 -215 19.0 -73 2002 - 1s 52 1906 17.5 -107 180s -36 198 +10 01524 39. Zebe 7 (concluded) Ivo Yaar OorfalFlu(cdriaetc)arTbooxntcFiNt-3y5-3o4ncoigneRnaictisty Study Su(sam/azzayt/doafy)Me+anAFoDoidtfCeroennscuemptfiroonm C-oAnbtsroollute rrunss SHotauxd.y MCoenatnroWle. M1e0a0npWme. \ DIFF. M3e0anpraWe. \ Diff. M10eapn pWe. s pire. s5e6 1291.69 tieens sias isslas -s2ssa 2z0l +S327 5co 21s0 wuse Cse iz iasel Zsaan 1oasais SCiallo 6oa 220016 7a 1a6s0 ase 2Su2l3e s1za sla isle Saasss iasnes -as 16 -isalas Ses 7a0 2 1s esllso aS3l0s a2l0s4 sseass 21502 artosl 772 26 2w6 el 19a 200 tao mZlieo 2a00z0 Gwelz 20 Se7e4 a2z2 Sele les oalnse -tae 7aa a2 222357 2 ie wo Csile 0wi7z lz es +se1s 2t0e4s ina are oStoels oe aa a 22011s 206 w18e3a 17 aziee a20077 zie 217 Sssiis 2a2l0s Sao 08 Ssoills Selo 5502 220s1 ewlse Csilsr 2a1lsa Sseasa a0t0s eo1iss s5e6 oe 320s7 2 o2wlss ws Csaolss aaalns Sua as Cwaze 2223ss soesls ses 220-6 110020 2208 219l0s 06-C1al0s 2250.52 wwree 2s2es sseeso Tos 25 tee cio 223 ser se es 601525 40. Tale 8 Eatimated Mean PH-3524 (mg/kg) Consumption Pex Day WSetaukdy Male300 ppFemale Male 0peFemle 21 10I.X1) 190..61 23..07 33.0 `5 653 s7l.o4 22.003 220.s0 150 66.50 77.51 2.i0s 2.212 112 sl5s 667a i1ss 22.00 116 s5l.o2 6636 11ss 21.s0 2202 5s.i0 6642 1rss 2080 20 26 pass s6i.0 1143 1187 3208 aas7 5s.is7 11s3 i17e 3328 aa3 5s.i3s Lo1e3 i17s 36 38 aass ssiis 133 1177 202 piwe 65..08 13s 1Ix6] aw6 aas3 s5i.s4 1133 166 sa0 aps3t s5i.0 11.32 1"5 s5a2 aa2 s5i3e 1102 11ss 586 aa 5s.i4 1122 1as 062 a<o0 ssiit 11022 1144 666 a36 aaes 102 1132 760 w307o 5523 Imnt 115s Mal1e 0peaFemle 01..09 11.0 oolse o0s. 0o.l6e o0l.s8 ooues 0077 ooss o0l7e ooluss 00.76 oous oollee oolea o0l.e6 oola 00.65 00..4 00.66 oolae ooles oolaa ooss ooluas ooluss oous oolss 0o.l4a oolss oolas oolss o0l.s3 oollaa ooaa oolsa 601526 o Table 8 (conctuded) Eatinated Mean P3924 (marks) Consumption Pex Day = ems E e ismmpre wirmmrare 7"J a " Goo sn s 2 oaras oan 0oah oass oi ou 07 & o Saosos Goo no oan RE oohh oouu ol os aa o HPEES a S oo uia Zs oosh oosa oh oa 455 SHoEsS anws naooosnas oooahh ooousk %3 120 o o aun u i a Ean oa oohi ooss [IPR l1o0d2 Ha O u on o o ooli oosa 601527 "@ Table 9 - oseseme at LA AMEE GNSS iow nose Woe 8 0 wee ea ee aa S yoguse B00 se 0s 0 ewe eee a 58& wRoESbose Bee 00 0 ee be ee @ romuues ion pase B00 se 0 ew wee eee songs Sse ese se eee ae ea Table 9 (conctueas Le on IT a an Ft 8 tine escoon me ry sm [FE g8 coun em wn sa LN ey Woe eee ca wow Woe eee ew Wo aa e r ae e ww Wi ea ea ae we 3 es a3 oz oz 43s 1s Bow mote a ae wow WL evsa emw Woe es aa aaa ow ttn, Wh. on Caes SASS.poeeeCs n we EE ve mae ot cto sin owweoiee J EE mE mT , e EE mo mR e Initial nusber of rats 65 65 100.0 65 65 100.0 50 50 100.0 50 50 100.0 o Swilen theoatt mnietoe s Behs cr:oc pire "Raoinsehdiunldcfeoraottepdadrieas)ton Bodo si PBOaE 7 0 sa 8 3 sls 8 1 es den 5 rum wo 2 200 5 BE HneFiR Hss oe $ (Incidence 1n mies + incidence in feanies) /total musber of anisals in the group x 100 5 2 re gu 0 so TT ie 10 (emersaety v0 Yok OTcEaPi(v0or)otrTioonntPo ROncepheenttty Stats Summcy of tess Fremantiy Obeeved Citmiced sions -- osvemasions uye fsm Fa] EE= occcoarmsaavirieonrnnsttbasipsioeeedsefaces es so ve : oo ve oo oo va SP LiHstir ing oflheahet $oCeso VHvI ea iPFa ae :3 Vo i[ e svva= arietseonthanakibtnoegnin)ad axes o2 va Potapea seers 1 oa oosg ve :oo 2a HoE o PeSitieeitteottoeoftngaaandonrsoontoot HHHE ER I i A iFi e sA HE s & note 1 To tear OroaF) Fuoatrea)tarTboonnicrPt3y92O4ncnogtnsicty Sty Somary OF Ophthalmologic Changes [em-- pe Cp Control-Oops 100ppm 30ppan 1l0hopem EEo mo-- nMisrosans wBe o90 1rs12b3a3d2e1 8 rostteraiortswcapsutar BmB waeF 2 190 S00 001 050 080 850 0 Cofimoechni eSochutamanyr)itaopcanitsy mWwehet n 000 1zFo p0 001 011 500 81zon09 iiarocpshaenoetpiahratiiannlry: cole: OTE: vS1e0 TsaApLleSs Meerhe otapkeeRntvaiaa1tohtecrtsro-oonbrit1a4el5 venus plexus fron sTmst 41 of the EE 0 croup g8 ((11)) Ccoonnttrroalr (1) Control a8& (((111))) cchooinngtthreooblrose (01)) wniigghh Dvoassee. rows 1(1)) cCoonnttreoolr ((11)) ciognhtrboose (0) 11d vans --- & Zable 11 (eonciutea) 0 Year OroaflFl(uBolreo)caTrobxoinciPtHy I-LOnciongReanttseity Study Sumsary of Lass Frequently Obaecved Ophthatsstogtc Changes -- Eres) Description of Abaormitty RiAgishnte BiBBaiaattteeerrraaalrl LAeitstne fate DPCiohfsrftouensrteicdorvlealtnetantssopeap(casicaticytoynd-ascyheotnotebloSoeditisaamvpliitnhg)mlcrophthaisos CVDeihrreyuesnpeiadleshucyphpeohrerfmoisicdiaall Kceirraetuiitatiison EuxrtoennisciveawpIenrctliacmimasltiFoenra(tpiotsitsblood sampling) Lentigtht Rigne CCDahhcrreooynnaitdceenistvutepiientcitsicviiatlhkseercaotnidtairsy excphthaiata pRrone Duirtofnuisce wLeentettospacity with teitte 8&gS jwiies BBBOOoWRmE EOEREEODNORR ODOMNSE mnOmMhEmoHOaERmED MMoDonobimE HMENoHMuSRn 8a pe "STCOPY AVAILABLE os EE [Re 8i Poe Bom Ha BEER OBI OBOE En ES PE BD BMD mas12 e Sammm Boodnem hommm dehn EMnINEDD LR gn Mw m0 SIE aSED IIR RGEML OmR G4N3 RS I mR fw mEniomohmadie ln in oid L&oo OdmEmami Bo ENE OE DEO DRn DRDGI ND o(GNmEm ERWI gnmm mnanm wpoonwe s Swmo BBeeEm NmiEmEi oTrerm mdrha EaElE Aa ND BUSEE ME dDNbR GIAEN e ie ofe Tn g EnoEnomHmEmE GnEaooaEm33daEmm Sdbuhh EERSM RmEanGEiR OGMoEn S FiEgEEi fEiE o23 fI m oeE BE E OF EE RE NogmonmEl MEN 0 SUS BI wna NOD DE ha DahEh ioEh EEoEn name des BEEYEE : oR hoad B3 EB.uh RmBu.d FBEE.R BNHEEDRE OWRIE E bE maz 12 sono Am NRRS OW Pm ohm cha MER 2S mmmmeoEmommmhmmmmm &GE dmmmenoaDhmimAmmlh WM oh DED 8 wdMhmERA E E n NR mwmdmm D n I D h WAR NR ER dn NER DRE ie hn nER NER OR I ool Tm oR oa GEER OMER NS na ogm nas bes N WSIEO DNEDNR UBRNEaLRm NRNnRR nInmmie Spohhnem dSpihemee mpSoeewe GGMabDoan dMamenSes nSdUvaRalmGe bal omar dsaoamSe gBsIanRg dedewEss eeflasiess BOP DMS Ae deT 4 Sad loses need Ihe Sites aieres eisess sie o_o --- o_o -- -- to Boge om Elon HEM Rie SEH GN pm oh NE DE S2s BWEem momaeme IA E E OR F B Tee rimmT mar 1s ae 8 gE oR RR OER ON wim Wi SER MEO ONE ono ER Ssiszel LnI lwlneae RR 33aeT ES 12.8 MRE 0.5128 an 12.0ee de G.0ese nn o.ies Ek fh JER An OE gE [EE LW [LE RR # pioEwoomOeMmEs MOhW BOmNWOR I Hi WWOMEE NORNGE OM mOhM bOHER a OME ooime 2B EpSEoOmNmMBmEEoENOMhGRe OWeOlID6OR sRBiEEeDD mRODsEEmSR oONlROeMEnE OwOMReD OiOmELe sooenmemDoosuoehme soooemn a "8 wee dues m3 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PowoonM ELD ER oale 3BaoA a nHwoz MO"s E s OB REa on We WE Maw oamaoBSon mon momomow 8 on 22 BEEEoEm oE m of LodN MOBoBoO&A hoa 39 FWeEm omes dmoSSoan noIon aon BE wow oR oR OREO OB OB o & om BEoMm oS OPE ORE OE HOF OBE oe 15 sem amen wow ww be aa aa sonoma oR oo% Sof dom ww ima Woo somo mon BW a dn woos i EEE GE PH EE OY OPE 22 opemomMmmma o`sodBOR2 0wBo oseHoafb oway fNooon oonma &a EwmRanomaammenoswe aone ooNa bBeorm an a na ono deoamaloWomoR ono odom no E bos mL Gu ma Wr AS WIE Me TR aes ox a 532 mwReomElo ommOmeMmnEsoR do BooRw: R n FOH Xm EBRiO3H%nm OB aw5namwWaodnme & wood ob onoon 8 omosmom non ame mm 1% ono modo ad Amo mom Won now owowou 8 aw 1 Yo Oat (let)Tonto ty-Omep--niet--y Stuy o Phssosacbon IP In ate wrnstyete values vrmp sGpeeitnie Mawes stein B-- TUwEE e ew r ats nwmm woww wan ow wom 2 preven ggB S CW onRatrmmol 1amo.01mai1-1i.aa05m2 o7no3-a8 Nawmetmo moanoNms cess ahesde retos o mwoeonwy 7 mo wNL wew ooEnrnn oN==nm EWhnieiRmmm elaeewsiness O oem mr d mwwo nn mwaowm fam, poe a . noo oawo ewo m w BAimm Memwm o oo akmom JnS oZ = 8 cnr [-- 2 = me1e0aees ec rt es Temsitenstsonsitsy o Fon SRS OUR J, S$ 12Mo. Pemal PPRe CoREReL Om101Eb6-1Em060 Ed6.5n.m8o.0 3Ned 2B en Bnen O2eBz OOeHBn ErIeTe NeIaNmN ee 152 -1tEev ee LE 16 (concoted) Teo Yer Oral (oie) Toxtety-ncossenictotynsStudy of Fluaracarbon F-35261 Rats inatsts values oe Gra spFecairtic Mbain Blibie Glucose aDcact Ketones 2E043nM0toerv,ormMnale LTTooormoaesns segewosss wwad nINre om its dr WE 2h Bg&o 2F=l4oeaW)ommm. ale LPThoaitheoan rpSeaosssss AwaRn oranr & dom Thee ese wa 4] ao+r] wMMeeo on 4] MW oIan e o uo ow n + wen cot: WTome e 1H0 sNlant stents 20 smoafrekreadte to market TABLE 17 190 YEAR ORAL (DIETA)BSOOLXUITCEITAYN-dOoNnRCeEOLGAEETANIRIY.ECILITNEYTuESkRTIUGMRDOYANO.F1FGLAUTORSOCARON Fik-2924 IN RATS ABSOLUTE ORGAN WEIGHT (GRAS) oo 100 pu une WIE WI roan wo wo &< abiSe0lvnetee 3SP6eolRstheizannBaA lanns gsR fas ndNaDodgRiaao &a2 KHosenhsceh!sts SSCEaHRIRARE sSh alrea Lh1ad1 ih PITUITARY B62E08L4-A0.006 S31E05+S0.E0020 func ono ba0ena SaKSSiihRtbihEwcieeEeln'ss Btaain Nets wets wo wn w WNaTn nNa dhBenauch SA SGiiEgaNgn gig dBa8t8 GGSaf aabsnr gEbBa oeineeo [aRdIoEakSE lHofiH0]:07 8 VEpRcEe 0055, TINRD TTAAIILLEEDD BDUONNNEETNT T1 OON RFaAwNGEDDATABina. TABLE 17 TWO YEAR ORAL (DIETA)BSOTLOURTIECTAYN-DBOuNtRCEOYLGEAETANIRIVCEIINTWYTEAERSRTOURDGYAN0FWEFILGUHOTRSO.CARBON FU-: 3924 IN RATS ORGAN VEIGHT/B00Y WEIGHT (3) ore 100 Pru we WE CED ow x ow xs e hKSrioeehEyls RS pFeasilnaeeeile I a eRn eae Rh a8B0s SaTomehsaehtnasts Piiut any ssSheaRuiEEe SUE00 8TeS0AiA0N2nNI0eSbno.on 2 rune Nets wets oon sw iw Sifovhlheae)ls SSSeetaoainbieotaaeI nnl RDSSeItsRuetSine,s PBHSaioahunuseasny F SRaE rnia SRE fGRhAeTHlEoYn Lan 2FB EG0R5. TTNOS TTARIILEEDD DDUuNNrET!T 1TO8U% AAuNeNEASTAB.in ate37 TRO YEAR ORAL (DIETR) STOXTICIOTNYE-OCTNECAOhRGEeNIIeGcIT,iY TSTUDOY OFu1nDReOCARBON FU-3024 TH RATS ORGANWEIGHT BRAIN WEIGHT IO) o rr 100 peu . wie Gow Wi mmo Wi mis 85a8 ALoKwiIiVRabeESleRa,tts s9Ssm.0aau4l9i4ni-1n.t3ae21 pp pp12.aa7i5s0m-n a1s4en520 Pfosie oRdeosa Soesaoh reune wes wes Gow alos wie CiSiitHbeeEiss CSsbhaaoLnnSltnauE e f dr a ae a ion Sanus AdHrieRlElSe cSSoaEmnber Sppaaannnaeemli s: TEBEG L8os. T0UR TTAAICLEEDD OBUEMETT]T TT OoNu n fan OAA T wn 2 ((EEMMEER OOMH MENoOmWE BERmoonR RFoormmaonR o3h < app Alao3Sse Ses 1509 Las outer Junsh " Aent 21m I 8 EEE RE BEE OE OEE Bz oma Moan ER sR ol Men MIRE OAR Am Eh in OME oN domino g 5 soins on PTT VRS 1 Me o28 iPPEEEOOOMMNEM GmOM ooOaMNE oaOEdmR ooHsRmh oBoOpERmR 52Bommmmowonan oox a@8 JeBAeEEn EEE WNlaalaam OsdwEs a7e IEabanse EaeRey abeeses Bn ooFFmeear oeadm o+n ema 42 g 2 CTE Koco a0 PETITARY WS 0 6. RA I ae1 NO YEAR OHA DIETA)RSTGOLUMTIE TuIn-NBCEOARTNILACEITaY sTuaBy orhFLcooRaEAsRON Fne3ese 1 mars JE ae _ rT TTR Ev TE ww sw I ww htsHoiitenen Sorat sIPphaRmmIIIaNIdUAEl PRION DSN lEasNLIlODR LMSTINR a mDneanimnee dwmedil ad mene lee 2g 8 ia sts ABSwTeImNe NGEENRTODO mSgIimDnoIe diGehndeealee a rene vers wen we wes a jjsooeery] GaN ii wr su. gPprOeiRilE aAe Tm.Nr iNTI UIRM50. dSNwrhuReny ee0n pewersnhs5a0e Spasfntosnteass EGdSaRemMmmiIlLiUaRmEee NORSARIeCEOOlNRM GlhSImhSnTmeErmN jme ameiencsa seeellinme feat _ EDSLEOLERIer een TG0 TTAaILiEoD SouTr 1ToOn I saw auras, s Br Nox 1a ANIMALS, BEST Copy pv ac n THO TEAR ORAL (DIETA)BSGTLUURTIECIATI-NRCEOLGACTNIIVCEITWYEANSTUSDRYOAN0FIFoLUnORsOCARBON rk-30re Tn Bars . ALEGoons wes LE Nels CNesm a WOw E 82 SSFm fEioneEneers DscGeaEifmRieliGl S SdDSmhamUeIImenIa,l DdSSOamEIibNNn nRdmnindnen Danan & Testes: edie SHRIRNIY Dhaai 3 seme wes wes wes wes naan bCSfeeieen * so ScaEelMEtGCLIeLElRG 3 so SColMRmTiEIas. nLT i+aomlT oinndso. LIND . 0 faDimRnaiLn, ppidrtiitrss cCclAdisRimlIoaNlo'Enm SGoElReRrNIblNNeElNe. LN owIsriLn emIli L neeissheleeieeaibee 83 4L0508ECcuIs TTioo TTAILLEED DDuUwTrTy 17 oonn mmaanoeaTaD,ita: iY AVAILABLE jy THO YEAR OWAL (DIETA)BSOTLOUXTIECITAMYO-ORACEUCASTKINVIECITWYanSTUGDnY aOFueFLFOoORnOCARNON F-103% Tu baTs JR ne oom 100 son 20 0 10 mn WT I WE CEE o Mow GSSheuiwtener WTO sw mmo si SomEmMeIaNlleSNdIlINET mmo so ANI mmo so nnaiaeas 38B2 THAeoievniseascs sDaeemwamenad IfIUaSIIeeOIR.dN D aGDlEtli eIlsNuiIaEne n samewailrmiihnteae Fema Gow CERT WTO so Nes mmo so Nes mmo sw Nes mmo se prdCpHviiiivreyEas sfoPwemraaisaleill See o la TGISr Ie NIRsT BUI ae LpeEieNlIoreeN ees hang.ssekazrieeama2imnsaeez eanseee eel RENIN NBN snes 2 FP SDERIEERCNEE R0E T5RRY rTNAO TRAILhEO wWIaT 1RuRn AhyRoaTa. | BESTCOPY AVAILABLE or 0RE IR TE TGEOMOMEEDOOmWOEOBDI oDWooabnE oH Of mHOoEa g. EIE EOEME OEME E BE MEHE oRmE Ioro oE@om g EEE RR BE om OT EI = 100Pu MINIS 6) glu LAW Dll sais ne Alun 2m BgEE EHMEEoS EREE E E OME FOm OI oEmB om BE Bm BE Bim om fom om CREE ocean mar wma mec a reatipsenw nisi6r BEST COPY AVAILABLE SSeoeem GGmamvye drae RdiOes DUhH nenwd JWeee Gdamm SmwoonGwhe L deaoeu Jom Him ma gees som ame B g EE# bn mGlEan mBy odmear fohme odeme uaeis 5aad JRE anien iNooW nea an san ad a aoiemga" m i y IR BeomonoL Gh mom In BEAL Ma fmm i BELomamlom Aut mn aim mn wo mwa Mabon ome on wooo IN Tees Thon don PH 4 5~ E toAsomNs. wSeiEanEs Mae5c TeA.TE on amen. sco ie vs, : BEST COPY AVAILABLE | en Tenee eet ote hoa AE Mma se lem ge as wn a jy So Masa an bos lhe ae a oom ahh Men Mo fun DNDoME aw ie aman g Shee Maen tr Me daa oe em 1 ae le 8 10 on Olin Ge dein doe bre ae pot The fm loboow Glaiier des abe mess ame aie - ame Boom Glam a dew lan bee ban 9 4 aor] BBEEEERR 1000a lines OOMNRa BBEoEE sea lm eee oSoeFEr 2Yrs omBHT oA | Hack BESTCOPY AVAILABLE SEER OR MoE HE OW 8 HOB br a mer ve ar er Te Tat oe ote mars aed umes sere BE oNmm OW ORS MR oMROEN Om Bm omk NBoommonmsmaomoy anwe pdnew onwnoaommnu GanI Snoonmn mn Joaoomat wom asl nw BH wh lo o RE mE mom OER MH aR Mom Sgag 3MmpooPmuoewowlmokemswastmyoySosonodldmod A noNWS lIoL ledomomMnoosoeEsommoaaSnoanmnnn = an wmmmivmnnes onpnrnnly = Tooren Gmmma hosze hDomeooblammmnoamnemro2oahmnoowwreoeomna nn oo bln Ge die des am oE = ne BmooooGmimnaaoMdaon omdmsoondIeLonLoman dmaln g1n annin dn ll mem amo den bw ammo Wooo los ama amo Emon mn eam ab 3:" mB MeanBat egiSInhscsg4e%tohe Bvoir 1a0cTnoev10ecooir miWnSANone - TABLE19 Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorochemical FN-3924 in Rats Summary of Major Microscopic Findings - Percent Incidence at TwoYears Oraan/fingings AORENAL PhPehoeBocecnhhirrooonmnooccyyttoomnas,, Malignant HEOPLASTICLESIONS? FgContrFoelmsale 50 50 FasloeHighfe5mle0sFaleMigFesmoie Male ouFemTe so So 4 4 0 2 8 0 8 2 0000022 LIHVeERpCaartcoicneolmlaular Hepatocellular Adenoma MAMAMdAeRnYocaGrLcAiNnDoma ACdaerncoimnaoma Fibroadenoms PIATdUeInToAnRaY THYROID C-cell Adenoma C-cell Carcinoma UTEpRoUlSyp 6 oa 6 0 0 0 8 :Ss7 psSoa2 : a0 S: oon0 B02 won 0 2 2 2 s 0 2 -2-2 20 0 0 :Su0 Soon0 ew ow 4 3 2 3 -9 20 0 0 S: on0 :Dox0 a 7% 7 2 J 2 -8 eee rere 2 NfoedsdtiaettisstiwciathllyFH-s3i3g2n4ifiacnadntcondtirfofleregnrcoeusp a(nai=mal0s..05) were found between rats + 50 rats/sex/group were at riski % values derived fron actual tissues examined. 01595 mn. TABLE20 Two Year OraFlluo(rDoiceth)emiTcoaxliciFtNy-39-24OnciongeRantiscity Study of Summary of Major Microscopic Findings - Percent Incidence at Two Years Qraan/Findings ADRENAL Nodular Hyperplasia Sinusoidal Ectasia HEACRoTrtical Vacuolation Myocardial Fibrosis Myocarditis, KIDNEY Chronic NPeeplhvriocpaMtihnye,ralCihzraotniiocn LIVER CHyesptaotiodcelDleugleanreraAltti.oVnac. HHyeppeartpolcaesltliuclarNodVaucl.e Megalocytosis Necrosis LuNG Alveolar Macrophages Perivas, Mono.Infi). Vascular Mineralization Pneumonia, Interstitial TESTIS/EPIDIDYMIS Poljarteritis Vascular Mineralization OVARY Tubular Hyperplasia THYROID. C-cell Hyperplasia URINARY BLADDER UTEERpUiSthelial Hyperplasia Cystic Glands MON-NEOPLASTICLESIONS Controls Hale Female High Male Female 50 50 50 50 Mid Male Female 50 50 4 22 0 22 8 30 2 0 8 40 4 " 48 10 36 22 30 1 10 28 4 10 2 30 2 12 es 10 1 88 8 60 60 8 0 36 80 6 16 52 280 260 30% 18 8 12 16 32 0 12 a"0-620 8 10 8 18 38 2 50 0 0 0 6 10 8a 20 ger 8 sev 2 0 12 20 42 2 2 46r ue sar 30 3 40 30 20 86 32 4" 1" E 12 78+ 18 88 18 8 12 12 0 - 4 12 - .` -- - 0 - ar - 230 2 0 9 9 6 un 7 1" . . 13 5 -1 -2 - 13 Male ovFemale 50 50 10 0 10 7 20 10 20 6 40 18 88 4 16 4% 12 0 224 E12 0 0 Ed 0 4 10 36 2 30 18 50 80r 8 20 188 -- - 13+ . 0 2 or -" 2 + 50 rats/sex/group were at risk; % values derived from actual tissues examined. * = Statistically significant difference ( a= 0.05) from controls. 01596 na. Avca1s] + 8 gIsf{ /J a &$0 fJswl * := i8alel ow ow wm ow om mm ww we ne i nov veex LECOD. GAP ONAL + 00 PH +30 PX oe 10 i 0 oar at (Bit) Toeiey-omonea nicity Sd of Psarcearien 924 in face n Hi 888 eo Jae 5gf0 & @ {T 4 , 2eway1 A " som : @ ow ow ow om wm ww we sno veex LEGEND: GROUP #-wCONTROL +--=100 PPM +-- 30 PPM == 10 PPM . 3] :7: fji: cB; : ;}: . ttRL) SEct A ty st of rr tn ! Ye 1 2 " se 0 ko Ll % 100 ne on car eco et som = tor | . tie 8 || 0 Year Oecanl e Diet) Top ricity-onconenniciacy Study oof yFisCorocharbon P3924 in Rats 1| 5: i 88 c f7bu g o 5 od , g J bl S ?.8 1 M s Y8 1 El 0 " se 68 sno eax Ll % 100 ue LOO, GRO COR 100 PN 30 PH + 10 on THO YEAR ORAL (DIET) TOXICITY / CARCINOGENICITY STUDY OF FLUOROCHEMICAL FM-3324 IN RATS APPENDIXITEMS 01601 17 Internal Correspondence Appendix Teen a ce: WFl. DSlL MGcrCaorrfmiizcnk-- 222200--225E--0022 fei FJ.aKl. USbueglg, -M.2D2.0-=28-20220-2802 se hugs 21, 1981 3M %<M. T. CASE =~ RIKER LABORATORIES - 218-35 som S. D. SORENSON = MEDICAL, IND. HYG. SERV. - 220-2E-02 See: ALr Monitoring, Project 33002107 ---_-- Summary mrAoLornoimtmooursneiidntogriiwnansgflhutaoosroecvbhaeelemunaitcceaolnpduoscsttusdeiidbelsei.naitTrhhrbeeoernpeuarnpicomosaneltamotifrneaatnhttemse.nt Tahney, sawmerpeleberleosuwltdseteicntdaibclaeteamtohuatntsf.luorochemical exposures, if Dera Arloromssaumspeldingin watshe cotwnoducyteeadr 30 FO-143." Me study has ainnimtahle fteherdeeinganismtauldy torfeatPmHe-n3t924 been in progress since April 21, 1. SArKroCeomas ssbiaylmipclmaeeasngsewleorfesaemcipotllhilenergctetidumbpeiisnn.geerasWcihtwhiotfhontemheetehxsacenevopetlriaolmne,dtiraseaamtoprmleenst fawlesoroera.nloca`aiTtrheedspaemorpniloetdrosp lsoofacmapttlehdeed naenaariremaljthuedrgaecrdkoso.mreapiTrrheeseenxothnaeatuisevtxecenopefatrionthe "usual or steady state conditions. eThveeryflo3w0 mriantueteosf tthherousagmhpoluet ptuhmepssawmapslincghecpkeerdioda.pproximately CTheentrsaalmplReesseawerrceh accreditation as aLnaabloyrzaetdoryb.y tThheisAnallatbyoircaatlorySechtasionfulofl the an Industrial Hygiene Laboratory by the 3M American Industrial Hygiene Association. 601602 118 agpentin 1rem nT. case a russe 27, 1001 The sample results indicate that airborne concentrations of pltiohnetsetntste:isatl fOnblyuotrahioiscrhbeobmrainsceiasl,hse,airtsifisisanjyou,dngiewndeerletyh.abtelocwrosdsetescetnatbelmeination Please call of there are any questions. /0 Aree sosien 01603 19 Ko. case BPsruaoimjlpedlcietngba4t281a360-033107 August 7, 1981 Appendix Teen a == NSuamzbpeire CCI81-20 C1123 CCL81-21 CCLELIS CCL81-22 ) CCLSL-2 Description 0t-o3p40o.f raCcokn.trol Rocm, same as above RhoDiu-gm3h.3"2.dosSeaFmMT-pa3lc9ek2r.4,ondtoospe of pra-eb3ao3ru2t.f1o8msiaanmicprhleeserxahabatouvset flo0z. RDo3ws3.8'. Sracm-p1l4e3r,ondotsoep of high dose rack. dsuapmleicaastecczs8a1m-p2l2e, using silica gel tube. mize 922-1225 922-2225 926-1236 1055-1236 925-1228 oi August 27, 1081 Compound ru-3924 rena ru-3924 mwe3sze concentration, mg/e? Co.003 <oime Loon <oulerd <o.00 casprt Looas o<s8 m rc-143 " Loon alrt rete 0.000 cai SMPLING METHOD: |FTCH--1309224 SDmIpCinsgielricamgeetlhasnaomtpsling tubes, ANALYTICAL METHOD: FFHO--319324 -- dgdeuetsreicvctahotrrio.zmaattioognr;aphgya,s echlreccmtsrtoongrcaapphtyu,reeldeectetcrtoonr.capture MALYTICNL REQUEST: #BO245. 01604 Internal Correspondence AppEIDIX 178M A TL. o. sibinext fom 3. D. Johnson Sewct Cue OAVcnetanolbyesTriwso7,oYfea1Pr9l6T5aosmxaSStaumdyp-lReastsfro(mRiSkeenrtSitnauldyRaNot.s H03o8u1sCeRd00i1n2)Rooa SCeonhltalivenecatleadtrtaaatscshdeeidsnctrRhiiebkeeodrn.eStpuOadngyeJupNlor.yotOo15Ic,o1lC1Aa9O8tO1tI,aZc.hfmoernTthtyespfleoarssaatam.hpelseaussmepvleeorsfs (see Cbaathctekamcihcbeaydl)Dsr.fveoVrrea8/nt2ar4la/yn8ss1if.serorAfeLdLortBogaarVn.piiceFsoftlvhueoarrpiernaegl.easdsaTht(ehoar.nFeVos)nueltipenarCvteormempeerrsceinatl ianillu5loi3ro6inn.eNopterPberosooenkntt$h6iTs5h,3a1t,iwtapsc5a3in.ntbeerfceornicnlgudweidthchetthisthesrteudyv.as Tmhoesaeirdbaotreneare sRaemmesnazc0h. gdgdapocniaist Riker Laboratories, Inc. 01505 121 appendix seem a .* Internal Correspondence VE Cries ----, | ~ 3 SR ---- From: J.D. Johnson - Sims owe oVAtntha"lysoies ToTfeoamrPlTaosnmaSSeanmayplemaste"fro(mRiSkeenrtiSneeulsyRaMot.e H0o3u61sedChin20Ro1om et e Fortyeplasmathessaemplseasshfersomosceinoctien'asl sraattes a(rIen sJoucbnm,ittIexd20f0or5,fTluaorsienese. IIRr38T6R4,isamn)d mIRie3n865e)sreandsac5cifceimaelse b(eIfRor4e921d,otiInRg ws'4922,IIobRtr4e9c2a3d,. IRThe4924, . ohSIRiteahVrethrfeiodcot.hahisrint`tHuyrwdahypcilecar-hsastmceasetaus5rdauymrpaltFreaaestceeofiwvioirerneaegchscPeoclsEeleIiexSvcIitFenerLgdonFaCtt-h1e3403c,odmacyarsnodlafftrreoorsnesdthoes.tilnosgsoom me numbers for these sats ace as follows: S nate Control Room (IR 3866, TR 3867, TR 3868, IR 3065, I 3670) 5 female Control Room (IR 4926, IR 4927, IR 4928, IR 4929, IR 4930) S male FC-143 Room (IR 3876, 8 377, TR 3678, In 375, TR 3660 fumale 70-163 Room (IR 4936, IR 4537, IR 3836, IR 3639, IR 2040) 5 male PU-3924 Toon (18 3856, TR 3067, TR 3088, Tn 965, TH 3690) 5 female E3524 Room (IR 4346, TR 4547, TR 4346, TR 4549, TR 4950) PClreeasTeesgettabvaiclkltoTeeusd v0ithspetcheifidactaa.nalyIstismayotbetothaantalvienicsacopfrattaisttieoen.of Sutin 01506 122 : BEST COPY AVAILABLE a = con Lane AppenBdinnteenChaines os Moy (psi) Kido Sigg ne OE oR Co Pleana s------F--rom. Asus A-133 ROBE | | 8 Seton mM] Aeckein| 81 Grew py A-15 IR Bea My + (a Yay 195 ie stes mM Des dagy "6 Ww oswey n| , Da gagy 47 F ses my 3 ifs arn 158 R493 B . sam = 199 jim asa F . Zo om 4d2> F " 2 sn 3 5 sup 20! Roya FE * * sa o 202 | as F " 4s sam < r ee ee ---- + 203 204 206 206 266 207 [i see Mo ik 3mm ik deen 3 fic 3am it 3g om Glen a) . " - "3 " - " * " 4s saan san cam s2n saw mpm oT 20% lil d20 F or IR w927 Ff 200 lwaa ns ar ir 4425 F a |R 413c 1 AIRi BRT NM 2g Gk de om as [= 3815 Mm ag (KET Mm a 27 !CIR 3%%0 . *l . . 2 . -y "s Feri dem #4] . a " #3 . - " - wesw J Ls (ew mi kn gen vse bse say = san 4 s=n og saan S28 { Recsisa Lo. V Pho sir G01607 1 23 Appendix seenn 7 A cepase Rebes 4 2g IR 4936 F | Fe-ludRam | % L501 214 R437 FP "ese 22e [Ik 3e38 @ "3 es 221 WR 3839 F " esw 22 tuo F hETI 223 {R 38se m| Fednelem |e sara 22 1% 3581 om a sawn 26 IR gsm | 2 saw ZUR Sem 4 sam 13 rR 3Eic "i 5 saat 3 2% 229 230 231 232 ik 4der F| Rowse 18 wis FE FE x ures PI IR 4450 Fo " esw |= PE [= esw 2 es = sn 1> 82 QA J | y } ! :; |i 1 i | | fi fom v. Pika rags, ' Gout | Moan G01608 124 Appendix seen 8 vo Year OroaflFl(aDrioetr)carTbooxniciFtHy35-24nciongennaitcsity study \ Blending Procedure of FN-3524 Diet Concentrate 1. P(Ap-p3r9o2n4in(a0t.e2l4yq/6kg2 o1f0 da1i)etintoabe10m8i1xeds)rasveasatedsisseoyllviendgeri,n ethanorl 2. aTTGhoeisibteisomonilsxueltdi.o5nm1Tvahseof g"erstaphdrauinnaoktlieesdancdyilntihnidlsearyaelrvssaes owfaalsne.ocn*-wetoprrrekiaemtdleedwditgirho(umonindo diet the pros 3. The created dist vas physically mixed for approxinatly 20 minutes using a Hobart blender. 4. GsAntfdatienprlleamscisexidnsgei,netdothpe&anfPsu3n9g(62c64.a5bdincineettlofcnoogrncaxenp4tp0rr.ao7txeimoahvtaeswliydsepr7x2eahd3o.u0orusctnitdnoeep) evaporate the sthanolb. TChoinscenptrroacteidounreofvas20d0opnpemoinn adiweeteskly basis to yield a FH-3924 m--e-------------------- 2, CCUOh.sDe.miAcnIaanlldsyutsiCtcroairlapl,ReCpChoreirmceiacga4ol2,s13CTorL.e,veaD1ii9ev0d.prtohofeo.fN;laetviLeoolntalo#f48De0it3sh1t6ai,nlollers(E&TOH) in the PH-3324 diet concentrate after deving to be less tran 1 pr. 01509 125  BESTCOPY AVAILABLE ap mica, sera 13 Appendix Teen 8 EES fom P. J. Colbert - 236-28 $2, G{LnCtoAnGarloyusnids Loafb CFh-o3w9.24(Ri(kTe-r299S9tCuodCy) 40F2C-8114C3R00(1T2-)2998CoC) Blended ose. April 29, 1981 31 Reference: RCoemqmueersctisal#17C0h7e9m,ica1l7s080A,nal1y7t0i9c6al Laboratory MCeotmhmoedrci#a'ls 6C3h0e-m0i4c8a1l.s A6n3a1l-y0t4i81cal Laboratory TChhoew,samaplloensg owfithF-3f9o5ur24bl(aW.nRk. GrEoLuFnOdSE)LabbleCnhdoewdsaimnptolesG,rowuenrdeLab received from L. samples were run J. in Sibinski on triplicate. 4-20-81 for analysis. The results are: All Compound Theoretical ppm Aucgt/ugalFM-pp3m928 Blank for concentrate 0 FM(-b3l9e2n4dedCo4n-c1e7n-t8r1a)te 200 28 7 FM-3924 Top Sample 100 . 105) ox Mid Sample 100 105 \ - Botton Sample 100 m F#-3924 Top Sample 30 29 Mid Sample 30 Botton Sample 30 27 \e= 30 7 = FM-3924 Top Sample 10 Mid Sample 10 Bottom Sample 10 n 9%- S00 - 01510 126 L. J. Sibinski CCD Analytical Report APpargiel 229, 1981 sms APPENDIX r7Ew #213 C"OPY AVAILABLE Compound Theoretical ppm Actual ppm (ug/g) FM-3924 Blank for 100 ppm Tevel 0 0 Blank for 30 ppm level 0 Blank for 10 ppm level 0 0 The level of ethanol in FM-3924 Concentrate (blended 4-17-78) was also checked and found to be less than 1 ppm (ug/g). The results are: 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 4/20/81 for analysis. All samples were run in triplicate. ound Theoretical ppa {o(actruaaldreas FC-14XJop Sample 300 326 Mid Sample 300 282 Botton ple 300 207 Blank for 300 ppm Towel 0 FC-143 Top Sample 30 28 Hid Sample 30 23 Bottom Sample 30 28 Blank for 30 ppm )evel : 0 Because two gf the three 30 ppm Tevel samplug were low, another! sfeotr aofnalsyamips.es Twehreererseucletisvedaref:rom L. J. Sibindi on 4/27/81 i a ~ -_-- 01611 127 . de: ME.TG.. CLaasmeprecht 212188--23 . J.D. Lalerte 236-1 CAonmaelryctiiacla] ChReempiocratls i229 UW0. FC.otMhcaCporramgiacdka 223260--3246-02 LR.. A0.. WPirnotkeorp 236--28 fepeennddiixx Trtreennd To e------------------ fom P. J. Colbert 236-28 Sect GLCIntAonaGlryosuinsdoLfabFMC-h39o2w6(R(iTk-e2r999StuCdoyC') #0F2C-8114C3R00(1T2-)2998 CoC) Blended 3M 2 June 15, 1981 Reference: RCeoqmueersctisal#17C1h7e2m,ica1l7s173A.nalytical Laboratory MCeotmheordci#a'ls 6C3h0e-m0i4c8a1l,s GA3n1a-l0y4t8i1c.al Laboratory wTietnhstahmrpeleesbloafnkMMG-r3o9u2n4d (LWa.Rb. ChEo+wFOSsEa)mplbelse,ndweedrefntroecGeriovuenddfrLaobm LC.howJ,. Saliobnignsk aorne:5-18-81 for analysis. All samples were run in triplicate. The results sample 74-3924 Concentrate (Blended 5/15/81) Theoretical ppm 200 /AcgtuaPlH-3p9p2m6 4 208 Blank for 100 ppm 0 - M-3926 Top 100 = Mid 100 == Bottom 100 ==> Blank for 30 pon 0 5 ; E F4-3924 Top 30 =-- otton = Blank for 10 ppm 0 M-3924 Top 10 Hid 10 Botton 10 o oe [/110089 ACN 0 i nl}| 27 0 | ns oni ls \ 10.0 C01512 128 "ELJ. 0Gl. LLazaemrtpe r- e=223c61-8h1-t3 6. Kirtan ~ tims Append: W. C. McCormick - 220-2-02 Appendixteen8 R-.Af.otPharporkaogpad-s236-22386-34 COMMERCIAL CHEMICALS - L. D. Winter - 236-28 ANALYTICALREPORT #251 % Led. SIBINSKI.- 218-3-3 fom Po J. COLBERT - 236-28 Soper GLC ANALYCSHIOSW O(FRIKFEMR-3S9T2U4DY(T-#20929891CRC0o0C1)2)BLENDED INTO GROUND RODENT 3M owe September 8, 1981 : Reference: aCnodmmeCrCcOiaMlethCohdemi6c3a0l-04A8n1a.lytical Laboratory ANNES wTietnhsafmopulresblaonfk FgMr-o3u9n2d4 r(aW.t Rc.howELFsOaSmEp)lesb,lewnedreed irnetcoeivgerdounfdrormatL.shJ.ow,Sibailnosnkgi TonheAurgesuusltts17,are1:981, for analysis. All samples were run in triplicate. Actual ppm sample Theoretical ppn g/g FM-392 Blank for 200 ppm 0 o 200 ppm Concentrate 200 218 +t B1l00ankppmfoTrop100 ppm 1000 00 / 110000 ppppmm MBiodttom 101000 pboel[110182 CC B3l0anpkomfToorp2 ppm 20 30 320 ppppmn MBiodttom 2 sod 3El ol Sh0anpkpmfToorp10 pom 2g 101.5 1100 ppppmm MBoitdtom 1100 woiwe N(o0l0s 2% wine Gul) GER FSTCOPY AVAILABLE 01613 129 Appendix Ten 8 Fro*m Swec T TR T T p -- COMMERCIAL CHEMICALS ANALYTICAL REPORT #290 R. M. PAYFER - 236-2B RODENTGLCCHOAWNAL(YRSIIKSER OSFTUFDMY-3#902248(1T-C2R909091C2o)C)BLENDED INTO GROUND Ee -- i -- Referenc-- e: -- Commerci-- al Chemi-- cales eArna-- -- lytic-- al-- Laborate ory Request #17780 chow, along with three blank ground rat chow samples, were Ten samples of FM-3924 (W.R. EtFOSE) blended into ground rat received from L. J. Sibinski on November 16, 1981, for analysis. All samples were run in triplicate with the following results: SSeammppllee - Theoretical PPM uAgc/tgua_FlM-P3P9M24 200 PPM Concentrate 1B0l0ankPPMforTop100 PPM 110000 PPPPMM BMoitdtdolme Blank for 30 PPM 30 PPM Top 3300 PPPPMM BMoitdtdolme B10lanPkPM foTrop 10 PPM 10 PPM Middle 10 PPM Bottom 200 1000 110000 0 30 3300 100 10 10 217 o108. n 110083 o 3129 29 ts 9o.4 10.1 47 57 9.5 Cm2g RMP/he de: GM.. WT.. CKaisresch- -2182-326-34 E.G. Lamprecht - 218-3 J. D. LaZerte - 236-1 VW.. CP.otMhcaCporramgiacdka -- 222306--23E4-02 R. A. Prokop - 236-28 L. D. Winter - 236-28 (2 copies) rAoT OPY AVAILABLE . 01514 130 de: MGTW.. CKaisresch- 2-162-326-34 E3..0G.. LLaamZperretceht- -2362-118-3 VW..C.PoMtchCaoprrmaigcakda - - 2:2336--234-02 LD. Winter - 236-2 Appendix ten 8 COMMERCIAL CHEMICALS ANALYTICAL REPORT #320 TL. J. SIBINSKI = 218-3-3 Fom R. M. PAYFER - 236-28 Sect GLC ANALYSIS OF FM-3924 (12999 CoC) BLENDED INTO GROUND Coie: MARCH 5,ROD1E9N82T CHOW (RIKER STUDY #0281 CR 0012) 33M Reference: Comercial Chemicals Analytical Laboratory Request #18072 wTietnhsatmhprleeesblofankFMg-r3o9u2n4d (r.aRt. chEoLwFOSsEa)mplbelse,ndewdereintroecegirvoeudndfrroamt cL.howJ., aSilboinngski wointhFsbtrheuarfyoll15o,win1g982r.esuAlltls: samples were analyzed in triplicate for FN-3924 sample Theoretical PPM Actual PPM ug/g FM-3924 200 PPM concentrate 200 Blank for 100 PPM 0 100 PPM Top 100 100 PPM Middle 100 100 PPM Botton 100 Blank for 30 PPM 0 30 oH Top 30 30 PPM Middle 30 30 PPM Botton 30 Blank for 10 PPH 0 10 PPH Top 10 10 PPM Middle 10 10 PPM Bottom 10 ey ibm 198 4 0 107 106 Ten 103 0 2 2 - 2 0 eat 8.8 of 9.0. ) Tok 5.7) | apd fZed / 7 RMP:df erpe ~"PYAVAILABLE - 01615 131 - cc: M.T. Case - 218-2 G.W. Kirsch - 236-3A 2E0.0G.. LLaazmeprrteecht- 2-362-118-3 Appendix Teen WV..C.PoMtchCaoprrmaigcakda - - 22203-62-2-802 - L.D. Winter - 236-28 Tb i------------------ ACNOAMLMYETRICCIAALL CREHPEOMRITCAL43S27 fom R. M. PAYFER - 236-28 Supect ome MGALRCCHANA2L2,YSI1S982ORFODEFNMT-3C9H2O4W (T(-R2I9K9E9R SCoTCU)DYB4L0E2N8D1EDCRIN0TO012G)ROUND 3M Reference: Commercial Chemicals Analytical Laboratory Request #18101 Three samples of FM-3926 (W.R. ELFOSE) blended into ground rat chow, along with one blank ground rat chow sample, were received from L. J. Sibinski on March 8, 1982. These samples were analyzed in triplicate with the following results: Sample Blank for 10 PPM 10 PPM Top 10 PPM Middle 10 PPM Bottom Theoretical PPM 0 10 10 10 Actual PPM Ug/g FM-3924 0 06 Len 9.7 Mim 9.9 RMP:df v/ 01616 132 Appendix ItemB ACNOAMLMYETRICCIAALL RCEHPEOMRITCAL#3S41 TE S---- fom R. M. PAYFER - 236-28 Seni GLC ANALYSIS OF FM-3924 (T-2999 RODENT CHOW (RIKER CoC) BLENDED INTO GROUND STUDY #0281 CR0012) ue May 28, 1982 SN | Reference: Commercial Chemicals Analytical Laboratory Request #18320 wTietnhsamfpoluers bolfanFkM-3g9r2o4und(W.Rr.at ELcFhOoSwE) sbalmepnldeesd, iwnetroe grroeucnediverdat fcrhoonw, La.lonJ.g SFiMb-i3n9s2k4i wiotnh Mtahye 1f7o,ll1o9w8i2n.g reAslu]ltss:amples were analyzed in triplicate for sample Theoretical PP ugA/cgtuFaHl-3P9P2M4 B2l0a0nkPPfMorCo2n0c0entPrPMate B10l0ankPPHfoTrop100 PPK 110000 PPPPHM MBiodtdtloem B30lanPkPMfoTrop30 PPH 3300 PpPoMu MBiodtdtloem B10lanPkPMfoTrop 10 PPM 1100 PPPPMM BMoitdtdolme Afonpfie RMP /nc 7 2000 100 0 . 100 100 300 3300 100 . 1100 1099-7 1000. 000 950 209h LeThee FE0 ee-111l09.05, 109 -F ou LE ea de: MG.TW.. CKaisresch- 2-182-326-68 JE..DG.. LLaazneprrteecht- -2362-118-3 WV.. CP.otMhcaCporramgiacdka -- 223260--G28E-02 BEST COPY AVAILABLE 01617 133 Appendix Teen3 ACNOAMLEYRTCIICAALL RCEHPEOMRITCA#L3S67 J om Re Mo PAYFER = 236-28 Sec, owe GLC ANALYSIS ROOFDEFNMT-3C9H2O4W SPL. 13, 1982 ((TR2I6K9E9R CSoTCU)DYB$L0E2N8D1EDCRIONOT1O2)GROUND Reference: Comercial Chemicals Analytical Laboratory Request #18608 wTienthsamfpoluers Sbinski on bolfanFkH-3g9r2o4und(W.`Rr.at ELcFhOoSwE) sbalmepnldeesd, Aug. 16, 1982. AIT samples were iwnetroe grroeucnediverdat fcrhoon'w, La.lonag analyzed In triplicate for FH-3924 with the following results: sample les, B2Bll0aa0nnkkPPfMfoorrCo2n10c000entPPrPPaMte 110000 PPPMH MToipddle B1l0a0nkPPMforBot3t0onPPH 307M Top 3300 PPPPMM BMoitdtdolme 1B0lanPkPMfToorp 10 PPH 1100 PPPPMM MBoitdtdolme Theoretical PAM ugAc/tguaFlH-3P9P2H4 20000 te 1903 5 . 1W 10000 igh n mopsae ilsloe n0 Lwail=aEy x 30 0 MmeEese g2e9 0 1100 10 n0n0 ot de: M60TW.. KCiarssech- -21283-62-68 JE..G0.0 LLaaZneprrteech-t 2-362-118-3 WV.. CP.otMhcaCporramgiacdka == 22306-.2668-02 LL 0. Winter - 236.28 -TCOPY AVAILABY E 01618 134 Comercial Chemicals Analytical Report 4368 . Appendix Item B T CCS i For R. M. Payfer - 236-28 Swe GLC Re-analysis of FH-3924 (T-2999CoC) blended fnto i ee round rat chow (Riker Study No. 0281 CRO0IZ) 3M i September 14, 1982 . | Reference: Comercial Chemicals Analytical Laboratory i Request #18610 Three samples of FH-3924 (W.R. Et-Fose) blended into i sgarmopulned, rwaterechorwe,ceiavleodngfwriotnhL.a Jb.laSnikbignrsokuindonratAugcuhsotw 27, | 1982. `These samples were analyzed in triplicate for | FH-3524 with the following results. Actual PPM | sample Theoretical PH ug/g FM-3524 |i Blank for 100 PPM 0 0 i 110000 P7PPMM mtiodpdle 110000 1w08o Lo. 100 PPM pn) 100 8 RMP:sk ? EiSTCOPY AVAILABLE 01619 135 -_-- > Fam 6. W. Kirsch NEED" - 236-28 Cformamteyrrciiaall Cchaepmeiscalhsie Sot GLC Analysis of F352 (1-299 Col) Blended into Ground Date December 8, 1982 || y : = Reference: RCeomeeerrcsiaMleeCshee,micals Analytical Laboratory H20T1.ei76n50i%3s1aCwmSapiitnlnelensatfnoooirfurFoFUnbU-l-3aN33no92kv2e4sGvrw(aoHiru.mnRd.1T3h,rEeoHrF1O9fo8Scl3Ehi,)oouvbiAslIneo1g"nmdmeesedesmn,pimlnewtanaorevgerrvoeeunncdsinoerniasterefcsrhoonirn Sample Theoretical 200 ppm Concentrate 200 Blank for 200 ppm 0 B1l0a0nkppmforTop100 ppm 110000 bpopmm BMoigdadelme 0 1%110000 Slane Tor 30 pom 5 S333000iobbpnoopmmm fBMoTrioodpsd1ol0meppm 333005 To"pem Top 10 1100 pbpomm MBoisdsdolme 110 om[en2 der E5WG1T.5. LLCoaasmmoporra-rceh2st18a-2i21i8-3 WC ietaren 2a R. M. Payfer = 236-28 pase TE V. Prothapragada - 236-GB Actual ppm ppm pa/g FM-3924 223 +05 0 0 n"52238WA "a ,, 3i2 45 9-, IH Ye i12 Jiasast BEST COPY AVAILABLE 01620 136 BEST COPY AVAILABLE Appendix 1ten 8 ACnoamlmyetricciaall RCehpeomritcal#s394 ToL. J. SIBINSKI - 218-3 fom G. W. KIRSCH - 236-28 Seuccei GMLACRCHANA1,LYS1I9S83OFROFDME-N3T92C0HO(NT-2(9R9IK9ERCoCS)TUDBYLEN#D0E28D1-ICNRTOO01G2R)OUND 3M Reference: Commercial Chemicals Analytical Laboratory Request #18854 wTienthsamfpoluers bolfanFkM-3g9r2o4und(W.Rr.at ELcFhOoSwE) sbalmepnledse,d iwnetroe grroeucnediverdat fcrhoomw, La.lonJ.g SfoirbinFsHk-i352o4n wFietbhrutahrey f1o6l,lo1w9i8n3g. resAullltss:amples were analyzed in triplicate sample Theoretical ppm uAgct/ugalFHp3p5m28 2Bl0a0nkppmfoCron2c00entpprmate 2000 B1l0a0nkppnfoTrop100 ppm 1000 k 110000 ppppmm MBiodtdtloen 110000 3B0lanpksnfToorp 30 ppm 20 3300 pppomn MBiodtdtloen 3300 B10lanpkpmfToorp 10 ppn 100 1100 ppppmn MBiodtdtloen 1100 1670. Log 0nS (20880 i . r0 a am 22s5 09 v=2\.s8 - GHK/heBran de: EMlTG.l CLaamspere-ch2t18-2- 218-3 J. 0. Lazerte = 236-1 WR.. KC.. MPcaCyofremric-k23=6-22280-26 WL.D.H.-PWeianrtlesron- =2362-2238-65E + AVAILABLE aDYN c0o115621 137 ---- re -------------------------- BESTEOPYAVAILABLE Appendix rtens CAnoamleyrtciicaall RCehpeomritcal#s403 To GemlizBIBINSKE =21653, Fam 6. WH. KIRSCH - 236-28 Sowce AGPLRCILANA19L,YSI1S983OFROFDME-N3T924CHO(NT-2(9R9I9KERCoCS)TUDBYLEN#D0E28D1-ICNRTOO01G2R)OUND 3N Reference: Commercial Chemicals Analytical Laboratory Request #19332 wTietnhsamfpoluers bolfanFkM-3g9r2o6und(W.Rr.at ECcFhOoSwE) sbalmepnledse,d iwnetroe grroeucnediverdat fcrhoomw, La.lonJ.g S7i4b-i3n9s2k4i wionthAptrhiel fo1l3,low1i9n8g3.resuAlllts:samples were analyzed in triplicate for sample . Theoretical ppn Aucgt/ugalFH-p3p9m24 2Bl0a0nkppmfoCron2c00entprpmate 2000 B10l0ankppmfoTrop100 ppm 1000 110000 ppppnm MBiodtdtloem 110000 B30lenpkpmfoTrop 30 ppn 00 3300 ppppn MBiodtdtloem 3300 B10lanpkpmfoTrop10 ppn 100 1100 ppppn MBiodtdtloem 1100 2070 ee 0010, 10993% tt n0 o 8 29/3 - 09. . 89x a uk/nc GH de: M3.T0.. CLaaszeert-e21-8-2326-1 W. C. McCormick - 220-26 WR.. MH.. PPeaayrflesron- 2-362-232-86SE L. D. Winter - 236-28 co1622 138 ----e-- e---------------------------------- Appendix tesC vo Year Oral (Dist) ToxicTiut-y3-5o24ncoignenRiactisty Study of Fluorocarbon Normal RangesatfRoirkHeermaLtaboolroagtiocriaensd, BlTnoco.d, ChSte.atPsaturly, VaMilues of Rats Erythrocytes Hemoglobin Hematocrit Mean Corpuscular Volume (MCV) Maan Corpuscular Hemoglobin (NCH) MeCaonncCeonrtpruastciuolnar (HMeCHmCo)globin Leukocytes Neutrophils 2-22% Lymphocytes 65-35% Monocytes 0-sv Soatnophils 0-6v Blood Urea Nitrogen (su) Glucose Total Bilirusin Total protein Atbusin catctm Alanine Antnotransferase (ALT) Aspartate Amtnotransterase (AST) Alkaline Phosphatase ~ Creatine Phosphokinase (ce) 5,000,000-8,000,000 ce1is/cu am 1-17 gra 36-520 57-77 microns' 18-24 picograns 30-308 6,000-15,000 calls/cu ma 500-4,000 cells/cu mm 5,000-14,000 colls/cu na 0-500 colla/eu mm 0-500 colis/cu za 10-30 mg/a1 120-160 mg/a1 0,141.0 sg/a1 5.57.5 g/a1 3.55.5 /a1 10.2-12.5 m/e 10-40 International unite/1 20-60 International Untte/1 50-200 International Unita/1 50-150 Internationai Unite/s 601523 139 Appendix Item c Methods Used for Hematology On Bleedings at 3 and 6 Months Parameters nies Methods Hematology Total Erythrocytes & Leukocytes Hemoglobin Hematocrit Differential cells/cubic mm a/ar * packed cells 4/100 vec Coulter Coulter CEloeucnttreorniMcosdel FN HIenmsotgrluonbeinntoamteitoenr,LaMboodrealto2r3i1e,s MoMidcerlohNeBmatocrit Centrifuge, International Equipment Co. Microscope slide C01GR4 140 APPENDIX ITEM C METHODS USED 1F2O,R H18EMAANTDOLO24GYMDONETTHESRMINATIONS FOR HETHODS USED F3OR,6C,LIN1I2,CAL18CAHNEMDIS2T4RYHONDTEHTSERMINATIONS FOR HePmaaratmoeltoegrys LEeruytkhorcoyctyetses HeHmemoagtloocbriitn Differential Chemistry TotBalloodBilUirreuabiNni,troGgleuncose AAllbkuamliinn,e PTohtoaslphaPtraosteein AST, ALT, CPC rinalysis Specific Gravity PH,GluAclobsuem,in,OccBuilltiruBbliono,d and Ketones nits cceellllss((11003/3mm3)) #g/dl %/100 WBC Methods and Techniques UlAtnraalLoygziecr 800 Hematology ClaByectAodna,ns,DicDkiivnissoinon& oCfo. Microscope slide mg/dl aI/ndtlernational Units/1 ~|| RTroatvoecnhoeln 3L6ab1o14rataoriIensc,. TS Meter, AO Instrument Co. A8nielsiLCaobmsptiaxny 601625 14 APPENDIX[TEN D PATHOLOGY REPORT OF RATS RECEIVING FLUOROCHEMICAL FM-3924 IN DIET FOR THO YEARS 01526 - 142 wETHODS Gross Pathology : - All rats which were sacrificed at the 1 year interim or the 2 year terminal sacrifice or which died or vere sacrificed in extremis during the course of study vere necropsied. At necropsy, an examination vas made of the external body surface and body orifices. The carcass was then opened and the contents of the abdomen, thorax and cranium were examined in situ and after removal from the carcass. Representative tissues and organs from each rat vere fixed in 10% buffered neutal formalin for subsequent histologic processing. At the 1 and 2 year sacrifices, wet weights were obtained on adrenals, brain, testes, heart, kidneys, liver, spleen and uterus from 15 randomly selected rats/sex/group. Body weights were obtained prior to necropsy from the same rats for calculation of relative organ weights. Histopathology Microscopic examination was made of hematoxylin and eosin stained paraffin tissue sections of the following tissues and organs, where available, from all rats from the control group (0 ppm) and the 100 ppm group which were sacrificed at 1 and 2 years or which died or were sacrificed in extremis during the course of study. aoadrrteanals (2) brain (3 sections including gfarnognltiala, copratrieextaalnd cobarstaelx and thalamus; cerebellum and pons) eyes gonads ovaries (2) testes/epididyaides (2) heart slmaarlgle iinntteessttiinnee (3 sections) kidneys (2 sections) lluinvger (2(2sescetcitoinosn)s) 1ymph node (mesenteric) mpaamnmcarreyasgland (females) pituitary salivary gland spinal cord/bone marrow (vertebrae) spleen - stomach thyroid/parathyrotd/trachea/esophagus urinary bladder uatneyrutsissourepmraosssteaste(suspected tumors) any other gross lesions Microscopic examination of tissues from the 30 and 10 ppa groups included all the above listed tissues except aorta, brain, eyes, small and large intestine, lymph node and spinal cord/bone marrow. 0281CRO012 (F-3924) 01527 143 rasrs } Grose Pathology LiversAt detshceri|beydearinimnatleerimratssacrfirfoimcet,he an100incprpeagsreodupinwcaisdecnocnesiodferpeadle/ptoasnsibcloylor compound related. There vere no necropsy Findings effect in female rats from the 100 pp group which suggestive of a vere sacrificed compound at | year. In rats which vere sacrificed at study teratnation or which died or vere sacrificed innoteedxtrfoermislidveurrinmgasstehse,conuodrusleesofansdtudryais(eTdS/DlOeSs)i,onsa,n miontctrleeadsedliivnercsideanncdeywealslow oF pale liver foci and leciens at the 100 ppa level in males and female. No gfrroosns thfein3d0ingosr s10ugpgepstigvroeuposf. a OctohmeproungdrosesffepcatthowleoregieseefnindiinngasnyveTrSe/DOtSypircaatls of Findings in ageing rats masses and fost, ulcers of an tchheishisntdraifno.otpaTdhee,sepailnecluIdveedrsmamamndarypalmea,ssepsi,scepdievstndsary enlarged itdneys. Organ setghes absoluTtheereandwerreelasteivveeralorgsetnatviesitgihctaslly(orsgiagnntibfoidcya,ntor(gpentbCr.a0t5n) vweairgihattiornastioisa) (n asic and fensles rats Increases in absolute fron the 100 liver weight ppm and group vhich vere sacrificed at 1 year. in lver:brate weight ratios 11 sales and females changes from the and were 100 ppm group correlated with compound considered toxicologically signtficent. related morphologic A significant decrease in group also was mean body veight in male and female rats considered toxicologically significant. from None the 100 ppm group ac 1 year of the other organ seight VAEiations (n significance. 100 ppm rats at the 1 year ineris vas considered of toricolopte absolAuttethleivecrervmeilngahlt saacndrifiinceL,ivsetra:tboidsyticaanldlyLivseirg:nbirfaitcnantwei{gnhctresrsaetsiosoccinurmraeldesin and feasles at the 100 Fatto also occurred tn ppm level. A significant 30 ppm males and females. increase in liversbody weight These fncresses in liver veight correlated vith logically significant. sorphologte iver changes and vere considered A statistically significant decrease in body toxicoweight in sNaolemsorpahnodlofgeimcalecsorratela1t0e0s pvpemrealosbosevrasvedconfosrideortehdertosxtiactoilsotgiicaelallyly sisginginfiifciacnatnt. organ weight variations and they were not considered toxicologically significant. azsicro0nz (e-3920) 0168 144 Histopathology Compound related microscopic changes vere observed in the livers of male and female rats from the 100 ppm group at the | year interim sacrifice, in male afnrdomfetmheale10TSp/pDaOSgroruapt.s from The the 100 and 30 ppm principal compound groups and in related liver male TS/DOS rats change vas megalo- cytosts, which was characterized by an increase in size of liver parenchymal cells due to an increase in cytoplasmic volume. The increased cytoplasa was of uaerfeinerleylatgirvaenluyladrec"rgeraosuendd ganldassv"ereapdpiesarpalnaccee.d tTohethecocaerlslermecmybtroapnlea.smicTheornguacnleel-les usicycoplasn ratio vas decressed by the increase in cytoplasaic volume fn affected cells. Most or all lobules in affected livers were involved and the centrilobular cells vere more severely affected. At the 1 year interin, megalocytosis occurred a 8114 to marked degree in 15/15 males and to a mintaal to moderate degree in 14/15 feasles from the 100 ppm group. The lesion was accompanied by ={1d to Soderate hepatocyte vacuolation, probably fatty, in 16/15 males and by minimal to 81d necrosis in 6/15. In femsles, minimal to mild hepatocyte vacuolation oAcscsuorcrieadtioinn o5f/15hepcaotnotcryotles vaandcuo1l5a/t1i5on100andppnmecrraotssisbutvitnhecmreogsailsocwyatsosniost seen. suggests that the progression of lesions 1s megalocytosis to fatty degeneration to necrosis. In 75/005 rats, megalocytosis occurred in males from the 100, 30 and 10 Pon groups with a dose response evident in incidence and severity. In female TS/D0S rats, wegalocytosts occurred only at the 100 and 30 ppm levels; the 10 P78 level was free of compound related microscopic lesions in females. The ithneci0d,enc1e00,of 3m0egaanldoc1y0topspims lienvelTsS,/DOrSespmeaclteisvewlays. In 0/50, fe4m2a/l50e,s, 28t/he50inancdide2n7c/e50vaast 44/50 and 1/50 at the 100 and 30 pp levels. The incidence of megalocytosis vas statistically significant in male rats at the 100, 30 and 10 ppm levels and in females at the 100 ppm level. Incidence and severity of hepatocyte vacuolation and necrosis also was increased in of these lesions vas statistically 100 ppm TS/DOS significant at males; the increased incidence this level. Five hyperplastic nodules occurred in males at the 100 ppm level and 1 was seen at the 30 ppa level. Presence of hyperplastic nodules indicated regeneration vas occurring in these livers. There vere 9 hyperplastic nodules in 100 ppa females and 1 in a control female; this increase vas statistically significant. Cystold degener- ation, characterized by sress of multilocular microcysts in the liver parenchyma, 0281CR0012 (P-3924) 3 01529 EI 45 4120 fron vas the i10n0crpepamsedgroIunp.maleIncriatdsencferomof tthehis100Leasntdon30inppmaalegsrouwpass and in females 4/50, 15/50, 8/50 and 6/50 at 0, 4t the 100 ppm Level 100, vas 30 and 10 ppm, stactstically respectively. significant. The sncressed In females, the incidence tncidence of cyetotd gros degeneration was 4/50 fn the 100 ppm group and 0/50 fn all ocho 1n Occurrence of these alkaline phosphatase, liver histomorphologte changes aspartate aminotransferase and correlated with elevations alanine sminotransferase Levels observed in 100 ppm male rats. The severity of Motomorgologis liver charges markedly reduced fncidence and tn Tessie seve pureliete sim sbonncn of change in liver specific Tere wae ws Hirect or serum blochentcal indirect cmpond values effort in in females. erLee SUeE than cloinvserideatredthesec1 onydeaarriliyntecormipnousnadcrirfeilcaet.ed, InproTbSa/bDlOyS rats, changes which vere through FH-3924 altered Liver sIentatbheoliadsrnenoaflse,ndaogesntoautsistsitcearlolidys,sigwneirfeicoabnsterviendcre{ansetdheinacdirdeennacles and ovaries. of nodular hyperplasia Chis lesion of the cortex occurred in vas 2/49, 11/50, 0/49 and males at the 100 ppm level. 5/50 at the 0, 100, 30 and Incidence of 10 ppm Levels Teopestively. hypecplasta of In females, the ovarian there was 4 dove stroma. Tubular related ssarrense of tobeler hyperplasts fs a non-neoplastic d1fuse tncrease in tubular elements bilsteral and associated vith sbeens of or the ovarian strous which wae veually markedly reduced follicular development. The incidence of this condition, vhich vas statistically significant at all droessepeclteivveellsy,. waAsn0/i4n8c,rea1s5e/d48,nci11d/e4n8ceanodf6/a4c7cumatulatthieon0,s o1f00,fos3s0yanadlve1o0leprpmsalcervoe-ls, phages 1a the Lung, wich wes probably sven significant in males and females at the 100 ppm Telased, as Sretietieeily level. The incidence of this condition at the 0, 100, 30 and 10 ppm levels, respectively, was 10/50, 23/50, 15/50`Tahnedre1w8e/s50teinimnaclreesaseadndta1c4t/5d0e,nce27/o5f0,neo1p5l/a5s0iaandsug1g4e/s5t0ivien fofemaalecso.spound effect 1a male rate. Incidence of primary liver tunors (hepatocellular carcinomas) iILnnevemflaelmeawslheesrw,eas tthh3ee/r5e0o,nlwey2r/e5o0c,c3 uhr1er/pe5an0tcoeacnedofll1up/lr5a0irmaartsyar0,cliinv1oe0mr0,sstu30ssnodrasnd4 vah1se0 psaptrpmo,ctehlerleus1lp0s0erctpispvdeelnyc.ass. aThsisnottncrsecaasceidstiicnaclildyencseignoiffitchaenste. primary There liver tumors vas no other in high dose incidence of nfeeomptllaesiraate oasicRo0n2 (me-3920) a". 01530 To 146 suggestive of + compound effect in female rate. Other sicroscopic lesions in tissues from FH-3926 treated rats vere typical of naturally occurring inflammatory, degenerative and ageing population of Charles River CD rats. Commonly neoplastic lesions in an occurring nflamatory lestons included chronic nonsuppurative fibrosis, mononuclear inflamatory cell myocarditis with associated syocardial infiltrate into the portal triads of the Liver vhich vas frequently associated with portal bile duct proliferation and perivascular sonomuclest inflamatory cell infiltrate and moltifocal chronic interstitial presents in the lung. There vere & number of non-neoplastic Lestons vhich, although they incidence compared to. control had group statistically levels, were stgnificent variation in not considered to be of toxico- logical significance. These included decreased incidence of chronic myocarditis n in 100 the pp females, decreased Lung of 100 ppm males, incidence increased of perivascular mononuclear cell infiltrate incidence of vascular mineralizetion in the Lung of 100, 30 and 10 ppm females, decreased incidence of interstitial preunonta in 10 pa males, increased incidence of vascular mineralization in the testes of 10 ppm males and urinary bladder epithelium decreased of 10 pra ifenmcaildeesn.ce of epithelial hyperplasia of the Stie of the included adrenal sare commonly corwrring degesrarive lestons cortical vacuolation and sinusoidal ectasta, fn this study focal mineralization in large puluonary artery branches in the lung, focal acinar atrophy in the pansress and chronic progressive nephropathy. Pituitary adenouss comon neoplasa in male and female rats. Mammary adenocarcinomas were the most and fibroadenomas also vere frequently observed in female rats. Overall, the health of the rats In this study vas excellent, with organs free of lesions diseases which vould have had an iapact upon survival or of comon fnfectioss the validity of the study. oSavrU eisree6L r.,GoA. rmt,itDQ e0clJings of Varerinary Fatholopises a9f[2or[e& 01631 147 0281CRO012 (FM-3924) -5- TABLE OF CONTENTS Table Number T Macroscopic Incidence for Males = | Year Interim............... Page 2 43 MMaaccrroossccooppiicc Macroscopic IInNcCiiddeennccee Incidence for fFOorr MFeamlaelSe.s..~nn| iYeeraereeIsnsteesriema.s.e.r.s.i.s..s.s.r.s.s.istns: Females...........................o.n. 5 4 NNooanw-nnceooppllaassttiicc IInncciiddeennccee ffoorr MFaelmeasles-- =1 Y1 eaYrearIntIentreirmi.m.....................193--1124 7 > YNoonn--nnccooppllaassttiicc IInncciiddeennccee for for MFeamlaelSe.s.........u.s..s.s.s.s.s..e.v.e.e.n.n..n.s.s.r.n..s12s77s2-n33n64 4 13 NNeeooppllaassttiicc IInncciiddeennccee for for Wales = Females 1 ~ Y1 eYaerarIntIenrtiemr.i.m....................e.r.r.i.s3? I1l2 Nvieeooppllaassttiicc IInncciiddeennccee ffoorr MFeamlaelSo.m.......u.u.s.u..u.s.n.s.nenrininisinonsnsssenssssinonisnss3bsl0sonsddsd) ATpapbeisndiFxumo Page TTM 2 SSiinnagllee TTasbbuullaatteedd AAnRiImMaAlL RReEpPoOrTtL=sn1ssYseanrnnInnnfeerniemeea.a..r.s.ies.sesssssesssess.2Is0-s00s0s0 3 TTiLsSsSuUsE ITAaVvEeRnLtOoTrYy. =ee 1suYuerarrrIenetnenrnninmnun.n.e.e.s.s.s.i.s.iosone.soseseissesininies2s2s2s86ss20ss03ss915s 9221CRA012 (F-3224) 01632 - 148 MaRcirkoesrcoLpatbcorIantcoirdieensc,e Ifnocr. Ma3les Table 1 FN-3524: Tuo Year Ora Toxtcity-Oncogenicity Study fn Rats - One Year Interfa Project Number: 0231CRO012 Spectes: Rat . sites Description Grow 1 Group 2 Yo visible lesions ee oatpraocpihtyy Liver Mesentpaartye/tan color Kidneyfat necrosts hydronephrosis cystic lesion sein natr Toss Soft aTissssue (thorax) Soft Tissue (leg) swollen foot. . 9 7 1 1 25 1 1 1 1 1 1 Titles: - GGrroouwp 21 CFOHN-T3R9O2L4 10p0pmppm 01633 Macroscopic Incidence Page: 1 149 NaciroesrcopLtscarIsntcotraieecse, fIonrc,Femstes Tre: 2 PRe228: Tuo Yea Oral Toxty-Oncasenic Say fn Rats - One Yer Intertn Project Naber: OICANIZ Spectes: Rat sitessescription Group 1 Grow 2 YBoevstate testons prattsatrryony aireedriersed Liver ges ss : > 1 Nesppheaeldryen/itaatne"d Tove xuirtenesy oneness Cenylsarcgedteston amarGyasSeissn,d nue ried san ss naastte Toss 1 11 vo 1 1: \ ' : 1: Totes: ~ GGrroou1wp2 tCONTeROL 1000pppm m 01634 * includes "possibly" Wacroscopt Inctdance Page: 2 - 150 MaRcirkoesrcoLpaivcorIantcoirdfeensc,e Ifnocr. Ma3les Table 3 FH-3928: Tuo Year Oral Toxicty-Oncogentcity Study in Rats Project Number: G28ICRO01Z Spectes: Rat SteDsescription Grow 1 Group 2 Group 3 Group 8 sNoratvnisible lestons dark ares oe opacity/cloudy aatcreorpnlyesion Ptattary ndaarsts//ennelasrogredh/argaiirscee/dd lfoecstion Thyroetndlarged" Adrenaetntarged/mass Throaxers(tinternal) fluid filled Thymusenlarged" henarrhagic/hesorrhagic lesion Lgmottled frothy tracheal exudate mcaosnsso/lradtasteidonlesion Hearntypereaic enPlaacrcgiead/"navsly Aocamepnate(internal) gsatso,magcahstermopftnyteosftifnoaold tract mfalsusi,d ofsielnetdus Esophaegnulsarged;thickened val! Stomacehdema/thickened val) eernolsafrognesdulrucgeareations" Sean1meIsnstestine hesorhage 1 7 81 11 21 11 21 1 `' 1` 13 101 1311 2 3 31 3 1 1 111 11 11 1 1 11 1 1 11 1 11 1 1 1111 1111 1 1 TetesG:roup 1 CONTROL 0 pp GGrroouupp 23 FFAN--3309224 13000popmpm Group & FN-392 10 pom * fncludes "possibly" Macroscopic Incidence Page: 3 01535 - 151 PRET 0 YeoTse aarteem-- eosmefr rns S180 0.3008 es rae Hers SEROTEY petess ok Wsaiscrimption wl pz ond wows i,psaste : . \ tr nt pate/pale lobes" won A10 5 4 5 mpa Lotiitvleseesd" tors tod91i 1 3; ii g Aon ' , . iCirs LW F : P { ba y mens :: . tasmHimaleotl"ttasarariemt) 2 1 : ': miri--e g) rie wie : : , weyA ove pvr rertn : se se r rdp J : a o1pDa3lla%e,roenrtlarsge,d" geiie eison 1 H:E 1 4 . , N F a N e } : i . Ter:aB R}ee lWe - Group 1 CONTROL 0 ppm 01536 * includes "possibly" Wesoente es pgs + 152 MaRcirkoesrcoLpaibcorIantcoirdfeensc,e Ifnocr. Ma3les FH-3526: Tuo Year Oral Toxicity-Oncogentcity Study in Rats Praject Nusber: CZ31CRO012 Species: Rat Stee) UrinDaersycrBliapdtdieorn - distended hheemnoartruhraigai/cfiTwalleld with reddish/dark fluid calculi Testsims/aElplididmis. Pernolsatragteed" enlarged/thickened/aass edematous. HammsamryalGlland sin mass WTiecsetronss/,infhliansdedf/ocoitrpcaudlsar/raised dermatitis/uicer lesion) inflamed area" inasirtlaosrsea ass thickening abscess Soft Tissue (n2ck) SoftmTaissssue (thorax) fase Soft Tissue (leg) Bone. swollenpaus/feet swollen Joints Group 1 Group 2 Group 3 1 21 1 1 1 ` 31 5 1 1 1 1 7 : 3 11 3 1 1 . ` 1 1 1 1 1 1 Table 3 Group 4 13 1 1 5 1 2 2 1 Titles: - Group 1 CONTROL O ppa. GGrroouupp 32 FFNH--33592248 31000pppaa Group 4 FH-3928 10 ppm 01537 * includes "possibly" Macroscopic Incidence Page: 153 MacRrioksecropLiacboIrnactiodreinecse, fIonrc.Fem3aMles Table FM-3926: Tuo Year Oral Toxicity-Oncogenicity Study fn Rats Project tuber: 0281CR0012 Species: fat sites Description Growp 1 Grow 2 Grow 3 Group 4 Wo visible lesions ee opacity/cloudy inflammation atrophy Piwi`tmearssy/enlarged/raised lesion henorrhagic/dar lesion Thyroiedrst enlarged Adrenal enlarged mass/raised lesion Thoraxpat(einternal) uid filled Thymimsass, Lung enlarged mottled ncoondsuolle idation phaelmeorrhagic Filled vith red fluid Lysphenlloadrege(dbronchial) Heart,pericarditis" Stomach ulcerations erosions reendlamrugceodsarlugaareeas/reddened blackish, yellowish fluid contents. Sal Intestine inflamed thickened walls . LargeimIpnatcetsitoinne mass ` 5 ` ` 31 21 1 1 2 a 1 1 3 1 1 8 3 3 s 5 1 1 1 1 1 1 2 11 1 1 1 1 1 1 1 1 2 1 1 1 1 1 - TiesG:roup 1 CONTROL ppr Group 2 Group 3 FFHN--23092244 13000ppppam Group & FN-3928 10 pp IN 01538 * includes "possibly" Macroscopic Incidence Page: 6 154 MacRrioksecropLiacboIrnactiodrefnecse, fIonrc.Fem3ales Taste FH-3524: To Year Oral Toxicity-Oncogenfcity Study in Rats Projoct Nusber: 0281CR0012 Spectes: fat sites Description Grow 1 Grow 2 Group 3 Group & Pancrmeaasss/nodule Liver pate" rass/nodule/ratsed Teston mcoitrtclueldar Tesion/pale foci/pale lesion enylelalrogveids"h leston dark redarea lobe Fougn/frreqular surface Spleendark color/dark brown enlarged" small Lymphennladaerge(dmesenteric/abdoatnal) reddened Kidneyenlarged, pale, pitted enlarged" ppiatlet,edpitted mottled pst congenital absence, left. UrinareynlaBlragdedder cmaatsesalt ourythickened walls mass. erst Utereunslarged #11168 with dark/bloody Auld ass cystic leston dark arealesion pcornogleanpisteadl absence of left horn, ovary agin mass. 1 1 1 2 6 8 8 10 1 +23 2 1 1 1 3 1 1 1 2 2 5 1 5 2 2 21 1 21 1 1 1 12 2 1 1 1 3 21 1 1 1 1 1 1 1 22 1 1 2 1 1 1 2 2 1 ' 1 - TitlesG:roup 1 CONTROL pp Group 2 FH-392 100 ppm GGrroouupp 3 FFMN--33992244 3100 ppopu 01539 * fncludes "possivly" Macroscoptc Incidence Page: 7 . 155 MacRrioksecropLiacboIrnactiodreinecse, fIonrc.Fea3ales FH.3526: Tuo Year Oral Toxicity-Oncogentcity Study in Rats Project Wer: OZGIGRO0IZ Spectes: Rat stee/Description Group 1 Group 2 Group 3 NamarayssG/lnaonddule sein afk cyst arastssed/inflamd/ulcerated lesion, footpad MraaitredTosless/itonninning Soft cTiirscsuulesar(lneecski)on Soft Triesdsdueensed,(legsl)and-1ixe structures msawsosllen foot 2 11 2 1 21 21 21 1 2 1 1 1 Table Group + 12 . 3 1 Titles: - GGGrrrooouuuppp 231 PPCOARN-3T39R92O26L8 301000pppmppomm Group 4 Fh-3920 10 pa 01540 Macroscopic Incidence Page: . 156 Non-Neoplastic Incidence for Males. Riker Laboratories, Inc. 3 FH-3526: Tuo Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Project Number: 0Z01CRO012 Species: Rat Table: 5 Tissue/ DiagnoMsiosd/ifier Adrena) Within normal 1inits Cortical vacuolation Nodulnaridhyperplasia, cortex moderate Sinusoidal ectasta, cortex Rorta moderate "itnin normal Minits BoneWHiatrhrinownormal Tinits srain Hithin normal Maits Esophagus Within normal Tints oe Within normal 1iafts Keratitmiasr,kedacute Heart Within normal Minis Myocaardiiteis, chronic nonsuppurative Kidnay Within normal Tints Cateutus Chronimcinpirmoaglressive nephropathy nid Hycdyrsotnephrosis moderate Hephrintiisd, interstitial, chronic Pyelitis, acute inna) Large Intestine Within normal Tiaits LiverWithin norma) Minis Grow 1 Grow 2 aemeenate eemesure 19 18 12 15 1 o 11 1 0 1 5 1 9 Ls15) C1155) (11) (1155) (15) (13) 1s 15 (15) (15) 15 15 (119) (115) oo 11 (15) 15) 1 15 11 o 15) 15 5 7 1 2 5 85 3 2 11 oo 1 s 11 1 o 1 o (15) (10) 15 1 (175 1]9 Titres: Group 1 CONTROL 0 ppa Group 2 FH-3926 100 pp 0) = Tota) Examined C0141 157 Microscopic Incidence Page: 9 Non-heoplRaiskteirc.LaIbnocriadteonrcieesf,orInMca.les3(continued) F-3924: Tio Year Oral Toxicity-Oncogentctty Study fn Rats - ne Year InteTraibnle: 5 Project Nomber: OZB1CRC0I2 Specs: Rat TossDeiragnosts/ Hosier rGeoawper1 eGeretobwasoe2n LiverHep(actoonctyintueeda)lteration, vacuolated 2 0 apiede) 11 o0 Hepataociytde vacuolation uo Hogalomcoydteorsaitse 155 maoisterate ss Necrosmiasrked 0a 5s asinndinal o 1s amiindima? Portal bile duct proliferation 5`1 8.2 : Portalaoinniaanaulctear cell infiltrate 71 21 Lung afte (5mom)n WKiitvheionlarcomracnropThiangtess 13 13 Aesteactiadsis 13 13 samorarhiagde 61 s1 siociearate s 32 Hyperpalaasrikae,d septal cell aid 1 1 1 Pertvaasicnuitaaar sonomiclesr fnffitrate zo 1s Pneumonaiita, interstitial, chrontc z3 .3 eaiintidnat 21 3 Vasculaarinimnianeralization `7 51 ait 3 8 Tioartoewsp: 1 CONTROL 0 ppm Group 2 F332 100 ppm 0) = Tota Examines C01542 Microscopic Incidence Page: 10 - 158 lonoplaRsatricLIinrcaitdoenrcteenf,ornNc.es (continued rofect WannPeRr3:52Q88:ITGoRoOY2er SOpreac)teTs:oshtaetnty-neopenterty Sess In Rats- ne ter InteTrnae:5 TsaShranasts/ ier yooUonde r(maerseenteTriice)s Vemorriugee WoAm rnhsaes orn wena Votes Mesenrteursytse, sfat Stetptiered,echronic vointn normal Mates iarwshterony Pacrergottiesrsetsechronic varatyrotawhe Pvgain rout Hitss iGtn roma Ves restraatete soma? ts SattaariynGlnoogrmal tines SolinInntesstionree atts Soint)hiConrdmoron tes senenn norm atts Neastshoreots stomarHy------ Test Vtoanrdrmaopertns Vita m Gowe1 mGowe2 Gimoo G3e3: 3oo w33n 3o tn1| {0oo 1: o5 Gio G3e 3: oS 5; o: (5 nwo Go7 Gm: 3| i| GBos o4m G3a oImH G3a o3m Ghay Gae G3n aHm 5s i; G3o Gpay Gjoa o4m TGortoewss: 1 CONT0RpOoLm - Group 2 FM-392 100 ppm 0) Tow) canines 01643 Marsa" Tebtoss Su1pe5982 Non-Hooplastic Incidence for Hales (continued) Riker Laboratorfes, Inc. FH-392: Tuo Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interin Project Humber: G201GRO012 Species: Rat Taste: TissuDeiagnosis' Modifier TestTiusb/uElpeigiadtryoapihsy,(caosnptienrumeadt)ogenesis nile Vaselar mineralization mild Thyrold WFiotlhliinculnaormhaypelripmliatssia, cystic roderate TrachWeiathin nasal Himits Urinary Bladder Within oral Miaits flGrowA 1 Grow 2 0 1 2 1 o i 9 1 (1m (12) 1o n1 o 1 115s) [5105] (19) (19 15 1 mites: GGrroouupp 21 FCHO-N3T0R2O4L 0190porpnpm 0) = Total Examines C01544 160 Microscopic Incidence Page: 12 PH To Yeo GraonTenrsosme eTesta or Ss emi 1 Rus - ne Tear nari rane nr: EGON? pete: ut Toe: 5 Tio tir arerrnatte sostatiitosn os ores --ol srpernrpa tes an oman -- on pA-- Hvasmarmeasts rsSiepteosort vite onAy rapndvon sara epantniiaer vies Gonre nwopassive rene wparwoiee s ericwsmrer stion Hyperplasia, pelvic epithelium pa Gon 1 sn 2 e 2 ; e s} :: Gh;; 5; dw[hoHoI an ddFhH haah GP e h E B i;: >:; GPhi oEon; Gh|: oh;; A :; 5: ii; ;;: !ii 5;5 i::1 ::: :; T a 1n coma 0m 1+ oat antes co1545 Wrest tame r16g1 13 Non-Neaplastic Incidence for Females (continued) Riker Laboratories, Inc. 3H Fit-3928: Tuo Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interin Project Number: 0231GR012 Species: Rat Table: Tissue/ DiagnoMsoidsi/fier LargeWitIhnitnestnionrmeal Tats Nematodiasis LiverWithin normal 1inits Hepatocyte alteration, vacuolated nile Hepatomciyntienavlacuolation nile Hegalocytosis, minieal mild naderate Pignent, Kupfer cell nile Portal bile duct proliferation nild Portal mononuclear cell infiltrate aaiilngiml Telangiectasis Lung mderate Within normal 1iaits Alveonliarlemacrophages Bronchnieiclteasts Hemorrhage nila perivamsocduelraartemononuclear infiltrate wile Preusonnitlae, interstitial, chronic Vascunliarlemineralization LymphWiNtohdien n(onremsaelnte1riiaci)ts Gop 1 Grow 2 eee eeeeen (112m 131) 2 1 (159 1o5 1 0 1 o 53 157 2 3 1 0 ] 2 7 0 3 0 1 1 2 3 2 3 2 3 11 23 1 (153) (151) 3 1 11 53 0 11 un 15 5 7 21 33 1 3 11 22 11 33 122) (110) Titles: GGrroouupp 1 CONTROL 3 ppa 2 Fit-3924 10 pp 0) = Tota Examined 01546 162 Microscopic Incidence Page: 18 Hon-teoplastic Incidence for Females (continued) FH-2920: Tuo Year Oral TRoixkiecritLya-bOonrcaotgoernftecsi,tyISnct.udy3in Rats - One Year Interfn Project Numer: 028ICRO0I2 Spectes: Rat Table: Tissue/ DiagnHosoids/fier Hamary Gland Within norsal Tiaits Galactocole Mesentary Hecrasts, fat roderate Steatitis, chronic moderate ovaryWithin normal Mats Panccyrsats Within norma Maits Pancreeaitidtis, chronic Parathyrotd Within noma Miaits PituiWtiatrhyin noma) Mafts SalivWairtyhinGlannodrma Maits sinWithin norma Mais small Intostine . spinaWlithCionrdnorm] atts Within normal Maits spleen Within norma Matts Henosiadierdasis sodorate StomaWcihthin normal Mats ThyroWtidthin norsal Mais TrachWeiathin normal Mats UrinaWriythiBnladnodremral Tiafts Grow 1 Group 2 : Pe (15) (15) 13 13 2 1 n n 1 1 11 11 1 1 C115 (11 1 0 (118) 1158 1 0 1 0 a5 [) (119) (1135 (115) (10 1 22 [E1Y (19) (15) (1159 15 (15) 1 15 (13) 1) 1 12 11 22 o 1 (1155) (1155) (1 1 (133 (115m [11 (1122) 11 - TiGtrloeusp: 1 CONTROL 0 pp Group 2 FN-3924 100 pp () = Total Examined 01547 163 Microscopic Incidence Page: 15 Non-Heaplastic Incidence for Females (continued) Riker Laboratories, Inc. 3 FH-3024: Tuo Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interin Project Number: 0231CRO012 Species: Rat Table: Tissue/ DiagnoHsoids/fier uterusWithin normal Tints Cystic glands marked Endonetritis, chronic ail Hydrasmeotdrearate Hyperpalialsgia, glandular roderate Hetaplaaisniian,alsquanous nile raderate epithelium Grow 1 Group 2 erererennn eenannen (1152) (157) 1 o 1 0 0 1 0 1 00 22 22 21 o 1 22 51 2 " 1 Smite: GGrroouupp 1 CONTROL 0 ppm 2 FH-3924 100 pp (0) = Total Examined 01548 164 Microscopic Incidence Page: 15 NoRni-kMeeraplLaasbtoircatoIrniceisd,encTene.forSMHales FU-3523: Tuo Year ralToxicty-Oncogentesty Stacy fn hats Project Misber: 0231CRO012 Species: fat Taste7: Tissues Hadi ier AererWailthin norma) inits Rerapnyain Corticaailrkdeesgeneration Cortiacail evacuolation aaiineinal Hesorrmnoadgeerate Nedutciaarrycecsell hperplasa aiainliost amaordkeerdate todulaarinmipoeartplasta, cortex maaidteersts Stnusoniaarnc)edectasta, cortex aaiinliesl mSoidretreaste sortaithin nares) 1iafts Hingra)aizlastion aceastaanderste sone Artaritis, synovitis; Joints paiaderate Sone arromwarked uiehin nora nits Gop 1 Grow 2 Gap 3 Grow 4 ws se 0s sc 00s SC 00s sc C1s9 oC3m0 o(s1903w0 o(0e(s39) (172 (12) so0 1110 00 09 00 0 00 90 01 02 20 o0 T w0os0 oe0 3omz 1o s1 oezons1 1os 32a1 0aoso sz0 00 61 3110 00 0a 60 00 31 02 o2s 01a Loe5 0022 9a31 010 eo 0zoo0 10 0010 0o o oeo z0 s1 71 53 09 00 os o 11 03 23 00 09 0wo3 feo o8 s0 oow 01 w2 a35 1 2eo 23s1 3i4 9 0303a z9 z5 00 3oz1 a1 o2a a C1B9 o(M30 (o19o0n1 CO0 C 0 CD0 00o 11eo00 00 00 aow 00 L Poao0 02 0a9oa 00 o Co ca2 tn0 en1 C 0 a 0 cnn 1 aa 5eo 09 90 01 o0a 0uw 01 Co9z0 (9 90 Ca0 lo0 C0an0 Boo ow o 0 oo CreGrosup 1 CONTROL 0 ppm GGrroouupp 23 F7H--339228 13220ponpm Group 3 F928 10 pm 2005%= nTostcahleEaxiaemdinebdeatn(s) 001165.49 Shc protoce? Scheduled Scriice(s) 165 Microscopie Incidence Page: 17 Non-Neoplastic Incidence for Males (continued) Riker Laboratortes, Inc. 3 FH-392: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Projoct user: 0281CRI12 Spectes: Rat Taste: 7 TissuOet/agnosis/ Modifier BranWithia normal Minis Rossessafd Hemorrhage moderate EsophWaigtuhsi.n noreal 1iaits oe Within normal Minits KCaetraartaicttis, acute marked Keratitis, chronic aid rarked Panophtnalaitis PhthsiPsarbkueldb rarked Retinnaliadtrophy HeartWithin normal 1iafts Endocarroddietrias,techronic Epicarditis, chronic afd Myocarmdiinailnaflibrosis ncioldaerate Myocarditis, chronic nonsuppurative sBiinlianal Kidney roderate Within normal Miaits Calculus mini) . smoadrekreadte Grow 1 Grow 2 Group 3 Grow 4 errnmenns emeneeiens smeeseiees seeeneees DOS SAC DOS SAC DOS SAC 00S SAC (1603m0 v (19) (3oo) (00 (00 90 ( 09 1 oo o 9 0 co 3 9 11 00 99 00 95 o0o o0o 32 10 90 80 92 C1B50m3) (w1 oCmw(s9 C118s) (39) (33k) (12) (3(M CDE W CDEa oz uo 0 1 0 1 9oo8 09 o1o 90 0 o1o oo 2 0 1 5 3 9 00 98 11 90 00 52 10 oo oc 0 0 0 1 oo oo oz oz 00 02 30 209 oo 0 2 1 00 00 00 02 230 1 a2 90 01 91 C19) 030) 3 (19) (300 (190) (32) (120) (31) 3 2 12013 om 9 1 ooo0 90 03 0oooo 0 2 1 1 oo 2 o 9 0 1 0 9 93 20 13 5323 01 04 91s2 01 2 3 28 01 911oo 12 01s3 Ao so os wm 2 1 aoo 72 41 az 49 ow0 92 11 61 90 1 1 01 (16) (30) (13) (30 (15) (38) (12) (32) 40 1 1 1 00 03 54 01 32 1 0 20 9o o0 o2 00 90 o oo o o 2 3 0 - mGirnoeusp: 1 CONTROL 0 pp GGrroouwp 23 FFHHN--3392223 13000pppomu Group & F-35241 pps 0) = Total Examines 005+ Unscheduled Death(s) 166 SACs Protocol Scheduled Sacrifices) 01550 Microscopic Incidence Page: 1 Non-Neoplastic Incidence for Males (continued) Riker Laboratorfes, Inc. 3 FH-3921: Tuo Year Oral Toxicity-Oncogentcity Study in Rats Project llunber: 0281CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modi fier KidneCyhro(nciocntipnruoegdr)essive nephropathy ainiaal mild nroadrekreadte ost moderate rarked Hydroneapfhlrdosis moderate Hyperplasia, pelvic epitheliva Mineraliilzaetion Nephraoisils Papillmaordyernaetcerosis Pelvicomdianreartaelization amiinliaal rodorate Pigasnmto,cocroantve. tb. epithelium protein resorption droplets nia Pelitmiasr,keadcute anna) ate moderate pyeloaneiphdritis, acute moderate LargeWitIhnitnesntionrema Viaits Nematodiasts LiverWithin normal 1inits Gow 1 Group 2 Group 3 Grow mrmemecen emememens meeenens oeemees DOS SAC DOS SAC 00S SAC 00S SKC ox 14 12 ow 4s s 18 8 15 22 um3 99 a54s 131 00 o0 12 0 0 1120 03 10 oz 3 1 0 10 0 10 0 10 0 10 19 z 0 11 0oz0 92a 1103 06 90 1 21 00 0o oo 9 90 > 08 11 0a oo 0 0 69 09 90 90 09 oo s2 0a 92 6 0 oo 9 10 2 2 18 51 oo 2 1 (16 (3ow0 (wMoWw 5 oa (16) (30 (19) (3) 20 0a ou om 10 ow 172s 60 wm7 17 15 41 0 o0o 9oo 01 01 02 0 0 0 00 09 a0 20 03 00 50 00 11 11 oooo ooo 11 00 20 00 00 00 00 00 00 332 2o 82 o0o &z 02 2 oz 0 3 39 0oo 00 0 10 10 01 00 01 09 02 02 30 o1o 09 11 31 0a 51 30 590 01 20 00 (O0 CD1 (D0 (A9 00 00 (15) (35) (12) (3) oo 2 3 0 mites: Group 1 CONTROL 9 pp 0) = Tota) Exanined Grow Group 2 3 FH-1924 FH-3928 13000pppmpm 0$0A5C+= UPrnostcohceodluleSdchDedeualtehdsS)acrifice(s) 167 Group & FN-3524 10 ppm 01G651 Microscopic Incidence Page: 19 Non-Heoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3 FH-3926: Two Year Oral Toxieity-Oncogenicity Study in Rats Project umber: 0201CRO012 Spectes: Rat Taste: 7 Tissve/ DiagnHoosdisi/fier Gop 1 Grp 2 Group 3 Group 1 eDrOeSmenSAeCn e0m0eSeemSeAeCs oDeOeSemeeSeAeCs eemeeees 00S SAC LiveArtr(ocpohnytinued) 9 0 oo 0 oo 0 1 0 marked Cystotd degeneration 9 o4 oo 9 2 om oo 17 10 1s mines) afd 61 oz 9 2 10oz o1o 70 01 a1 Fibrosniosderate 6 o1 ooo o1 2oo 0 01 01 afd marked 90 90 00 00 0 oo 9 01 10 Hematompiolidesis, extramedullary 60 11 00 oooo 8 90 00 00 Hepatoaciytde alteration, basophilic >o 21 60 13 02 3 3 00 00 Hepatorcoydteeraatleteration, vacuolated o 1 1s 92 oc 3 00 3m 00 0 ow ainiaal mild 22 17 00 9 8s 9 0 39 01 0 1. . Hepatomcoydtearavtaecuolation o8 12 105 a3 07 1& 91 38 miinlteaa) o1 61 01 02 uw 9 3s 7 2 5 moderate marked 20 20 3 om 31 1&1 2 00 01 Hyperplastic nodule Megalocytosis oo oo 5 0 0 1. 8 21 42 00 12 miniaal 6 0 2 1 31 12 ail moderate o2 o9 45s 110 o1o &3 09 05 marked Mitotic activity, fncreased a 0 3 7 3 0 2 0 9 9 0 0 9 0 1 0 ila Necrosis oo 21 00 73 5 o 80 10 02 maifnlidan 190 03 21 08 20 01 01 moderate marked 11 2 9 0 0 0 0 oo 2 oo o 0 0 0 Pignent mininal ooo0 01 21 00 00 09 22 Portanl ibidle duct proliferation sa9 81 a1 0 5 o 1 00 33 mininal oo 2 o 1 3 1 1 mGirtoeusp: 1 CONTROL 0 pp 0) = Total Examined Group 2 FN-3923 100 pp 005+ Unscheduled Death(s) Group 3 FM-3524 30 pp SACe Protocol Scheduled Sacrifice(s) 168 Group 4 FH-352 10 ppa 01552 Microscopic Incidence Page: 20 Non-Neoplastic Incidence for Males (continued) Riker Laboratorfes, Inc. 3 FH-3924: Tuo Year Oral Toxicity-Oncogencity Study in Rats Project Number: 0281CRO012 Spectes: Rat Table: 7 Tissue Diagnosis/ Modifier Liver (continued) Portal bile duct proliferation rmoidledrate Portal mononuclear cell infiltrate afnioa aroidlorate Telangiectasis id LungWithin normal Miits Alveolmairnimnaaclrophages nmiodderate Atetectasts mared Edema aid moderate Fibrosimsarked Granutowinlad aid Hemorrhage afd moderate Hyperplmaasrikae,d septal cell and Mineramloidzeartaitoen Hecransiis d marked Perfbronchial Tymphotd hyperplasia perivaasicudlar mononuclear nfiltrate ininal ail Gop 1 Grow 2 Group 3 Group 4 semen memeneeas semen eeeeeees 0S SAC 00S SAC DOS SAC 00S SAC s1 oa5 7% oe 2 7 o0s 0 oo (16) (3) 1 5125s eo 21 2 0 30 10 10 11 00 1 00 oo 6 21 12 3 o1o 69 oe 95 1oo0 13 1 2 11 oz 21 62 oaoo 31 ow0 o0z o0z 7 3 8 ows 3 10 15 12 oso ozoo 17 1oo o1e o0m oo 1 0 0 9 0o 10 20 (19) (31) (15) (35) (12) (38) 00 13 01 69 uwoo 25 o2w uozy 1 60 161 05 82 02 181 00 0 10 09 00 12 00 09 10 9 0 0 90 1 9 00 00 09 9 o0o 09 o0 00 o0o 0 01 9oo 0 03 9 oo 1 8 0 2 1B & & Ww 2 7 2 1s 1 3 3 3 3 413 00 o1 o0 21 09 00 00 01 0 0a 30 00 11 32 20 09 90 0oo 31 03 22 99 o 00 9 o o oo 0 190 6 oo so 10 01a0 8 oo o 1 0 2 1 6 6 12 1 ae - TGortoeusp: 1 CONTROL ppm GGrroouupp 32 FFH--33992244 31000pppap Group & FN-3928 10 ppm 015a 53 0) = Tota) Examined 0S0A5C UPrnostcohceodluleSdchDeedautlhe(dsS)acr fice(s) - 169 Microscopic Incidence Page: 21 Non-HeaplRaiskteirc LaIbnocriadteanrcteesf,or IMnac.les 3(continued) FH-3024: Tuo Year Oral Toxielty-Oncagenteity Study in Rats Taste: 7 Project ser: OZBICR012 Species: fat TiasuDei/agnosis wad fier Lungpe(rciovnatsicnuuelda)r sononuclear Pneumsoondte,rsftoereign body pneumonmitai,raitneterstitial, aaiindiont Throsbmuosderate Yascanasrinsifn!eralization aoiodderate Lym Sinnoudseoidal ectasta Lyson toceno(caebrdaotmeinal) Wenorranalgae Sinasofadraclsectasta Lymphdittnoicne n(omersmeante1riiaci)cs Hesarehiangeit amiddrate pigaeantid Sinusoioeealraetcetasia Hesenotaatry patyarseaerrcietdis pancrWeiatshin normal 1iaits Resnaraiantirooaptny ae oocerste infiltrate chronic wrGroetpturer1s seGurrotwvesee2n soGermomwanzer3s sGerorwen4e ws SC 005 SC 005 SC 00S SC oeo 03 092 00 00 01 2 owo 00 00s 28 00s o1om 0 o1s 92 95 1130 00 00 00 a0 woozw w0 ow1 ow0 ow1 no ow5 v0 ow1 10 21 (0 000 (oo000 (0000 (a C 0 (D2 C 0 (D0 CN0 9 o0 99 00 00 11 o o2 20 00 92 11 (w2o(m (owm2os n0en3 212+ 0oz 3oz 09 91 o1o11 01 99 01 a 00 22 11 00 00 aso0 11 60-02 a0 (oaa5 (n9 (n1 2nia0 oI z 0 0 1 0EE (1L3)ow (1mmo(a8 (01 0o3m Ieo E0 E1 E9 E1E E9E Ipozroz0 3ora2 z2 a1 20 a1 0a 93 0a 30 00 ou1 ow7 Booow (0an1 a0ta1 00 9 90 0 C0an9 0os 22 a3 o 3 32 02 &9 (a2 la2 09 (oebom 01 os 01 mGbroeups 1 CONTROL pp GGrroouwp 32 PFiAiL-33992266 31000pppmp Group 4 F-3926 10 ppm 0) = Total Exaained S0A0CSs= pUrnostcohceodluleSdchDedeualtehds)Sacrifices) - 170 01554 Micrascopie Incidence Page: 22 lon-NeoplRaiskteircLiIbnocriadteonrcdeesf,orIWnca.les (continued) Project Masher: 0281FC-R3I912265STpueocieYso:urRaOrtal Toxicity-Oncogenicity Study fn Rats Taste7: Tissues Toditier [ Retoar-- atrophy Hypefrpleasia, acinar cel Wperstsaosdiear,stelet call ronitteerate Pancremaatrikteist, chronic sotyartiatridsis mSaordcearsste [wi-- shin norast Times Fibrosciesdnrate Wperaotiaseia mmadreereaete Preatwtiatrniyn normal Tims Wopsetrslasia Prepatial sGirtaend Breputaioatneraadtmeits, scate Prostate marked EWtietrhminsontoerrmaatle1iits pWrpoesrtsaattoaidsteiirasa,teacute aaiindinat maadrtkreate Gap 1 Gow 2 Gram 3 Grow 4 Gos Se bos So Sc 005 Si 5eo 01 9oo 01 a2 09 0oo1 55 2oo0 3a o1 o2 90 o1 oeo z2 0oz1 01 20 00 a9 oooo 00 20 aoo 11 02 o csoo 54 00 0o 11 09 oao 2 ooe z2 09 0oo aoo0 0a 2 Ciowm (12m8omo(o9 s(19ow (0s(2 aso0 50 0oo 11 00 00 cooo 111oz 2a 20 00 > 5eo 90 00 a1 11 00 03 32 C9n0me(e m0 (9TE (m0 3) a2 22 00 ooz ooo 012 21 22 Caat:o (n0 eaoo aarn0 (a3 ca2 SSoo 0ieoo aoa1 aooo (12)5 (3m0 (151) 00 (2o (30 (0mmo w1osw m59 oaa 0am9 soowo SPose 3os 0133 03 s1 2 S 35io9 a1 30 a0 20 22 oPouzo15 o1o a111 9oaoo P Lr30 0 0 1a31 9z0oao nGrowup 1CONTROL pp GGrroouupp 23PFR3H323325102p0 1pmp Group' 4 P3024 10 " 0005+ UTnosuclhedcualneidneosesth(z) - Shee protacat Scneanied Sacriticets) 171 01355 Microscopic Incidence age: 23 Non-tecptaabsetricLacnoirdateorrissf,or Ttne. s30(continued) P1232: Tun Year Oat Tasterby-Oncogentc ty Study in Rats roject tater: oxIERIOL2 Species: fat Tote: 7 [ ot ier prosStraotsetactainstisi,needw)onte Satiaviapnhaennosrmal Tints Srhotaogmeynmitissi, chronte winseromny cyt, ra-- nt inclusion Sermatinties, chents rodepamirtisdts, wcerative eer wet StttInntesstionmea Vis Posars-- reortrraattse Spinnt ncongnorma Tints Semnin sort Tins roomsTine Firasrosdteariattee Vesstoimthestss extramedullary, inroads pmrotets eostdamranstts wanrate terpreu-- ow 1 Grow 2 Gow 3 Ge wae ws we ae se oes socc 50 a0 50 a0 11 a5 oo CCOR (BO (EDEw 0 soSoc o1 lasho ss0 ooToosoo as5o%a CRJl ON CtNotNe CToPmT (Da So 5 0a00 ai5o oa oa sCosa 0a0s 1100 oaoss S Doo s:sa 4s qa d 1TSea5s5 0so0s o0 (gCEH (EMRD CeotDy (Haed S asi1F2N5 5Sa 005 s0o o1oooa Cw BC e (mh CHeCt DtCd GCCE GTREO (Beeoes om oh o So aahsas0 ase GG Cis1 a3ias5 9a5 o0a0 00sow 1do0 320oo0 2i 210 PPeesdoss e eaa0ss sShono oNmomna soa sa s I Somos om osS 1s SCoilsa e0 oooooo aaooss rGireravosy 21 Fc3o3r0m 010o5npn GGrrooww 43 FsoAzI 310 oomm 30)05= nTsoetnaesEuxiaamdinoeedatn(s) 1016 SK brass Scnened Sacifice(s) 172 01556 Microscopic Incidence Page: 21 Non-teoplRaiskteircLaIvnocriadteonrcieesf,orIMnac.tes3H(continued) Project tubers OVIFCUR-IO5N28:STpuaoceYse:arAuOta) Toeity-Dncogentesty Study in Rats Taste: 7 Tissues ociier StomWaicthhin noroat its tae moderate Gastrimtairsk,edacute Hinerataoziartaitoen Hecrosatsia cer eoerate ooLcaerireadte Testwiiss/hEiptnaincoyrmias atts Leydigsicneilaahyparplasts Hinerantiitzeation Pearteirniatnits aitteerate Tubaloearatkreodpny, aspersatogenesis saiitnimat mmoatrekreadte Vasculaarinmiinnneralization amitterats Tryruoittahin noroal Yinics erst, ncioltelord Fotiseaaittar mperpiasia, cystic msoatrekreadte Grow 1 Gow 2 Gap 3 Grom 4 Ws se 00s SC os SE 005 SE C1m6om0om (19) 0om w(1n9) (39) Cn1k0 :3 90 z2 o0 11 00 0o 3o 100 00 00 0o o1o o0o o 00 00 0oo1 01 03 so o9 z0 ooo o1 o0 0a oo Io9 o9z ooo 0101o1o s1os 00 05 o1o 30 01 C1B5)o(x3) (1o9n0o30 (0os (3ow) (1w20o0w3) aso 09 11 9oo oo o9 0a oo o 11 09 11 o9 o0 20 oLs0 90 o2o 32 o5a o0o 41 a111 090 01 11 09 oao 21 343 20 s1 0420 91s 5110 01 01 o1o 00 oao oo T voozo: 0 12 111oa 5so 00 o3z 13 900 5oz o1o o2s oEoEE1 E oz E oz E1 E3 Cn2os0 (w1 o(m2 1n9)o(n3 (1a9 o03 a5 11 o1 oo1 00 03 o0o aa 5 01 9oz1 11 00 00 1o a o1o 02 21 oao 00 00 1 iGnreows 1 COmTROL 9 pon GGrroouupp 32 PPA3L9352231 31003ppnp Group PA3eRe 10ow 00)05+ UTnosuclhecEuatnecinSseath(s) 173 015e5e7 SKC protocol Scheduled Sacrifice(s) Wieroscapic Incidence Pages 25 lon-HeoplRaiskteirc LaIbnocriadteonrciessf,orIHnac.les 3(continued) M3926: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Project lumber: 0231GRO0I2 Species: fat Table: 7 TissuDei/agnosis/ Wodifier ThyroHtydper(pcloanstiian,ued) cell aid Hyperplnaosdiear,atefollicular cell aid TrachWetainobranchial cyst Within normal 1imits oTrsatcheftis, acute aid Tracheitis, chronic roadiodrate UrinaWriythiBnladndoemra) 1imits Carcatus Cystitiisl,aacute oderate Cystitmiasr,kechronic sila Epithelial nyperplasia, papillary arced Eptinelia) hyperplasia, simple eaoidaerate marked Hemorrhnaiglee cer marked Gop 1 oererens Grow 2 emeeemeen Group 3 semecatees Group 4 eoessinens 0S SAC 00S SAC DOS SC DOS SAC oo 11 2zz2 00 3 3 0 0 2 1 56 oo oo 90 oo 2 0 1 1 0 5 0 0 oo 111 00 za 10 1 C19) (3) Bow (18) (29) 182 (15) 15 (3) oz (11003 5 oo o0o 3 3 oo 1 1 9 0 0 0 50 so 99 oz 2 0 1 3 9 0 2 7 oo o8 90 2a 00 15 05 82 (13) 03o) (1u3)o(2) (1ou) (3 B9C51) (3) 6 ao 10 9 oo 1 2 9 12 11 92 5 1 0 0 1 2 0 92 oo 1 1 0 0 02 2 0 s3 o0 01 09a 03 11 203 32 o 6 eo 0o 10 01 93 90 2 23 50 21 1 90 2 oo 0 2 8% 3 1 0 2 25 10 2a o3o 11 12 01 230 oo 19 93 0 1 3a o0 t3 9 0 9 3 co 19 10 90 03 92 02 90 oo 0 2 3 1 2 3 So mines Group 1 CONTROL pp Group Group 2 3 FFHH--33992288 13000ppyrp Group 4 FH-3221 10 ppm 00)05+= TUontsaclhedEuxlaemdineDdeath(s) - 174 SACe Protocol ScheduledSacrifice(s) 01558 Microscopic Incidence Page: 2 PHI2: TeoW To[u rA iaTeintTrm-oLncoSnernaeE y Stat In hts roiect Naber: Q2UCROIZ pecs: fat Tote: Taser moter po TSroirnennovremronvtinta mpoete Orheearatera etmiooectnan mheees I --oven SN estopmyenooh persona Jroocnrets JosteApresiasta, cortex SiusorHsyvoctasa, cores bmrieors rorsTht--omg Vs one Wrerpe raes Arteftai, bsports: fonts Gow 1 wow 2 Grow 3 Gab ww ee CPSomya Gp1en1n (p1mesa (onoen P ePeYrsystoai Trt ot8d Vryooossss 8issso tbsd PYprboososs oir s to5s d TSPosLb ooss a5 horotos bh0 oobe S$tsyy soosberbse oss s oaasd PPForlsoosss oa ss 10oss sop PPPrsYos0obs0 stodosoo 3boso YSSsebrbaols hs ao ob3d o8s wPrahy aior ba aswndosBoonas STPoesr PbbwRs fsoosbr33dsg CPaElaREn ACh8RoSm (oea eem aesrDss CPg hheo e Chehg a (0e h s a in aa n) Se sl ss Ss LaGSropw 13t cToruEttm Boom ma . S S1on+ TvootneEse neesmiepsetra)rrtiesn Wicrascontc. Testes Paes 27 01559 175 Non-NeoplaRsitkiecr LIanbcoirdaetnocreiefso,r FIencm.ales3M(continued) FH-3921: Tuo Year Oral Toxizity-Oncogenicity Study in Rats Project Nusber: 023ICRI0I2 Spectes: Rat Taste: 5 Tissues Diagnosis/ odsfier Bone Marron Within norsal Mats BraiWnithin normal Minis Chiara) Gland cyst moderate Inflammation, chronic moderate Esophagus. Within normal Mais oe Within normal Mais Cataract Keratitis, acute marked Keratitis, chronic Panophtahaildnitis rarked Phensis bulst anderate Retinalagatrophy anderate miried Heart Within nora) Minis Endocarditis, chronic Myocanrdiiadl fibrosis mid iyocamroddieirsa,techronic nonsuppurative ini amidderate Pericarditis, chronic Kidney moderate Within norma Vinits Gow 1 Group 2 Group 3 Grom 3 ermnnenann emenemens menses eee DOS SAC DOS SAC DOS SAC DOS SAC (29) (25) (16) (3) (OC 0 (OC 2 3 25 15 1 0 9 0 0 (2B50o25) (1185) (3x0 (D3 CO0 (1DN1 (D0 (OC (OC (Din 8 e8 092 93 98 0oo o1o 11 2 0 0 0 8 a9 5 1 oo 9 9 oo 9 oo 1 (15) (20 (1) (2) (25) (20) (20) (21) Boa 1B nos ow aoa Cvoo(za) (uo03ox CA2C 1 A1l 2 19 31 9 1 3 0 io 0 9 0 0 9 3 10 0 0 0 2 9 9 0 9 39 0 90 1 9 35 81 09 a1 00 00 01 22 1 01 9 50 51 19 02 02 o 1 oo 9 33 20 10 53 00 0 21 82 22 0 21 82 0 50 21 31 33 C29) 025) (16) (3) (2) (23) (29) (22) wow o13ow 2 voz os 5 5 a 9 a 1 3 2 s 20 s3o 91 2o 31 21 02 92 03 23 1 Sow0 o20 21 290 s 3 a3 s1 a 9 2 oz 1 1 2 2 s zos0 o0 01 1 0 22 33 3 0 2 1 0 0 2 (299) (255) (19o) (o30 (2)1 (233) (289) (222) EE EE _ TGitrloews: 1 CONTROL O ppm Group 2 FH-3924 100 ppn GGrroouwp 43 FFIH--3329224 1303 ppppmm 0) = Total Examined D0S= SAGs PUrnostcohceodluleSdchDeedautlhe(ds)Sacrifice(s) - 176 C0LGG0 Microscopic Incidence Page: 23 Non-Heoplastic Incidence for Fensles (continued) FH-2326: Tuo YeRarikeOrralLabToorxaitcoirtiye-sO,ncoIgnce.nfci3ty Study in Rats Taste: Project Humber: 0221CRNI2 Species: Rat TissuDei/agnosis/ Hodifier Kidney (continued) Cancatus Chronimcodperroagtreessive nephropathy inion) nid Poderate marca cyst moderate Hematopotests, extramedullary amoidderate Hydranepnrosis moderate Hyperpalialsia, pelvic epithelium Mineralmiozdaetriatoen nila Mephaitiisd, acute Hephrosis aid moderate Pelviscaraicneedralization mininal aid maordekrdate Pignent, conv. tub. epithelium minfaal mild Polyarteritis Protemiondreersaotreption droplets ail smoadrekreadte petits, acute aininal eGmrmoewren1n eGmreomupenen2s sGeereoewnece3s cGecreoewecees DS SAC 00s SAC 00S SAC 00S SAC oo oo 10 00 B 34l2 ova 52 13m 00 ow1 2 2 1 1 19 00 2 0 oo ooo0 90 03 0100 9a 09 10 a1 9 0 9 1 41 09 91 33 20 z0 2 92 0 9o 0 8a 2 2 0 70 19 2 3 9 3 30 2 0s 02 03 os6 nsoowm s8 13 1r0z 0122 5 02 03 51 50 00 90 a4 31 23 5 21 51 oooo 51 9c 2 00 9 02 10 5 0 2 90 00 oo 9 01 21 o7os naotw o5z 51s 52 5 01 23 31 00 30 92 12 30 11 02 10 85 99 a1 02 31 33 02 11 30 21 29 03 9 35 32 30 23 3 1 29 12 2 1 0110 12 1 91 1 01 2sr oR sBR2 55 57 81 o3z 1112 90 38 31 20 02 82 12 92 8oo3 &0 1233 o3o 25 21 22 30 11 30 11 1 8 2a 0 . Titles: Group 1 CONTROL 0 pp Group Group 2 FHM-3928 190 pp 3 FH-3024 30 po Group 3 FH-3928 10 po 0) = D0Se UTontsaclhedEuxlaemdinDeedath(s) SACs Protocol Scheduled Sacrificels) 177 Micrascopic Incidence Pagai 27 01661 Non-HeoplaRsitkiecr LIanbcoirdaetnocreiefso,r Femles (continued) Inc. 3 FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study fn Rats Project Nusber: 0Z81CRIIZ Species: Rat Table: 3 TissDuieagnosis/ Hodifier Kidney (continusd) Pyeniziasf,dscute pyelonephritis, acute csoadrekreadte Vacuoliatniionna,lconv. tub. epitheiun wild Large Intemsotdienreate Within normal 1iaits Hematadiasis Liver Within normal Vinits Cystoniid ldegeneration Hematompioniiensails, extranedullary aid Hepatomcoydteeraatleteration, basophilic minis) aid Hepatoscoydteeraatleteration, eosinophilic aie Hepatorcoydteeraatleteration, vacuolated Hepatoicyltee vacuolation miniaal nmiodderate aarcad HHeygpaelropclyatsotsiicsnodule aaiilninal soderate marked eGmrroumpcan1n eGmreomwemen2s eGmreoeuepnee3s sGereoewneces DOS SAC 00S SAC DOS SAC 00S SKC 50 10 10 99 91 19 11 02 v1w o0o 00 9o0o 2 1 0 0 0a 2 02 2130 0s 2 2 a 2 uw 09 10 92 9190 12 9o 0oo 293 91 02 (a2m iz2) (1103ow (N1 C 0 C2HO0 11 3 3 2 0 0 0 (291) (023) (19o) o(3o0) (24) (2o)z (24) (2)1 05 99 0 0 4 4 0 9 5 9 02 02 3 00 91 0oz 48 22 01 233 30 9 1 oz 09 30 10 0 20 17 00 92 a0 01 91 3s 2 1s oz 02 oo 53 03 22 11 12 o2 09 90 a2 83 22 02 216uo0 0 92 35 00 05 2 1u5 o12 oo wom 5s ow 06 15 ow s1w114 9 ow 2s 73 a1 3 ow 301 22 5 wo 11 11s 19 2 1 2 2o 01 m2 om7 90 81 02 0 o5 o a9 om1 2 9 0 1 02 0 29 50 oo 3B oz 90 o0 20 0 0 TiGtrloeusp: 1 CONTROL 0 ppm Group Group 2 3 FFH--3309224 81300pppmp Grow 4 FH-2923 10 pa 0) = Tota Examined 00s= Unscheduled Death(s) - 178 $aCe Protocol Scheduled Sacrifice(s) 01562 Microscope Incidence Page: 30 loa-Hizoplastic Incidence for Famlss (continusd) Fli-352: Tuo YaRariteOrralLabToarxaitcoirttya-sD,icoIgnecn.ici5t1y Study in Rats Prajact uma: SITE Spates: Rat Testa: Tsaus/ Diagnosis) Eacitier Liver teostiniaa) Hite azzivity, dncrassed magirate eon ata aati aig adierte pigunt1, rdrdaw Satan aild pigs, haptieyte aStiiactant Partzl 3i1s duet praliraracian aio We taarirdt Parti monoseeiann cal faffiteac iia fiz Padarity Tagtaiiiats ngids part proses Rvealasirsi mirsghiges aie outirite Aessaetiaseis [7 Eon:aie Granstoonat: airi sid Gop 1 Gop 2 Grp 3 Gros d rremnnens amreenees eames emeeeneen 00s SKC 05 SAC 205 SC 305 SiC ros oss 2x3ezaso l tora) so 5d 5 8 2 oa i312 12orsdr 2 91 1oz ) zor 1 6 3a 30s3312 13 3> 93 3 SToorr 30% o1z 12 2eso0s s> os3 d2 oa103a 3 3iods toro: on cos G7 503% 1:2 soz Pes omo1or 35 io 31a a B1o3s8 : L Eo am s 32 s Toy 1:2 as EE OE EE A ola ws 12 wa 3 wn IEE CS) 03 0103 (TE EE L (nz F1I : 3s2 rs o rw1:i EE E EE o Po or emy3a s y bo ez 53 Sosy rr 1s ios los soe a3 2 [I 1 >5o0f2 3 wvyo 1d1 a: s50 o: 5azooa sizroa 5FE 5TE S2R s TE aSE sSE A11 Titles: - SGrreaspp 21 FCOIUTLIOEL %3oppea GGrroasys 21 FFiReE}T 3103 ppoann 000)5+= UTontsaclhacEuxlnaidnaDdaathi) 179 Sis Protocol Scheduled Sacrificals) 01563 Hicroscopic Dieidzie: Pager 31 JonokeopaRsitktecr LIansciodreantcoerifso,r FIencmeales30(cantiniod) F-35281 Tuo Year Sra Toute ty-Oncogentcity Study in Rats Taber 8 Project Masher: ZOCROIZ Specs: Rat Tissue/ nditier nsAe(nccrornnatgien hdeerste Wporptaasriad, septal cell Winer ariaation Pelvicimtiemeratization Perivaacaatar soroniclear fnfiTtrate Saimein Pigmenmtadarste Preuriavoids,eractoenic Papcmarn,isate exatative Siatearste Pressonattne,raiSsrorhopneimania Pnsonitns,ionnierstitiat, chronic hdaers Throrneasters Vascutopr ayimeraiztion Lyon odea(tmeesenteric) Nermeonrirnnangaereat Timits miodeerate ratpartiareitis terse Gap 1 Grow 2 Gra 3 Grow a sSss 0s 37 8ao4s 8sea o0Vool1 os0ieozor11 10on z1s0 2 o1 So0 05 5a 09 0 90 o101 o1 390 10 00 6eo 53 11soo 9a 30 00 00 6DCo7s1 e4s1oas sw os o1 sso 4s 2 eo 11 oS 1 ooo oo1soooo oo 5 oo 10 0 50 GSoo TS 0oooo eo 1100 10 3oo0o aos 0TS0 65 oz5 ooo5 0120 ooo a9 09 10 SGS S5 os 99 si eoolo o2 a10 00 D[ s E 2s S eo zoa S5 o0 Xow o5 o9 ow o% aso0 won 11a0 a ow 2 oE w Ea Ex (em Cm aE wom (an (new D Tl0 EU 051s0 S0 Ea a ao oVoso 6s 3 0ozoz 01 oooooo oa 0bos8 S00 eo 1 ooo 9 os TiTtotreesns Grovy 21cP3o323m01g9o5enpom GGrroousp 3& FP3h2os4 310 pponm 02S)0h5e+eToUptrnosasc)ohceeEd!xualneStdcnhaeDedeualtehdsS)aifice(s) 180 01564 Wierascop'ic Incidence agoe: 2 Non-Neoplastic Incidence for Feaales (continued) FH-392: Tuo YeRarikeOrralLabToorxaitcoirtiye-sO,ncoIgnec.nici3ty Study in Rats Project Huber: 0281CR0012 Species: Rat Taste: 2 TissuDeisagrosts/ Modifier Lyaph toda (mesenteric) (continued) Stnusorfoddaelraetcetasia HammadriythiGnlannodrman limits. Galactocele Lobular hyperplasia modarate ouryHithin normal Hats cyst Tubulamrilhdyperplasia roderate rarked Pancreas Within norma Tiaits Acinarsiatnriop)hy aid eacarate aarced cyHyspterplasia, slat coll nila Polyarteritis corked Parathyroid Uithin norma Miaits Hyperplialsiaa Stnusoida cctasia Pituttarysaderate Within normal 1iaits Hemorrhage Necrosmiasrked moderate Pigaent, brown moderate rGreomw em1 mGermoewnne2s sGmreeoewseee3s Grow eeeeoenens 0S SAC 00s SAC DOS SAC 00S SAC 1109 98 03 0oo 1 1 9 38 (294) (923) (1o) p (3 (2ow) (2) (28) (22) ows PE EE EN | 3 0 1 2 1 oz 2 1 0 0 2 0 0 3 (2v9)o(2u3) (110) (3ow) (21) 2 (2) (2B9)o(B21) 3.03 5 05 2 3 1 0s oo o9 22 ur5 i& 73 01 53 58 07 52 12 o0 23 92 90 (20025) (19) (3 (1) (1) (2) (2) 2 15 12 oo 1 ou DB 5os1 31 33 81 33 90 a2 2 83 12 50 3 o6 1 8 805 23 21 93 22 55 01 91 00 o3o oo 3 2 2a 21 5 8 1 9 2a 0 0 1 9 2 0 ct 3 9 1 2 0 0 oo 0 3 9 1 CHO (NIA (1) (13) (19) (13) so 6 2 1 1B 1B 1 vo 00 90 11 95 39 03 2 oo 0 1 9 3 3 CE atE (19) (30E) E (2) (20 (29) (21) s 7 3 ow 3 4 5 1s 13 0 3 02 03 3oz a3 22 15 19 0 5 09 83 33 33 2 95 5s 5 01 31 08 oo 08 20 00 _ TiGtrloeusp: 1 CONTROL & ppm. Group 2 FH-3323 103 pp Group 3 FN-3922 30 ppm Group 4 F-39024 10 pa 0) = Total Examined D0s= Unscheduled Death(s) SACs Protocol Scheduled Sucrifice(s) 181 Iieroscopic Incidence Page: 33 01565 Non-NeoplRaiskteirc LIanbcoirdaetnocredefso,r IFnecm.ales3(continued) Project Wmber: OZB1CPRAO-ID5L224: STpueoctYese:arRaOtra Toxicty-Oncogentety Study tn Rats Table: 8 THasDuiea/gnosts/ oder SattVvairty iGlnaonrdms] fats HeSmtoarlrahdaegnets, chrontc aaoidearate scinwitnin normal Timits Aeanthwoislise Pododesramrakteidtts, ulcerative vicer mcerate Saal) Intemsatrikneed wviitcheirn nora) atts SpinaWlithCionrdnormal 1imits Watactesoerate spreewnithin normal Tims Henstopionfeisits, extramedullary, maoidterate Wanosimdaerrokseids maoidterate Stomach marked cWoieeennin normal atts Gastentosdtse,raatceute Granutmoondserate animal fncressed rGoowrs1 rGreotw in2 eGeeomns3 tGirones4 EEE EEE ES CB0o2a0 (1w9)o(z3 (19o) w(20) (20o)w C2o0w) 10o 00 o1 01 51 00 0 1 00 00 01 00 01 00 o0 (RoCoH Co0 r 1 (H0 CHoz H3C1D 11 00 00 ooo0 00 o0 00 00 11 11 11 00 0 2100 00 00 00 00 0o (2100290) (100 (300 (DoCoO (0D0oo o0s w0 om1 1oo 0o 00 00 (2zo(o2m9 (1195) (Womw (O0 000 00 00 1100 00 o0 00 00 oo 0 C2e) 0u2 (18s) o(3w0 (2)so(m2) (2o) (w2) 7 02 z0 ooo10 10 4o 41 1 ro2 o 0oo 31101d : o0wo60 wooss o2 om1 1 s 0woz3 omas3:osos o1o (25) 0250) (161) (300 (26o) (o2) (21) (2) wa os0 nooow wz ow o5m oa0 a5 0 d0 o1 2100 01 oeo 53 :oz ooos 11:oo ooo: oo 0 3 1 oo a 0 TGrorioews: 1 CONTROL 3 spn GGrroouup 32 PPHR-e2a9s2a4d 12000ppome Group 4 P2928 10 pom o005e+ UTnostcahedEuxtaemdinDeseaths) - 182 SKcn protocol Scheduled Sacrifice(s) 01666 Wieroscaptc Incidence pages 3 Non-Neoplastic. Incidence for Feaales (continued) FM-3926: To YeaRrikeOrraLabToorxaftcoirtiye-sO,ncoIgnce.ntci3ty Study fn Rats Project Number: 0201CR0012 Spectes: Rat Table: 8 Tissues Diagnosts/ Hodifter Stomach (continued) Hemorrhage Mineramloidzeartaitoen nid Necrosiasid soderate cer marked Thyrotd Within normal Mats Follicular hyperplasia, nild marked Hyperpmliansiiaaa,l C cell nila poderate Wtinobranchial cyst TrachWeiathin normal Miafts Urinary Bladder Within normal Miafts Catculus Cystitmiasr,kecdhronic Epfthel a1 hyperplasta, marked Epithelial hyperplasia, ail moderate UterWusithin normal 1iafts Cystic glands amiindaal moderate Exudatmea,rkTeudnena] soderate cystic paptilary simple Gop 1 Group 2 Grp 3 Grop & rmememens amemeneens emeeren emeemanees DOS SAC 00S SAC DOS SAC DOS SAC 16 00 00 11 00c 90 00 9 0 10 00 00 12 00 01 00 11 00 1 0 1 93 0 0 1 00 00 0o ooz 0oo (29) (25) 2 2a (13) (3) 2 oz (20) (18) 1B 2 11 00 900 01 00 00 9 9 1 0 0 90 13 13 oo oo a0 02 01 12 oo 1 1 0 0 21 00 11 (25) (225) (1144) (3m 0) s (25) (2o1a) (2v5)o(2s5) (123) (3o0m) (2ow) (2a1) 1 0 oo o 0 oo 00 oooo 09 o0 oooo 10 0 0 9 0 10 00 90 7 0 1 1 2 0 o 1 1 2 oo 10 0o 00 C2a8) (2v5)o(u16) (3oo0 (2v0)o(2w3) 2 0s 2 oz 3 3 o 0 1 oo 0 1 21 11s5s 12 02 oe 03 1os 01 0oo o1 oo 1 90 0 0 00 o0 o0 00 00 ooo 00 09 11 (23) (22) ow ou o0 0 00 00 00 00 00 3 (2x0) (222) (2a5) (2a2) o 10 11 00 10 00 02 a2 (226) (2o2u) 3s 00 00 22 03 01 0 oo TiGtrloeusp: 1 CONTROL 0 pp Grow 2 FN-3926 100 pp GGrroouupp 3& FF-N3-93592244 1300 ppap 0) = Total Examined D0S= Unscheduled Deatn(s) SACs Protocol Scheduled Sacrifices) - 183 Microscopic Incidence Page: 35 01667 Non-NeoplaRsitkiecr LIanbcoirdaetnocreiefso,r FIencs.ales34(continued) F-39206: Tuo Year Oral Toxicty-Oncogenteity Study fn Rats Project Number: 0281CROOI2 Species: Rat Table: 8 TissDuleasgnasts/ Hod rer Uterus (continued) Hydroneptraa Hyperpmlaarskiead, endometrial Inflarmoadteiroant,eacute Netritmiasr,keadcute Polyawritelrditis moderate SGorpee1 eGnroewpmas2 eGreowns3 eGreowns4 Ws sc 00s SK 00s SC 00s Sk 91 00 11 00 0o 01 01 01 00 00 00 00 01 11 00 0oo o0o 10 00 90 1 00 90 00 10 00 00 o1o 0 0 o oo 0 1 oo0 o0o ooo 00 o0 00 11 TGitrloeusp: 1 CONTROL 0 pp Grow 2 P3926 100 ppm GGrroouupp 43 FFNH--33992244 1300 ppppm 0 = Total Examined 005= SAC Unscheduled Death(s) Protocol Scheduled Sacrifice(s) - 184 01568 Wicroscapte Incidence Page: 36 NReiokpelrasLtiibcoraItnocritdeesn,ceIfnco.r Ma3les FM-3926: Two Year Oral Toxicity-Oncogentcity Study fn Rats - One Year Intertn Project Number: 0Z81CRI012 Speces: Rat Taste: 9 Tissue/ Diagnosts/ Noditter Mammary Gland N PituiAtdeanroycarcinoma Adences Grow 1 Group 2 a a cn (10o) (1 1 1 Titles: Group Group 1 2 CONTROL F-3924 O ppa 100 pp 0) = Total Examined 01569 185 Microscopic Incidence Page: 37 Neoplastic Incidence for Females Riker Laboratorfes, Inc. 3 FH-3526: Tuo Year Oral Toxfeity-Oncogenicity Study fn Rats - One Year Interin Project Number: 0281CR001Z Spectes: Rat Table: 10 Tissue/ Diagnosis/ Modifier Mammary Gland Adenacarcinom Prtattary Adenama Grow 1 Grow 2 rmemnmene emeneenenas (1s (1s) o 1 15 C15) 1 2 omits: Group 1 CONTROL O ppm Group 2 FN-3924 100 pp () = Total Examined 70 . 186 Microscopfc Incidence Page: 32 Neoplastic Incidence for Males Riker Laboratorfes, Inc. 3 FH-3926: Tuo Year Oral Toxtcity-Oncogenicity Study fn Rats Project umber: 0Z81CRO012 Spectes: Rat Table: 11 Tissue DiagnHoosdisifter Adrenal Carcinoaa, cortical PPhheeoocchhrroonnooccyyttoonaas,, mbaelnitggnnant. Heaolyaphoreticular neoplasa present Bone.Osteosarcoma BrainAstrocytons, benign Oligodendrogh fama, benign Hemolymphoraticular neoplasa present ere Henolyophoreticular neoplasa present. Heart Hemolymphoreticular neoplasa present Kidney Adenoea Hemolymphoreticular necplasa present Liver Hepatocellular careinoss Hemolymphoreticular neoplasa present LungAdenoma Henolyphoreticular neoplasa present LymphHetmiooldyemp(haobrdeotniicnuall)ar neoplasa present LymHenmaondgefo(seasrecnotmearic) Hemolymphoreticular nesplasa present PancArdeeansoma Islet cell adenoma IHselmeotlycseplhlorceatricciunloamraneoplasa present Parathyrofd Adenoma Pituitary Adenoma SalivHaermyolyGlmapnhdareticular neoplasa present Grow 1 Group 2 Group 3 Grow "DeOtSeeterSaAeCs eDcOeSmiiSAeCn eDeOeSiecSAeCs eDOSeSeAC (15) (30) (19) (30) (10) (3) (12) (39) 1 oo 1 0 0 0 oo 11o o0o o0 0130 01 13 o 10 0 00 Co tao ( 1 0n a0 ce o0 (n n0 eo0 (16) (310 (18oo) (31) (00 o0o ( 0( 00 1 0 0 0o 0 0 0 0 o 1 0 0 oo 0 0 C1203o( 1 0 M CDoo E0 I C0 Y0 (16) (36) (19) (31) (15) (35) (12) (39) 15 20 10 0 (15) (3) 5 (19) (3) oo (18o) (3505) (120) (381) (161) (36) (191) (30) (151) 0 (38) 10 (12) (38) 21 21 1 2 o1o 01 11 11 0 (16) (30o) (19oo) (301) (15) (350) (12) ( 38) 00 31 CoCo 20 (a(n 111 (On (alo o 00 01 00 Co w (ooBo (D EDo CoOD1 10 10 10 9 C13) 03 o (119 (290) (109) (3o)o (1o) (I0) o1 o 11 01 01 oooz o0o 1 10 COIS 10 (1018) 1 0 (91) 0 (N28 oo C15) 03) 01 (17) (30) 01 (15) (33) 0 (1) (36) 5 um (12) (32) 16 (15) (30) 1 1B (13) (33) 6 16 (10) (32) oo 1 9 o oo o - TiGtrloeusp: 1 CONTROL O pp Group 2 FH-3926 100 pp GGrrooww 43 FFHH--33992288 1300 ppppm 01571 0) = Total Examined 00Se SACs PUrnostcohceodluleSdcheDdeautlne(dsS)acrifice(s) 187 Microscopic Incidence Page: 3: NeoplasRtiikcerILnacbiodreantcoerffeosr,MaIlnecs. (continued) F-2928: Tuo Year Oral Toxteity-Oneogenefty Study fn Rats Project Wusber: OZ0ICRIIZ Species: Rat Taste: 11 TissuDeisagnosis/ Hoditter seinBasal cell tumor, bentgn FFiibbrroosnaarcons Keratoscanthona LiPpaopislalrocnosa HSequlasoyumsphocreelticcaurlcairnonsesoplasa present SaalHeoIlnytaespthionreeticular neoplasa present SoftHeTimsasnugziso.sa(rhceoadn)s SoftZTyimsbsautesgla(nndeckc)arcinons FFiibbrroonsaarcons Soft Thssuas (thorax) Liposarcana spleeHnenangfosarcons Henolyephoraticular neoplasa present StomaWcehsolymphoreticular naoplasa present Testis/Eptdidyais ThymuHsesothelfoas, benign ThyroHiedsolyephoreticular neoplasa present C cceeln cadaernccionnoma UrinaFroyllBicaualdaerradenoma Papi tom Henolysphoreticular neoplasn present HemolMyamlpihgonranettic1yualpahronSay,stIemymp[#hacayftfieccted) HaMallfiggnnaanntt IIyymmpphhoossaa,, aisxteldocytic aGeertotwures1s eGvrreotwesee2s seGersoswanee3rs sGesrmoswneee4s 0s SKC 0S SC 00S SAC 00S SKC CON0 CN0 C 0 CH0 L1 (n0 es0 T1o0 01 01 00 01 90 1 T1z0 00 00 00 00 00 00 01 00 00 91 o0o 390 00 (1R 0 (30 E (M30 CEOED Calo Co1 to0 ca0 ta0 ca0 ta0 t0ao0 00 11 00 00 00 090 00 (O0 ro0 (a0 rn0 (a0 to0 (n0 en1 (O to0 (0Ca0 (O0 (a0 (n1 ia0 C16) 0 (30) (19o) (o30 9 (15) 0 (3) 1 (12) 0 (3) 111 01 o6 o1o 915 900 0 (161) (30) (109 (300 (190) (3o) (10) (30) (18) (30) (190) (3Da) (190) (3o) (120) (3)1 (D1C0O ( 1 0D (OoE Co (D 0 2 00 C12oe) (30) C11) (200 (19o) (32 (100) (33) oz0 01 00 00 11 00 00 (13) 03o (180) (0o (10 3032 (10) (31 10 00 00 00 t r0en 2 0 301 1 0 90 01 10 00 20 00 10 00 TiGtrloews: 1 CONTROL O poe GGrroouupp 32 FFHH--33992204 31000popepm Group 4 FH-3920 10 ppm 00)0e= TUontsac)hedEuxlaemdineDdeath(s) 188 SACe Protocol Scheduled Sacrifice(s) 01672 Microscopic Incidence Page: & Neoplastic Incidence for Feoales FH-3924: Tuo YeaRrikOerralLaTboorxaitcoirtfye-sO,ncoIgnec.ntc3ity Study in Rats Project Nusber: 0281CRO012 Spectes: Rat Table: 12 TissuDel/agnasts/ Hadifier Adrenal Adenoma ACdaerncoimnao,sa,corctoirctailcal Pheochronacytoma, benign HPheemooclhyrmopnhaocryettoiscau,larmalniegonpalnats.m present. Aorta BonHeoHmaorryomwphoreticular neoplasa present Hesolymphoreticular neoplasa present BrainO1igodendroghfoma, benign Esophagus. Homolymphoreticular neoplasa present ere Hemolymphoreticular neoplasa present Heart Hesolymphoreticular neoplasa present Kidney Henolyaphoreticular neoplasa present Large Intestine LeHfeoanoylyomspahrocroentsicular neaplasa present Liver Hepatocellular adenoma HHeepmaotloycaeplhlourleatriccualracrinnoesoaplasa present LungHemolymphoreticular neaplase present LymphHeNmoodleymp(hmaerseetntiecruilca)r neoplasa present LymphHeNaoodleyap(htohroertaciiccu)lar neoplase present. Mamary Gland A`dAednencoacsarcinoma Carcinons FHiebmroolaydmepnhcoeraeticular neoplasa present oGmreomweren1s eGmreeomwemen2s mGereomuepee3en DOS SAC 00S SAC DOS SAC (29) (25) o (15) (30) o0 (26) (23) o0 00 09 0o 11 00 2 0 oo 0 01 00 10 20 10 10 C20 (2) 2o (10 0030 (0C0 (25) (25) (16) (30) (0 (0) 2o 0o 00 (25) (251) (160) (30o) ( oHo CO C15) 02) 10 (13) (30) 0o (25) (20) 00 (12)oo (13o C0 00 (25) (25) 1 (16) 1 (300) (20) (239) (25) (25) 50 (16) (30) 10 (2) (23) 00 C2o) (o2) (110 (80) (Do COoo (251) (259) (160) (30oo) (20) o (2) oo 9 o4 12 00 0o 50 10 0 (295s) (25o) (161) (30o) (20) (2o)o C3020 (N0 C 0 (N1 CD0 CO C00 (0000 (n1 to (2+ 02)3 (1s 0 (& 3 s(2) (25) 2 1 0 o oo 0 1 5s & 0o 1 0s o oo 78 20 0o 0o sGermoeuepeeoe4es DOS SAC (20) (22) 91 00 0 01 00 20 (o0 l 00 (9)( 0 00 (DD0 (20) (21) 0 (D2 00 (281) (22) (28) (22) 20 (N0 COo 10 (20) (220) 0 +0 (23) (22) (1DO0 (oo l 0 (23) (223) 00 0 1 u0 - TiGtrloeusp: 1 CONTROL 0 pp GGrroouupp 23 FFHN--33992284 31000pppmp Grow 4 F-39022 10 ppm 0) = Total Examined DOS= Unscheduled Death(s) . 18 SACs Protocol Scheduled Sacrifice(s) : 01673 . Microscope Incidence Page: 41 Neoplastic Incidence for Females (continued) FH-392: Tuo YeRarikeOrralLabToorxaitcoirtiye-sO,ncoIgnce.ntci3t4y Study fn Rats Project Nucber: 0Z81CRO012 Spectes: Rat Table: 12 Tissue/ Diagnosis/ Modifier Grow 1 Group 2 Group 3 Group mrremenaen emenemens emeeenenes eeeeeneeas DOS SAC 00S SAC DOS SAC DOS SAC NesenLteairoyzyosarcom (O 000 (0OC0(0O1 ( (0 0n 00 ovary. (25) (22) (16) (30) (25) (23) (28) (21) Lefomyoms 1 6 90 0 o o o 0 HTuebmuollayrmphaadreneotmiacular neoplasa present o2O &0 00 03 0oo 02 01 00 Pancreas (20025) (10) (30 (1) (1 (2) (20) Acinar adenons o o oo 1 0 0 0 0 IIsslleett cceelll) caadrecnionmoass oeo 11 00 00 00 02 00 00 Hemolymphoreticular neoplasa present 20 60 10 20 ParatAhdyenrcomtad CoHoO (00)1 (1o6o (105 (109 (180) Pitattary C22) (20) (15) (30) (2) (20 (29 (21) AAddeenncozcaarcinoma B9 u0 12o 230 20 61 200 150 siFnibrona (N1C2D C 0 CC H3 C0 ( D H 0 N0 Fibrosarcosa oo 0 0 1 0 0 0 Ligon 0 00 11 00 SaalHemIonltyemspthionreeticular neaplasa present C2o0 0o25) (100 (30 0DCO0 (D2 LO0 Hemolymphoreticular neoplasa present 0 00 0 10 Soft Tissues (Teg) SOC 0 (NCO (00 (0 Hemoymphoreticular neoplasa present oo 1 0 0 0 0 0 spina Cord (25) (22) (15) (3) (0( 0 (0( 0) Hemolymphoreticular neoplasa present 1 9 0 oo 0 0 0 0 Spleen (25) (25) (16) (30) (20) (23) (23) (2) StomHaecmholymphoreticular neoplasa present (253) (250) (160) (30oo) (260) (230) (282) (20) Hemolymphoreticular neoplasa present 10 92 0 1 0 1 0 Thyeus (OC (OC (Di (00 Hesolymphoreticular neoplasa present o oo 1 0 0 Thyroid (25) (25) (13) (33) (20) (18) (23) (22) Adecneolclaracdiennoommaa 9 10 o0 o1 0o 11 01 00 cell carcinoma oo 1 1 0 1 0 1 Hemolymphoreticular neoplase present 2 2 9 0 0 oo a 0 UrinaTrryansBiltaidodnearl cell carcinoma (25) (250) (13oo) (30o) (23o) (2o0 (291) (22) Hemolymphoreticular neoplasa present 10 00 10 20 TGirtoleusp: 1 CONTROL 0 pp GGrroouupp 23 FFHH--33902288 13000pppmp Group 4 F-39023 10 ppm () = Total Examined 0$0A5C+e UPrnostcohceodluleSdcheDdeautlhe(dsS)acrifice(s) 190 01674 Microscopic Incidence Page: 12 Neoplastic Incidence for Femles (continued) Riker Laboratories, Inc. 3 FH-3926: Tuo Year Oral. Toxicity-Oncogentcity Study in Rats Project Number: 0281CR0012 Spectes: Rat Table: 12 Tissue DagnoMsotdsi/fier Uterus HAedmeannogmiaona Letomyoma - polyp Hemolymphoreticular neoplasa present HemoMlaylmipghnoarnettiTcyuslpahronSay,stheaist[4iocayftfieccted] Malignant Tymphosa, ysphocytic Lysphosarcom Gop 1 "DaOtSaeiSatAaeCs (25) (25) o1 o 1 20 [S2 000 30 5 Gop 2 0ec0eSmsSieAnCs (10) (30) 0oo 0o oo o 01 00 C11 0000 00 oo o Group 3 Grow DeOmeSeiSeAeCs DcOeSeeiSeAseCs (20) (23) 0 (26) (22) 00 10 0o oo 0 0 1 22 13 10 00 A 1 L 0 &NC 0 02 0 0 o0 TGitrtoeusp: 1 CONTROL 0 ppm GGrroouupp 23 FF-H3-9329428431000ppapm Group 4 FN-3924 10 pp 0) = Total Examines 0S0A5C+ UPrnostcohceodluleSdcheDdeautlhe(dsS)acr fice(s) 191 0187S Microscope Incidence Page: 23 IndividSuuaalnarMiazcerdoscSoipnigcleaTnadbuMliactreodscoMpniincalObRseerpvoarttions. F-39242 Tuo Year Oral TRoixkiecritLya-bOonrcaotgoerniiecsi,tyInSct,udy3in Rats = ne Year Interin Table: 1 Binal Masber: (R-SS16 Sea: Male Group: ( 1) CONTROL 0 pps. Fate: (beets 53) 1 Year Interin Scrifice Macroscopic Observations: Microscopic Observations: Kidney LuLynsggh ade (esenteric) Pancreas PSauralalthyIrnotiedstine Thyroid Ho visible lesions. "Chronic progressive nephropathy, wild "vNaostcuelxaarninweidn,eraaliisziantgion, ainisal ~hcinar atrophy, ald ""NWoittheixnannionreada,l ilsimsiitsn.g Fever than protocol nusber "hot examined, aissing The following tissues were found to be within normal linits: Brain, Spinal Cord, Bose Marrow, Spleen, Liver, Heart, Stouach, Large Intestine, Urinary Bladder, farts, Testis/Epididyais, Prostate, Mammary Gland, Pituitary, hdrensl, Trachea, Esophagus, Salivary Bland, Ere, nial Masber: 1R-SSL7 Sex: Male Group: ( 1) CONTROL 0 pp. Fate: Oheeks $3) | Year teria Sacrifice Nacroscopic servations: Nicroscopic servations: Kidney LPuanrgathyroid Thyroid Ho visible lesions. "Chronic progressive neshrogathy, siniaal N"oats.caelxaarsinseidn,eraailsisziantgion, sild "Not exanined, aissing The following tissues vere found to be within norsal linits: Brain, Spinal Cord, Bone arrow, Spleen, Liver, Heart, Stossch, Seall Intestine, ALdarregnealI,nteTsrtaicnhee,z,UrEisnoaprhyaguBsl,addLeyrm,phAoNrotdae, Testis/Epididyais, Prostate, Mammary Gland, (aesenteric), Pancreas, Salivary Gland, Eve. Pituitary, Animal Masher: (R-S520 Sex: Male Groups (1) CONTROL 0 ppm Fate: (leeks 53) 1 Year Interin Sacrifice Macroscopic Diservations: Nicroscopic Observations: harenal Kidney Ho visible lesions. "Sinusoidal wierate ectasia, cortex, bilateral, "Chronic progressive neshropathy, ainisal SPpreocjieecst: NRuastber: 0281CA0012 601676 Susmarized STAR Page: | 192 Summarized Single Tabulated nial Report (continued) Individual aRcirkaesrcoLpaibcoraatndoriMeisc,rosIcnocp.ic3O%bservations FAS: Teo Year Oral Tnicity-Ocogencity Study i Rats - Oe Yeur InerTiaale: 1 AFnaitnea:l (NGaeebkesr: 591)8-31Y5e20ar InSteex:rnWaSlaecrifiGcreoup: (1) CONTRI 0 pa HicrLoisvceoric Oservations (continued): Lnygn de (aesenteric) FiPatruaitthayrryoid "Hsienpitnoaclyte alteration, vacuslated, focal, a"vtascuclaanrinsien,ersailsisziantigon, sinissl otat. eexxaamiinneedd,, sniostsiinngplane of section BTrhaeinf,olSlpoiwnianlg tCoirsds,ueBsonweerNearfroouw,n tSpolebeen,wiHtehairnt,noSrmtaolmclhi,niStusa:ll Intestine, Large Intestine, SUarliinvaarryyBBlaldadne,r,EyBea.rts, Testis/Epididyeis, Prostate, Thyroid, Traches, Escphags, Pancreas, dFantien:al MNeaebkesr:5)10-135T2e2ar InSteexr:nKaSlaecrificGeroup: (1) CONTROL 0 pa NaroLsicvaepric Observations: WicrKosicnapeic Disrvations: Liver Lung FaTrhayrtohiydroid "Light {pale tan in color, ""FOovrotnailcapornoognrcelsesairvecenlelphricnpfaitlhtyr,atea,iniinnailaal "VHaesscrurlhaarges,inemrlatliifzaactailon,, ialiild Ferivascalar sonouclea infiltrate, aild oott eexaaniinneed,, asiissssiinngg rTaheinf,olSlpoiwnianlg Ctoirsds,uesBonweerMearfrooun,n Stpolebeen,wiHthairnt,noSrtommacLhi,nitSsw:all Intestine, Large Intestine, EUsrcipnhaarqyusB,laLdehr, ANoodreta,(sTeessetnitse/iEcp)d,idPyaanicsr,easP,roSstaaltiev,aryNaGmlnarny, lEayned., Pituitary, freml, Tracks, nFaite:l eMaksheer;$9I) R1 Sfour InSteex:rnMaSluecrifiGceop: (1) CONTROL 0 pa Waroscapic Osermations: NicrLoiscvoepric Ghservations: Lng Ho visible Lesions. "PFoorrttaall sboilneomdclcetarprcoellilferiantfiiolnt,ratael,dwild heorrhage, mitifecal, aild TBhaeinf,olSlpoiinnalg Ctoirses,uesBoweereMarfroounn,d tSoplbeeen,witKhiidnoeyn,ormHaelrtl,iniSttso:wach, Seal Intestine, sPrpoejceicets:Maasther: ZBICRO12 C0167g ? Suarized STAR Page: 2 193 FO TobYee Bhl Taetimae mtA A et tT Susaarized Single Tabulated Anisal Report (continued) ri es TT ie JO [Sa-- gi e-- s osSE nis apt a Ea cot sr i Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, ant, Adrenal, 1. TE ei S w[ratiIe oe of ot rnin, 2231 05 or ty S ----T --ee . fsoens e--s--ie ie hetty otes wretfeu Ltobr,ilhnorartsiBto:scA,pS,t Bttte went TE ie Trachea, Esophagus, Lysph Node (sesenteric), Pancreas, Salivary Gland, Eye, Spleen. SA sg Soar iss i, 2ar A L rr n------. os nvoyA e BToelite ts wre fmt win St atone ees i, Sy itveA co167e 8 Sarin S70 ue 3 i 194 SInudsirviidzueals SMaicnrgolsecoTpaibclaatneddNiicsrolscpRiecpotrotse(rcvoanttiionnused) PRIA: Tuo Year Gra TtoseircitLya-bDocroagteonriicesi,tyISct.udy3i8n Rats- Oe Year Iterin Tale: 1 Ffiotei:l (Naasskbsers5I9RI1 5YKew InStecetrfaSlueerificSeeog: (1) CONTRIL 0 pa [ry -- Wicrohwearpiocs Ohsrvations: Liver Stnougsch ko visible Lesions. owdtuelaatrebypeplasia, corte, wilateral, PPoorrttaall sbioleendculctewprcoellilferiantfiiolnt,ratmei,ldwild Haeipeatocyte alteration, vicualated, mitifocal, FHeortivwarscsailnaer,swoainssicnlgesr infiltrate, alg TBhreainf,ollSopwinianlg Ctoirses,uesBoweereNafrroouwn,d Stoplbeeen,witKhiidnneyo,rbmertL,imiStmsa:ll Intestine, Lirge Intestin, UErsionapruysH,atLeyrw,p hNoaret,(eTessttiesr/)Ei,diPgaynacsr,easP,rosStaaltiev,arPyitGuliatnadr,y,EvT.hyroid, Parathyroid, Triche, GFarei!l rdkoesrsS3R1315Y0or IntSeercisKaSlceriicreou (1) CONR0IppL Hacroiscdanpeiyc Observations: Wicroewratpie Ohsrvations: Kidney Liwvyer Pancress "Silteral hydronephasis "wbiolceaditis, cranic rnsppuratioe, focal, hCyatlrcoleugsh,rapseilsv,icbilateral, aoterate F"oarstcaallarsonsainnecrlaelsiratcieolnl,iwfiilldtate, wild iPumcreeataittriosp,hy,cofnoicacl,, dfoodcaelr,ateaild Te folloring tissues were foun to be within sorml Linits: TUBreraaiicnnha,ersy,SpBiEansdalogpeC,uorsdH,,ortLBaoi,ngehTMeaNsrotrdioeswi,(EspSsipeldnedetrnea,isc,S)t,oPmraoScsuhtl,aitveSr,eyalPliBtluIainntt,easrtyEi,en.eA,reLaarlg,e ITnitresotni,ne,Parathyroid, SPpreocjieecst: Nhuastber: QZBICROOIZ 01579 Susnrized STH Page: 4 195 SInudinvridiusale SMaicnrgolsecoTpaieclntediciraoslconAierBter(actonitoivnused) P28 To Year Ga TTointceritLyo-crosgoermiisc,dynSct,ay3in Rats - ne Yer Inter Tae: 1 eFaitnee eNakveer:5(3R151er ISteatiaSlceificreomp: 1) CONTROL 0p [L--iver Weroslicnpeirc Bsevations: wns Hae tan PPoorrttaall isloelduecsprcoleilferiantfiiolnt,rataei,lwild Peruserhsaag,instaelrtsitfiatciaall,, mc1raic, acl itd perplasi, seta cel acl, ald The folowing sss ere fund o be within sora Lite: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stomach, Sell Intestine, LTasrgied,IntPesatrinae,thUari,narTyacBhleasd,derE,soAboarteas,, Tresthis/NEopdiediduyeasiesn,erPriocs)t,ateP,arcPrietausi,tarSyf,ivAadrryenalli,d, Ere, iFaaten tNhatbser S5D 15eu InSeanrtiaSlweriicGerup 1 CONTROL 0 pon [I ---- Kerosacrpeic Oserntions: ver rg Ho visible lesions, Fiepsllriaittsri,,,astitele,atbiitlaitae,ralc,oansc,infoc, PForotratl sBlenduuctsproclailferfaitlitonr,atiet,dil Hesrrhage, tifa, ald TiBhrneaainor,lylSolviaivsnlgerCt,oirsesk,utessB,oworTeeFsatroirsuowd,atSnoliebeea,w,itehaiPntro,sotraStaoel,ncPihin,ttuiSstu:alr]y, taersetsi,,TLraragde,InPteasrtisnteh,oid races, Exghees, rsh ode arenters), Prress, Salivary lad, Fre. iFaaten taebkesr539516e0u InSaenrtaaSlweriicGerout 1) EONEOL 0 gon [-- Nersictric Osertions: Pancras Fratyr Ao visible lesan. "Furcnriecairtgsr,escirvoens,eptfroocnaalt,hyw, dil Jcoinvnisntrda,p,afocianl,la1n6of section PSropjecct:Naatsr: OIC 01680 Sonrized SHE Pug: 5 - 196 Stnutrizted SaitetrTeaa--t1ed--Hiesr--lone--,rth. acotneto I Te Yer a Totetn ot ets - Ge ee trTioe 1 roea rs3 Yo teinaSeeriof g 410 OL [-- ieheeneilSoanettrseeeeyweeeononsd S1otbereeiLThroenpnudetsKiL.rtg:, rSotmoainc,, SBaoltannetHio,l a ees, on vt morc sy os or aehet TSeae Wsaerienn 410 GN Neroconic Omrtios [-- to vise in, howt J rpnays --rot-- , Toss Peatrie mse, wit,iait4 tin Teheei enmniteEtoiinsoonweeMraueann,oyserbew,itoLiersrEedplaeisseiogst,eosSaaen,h,HoStly,notmioons, inn Euan, oo ht arse oon Siwy hr re Feee eoner5E 51 erenaiiSeorcog 0 O00 [ Kirirwv-- vswetnin Sen Lf hin font a he heck fit. o--r BrrMantigpprhoyominrvie svwaalgttnhoni,lswi1rdin tary em dei Tihe eelntiteEHo oirosonweeBRarutonon,tyoreebew,thSLinrosrporltt,KiySto:ue,vslel Msoine,rit, ster, Tuten nbn oh oi etre, Pree, Sours Sen -- Project Noster: 0281080012 C016 a miess = 197 STnodniriidzuad RSaacgreosTcpailtaneddMirciraoslcopRiecporotsr(attiionnds) AIT Teo ear Bal ToRxiiceityLdancvogreiacistynSrt.uy3i0n Rats - Oe Yer Intern Tes 1 Fraeel tVhotbesr: S1B515Y0eu InSteevrWaSloeriicoe u {11 GOL pn [an-- ey -- Buk etic lesion, 0.4 c di, ei, [KSaaree rr-- or Haortonuiinrdop,esiisviengaptronathy itd [ AElvte,olacrormecrsp,haagsst,emristioca, wile Phehun, snterstitial, Gvanc, sltifacl, Fatresrtehsrid Faucreesxtaiitnid, corani0c,lafmoalo,f sietcdtion Sina tare Jat emine, isso The felling tissues wre found to be within arm ints: LTBraiatgiihn,YGSiopledeane,saLt,iveerPr,as,HteaatrSet,,enFSiattoyamiatcSahar,yn,SseKalErlreeInn,testTihnoe,idL,argreicoInetne,stEinxes,hgUerisn,ary Bladder, horta, iFiaten haabkeer59A517Y5eu IaerrtaFSuerfwicee r 1 EOL 0 on [---- Rcrosicipnic Dssaaions: PLrospthNoered Caster) a visible Lesions. Faetvisccaainvteryalimzsatiinogn, anit Jak vines, ot in plane of section Trhaeino,tSlopiin Ctoisrseueosnwererofonu,nd tpolbeeswitLihnienr,eremaalt,inLtnsg,: Stomach, Sul Intestine, TCresi,oaHsaicnhee,, LEisnupE,atePrr,iredeonrtSaWienrs,SSanus,EeMeasry 1am itary, Mrinal, iFaaten tNsakbe S5114515e2a InSetnesreSmoirssicGeroups 1 EONRL 6 on MacroescsoepnicarByasrations: Micreorstc Gserations: itn elon nokta as, 1105 a. ay ------ Llctu, pelvic, wilateral FSpaegcieets:YRart s OBIRO1Z 01582 Suanrized STH Page: 7 19 8 SInudsinvriidzuaeld NSaincgrleescToapbculsatnedMifcnriomslcopRiecpoOrbtse(rcvoanttiionnused) FII924 Too Yer Oral TiostiecritLya-bDonractoogriiceist,yTSoct,udy3%in Rats- One Year Interia Tae: 1 fFaotie:e eaeblosrt $9I)RA1SETEear InSetsesrFeSmaaclreifiGcerow: 1) CONTROL 0 pp HicrosLciorpeic IOnsteerstvianteions (continued): Lg Nesntary UParriantahryyroBildadder theres "HPortecenairan,edn,tesrisstsiitnigal, eric, witifocl, aHelsdorrhage, local areas, wild HFcerroisvaissc,alifrat,sonnoodmuellaer,arsiondfrialttreate, aild HSotteateixtsiisn,edc,hroanoitc,insopdlearnaeteof section o"Htyperepxlaansiinae,d,salinsdsuilnagr pitheliv, ailg Netiplasia, sauaous, slinular, wild TEhreinf,elSlopniimnlg Ciosrseu,esSownerMearfroouwn,d tSoplebeen,witLihvienr,noSrmtaolmsclhi,miStse:al Intestine, Aerts, Dury, RPaenucnraerays,ElSianl,ivaPriytuiStlaardy,, EArder,enal, Trsid, Triches, Esophagus, Lygh hee (nsesterich, Fraiten:dbMeasehser:9I)RA1SEYSer InSetx:iFSeumaclieficGerow: 1) CONTROL 0 pa Nacroscpic Oservations: NicroHsacorpeinc servations: Livterrey lng Parathyroid Ho visible Lesions. "Sailndusoidal ectasia, corte, focal, unilateral, S"Poerltvailc ssoiwnenruaclliezaartiocnel,l aiinnifaialltrate, sinisal sHcenaalrrahrages,inmelatliifzoactailo,n,wiwlidld ot exanine, not in pane of section TBhreainf,ollSopvinianlg Gtoirsds,uesBowneereNarfroourn,d Stoplebeen,witHheianrt,norSstaolnaclhi,mitSsu:all Intestine, Large Intestine, ULryiansahryhaBelad(eaers,enhteorritc,h,WeParnucsr,easD,rySa,liRvaorsyarGylaEnlda,ndE,re.Pituitary, Tyros, Traces, Esopages, PSrpoejceiecst:Nfuastbr: 028108012 01683 Sunarized STAR Page: 8 ~ 199 Sduimvnirdiuzaeld SRianrgolsecpTaibculaantdedidcrionsacopRiecporOtbse(rcvoanttiionnuesd) FA-3928: Teo Yer Gra TkniecrityL-iOocroagterniiecsi,tyTSct,udy3%in Rats - One Year InterTiaale1: fFaotiel eNsatbeer: S1D4518Y8ear teSreixaFoSimclreidiGcreow: { 1) CONTROL 0 pa WacSrosicanpic Oration: Wirahsecrpoincs Oomrvations: real Kidney LiLvnegr SSpiineaml Cord a"Liairt Tenolsa,rgnedck. "Sairinesssidl actsia, corte, milters, HCyopretripclaalsidae,genpeerlavtiiconp,itwhiellaitoenr,alw,iladild Ccyasltc,uluesd,ulplhariyc,, wuinlidlateral iSeamortrahcgtee,viaicfautsie,onb,ersalttiefecl, wild ""lHaetroesxindienrea,s,iwsislidng TEhreinf,olBloonweinMatrriosws,uesHeaerrte, fStoounnacht,o bSeealw)ithIinntesstairnmel, LLiamrigtes:Intestine, Urinary Bladder, horta, ULtievro,NodDeir(,waNsateearry),SaPdan,crePaist,uitSaarlyi,varTyhyrBloaindd,,Farrea,thSyrtsni., Trachs, Esophages, fFaoew:l tNohsebtert $I3R1AYSEeSr InSteexr:ieFeSmcarlieficGerow: (1) CONTROL 0 pp NacrosctoupiitcirOybservations: WicLroiwearpic Observations: FaNrawtnhryyroSlsang "Sligtly enlarged "pPoorrttaall obinlsenidccltarprcoellilferiantfiiolnt,rataei, wild oaltactwaacseilnee, sat in plane of section TSLhaueirnef,olISlnpotiwenisantlgineGt,oirsdsU,ureisBnaorvnyerNeBalrafrdoodunen,rd,tSpohloerbetena,,witKUhitdienrneuysn,,ormHDaeulrytl,,inLiPutinstg:u,itaSrtyo,macAhr,enSamla,ll TIhnytreasitdi,neT,raches, Erahagus, Lia had (esnters), Facreas, Salivary Shand, Eve. SPpreocjieest:Maahter: 021CRO12 01684 suri pgs 200 Seuntridzd RSviigrecTLeaalrwatelnMi,eorlroepeorDtincronttiionuned PHL To er rl Tks Spm tr 1 ats Ore Ter Terie Fi 5 rer eI rn rics pp ------ [---- po Hewrhge, Toca ares, trate BCrion aSieoe,CovSeirouws MtraotnossStteen LSvosegCrDirnye, Porkt,ySnoyc,, rSoul4n7tesitirn,e rts Fast The Ebest ener Futev uy Sn re eis avers ds ow Fede Gr | GOEL 0 yn Warsi Boarations ir ACparienswsi,ntweir,searnd, soderate oy Stee, sito, wa he foloneg tse wre nd ts be within nora it: rE ay ers tay teE as Dory, ovr ns, asa, Mott Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stosach, Seall Intestine, Tt, Posi Large Intestine, SFe t toke A1 er oSeoreSare cSo 1) On [---- ois te aster BSeiwrprogea, wpiif, ald EBriieneSopna,Govrtavye ttrionrs Sbpeo,t OKiynorntt SSooyc,FStul,sienn, Tors, Petr, Tren, Bethan, nes, Soi Ss re Seiese:wtetr, EEO .016:85 wrest 0 201 SInudniavriidzueald MSaicnrgolsecoTpaibculaantdedMidcnirnoaslcopRiecporOtbse(rcvoanttiionnuesd) FI-924 Tuo Year Oral Fiker Liboratories, Inc. 30 Toxicity-Dncogenicity Study in Rats - One Year Interis Table: 1 fFiatnea:l (Nbaeebtesr:531)8-4161Y0ear Secs Fesale Group: Interin Surifice ( 1) CONTROL 0 ppm MacroPsictoupiitcarDyservations: Uterus Nicroscopic Observations: ALdarregnealIntestine Lung PPaanrcartehaysroid Uterus. "Slightly enlarged "Sightly enlarged "NSeiwnautsoodiidaalsisectasia, corte, ail ""APlavnecorleaartitsiasc,ropchhargaensi,c,auflotciaflo,caali,lwild "hot examined, not in plane of section "NHeytpaeprlpalsaisai,a,sgolaanrdsul,argleapnidtuhlealri,ua,aiwlild The following Brain, Spinal tissues vere found Cord, Bone Narrow, Stpolebeen,wiLtihvienr,norKmiadlneyl,isHietasr:t, Stonach, Small Intestine, Urinary Bladder, Aorta, Ovary, Namsary Gland, Pituitary, Thyroid, Trachea, Esophagus, Lyagh Kode (aesenteric, Salivary land, Eye. Arial Muster: 16-4620 Sex: Fesale Group: ( 1) CONT0RpIpsL. Fate: Weeks 53) 1 Year Interia Sacrifice NacrosEcroepic Observations: Nicroscapic Diserations: Ere Kidney Lung Urinary Bladder "Brophy, right ere. "PAatnrocpphhyt,halwaiiltaitse,raill,atwearrakeld, sarked "elvic aineralization, sinimal "Heworrhage, mltidocal, ald "Not exasined, nissing BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonweerNearfraouwn,d Stpolebeen,wiLtihvienr,norHmeaalrt,LiSnittosw:ach, Suall Intestine, TLriarcgheeaI,ntEessotpihnaeg,usA,ortLay,wphUteNroudse, (Onveasreyn,terNiacn)m,arPyanlcarneda,s, Pituitary, hirenal, Salivary Gland. Throid, Parathyroid, minal Mander: [G-429 Sex: Fesale Grows ( 1) CONTROL 0 ppm Fate: (leeks $3) 1 Year Interin Sacrifice NacroSskcionpic Observations: Microasacroepniacl Observations: "Hair loss, bead, neck, face. "Cortical degeneration, focal, unilateral, ail SPrpoejceicets:NaRsabter: 0281CRO012 01686 Sumarized STAR Page: 11 202 SInudmimvairdiuzaeld aScirngolsecoTpaibculaantedMiAcnriomsalcopRiecpoOrbtsecrovnattiinounesd) F324: Too Year Oral ToFxiiecrityL-iObnocroagteonriiceis,tyISnct,udy30in fats = Gne Year Interia Tables | fFaitnea:l (olbeeksr:519R-4162T5ear InSetxe:rFeSwaaclreifiGcreoup: ( 1) CONTROL 0 pp Wicrfasocrotpsic Observations (continued: LiLuvregre Intestine Parathyroid "HNeontateoxdaisaisnieds, nissing "HFootrtaelxabiinleed,duncott prinolpilfaenreatiofon,secwtiilodn BTrhaeinf,olSlpoiwnianlg tissues were found Cord, Bone Marron, to be within normal Linits: Spleen, Kidaey, Heart, Lun, Stomach, Swall Intestine, LUyrsignharyNodBelad(daeers,entUetreircu)s,, OPavnacrrye,asN,anSaarlyivaBrlyandG,lanPdi,tuiEtyea,ry,SkiTnh.yroid, Triches, Esophagus, Ffantiee:al fNhaeebkesr:$31)8-4163Y0ear InetxetrnFeSsaaclreifiGcreoup: ( 1) CONTROL 0 ppm MacrLoiscvoepric Qservations: Microscopic Diservations: Li[vrere Puanrgathyroid Thyroid "Possibly slightly pale in color. Calculus, pelvic, wnilateral, ssderate "aHielpdatocyte alteration, vacuolated, mitifocal, a"Htesorerxhaamignee,d,mlatiisfsoicnagl, ald "hat exasined, aissing TBhreainf,ollSopwinianlg Ctoirsds,uesBonweereMarfroouwn,d Stoplbeeen,witHheairnt,sorSntaolnaclhi,nitSsm:all Intestine, Large Intestine, ULryisnsahryNoBdlead(daeers,etAeorritcal,,UtPearnucsr,easO,varSya,livMaarsysarGylanlda,ndE,ve.Pituitary, Adrenal, Trachea, Esophagus, dFaaitneasl eNoksbeers $136-4163Y1our InSetxe:rFeSmaaclreifiGcerow: (1) CONTRLL 0 pou Racroscopic Observations: NicroKsicdonpeiyc Oiservations: LLyunagph Node (aesnteric) PUarriantahryyroBliaddder ho visible lesions. ""Heelwvoircrhaagien,eralloiczalatiaorne,as,sinwiimladl ot exanined, sissing "Not exanined, not in plane of section "Not eanined, missing Trhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonveerMearfroouwn,d tSoplebeen,wiLtihvienr,noHremaart,liSntiotsm:ach, Small Intestine, sPpreocjieets:hhaabter: ZERO c> ois87 sunrized SP 2 = 203 SInudnisvairdiuzaeld MSaicnrgolsecoTpaibclantdedMiMcrrionsalcopRiecpoOrotse(rcvoanttiionnused) F-S924: Tuo Year Oral ToRirkiecritLya-bGonrcaotgoerniiecsi,tyISntc,udy3i0n Rats = One Year Interia Table: | Ffaitnea:l tNhoenebkesr:531)R4163Y1er InSteerxiaFeSmaaclreifiGcreows: 1) CONTROL 0 gpm The fNoilclroowsicnogpitcisOssueesrvvaetrieonfsoun(dconttoinbueedw)i:thin normal linits (continued): ELsiorpgheagIunst,estPiannec,reaAso,rtaS,alUitvearruys,ElaOnvda,ry,ErNe.anaary Gland, Pituitary, Adrenal, Thyroid, Trachea, Fmaitnea:lMNeoeskbser:$31)8-4163Y2ar InSteecrtiaFSeaacarlieficGeroup: (1) CONTROL 0ppm MacrPoistcoupiitcarOybservations: Nasnary Gland Nicrohsicroepniacl Observations: KLiidvneery LNuansgsary Gland Psiatruiytary "Slsiugrhftalcye.enlarges with a dark red focus on "Sudaalrlk srpehderfilcuaild,maLsesf,t 1i.n2guicnnald.ia, containing "Sinusoidal ectasia, cortex, focal, unilateral, "sCiolndic progressive nephrapathy, aild ""HHeespaartrohcaygtee,vaauclutoilfaotciaoln,, amulldtifocal, wild "Galactocele "CCyshtr,oniucniliantfelraamlmation and hesorrhage in cysts. "bdenon BTrhaeinf,olSopwiinanlg Ctoirsds,ueBsonweerNearfroouwn,d Stpolebeen,wiHtehairnt,norSataolsaclhi,itSse:al Intestine, Large Intestine, iLynnaghryNodBela(dneers,etfeorritcs),,UPtaenrcurse,asT,hyrSoaildi,varPyaraGtlhanydr,oidE,ve.Trachea, Escahages, Ffaitnea:l hNeoeslbesr: 531)84164Y0ear InSteex:rnFeSmaaclreifiGcreoup: ( 1) CONTRpOpL Macroscopic Observations: NicroLsicvoepric Observations: PLaurnagthyroid Ho visible lesions. ""Heespaartrohciygtee,vaaciulodlation, multifocal, sininal "hat exanined, not in plan of section BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonweerNearfroouwn,d Stpolebeen,wiKtihdianeyn,ormHaelartL,imSittso:nach, Sell Intestine, TLhuyrrgoeidI,ntTersatcihneea,, UErsionpahrayguBsl,adLdeyrs,phANoordtae, (Uetseernutse,riOcv)a,ry,PanKcarsewasr,y SGallanidv,aryPitGuliatnda,ry,EyeA.drenal, SPpreocjieecst:NRuaetr: 0281CRUOI2 01688 Sunarized STAR Pag: 13 204 IndividSuuamlarMiazcerdoscSoipnigcleanTdabNliactreodsciapnclBseRerpvoarttions F924: To Yer gral ToSxiitcairtyLOicboogretnoirciietsy, TSoca.d in Rats - One Yeu teria Tale: 1 Fnaat:l hNeakbeer: 513516Y%or ItSeertinaSlcerificGere: (2) FES 100 on Nroscpic Baervations: Hicrolsicvpeirc Ohservtions: to visible lesions. PFoorrttaall bsinleecdlctenprcoellilferiantfiiolnt,ratsen,iassilnisal Hepatocyte vacuolation, local areas, soderate MNegoatlocIyotbolseiss,fimlalrekdedvith aarkedly enlarged SFtaorsatchhyoid dheeilpsaaptlsoaccyoeftsescF.iunreslCeyerlglssrarenqnialanarragecesdyttbooyplcisenelclrwehaisceh in rsaedbiraannt.ofIndescrueeaseLdousiaeeslitnhgerefro1n3 3central twoltpieprlipehevraaclu.lesN.ay enlarged cells have oHott eexxsniinnee,, naoitsi1ngslan of section Trhaeinf,ollSopwiinnagl otirss,uesGosneereMarfroounn,d tSolebee,witKhiidonwyo,rHseartL,inLsn:g, Small Ttestine, Large Intestine, UErcipnharayssS,adLeirg,h fhoera,aeTsensttiasi/cEli,diPdaycarse,ssP,rosStaaltiev,arPyitGuliatnadr,y,EeA.drenal, Thyroid, Traches, rFaitoed GNaarbiesr:53R1 51 9Yer InSteeriseKaSlcerificreout (2 PSHE 100 po Neroscic tservations: MerTosicneeic servations: Liver lng fPairtautihtyarroyid ThSyprlaeimd a visible lesions. "eCpoantiecytperogvriecswsoilvaetionng,hrmataitfheyc,ala,iniweialld sNcegalloacyrtossiinse,ralmiazrakteidon, ald Fdlreeon, interstitial, chronic, mltifocal, o"Ftsertievixgsaacirasnlers,taaoslnisoismsicnlgear infiltrate, ail oHetwsecdaerianies,, iwsiildng BTrhainf,olSlpoiwnianlg Ctoirsds,uesBonweerReafroounn,d Htourbte,wiSttohwikncho,reSesalLiImnittse:stine, Large Intestine, SPrpoejceicet:Nfaabter: 0281CRU0I2 01689 Suwized ST Pet 4 = 205 SInuiairsiuzalg aSiiobgseecLTnotilwarattedrdiMeir,sol06k,omrstesctoinotnin PRA Ta er a Toit rane Sty in ats - Oe Te IterTiaae 1 rFaae tYeekr9110er nSeerWSeuries (3 A 0 iTheyfJ lloBwaiotgei, st-- so,wiTe-- efkau t-- aoibresw,heProsatratees, WLrieten,CcTntaioeu):Snes, rh Rte steric, een ay Sus rn Foiite tWkaers511 e1w ISnternlSeriont 3 FR 00 [---- Wirssmic trations [-- r=e tenon tEerttslewntaanocul initrte wild Hepatocyte vacuolation, multifocal, sild ws esi wi Megalocytosis, sarked ltt, ssi WWThiiennegylSBoyanme,aseahstoeewrTeterootnna,dotpileaes,i,hinFeo,saawtrlstFiiaStiv:tc,,MSuelmIntTeostrinse,, Parathrid, Trae Evi, teh ode arr) Fares, ulvry ons re eFiie tWkoert5B1 1Eeur tSasrtalriecges {DFT 10 [[rr[roam-- ------ Slightly ple, tnshrtion calor. Te psSoratrtaal rbsioeacclihoirnocne,tlelraiitnitioinl,rstw,eieasltdrte ws VYireelenoer,assmeiassmbtrase,snalewilt Ahratois et efionuen afnng The follwing iss wre fund to be within orm Limits TCBrraiaan,thSipieonalnr,Co,rdw, LBsonhe MMaNarretoiw,,rSepalrentenee, TK,idoneycyr,EenHaersair,tn,eSS,ttomnaPcsah,snaStekaellRErInsetaesntyin,e,Men, sMoieet:Ymetr, OBER C01690 sawimsmrns - 206 Siniriooe cip eealr aotseebia lsSporBtecaotnotnin R32 Te To rlToneySpry St et 0 er trTeoe 1 ot Tromei a worse Beton: Nero ert: -- on p[rrianicoil cal tre ate, ile i" emnikiata etare a a eeswtaoe Th elniog Hoses wre fun 0b iti rel ite eBCreairen,atSptiinaleaCordet, rBoynBe ovMaariroerw,sLr o htr etr o eeesto Spleen, Kidney, Heart, Stomach, Seall Ms rt Intestine, ------ To ee va Voraate Betis: Si t se of rg 0 sppiohwe rat: ee rn pa, VaL i" a ea enaien , ae18 Hepatocyte vacuolation, multifocal, wild oJ v ve-- atsnsy-- uesres at aSheiantySenemsvstt,rseBwwroetnrfodn ytoebewthbintoSrltrhiioStul] tsi,aLr bntetooe tr ot sett ee ie ort Ja: 2 c0o16 114 SInudmimvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMiAcnirmoaslcopRiecpoDritse(rcvoanttiionnused) FRI: Tao Year Bra TRniikceirtyL-abOocroagteorniceisd,yISntc.udy3%in Rats - Coe Year Interia Table: 1 rFaitne:d eNoksbeer: $3R)3120Year InSetcetrMaSlaecrifiGcreoup: (21 FR-IS20 100 pp RacrosEceapic Observations: stn WicrLosicvoepric servations: LEiveer LPuunrgcreas RTahryartobiydroid trinry Blatter "Fobclaelaticnogr.neal opacity of right eye du to eye "ltahtieghr.al hit thinning, ventral abdonen and "Pale tin in color, e"Proarttialtisso,nonausctlee,aruncielllateirnafli,ltrmaatrek,edail BHoepraatlocbyitleevdauccutolaptrioolni,feriaftfiuosne,, wisloddeate Nheegcarloosciyst,osailst,ifmoacrakle,d ald o"btascuelxaarnianidn,eraaliiszsaitnigon, wild "lFaatlliecxualsairnedh,ypenroptlaisniap,lacneysotf ,sewcitlioanteral, lstd.ereaatseine, sissing TBrhaeinf,ollSopwianlg tCiosrds,uesBowneereMarfroounn,d tSoylebeen,witKhiidnnenyormhaelartL,iniSttso:wach, Seal ntestine, LUurhge TNnotdeest(ianees,enAtoerrtiac,),TSeasltiivsa/rEypdSildaynaei.s, Prostate, Pituitary, Arenal, Traces, Esophages, Ffaotea:l MMeaeskhser:53I)B-1 2Y2our InStexe:raSlaecrificreoup: |2) FESSZE 100 gpa NacLroisceapric Bserations: NicrKoisdanpeiyc Obserations: Giver Lung Lyn Node (aesnteric) "Fale tan in color, ""Cohrrtoanlic spornoognrcelsesairvecneelslhrionpfaitlhtyr,atew,ildald HPoerptaatlocbyitleevdaccwtolaptriaolni,fercaotaitorni,loabilnaira,l wReegraalotyetosis, aild "Vascular aineralization, winiaal HHeensoorrrrhhaaggee,, laoicladl areas, soderate Hesssiderosis, aild BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonveerMearfroounn,d tSoplebeen,wiHtehairnt,noSrmtalowl,initSse:al Intestine, Large Intestine, SPpreocjieecst:NRuastbr: O8ICRIOL2 01692 208 Sumsarized STAR Page: 17 ISnudainvriidzuaeld MSaicnrgolsecoTpbiaclaatneddWiMcirossacopRiecpor(ts.er(vcoanttiionnused) FI-I98: Tuo Year tral THosiitceitLya-bDocroagteonriicesi,tyISnct.udy i Rats = Oe Your Interia Tale: 1 fFaotiel hNeoetkhesr:9IR1Z2Yeu InSteexr:inKaSlaecrifiGcerow: (2) FASE 100 pa Th folloeingTtiLssuep s vere fou-- n to be xithin normal Linits (continued: UTrriancahrsy,BEasdoprha,gusB,orPta,ncrTeeasst,isS/aEliidvairgyyaSsL,ndP,rosEtya.te, Pituitary, aren, Tyrac, Parathyroid, Ffaotea:l (Meassthser:$R971Y2e7ar InSetcteaSlaecrificreout ( 2) FAST20 10 gon Nac[rotweapdic Ohsrvations: HicrYoiwtanpeiyc Observations: Liwr Pwanrsathyroid Tetis/Epiidnis "Pale tan in colar, ""Cphorrotnalic spernoogrmecslseiave cemlp)hroinpfaitlhtyr,ates,iniwaislld HPoerptaatlocbyitleevadccutolaptriloinf,ersaatlitoinf,ecsli,dile HNaecgrleohciygtea,ssl,ocsalildares, wild J"btaleexaantirnoep,hy,notasipnerlmatongeenoefsisse,ctiLooncal areas, in STeheinf,olSlpoinniaalg Ctoirses,ueSsonweeraerfroouen,d Stpolebeen,wiHtehairnt,soSrtmolmaclhi,stSse:al Intestine, Large Intestine, LUriinaaryNosBela(daeers,ntfaorriac,,PProrsctratees,,PiStauliitvaarryy,lAainrde,nlE,ve.Thyrid, Traches, Esophagus, fFaatiel hNeaeskbesr: 11RT1IY2er InSteexr:inlSeacrifiGcerou: 2) PSEZE 100 pa Nacroscapic Osernations: HicLroiwaepic Observations: Lng PTahryarhoyidreid ko visible lesions. "pNoergtaallocystnoasnissc,lesaordecraetle infiltrate, wild "AFlvreoelaornsscirnotpehrasgteist,ials,ltcihfruacnlc,, wailltdifacl, aHelseorhage, maltifecl, wild APteerilvlacstcausliase, sfoovaslu,clweirldinfiltrate, aild oNott rsxeseniinend,, aaiissssiinngg SPpreocpieest: atsathe: OICKIOIZ 01693 Sunnarized STAR Page: 18 209 SIunstevairtiizaeld BSRiTntoglseecpTLiaobcrulaaoterdisNAin,icnranolcso.Rpecposrter(actonitoinnused) F521 Ta Yer Gal Toscity-ncogeicy Sad in Rats - se eur InteTrante 1 iPntael eNkaese5W3 1Tear ItSeerxtinaSlaecrifiGcerou 3 LEA 10 on Wcroscpic Gserations (cantimedls rTuhinf,otSloyninn Ctirsdsueos vwreRrrfoonu,n StolbeewwiKtihidnorayremurti,ntStso:mach, Sell ntstine, TLrratgoaI,ntEeshtainges,UriLnarhy doeser,ureonrtte,rirT,ehPiaErpodsi,raSst,brPryaslaatd,yFEtreesary, Ween, iFnel tYherts ST01TYear oSeerrRSaueriice 1 21 PAE 100 on [---- Wers.cpriecr Osentions: Lnpy Nee steric) Slhry Gis ep -- rSaarnate sprorgresosiveceoplhrionpitlhiyr,ata,niam1al oepratolcyitlee vaascclparioolni,fersautlitoinf,acaali,l mild SNeesarlroaygteo,isT,oialdares, deste Jaott smianneed,, awissssiingg The otloving tissues wre oud to be within arm ints: eBTriranaiancr,hy,SLpiEansatlpen,Cosrdf,,orPBtonenreeTeMeassr,troiwEs,sEeoSpiloeaern,s,HeaPrrto,stSattoemaciha,ttSaaarlyl, IMnteesntiane, TLharroged,InPtesatitne,a, TFiatael hNeabber:59RT1 SYeu InSteernWaSlreificGeros | 21 FIST 100 pn [Si-- Tisaes-- tara) Werslceeirc stration: "Saub.catiees sss at thoracic inet, 1.2 cn pPuortratla bsilrdaot prcoellilferiantfiiolnt,ratme,6itd Hepatocyte aaslation, wltifacal ile ny Waniry shang "vMseegaalllaocarytoisscrirsso,iphnwgotediesro,antse,iwtilido, il ercareciunnronron are f thoracic niet, aArbtsy, ssmopuadairecays oefstaroatrocdeuclt in Torntion Hh sitet tivity, acl SFprecaieets: NRaaster: CEBGROIZ 01694 Soanrized ST Pugs 19 210 SInudaimvairdiuzaeld SMaicnrgolsecoTpaibculaatndedMihcnriosaslcopRiecpoOrbtse(rcvoanttiionnuse.d) Riker Laboratories, Inc, 3 F924 Tuo Year Geal Torcity-Oncogenicity Study in Rats - ne Year Interia Table: 1 fFaitnea:l (MHaonedke:r:531)6-S17SY6ear InSteexr:inMaSlaecrifiGcerow: ( 20 FASTA 100 ppm Microscopic Observations (continued): Parathyroid Pituitary "Not exanined, not in plane of section herons The following tissues were found to be within normal linits: UBrrianianr,ySBpliandadlerC,ordA,ortBao,neTeNsatrirsow/,EpiSdpilceyean,is,KiPdoresyt,atHee,artA,dreSntaola,schT,hyrLaairdg,e TIrnatcehsetsi,ne,Esophagus, Lysgh Note (nesenteric), Pancreas, Salivary land, Eye, Saal] Intestine. final Masher: (R-TTST Sex: Male Gro: (20 FRITH 100 pga Fate: (Meeks 53) 1 Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Spinal Cord "Slightly tan in color, "Chronic progressive nephropathy, sininal "Portal acnanuclear cell infiltrate, aild Hepatocyte vacwlation, multifocal, soderate "Nvaesgcaullcartoswiinse,ralaiodzeartaitoen., aild "Pheotriveaxsacsuilnaerd,soinsoinuncglear infiltrate, aild The follosing tissues were found to be within normal limits: hBorratian,, TBeosnteisK/aErpriods,idySapilse,en,ProHsetaartte,, SPtiotauaictha,ryS,ealAldreInnatle,stiTnhey,roiLda,rgPearIanttheysrtoiinde,, Urinary Trachea, Bladder, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Sland, Eve. final Maaber: IRTAT Sex: Male Grow: (20 PAST2A 100 poe Fate: (Meeks $3) 1 Year Interia Sucifice Macroscopic Observations: Microscopic Observations: Kidney Liver LPuanrgathyroid Testis/Epididyis Xo visible lesions. "Chronic progressive neshroathy, ld "Portal sononuclear cell infiltrate, aild Hepatocyte vacuolation, multifocal, aild Negalocytosis, moderate Necrosis, mltifocal, wild "~HHoetsorerxhamaignee,d,locnaolt ianrepssl,anailofd section "Vascular sineralization, aild PSrpoejceicets:MaRsahter: 0281CR0012 601695 211 Suarized STAR Page: 20 SInudainvairdiuzaeld MSaicnrgolsecoTpaiuclaatneddWincirnoascoRpecpoDrtser(vcoanttiionnused) FIIT4: Tus Year Bal TiostiecritLya-boDrcaotgoerniceis,dyISnct.udy1in Rats = Oe Yeur Interin Tale: 1 nFaitae:l hNeaeblesr: 53()G710Y)our InSteerxiaMaSlaecrifirceoug: | 2) FNSE2E 100 pon Nicroscopc Observations (continued): BTrhaeinf,olSlopwiinng Ctoirsds,uesBowereNarfroouw,n Stoylbeee,wiHtehairnt,seSrtmolmacLhi,nSsm:all Intestine, Large Intestine, LUyroipnhardy eBlad(daeers,eatbeorritca), PPraonsctraetaes,, PSiatluiitvaarryy,BlMarned,nlE,ye.Trad, Tache, Esophags, nFaitne:a Gaebeeksr:591)BT1HY8our InSteex:rnlSeacrifiocep: 2) PSEA 100 pon RacrLoiscvoepric Dservations: NicrToiscdonpeiyc Observations: Liver Lung Parathyroid "pale tan in color, "PoCrotnailc spornoognrcelsesaivre cneellphrionpfaitlhtyr,atseiniaaialld Hweipeartaotceyte vacuolation, centrilabuar, RNeecgrlooscisy,tsfiosc,al,wiladininal "Pvarsecsuslaorn,ainienrtaerlsitziattiiaoln,, cwhirlodnic, local areas, Paelrdivascolar sononcloar infiltrate, ald ot xanined, not in plane of section Trhaeinf,allSopnianlg tCiosrds,uesBowneereMarfroouwn,d tSoplbeen,witHheianrt,norSstaolwacLhi,nitSse:ll Intestine, Large Intestine, UErsicnpahraygusB,ladLdyegr,h ANoordtea,{nTeessetntiesr/iEcp)i,iPdaycirse,asP,rosStaaltiev,arPyitGuliatnadr,y,EyeA.drenal, Thyra, Trache, fFaitnea:l (Nhaebekesr:53R) 51 7Yar InSteecrtinFeSmaaclreifiGcreoup: (2) FA-I20 100 pon Wcroscopic servations: WicrKoiscdonpeiyc Biserations: Ler PLargathyroid [i Ho visible lesions. "eCahtroancicytperogvraecsusailvaetiomne,shrwoaplittiyf,ocawlildaild eRseograrlhoacgyteu,ssL,ocaalildaress, saderate lettaplxaasniian,e,sqnuoatseisn,pgllnaenioaflars,ectaiiolnd PSrpoejceiecst:ushahter: 0281CR12 01596 Summarized STAR Page: 21 212 SInudninvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMiMcrrionsaclopRiecpoCrhtse(rcvoanttiionnused) F-S924: Tao Year Oral ToRxiikecrityL-aObnocroagtoerniiecsi,tyISnct.udy3i0n Rats - One Year Interia Table: 1 TBhreainf,olSlpoinriagl Ctoirsds,uesBowneereMafrroouwn,d Stoplbeeen,witHheairnt,nerSstaolnacJhi,itSse:ll Intestine, Large Intestine, LUryisngahryNoBdlead(daeers,enAtoerrtiac,),OvPaarnyc,reaRsa,ssaSrayliGvlaarnyd,GlPanidt,uitEavrey., Adrenal, Thyraid, Trachea, Esophagus, iFatae:l lNeokosbs 11R-147Y6e0ar InSteexr:nFSeamcarlieficGeroup: { 2) FA-3924 100 pon Macroscopic Oservations: WicrLaiscvoepric servations: TM Spleen Ho visible lesions. "NHeespatlooccyytteoivsa,coalaltdion, multifocal, ainiaal "AFlevreiovlaasrculmaarcrospohnaogmecsl,eawritiinffailctlr,atea,ldaild "Hesssiderosis, aild BTrhaeinf,ollSopninianlg Ctoirsds,uesBonweereNafrroouwn, to be within roraal Limits: Kidney, Heart, Stonach, Swall Intestine, Large Intestine, UTrriancahreya,BlEasdodpehra,gusA,ortLay,wpUhteNraukse, (Dnuerseyn,terRiacs)e,aryPaSnchraena,s,PiStauliitvaarryy,GAlarnedn,alE,ye.Thyroid, Parathyroid, Ffantieo:alWKeoebkesr:531)R-41T6Y1ear IntSeexr:iaFSeamcarlieficGerows: ( 2) FA-3924 100 pon Nacroscopic Observations: NicroLsacrogpeic IOnbtseesrtvianetions: Liver Lung PUarriantahryyrBoliaddder Uterus a visible lesions. H"Heenpaattoodciyatseisvacwlation, sultifocal, aininal "NVeassaclualcayrtoasiinse,ralsiizniantailon, wild AHlevseoorlrahragem,acraolpthiafgoecsa,l,milatiilfdocal, ail "Not exanined, not in plane of section h"Naettapelxaansiinae,d,seaainsosuisn,g glandular, wild BTrhaeinf,ollSopwinianlg tissues were found Cord, Bone Narrow, to be within normal limits: Spleen, Kidney, Heart, Stonach, Swal Intestine, dorks, Duar, MPaasnecarreays,laSnadl,ivPairtyuiltaanrdy,, MEryee.nal, Thiroi, Traches, Esophages, Lysgh Kode (aesenteric), PSrpoejeccst:bhetr: OZBICROIZ 01697 Sunnarized STH Page: 22 213 SInudmiaviidzueald WScinrgolsecoTpaiuclaatneddMinciraolscaBiocpoOrbtse(rcvoanttiionnused) FIST Tuo Year Gal TkoiecrityL-aObrocraotpoeriiceist,yISct.ady38in Rats = Gn Your teria Tale: 1 fFaitnea:l (Khoebreer: $13601Y6o5r InSetnrtaFSaclreificreap: (2) FRO 100 pn NarSosiconpic servations: NicroLsicvreic erations: tunrgy PSalraetehyroid eres hair Tos, bea, neck ares. "oPorrttaall aboiloensaclcetarprcoellilferiantfiiolnt,ratiei,dwild HNeepplaotcayrttoesivsi,oldateirone, mltifacal, sinial lHeosodriraaggoset,s,Locnaaltaeraeatse, dsecetirone eKsotcseixdsrisnesds,,awaildin plane of section ironies, soderate TBhreainf,ollSopwinianlg Ctiosrs,uesBowneerearfroounn,d Ktoidbneey,witHheirnt,orSatloscLhi,mitSse:al ntesioe, Large Intestine, ULriignharyhleataenrs,ntdaoitca),,RoPamnacrryeasl,anSda,liPviatruyitSaarnyd,,AEreen,alS,kinT.yoid, Trche, Esophagus, fFreiral eKsatteer:$9715Yar InSteear:nFeSmcailfeicreat (2) FR 100 pn Nacroscpic Osarvations: Neroslicvoeirc servations: Hnagar ang thPearreasthyroid fo visible lesions. eNpealtoaccytoesivsa,cwesldaetriaont,e witifucl, ainial SPlovretsallarilaescdriocsthagperso,lifweurtaitifoanc,l,alweile SJaolticetxosceilnee, nat in plan of section betaslaia, sours, slinula, wild The folowing tissues sere ound to be within orm] lints: LBLraiargighne, IMSnepteiensatalienesC,mortdUe,rriinBcao)rn,ye MBPaalrnarcdorewer,a,s,SpAloSeraetlnai,,vauKriydynGe,ny,dP,iHteuaEirvttea,.ryS,tomAarcehn,alS,malTlhyrIonitee,stiTnaec,he, Exophages, PSrpoejceicets:NaRabter: C8ICROIZ 001698 Summarized STAR Page: 23 214 SInudsiavriidzuaeld WScinrgolsecoTpaibclaatnedMihcnriomslcopRiecpoOrtser(vcoanttiionnused) PAI: Tao Your Gra TiostiecritLya-bDocroagteonriicesi,tyTSoct.ud in Rats - Oo Year Ineria Tale: 1 nFiittere eNsatbeer:$B3A1TTTear ItSeernsiaFeSmaaclreifiGceroup (2) FRITH 100 pp NacrosWcearpsisc Dhservations: MicrTosicorpic Observations: ny tLeonhisNode (senteric) "Dilated, filled with cloudy fluid. "HNeepgaltoaccyytteuivsi,cuasliantiinoanl, wiltidcal wild "hirleswonis, interstitial, craic, wiltifocal, HFeetroirvhaasgael,irwsulotniofuucclle,iaidlndfiltrte, aild bkyodrdoiwagtnross,is,todinraadteequate section Endoniritis, chronic, ald STaheinf,alSlpoirnianlg Ctoirsds,ueBsonweerMearfrooun,n Stpolebeen,wiKtihdioneys,orhmelartL,isSttso:mach, Seal Intestine, PLaurraethnytreis,tinTer,ichUersi,narEysoBhlaagsuiso,,PAaocrrteaa,s,OvaSray,lvNaawmaSrayndE,lanEdv,.Pituitary, Mesa, Torsie, Ffiotie:l BMeassthesr: $I3RA1TRY0ear InSteexrnFeSmcarlieficSerougi { 2) FA-24 100 gon Nacrowapic Dhsrvations: NicroLsicvoepric Oaservationst FLanrgathyroid Thyroid o visible Lesions. "FHoerptaatlocsytneanvuaccloelaarticoenll, iwnaflitlitfroactael,, wsiilndisal eNoergralhoacgyeta,ssL,ocaalildares, woderate llaotdieaxgannoisnies,, niontadienqupaltaeneseocftiosnection TBrhainf,ollSopwinianlg tCoirsds,uesGownereMafroruonnd, tSoplebeen,witKhiidnaeyn,ormHaelatL,iniSttso:nach, Sul Intestine, TLraircgheesI,nteEsstsipnhea,usU,rinLauryaBNaotdteer(,weAsoernttae,ricU)e,rsPsa,ncrGeuarsy,,SaNlaiwvnarryy SSlaannde,, PEivet.ertary, Arenal, sPrpoejceicets:NaRaster: Z8ICROOL2 01699 Sunnarized STAR Page: 24 215 Susarized Single Tabulated Mniaal Report (continued) Individual Macroscopic and Wicroscopic Observations Riker Laboratories, Inc. 30 FI-3924 Tuo Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Sonal Fate: (Neaebekr: 531)6-4118Y2ear InSteex:rnFeSmaaclreifiGcreoups 2) PA-3F24 100 pp Macroscopic Observations: Liver Hicroscopic Observations: Liver Spleen "Right Lateral lobe herniated through the diaphrage into the right thoracic cavity. The lobe within the thorax is wttled dark ree. "Hepatocyte vacuolation, wiltifocal, aild Telangiectasis, soderate Telungiectasis in herniated Liver lobe. "Heaosiderosis, aoderate The follouing tissues vere found to be within normal linits: Brain, Spinal Cord, Bone Marrow, Kidney, Heart, Lung, Stomach, Seal] Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Namsary Gland, Pituitary, hdrenal, Thyroid, Parathyrolc, Trachea, Esophagus, Legh Node (aesenteric), Pancreas, Salivary land, Eve. nina Musber: (RATS Fate: (Meeks 53) 1 Year InSteexr:iaFSeascarlieficGerow: ( 2 FN-I924 100 pon Macroscopic Observations: Skin Microscopic Observations: Adrenal Liver Lung Nasaary Gland Parathyroid "Seal subcutaneous wass, | co dia., behind right shoulder. "Sinusoidal ectasia, cortex, focal, mild "Negalocytosis, ild Piguent, Kupfer cell, brom, ail Hepatacyte vacuolation, multifocal, eile "Vascular sineralization, aild "HAeevnoorcrahracgien,onlsocal areas, wild "Not exanined, not in plane of section The following tissues were found to be within normal liits: Brain, Spinal Card, Bone arrow, Spleen, Kidney, Heart, Stouach, Saal] Intestine, LLyasroghe NIondteest(innees,entUerriinca)r,y PBalnacdrdeears,, oStalai,varUyterSuhsa,nd,OrEyye,. Pituitary, Thyroid, Trachea, Esophagus, SPpreocjieecst:NRaastber: 028180012 01700 Sunarized STAR Page: 25 216 . SInodnivriiduzadl aSirnaglsecTpaiatneddWneriosacaRpecpotrthsa(rtvtiinonds) PIE: Too Ter GalTosrieOrncLoorgsetonriie,cnSe.ty381 Rats - Oe Yar tari Tate 1 fFaea tshtrss51D718Y5eu InSteerFSemwireicGeroups (21 PST 100 pon [li-- er ---- WerCeaspaptcusBsrvations: Gr Awarnathyroid Stigty ple tSaetpaxaoiytne,coitsaitnig, witifecl, ald S[rechsvcttsts, foal ald ot rains ot 10 plan of section STaheinf,olSlowinnag GtoirsdsyueBsewnreNaorruodw StolbeewwiKtihdinneys,earrat,LimSitos:w, Sell tetin, TLhrntgidn,trctaihnee, ULrinparyNdoeire,stoert6,,WeFruec,raDsu,ryS,alMiwvkaaryal1aanmBePeitta, ren, iFlnel tahbtesr: SBD A1 TYear InSteerFSoureiicGerow {2 AA100 on [---- Wcrocrpeniacl servations: Karey ar Fnrywtary Gers oo visible Lesions. EhRe T p-------- "ehlrvaiiccnparworgraetsmstiiveonn,ephsreopaatthsy, ild SCaintttao,spealavailcation, mitifecal itd "Fsssclolopawsnsl,ianiitdio, ald Setitraussia, swum, saris, soderate Heras, lanl e5the on, odeate rTaheinf,olSlownianlg Ctirsdsueos nwreRroround, Stolebee,wihthairn,erSmtaolwacihn,tSs:l Intestine, Lrge Intestine, LUroipryNe10ae,tefoircte,rFaarcyrnso,vaSryunShyakySaTnr,anBe,. Pastor rahe, Eps, SFpreocieets: NRaatr: CEBGROIZ 01701 Susmarized STAR Page: 26 217 Snudniriitzaeld SRinoglseeTnautanedsrniaalspReporat.er(caotntiionuned) F152: Tao Yeu Gal TRieuLiavtraes nSea.d3i0n fats - Doe Yeu Intern Tate 1 fFiatea tWhaente SAB 1TYeu InSteaetrFSoorwfliceers (2 PST 19 pn hcroscpic Bssvtions: WicrsCcoeiec nsertians: Giotwor ng FPiartatheroid Troarteeisd Wars Fo isle lesions. opteixisnivewr,alimzisstsiionng, ald SNaepataalootyeosahc,elstiieotne, mito, sisinl HPoetrritvosgteu,ewmitilfoael wfilidltrate, wild Pwieeon, ateattis, case, sitio, JAeeroemine, wssing JJaokcwaimsse,, iismsdienpgte section etilasi, soases, slntlar, ile TBhreinf,olliownilng Ctoirses,uesBewnreMaroruowd, tHoibeenwitehritnyarSommclhi,ngSs:wi atestie, Large Intestine, SriinlarayylBaltaendr,,rfeo.rte rryy amar Eland Biren Lrph Ho sede, Fueree iFiaten tNhaatbse5971 eur ItSeerreSmairsdinfero 3 LSA 10 0 [I entry---- Wicrs[cepoicnOsertions: ve LYenagmtary PaSrlabtahyrryoiddla Sul fur mss 1 15 cn net to the right ovary. sFaatretxsiotvn,iciiseninegll infiltrate, ala PHoerptsatlonitleevaaccolaptrioolni,fermalttioinf,ocial,esin SYeesarlrcapgoestI,ssanianrtes, itd aSctraoistses,, fct,onbc,tsiewtieerte Jaat vseiinness, emitssningpov of section he faloning tissus wre oud to be within mera Limits: UBrragien, TSaptientailneC,ordW,aBronye BMaarsriowe,, SAplreten,, UKtidrnaesy,, HDerayrt,, NStaonmaacyh,BlSawnidl,l PIinttueisttairnye,, rem, PSrcojoesct: haatber: 081RO12 01702 218 Serine STH ug 27 SInudsinvriidzuaeld RSaicnrgolseceTpaibculaantdedKidcnrionsaclopRiecpoOrbtse(rcvoanttiionnused) Riker Laboratories, Inc. 3 F-3928: Tuo Year Oral Toxcity-Oncogenicity Study in Rats - One Year Interia Table: 1 fFaatien:al (NMoesedkesr: 53I)R-4179Y3eu InSteexr:iaFeSnaaclreifiGcreoup: ( 2) FA-3924 100 pon The fMoilclroowsicnogpitcisOsubesservwaetreionfsounfdcontotinbueedw)i:thin norsal Linits (continued): Thyroid, Trachea, Lysph Node (sesenteric), Pancreas, Eye. FAnaitsea:l GNhuesebte=r: 531)R-41YG0e6ar InSteexr:inFeSmaaclreifiGcreoup: ( 2) FN-3924 100 pn Macroscopic Observations: Microscopic Observations: Liver PLaurnagthyroid Uterus "Ho visible lesions. "Hepatocyte vacuolation, multifocal, aild "HKeevgoarlrobcaygteo,sisl,ocawlildareas, wild "Hot exanined, not in plane of section "Hetaplasia, squamous, glandular, aininal The following tissues were found to be within normal linits: LBarragien, InStpeisnatlineC,ordU,rinBaornye arrow, Spleen, Bladder, arta, Kidoey, Heart, Ovary, Nasary Stoasch, Suall Intestine, Eland, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lysgh Mode (mesenteric), Pancreas, Salivary Gland, Eye. Animal Nuaber: (RABI Sex: Female Group: ( 2) PA-I924 100 ppa Fate: (beets 53) 1 Year Interin Sacrifice Macroscopic Observations: Microscopic Observations: Liver PLaurnagthyroid "Ho visible lesions. "Hepatocyte vacuolation, mitifocal, aild "MHeegaaolrorhcaygteo,sism,ultwiiflodcal, ail "Not examined, not in plane of section The following tissues were found to be within normal liits: rain, Large Spinal Cord, Bone Intestine, Urinary Narrow, Spleen, Bladder, forts, KUitdenreuys,, HOevaarrty,, SRtaosasaacrhy, SlSaanael,] PIinttueisttianrey,, Thyroid, Traches, Esophagus, Lyssh Node (nesenteric), Pancreas, Salivary Gland, Eye, Adrenal. Species: Rat Project hasber: 028180012 Go1 703 19 Sunarized STAR Page: 28 2 IndiviSduuaalnrMiazcerdoscSoipnigcleanTdabaKliactreodscoipniaclBaRserpvoarttions F392: Ton YeHairkeOrralLibToorxaitcoirtieys-,GoTcoocg,ici0ty Study in Rats Tale 2 Ffaitnea:l eNaetsart100I)RITSeIrDaiml SSeaxc:riWfailcee Groups (1) CONTROL 0 gpa NacroSsicnoic Dsarvations: Microhscroepniacl Observations: heart itn Liver Lng PPiatruaitthayrryois Surroid "hTasoetdai.nflamed Lesion on right rer CToretdioclaulryvcaeclsllahtyipoenr,plaestiiaf,ucwiatli,foacialld, aild "ATcoacradiarteiass,, cwhdreornaitceronsppurative, "CPherlvoincicspirnorgarleisnsaitvieonn,epsoipnaitnhly, anise] "fPoorrttaall sbuilneaodcclatarprcoellilferiantfiiolnt,rataei,ldainisal "Pasocealuanr,siivnetrearlsitziattiiaoln,, wininal chronic, sultifocal, Paelrdivascular soooniclear infiltrate, saderate Hoetr.oenussine, sisting ""lFotdoedxraamaiintei,s,isstlicnegrative, bindleg, wirked The following tissues were found to be within norma Liits: Brain, Spinal Cord, Bane Marrow, Spleen, Stomach, Seall Intestine, Large Intestine, Urinary Bladcer, Aorta, Testis/Epididyeis, Prostate, Trachea, Esophagus, Lyaph Node (mesenteric), Pancreas, Salivary Bland, Eye. Fdaotie:t hNoeteher108R)I5TeIr9winal SSeacctriWfailcee eos: { 1) CONTRI 0 pa Nacroscoic Dstrvations: Nicroscopic Observations: reat HEesacrptages tLiivdery lo visible lesions. "SCionrutsiociadlalacawcotlaastiiao,n,corstletsi,fomictsi,foiclald, ald "ltoyt.scretaistiinse,,chirsosniincgnovsuppurative, "Cwhirtoinfioccaplr,agraelsdsive mehropathy, ilg "Pfoorrttaall bsialreamdccltewrprocleilferiantfiiolnt,ratmei,ldwile Hienpatocyte alteration, vacuolated, multifocal, X AS400smopnonseMsacacorseemoipsiucsOBoIwEeRnMT.IHONL| S THisdEe100o) fMElMES, Seoy oraseron SFpreocpieecst:Nfaabter: O22 C01704 Susnarized STAR Page: 20 220 SInudaiavriidzueald MSaicnrgolsecoTpoiuclaatneddNincironxlcapRiecpoOrhtse(rcvoanttiionnused FIN: Tuo YeaHrikOerralLiTdxriactiatiye-sO,csIgcn,ici8ty Stuy in Rats Tale: 2 nFaitels rRotsser:1061)03T5a1r9ainal SSeuaetifMiaclee Group 1) CONTROL 0 pp HcrLosicgopc Barvations (catinued): vPaasrciualsacralsairnesroanloinnuactlieoanr, iinlfdiltrate, aserate wPrreiustneis, interstitial, chronic, mitfocl, SThaeinf,olSlpoiinnag Ctoirses,ueBsoneereMarfroounn,d Stpolebeen,wiStthionncoh,rmSalLimiItnst:estine Large Intestine, ULeyionnaroydBeas(iaese,stfearticah,, TPeasnicrseiaEsp,diStalpiivsa,ryPBrloasntda,te,EreP.iitary, Thoid, Parthyrotd, Traces, Fiaeted earbieer: $01)5S5ac2rificedSexi:n feaxlterenisGrog { 1) CONTROL 0 pn [Sriny ---- LSilveeen HcroMseaepnac Barvaions: thiordte Lier Lng "loteh ind astute lcerated. ealrges "CWoretaicralyaccellaltbiyopne,sllaoscia, awraletsi,focwaill,d aild "rWnyciarcdiaplrofgirbersossiivse,smeartiipfaotcha,, wriladte esdseraitec violation, centrilobular, "Psoecaaonra,siinnetaelrsitnittiioanl,, cwhirlodnic, local ress, Eiileem, Local areas, ld Psairnathyroid Siem touch oTFtihbraortsaissn, ep,leursails,insgil oSdeotteeoriaetsitss,, sasltcerraateivdeu,alrybl,indilnecgr,esssierdked "saosr,tesbmcoul, marked TBhaeinf,llSopsiinnag CtiosrsduesBownerearfrooned, tSoeaBle wIinttheisntinse,rsLarLgieniTtkse:stine, Urinary Bladder, hort, TFaUctriuSsEsp,iiStdtrvaasr,y PErloasntda,teE,e.Pituitary, Thyroid, Teaches Excpbage, Lys ode (esoteric), SPrpocjieocstssahte: CZELCRONIZ 601705 Somaizad STH Page: 0 221 SIundminvriidzueadl MSaicnrgolsecoTpaibculaatneddWMircirnoaslcoReppcorSt.ose(rcvoanttiinounesd) FSP: Too YeKairkeOrralLbToornaitcoiiteys-,Gclongce.nci3t0y Study in ats Tale: 2 Ffaotei:l ONeosttheer:991)5S2ac3rificeSdeixn MexlterenisGroup: 1) CONTROL 0 pa NacrosScooftpicTisOsbuseesrat(Dioornass:) stonch WicroHsacraepmc Disernations: Hiedanrety Liver tng Sprtonstate stonch "Hassasc,le10a5nd9rxib,4 ceaxteinndiLnigtianxtiolla involving lHeaist tshoofrtaacnic cfaavtittyy,, collapsing left lung. "Haalrlidse,nstos with posible ulceration in "CSoirntuiscoaildalvaeccolaastiiao,n,Comrlttsi,fodciaflf,usea,ildaild ""HOyhcoanridciaplrogfribersossiivse,aempthirfoopactahly,, waiilldd "Foarcttaall bsialmeondccletarproclelilferiantfiiolnt,ratael,daild "Hveapsactuolcarytesianletaelriaztaitoin,on,vacaailsdlate, sild HAelvseoorlrahragweacfroocpahla,gesw,ildwild "FFirbroossaatrictoinss,actuhtoer,assepprative, marked Vaecltlerdaiteffecrolmltaigaetnedf,orhmaitgiholny,cellular vith cer, waked TBhaeinf,ollSopvinianlg Ctoirsds,uesBownereNarfroouwn,d Stoylbeee,witShuailnlsaIrntmelstiLnien,itsL:arge Intestine, Urinary Bladder, arta,TestisEpidityas, Lysgh Node (aesenteric), PPaintcurietasa,ry,SaTlhiyvraoriyd,BlPaanrda,thEyvreo.id, Trachs, Esophages, Ffaitnea:lGNeoeskbser:1080 ) Teraina SSaexc:rifWiaclee Geo: 1) CONTROL 0 pa MacroPsictoupiitcarOyhserations: WicroHsacroepnc Obsernations: ier LiLuvregre Intestine "Sul red Lesion, ""Cehdrlolniacryprcogerlesbspieverplsamshiraa,ptmhiyt,ifsoocdaelr,atweild HPeeulvtiocdiaainsesr,liczoaltoinon, 8ild "hPoerptaatlocystneenasltcelreartiocne,l vaicnufsillattreadt,esoadielrdate Portal bile duct prliferation, ald sPpreocpieets:Nfuaatbrt CZAICRO0L2 01706 Suancized STH Pages 31 S222 Riker Laboratories, Inc, S10 on ha pra ie he Kidney Chronic progressive nephropathy, soderate on Ta eT nt Sa ne ts, wir te, FE: nr 001707 ows 18 223 SInudsiavriidzuaeld NSaicnrgalsecoTpaibculaantdedHiicmraoslcopRiecporOtbse(rcvoanttiionunesd) Riker Latoratories, Inc. 30 FI-3924: Too Year Oral Toricity-Dncogenicity Study in Rats Table: 2 final Nosber: IR-3525 Sex: Wale Groupt (1) CONTROL 0 pp Fate: (ets 106) Terwinal Sacrifice Nicroscopic Observations (continued): RTohretaf,olPlroowsitnagtet,isPsiuteusitvaerrye, fTohuynrdaitdo, bTerawcihtehai,n EnsoorpmhaalguLsi,siLtyssp(hcoNnotdienue(ds)e:senteric), Pancreas, Salivary Eland, Eye. foinal Mosher: IR-3526 Sex: Male Group ( 1) CONTROL 0 pps Fate: (Heeks 108) Teraimal Sacrifice Racroscopic Observations: Wicroscopic Observations: Kidney Liver Lung Xo visible lesions. "Chronic progressive nephropathy, ail "PPoorrttaall sbiolneonduuccltearprocleillferiantfiiolnt,rataei,laild Cystaid degeneration, focal, aild Hepatocyte alteration, vacuolated, ld "ascular sineralization, wild The folloning Brain, Spinal tissues were found Cord, Boe Narrow, to be within normal lisits: Spleen, Heart, Stonach, Seall Intestine, Large Intestine, UTrriancahreya,BlEasdodpehra,gusA,ortLay,spThesKtoidse/E(paiedsiednytaeirsi,c),ProPsatnactree,as,PitSuailtiavrayr,y Adrenal, Thyroid, Eland, Eye. Parathyroid, final Muaber: 18-3528 Sex: Male Group: ( 1) CONTROL 0 poe Fate: (beeks 106) Terainal Sacrifice NacKroisdcnopeiyc Observations: MicroAscroepniacl Observations: Kidney Liver Lung. Pituitary "Hydronephrosis ""CCohrrtoinciacl parcougrselsastiivoen,nefpohcraolp,athwyi,ld moderate Hyronephrasis, unilateral, soderate "PPoorrttaall bsiolneonduucclteaprracleilfleriantfiiolnt,rataei,ldld Hepatocyte vacuolation, sultifocal, ail "Vascular wineralization, aild Paeunania, ald interstitial, chronic, multifocal, "Hyperplasia, focal, pars distalis, ld BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueDsonweerNearfroouwn,d Stpolebeen,wiHtehairnt,noSrtsoaslacihn,itSse:all Intestin, Lirge Intestine, Urinary Bladder, Aorta, Testis/Epididpais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Species: Rat Project Musber: 0281012 01708 224 Summarized STAR Page: 3 ISnudnivriidzueald NSiinrgolsecoTpbiucl4tneddiciraoslopRiecpoOrtnar(vcaatntiioonused ker Laboratories, Toc, 3% FN-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 nFaiteas.l Gaebeeksr:1061) 0Te5rsina SSauesifMilcee Get 1) CONTROL 0 pp The fNoilcorwoisncgopitcisBssueerawterieonfsoun(dcottoinbeuewdi:thin serml Liits (cntineed: Loh ode (sesntaric), Pancreas, Salivary Gland, Ee. fFaotaesl GYebeoksr:901)03S5a2c9rificeSdenis xaltereisGrp 1) CONTROL 0 pp WrosScipnic Bhervations: iver Wicrssrcoepilc Oharvations: LKiivdenrey Lng trceasbbodfsdbrcat,itsisd,witshhhoiwe.Los, sone aiTsoned, ale sas, 1.2 ca a, in It Dateral C"ovrtaincealparocgurleastsiivoen,epwhsolptaitfhocyl,, ialidl oHretpaatlocselolaulnacrlecawrccievlolnsfiltrate, ald Tdriafbeerceutlairstpeust.ters, fairly weil "vascular sinealization, wild Parreastthaytreoid tSailnivary Gland rinury Matter JJdootet.anee,xassiiunbnepel,,ewramaialv,siinsngodpelraanteeof ction Joiltcerw,anbiancekd,,asoisnin,g sarod "Eithelial bypass, simple, diffuse, wild TBhreainf,olSopwiinnalg Ctoirsds,uesBuseerearftouon,d Stolebee,witHheirnt,orSma]micLhi,stSs:ul ntstie, Large Ttetine, hFoarcar,esT,estEirse.Edits, Pituitary, Thyroid, Trche, Esophagus, Legh Node (sessteric), FTiatea:lOMeaskeer:108I)RTIerSinal SSiecirifMiaclee Groups | 1) COMRL 0 pn [-- -- Niroscrptic omrvations: Liivheery ko visible lesions. Woscniaarsdlitis, chronic snsparative, foal, "oOrvtoanlic sporoongarcelseswivrecaelplopinaftihltyr,atea,ildaild CPoprttoalidbidloendautctiopneo,lidfoecratli,ons,edieirdte Heatocye alteration, vacated, aild SPpreocjieecst:Naathe: ZEICROLZ 01709 Soaiaed SHE Page: 4 - 225 Sumarized Single Tabulated imal Report (continued) Individual MaRcirkoesrcoLpaibcoraatndoriWeisc,rosIcnocp,ic3O1hservations F394: Too Year Oral Toricity-Dncogencity Study in Rats Table: 2 Ffantien:al (NMuesebkesr:1061)R-STSeSr0ainal Sex: Male Sacrifice Group: (1) CONTROL 0 gpa Microscopic Observations (continued): ung Splem "PVearsicburloanrchaiianlerIaylsipzhaotiidon,bypaeirlpdlasia, nild "Hesosideronis, aild The follouing tissues were found to be within normal lisits: Brain, Rorta, Spiral Cord, Bone Testis/Epididyais, NParrorsotwa,teS,toPsiatcuhi,taSreya,llMrIentneaslt,ineT,hyrLoairdg,e Intestine, Urinary Bladder, Parathyroid, Trachea, Esophiqus, Lysph Node (sesenteric), Pancreas, Salivary lan, Eye. Ffantien:al(Mlaesehker:1061)R-ITSeSrIaiml SSaecx:rifMiaclee Group: (1) CONTROLO pp Macroscopic Observations: NicrKoiscdonpeiyc Observations: Liver Lung Ho visible lesions. "Chronic progressive sephropathy, aild "Hepatocyte vacsolation, sultifocal, aild Portal sononucluar cell infiltrate, sininl "PVoaesucsuolnaira,wiinnetrearlsitziattiiaoln,, aild chranic, local areas, wderate BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonweerNearfroouwn,d tpolebse,witHehairnt,noSrtmoaalaclhi,miStesa:l] Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididpais, Prostate, Pituitary, Arenal, Thyroid, Parathyroid, Trachea, Esophagus, Lysgh ade esenteric), Pancreas, Salivary land, Eye. Ffaitnea:l (Nbueaebtesr:1061)8-T3e5r2aimal SSeaxc:riMfailcee Group: ( 1) CONTROL O pou Macroscopic Oiservations: Pituitary Kidney NicroEsrceapic Observations: Heart Kidney Liver Lung "Raised red ass, 0.4 a di. "Fluid filled cyst, 1 ca dia, in right kidney "Retinal atrophy, focal, aild "Myocardial fibrosis, focal, wild "Chronic progressive nephropathy, aoderate "PCoyrstta,lcsoorntoincuacll,eamrarckeeldl infiltrate, aild "PVoarstcaullarbilseinedrucatlizpartoiloinf,eraatiilodn, aild Preusnia, interstitial, chronic, multifocal, aHeisgorrhage, local ares, sild Perivascular sononuclear infiltrate, wild PSrpoejceiecst:MuRsatter: 0201080012 cS 01710 Susearized STAR Page: 35 : 226 SInudnirviidzueald RSaicnrgolsecoTsuibculntdedMMcirnoaceRiecpoOrther(vcaotinotnisn P3024: Too Youirtear LiTboanactiotieys-,GeTgcm,ici3t0y Stat in ats Tie: 2 oFaate]s eaeres106() ITSerinl SSecxriMfaclee Grup ( 1 CONTROL 0 pan HcrosPLolypasiict KBotuervetsieaotnasri(cc)antina): Siem "Hensornhag, ald Hewcideronis, wild The fotos tissos wre found to be within ermal init: HBorratian,, TSpeisntals/CEoirdd,idSnanie, NParrorsotwa,teS,tonKaichr,a,SealT]hyrIonitde,stiPnaer,thLyarragied,InTtersatciense,, EUrsionapruysB,laPdaesrc,res, Salivary Gln. FTuaea:leWeatker:106I)RTIerSinal SSceriifMiaclee Group (1) CONTROL 0 pn WRccrroosSccalapepiicc Baernations: Baarvtions: hBoert Liivdeorry wg prSolseteate "ale circular dpresaed are, 0.4 ca dia. l"yosccridmgirteinsi,a, cnenadiecqustoenuspepcutriaotnive, Dwoniitc ,progwrielsdsive sepheopatiy, ild FWoeratthaersteeonvcctlleawticoenl, "atcali sinealiation, isnlftiilftrcaatle,, wil4 aailld Pledusnis, intweatitial, drone, wltifacl, FPrrobsvtatsictasl,r ssoantnea,clseunpeorianftiilvterat1e,6wild HFeiwbsriodseisr,osltosc,alwialrdes, senate The folloiag tisses wre found Lo be sithin normal Liits: CBHroiaritgna,,TaSekpseitnsaalreEsCponirtgde,irdiBocsn,e,PNaPurirrtouewi,sta,rSyt,SosaalKciehv,anraySe,aElllaTnhdIy,nrteas,tinPea, rLaatrgheaI,nteTsrtaicnees,,UrEisnoabryigBsl,adder, Fiaae:d ONasbher:105I) SSiHrificedSeic KaaxlterenisGroup (1) CONTROL 0 pn [eThps -- Pacress "satturigsbege colores ass, 15x Sc fn irreosuonfdipngcrpheencoamdealdyeing to peter ress of righ nd 0k atwsd SPproejceicet:aRbaetr: BICOL2 601711 Susearized STIRPage:36 227 Susaarized Single Tabulated Misal Report (continued) Individual Macroscopic and Microscopic Observations Riker Liboratories, Inc. 31 FI-S324: Teo Year ral Toricity-Oncogencity Study in Rats Table: 2 Aoinal Nasber: 1-354 Sex: Male Group: ( 1) CONT0RpOpLa Fate: (beets 105) Sacrificed in extreais Macroscopic Observations (continued): Pancreas (continued) Kidney Testis/Epidideis Liver Nicroscopic Observations: renal Kidney LLinvger Lyssh Node (eseteric) Pancreas Parathyroid PiStuulitaIrnytestine Spleen Stonach Testis/Epididyais Thysas Thyroid Urinary Bladder, "liver lobes. "Pale wd pitted. "Right testis saall. "Padlieanweittehr yienllroiwgihsth acnitrecruiloarr lolbeesion 0.3 ca "Cortical vacuolation, diffuse, soterate Msoeddeurlaltaery cell hyperplasia, local areas, "Chronic progressive nephropathy, soderate Halignant Iysphosa, histiocytic "HHeepsaotrorhcaygtee, vdaicfufoulsaet,ionm,rkdeidffuse, marked Walignant Tysphons, histiocytic "Hesorrhage, aild Walignant Iysphons, histiocytic "Halignant Lyshous, histiocytic "-Hbodteneoxnaamined, sissing "Haliguat Iysphons, histiocytic ~Malignunt Lysphons, histiocytic "Halignint Iysphons, histiocytic <Tubale atrophy, aspermatogenesis, unilateral, rked "MNaallitginpalnet sIeycstpihoomnss,ofhitsutsioorcytfirocn thysic and sediastinal areas. MNaoltigencaanntineIdy,sphaoinsss,inhgistiertic BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueBsanweerMearfroouwn,d Hteoarbte, wTirtahcihnean,ormEaslophlaigmuist,s:Salivary Gland, Eye, Large Intestine, harta, Prostate. Species: hat Project Musber: 0281CRN1Z 01712 Suaarited STAR Page: 37 228 SInudminvriidzueald aScirngolsecoTpaibculaantdedMiMcnrionsalcopRiecpohrtsar(vcoanttiionnused) PI-INN: Too YeaFrieOrralLaTboorxaitcoirtiye-sD,coIgnecn.ici3t0y Study i Rats Table: 2 Ffaotie:l WNeaesksh:1081)35Te3r6aiml SSaecxriMfailcee opt (1) CONTR 0 po NacrSostconpic Dserations: Wicroasrceapniac Observation: iLudrogeey Intestine Liver Lung stn "RaaibssecdessL.esion, 1.5 co din, pears tobe "tSoinruiscoaildalacescotlsatiiao,n,cofrotcra,l,fowcialld, soterate "ACeantroadniaprsosg,rescsoilvoen nephropathy, sinisal "aritdal hile ct prliferation, sultifocal, PHoerptaatlocsytoenovnacclueoalraticeolnl, iwniftilitfractael, waiinlidaal "Phearsicvailsacrulaairnrsaolvizoautciloenr, siniflidltrate, aild KeRrasisteodcaLnestiioonnfron back. BTrheinf,olSlopwiinnag Ctoirsds,uesBowneerearrfoounn,d Stpolebeen,wihthairnt,noSrtmoamlacshi,tSse:al Intestine, hort, TLeoshti/NEapeidi(edspeisst,erPirco)s,tatPea,ncrPeiatsu,itaSrayl,ivaTrhyyroGilda,n,PaErraet,hyrUoriidn,aryTrBaclhaedse,r.Esophagus, nFiatnea:] GMeoeskhesr: 733)5F5ou7nd DadSex: Male Groups 1) CONTROL 0 pp Naroscapic Oiserations: LiLvyewrh bode (abdoninal) ibdonen (interaal) WicrPoisctoupiitcarsyervations: hEeeart Liver ng LPyaonschreadse (aesteric) Parathyroid h"heeyalpayluep nodes enlarged. Halatttialcohbeudlatro,ofwlnetsahny,sa1sesf,t 4inxgu3i.n5alx 3.5 "Haerseoar,thagc ass, 0.7 co dia. h"aHltigeuxaannitneIdy,shsoinsss,inghistineytic "Nhaelpitgouciynttelvyascpshloast,iohni,stidoifcfyutsiec, marked HHaelsiogrurahungte,Iylsohcoanls,arheiss,tiwseopetriacte oott eeaxsaiinoendd,, ssiissssiinngg tot easioe, sissing Psrpoejceicetsahsahte: 02810K012 01713 sawing sg: 9 229 STtorua aSvigepe TLiaelsaatietodRnb,iaarlemRphtaGctnitinnn) 328 Toto ba Teer cect Say in Bate Tae 2 eFtr erns 7BFonw od le ows {1 Ln [TaIrerdiny------ TFaol.ia hon, bistiatic H[wooyero spe weerwon sliagits tn jSoiem seiints,waslidn rBheiinerSlSaiirCtorsyra,tsoeeweTrReasftoruongd K0btebyes,isShtnootaier,SmalHLientmeeatiT,reL,rgsnpeot,i,livery ln, aFe eoher0)1T5ent iSo eal es 1 6 6 [ tHiveenn-- S"Nailtienrueiciswea,} 0r2e dn WSeirrawen Bsns Ji trticl alation, fol, ald Kidney ~Chronic progressive nephropathy, sild oyLiver MSlMalciigrntranttswlyayarppoihorsntab,iohhnitas,tiiidoatcyiticc fLdtote steric ovelbavnrmoeatlssvstitnIopnleloaf steteinaid SoViteeew ate psEtaeniya,tpaeoet,ntsipiinntngs,drfest, ia he fotleneg tse wre fm tb iti sr Hints Tees ont, Tra, Toe Extn Far, liv Ss re Brain, Spinal Cord, Bone Marrow, Heart, Stosach, Seall Intestine, Large Intestine, Aorta, Hee Species:bRaaetr: on 601714 Sussarized STAR Page: 39 230 SInudsinvirdiuzale MSaicnrgolsecoTpaibcul4antdadHiicnraolsoRpecporOtbse(rcvoanttiionnasnd) Hiker Laboratories, Ic. 31 FN-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Tale: 2 eFaatel: ONasbter:1001)03T5o3r9aina SSearc: failcee Grog: 1) CONTROL pe Ncrosconic Bervations: Wicroisdcopiecy Oomrvaions: LiLvaregre Intestine Lng Fiftauritthiyroyid ThSrleeee visible Lesions. "ron progressive oghraath, aild "HoHerseatatatoladcirsaotsneiosnv,iacclcweolalarotnicoenll, imniftiilftorcaatle,, wailldd "Psocraalcnaira,siinnetaelrisntaittiioaln,, cshirlodnic, mitifoca, aPeirlivascalar asansclea infiltrate, ald "ostt,exaarinsedd,stsaeltisin plane of section i"thsicssbirdaenrocshsi,l aeirlsdt BTaheinf,olSlpoiwnianlg Ctoirsds,ueJsonweerMearfroouwn,d Hteoabre, wSittohniancho,raSelal]LiIminttse:stin, Urinary Bladder, dora, STaeltiivasr/yidSiadny,isE,re.Prostate, Hire, Tach, Esophagus, Lap Hoke (ester, Pancreas, Fiaatea:l eYkboer:60R)3F5ou0nd BeadSens ale Gro: | 1) CONTROL pe Hroscpic Bservaions: HicroosnceoicHasreornvations: Live Lag PSrpositnateCord tTrhyirnoeiyd Blaster o visible Lesions. o"otrtaelxansionaedn,cliesasrincgell infiltrate, wild "FsecraallaBilienetrualtizpartliiodn,ertailogn, mild oAltveoplaasrinwecdr,apahiagseisn,g 11d oittiaebxrasaicnhedi,alwisesrisntg Sot sxsine, wiseing BTahinf,alSpllieneng, tKiisdsaureys, eHreeartf,ouSndtotaochb,e Swmiatlhlintoersetse,linLia:re Intestine, hora, FTaectriess/sp,idSiacliyviasr,y GPliatnudi,tarEyv,e,Hreal, Parathyroid, Trachea, Esophagus, Lop bode (sesenteric), PSrpoejceicets:aRbaetr: GZBICROI2 C01715 sunriz spge 0 231 SIaniuvruiazld RSkrieogrekpTLiaocarntaddiRnir,asclnae:ioca9tB.arcvoatnitoinn PL To Yar rl Toniccgi Say ats bie 2 eFuae eae 10I ) TorS t rfcaee Gen 1) OO 6 [ Wersi-- onni B--urat--iont Huse sion on Let ree etd. wt iaey DtSormircialetieselmsii, satfoela,,piw,ladaires ir FPetraal sbilerdatt roclihfrrtiaon,ea,idid Lung VerJastecurlnaer,,siniienraesliiz,attieow,na,rtowsirledrc, wits, sinstte StPoetacmrauivrnati,tssosnctgwtoiveniilsritse, aawlded WTieniesyiHioanhis ot iaeise,, waig roThire neelSPiotasntrCsso,rad,osostw,erPoesrdoSttoebn,e,iTrhatons,u,Sraolihcihi,i,tS:uLligth NienweLgeett)ioac,res Sin Sia, Ee. iFine:lhasnes1085) 5T0rea SSrracle Ge {1 COUR 0p r[oTaensaO-- pwiaoriaises Sth teste sll iis ric wrogrssve shat, tate LiiPrvoegrrop s -- ew"SHeeprasathoacy,ntie,vasaicusiotliantcioe,nl,,sisulttariafnotceal, aild [eir--. tweiiereterristtis, warp, ald late, ye Ao wae, eng hreieinf,olGlMwidinniagr,CirsK,raabyiworPeBorsfooiunen,d, Stoelboen,witHheitn,srhwlkcih,itS:ul Itstio, Lire ntesine, Pitan, Wren Pros, Trios, Sivas Suds Er, [a Species: Rat Project Nusber: 0281CR0012 3 co1716 [e------ 232 RiTnToMoowtaTt toercncconontoBt Sussarized Single Tabulated Anisal Report (continued) a2 Po vaay en Se ag 1 oe rsGTlsinrato: reriac tie,t07 e rmeaiaBenrrie: a tal rt celtic, tts bttotse SaSSvooeemtepi soenss, scnoo,4pps,ttsei4t crn j-- AePrdaeettrata,roneewartaie of wc HSTioeetmneanis SbweeremaTnonn,,wpieratt, wi, Portes, ure TirheeeelSFoantSetsoeroer,earfroodnS0oo0ciilsSslLmsrtoi,teLyct,ioS, nbrinGyu,BOsh, eet eida, Easd vok nn 1 0 wr Macroscopic Observations: rLimveri Burton: beoFsw friaresd aoeanen, 25x t,o tot SSrlighiitly spatlteionn,,cemti, os,tebee STSi rornveiresatmipoivota,etna1oavewoan, 8i pirnievdy, sVpoi:tebt: any 601717 Sid 0 Ps 233 SIunadniavriiduzaeld SMiancgrloescoTpaibculaatneddiMcrionsacopRiepcorhtsa(rcvoanttiionunesd) FI-3P28 Too YeHrikeOrralLibToarvactiotriye-sG,oclongce.ici3t1y Study in Rats Tle: 2 SFoaitnea:l (Nhaebesr:1081)0-Fo3u5nd DeaSdex: Male Group? (1) CONTRDL 0 pp NicrSestconpic Observations (continued): Spleen "boifloadteerraalt,itairs,kedulcerative, hindleg, "Haelsdstopoiesis, extramedullary, increased, aThie ,folSloiwilng Gtoirsds,ueBsonseerMeafrooun,d Ltiovebre,wSittohaianchn,ormSaelllLiIsnittess:tine, Large Intestine, LUryiwnharoydBelad(deers,taAotreta),, TSeasltiivsa/rEypEfliadnrdi.s, Prostate, Thyroid, Parathyraid, Trache, Esophages, FfaotieesaltKhoessbeer:85R) SIacrificedSexi:n eWxaltereasGroups { 1) CONTROL 0 poe WacoPsictoupiitcarOyssrvations: FicrLoiscvoepric Observations: brreannal idney Liver LPintguitary touch aaslse, 0.4 0 dia, ""Sliinguosdoeinddarlogalciaosnisa,,becnoirgtne, moderate LaanrigfeornsesppollyahseadrcaolmpocseeldlsofinLacregree,braflaircloyrker, "FGyaerleonnephprriotgirse,siavceutme,phraiolpdathy, ainieal ortal sononuclear cel Hepatocyte vacuolation, ipnefriilptorrattael,, wsiolddeate -"bHtaesncounlaa aeralization, aild Erip-- TShpeinaflollCoowrid,ngBtoiessuKeasrrowwe,reSfpolueennd,toHebaertw,itShmialnlnuInrtmeastilnien,itsL:arge Intestine, Urinary Bladder, fLoyratgah, NTedsti(sa/eEpsiedtiecryincis), PParnocsrteaatse,, STahlyirvoairdy, EPlaarnda,thyErpoei.d, Trachea, Esophagus, foieal Naber: (R350 Sect Male Group: ( 1) CONTROL 0 pa Fate: her 108) Terainal Sacrifice Macroscopic Observations: NicraHsicropeisc) Observations: 40 visible Lesions. Cortical vacslation, witifoca, aild PSpreocjieecst: NRaabter: OZICRNIZ 6017" 18 Sunrized STI Page: 4 . 234 Sduisvairdiuaanld aSicnrgsleepTiaclaandtWcMriossacoRnecpohrtrn(ctointoinnuses) PIR: To YeHrikeGralUbToxaiteutiy-oGsc,opIecm.ici3ty Sty in Rats Tie: 2 aFaate]: eabseer:108U)RTIeSrai! SScerifMilcee Group: (1) CONTROL 0 pn Worosanpecy iarntion (eatin): Liver ung PLayathyrNoatied Gesteric) TPhitrueiitary "ric progressive prepay, itd Portal mononuclear cell infiltrate, sild Hepatocyte vacuolation, periportal, wild "slHeicpvaaetrorcytienevaacluionlattiioon, lisited wild to one area of APevrievriscsaalcroephasge,sainnofalltrate, wile JHaettorwrahnatge,d,1n6ot in plane of section TCyeset,l pearisrcdiinsotamlis. SUThrieienaf,rlylyoBalnaamdgderCt,oirsdKssossDtoanveerTNesatfrsoruTn,EdpdStoildebeeei,wsi,hthaPirnrto,nsotSramttaoelmcTLhri,atScee:usn EIsnotepsutisn,e, PLangcreeasn,testine, Siivry Sh, Ere. Fiitae:nGNessbkeer:861)0S3u5c0riicedSeI:n mMtlreeisGroups (1) COMROL 0 pn NcroTsictoupiictiByserations: HerLioviec Marnations: Heart Lineyr FiPtaruaitthyirysie SiTtweat eSlsiegrhthlaygpcalaee, 1.41 0.8 a. ~eHpsysoitctoarcidyiottei,s,iwcclehdrloaniiocnn,onsmuiptpiurdaetcilv,e,ald "asclar sinealintion, wi "oAaltvveooelnaarsseac,ropihsagiensg, sinisal JHoetwseidaesroesdi,iwsisldng iSTahneianfr,oylSlBpoanudadegrCt,oisrsHduierBst,nwrTeaersfrtooiuwsn,EtsiKtdiodinbdeerya,wsi,SthtPirnoosn,toartmeaS,lalML]rietImetl:a,sinTea,chLsi,reEsIpnhtegsetsi,ne, Linn ote lesteic], Pscrss, Salivary lad, Ep. SPpreocjieecst: NRaabter: CAICRIOL2 01719 Sonrized TAL Pag: 44 235 Sduiavnirdiuzaeld MiancgrlosecoTpaibcalaantdedMiMcironsacopRiecpoDrtbwr(vcoanttiionnused) F392: Tuo YeRrikeDrraLiTboorsaitcoirtiye-sO,coIgce,nici3t1y Study in Rats Tile: 2 fFiotie:s eossbteert106S) TZersimal SSeuxe:ifMiaclee Geo: (1) CONTROL 0 pa WacroSspcloepeinc Dournations: NicroHsacorpeimc Observations: Liivtery Lng PPaanrcartahysrsid FPriotsitiattaery Slee "Circular raise lesion, 1.2 ca di. "CToerdtuilclalryvaceclsllahtyipoenr,plamsiitai,folcoacla,l aairleds, Cshordoenriacteprogressive siphropathy, sodrate JPoorrttaall sbialoeomdccltearprocleilferiantfiiolnt,ratael,dwild "Ffaaesscslnaira,aiinnetaelrisztaittiioaln,, achirlodnic, miltidocal, "wiiclidne atrahy, aild l"aHitercoannine, not in plane of section "Hrersowsgaitiotsiisr,cownate, saparative, wild TBhreainf,ollSopviinnagl otirsds,uesBowneereMafroruonnd, tHoeabrte,wiStthoinnchn,ormSaelll.TiInnttse:stine, Large Intestine, rSailniavayryBlGaldandde,r,Eroer,t,TestisEpdidyais, Thraid, Traches, Esophagus, Lyph de (eseneric), JFaotiee hNeasbser:8)SFSoun DeadSex: Male Grow: (1) CONTRL 0 pa WacroHsacsrpeinc Observations: Wicrorsceonpacl Observation: htaert Ltgoey Intestine Liver LLranogph Node (aesenteric) "Left enlarged by 3 1 co din, was. "PShiemsscohirdoanlccyetcotmassi,a,becnogre,s,wnwiilladteral Moytocasrdairtiisn,,chsriosnsiicngnovupprative, rwoitvifeocaplr,ogrseislsdive aeprapathy, aile Footrtaxlansionnedo,ncpliesasicnegll infiltrate, wild HFeopcaatlocybtielevdaccotlaptrioolni,fersauttiiofn,acsao,deiraltee "NWeacsrcolsairs,swilnteailfiozcaatli,ons,ieaild ot exanind, ainsing SPpreocjieecst: NRuastber: CBICR00L2 CO01720 Suanriaed STH Page: 43 236 SInudmimvairdiuzaeld MSaicnrgolsecoTpeibculaantdedMiMcarionsacopRiepcorDt.ber(cvoanttiionnused) Kite Lbaeatories, Toc, 30 FH-3924: Two Year Oral Toricity-Oncogenicity Study in Rats Tbe: 2 MFaotie:n Gaeaebkesrs8D)ISFoSuEnd DadSex: Male Grow: (1) CONTROL 0 pn Wicroscspc Dbservations (cantinued): FPiatcirteasrsy SSuallilvaIrnyteSshtainnde "oCtyt,espianrsedi,stsailsissing oott exuanniinneed,, ssiisssuiinngg Th following tissues wre found to be within sarml Linits: rain, Spiml Gord, bre Narrow, Spleen, Stomach, Urinary Bladder, horta, TestsEpididyis, Prostate, Thyroid, Parathyroid, Trachea, Esophagus. Ffiitnea:l (Reasbtesr:108I) RTeSrminal SSaecx:rifWiaclee Groups ( 1) CONTROL 0 pa Nacroscapic Doservations: HicrFoisdcnaepyc Observations: Liver Lng PrPoursattahtyersis to visible Lesions. ""FCoarrtnailespornaogurcelseswirvecselelhroinpfaitlhtyr,atem,odearialte HPeoprattaocbyitleeadlutcetratpiroonl,ifevriaotiloan,tew,ildaild "APlevreiovlaasrcalsaarcrosgohnaogemsc,lelutiifnfoicltarlateo,demroadteerate VParsecsuslnaira,sivienrtaelrisztaittiioanl,, aild can, mltifocal, "dsot.eresxtaesine, not. in plane of section Prostatitis, cate, suppurative sodeate BThreif,olSlpoiwnianlg Ciosrsdu,esBonveerMearfroounn,d Stpolebeen,wibthairnt,noSrtoamacnhi,tSse:al) Intestine, urge Itestine, : LUyraipnharNyodBelad(daeers,nthuerrtisc,, TPsatnicsr/eaEsp,idSiadlyiavsa,ryPlitaunidt,aryE,ye.Arenal, Tora, Traches, Esophagus, rFiitnea:] tNeosstse:10120-S35u5r5ificedSeci:s MeaxlterenisGroup: 1) CONTR0pOaL Nacrosicdsopeiyc Observation: inary aber Nicroxraepailc Observations: "ohlaulre,geedn,lafrlgueisd wfiilldleh,drwcanlelpiaoppseiasr,s heorrhagic. Cortical vacwolation, local areas, soderate SPpreocjieecst: afsahte: O21CKOOL2 001721 Sanrized STR Pig: 46 237 Sussarized Single Tablated Misal Report (continued) Intividual BaRcirkoesrcoLpaibcorantdoriMeisc,rosIcnocp,ic3O1bservations . F024 Too Year Oral Tonicity-Oncogenicity Stady in Rats Ta: 2 Ffaitnea:l tMhasebsers1021)0-3S5a5c5rificeSdexitn MeaxlterasGroup 1) CONTROL 0 pp Hicrotsocrotpisc Observations (continued): Heart titoey Liver TM PrFaorsattahtyerold sual Intestine StSolneamnch Urinary Bladder ""MHyiurcearratliitziast,ionc,hrosniilcd novuppurative, "wbiethirfoosciasl,,taabiullar, soderate PHaypiirlolnaersyhrmoescirso,shssi,lsoderate Twuibtuhleelsiudni,latsecdatwtietrhedloiwn,eablasiszpehdilitcubales. "HPeopratatlocybtielevadcucotlaptrioolni,fersauttiiofna,caali,ldaild "Ahiavsecsallaarr msaicnreorpahlaigzeast,ionw,ildaild "lHaetsarerxhaaignee,d,foncoatl,inaiplldane of section PErdoesntsa,tiitnitse,rsiwtaittei,al,swspnutreartaitvee, alg ~Fietvheirnthnaonrsaplrotloicnoiltsmsber dHeesnoss,idesrbomsciso,saali,ldsoderate "EHpeiatohrerlhiaagle,hywprekrepldasia, sisple, diffuse, ald Crstitis, acute, moderate rThaeinf,olSlpoivnianlg Gtoirsds,ueBsonweeraerrfoouwn,d Ltaorgbee Iwnittehsitninreo,rsaTlestliisn/iEtpsi:didyais, Pituitary, Thad, Traches, Esophagus, Lyaph Ne (nesenteric), Pancreas, Salivary Glan, Eye. Ffaotien:alhKeobser:1081)0-T3e5r5ainal SSeacc:rifMiaclee Group: (1) CONTR 0 pa MacroHsacorpeicl Oiservations: Nierahsacroepniacl servations: Liindenrey "Right enlarged by ease, 2x 1 ch. "CaLrarcgienonne,oplcaosret,icaalo,stwlyilaaetcerraatlic. Cells fschaeneyt,s.polHyihgehdraailtotaircranagcetdiviitny,cordMsitainpdle "CTounngicsetparsotgarseesss.ive nephropathy, ald "PPoorrttaall sbniloensdculcetarprcoellilferiantfiiolnt,ratsei,ldaild Psrpoejceicets:huhastbr: OIRO toa Summrized STAR Page: 41 238 Sussarized Single Tabulated Mnisal Report (continued) Individual Nacroscopic and Microscopic Observations Riker Laboratories, Inc. 3% FI-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 foinal Koaber: IR-355 Sex: Male Group ( 1) CONTROL pa Fate: (leeks 106) Terainal Sacrifice Microscopic Observations (continued): [e Parathyroid ~Preuacnia, interstitial, chronic, mltifocal, aild MPeetraisvtaastciuclanreospolnaosnauclear infiltrate, aild Vascular aineralization, aild "Hot exanined, not in plane of section The folloving tissues were found to be within normal lists: UBrriainna,rySBpliandadlerC,ordA,ortBao,neTeMsatrirosw/,EpiSdpildeyevni,s,HeParrots,taStteo,saPchi,tuiStuaarlyl, ITnhtyersotiidn,e,TrLaacrhgees,InEtseospthiangeu,s, Lywh Node {aesenteric], Pancreas, Salivary Gland, Eye. fninal Nosber: (R-SS7 Sex: Male Groupi ( 1) CONTROL 0 pou Fate: (leeks 108) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Liver Lang Thyroid Xo visible Lesions. ~Cheonic progressive nephropathy, sild "Fortal soncauclear cell dnfiltrate, wild vHaespcautloacryteaianletrearlaitziaotni,on,vacsuiolldated, ald Poesaonia, interstitial, chronic, miltifocal, ald "Hyperplasia, cell, wild The folloning Brain, Spinal tissues were found Cord, Bone Narrow, to be within normal lisits: Spleen, Heart, Stouach, Seall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, hdresal, Parathyroid, Trachea, Esophagus, Lyaph Node (sesenteric), Pancreas, Salivary Gland, Eye. fninal Mosher: 1R-3558 Sex: Male Group: ( 1) CONTROL 0 pps Fate: Glest= 104) Terainal Sacrifice Macroscopic Observations: MicrPoistcuopiitcarOybservations: KiArdenneayl Liver "Raised mass, 0.9 co dia. "Sinusoidal ectasia, cortes, ald "Conic progressive nephropathy, ald Calculus, pelvic, siniml ~Cystoid degeneration, focal, winimal Species: hat Project husber: G281CRN12 00172233 Sonne STH Pag: 80 239 SIanriud MSiteee TCcairttvaeironmleAsrBtas(acitovn) 2: Tt rl Toco Spicy tty fn ts aie 2 e Fate tohe 14) ern SSoui {10 COL [ Hibtr-- et -- tftianie, i ln of scion Diem Tots, ae WiheeelyoSBnaekoitnrstheewrTeRafotootntrtostb,e,wiith,iFnrSostsatlc,h,TLSotil:, tTsani,, SLpiraeiIn ti ee ate, ron Sty Bt re iPe tae 8 StdSoin a rnse {11 COL 8 ropscinic Burtos fail,crIaovceerrkpwsr, eGres - tCononraelidahtsanndnmtte11gl2 cm1h tLeofrro t ayeoeee ial) spriitty nertosrtusetsre, [oivne -- Th vrs wae, ses, it ewan, mitt, se ILiver SMPTalrooiuugntrtaiannntg,plhystiupyhrou,soad,,gsihirsitieoscyttic iJet-- n A rFoirgtwh,erapliaTceaatsmr Shem B--ieler -- Sheitesnleosininse,rpsorsownrte,onFtduerebns,iWtSnhoet,wsrTLoreiosttssiony,ar,ocraMna,teE, abt,s ton Sy ty Ee Scien at Project Nasber: 0281CRO012 s [------ 602732 240 Suaarized Single Tabulated Mnisal Report (continued) Individual Macroscopic and icroscopic Observations Riker Liboratories, Inc. 3 FESTA: Too Year ral Toricity-Gncogenicity Study in Rats Tale: 2 fFiatnea:l (MVaesebkesr:106()R3Te6r1aimal Sex: Male Sacrifice Grows ( 1) CONTROL 0 pp. Macroscopic Observations: Soft Tissues (leg) MicrosKciodpniecy Observations: Mreal hone KRiodnneeyNarrow LLiavregre Intestine Lung Parathyroid Pituitary Spinal Cord Spleen Testis/Epididyais Thyroid "Risgwhotlleann.d Teft Nindpan and right forepan "Right Edney polycystic. "Cortical vacaslation, sltifocal, aild Medullary cell hyperplasia, witifocal, aild "Afrotrherlietgi,s,arstyensovitis} joints, hindles, ""CNhortoneixcanpinreodg,resssiisvteinngephropathy, ld TPyesltv,iccosritniecraall,izuantiiloant,eraaill,d marked "~pNoerataatlofsioansoinsa,clceoalroncell infiltrate, ald Portal bile duct proliferation, ld "perivascular sonanuclear infiltrate, aild VPraesvcsuolnaira,ainienrtaerlsitziattiiaoln,, cahirlodnic, multifocal, Haelsdorrhage, local areas, soderate "Hot exasined, wissing -bdenons Hot exanined, sissing ""HTeuabousliedeartorsoipsh,y,aialsdpernatogenesis, soderate Polyarteritis, naked "Hot exanined, nissing The folloeing Brain, Heart, tissues were found to be within normal lisits: Stomach, Seall Intestine, Urinary Bladder, Marta, Prostate, Traches, Esophagas, Lyeoh Node (nesenteric), Pancreas, Salivary Gland, Ee. final Mader: (R352 Sea: Male Grow: ( 1) CONTROL 0 pou Fate: Obesk= 108) Terainal Sacrifice MacrosSckoipnic Observations: Spleen MicrMosrcoepilc Observations: "Raised ulcerated inflassed lesion, right rear footpad. "Several pale foci. "Nodular hyperplasia, cortex, wilateral, wierate Species: Rat Project Maker: 21080012 CO1725 Sumarized STAR Page: 50 241 Fra : Ts oHreeteoneot neSreiectiSaoy nhs `Sussarized Single Tabulated Anisal Report (continued) aie 2 oFe nnasoSnan eas 1Go ncn Bnet cuit wi inlsat-- e spt, 414 wHonre ete r TPeosde masertn,woairsie,,ad rHe s Jy a estat ra e i SAi i, itgin, ini, urn a enaststeSveo--Sno--omSes--,tyihe,KkrninmBrat,e,ohtts, E A enT tn rsaa"t Burton Tstt wit 1e1d031 Ia-- i onrit,tevmoiena,iwsisaen,t ht bSrnone nbie deao ie Harsneapoie sont, ste Liver noi it obs ae Hepatocyte alteration, basophilic, soderate f-- a emaett. wo,anewtaitee, i Hepatocyte alteration, vacuolated, soderate Freeen lhotst, te, sap, bre nts Species: Rat cnn 601726 Snot $8 pe 5 202 P`ISKnuissardTiuzaoeldYotSuiNronogrlnrealiTLaicTbauolraautietrdcciAcrneineia0lt,cReepoMrtasS(mcaaonyttiiniouoneda)ts Toe 2 Foite tarkt10(8 T5era5oSSciaFlcee emg 1) CORO pn WcroSTsopnrisc Burtion (nti: T[alocrn STohrieeaf,olGTloweritnhgsbotlniespsrudesera,eSPf0a0ur,s0eSt,bwechaT,htcShhusl,o,rEnxathasLeiisnt,,esLLahrgeonieeetsinerUircr,y ld, Sliven Be. Feivl:a trhste 10B 9 TorsS o Srifaclee at 1 GOEL an [ [Kii--tes p--a---- Pale srs in carte of one ihr, ro "wltiilcraerl cclll ape,stmeit,ifesctl,iwlld, oret ron Sr wotiefia ene,s,lidsissing---- ity Dic roses Myocardial fibrosis, hmaaltaiftochal,, wtiladte jr rCyrTtsitedp,euoncfiihlalaantlgeedircailtln,isplsroaidoevrsnateaeesni,pn rcaaertdsesensith ung ASFenreaalplstmseowmwaatlhaesnitoicnoa,nl,wl1il6itifeoa,baete PPutrrieetsiys JJaamovmnaiinode,s asoti1aae of section . GTSielntoivrEyrisdSitaonndis oaNateavwhaasiisninso,,n,saifssaonnsg, ate hTrerianfie,lSltiTenrnga,cihS,stommvascph,wsrSe,ulf]oinadhttioloobndee,wiatLhusirnetsnerelsrtiiEnie,.tr:inry dhe, rt, ratte, [rerlm Ne: OREN 001727 B Sussarized STAR Page: 52 243 Srortia eSicgetarsloaerraeleReMp ecamvn) Pt eo Yb rl Teter cic Sf n Rts oie 2 i ns pTeoa ae ot 1 0 on rnc Orton: jel prhg a, 77 ca srt rn Jo--CiA-- S foE dirn [ooeren Mtpeoineet,esevtireasici,on Will Hins metne i arone ovritbgsaitpiefn, aid wynawe ttre a a teesoyo eToriaete TToook wiiunnttts sisongi bS+ite sat Loraereonnt as ws coment of hr, ull tno Aresn re pi oe of She a tale, neat, JTVio,ew ater otttiieldvnittny,t sssiiimgi OBy n ee ten rs-- hws t-- ists Fit ars B To e She oy 1 Le J JSLty-- Sal dk ion. i tphopin sr its Kidney ~Chronic progressive nephropathy, wild -- Foro 6y01728 . Susaarized STAR Page: 53 aa SInudsiavriidzuaeld MSaicnrgolsecoTpaibculaantdedMiMcnrioosaclopRiecporster(vcaotnitioonused) F-39242 Too YeRairkeOrraLlabToorraitcoirtiye-sG,ncfoogc,enci31ty Stody in Rats Table: 2 fFaaitsea:l UMeoenbke=r:106()R-ITSe6r6nial SSeaxc:riMfailcee Group: ( 1) CONTROL 0 ppm WicrLaiscvoepric Observations (continued): Lung PPaanrcartehyarsoid Spleen "fPoorrttaall nbiolneucdlucatarprcoellilferiantfiiolnt,rataei,ldsild aPserailviasrcalsairnesroanloimziactlieoanr, sinifliltrate, wild ""fPaotlyuexratmeirnietdi,s,nostodienraptelan of section ~Hewosiderosis, ald The following Brain, Spiml tCoirsds,uesBoenereNafroruonwd, tLoarbgee wIinttheisntinneo,rmaUlrinlaisriytsM:adder, Aorta, TestisEpididvais, PSruoaslltatIen,tePsittiunei,tarHye,artT,hyrEoried,, ETsroapchhaegsu,s.Lysph Made (sesenteric), Salivary Shand, Stomach, MFatie:lHKeosskheer:106()RTIeSrEsinal SSaecx:rifMiaclee Group: 1) CONTROL 0 ppm Racroscopic Observations: Skin NicrSopslcoepeinc Observations: hirenal LYiivdenrey Lang Skin Solemn "Raiinsfeldaspneadpillelsoinon,typreighmtassreoan bfaocoktipadr.aised "Tuo pale foci. "CNoordtuilcaarl hvyapecrspllaatsiioan,, Cmourlttesi,focfaolc,al,siladild ""CFhorrotnalic spornoognruecslseiavre cneelplhrionpfaitlhtyr,atea,odearialtde "VAalsvceuollaarr saicnreorpahlaigzeast,ions,nilmadl "PPearpiivlalsoncau,larbacskononcler infiltrate, sinisal Fododeraatitis, ulcerative, hindles, aurked "Necrosis, local areas, sderate Trhaeinf,ollSopwiinnagl tCiosrsd,uesBowneereNafroruonwd, tHoeabrte,wiStthoisnachn,ormSaelallLimIinttse:stine, Large Intestine, UErsionpahraygusB,ladLdyers, Ahooreta,(sTeessetnitse/rEicp)i,didPyaanicsr,easP,rosStaaltiev,arPyitGuliatnadr,y,EreT.hyroid, Parathyroid, Trachea, PSrpoejceiecst:NaRabter: O2BICRAIZ 01729 Sussarized STAR Page: SF 245 Said Sle td in bet Gi PEA ToSoalhToeSinic St nt Individual Macroscopic and Microscopic Observations oe2 Bii ea Sevet TG Sm rriitposiw BBuervii:n Bites wat ie, it art tin, Gl, in on beSotatiniiaeonttcpar,inimeahlittn, sit itoews HaeVataa mit, seaini Petet,siheitt, si Hepatocyte vacuolation, multifocal, sild eas Pituitary bE Hyperplasia, focal, pars distalis, sild BoIeeleh itnei,i arerefsnd tSh baieesitSssor ,rydSulLitE ti:on,y Le tio Ro WnnSSebe 1 $7 iKRocernyterBurnie TTiiee, oite,abeSaw ebrnsttos oSp tiitiegtwts,efls,saeiso t.r SKTroit lvteeter w,atpwe t,,iiaeroaeld im Taonte TH Feiarttser ansire,o bode, He ok toe of sti siinabe: enon 0017350 Si i 5 246 : Summarized Single Tabulated inal Report (continued) Individual Macroscopic and Microscopic Observations FN3924: Too YeaRrikeOrralLaTbooxriactoirtiye-sD,acoIgnecn.ici3t1y Study in Rats Table: 2 foinal Nusber: 16-3571 Sex: Male Group? (1) CONTROL 0 pp Fate: Wests 106) Terainal Sacrifice Microscopic Observations (continued): SpSleeaeln Intestine, Testis/Epicidyais "Palyarteritis, sesentery, arked "Hewosiderasis, aild ~Polyarteritis, wirked BTrhaeinf,alSlpoivnianlg Ctoirsds,ueBsonveerNearfroouwn,d to be within normal linits: Stosach, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lysph Node (aeseateric), Salivary Gland, Ere. final Noster: (R-3572 Sex: Male Group ( 1) CONTROL 0 pps Fate: (Meeks 108) Terainal Sacrifice Macroscopic Observations: WicKroisdcnopeiyc Observations: Liver Lung Pancreas Parathyroid Stonach "Ho visible lesions. "Chronic progressive nephropathy, sinisal "Portal sononuclear cell infiltrate, ald Portal bile duct proliferation, sil "VHaespcautloacrytseinvearcauloilzaattioino,n, mawlitlidfocal, sild "Hyperplasia, islet cell, moderate "Hot exasined, not in plane of section Hot exasined, issing The falloving tissues vere found to be within noreal Linits: UBrraiinna,rySpBilnaadlderC,ordo,raBo,ne TNeasrtriosw/,EpiSpdliedeyna,is,HeaPrrto,staStuea,ll PiItnutiesttairnye,, ALdarregmel,IntTehsytrionied,, Trachea, Esophagus, Lyaph Node (aesesteric), Salivary land, Eye. Minal Noster: IR-IST3 Sex: Male Group: { 1) CONTROL 0 pa Fate: Geet 106) Terainal Sacrifice Macroscopic Observations: NicProasnccopriecasObservations: renal Kidney Large Intestine Liver "Saal circular pale sass, 0.5 co dia. "CPohretoiccharlossvcayctuooslsa,tiobne,nigwnl,tiufnoiclaalt,erawlild "Chronic progressive nephropathy, ald Hesatofiasis, colon Hepatocyte alteration, vacuolated, sild PHoerptaatlocbyitlee adlutcetratpiroonl,ifebraastoipohni,lica,ilaild PHoerptaatlocsyotneonvuacclueoalraticoenl,l imnaflitlitfroactael,, sild aild SPpreocjieecst: hhuastber: C281CROI2 01731 Susnarized STAR Page: 56. . 247 Suarized Single Tabulated faimal Report (continued) Individual Macroscopic and icroscopic Observations Riker Laboratories, Inc. 3 FI-3924: Teo Year Oral Tovicity-Gncogenicity Study in Rats. Table: 2 fFaitnea:l OMheaebtese:108()R-TIeSr7sSinal Sent Male Sacrifice Group: (1) CONTROL pp. Microscopic Observations (continued): Lung Pancreas Parathyroid "vPaesrciuvlaasrcuslianrersaolnioznautciloena,r ainlfdiltrate, ail "Aimar atrophy, soderate "KIosltetexacnelilneda,densoomtain plane of section TBhreainf,ollSopwiinnagl iCosrsdu,esBovneereMafrroouen,d tSoplbeeen,witHheairnt,norSmtaolaaclhi,mitSsm:all Intestine, Urinary Bladder, forta, Testis/Epididyeis, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lyooh Node (sesentericl, Salivary Gland, Eye. Anaad Noster: (R-S74 Sext Male Group: ( 1) CONTROL O gpa Fate: Geeks 99) Sacrificed i extresis, NacSroksiconpic Oservations: Thorax (internal) Heart Liver KiTdensteiys/yididyais Microscopic Observations: hirenal Horta Heart Kidoey Liver Lung PLaynscgrheaNsode (sesenteric) Parathyroid "Ulcerated right and left hind footpads; circular shite subcutaneous wass, 1.5 ca dia, in right inguinal area. Filled ith Fluid. "Slightly pale and flaccid. "Slightly "Pale and pale pitted; 1.5 ca cyst in right bidoey, "Testes suall "Cortical vacuolation, mitifocal, wild "NUencirofsoirsa, inltoicsaall arneeacsr,osissodeirtahtereactive cellular infiltrate. "Myocarditis, chronic nousuppurative, witifocal, ald ~Civonic progressive nephropathy, marked "OPosrtt,alunsiolnaotneurcalle,arwacrekleldinfiltrate, aild "PPorretwaslonibai,leidnutcetrsptriotliiafle,racthiroonn,ic,ilddiffuse, wterate Perivascular sononuclear infiltrate, ail Edens, local areas, marked "Nhoctinaerxasaitnreodp,hy,aiisslieng "Not exanined, not in plane of section PSrpoejceicets:MuRsabter: 028100012 01732 Susmarized STAR Page: 57 248 Susnarized Single Tabulated Mninal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc, 3% PN-324: Too Year Oral Toxicity-tncopenicity Study in Rats Taste: 2 Raina] Fate: Nusber: Geet (R374 Sex: 99) Sacrificed in Male Group: estresis Nicroscopic Observations (continued): PPriotsutiattaery Salivary Bland skin TestisEpididyais (1) CONTROL 0 pps ""PCryosts,tatpiatriss,inatceurtaee,disauppurative, soderate ~"FHoitbreoxma,sinseudb,cutsainsesoiunsg, inguinal Potoderaatitis, ulcerative, hindleg, irked "Tubule atrophy, asperaatagenesis, bilateral, woderate The following Brain, Spinal tissues were found Cord, Bone Narrow, Stpolebeen,wiStthoisnacnho,rmaSlealllisItnst:estine, Large Intestine, Urinary Bladder, Thyroid, Trachea, Esophagus, Eve. Aisal Rusher: IR-3576 Sex: Male Group: ( 1) CONTROL 0 pps Fate: Geeks 55) Sacrificed in estresis Macroscopic Observations: Skin Aodonen internal) Nicroscopic Observations: Kidney Lng Parathyroid Spleen Urinary Bladder "Hoist area around genital papilla. "Ltarrgaectasnoounftooodf gus in gastrointestinal in stomach. "pHeelsvoircrhaagien,eradliitzfautsieo,n,mawrikledd "Not exasined, not in plane of section ~Hesasiderasis, aild Not exavined, issing The folloving Brain, Spinal tissues were found Cord, Bone Narrow, to be within norsal lisits: Liver, Heart, Stosach, Seal] Intestine, Large Intestine, forts, TLeyssthis/NoEdpeidi(dsyensiesn,terPirco)s,tatPea,ncrPeiatsu,itaSrayl,ivaArdyrenBlaaln,d,ThEyyreo.id, Traches, Esophagus, fainal Nusber: (R-35T7 Sex: Male Group ( 1) CONTROL 0 pp Fate: Oheet= 106) Terainal Sacrifice Macroscopic Observations: Nicroscopic Observations: Kidney Liver "Ho visible Lesions. "Chronic progressive nephropathy, soderate "PPoorrttaall bsiolneonducclteaprroclelilferiantfiiolnt,rataei,ldaild Hepatocyte vacuolation, multifocal, wild Cystoid degeneration, multifocal, ail Hepatocyte alteration, vacuolated, ald PSrpoejceicets:Muhsabter: 02BICR1Z 011;733 Susearized STAR Page: $1 249 SInutminvriidzuanld MSaicnrgolsecoTpaibcalaantdedKiMcrrionsalcapRiecpoOrbtse(rcvoanttiionnused) 3724: Too YeHrikOerralLiTbonriactiotryi-eOs,cogIencn,ici3t0y Study in Rats Tale: 2 Ffaotae:l (Meatthser:1081)35Te7r7aimal SSaecxriafilcee aug: { 1) CONTR 0 pe NicroLwuanpgic Observations cantinud): NPesuerteersy sSullel Intestine Thyroid a"vlaysrctulearritsiisne,raslrikzeadtio, aild "Faollyyrutretreiittiiss,, easretnetsery, sierate "eospnti,decraalsliesd,, aaiilld BTrheinf,olSlopwiinnag Ctoirsds,uefsownreMarfroounn,d Hteoarbte, wSittohmianchs,arLmilreLiIsnttse:stine, Urinary Bladder, Aorta, LTreaspthisNEopdiedi(dapeissn,terPirco)s,tatSea,livPairtyuitBalranyd,,MErreem.al, Paratyrad, Trache, Esophagus, Ffaotiee:al eRkabeer:108I) RTeSrninal SSaecc:rifWiaclee Groups { 1) CONTROL 0 pp NacrPoistaupiitcarOybservations: Sin Hicroiscdapeic Observations: ler lng PPriotsutiattaery Salivary Shand sin H"ehwaoirrnhauglicceruatsesd, i0n.f7lacmaeddial.esion, 15 ca din, 104 hind foots. "CWhyrtornoiochprroosgirse,ssiuvneilanteeprharlo,patshoyd,eraaitled Calculi present in ureter of hydronephrotic. "fokritdaoleya.nsnscloar cell infiltrate, aild sPaorltaal rbilseivedruacltizpartoiloinf,erawtiilodn, ald "Veesoonrrshage, Local ares, awderate ""Sraolsaadteniittsi,s,wcahtrso,ics,wpwuirnaintailv, solerate "oVdeordyerviunaiintails,Lesuilocne,ratoinvley,onheinddlucetg,afsfaerckteedd. BTrhaeinf,ollSoprinianlg tCiosrsd,uesBownerearfroouwn, Stoplbeeen,witHhairnt,seSetmo!macLhi,nitSs:ua teste, Large Intestine, inary Bladder, rts, Testis/Epididyets, Mroal, Thyroid, Parathyroid, Traces, Esophages, Lyah Node (sesnteric), Pancreas, Ere. Species: Rat Project Nusber: Z8ICRO12 01734 Sunirized sR Page: 597 250 pr i hi origni Susaarized Single Tabulated Aninal Report (continued) FN-3924: Tua Year Oral Toxicity-Oncogenicity Study in Rats ner ver 7 on Kidney Liver i" fwbwi Chronic progressive nephropathy, marked Portal bile duct proliferation, wild a ennomie i Hepatocellular carcinosa Ee arma he --piaher Sie lw i e its s,ain, car,iie ie Species: Rat cnn c5o173s Swi Cas SInudaisvriidzuaeld MSaicnrgolsecoTpaibcalantdedWMincirooaslapRiecpoDrtbur(cvoanttiionnuses) FINA: Tao YeaHrieGralLbToornaitcoirtiye-sD,coTpoecn,ici$t0y Study in Rats Tale: 2 FIantien}l eNsasteer:29I)0ASSaTcSrificeSdexi:n FeexmtarleenisSeog: 1) CONTRL 0 pp WicroLsicveepc Oservations (continued): Lug FaLirghesNae Casas) SSapliivnarCyorSdlang stloencmh Wrinary Hatter ""aHlailgirgaunntt IIyygmhhoonwss,, IIyypghhaoccyyttiicc "Hmeasloirgrnhaangte,Iymslhtoinfsu,caIly,shiolcdytic a"lloitgreaanstinIey,shiossssi,ngLysghacytic "aHlailgirgannstt IIyyhhoonwss,, IIyypghhaoccyrttiicc "Epietrhelial hyperplasia, sisple, diffuse, wild TIhrnf,olHleoarritg, tSiwslsluesInetrsteiofeo,unLatrogebeInwtietshtiinne,saframrlt,LiUntitesr:us, Ory, Naary Shad, Pitsitary, Tracks, Thyroid, Parathyroid, Excphagus, Ere. fFaotae:l (Measbtse: 9A)SFTou)nd DaSde Fesale Groups (1) CONT0RpOpL RacrPoixtauiptcarOybservations: Nowary Eland NicroKsciarpeimcl Observations: idhey Liver NLanywryNotGlean(daesentaric) Pituitary thSpelresm "uhletsirlrohhaugliacrmssass,s,0.48.5c1a d3i.a5. 1 2 en, in right alla, ""Sriemlsiscidaailnetraalisza,tioc,oratiel, senate "Vfeoprhtraolsiasg,netnucblleanrr,cweallrkeidnfiltrate, aild PHoerptaatlocbyitleevdaccwtolpartoiloinf,erlattiiofno,caall,daild oLotbuleaarsihynpee,rplsaissisaing ehoercrrohsaisg,e,somdaerakteed ""Cpyesstsiicdegrlaassiss,, wsioltderate STeheinf,olSlpowiinnag Ctoirsds,ueBsownerNeafrroousn HLeoarbte, wLiutnhgi,n nStoorwmiaclh,LiSmeiatls]: Intestine, Large Intestine, USarliinvaarryyBGllaadd,e,TrAee.rts, Dury, Trache, Thyroid, Parathyroid, Esophages, Pancreas, PSrpoejceicets:NaRabter: O2ICHA12 017y 36 sized ST pe: 81 252 Saawdrizved RSaagteoTnaiul1tneddWicarslcoenratra(ctaitionnun) Hier Lieatrie, I, 3 F%-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Tae: 2 FSiatreanawabver8A0 SSuriticedSear FsaeirlesnisGeo {1 COME 0 po [ WSirnit -- Stiavemrch Wicroicriaeminet serations: ffoorrtts trey LLiynnye de Gesatric) PHahrsitityrroid Sin oe TShuiesdd mthsi,ch0s.e5cIidei.ith scabon ight lisgieh,ly le SHaindteFnilrleedseontd in 1ft itor. J Siveraliration, witi--roc--e, sie Sweiatriefiatcails,, wrraintee sonsprative, APeelrvioc ss,inrhalainrtion, ured oOpse,slacnoritei,calv,iecrpitehelion, diffuse, itd uHerpastsoetveinvmottiivoe,nmwt1i6ecl, a6 JJaatt eeiinnee,s oaitssiongplan of sectisn c"erosnrind HeSivnsiledsrioinsfroan1sie. Stonach "Mineralization, wucosal, sild TrGhareiynf,,olSRlioownrianyCtoiSsrastvue,es nwTrreaNacrfhr,uown,TStooailb,e wnEietsshithnianegr,maLleagrieentIssn,t:esStailni,vaUrryinGalryn,laEdree,, Urs, FAnaineal hWoutsbser:52I)R-S4a58c0rificeSexi:n stress Fesale Group: ( 1) CONTROL 0 pa. WcroBscrpiitcnsyervations: Weroorpeinct Bsentions: foFrtp Fianigryw lant -- Fastoeid Ealrses rk red as, 05 a ine JSoitnvaaisaoee,ctmiss,sincorte, ald JJaett cvoeianiende,, issssiinngg SSaattwuisrieed, ot in plan of section FSoacgieots:MRaawtes emicetz 01737 Swerized ST Page: 47 253 SInudmimvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMiMcarionsacopRiecpoOrtburcvoanttiionunesd) FI-I920 To YeuirterralLaTboorxactiotryi-eDs,ncoIgncn.ici3t0y Study in Rats Tale 2 fFaotei:l ONlaebtesr:521)45S8ac0rificeSdexi:n FeextmrleesisSeo (1) CONTRL 0 pp i HicrPoistcoupiitcarOyhsernations (continued): spleen "HeMseoriodnerosis, woderate STeheanf,olSlpoviinnag Ctoirsds,ueBsovnerNearfroouw,n Ltiovebre, wKiithoieny,noHremaarlt,liLmuintgs,: Stonch, Sal] Intestine, Lirge Intestine, Urinary Bladder, Uerss, Gvary, Trachea, Thyroid, Pascreas, Salivary land, Eye. Ffaotei:l (MMaesekhser:89()45Sa8c1rificedSecitn eFxemraelneisSropi | 1) CONTRI 0 pa MacraRsacmonpacryOSblsaenrgvations: LSiplveeen Hicrohsicroepniacl Observations: Liver Lung PNaorrawtahyyroSildant Sle "esroaltdeerd.mass, 63 61 3 ca behind right "Flosasrigbeldy slightly pale an swollen. "FSoirntsaalitsaolvoencctlaesair,ceclolrteisnfiltrate, wild HHeeppaattouccyyttee vaalctweorlaattiioon,n,bwasaolpthiilfioca,lwaiilldd "Hheanstcolpasriessiinse,ranlitzraatsisoinu,llialryd, sid Fsirledunia, interstitial, chronic, sultifocal, "oMtevecxaaricniend,onnot in plane of section "hwermkaetdopoiesis, mtrasedallary, increased, BTrheinf,olSlpoiwnianlg Ctoirsds,ueBsonweeraerfroouwn,d Ktiodobeey,wiBtehairnt,norSmtaolmacLhn,itSse:al) Intestine, Large Intestine, LUrainharNyodBelad(dseer,stdeorrtiac,, UPearnscsr,easG,urSya,livFairtyuitlaarnyd,, TErpa.ch, Thyroid, Essphagss, nFiatnea:] (MWoesehkesr:10I5R-0T5e8r5aiml SSeaxc:riFfeimcaele row: (1) CONTR0pOaL MacroEsceopic Disrnations: Nassry Gland "Exentee.mioe post bleating inflasmation of right Fiirnaguinnoadlu.lar iss, 1 51 3c, It sPpreocjieecst: hRaabter: OZICRNIZ _ 201738 sunrired ST Page: 65 254 SInudsimvairdiuzaeld MSaicnrgolsecoTpaibculaatneddHiAcnriossaclopRiecpoOrbtse(rcvoanttiionnused) FASA24: Tao YeaRrikeOrralLabToorxaitcoirtiye-sG,ncoIpnec.nici3t0y Study in Rats Table: 2 fFantiee:al GNoesbter:105I)R-ATSeErSminal SSeaxc:rifFiecaeale Group: ( 1) CONTROL 0 poo Microscopic Ohservations (continued): MErreenal Kidoey Liver Lung trRaasrnyary Gland PaSprlaetehnyroid Uterus ""SPiannuospohitdhaallaiecttiass,iaw,ilcaotretrea,l,sasrakrekded "PCehlrvoincicaipnreorgarleiszsaitvieonn,epahirlodpathy, sinial "HNeepcartosoicsy,tefvoaccawlo,laatlidon, multifocal, sild "PAelrvievsalsacralmaarcrsopohnaognecsl,eaarldinfiltrate, aild "FTiubbruolaasrenaodneanom, wilateral ""HNeostateoxpaoniienseids,,neoxttrinasepdllalnaroyf, seincctrieoansed, "Cwyisetriacteglands, marked TBhreainf,ollSopwiinnagl tCoirsds,uesBoenereMafroruonwd, tHoeabret,wiStthoisnachn,oraSamlalllimIinttse:stine, Large Intestine, UPrainncarreays,BlaSdadleirv,arrytlaa,nd,Pituitary, Trachea, Thyroid, Esophagus, Lysph Node (eseateric), Ffantien:al WMeaenkbser:1051)R-T05e8r8sim SSaecx:rifFiecseale Group: ( 1) CONTROL 0 ppm MacroEsceopic Oservations: Phiitrueintaalry Wicrohsecroepniacl Observations: ne Heart KLiidver Lung Parathyroid "Shight atrophy with corneal opacity, right "Enelrea.rged "Left adrenal enlarges. "~SPihtmhssoiisdablultbi,usso,dercaotretes "Awyiotciafrodciatlis,, chronic ald nonswppurative, "~CFhorrotnailcbpirloegrdeuscstivperoaleipfherroaptiitohny,, aaiilldd Hepatocyte ~Faeueonia, vacwolation, interstitial, muclhtriofnoicca,l,miatiilfdocal, aPielrdivascalar sonouclear infiltrate, aild HHoetsoerxrahsaignee,d,Loncoatl ianrealsi,nealodf section Species: fat Project Nusber: 0281CRO01Z 017: 39 Suanarized STAR Page: 84 255 STuundroeud RSaitgoTniut1nod MiicarolseRmeipBtoacrvtatiioonn PHA: To YeiuverraLTiroatcoriDscorpeirit3y Std in Bats Tae: 2 oFiitel eosee,165 Terai SSars eFoeuls Seg (1) CON 0 [I ---- JrPituitary ~Shedesnsomdse.rons, itd reThareitf,olStlyhoiamnsag, Gsoavsvtys,eeeFaeeorfoyounnhdatSdotbaeacwch htSehulTsrnoeldsiinnEt,xsa:Lhorng, tLesYteRo,deU(rArRyEBTlLadCer, Pucrus, Sry Sd. eFuit:ntYeekr10B5 5T0ro SSeeicfiFceeit Ges (1) ONL 0 pa Wcoscoitsacrytartions: ers RTanedwetanrt0u5s4,0033ocyr dina.68 born see Wcroseoasnc Obarntiss: are simoifl actasi, contr, ile Kidney Lr CpPTharerrttoaavnlliccssipetlroaagfrmtecseisniorvonel6,in1efpeihrrflaoitepilaottnhr,ya,taeis,iidldald wbryy pSHeeetpraetvoacitytteenua,lwtsetreaastninocgni, vvaecuorlaatetd,,aiildsan PPrreasrsie cJoimaasrognh,atritn epa of scion Haeirtsi etreioemsls, wrked eThseif,eplioan tCiasdsyuesBiwnererfron,d inary Bier ray avy Stpaelyebes,wriathhhuienr,,soTSrteeonicn,hi,tEeSsaplisI,tyta,h aLie enstaot,e) Sib San, Ee, FeiiteneNsaer,15) Teaial aSer:iFeosie Gros 1) SRL 0 po Wcosaorpcy Sihdari: Sailt,u3l1a81a3ssc,h3r32ocah,aranil Lrg SPpreocjieecst:NRaabter: CZHCR0I2 01740 Sanaarized STAR Pag: 65 256 Snurized Sie Tait ial ep Cctv Individual Macroscopic and Microscopic Observations PE Ts voRrikear LaTboorartoryiesc,aIpnic,ctSyN Sst n ats oie 2 eTurea eosee109T) TTorsel uSreiircles rw 1 COUR 0 [I rm ---------- Sian wets crtes, wind iowHeart. "SWeMyrvoiciairedait,pivsr,iaecmehresonsi,csnosansuitppau,rativael,e arPoersies Aeotsitwaartre,wia0saais,lemioftsoc,ionain SSGiirnnr Bs oSotemvt,ieiwd,,aiwt1a1i0gn Vara iTenm trhsnreieilstr VTUhrieenFySoBiluaeeCnrytseeewrSetror,onPLitortb,to stiotTshochennso,urlTrLeoient,n:aehaLr,g nittiht,e esta), Pour, i oFirea eTseer10T 5 TorsS o Srifriceele rot (1) COR 6 [r---- Wren urate: tose ess, wl ity tvSriacialaparltaaeiian,,sreloncoa,l ,rseoe,lasionfts Liver oh tte aster SPAeoerputaimltcisscenwo,annurcllaiesvasroiinc,eollniisnHfiileltera,te, mwdild PaHioarsetes Sioeoowvnniiaeht,efaessoscion bTWheianeylSdopinarstCoovbs,rsaewaetrrnnodnOt0 uorbse wFitHhviitn,oSordn,cN,TtoS:eu,l Tteossto,xLugge testo Sin ay 1 3 criens:abrt: eR 1017 01741 . Susarized STAR Page: 66 257 Summarized Intividul MSaicnrgolsecoTpaibculaantdedMiMcrrionsalcopRiecpoOrbtse(rcvoanttiionnused) Riker Laboratories, Inc. 3% FI-3924: Too Year ral Toxicity-Dncogenicity Study in Rats. Table: 2 BFoaitnea:l (Mbaesebetr: 881)h-F4o5%u2nd Sex: Dead Fesale Group: (1) CONT0RpOpL Macroscopic Observations: NicrPoistcuopiitcarOybservations: hire Liivdearey Lung Lyosh Node (seseateric) NPaasraaatrhyyrBoliadnd Pituitary Spleen "Enlarged, 0.9 x ca. ""SOivnounsioicdaplroegcrteasssiiav,e cnoerptherxo,patshoyd,erastienial "VHaespcautloacryteaivniecrwaolliaztaitoino,n,slstilidfocal, sild Perivascular sononuclear infiltrate, ail -"LHoobtuleaxranihnyepde,rpliassiian,gsoderate "Not exanined, ot in plane of section -"MHeesnoasniaderosis, aild The folloeing Brain, Spinal tissues were found Cord, Bone Narrow, tHoearbte,wiStthoinnachn,ormSaelalllimIinttse:stine, Large Intestine, Urinary Bladder, forts, Uterus, Dry, Trachea, Thyroid, Esophagus, Pancreas, Salivary Gland, Eye. iFantea:lGNeaebkesr:109()R-T4eSr9m3inal SSaecxr:ifFiecmeale Group: ( 1) CONTORpOpL. Nacroscopic Observations: MicroAsdcroepniacl Observations: Liver PLaurnagthyroid "Ho visible lesions. "Sinusoidal "Hepatocyte catltaesriaat,ionc,orvtaec,ualmaatrekde,d wild Hepatocyte alteration, basophilic, aild ""HVoatscuelxaavrinaeidn,eranoltizaitniopnl,anesiolfd section The following Brain, Spinal tissaes vere found Cord, Bone Narrow, Stpolebeen,wiKtihdinneyn,ormHaelartL,iniSttso:aach, Seall Intestine, TLhayrrgoeidI,ntEessotpihnaeg,usU,riLnyasrpyhBlNaodddeer(,nesfeonrttes,ricU)t,eruPsa,ncrOevaasr,y,SaNlaisvsaarryy EBllaanndd,, EPyiet.uitary, Traches, Species: Rat Project Muster: GZ1CR01Z c, ore . 258 Suarized STAR Page: 67 SInuduiaviidaunald MSaicnrgolsecoTpaiuclaatneddiMeriossacoRpecpoOrstar(caotnitoinnsns) FIFE Ton YaSrikeGralLaTbooriactiotriye-sO,coIpe,ici3t8y Study in Rats Tie 2 aFataes eNatseer:91)4F5o0nd BedSoc Peale Groups (1) CONTROL 0 pu [I iiney -- inary adder WirPoistcupiitcarsyervations: Hresal fGoirdotnsr Linvge tLuirgyh bade Gaestaric PuPrasrtehyrsid PiStuuliltaIrnytestine WSieneeny Blaster RifgihltleKisdintyh srpeleownsislliyghtfllyide,nlarges "llaargie., 4.53 2 co Filed with Large, hard esorehgic sae, 0.91 0.6 a Soinesooiftpalarapcretssen,t cartes, berate oFytelonnsahrritiis,sissseitneg, bilateral, saterate dMsrhroopntrso,saib,lab,ilatbeirlaalt,erasl,orttodeerste eZnpsictloarrthsianletaelriatnitoino,n,valudlted, ail JJiotthienxsoirnuel, sLiisnsson oote oafuspiaoirndpraeissesting Jfoitveeased, not in ple of section JHoetuoesxdseirnoes,,aiassstienagte ppirtti byprpsis, pupillary, diffuse, Cilclus TSahinf,alSopianlg CtoirsesyueosnwearAeafroounn,d teoatbe, iStthoianchs,orLeisreisIttse:sioe tars, Mawary Gln, Traces, Thyrid, Esophagus, Salivary Shand, Er. Fnaiea:leNsoteers1091)RATSeTraSinal SSaecu:rifFiecmeale Soup: (1) CONT pon HcrosictoupiitcirOybarvtions: Hany Bld Pacress WorssNcroepsiacl.Bserations: e"oSarirlhaTgoibclarauast,s,0.82.c7o%da1.53 1. ca it "sauilllal,obar ass, 3 07 ca, are of sicress. "Simasitl actsis, corte, sodarte SPpreocjieecst: Ntabter: OICROLZ "01743 Saanarized STAR Page: 68 259 RISIus:snarTineznedtSMeaiTrcnirgkeoleseacoTLpabiTbecuslia4ttnodetrdyMi-iAeccn,rioonpsanclmeoi,pRciecipo3tOr0yterS(vcaaonditoininunsedR)as toes 2 oFiitel eeser15TTTSrail SSurrfFioceie Sag (1) CON 0 pn Wrosictooprc Ooertios (tind: lw Fara o-- nclor cal filtrate id peaprtalarbtieaulacstipoolnf,eriatcitona, lil1d LKoanry Slt Paces ATLalolvelacrlwspcecrrwpschaagnoeinss, ld PCapruti,n saplaldaiftedeittihtievaios of Fnitauiitruye bers "aaevoannsise, st 0 pie f ction "econ Sul circueribed pupillary lesion, rTUhraeiinaa,rlypoBinaagdrtLiossdrukeBss,oarTeWarcfhreonnyny StooptbeewtwietEhtisnyspoatro,nshLi,nhtSs:aoldeatsatainme,tL,rgSlInaetyinSeu,sy Be, br. FoiitelNNesaer78R) SEucriticdSuisn reemsssSap (1) COMO 0 pu -- tity any lst ATaue,, 0283132036h1,5 co in lft ail, JKiietoy r"aSiillietiy0p4alce daid.itceid islrigihtply Wcrorsceniluration: real Ailey Wltealy tical vation, acl, trate eSitmrayocaslel iosw, afosrt,e, soifdra, ald tots ACrolrtiiscaaltidgoena,ra1t1i4on inal tio ass in Isa eis ros, of a derate lstic rte in section of asstay sited for itn tw CHyewaupesn,teanctcooetrrretiiiccrwaleclyes,mlpisshnteonioodfsne,.ahpdiaffutse,, wre wrk Sucion: at Project Nusber: 0281CR0012 ; 01744 Seanez STH Page: 0 260 Sussarized Single Tabulated Anisal Report (continued) 32: Ten Yeiw rralLiTcsotiortieBscopnmti,ci3ty Std in Ras Individual Macroscopic and Microscopic Observations Toes 2 eFiiten essres 814S5u%riticedSvin FxtlreestGeos 1) ORL 0p Wcro(so4pc Ousrvations (tine: "Ksiavla ssicvreorpahlaigzeast,ioi,nwnield yVParwrayohtheaanadsntricl tSTieovwveavastnoreeo,, asin ot 0 lane of sction HSolityurSunt Siew aJSeevasovinrtarnoonntts,,sessiibnagte Win Baten Epis persist, sole difse, wile WOTahyein,f,olyroaicanegs,CsoTdsyosrotev,erteErvfouennds,taorbae,cwiSrtaheivnchnEpr.mSlalisttee:in, Large tation hrs, Foirteaebtee105T) TTeo SSuus rFofuls Sag 1) CONTROL 0 an WWcerroossrctonepice thsaraticns: Ossi: re ity Lr wy oJry -- FPauncsrmeaesid Sieers Ait tren ease, SYeiiunlaty cwltlispie,pcioartiea, wfroke,d ald rPaincesporaaressiinoeno, ssdt, anil traall sbilecfuclk srcleiflernaftilotna,teil,eald Ateolrvdveiaircoannl,rshaadmgnsait1e4sIattiotn , ald TJoonaltaenrnisone,notainn alatna sction WSnientnndteroremsr,oNtiaatt]ds er Shraeiioo,rlSodnyningrCiadsoyutoenveraWearfytoond,lHtueornbte, wtSitttohuiitnchs,,aSleTlalcLeinntta:rtoted,,LrEgssIintee,tinSe,ly las, Eye. fiSpecies: at 01745 Sunarized STAR Page: 10 261 Snainirdiuzld MiaNncgerlowsecoTLpaaiuoclratatanadrdiMsrisi,carlnoc.sRecpo3trthrtvaitinonos) PISA: Too Year BalTesi rogeicity Sad in Rats Table: 2 oFuae:n GNeaeke105) 4T5erinal SSeucsriFfecles Geo 1 CONRL 0 po [I hut Wersicropmic Baervations: Yraennt ert ine fr ung bTuroyt FPiatsteors Gare uLsosi, t0.r7 eca drae.ly elarged. SDilviaasiimtilrqclitosni,neciogrtne, awrked Siystiirodcilts,,aclraic ronupurstive, reienne sreorraelsiimavteions,erSo1a6thy, soteate Fwpeerlase, eivic pithelion acl wes, Heptacyte vacation, ltifecal ild "hHaepetattioacsytvetiamlrstaeircnataiitoiens,nn,bafsaoipdlhtirliact,e,sisldlg cilianraariovign,s write eJotreoines ok 0 plane of secticn Tete stats, snterate rTShitenhfdotFCloaoriwntagyotniSesasnuMdea,srroeTnra,ecphfiauonndT,ototiob,mecwhiE,tshgiShnogiolsr,anlLeinsgihttedso:eLuareseIntteastrince,Sienlavray llaatne,r,Ee. MFAanitneal eMaedker:102I)R-4F5o9u9nt odSex: Fesale Group: ( 1) CONTROL 0 ppu WerosVcaauprcyWSalrnadtions: tSawnch einay Batter [ria a-- lNoetesn Stepans "gSpprcriassreestswirnesgnass, 2.55 21 1 ch, in Jooieisenofdswlislpetesdssulc1er5a3tio1n.ca, with Hohtessiu ttaokebn duu a0 paoslt.crten changes "ailmsioigtnal Leychotnss,, choirsetsi,sotmircked SJuatlimgnitsDeegseisnsonbistisetic PSrpoijeecst:Nhaabter: CBICHAL2 601746 Soaaiaed: TH Pig: 71 - 262 aSadnvriield tSiongkleoTpaiulatandBclrioaslcpRieptu.racotnitoionnt PSK To Yeiu eGaLTieeactritco0a0m,icty Sty in ats Tae: 2 iPtnel MNeaer,16T2 FouSnd BeSak eis Ge: (1) EONROL pn Werosecnotpc Osantios tier: ctaridfitai,s, sednc nnsprtiv, tne apPelerlgseiassits,Irgaeiobnit,ciopb,ishittiidcr,ic ec ares, we tLgwe Itstion liM[ gepguhraonstis,a yltouobnutloasre, p bbwiiilstdtiiccrytiicc wo aeistghrgte,haoletaM,st1i1c4ric Lh ote asstric aigne Iahos, Miticric Naswary Eland "Malignant lysphosa, histiocytic Ovary "Malignant lysphosa, histiocytic PPPatnacirrtesaisere J"JMaaatliegannaintnItysphnotsa,1hipsatinocyotficction . Staroned SSeecavsrs,esmc,aniltddre TUhyhrorid Maser aMTaaliiitgnhnealtniatlyIMygahphaoosna,w, bheiissttisioccyr,tiicc ifs, aild werss eign phon Matiotic hrei,felploinnag iGostuowerearfroawd, tSouble wniethsiinonso,naTlraicess,:Slay Gln, FeirtaeleKseer90 ) Fou tedSec ele Seu (1) CONROL O pn Wcrosacrpiyc Biadrton: Wicrowscranc Ovaries: orreetn "TSTearootnneofsiOtrwiusc, s3ab1sc,4t34e7xesc1o5xin 2r0igaht in tollpas,sted evJecectraarasisii,oteew,,ileastnirsaels,ynwvrsigsptrtive, wii, ald PSpreaceitesWabtr: CAIOI2 01747 Surin stm pe: 7 263 Snairinaead MScirgoencToopantdeWicrnolscoeprstsrCacinotnisnn PS To YeNuaGwaLTaeeactritS,cqemiecty Sty in Rats Tae 2 rBenl Yr BAFo S vtSo Fie Gu (1) CONN pn [rprre ------ [PicPsimrT anatio-- y 00 -- uw fearstraalsiy,leaifbclnes,rglwitrerteion, ile-- Vias Sit or-- y SiHeeimter Hepatocyte vacuolation, multifocal, wild AHTeuepaaetgorecycttessraslat,eirnaattlidoino, neosiilneophilic, soderate Spavorn,ipimtiriy ofrkorapitniotinnyt a plan of section SSeiovners, itd rTrhateief,,olphlawiirnaeg,GtoiTrssdscyueeosn,veeTroforotunn,d SEtotxabpecahsttsuhaLlonhonreomskiLnist,easLcrrgit,esPtrei,sU,rSryeDradhed,. Foeirl tehart,15B) 0Te2rsoal SSrrifFceste Sg {1 COOL 0 0 Macroscopic Observations: ERirtreeitiy [Kiraann -- bteert itor jir. PHaristtiyoid : SCHoiargnnhedaaaoptnpeymars1sc0rloeuddeiyk.. oe ptt, SCiomrtsiictalaldeescetrtsi,onc,rit,usu,rkewtried Ttereaagtesr,,amnietmensgprtrtive "iirevnreescpereaslseniavteions,epbropathy, wrked SACeyesnbtr,otcerogreteicaa1tlsdatorne,asurpithee' ld eekaenrtoet, wt 0 pan a ction -- Page ber: oaicior2 01748 Swit sre 264 Snudnoavriidauatd NSainrgolsecoTpaivclaatdedMiMcirossacopRiecpoMrter(vcaotnitionnusnt) PRN: To YeBrhaGralLaTtsiactuGiceos,geIicc,ity Stay in Rats Tate 2 aFinteh essoers1091)40T0er7siol SSaecriFfiocaels Groups | 1) CONTROL 0 pn KersScipriec Bertin (cantons Were ir th re-- m inits eae tha proocal nse SfToahreitnsf,,olSDlpuwirinyna,g GMtoairssdsiyureyBsowEnlraenRda,ovauTnrd,icSthotsa,bsehThw,yirtoShiiadn,laErIxnpmtheasgLteiisnn,t,sy:LerhghIfnete(sateisneenteUrirc)a, PSanlcardeaes,, Siivry Sat. Fiaatentshostrs1615-T0o3rin] SSeciiFfoials Group { 1) COMRL 0 pn [I Tier -- WeroScipnic stration: pr wort Liitvoeery CirLictuelraarl roabis,ed lesion, 0.6 a 6a. Left ui loss on forelats SCiorntiacailaepcoaesatii,onc,ort1eF,iemeo,dersauteerte Hwrictairfioctails,, wCilrdiic snspratives eSabevailc ssimwaoltimetioce,liitndfiltrate, ald Frta bile duct proliferation, ail Pwannay Sant FSHeierlpbuavttaaocscyeetuleleraltseoroanticolnb,arvaciunoflialtterda,te,wiladle FiPuairsttrryoid JSitervoeined, ot in plane of section SiSenen Seetwshiodesrs,isi,leeile STaheinf,olyoinimn,g fort, Wares, Ctoirsds,ueBsonweeearfroodw SttoabschwyitShionl]soInatestLiinnei,ts:Lire Intestine, Ovary, Tacha Trot, Esha, Ly ode (aeenercl, UPrricnrareyssBlader, Saiviry Bnd, Fe. SProojceict:aasthe: ZBICRNIZ 017. 49 Suonwizet 51 Puget 265 Sduisvnirdiuzaeld MSaicnrgolsecoTpaibculaantedWiMrcirnoaslcaRpecpoOrtbur(vcoanttiionnused) PRIZE: Too YouRrikGeralLiTboornaitcoirtiye-sO,csIgcen,ici3t0y Study in Rats Tle: 2 JFaatel: WNeasbtser109H) OTeHraimal SSaecxriFfeimcaele Seo: { 1) CONTR 0 po NacrosNceorpeiacl Observations: Wicrowdorpeinc! Observations: tEasrotpsanes Kidney LiLvaregre Intestine Pvaarratyhyroid uterus "Left adrenal large. ""tSaitnoeaaiseiaolede,caissiaa,ingcorts, marked J"Cohtroenxicanpirnodg,reasissisviengsepropathy, aild tPaetlviecatsiisneer,aliinsastiionng, sild JHoerptaatlocByitlee vdiuocltatprioolni,fersaatlitoinf,acaali,ld aild "Wcppsr,alwaisliatcerdaelle oitthienxannionremda,l nloitniitns plane of section Fewer than protocol nusber STeheanf,olSlpoirnianlg tCoirsds,ueBsownreMafroruonnd Stpolebses,wihthairnt,saLrumnl, LSitsotwss:ch, Swall Intestine Urinary Blader, EYeow.ary Elan, Pituitary, Trache, Tyrol, Lyigh Node (aesenteric), Pancreas, Salivary Gland, JFaotien hNeasbosrs7)1RASGaDcrSificedSenisn FetormelneisGro: 1) CONTR0pOpL Wacroisadpiec Obsrvations: Lung WicrHoixroepniacl Observations: heart itney live Lug "RSilgihgthtlaypipciatlteLdobe comolidated and sonevbt ecnrlaairgcedprpeowsssaiibal.y tur, was, NHeecsraotsoigso,iesTiosa,l xatrraes,etlsoldaerrya,te sultifocal, "aHlyodcaritis, chronic sosupprative, wTlatliifgoncnatl,yispobeorna,te Ipshocytic CPherlovniiccspierreaslisniavteionn,ephsrionpiamtlhy, moderate --WHaelpitogcnyatteLvyapchwoolsa,tioIny,apshiodcyztaincl, soderate "WVaaslciugluanrt sTinyesroanlisz,atiIoyns,phoaciyltdic Lirge circussribed ass with xtmsive SPpreocjieecst: MRaasther: O21CKNI2 01750 sunrise spe s 266 Sumarized Single Tabulated Misa) Report (continued) Individual Macroscopic and Microscopic Observations Riker Luboratories, Inc. 3% F304 Tuo Year Oral Toxicity-Oncogenicity Stody fn hats Table: 2 fFiatnea:l WMeaeskhesr:11)R-AS6a0cSrificeSdexi:n Female Group: extresis { 1) CONTROL 0 pps Hicroscopic servations (continued): DPaurraythyroid Pituitary Spiml Cord SpUlreienanry Bladder ""ONyostt,exuanmiilnaetde,ranlot in plane of section -Menons Malacia, local ares, soderate "Hesosiderosis, aild "Epithelial hyperplasia, simple, diuse, wierate BTrhaeinf,olBloonweinNgartriosss,ueSstowsearceh,foSuwnadlltoInbteeswtiitnhei,n normal limits: Large Intestine, forts, Uterus, Nassry Gland, Trachea, Thyroid, Esophagus, Lysph Node (sesenteric), Pancreas, Salivary Eland, Eye. Fmaitnea:l (hbuesetbser:1051)8-T4e6r0s6inal Sex: Female Sacrifice Group: ( 1) CONTROL 0 pp Macroscopic Observations: PiWatsusiatrayryGland Uterus. Nicroscopic Observations: Adrenal Heart Kidney Liver Lung Lyssh Node (sesenteric) NOavaanrayry Gland PiPtaruaitthayrroyid Uterus ""ESnulalrgemdis;s,cir1c.4alcaar dia., dark Lleesiiton,Lat0e.r4alcaardeiaa,. "Dark {uid filled lesion, 0.5 x 0.6 ca, right horn. "SCionrutsiociadlaldeegcetnaesriaat,ionc,ortbeixl,ateairladl, soderate Pheochrosacytosa, benign, unilateral "wAiytoicafrodciatli,s,wiclodnic nonsappurative, "Chronic progressive neshroaty, aild Pelvic sineralization, ail "HHeeppaattooccyyttee avlatceorlaattiioon,n, vaaclutailfaotceadl,, ald sild "PSicgaetette,redsosduearlaltefoci of dark brow "Hpeisgorerehnatg-el,adeanildmacrophages within alveali. ""bNoetnoecxaarnicniendo,nwissing "Hot examined, not in plane of section "AHeydrroomnetra, warked BTrhaeinf,olSlpoiwmianlg Ctoirsds,ueBsoneereMarfroouwn,d Stpolebeen,wiStthoimnacnho,rsaSlealL]isiItnst:estine, Large Intestine, SPpreocjieecst:aRbaetr: OZ810R0012 C01/5-1 Smwrized STR Pg: 14" 267 SInudainvriidzueald MSaicnrgolsecoTpaibcalaantdedMiMcrirnoaslcopRiecpoOrtbr(vcaotnitionnused) PRIA: Too YouHrikearlLibToorsaitcoirtiye-sD,coIgce,niciStUy Study in Rats Tae: 2 TFaatea:l Oalbeekr:1051)34T6e0r6aimal SSeancsriFfiacle e rap: 1) CONTR 0 pon Th fNolilcoreoicngpitcisBsuseesrawterieonfsou(ncotnotibneuewdi:thin normal lists (continued): Urinary Sasir, fara, Traches, Thyroid, Esophagus, Pancreas, Salivary Bland, Eye. fFnaien:l OWasshters0I)RASKaDcTrificeSdexf:n FaetmraleeisGeo: (1) COMTRL 0 pp NacraSsocfpticTiOsseurensat(ieocnhs): Lywh Note LSipnleeen NicroKscraepinc Observations: fhoorteafarron EEseophages Ltiivdenrey Lung Loh hee esata) "elstaerngeeglIanhd Linkoedesstrourctsuarleisv,arpyossibly "Eshhlurngtse,d axillary, hepatic, sesmteric and --rionstiebrlnayl slliighatly1ppale.sods. "Comideraly large, "Haalliiggunnntt hphoonuss,, ILyympphhcoycyttiicc aYloigduiaagnntosiIsy,shionnsst,eqIuytmehasceycttiicon "aliilgirgaunstt IIyywmhhoonnss,, ILyymmhhaoccyyttiicc H"aalliiggruarntt IIyywmhhoonwss,, IIyymgphhoaccyyttiicc Hceesosrrshage, local ares, aild eWsaolrirgnhagte,phsoodenr,ateIsphocytic aWpapsesairviengmlLiyrmghuaecnytteosf.noAdLeL boytshurtunroedes Rtousrayry Sand PSaalriavtahryyroEildand sStloenceh thTehyrreosid "Welxiagninnaetd aligrant Iwyeynrspehhoosnnissn,,ilIaIryyipalphyhaocciynytvtioiclcved. oSltot esxxaassinneed,, aniostsiinnglane of section h"eanloirgruhaangte,Iyswbhmonusc,osIly,ghsaocbyetriacte "WHaalliiggrnanntt Iyynpphhoonas,, IIyymwphheoccyttiicc aligrant Iyshons, Iyphacytic BTrhanf,olSlpoviinnag otirsds,ueHseavretr,e Sfeoauln)d tIontebsetiwniet,hiLnarngoermIantelsitniintes,: Urinary Blader, Pituitary, Specie: Rat Project user: 0281CR0012 4 01752 Somrized STR Page: 77 268 Susearized Individual MSaicnrgolsecoTpaibculaantdedMiMcnriossaclopRiecpoCrhtse(rcvoanttiionnused) PU3T24: Tao YeaRrikeOrralLaTboorriatcoirtiye-sO,ncoIgnecn.ici3t0y Study in Rats Table: 2 Mrinal Fate: (MHaedsetr: 410)6-4S6a0c7rificeSdesi:n FeexstarleenisGroup: ( 1) CONTROL 0 pps. The Nicroscopic Observations (continued): following tissues were found to be within normal linits (continued): Trachea, Pancreas. Aninal aber: (R-4609 Sex: Fesale Group: ( 11 CONT0RpOpsL. Fate: Geeks 105) Tersiml Sacrifice WacroPsictoupiitcarOybservations: Masaary Eland Nicroscapic Oiservations: Adrenal Heart Kidney Large Intestine Liver Lung Nasuary land Pancreas. PiPutruaitthayrryaid STphlyereonid Uterus. Raised mass, Hass, $14 ca|,cothrdioaa.t areas ca dia, leit alla, ""SWiynoucsacritdiatlis,ctachsrioan,icconrotnessu,ppsuroatritvee, witidoaal, sild "PCehlrvoincicsipnreorgarleiszsaitvieonn,esshorodpeartahtye, ild ""PNoorttaelxasnoinnoendu,claeiasrsicnegll infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacwlation, multifocal, sild "Previonia, interstitial, chronic, mltifocal, "aCalrdcinons Highly cellular very undifferentiated taser. ""Nhoctineaxranaitnreodp,hyn,otsodinerpaltaene of section ~-Hhedseonsoindserosis, nild < cell adeno "AFietwheirntnhoarnmaplrotloicsoilts nusber The following Brain, Spinal tissues vere found Cord, Bone Narrow, to be within normal Lisits: Stomach, Seal] Intestine, Urinary Bladder, horta, Dray, Trachea, Esophagus, Lysgh Node (aesenteric), Salivary Gland, Eve. PSrpoejceiecst:Mafsabter: G281R0012 01753 Sunarized STAR Page: 78 269 SIunairta MSioolweaTeiaslwoaitscl,relooe,pct3u.ractoinotnin FA To ee Bal Toi Scopmicity td fo ats wie 2 eFilies taasre 10T9) TGorso SSeerFiefl rw 10 ONL 0 WNaeraemrnyOsSmrrdattic:s; Aus tla a, 037.813 res nr SCeossriiretsrpweiaarattie,n, umailteow,, dwdete og Aitvovertate,sacmsieitc,o,,tslidien,eaidil JraHariyrlt SFotlonoiwen, a 1 le of scion TCrheienfoelSloopsoenng,Ctoarsi,etsosweeMrtnrr,tStioeben,,itWKeiienn,n,oDorrr,,tsTtr:oiccoht,, oSli,notxipono,s Li Rte ana, Pca, Saar in, re. Feiae eoswe:192 9 Terkel SSrefiFceee Sg 1) OU Opn WriharipyaSnrd c: Aoinnt3iceh,in0,1 86sl. e 4c fay iTrebri2ia at ie, [rrinys-- SiGmeaip,stnst,agactrst,eisonfts onge SSAoevmeaart,scwfoeapane,ns,w4i4snitios, ad Way lnk AvFlaitttoseo Pnistteyis HHTtiovstarnspres1 le of scion ee aTieentshnlratiei]sur rThie nFolSosaie Gtrsyeovwerfosd 4tob,e iKtiigerp,oerrtLiStoec, Sul tin cfins: tt 001754 svi margen 270 STaainnruiaale RSiirorle iTaeaslanaretieBnie,arlnneiReprtactonitionuned) PL Te tor a ToiScopmicity Stat fn ats Tole 2 iFka:l tWhaars15A) Tzrsoal SSersifFcree eu: (1) CORO 0 pa UThreefinlseoogtstisBeauraawtrieBofsio,ed n0htobee,niuhy,orTarleni,iTtor(sc,oGntuiba [EE Feta:ltahsver1T) SSuriceerin sForeeGe (1) COUR 0p rsiptnarvtions -- Massary Bland "MWases,rt10e,x 8 x 5 cu, inguinal area; surface [Lrivtenra pa-- boCuma Ltgre ntestine og aPtaairytayads bw iVnee Mater ~hpears pale HSSeueattnopiiiaewissa,chawet,r,sectaoratlelas,rya,40wld eoonrcpastiveesnipnitgcant, halld e Local aes, SsJkotastaisntv,iiantia, aiprtl, wild Sirreonirs,rtitiieos,sallde rweeat, artis, Sonic, mitt, JLSaiomcaoaimna, isots1 hae of section SSweprmiamtleslnsp,epsstir,stsril,, cirseust,,id STiewntrhnenrtatei]ieube ihTernefsolsSlowLninnggGtoiNvsets,.uebsaowmreertfoeornn,atcorbr,eawSi,tthoikSnchs,lnsylu]iSaitnetgn,:tiEoen., hors, Bury, Tce Species: Rat Project Nasber: 0281CRO012 CO: 1755 Sunrise STH Pa: 30 271 Summarized Individual MSaicnrgolsecoTpaibculaantdedMiMcirsoaslcopRiecpoOrbtse(rcvoanttiionnused) Riker Laboratories, Inc. 30 F324: Tuo Year Oral Toricity-Oncogenicity Study in Rats Table: 2 Aisal Kuster: [B-4814 Sex: Feaale Group: ( 1) CONT0RpOoLn Fate: Geet 105) Terainal Sacrifice Macroscopic Observations: UtNearmuasry Bland Microscopic Observations: Khiidrneeyd LiNvawemrary Bland PPaanrcartehayrsoid Pituitary Spinal Cord Spleen Thyroid Uterus ""MLaasrsgeingepleartiinneoauls area; possible cervical wass, silk 2 co erst. dia. ""SPienluvsiocidaailneercatlaisziaat,ionc,ortseisr,insolderate Cranic progressive neshropathy, aild "Hepatocyte vacuolation, multifocal, wild "enccarcinoss ""JAoctinaerxamaitnreodp,hy,notwiilnd plane of section -#denons "Ho diagnosis, inadequate section "Hesosiderasis, aild "tisbranchial cyst "FTohliysp was the ass at cervix noted at necropsy. The following tissues were Brain, Bone Narrow, Heart, found Lung, to be within noreal linits; Stomach, Swall Intestine, Large Intestine, Urinary Bladder, Horta, Ovary, Trachea, Esophagus, Lyaph Node (nesenteric], Salivary Gland, Eve. Anisal Nusber: R461 Sess Fesale Group: ( 1) CONT0RpOaL Fate: (leeks 105) Terainal Sacrifice Macroscopic Observations: HicroAscroepniacl Observations: horta Kidney Liver Lung PaNraastnhayryroBildand Spleen Uterus "Xo visible Lesions. "Sinusoidal ectisia, cortex, aarked "Hot. exanined, aissing pelvic wineralization, sinisal Portal bile duct proliferation, aild Hepatocyte Hepatocyte alteration, alteration, vacuolated, basophilic, ald aild "PArlevueaoolnaira,sacirnotpehrasgteisti,als,ilchronic, #ild ""HSoatlaecxtaoscienleed, nat in plane of section "Hesasiderosis, aild "HFietvheirn tnhoarnaaplroLtioscioltsnusber Species: Rat Project Nusber: 0281CR0012 Cc 01756 Sumrired SUR Page: 81 = 272 SInudinvirdeuadl RScinrgolsecoTpaibclaatneddNiirnoasclapRiecpOthsecrtaitniaonesd) FR To YeHrieGralLaTboorvactiotryi-eGs,ncoTgce,ici3t8y Stdy io Rats Tle: 2 rFaiea:l rNatbeors10153ATLeTrSinal SSaaccriPfiecaele rou (1) CON0TpRp Hicroscopic servations (continue): TSUhareiinnaf,roylSlopBsilianndagerot,risesO,uvaerBsyo,neerPeaitrufriootunan,rdy,HtoeTabrrea,cweSistt,heinnTchhn,eoromSlam,lallLEsioIspnthtsae:gsutsi,n,LeLgahrgeNoIdnete(satisneen,eric, Pancreas, Salivary Slant, re. Fiaaten!] Ooessbkeer:10456T1er6inal SSaecnsrifFiecueale Grog: { 1) CONTROL 0 Nroscopic servations: Wicrohesrcepniscl Ohervations: Hert itoey Liver ny oHaarywa Slant PSaorlaetmhyroid o visible Lesions. ""Cyosrctaircdalialdegfeinberraetsi,on,foscnaill,atweirladl, warked Wwolctaidfiatcils,,wcihlrdonic srsapurative, "fierlavinccspirmorgarleiszsaitvieons,epsoipvaimtahly, wild FFoerttael] sbiolme cdulcetaprcoellilferiantfiiolnt,ratwei,ldwile HHeeppaattooccyyttee vaalctueorlaattiioonn,,vmalctiilfaetceadl,,iwtidld eVraisvcauslacralsanrersaolniazmactlieoa, winiflidltrate, sderate ovteaexlsiancer,opahiagseisn,g 11d "Sooptt,exwaiilnaet,eanlat in plane of section Hescsidross, wild STAahoeirntf,aolSeoprwiiananslg, otPriisdts,uuieBtsoanrweye,raerTrfraoocuwhn,edn,StooTwbheysro,wtidt,ShiunElsophrIanmtuess,tLiinLmeiy,tgsh:LardgeeIn(taesrtsineen,icr,inaPaycrBelasd,e, Salivary Slan, Ere. PSrpoejceicets:sahte: CZELCROIZ 01757 sowing 273 SInudainviirdiuzaeld MSaicnrgolsecoTpaibculaantdedMiMcnriossaclopRiecpoDrtse(rcvoanttiionnused) FII8: Tao YaKriketrraLabToornaitcoirtiye-sD,coIpnecn.ici9t1y Study in Rats Tae: 2 fFaatie:l (Weaeslhesrs79I)RASLaIcTrificeSdexi:n FeexmtarleeisGeo: (1) CONTROL 0 pp Nacroscapic Dhsrnation: LDivreyr WicrobsrcsepacdObservations: Liver FLanngwary lang bry PRiatruaitthyarroyld ""HFeaslserrhLaegfitclaatsesr,al5lcoabedidaar.k 1reedf.t ory. "Stinensoofidpaalirecptraessiean,t corter, wild oNretcraolsiss,onodniuffculseea,r cwealrlkeidnfiltrate, ld Rcaosmseinvseatnaercyrosiinscroefasoeneinlaoibteowsietshin rather "valsocveu,lar sinealization, aild o"Lteioewaosnisne, sissing Lnaercgreotwiecl,lprdoibfafbelryentairaitseeds efsropnlaasns,ovaioduscttl,y "oltt eeaasniinneed,, naoitssiinngplane of section Tbhreainf,ollSopniinnagl tGoirsds,uesBowneereNafroruonwd, tSoplbeeen,witKhiidnoeyn,ormHaelartL,iniSttso:sach, Small Intestine, LLyrigh aNotdeest(nees,entUerriinca)r,y lPaandcdreera,s,AoSratlai,vaWryerGslsa,nd,TraEvcek.s, Thyroid, Escphages, nFaiten:a Goesebkesrs3)(1-S0a1cr8ificedSeni:n FexetmraelneisGroup (1) CONTROL 0ppn WacrPoistcuapiitcarOybservations: Nanna Slant Ricroascroepniac Observations: XiEsdoopehyagus LLiuvnegr FaTraawtwahryyroliad d Pituitary a"Liasrgeedumlcaesr,ate1d.1mcaass,dia1.037 5 9 cb, right arly area. "Simsoidal ecasia, corer, wild "HPoetlviecxasiioneedr,alisziastsiionng, sinital "oarstcaallarsoanionnecrlaelaizratcieoln, ianiflidltrate, ald PAelvreiovlsacralmaircrsoopwagneusc,iear1infiltrate, sild oott eexxaaiinneedd,, naoitssiinngplane of section Menon PSrpoejceiecst:usahter: 0281030012 Ci 01758 Sorin Pg 83 * 274 Snanrtio Sa rlee attoedyrfelceseMtom(actitovnn FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats ae 2 oe vaSatentSo FevisGn 1 Go [ Fs -- Stes,esmcutweastose cle t eetyet stipeorn mssopried wit wat varisii, sit, tte, ae I eeSo rnvoipsoe,e-- trs Po-- oteth,Slillyestnans, ELueeWearten, o Fibas fBna, 8so re og {10 GOR So [ proo -- --th steel se, eprr[oioesmSorte Eris vasefo -- FCson aMiegsryiaa,yhatc ferorm Tereeteeotna,ttiboant,s ured - i eeiggntreioe,eomhntrarc ryHoweyotBostrc Eceeyt tt. 18 pe of sto Tfrant t mHieetni,abosne,sbteee Souorf aa --n--taont, ralden eit En pois sl, tte, aid he lC ve ms es weeefnond o0ubt,thn svoireiiLtoge esti, rt, War, ry, Torta: ange 001759 Sussarized STR Page: 84 275 Seized Sle Tate bial Reet cntvnt Aninal Musber: 1R-4619 Sex: Fesale Group: ( 1) CONTROL 0 pps nr Kidney is si "Chronic progressive nephropathy, aild Pa Wer; Species: Rat ROI 01760 Sussarized STAR Page: 85 276 SInuinvriidza)e SRtianafgorhnoTLpobaiolranstdoerdNiiisc,nraoTslcca.Ripcr0atar(vcatainoinnse) PETA Tao Yer Gal Toncity-nogeicty Stay in Rats Tie 2 aPtiee eNkoee 21 ) Fund rdSes Fouls Gro: {1 COMRL 0 pp [ Sir -- Sulolws cair1c6aTlaesaioln osnideb,ack slight her fr tne aRasGisi,end7a0rce1s,gii0s,1n6riighdtahresssn.l0lasyrfaarceesof13rigchnt F[iitutary BuKiktorres ageplpatrinleiadeH,II, Stig tottied Wcrorpeinct Oserations: ort Jo nine, isson pe Kine TPherlovincesrmaelpizeantisons,praoraathtye, sdeate owpieeataia, pelvic sritheion, lscal ares, frung eApvaattaacrtewcvriecehiiagtsio,n,alpdrigrtal, sfeate PHaraskheyoSildant Frito SSioltctraacienleed, sot in plan of setisn ot eine, aasig tin ier, focal, sderate Trrhaieinno,atlSnaiibvnagertCiosrWstuaersoesww,reaFarorrusowd,TtrSoa1c6boe0m,,witTehoiionti,edr,SmoaxnlaicbHsai,nutsSs,e:llLonhtotdie,(aLesrngterIintcehstiPnae,nes, Salty Shan, Ere. Fiintel dakbesr:0G1 STurficedSe1x0 eFxoutlrsasGro: | 1) CONTROL pr [o--e ------ pe---- WcrorpieclOssian: Erepnits ElyKievierer pRiityl, origtaeoe,. 1% 1253 cn, rigt opwielrls,slant St vamRopn, sssing---- ChFTaaitnraviaretadcotwsc,nirowunmaailslltliaetraaeatwrtaoilocnne,,l vsicinesfliaallttreadt,e, ailtdd Psrpoijnest:haabter: OIC C01761 Sanrive st ges 277 SInudminvriidzunald MSaicnrgolsecoTpaibculaantdedMifcnriossalcopRiecpoDrtbar(vcoanttiionnused) PIA Tao YuHrikeGralLiTboorsaitcoirtiye-s,DcoTpice,nci3t1y Study in Rats Tae: 2 fFaatiel HMaesehser: 96I)RASLcZrSiicedSexi:n FeetmraelneisSeow: { 1) CONTRL 0 pp WicrLoiscgapc Oservations (cantined): LHaussahryNoEtlean(daesenteric) PTihtyuriotiadry verse "pPamecni, interstitial, chronic, witifocal, AFvereisvlaasrcuslaacrrospohvaogmesc,leaalr-dndiltrte, wild "FSiibnruasaoidearlonectsia, sofeate "Foblolriocunlar hyperplasia, cystic, wilatera, twhilidn sors lisits Fever than protocol muster TShaeinf,olSlopwiimnlg Ctoirsds,aeBsoweerNearfroouwn,d Staolebeen,wiHtehairnt,noSrmtaolnclhi,nitSse:al Intestine, Lurge Intestine, Urinary Bladder, rts, Dury, Tracks, Parathyroid, Pancreas, Salivary land. Ffartiee:dMMeaesthser:100R)4S6ac4rificedSexi:n eFxemraelneisSeow: ( 1) CONT0RpLp WacrPoistcuaiptcarOybservations: Henney Bland ung MicrHoiscroepinc Observations: idney Liver tng Nasnry Slant oury ""HUelvcoerrrahtaegd,icempasstsi,c 0s.a6ss,ct4d1ia4. 1 35 ca, in 1sl0t1ilmoiblallaarthsraosast, a6r.e5asx 5.51 3 ca, in right "hailnsgeudinacliracruelaa.r nodule, 0.6 cb di. in leit Ia S"Cihnruosniscidparatgraesssi,ve csoerhtreo,paateyr,atwienisal "PFeolrvtiacl isnoenrsanlcilneaatriocne,lsiilndfiltrate, wild PHoerptaatlocbyitlee vdaccotlaptrioolni,fermaatlitoinf,ocawli,ld aild "sPioledacnl, interstitial, chronic, witifocal, RLeitrugteateitcansetpuliassnof susary adenscarcinons. "MFeivborcaadrecnionnosns "tpt, wilateral SPrpoejceicets:MuRsabter: GZBICROIZ C0176% Sunarized STR Pages 8 278 STouirtifoue Rivneae TLcaauraaatnerddireio,anleseB.eMtescroanttiionnu) PH: Ta Yur Ba Teib-Bcscty Seat in ts Tate: 2 oFbn eYrsoB2Se4rvicedSein Fiwrioensrns 1 CORL an [oAtitherr---- trotimbit tn ste of ston ive TJeopireis, wtradulry, inrist rThae nfllSoepvitogeiarstysooewrWerarfono,ndTHtoeorebte,saSTtvrhca,ssoSrsaa]Lbinetees:inig,hLhugde naeetirni,cl, Faces, Sry an, En Fere eoersoyTSureticerd 1s rFoeenGrp 1 GORD 0 pn NersacpwiiatcyartyHerdtions Stnatresadum t2o0radeadrwesf, 1m.i2lcoidi. rsboreterdtartionst SSoeaptwitahts, rn Canta JSonpt-- ipoan So en wit brrt Jnieidran pcor,s,wriiekooatwe cntion, ihtor fDtrarirtrervecssiievletogon,vwhaltti,stosw,raadaa wYPeyrwaaryitand HTJootewrrainedn,Tosat es hts in plane of section SiPeeway hSotiers, at TT ihenflle oving iotsayaovweeresNafroruonwd,rotSootnbseechwLyiothSinoromksateiLnniogsr:Lcrhg, Ptreseas,Sarliivaary SBaland,e, SPpreocjieecst: NRuaatber: Q2BICRO0IZ 01763 sari srg 279 ASIunsisvairdTiuzoaeldYRSuTicrnirgkoBlaeaclpTLTiaabceausla4tctnoderdiiAerOn,icosganileei,iReccpto3sr1ytet(rcoovnytiinIsuneda)ts oie: 2 eFrtt rwker10D9 tTsosa SSaucriFfiociee Sag (1) COMO 0 pn WMerorstcnsiictyBBaaraarttiioonnss:: Suse wan, 09 cud. Kairtenr P"PeDcirccornsscpicrywogtrroiensss,iivcbenie,gv,seiwntisel,temodderate Puvnsrerses JJSaaasctraalitnsesdrv,aalcssitlnatt1iiooh,naleitdof ase,ctionald Piniltytors Siem JSJeaasteraindirsoeni,, s1ssding hrUeitnftlaBroreg,ArtriMosasnureBsyweelroedSf,otuoTnidrcoa,cSbheuwTlihtheaidn,tnorEembalaLeLrsig,t:TLtehstnboed,e U(reineanryarBiacb,erF,ofcorats,, Salvay Shandy Ere Fnaite! estres194) TGerao SScxifFicoee Gru | 1) CONTR 0 po [ti-- ty -- Kana on AFire n1a1n054.5c3n43 35 a rigt ater wien wToilsar a, 73635 ch, Wraarepn) Baartions: Stillnarsy caacltapieasctorote,, nmiddee, ald hart ity rDweeiatraiifreoasrlo,,gsarlsdiovensnemosppthryt,inwedrte ir "Fata srociow cal ahr, id ' Portal bile duct proliferation, soderate ng Psriirn rabies, ad Hepatocyte alteration, basophilic, woderate er APdewrsaocpsutacaiivrosnssraimesieewesaiplraece,in w4ild ory iilryasnm.o, wilson ont, iiaer SPpreaceieets:NRaabter: OHO 01764 sunine spe 280 SInudairviidzueald MSaicnrgolsecoTpaibculaantdedMiMcnrionsalcopRiecpoOrbtse(rcvoanttiionnusnd) 3924: Tao YeaRrikDeeralLiTbooxriactiotriye-sD,ncoIgnecn.ici3t8y Study in Rats Table: 2 MFeatien:l (MMuesebkesr:1051)6-T4e2r7ainal Ses: Female Sacrifice Group: ( 1) CONT0RpOpL NicrosPcaonpcirceasObservations (continued): Parathyroid Pituitary sUtkeirnus ""NIostleetxacneilnleda,densootnin plane of section "MFeibnroomns, subcutaneous ~Eystic glands, wild The following Brain, Spinal tissues were found Cord, Bone Narron, tSoplbeeen,witShtionsacnho,raaSleallliniItnst:estine, Large Intestine, Urinary Bladder, forta, Trachea, Thyroid, Esophagus, Lysph Node (aeseateric), Salivary Gland, Ere. Ffaitnea:l(MMeaekkesr:1051)6-T4e6r2s8inal SSaesc:rifFiecmeale Group: ( 1) CONT0RpOpsL. Nacroscopic Observations: PNiatsuaiatrayryEland Nicroscopic Observations: hEisorpehmaaglus. Kidney Liver LuNansgsary Shand Parathyroid Pituitary Hass, "nll n1o.d2ulceo,diLa,S ca dia., right arillai possible silk cyst. "Sinusoidal ectasia, cortex, soderate ""PNeoltviecxassiinneerda,liaziastsiionng, ininal "Hpeorattaaleybtielealdtuecrtatpiroonl,ifevraactuioolna,teda,iladild "HVeapsactuolcaryteainvearcauloilzaattiioonn,,mualltdifocal, aild "SAadleuncotnsa,celpeapillary Staoals]evheirgalhlyLacregleluglaalractsoecoopellass.a lying adjacent "Kot examined, ot in plane of section -Adenona TBhreainf,ollSopwiinnagl tCoirsds,uesBoenereNarfroouwn,d tSoplebeen,witHheianrt,norSmtaolsaclhi,sitSse:all Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Dury, Trachea, Thyroid, Lysgh Node (esentericl, Pancreas, Salivary Gland, Epe. SPrpoijceecst:WuRsabter: 0781080012 01765 Summarized STAR Page: 90 281 SInudairviidzueald NSaicnrgolsecaTpaibculaantdedWiAcnriomsaclopRiecpoOrbtse(rcvoanttiionnused) P3928: Tuo YeaRrikeeralLabToorraitcoirtiye-sO,ncoIgnec.nici3t0y Stuy in Rats Tae: 2 fail Fate: (Meueabkesr: 43R)-ASEaTcSrificeSdexi:n Female Group: extresis ( 1) CONTROL 0 pp Macroscopic Dservations: Liver MSapslaeaerny Gland Wicroscopic Observations: hired forts Esophagus Kidney Liver Lung Nasaary Gland PSaalriavtahryyroiSdhand Spleen ""dSelriyghptallyeenlarged -Lawrigteh subcutaneous ass, 63 10 x necrotic areas, containing 2.5 ca, dark brown Fluid, ventral abdosen. "HSeimnautsoopiodialesiesc,taseixat,rasceodrutlelsa,rya,ildcortical, wild HHoott eexxaamniinneedd,, aaiissssiinngg "VCahcruoanliactiporno,grceosnsvi,vetpbh.roeppiatthheyi,us,sisnoidmelrate "Hepatocyte vacuolation, centrilobular, marked ~Hheasscoarlhaarges,inmeirlatliifzoactailo,n,ailldd "AWeeolclardicfifneornenstiated, ductalar pattern, areas of erate aitotic activity, large areas of "Hnoetcreoxsaissi.ned, not in plane of section ""HHoetmaetxoapssiineesdi,s,miesxstirnagnedullary, increased, wirate The following Brain, Spinal Ciosrsdu,esBosweerNearfroouwn,d to be Heart, wSittohsianchs,orSsmalalllisIinttse:stine, Large Intestine, Urinary Bladder, Uterus, Ovary, Pituitary, Trachea, Thyroid, Lyaph Node (sesenteric), Pancreas, Er. Ffantiea:al(Mbaesethser:105I)RTAerEainal SSeaxc:rifFiecmeale Group: ( 1) CONTROL 0 pps. Macroscopic Oiservations: PiNtausaiatrayryGland Microscopic Observations: renal HeEasrotphags s~Lsob,alar0.7macssa,d8iax 61 4 ca, right axilla; lobular aass, 91 7 x 3.5 ca, leit inguinal. ""Shiontuseoxiadsailnede,ctaasiisas,ingcortex, saderate "Mwyaotciafrodciatlis,,wiclhdronic nonsuppurative, PSrpoejceicets:MsRabter: OZ01CRO0IZ C0176 Susnarized STAR Pages 91 282 SInudsinvirdiuzale RSaicnrgalsecoTpaivclaatneddNiicnraslcoRpecpoOrbtse(rcvoanttiionnused) P3124 Tan YuHrikeGralLabTooriactiotryi-eOsn,coIpce,nici3t%y Stady i Rats Tale: 2 fFaotasl tohbeeir:101504T6er3anal SSeaxc:riFfiocaels Gra: 1) CONTROL 0 pon Hcrasicepirc Obserations (continued): Live Lng Haury Slant PPiatruaitthiyrryoid Solem "Fpoerltvaicl ssioanracllizeaaticoe,llaifniilmtlrate, wild FHoeratatlacbtieleadltcetratpirolni,devraactsioolna,tea,ldwild HHeeaptautcayyttee aalltteerraattiioonn,, beasssoipnhpihliilc,ic,woaeirldate "Psecrailvaasrclsairnesaolnionmactlieoanr, lfidltrate, wild FHieborrarshdaegneo,nsmitifocal, alld Foibhrosaduetnoosn wre fibrademons, reas of otcreaxsasinen,d ncaytstiinc parleaans oifn steocrtiso,n T"hHeeuraotnosoiesis, mtrasdallry, increased, Hleodsideronis, aild BTrhainf,olpoiwinnag Ctoirsds,ueBsonseerMearoruonn,d Sttoonbkechw,itShienllerImnatlestLiinmei,ts:Lurge forte, Wheres, Day, Trach, Thyroid, Lyaph Node (ester, PInatnecsrteianse,, SaUrliinvaarryy BBllaadne,r,Eye. Faaae:] eNsatbeer:$01)4F6o3u5nd DeadSens Faale Gro: (1) CONTRO 0 pn NrosScaplilcInBteersvtaitneions: Wawa Slant Werosrceoiacl thsenations: ECroephag doy iolunnssppeearss iinnffllaammeeddsietrh reddish laid; "hcaesc,u.7x 1.8 x 2c, wltilobalar and uglhcetratbeedi,geriignhtcoilnog,uinsaplh;ersiacsasl,, 2 a da, in leit nila, "SYiomuatsspiodiaslsiesc,tasmitar,amcdourltlea,ryw,ildcortical, ostoretxeaine, sissing ovtansexipnreog,rensissisviengepbopathy, aild Pelvic siersization, sinial sPrpoejceicet: Naotbo: OZAICROLZ co1767 Sanrized si Puget 7 283 Sndoiuvwirtiuzaeld RSiicnktglesecTLpiaoisrstateonrdiHeiisc,aralnscco,Rpecp8ratra(ctointoinnu) PSA Too Yer eal Toscity-Bcopeicty Stay in Rats Tie 2 iFavtea tNhoeets 41FAon edSes Fowler: 1 COMRL 0 po Wcroslcpric Osevtions (continues Heaupattapcstresiic,aetriaotni,ldliiffnu,se,alwdild [ "Ktsistattliaeaiaccitmilrvaiiltyis,saeitnicorne,as#e1,4sderate [--r-- fiErcirueresciivnoenros. PaHraithtyoid Sth sind oJatt amiioned,, sitsiingple of section Slt canoe, aieiny Sie Swenitgoeieis, mraselary, incre, Troe tiabancia ent hBrieinnfr,oylSlhwpaiebnegertC,iosdKs,uoersBtewnrWeaNararersuo,wd,BtHaorabyr,,wTiSettchahiinec,he,LaSaaplLdiIenst:es(tnienes,ntLrairgce, IPnatnecsrteianse., oFiierl tbieer:165U) T6oriml SSerxifFicoel Grom: | 1) CONTR 0p RcrostcapircyOSsiaen an: lier Werosrcpeicl Osarvations: sKnretr Cwrr Intestine Lng Fa irs FPiaaratthis uSisltinyrirgihtseildaark smeanre0.t6oc befailek, e1s8t8. teal ab, aSrtuicsalivasaseaatsio,n,sofrtus,l lidtd A"opvseanraprobgroessssiv,e sselrtiofsaaa,l iwitled SHeawpttautoateetsv,iocloalotnion, sltfacl, itd ueVpaaetotlcyoesiaawlltrteelrriaatatitiooinn,onsblaaaiitdlecd,, laldd AAavhettaapsircrpaaphnge, ald cJoinvaisntlryo,ok#1i4n plan of section Jaen SPrcoijeent: Nfaathr: OOH C01768 Sumarined STH Page: 35 284 Snusisairdiuzead NSiahinrkgoelsrecTLpaiibbcuolaaatntdrediReAcsn,risoanslca,pRecpo3hratrv(caotnitionnused) PHS Tao Yer ral Tesch Sncapicity tay in Rats Tate 2 aFuea: enseer,1051)4T8er%ainal SSeanctriFfiociee Geoupt 1 CONROL 0 gn Wcroshcmeiec Osenticn (continues [E---- TBDhaaeiynf,,olTSlwapitinnsg,tCiosTrstr,ueasBo,wnereEarsfroopwde, ntSotoabLeiychws,ithSNiaonielraIanstekstLeiinmreit,,e:UrSiavalrvyaelyaSdarn,,oErpt,, Wheres, aFuren:t GYesahre: 82T) STacrificeSd ein PeexarleesisSa | 1) COUR 0 pe Wcroscpic Bsarnations: tnPituitary Werslcoeic Bsernations: oKiene ttengr ~FRuedcdaeneadremaassso,f 1cocmooldiiaa.tion in ater art soof urisghtpaanlde left lung. aTerbtviictss,erastainta,tisonh,edile WGnreaatleipartoioe,sicnosrtiecparl,aaatlhdy, ald HSreepatmsirat,s asataeltsiuond,sipveeriToorall,reaid,rate wFeartiea, wtifaal, ite FMSaisrasearyy Gland eres v~SBeaowlascnittocreslses, trate etic hans, aterate STaheinf,olSlpwiinnag tCoirsds,ueBsewnreNaorruodw htoabre,wSitthaicnha,rSmlLiInnteesstine, Large Intestine, LWripnryNeB14e8esro,tebrrtiecy, Darcyresr,ahSea,baKryenGt,nToi, Farthyrsi, Esphages, eFaiked eYbh:1654) T6rwial SwersiFtees Grou 1 COMROL 0 pon RcroFsiptuiictirOysarations: Werorpeiacl hearations: Fas hss, 05 c di. SJoitnseiitnlew,tasssisai,oncartes, ald SPpacgiest:aabter: mia 01769 Susnarized STAR Page: 285 Suarized Single Tabulated drial Report (continued) Individual MaRcirkoesrcoLpaibcoraatndoriMeisc,rosIcnocp.ic1Observations FI-3924: Too Year ral Toricity-Dncogenicity Study in Rats Table: 2 MFoaiteea:l (MHueaebkeer:1051)8-T4e6r3a8inal Sex: Fesale Sacrifice Grows ( 1) CONTR0pOpL Nicroscopic Observations (continued): KLiidvneery LMuansgnary Bland Parathyroid Pituitary Spleen Uterus ""PCohrrtoanlicbiprloegrdeuscstivperonleisfherroaptaitohny,, aaiilldd Hepatocyte vacuolation, sultidocal, soderate "VHaostcuelxaarninseidn,eraaliiszsaitnigon, sild "Hot exanined, tot in plane of section Ho diagnosis, inadequate section ""CHyesataiscidegrloansdiss,, naairlkded The following Brain, Spinal tissues were found Cord, Bone Marrow, Hteoarbte, wSittohsiinchn,orSmeaallllisIinttse:stine, Large Intestine, Urinary Bladder, Aorta, Trachea, Thyroid, Lysph Node (sesenteric), Pancreas, Salivary Gland, Ee, Dury. minal aber: (R-A639 Sex: Fesale Group: ( 1) CONTROL 0 pp. Fate: (beeks 56) Sacrificed in extrenis Macroscopic Observations: LSikvienr NicrKoiscdoopeiyc Observations: Large Intestine Liver LNuansgsary Shand Salivary Gland Spleen Uterus ""MSildisgthetrlnyalpasluebcutaneous sass, 8x B13 ca "pCehlrvoincicsipnreorgarleiszsaitvieonn,epwhirlodpathy, ails ""PNoerataatlofaiosnioss,uclceoalroncell infiltrate, ail ~Hesorchage, miltifocal, ald ""FNiotbroeaxdaennionaesd, aissing "Heuosiderosis, aild "dithin normal lisits Fever than protocol nusber BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonveerNearfroouwn,d tHoearbte, wSittohmianchs,orSueaall]LiIsnittse:stine, Urinary Bladder, Aorta, Gury, Pituitary, Trachea, Arenal, Thyroid, Parathyroid, Esophagas, Lysph Node (sesenteric), Pancreas, Ere. Species: Rat Project Master: C2010R0012 01770 Suaarized STAR Page: 95 286 IntiviSduuan)riMaacerdosSciinpglce 1TndauMliactreodsciopniaclseRrovrattions F398: Tao YuFrietrralLibTosriactiotriye-sG,coTgoecn.ici3t0y Stady i Rats Tae: 2 fFaotiel tahebsekre? 90I) TFoTund DadSex: fle Geo: (2) FRITH 100 pe MacrosScionpic Ohsrvations: tSpuleren Wicrohsecrapeinct Observations: fEosorpahagus Liivteerr Lng FLaoschresNsote (asesteric) PPiatriaitthayrryoid Prostate SsaullilvarIyntGelsatnidne Soft Tissues (hse) stem TTrhaycrhoid inary Hatter "Hoaask, w5d1 e4nlaar,gedT,ei side of bead, ottind "noretiocfalpavracporleasteinotn, aild oott esxxaankiinneedd,, asiissssiinngg S"oOrvtoanlicsapnroogmrcelsesairveceplblraipnfaitlhtyr,ates,insiienailsal PWaecpttaolcybtielevadciucotlaptrioolni,feiraftfiuosne,, ssiondienrlate "NVeagsacluolcayrtossiimse,ralmiazrakteidon, aild ~vheeolrrahrages,ic#ro1h4ages, 4119 Jott eexaanmiinnekd,, saiissssiinngg oott exaansiinneed,, ssiissssiinngg aHitthiunasvienrea,l wLiisnsiitnsg HFeenwenrgitohsanirpcrootnocol suse Lwisrclgenefrsopnlaswidein ocfombeecdt.iveSotliisdsuaereaansdand Ltarogescurorvouenrdisngvawssccullea.r spaces. Infiltrative --haelnetopuiesis, ntrasedullary, increased, lHaetrseixdaernaisnies,, iasislidng aJtt eeaassiinnee,, wsiissssiinngg TBhaeinf,ollSopwiinnagl Gtoirsds,uesBownetreMafroruonnd, tLoarbgee wIinttheisntinseo,rTsaelstlinsiEtpsi:didvais, Eve, Heart, Stomeh, SPrpoejceicet:MaRsahter: 081CR0012 01771 Susmarized STAR Page: % = 287 SInodairviidaunadl aSicnrgelsecTpaiuclaatneddHicrnoaslcoRpecpohrter(vctonitoinnused) FIST To YeRairkeGralLabTooriatcoirtiyes-,GoIonqc.eicStNy Stuy in Rats Tale: 2 iFanea:l Oeesrte: 40()RF5ou6nd DadSe: Mle Group (20 FRA 100 pon HcrSasicoepic Bsermtions: Liwvienriy Blaster NeroPHsracoraspttcatseervations: KLiidvneery ngi SiPanstte einiy Baste cPosasitbley sfliagnhptaltyspale and mottled. Dirsatdeidsehdfilnukisd.bios ad 110d vith Slightly enlarged and thickened. cwritiiftoasl,, iclreaic sensative "FHDoerrpettnaailecystpeorongvranecsueslilavteicoeanp,lrsmiptnftiihfltycr,aatlei,,lialld "Cisactaloyrdaepneeearlaitziaotni,onw,itwiiflodcal, ald FFortousfaetniattiist,iss,atuel,cersaptiuvre,tinnrgiedried Cystitis, acute, diffuse, wried TSeThsaetiif,solESlpopisadiialgdptCiinsst,s,uPeiostnuveietraHerayrfr,oouwnM,dilLroeebm,e,wTihtShroienw,ae,rPmaaSrluaaltLlhiriIotnist,:estTirnaec,esL,irEessIphnatgeesst,ine ort, Loh Nake arsenic, Pures, Salivary Glad, Ere. iFaae:l eeerks1061)05T7e0r0inal SSaeccriafilcee Groups (2) FSA 100 pn Rcrasbcaoipnic Berton: Wershsiarpwiacl Bsevations: bain XHiodrotey Lligveer ntetine "Dtrekrairoer, ripgohstsibcloyreohladlesboarsrhhesres,.on "Haarttriccayltovma,cuobleantiigonn, mltifoca, sedrate LMiargeernseopgliatstmewctahlsconitnraclrictayv.itation, H"yvsacnrediparoFgirbersoisinse,naeplhtriofpaotahly,, iilled TAeowrttoadinvios,mcoaloncell infiltrate wild FHoeeattazlerbtileevaaccotlaptrioolni,fermalttiionf,ocwai,ldsinioal Cita degeneration, witidocal, ald RHeepaalteocryttoeisal,termartiieodn, vacuolated, eild SPpreocjieet:Nhaabter: BING 01772 Snrized STH Page: 97 288 STunmairviizdeedn aSirnoglsecpaibclaatneddMhiceraoslcoRpiecprrta(tcoinotinnused) ier Loratrie, Ic. FN-3924: Two Year Oral Toricity-Oncogenicity Study in Rats Tie 2 iFatee Goweeer,1058)7Te0rinal eSasctriafilcee Gro (2) LIV 10 an Wcros(c4pic Oserntions (cntoueds TPhpraorrsaettahetyeroid "Hsvaalra msicnralaiezt,ioa,idald roetstteiratthisn,d,senotte1, ssglparnaetiofvessecitnioinnal "a, caloid hSTeianoatltCaoowrritgsoso,sFsFrriowtnr,teopfnieneTd,ratcoShoebsmecwEhi,sthhiSnealsl,oIaLnitegsLhtiitnoeed,:er(aerntyerliac)d,e,Prhcorrets,, Suir Sat, re. oFiiteeeNsaveer1690 ) Trsival Serrtifaclee Gros 2 LITA 10 90 Wcrosacrpiyc BSsvnations: Kietoel fi [EerOt -- lriines SSbcratluens sass, $1315 a. i hte ised circular Iason 1.1 a diy iin lobe, svceacrtprefreesoisne,eforals, twi,ld Septuote waalaion, diiuse, asriteetde eNeagtaaccrytasssl,tasaattieorna,ievcislates ail Lng HPaariatthiyroid P4rostate "HeVyvpeearinplnsas,tsiicnertnaosldituzltietiiaon,, cwvdeeiact,e watifoal, he SHAylevpeeroplsairssiancrosplheagrets,e aild TFoipresp,iaisacefoncael,setre Lfiovreasaisoan,id mapas with abst collgen STUahreiinnaf,roylSlBoiawinbneCtroirdsR,stuBaonwTereesatrifrsuolwnantSdopiedberenr,wsi,tShtoirmneacoshr,sa,SleTliolnotrnsde:,srtscehesL,argEexbIangteesst,ine, uh ode (enterit, Pac at, Savy San, Er, SPrpoijeest: ahbtr: OIC 01773 : Susmarized STOR Page: 98 289 SInudmiavirdiueadl MSaicnrgolsecoTpaibculaantdedMiincarlocaReppoOrthse(rcoanttiionnused) PRIN Tua YaRrikeGralLaTbooriactiotryi-eGs,copTecn,ici3tKy Stady i Rats Tale: 2 fFaoea:l tMhbneksrs1081)05T0er2inal SSaeccriWfailcee ou ( 21 FITZ 100 pp Rcrosteepic Biervations: Wcrusicovpric Oarvations: aArena Ldiveery Log PSiltueitary "Exbtoendsivseamiplnifnlga.sstion in right eve post Hotties ""Suiompshotiadllataicst,uss,nicloartteer,a,wiwlrdked iTroorntiacsporaognrcelsseiwvecaelglbrfpialttrha,tea,ildald PHopratatlacbtielevdicotlatprioolni,ferfautisone,,aoldderte sNceagllaacryossiinse,ralmiazrakteidon, ald HPevrovlaasrculsacrrosphoagnesa, rilfiltrate, wild "Steysscts,idaerrsasdsi,stwaillids TFUrrhaiinnaf,roylSlBpoliianndagderCt,oirsesH,uoerostn,eerTeMeasrftroiousnnf,dEHptdeoiabgren,awsiS,ttohmiPanrcohsn,toartmSeeaa,ll]TlihIsyntrtsae:s,tiPnu,raLtuhrreldI,nteTsrtaicnhee,s, Esobags, Log ode fosanteric), Pancreas, Salivary Eland. iFantasl hNealbeer? 79R)7S0ac5rificeSdenitn aexlreenisGrp: 2) FRO 100 pon NaroPsictpuiictarsyervations: Wicrohserpeics Ohervations: iter Liver um Fiptaucirteasrsy "od aa, 1 cn "CSoirmtiscsailalvaceucotlaastiiao,n,cofrotcea,l, aainiinmiaall "CPvraenliocnppirvoigtrse,ssiavceutee,pharsoptartahtye, aild "oForrttaall sbiolendacttaprcoellilferiantfiiolnt,rataei,idwild HNeepaltsacoynesvi,csosliantiimoanl, witifocal, aild sHcivaeollaar ascinreorpaalgizeast,ion1,16ald iHenorarhaagter,ophmyt,iffooccall,, sailvigal "barons sPpreocjieecst:NRaabter: OBICROIZ 01774 Suanarizes STAR Page: 99 290 Sumnarized Individual NSaicnrgolsecoTpaibculaantdedNiAcnirmoaslcopRiecpoOrbtse(rcvoanttiionnused) F392 Tuo YeaRrikeOrralLasToorraitcoirtiye-sD,ncoIgnec.nici3t0y Study in Rats Table: 2 fFantieo:al eWuksbeer:791)R-TSTaOcSrificeSdesi:n Male Grow: extrenis ( 2) PN-IAZN 100 ppm WicrPorsocosptiacteservations (continued): SStpolmeamcnh Testis/Epididynis Thyroid "Prostatitis, acute, suppurative, aild "~EHedseons,idesruobsmicso,saali,ldsoderate "sTiunbiunlael atrophy, aspersatogenesis, unilateral, "Hyperplasia, cell, ild The following Brain, Spinal tCiosrds,uesBowneereNafrroouwn,d to be within Heart, Sell nIonrtmeasltinlei,mitLsa:rge Intestine, Urinary Bladder, Rorta, Parathyroid, Traches, Esophagus, Lysph Rode (nesenteric), Salivary Gland, Eye. AFoaitnea:l (Nhaeebkesr:106()R-5T1e0r0ainal Sex: ale Sacrifice Groups (2) FR-I924 100 pom Macroscopic Oservations: KPiitdunietyary Nicroscopic Observations: hirenal Heart KiLdaorgeey.Intestine Liver Lung PPiatruaitthayrryaid SpTlesetmins/Epididyais ""ERnaliasregdedw,assp,ale0,.9p1it0t.ed7.ca dia. ""MSyiomcsaoriddiatlis,ectcahsrioan,icconrotnesxu,ppuwroafteirvaet,e witifecal, ald "Chronic progressive nephropathy, sarked ""pNoerstaatlotisaosniosn,uclceoalroncell infiltrate, aild Portal bile duct proliferation, ld Cystold degeneration, focal, eild sPcreaulsaanria,ainienrtaerlsitziattiiaoln,, cshirlodnic, multifocal, "Hayipderplasia, wild H"Heersocsnisderosis, ald "Tubule atrophy, aspersatogenesis, bilateral, wPoiltyraartteeritis, nirked The following Brain, Spiml tissues were found Cord, Bone Karrow, to be within normal lists: Stonach, Seal] Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophages, Lymph bode (nesenteric), Pancreas, Salivary Gland, Ere. SPrpoejceicets:WaRsahter: 0261080012 01775 uric st page: 0 = 291 SToniavriidaeandl SBiirntogelsrecTGpabiusclaatatuedidoWMisci,rnaalsco.pRiepco3rOths(ecvoanttiionunesd) PIR: Ti Ter Bal Toisty-ncogeicity Stay in Rats nae 2 rFauteah ebeekrs1081)7T0er5ainal SSeuriifMilcee Groups (2) FIA 100 pon NcrosNceospeincterOyserations: "ltousat cofpthiecatLeosni.on, 413 a di, possibly Woroscraepaicd Barnations: "CSoritiscaallvacctautiiao,n,cofretcea,l, rsoddeenrttse Liivneery aordeulnaer hprpoaprrleassinie,ocpirtoessu,thfya,cila,ldsoderate Fartl seonclew cel infiltrate alg Peoprattaocbyitlealdtuecrtatpiroonl,ifecruatliaont,ea,ilwild BWpeelrslyatsatincs,nodmudleerate Nesrsgnery nastelar inealiztion, ross Lesion was Large wild sic stricture with asonnyanhceslaesaidoirnifnlamamaftoryaiccerlolpshgweisthianndte Pesthesi Joltle.asine, sising STliivdry Slang Trin oett eeaasisneed Jo eigreis, iissiinngg insenate section TrUhraeiinnaf,rlylSopMisanodalgdeot,irsfs,uaersBao,wnerTNesatfriooswnE,dpsiodliebdsei,wsi,HthuiPrnr,oostoSattmoemacLPhii,ttuSeit:uarly,InEtxecstbianes,,Lrg Intestine, Lesh Nae aetateric, Pures, Eve. FTiae:neNsabter:1060) 0Te6rina SSiercifMiaclee Grog: (2 FRR 100 hn [I fri v-- Wcrssroepniacl Bservations: [hearrte itvoerry "Slightly pale "Jeonttieaalnivneadcatsiisosnin,g sltifoca, wild owcirdtihtas,, icsraan]e seospprative, "TlGFoerrtatnsleastpeernoogcnrusellseaswitrvieocnneel,lphrcioenptfaiitllhtayr,baatmleaarrka,elddarked BEesltoeotdoesgsen,erantriioend, witidoal, ald SPpreocjieecst:ahbaetr: GBICHOL2 01776 sacized spe: 11 292 Susmarized Individual MSaicnrgolsecoTpaibculaantdedMiAcnriomsalcopRiecpoOrbtse(rcvoanttiionnused) FI-3924: Ton Riker Laboratories, Inc. 3% Year Oral Toricity-Dncogenicity Study in Rats ' Table: 2 frioal Fate: (NMuesebkesr:106I)R-3T7e0r6sinal SSeaxc:riMfailcee Group: ( 2) PRIA 100 pa Ficroscopic servations (continued): LuPanngcreas. Pituitary ""Nvoatsceuxlaasrinweidn,ersailsisziantigon, aild "oyst, pars distalis The following Brain, Spinal tissues were found Cord, Bone Narrow, tSoplbeeen,witShtionnacnho,rmaSleallliniItnst:estine, Large Intestine, ULryisngharyKoBdlead(dneers,enhtuerrtiac,l,TeSsatliisv/aErpyidGildaynadi,s,EyPe.rostate, Thyroid, Parathyroid, Trachea, Ffaitnea:l (Rluesebkesrs108R)-TTIe0r7siml SSaecx:rifMiaclee Group: ( 2) PAIS 100 pha Macroscopic Observations: Liver Nicrostopic Observations: Kidoey Liver Lung Lyssh Node (seseateric) Parathyroid Spleen "Sccaattdeirae,d pianlelefiotcilaatnerdalpinlkober.aised sass, | ""CPhorrotnalic spornoognruecslseiavre cseelplhrionpfaitlhtyr,atew,iniaaialld Portal bile duct proliferation, ild HEyesptaotiodcydteegevnaecruaotliaotni,on,focmaull,tifsoicanl,i soderate Hepatacyte alteration, vacuolated, soderate Negalocytosis, mirked "Hvyapsecrupllaarstwiicnernaoldiuzlaetion, ild Alveolar sacrophages, sild Hesorrhage, focal, ail "~NHoetsorerxhaivignee,d,sonfoetraitne plane of section "Hesosiderosis, aild The following Brain, Spinal tissues vere found Cord, Bone arrow, tHoearbte,wiStthonianchn,ormSaulalllimIinttse:stine, Large Intestine, UErsionpahraygusB,ladPdaenrc,reaasr,taS,alTievsatriys/GElpainddi,dyEayies., Prostate, Pituitary, Adrenal, Thyroid, Trachea, PSrpoejceicets:WaRsabter: 0281080012 COL 777 `Sussarized STAR Page: 102 = 293 STuonavriaz)ed SRianrgelnecToapwiul4atdcdriosaanpiRecporGth.se(rcoanttiionnused) PSE Toe YeHrieBralLoTrssctrotryi-sB,roIpce,icty Stay in Rats Tie 2 iFantel tRaohe160) ESTcrificedSar1t aerlesee 2 LET0 10 pn [ tn -- Werscrpaiact servations: iEarpt s iltvoer we LSoiarNeeGhGdastric) Sim "LeefntsaLlobieatcioomnpleotfelryigchton1egli.dtad partial "Cooritircal Dvpaecpaltsioina, cIosratle,arfeoasa,laiHli oaitgnvnitneI,ihoMw3s,61histiocytic Swysickaridait,s,aeldvan mosprative OWvleignutpragtgehsoinn,s eNipshtriasnotthiyc, aild TYoerpttasebteecfuultatpiroonli,fesralttiiofn,cail,le1d sraelsaaleisna,tianltdion, sila bWeiagrasshloti,acli,stiasloetic rSassssipefairlatnrcaetioofncoonfslaipldaatsitoincdoe to oMtstsirseotnilc,tmoesIinphocris. TSaelwiigtueartasIso,nasl,e Nistiotic rTShtieenf,,ollTSooywtinnhegEtGosrpsdyuasB,wnreNParurorsodtwa,tetS,otbaFsihaw,iitthrSisan,lsTaTsrtseas,tLiiinPt,sr:Laartgesn,estTiranhga,n,UrPinnacrryeBsl.ader, iFateeh eNeolne1080 ) Terinal SSeinctriafilcee Group 2) FIT 10 pn PTSer -- Wcrscrpeinct oserations: KiGdinrey Scatterd ytlonis foci. NTaarlanac ppreorresain,e eoprtoepsty, ild FTarrtt sbnloenidccltewrtcialflraitnifiolnt,ratiel,ealg FTpeantloocprteisria,caalalcdion, ius, dete Foto alteration, bushi, itd sFproijeese:haabter: omic 01778 Summarized STOR Page: 107 294 Susarized Single Tabulated Animal Report (continued) PIKndividTuoalYMua[ rcroBsacloTpicai acndtMiSccroosqceoipicctyDbseSrtvaaytioinnsats Tae: 2 oFiitel ewseer10) Terai SSewsrfailcee rat (2) ATH 10 [TIo ------ Paratyoid "Ptseapr asisrsaolmioztmiloenn, fiilletrate, aid ok aint tn pan of stn rTBhraeirfnyolSoBpiaenbegartC,iosrsrtuetso,aerTeaskfoan tiSo1ab0er,w,itehPrinrtaposSratatwlicPihtnyrtstS:ruyl, Ihntiesdti,ne,TLerkgh,IeSthina,e Uo ote eterich, Pures, Say Sty re FMAintineal eMueseber:10IR-T37e1r0 ai SSeuxr:tiMaclee Group: ( 2) FN-3924 100 ppa. WMaccrrooHsgceaoappitcc Observations: Owarnticss {Nieotowonr Ly HTrtaiittay uied as, 09 cr di, tvorotinal pvoiraealsaitvioen,wfreceals, ts,ohaatleg FPuorrtaal abinecdicenolcearlatfiilotnr,atae,ilwld peasttaayttee ascliaaaattiioonn,, amclatlitteecyliilleo Aenlsarltoutra,lianltdion, alg APesivienisisacrrsphgme,i10Irate Wid Strilsaesia, cel, ite Utara erst hrraeino,rlSodpninniga rGHoivsrtatreB,ewrTerefootnndrtSoiebsev,wiethtirne,sstaSotteao,ircL,aittSre:aoli,nesTtriancge,s, LEugsepIan,es, Uh kode asentarich, aces, Sia Sands Ee, . rFietel Naesret1001) STTerai SSeuxrticlee rou 21 FTE 10 0 [ WarosTtenr-- ic erat-- ions: tops large ad tn, real Giatlicial bapcwarplltaiioan,,cwalttei,fcafl,cwlidle PSroijeocnt uhbter: CAICROLZ oi 0179 Sanit Sg 4 295 SInudsisvairdiuzaeld MSafiicnkrgeolrsecoLTpiaibbcuolraaanttderdiHeAisnc,irsoaTslcc,oRpecp3o%Orbtse(rcvoanttiionnused) H-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Tale: 2 aFaated: hNeabter108R)7T1e2ranal SSeaxc:riafilcee Gram: 2) FRSA 100 pn Nirosicdpniecy servations (continard: LiLvaregre Intestine ng pPaanrcartehayrsoid Siem "Freaunaitdciaprnosg,rescsoilvoen ephropathy, wild eCprattosicdytdeegvriacrwaltaitoino,n,focdailf,fussei,nimoadlerate "Naesacllaacrtoasisn,eramlairakteidon, wild <Aelivneaorlaratarocprhoyp,hawgielsd, 11d oSetacexsaeirnoeds,,nowtilidn plan of section TShaeinf,olpowiinnag iCosrsdu,esBowneerearfroounn,d tHoeabte,wiStthomiancho,raSmlallLinttess: te, inary Bader, bora, STeasltiivsirpyidSiatnydi,s,Ere.Prostate, Fiuitary, Thyroid, Traces, Ecphaes, Lygh ode (sesentricl, FTaotei:l Odeoseters106T) ITeSrina SSaec:rifKiaclee Group (2) PASTY 100 pn Nacrosrcepnailc Osernations: Hcrsshrceoniscl Osernations: Liidvneery Lng Pancreas farathyroid Badlaa.egd involving hessrrhugic mass, 21 1 ca ShineudsuolildaaylceelcltaWspie,rlcaosrites,, wwiilldateral, aHierairerdhge, lateral, wrked bSyroesnsclaypssubloartmeadlaraedsrenoaflorcgoamnlieztienlgy replaced "vhaenoircrhpareo.gressive ephropathy, wild HOepsattoacytdeegevnaecraattiiono,n,fociaflf,uswei,ldsdarate "Naesgcllocayrtoaniinse,rasldiaetriaotne, wild velar wacrphages, ai1d ~HpAocetirnpaarlrssaiitrano,ep,hyl,neatwtilicdnelpll,anseodoefrasteection TBrhainf,alSliisnagl tCiosrds,uesBowneereMafroruonwd, tSolebew,witHheianr,norSmtaolmacLhi,nitSse:ll Intestin, Lirge Intestine, SPpreocjieecst:afsahte: QZBICRAT2 01780 sonrized st pie: 105 296 Snusisvairtiuzaeld RSikcnTegolrescLTpaabiourlsantoderdirsAon,insaIlce,Rsepo3rBtsr(actonitoinnused) P28 Too Yer ea Tacit Bcopeicity Stay in Rats Tate 2 iFale twhoeet:00T) TSeainal SSewsrifWiaclee Grows {2 F410 an The ailcirowsicgpitcisOssueasrvwartieonms dcoontbina:ihin saa inary later, Korte TesiafEsdidats, rostite, PLiiaiitstayc,ntTirnonid,: Trche, Espa, Uno Noe wskteric, Salivary lan, Ere. Fiantel twhabts:ET9 ISuErificesSeicn ReareesGrows 2) F010 an [I fri -- Shin Kicrsrcepinct Bsentions: sain i.tner ung uZlceerated mss, $x 413 cn, containing ratotavmieessofnderwaeslets miavtees0g ares, Jasibly tr ar Ean acs. SNioniariahpcepalssii,scocrotret,e,aflodal, aiiasl AeNtislttiitpiecsuplilatshsi of Iyal gland "rGroinnorngrienswivienngephreospaathsy., il "eFpuartaoyMtelafcultatprionl,ferfthioen,, smairinst aWsetaalloayrtosminse,ataidzetiaotne, ale vheelairsstirasphnge,aaldinfiltrate, alg . PaSnicreTaiss.saes the) T~hcarianlaer hantearsonlpahsytn,r,csioindnfenirslattreative, with axtssive mcrosis, Suess etaplasa. iin fron stor Testis/Epicidyais Treid stTyhab,al sgblmancdonclle,arlwyaervtidsent, "CVLraeisrtc,iuglacrecelwll)ioniehdrsalripzahtaiosni, ffooccaall, sim winisal TShienottlCooritn etiossuResrw,ire Sfhoeuen, toHebaerswitShainlnonremasltiinvgi:Large forth, Prostate Fititun Piha, Trach, Espus, Lr teRsodtei,(eseoitnerryicB,lader, Sahivwry hats Er. Sfpecieas: Rapt ---- o1781 _ Suswarized STAR Page: 106 29 7 Sunarized Single Taulaed Misa Report (continent PEIndEividTuoalYMeaHrceroresacloLpoiTrcsoatnocdriMGiscc,roospnccno.piiictOybsSertvaaytioinnsRas Tie 2 rFaeet tNhaevetr:100T) TTerwinal SSecrrifWiaclee owt {21 FASTA 100 on WcroHstpuiictrOyserations: Wcrowapic Besrvtions: - Kidney Huised ms, 05c di. "FPCuhorrrotnaaicbsipmlreoogmrdeclstseiavserlcnieeflpehrrfaotpiiaotrnh,sy,t1w,1idldald [ STiAetsestimst/apryidianis Toward AvMenegalslaoacrytoassecirrsa,otpiwhnigaldtei,ona,ldald "Sreovmere, wile SSipnrrpataisziaati,os,catla,blael,e wild rThaeif,elSliinng CtoisrstueBsowerereoou,d Wtoatbe,wiStohniincha,rSmellHiInttes:tine, Large Intestine, LUrionarNyeBeabosetrerRitche, PFroasctaetse,, rSivala,tPGrana,tEor,. Trichs Excnages, iFane:l eYsolr:108T) TEerainal SSaeciriWfailcee row: {2 FHT 10 [[atist-- s Werscoopric Bsarations: plrwe wn tuFcariesr Toit oJsortrtheadgic lesion, 0.3 ca dis. eporntacl srooagnrecslseiwvecsaglhroipnaftlhtyr,tew,iniaolald pWaetaolocprtessia,cawaatriisodn, dius, sochrte aTetmtoartesianerraaitsiaotni,s,basasihdilic, oferate Fariolnt, arstitial, onc, foc, SJieeentnscolt atoms Fhelalcatar nyperplasia, cptic, wilateral, Shaeinf,olSlpwiinnag tCiosrsdueBsonwereNaorur,d Stolebee,wiBtheirnt,arSomwicihn,tSs:al Intestin, Large Tkatioe, LinuwyteBakelesyartte,,TSsatliavrarpyidSianndass,FeM.rosate vent, Frsthroit, Trach, Expats Pfropet--habe: OBIROL2 601782 Sunarized ST Page: 107 298 Summarized Single Tabulated Aninal Report (continued) Individual MRaickreorscoLpaibcoraatnodriMeisc,roIsncco.pic3Observations PUI92A: Tuo Year Oral Toricity-Dncogenicity Study in Rats Table: 2 fail Nosber: 16-3719 Sex: Male Group: ( 2) FA-3S24 100 pou Fate: Geet 62) Sacrificed in extrenis Macroscopic Observations: skin Lifvbdeornen (internal) Kidney MicrKoiscdonpeiyc Observations: Liver Lung skin Spleen Thyroid "Large subcutaneous wass in ventral cervical caroenst,ain5ixng6dxark6 rceodi Fmluulitdipwliethciynstssass. "Slightly pale ~Stonach and small intestine gas filled. "Rough surface with patchy pale areas. ~Pigaent, conv. tab. epitheliun, soderate Nephrosis, tubular, aoderate "Hepatocyte vacuolation, multifocal, wild Necrosis, focal, ld Hesatopoiesis, extrasedullary, aild "ascular aineralization, ail Hesorrhage, local areas, soderate "fMiebtraosstaartciocman,eopsluabscautaneous Nell differentiated necplasa with soderate collagen foraation. Large areas of necrosis. "Hweanrakteodpoiesis, extrasedullary, increased, "Ultisobranchial cyst The following tissues were found to be within normal lisits: Brain, Spinal Cord, Bone Narrow, Heart, Stosach, Seal Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (mesenteric), Pancreas, Salivary Gland, Eye. Animal Nosder: IR-3723 Sex: Male Group: ( 21 PU-3924 100 ppu Fate: Gheet= 106) Terainal Sacrifice MacrLoisvcoepric Observations: "Enlarged with scattered pale foci. Microscopic Observations: Adrenal LKiidvaeery "Lortical vacuolation, focal, ald ""PCohrrtoanlicsopnroongircelsesairvecenlelphirnofpialtthrya,tei,ldwild Portal bile duct proliferation, ail Hepatocyte vacuolation, multifocal, soderate NHeegpaaltooccyyttoesiasl,temraartkieodn, vacuolated, ild SPpreocjieecst: NRuastber: 0201CRO012 i 01783 Summarized STAR Page: 108 299 SInudainvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMiMcirsoaslcopRiecpoOrbtse(rcvoanttiionnused) FI-3924: Too YeaRrikreralLaTboorriatcoirtiye-sD,ncoIgnecn,ici3t%y Study in Rats Table: 2 Meinl Fate: (Mbaeedtesr:106()5-T1e2r3ainal SSeawc:riMfailcee Group: (2) PR-IS24 100 pp Wicroscapic Observations (continued): Lung Spleen Trachea "--HVeassocsuildaerroasiinse,ralailzdation, sild "Tracheitis, chronic, ail The folloeing Brain, Spinal tissues were found Cord, Bone Narrow, to be within normal limits: Heart, Stosach, Sall Intestine, Large Intestine, ULryiingahryNoBdleadLdaeers,enhtoerrtisc,),TePsatnicsr/eEasp,idiSdaylviivsa,ryPrBolsatnadt,e,EyeP.ituitary, Thyraid, Parathyroid, Esophagus, AFantiem:al WNeoeskbser:801)6-S5a7c2r4ificedSexi:n Male Group: extrenis (2) PACITZN 100 pp Wacroscopic Observations: skin Lung Spleen fodonen (internal) Kidney Liver Wicroscopic Observations: torts Bone Heart Kidney Liver "LaLregfet, isnugbuciuntaalneaoruesa;ascosm,pl7et1elbyx 5 cb in surrounding Left hindlisb. Mass very firs, hard and gritty upon cutting, Boney in appearance. "RTaeifsted,Tobweh;itirsahi,sedcicricruclualrarmaslse,sio0n.,6 ca dia., 0.3 ca dia., in right diaphragaatic lobe. "EHnalradr,gebdoney, soltilobular mass, 2.55 21 2 a, in orentus. ""SHayadlroawheiptoissihs,leslieoint, 0.2 ca dia., aedian : 0o.b4ercasdmailal, pLaelfet yellatleorwailsh loLbees.ion, "Not examined, "Osteosarcons, ising indie Large neaplasa ith abundant new osteaid and "tbyoocnaertfioarlsatfiicbnr.osis, focal, aild "CHhyrdornoincephprroosgirse,ssiuvneilanteesrharlo,patshoyd,eriatles Neshrosis, tubular, soderate "Hepatocyte vacuolation, centrilobular, wderate Negalocytosis, ald Malignant Iysphons, Iysphocytic TLaorogegroLsysmlphyobdleassctriicbecdelnlosduiletshcvoemspiocsueldarof niurocnlestaenodshairgchonaitceetlilcs.activity. Ditfersnt SPpreocjieecst:WRaasther: 0Z810R0012 co17I.84% . 300 Summarized STAR Page: 109 SIonniriveld SMicgtloescToapul1t4edRIcrnoisacoBngcetO.ancvattiionnn.t Pat To YeRueBwalLTioeactcinc,ongci.ct0y Sty fn ats Ties 2 eFirtee Naerset 2WSTacrificedfein lateresiaeos (DFR 10 0 [I v ------ sesarlthages,isTrolaiztaireoans,, swdledate rNiotidn naeaetayses of sstosrcon Hpiaerannoid pSetnrpreeoesnsts,owned, ntra, incest, sid Lieeal semen TTBhreeifnenSlptoaensCot,ivstsyuePsroowseteartere,fosPnaottStotobywe,acwhiMthrSiunal,srtTelrsactieinsn,t,eE:Lasrgpe ,ateCsot,eUkrisstleardie,c Pure, Sway St, re. FiinteleNsoert10B) TTerai SSuerifmilces fog (2 FR 10 an [5I ---- [ane -- To bert fitwor "aetsdsosepiinngf.usion of rigt ne sie Ae To wars ait salle, eetppihlraiotaiylsa,taiyse,itwsidlaeurnatl,, abriksndds, OSirvaocinairfdcit,pirso,gwrietlsadsimveermoapsas,ivaenual oatrtaa bsilae dmuckesrclb}ertiioin,t,ailald wn aHsCveopatatntaoadcrtytdeoaenv,aagclurimoelaabsti,ieoonsn,f,mcusl,itisfiaollcael, wild MFueelatarrorobtees],raeird [-- Ao erate nt 10 Lan of sction ehreainf,nolSodpnaiagrtLoirteseoweereertfniognsdEd4p3Lerbeea,si,tSitrosmoaucnht,aes,SaPLliaItan:tres,tinh,eaar,e Ttreotii,onTrchs, SFpeaciees:Naabter: oiioLz 001785 Susearized STAR Page: 110 301 STnowiavriidzuaeld NSairngalsecoTpaiuclaatneddcnirslocRepotrtha(rcvottiionnusnd] BR3924 Too YeHrikOerralLiTosvctiatys-G,cogTecn,icity Study in Rats Tate: 2 aFlae Gteber:1087) 2Te5rsinl SSaecriWfailcee rg: (2 PRT 100 pn The fHocllroowsicnagpitcisusuresatseireofnou(nattiovbaen)wi:thin oral Lists (continued: Eigse, Lip tae aseseric, Facren, Salivary Els. aFatae: etbkr:106R) TTerinal SSueeifWiaclee Grog: (2 FAV 100 gn RcrosictauiictiByiarvations: HicrLosicepirc Bserations: [hrrese Liavneer ung SPiltueitiry Testis Eidiepis RSauisledshcateterreed splelefsoicni,. 0.4c din oSitnuseoxidaailnds,etasss,ingcartes aininl v"oartnalesporoongarcelsesairvecenlelphrionpfaitlhtyr,atea,ilwild HHeepaattuoccyyttee vaalctueorlaattiioonn,, vaitoilfaotcea,, aweirlate sRceapllaarcesisn,ealsiondaetrioane, ald H[eorrryhage, wltifacl, wild Sdutli]erepasptiiltleasr,y oxlase ona his, ell Steastorsoindross, aild "star sneralization, sisal TShaeinf,olplwiinnag Ctoirses,uesBoanerearfruonsd, Htoeabre,wiStthoimnachn,orSmeallliInnit:estin, Lirge Intestine, Fianreas,HaSdadtiev,arKyarEtlaa,nd,ProEsvtea.te, Treie, Parathyroid, Trichs, Lys Note aesesteric), fFaoteisleWeeer:108R) TTerinl SSaecirifWiaclee rou (2 PRITZH 10 po WarosLciovperic Ooarvaions: HicroMsraepsisct Barvations: "arlieghrtaiLsaetderawlasT,oe1,.33 0.8 ch atari "NLoodrutliacra bwpaecrspllaatsiiosn,, cloorctael,armeist,ifsoecdar,ate sReearlery cell Wperslasa, focal, wild SPrpoejceicet: aftater: CAICHOL2 0y738 sunrise sarge; 1 502 SInudmimvairdiuzaeld NSaicnrgolsecoTpaibculaantdedHiMcnriossaclopRiecporOtbsecrovnattiinounesd) F-39242 Tuo YeaRrikeOrralLiTbooxriatcoirtiye-sG,ncsIpnecn.ici0ty Study in Rats Table: 2 MFoaitaea:l (Neaebekr:108()R-ITTe2r8ainal SSeaxc:riMfailcee Grow: (2) FAITH 100 pon Nicroscopic Observations (continued): KiLdivneery tung PiPtanucirteaasry TShpylreoeind ""PCohrrtoanlic sporvoognrcelsesairvecenlelphrionpfaitlhtyr,ates,odearialte PHoerptaatlocbyitleevdauccutolaptrioolni,fercaetnitorni,lobiullar, aCyesrtaaitdedegeneration, focal, aild HNyepgearlpolcaytsotsiics,nodsuleerate Large lesion with good preservation of Ivoibcaulsalratesdt.ructure, Kost cell of nodule "HVeassocrurlhaargei,nedriaflfiuzsaet,iosno,ierwaitled "hFceivenrarthaatnropphryo,tocaooldenruastbeer a"Htesoesxiadmeirnoesdi,s,4iwsislieng "Fworlkleicdular hyperplasia, cystic, wilateral, The following Brain, Spinal Ctoirsds,ueBsonweerNearfroouwn,d Hteoarbte, wSittohaianchn,orwSaalllLiInnittse:stine, Large Intestine, LUyrsignharyNodBelad(daeers,etAeorritca),,TSeasltiivsa/rEypidGildanyda,is,EreP.rostate, Parathyroid, Trachea, Esophages, Ffantiee:al WNeaebkesr:80I)R-SSa7c2r9ificedSexi:n MexatlreenisGroup: ( 20 PA-S928 100 ppm Macroscopic Oiservations: HicrKoiscdonpeiyc Oservations: Liver Lang SpPlaeraetnhyroid Ho visible lesions, ""CFhorrotnalic spornoognruecslseiavre cneelplhrionpfaitlhtyr,atea,iniwsialld HNeecpraotsoicsy,teavlatciufoolcaatlio,n,wimludltifocal, aild RPiegseaelnotc,ytopsoirst,al,aarlkedd "Hweassocrurlhaarges,inleorcaallizaarteiaosn,, lwidld "NHoetsoseixdaenrionseids,,noatldin plane of section SPpreocjieecst:Nauutber: Q281CRNOIZ CO:1787 sunrise 2 303 `ISnudsiavairdiuzaeld aSciHnirgkolesercoTLpabibecualaatntadeidsKscAnr,iossaIlcnco,Rpecpo3Orter(ncaotnitionnused) PIR: To Ter ral Txicty-Gcogeicity Sty in Rats Tae 2 aFatae sakrss60) S7c2ificedSein MeatlreeisGroup: (20 FIA 100 pn NicrasTceosptiicsEOsderiatisons (continued: "sear ineralintio, wild TnHhaeiynf,ollSloinaivodageCt,irssKtuietsoawnrPeHraofrtorauonswd,tHoPaiBtreu,itwaiSrttyho,iwnscAhnr,oerSama,lLTihnIyntrtsoe:isdt,ineT,acLkarsg,e EIsntpehsatninse,, Lup Rode esntric, Freres, Salivary lard, Ee. Ffietientohbseer:08() RTeTrwial SSeexrWiafle rows | 21 PSA 100 pon WcrPoistcupiitcarOyservations: Ncrosrcepailc servations: Ktiitveney Raised ws, 0.4 cdi aSrtiiscsalelvaccatlaaitaio,n,cofrotcea,l, aintimdal ""Cphurornaiciplreogrfeestsivperasifeerrtpioyn,, asladkerate satcyte acolation, sltifoca, wild Lnugp hde (esnteric) PiPtnucirteasrsy sien "MPneisggaculleotac,rytopwsaiirnsee,saclwhiiynludtli,ona,inwiialld JJiogtuoxta,soinl,e aising aSettoomders, wile hraeinf,ollpoiwing Ctoirses,uesBownreNaorruowd, tHoeabte,wiStthoinica,rSamallHinInttse:stine, Lure Intestine, rSailmivrayrylGaladned,,Efreo.rte Testis Esti, Prostate, Thre, Parathyroid, Traces, Esoghaes, TFaatael hNeabter:108R) TScSificedSeix MealreesGreg: | 2 PREZ 100 pn WcrosSouplicnOtseetrivnateions: NcrsotcoincedBserations: read Spheenriicnalgasos,jfeant,,0.a5ttaachieda, ner "aalairdgeed waitlr.ic rae with wosios. Sinusoidal actin, carts, multifocal, wild SFrcaecnoter: CEBIRO1Z 01788 sanring sw run 1s" 504 Sduimvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMiAcnriomsaclopRiecpoOrtnercvoanttiinounesd) FI-3924 Too YeKrikOerralLaTboorvaitcoirtiye-sD,ncIongcm.ici5t0y Study in fats Tae 2 fFiatnea:l ebkeer:10I8 SSaLcrificeSdeixn aexlteraisGroups (2) FI 100 pa Microsicdonpiecy Observations (continnd): Liver TM Pancreas PSarlaetwhyroid Thtyornocihd "eCpatlaccuyli,epevlivciwclation, wtifocal, sild CNresgtlooicdytdoegiesn,ersaotdieonr,itemltifocal, ild "WHeassocrlrahragea,inmeirlatliifzoactailo,nsiilldd "IEsnlceatpscuellaltesdd,eswoenlsl ifferentiated tus. ot(roesxsaniLneesdi,on.n)at i plane of section hecersossiidse,rasmsa,saa,ildsoderate "Hperplasia, cell, wild Tbhreainf,ollSopwiinnagl tCiosrds,uesBowneereNafrroouwn,d tHoearbte,wiStmhaliln nIontremsatinlei,nitLsu:rge Intestoe, Urinary Dadder, aSraltiav,arTyelsatnids/,piEdrei.mis, Prostate, Pituitary, Trachea, Esophagus, Legh ode (neseteric, Ffaotei:lWMeoeskhser:45I)BF-oTu0nd DadSess Mle Group (2) PERE 100 pa NacroKsicdonpeiyc Ooserations: = "Bilateral marked byironhrass. WSilneeey Blatter "pEexprndsedsvuiatlhlehrard calculi searing about Wiroscopic Observations: 08 a dia. Mreal "Simsaital ecasia, corts, foal, wild tiEdeney ""HPoyteleoxnpaisviintdi,s,aicssaitneg, snderate Lire Intestine lHoyttreonxeshirnoes,is,sisbsiliantgeral, soderate LiLvnegr e"Hgaaslcoaclyartossiinse,ralsiizladtion, aild Lyn Node (sesesteric) Hiveclar sacrophages, ai1d ot easined, sissing FFarcerpetniasl Gland dPraetpuetxiaaslinead,dsnis,sinsgte, marked SSaallivaIrnyteSsltainnte ot. tained, issing tot exuained, sisting HFPESRITNiEeAnL AREMAA.RADlIsOoPAIeOCUNSDOIMEORUVTAHTI--NS|GRHOWANIR-13WHAITCMoanoomre;TrFEeDatM. eSainds - OTMFaULpeeenriasT,ED mAs(DhMeeinede. 12 S 4NE5MS HERES HOLE AAR species: Rat Srey Grameen Project aber: 021CKO12 0! 1789 Sarin spe 16 305 SInudnisvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMiAcnriossaclopRiecporOtbsecrovnattiinounesd) FA-3H24: Too YeaKrikeOrralLabTooriactiotryi-eGsn,coIpnecn.ici$t1y Study in Rats Tae: 2 Ffaitneasl tNhaebekesr:45()RFSouTnd DeaSdex: Male Group (2) FIT 100 pa WicrSapscloepeicn Observations (continued): Urinary Bladder HAetsroospihdye,rossoidse,ratoederate "wEpriktehdelial hyperplasia, papillary, diffuse, rTaheinf,olSlporiimnlg Ctoirsds,aeBsonweerRearfroounn,d Hteorbte, wSittohnianchn,orhmaartliiTtess:tis/Epididyais, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophages. Ffartiea:aleNoknbeert52I)R-FI7o3w5d DeadSex: Male Group (20 PHI920 100 ppm Macroscopic Osservtions: NicroEsceopic Oservations: KiLidrngeeyIntestine LLivnegr RLiyrwahthyNroodled (senteric) TSeustlisEInptiedstiimneis ho visible lesions, ""HHoitnereaxlaniiznaetdi,on,wistsaibnuglar, #ild ""NNoetcroesxiasn,inecde,ntmriislsoibnuglar, sarked ""WNaostcaelxaarsioiende,raaliiszsaitnigon, #ild ""hNaott eexxaanniinneedd,, not in plane aissing of section "Hascular ainralization, winieal BTrhaeinf,olSlpoirnianlg Ctoirsds,ueBsonweerNearfroouwn,d Stpolebeen,wiHtehairnt,noSrtmoamaclhi,itUsr:inary Bladder, Aorta, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Escphages, Pancreas, Salivary Eland. Ffaotei:e WNeoeskbser:108I)R-TSeTr8a8imal SSeaxc:rifMiaclee Group: 2) FRI 100 pa MacroTshcyopriocidOiservations: LPiivteuritary Nicrahsacroepniacl Oiserations: Heart ""PHoesssoirbrlhyagiscligLhetsliyon,enl0a.r4gecda. dia. "Scattered pale foci. "SNiodmusloairdahlypeercptlaassai,a,cocorrttee,r,aifnoicmaall, ainisal "Hwyiotciafrodciatlis,, aclhdronic nonsuppurative, PSrpoejceiecst:NsRabter: anc n C0190 Sorin si page: 15 306 SInuiavnirdieaaeld SRianrgolseceTpaibcalaatndedMincironsacopRiecporOtb.se(rcvoanttiionnused) Riker Laboratories, Inc. 91 FN-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Tale 2 fFaatie:l ONhaeabkeers108I) TTeErainal SSeacctriflicee rou: (2) FISEE 100 pn Wicroscapc Oservations (continued): tidy Liver tng FPiatrsaitthayrryoid Thyroid Trachea "tPhrerloonneegprrigtriess,siavcesm,ephirlodpathy, ainiaa) "HCeyptaotiodcytdeegveanceuroaltaitoino,n,mlwtlitfiufcaacla,l,aialeld Hepatocyte Hepatocyte alteration, alteration, vacaslated, basophilic, asoedreraattee ~Nveagslcloacrytainiesr,alaiizladtion, aild HHovteoslaarvimnac,ropthiasgseisn,g ald "ohteroxnasnined, aissing "Cyst, subepithelial BTaeinf,olSlpoirnianlg Ctoirses,ueBsoenreNarfroouw,n gtolebee,witShtoimnacsho,rmSlmalLlimiItnst:estine, Lure Intestine, UParnicnraerays,BlaSdadleirv,aryorGlta,ndT,esEtyies./EpLdias, Prostate, Esophagus, Logh hae (esenticl, nFaie:nhoesehkesr:106R) STeTrainal SSuexe:rifMiaclee Grou: (2) FSE2Y 100 pp NacrFoistcusiptcarOybservations: Lwiavreern MicroWscroepinc Ohserations: tart ide Liver ""Shcaastteerweadsa,le0.5foccia.dia. "tidgih.t aadsrse,nal greatly enlarged de to 2 ca "aCtarrocpihnyo,ns,eactoirctailc,al,marwkieldateral Laicrtgiev,ityw,ellexdtiefsfievreentnieactreods,is.higNhakmeidtotic sgelcaondn.daryMaalttriopglehysoeftasctaratseess.in contralateral "MWyyaeccaarrdiitalis,fibcrhorsoinsi,c lnoocnaslupparueraast,ivea,ld "lCoocanlicareparso,graeslsdive nephropathy, marked "oHerptaatlocbyitleevdaccutolpartoiloinf,erwalttioinf,caill,dalld RNeegtaulsotcayttiucsisse,plaaislee Psrpoejceicets;Nhaastr: 021CR012 o1791 Sumnrized STH use: 16 307 SInudmimvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMiMcnriomslcopRiecpoOrbtsecrovnattiinounesd) FIRE Too YeaRrikOerralLaTboorraitcoirtiye-sG,ncIongce,nci3t0y Study in Rats Tale: 2 fFaotie:l (bleeekrss108()RITTeIr9ainal SSeasc:riWfailcee Grow: {2) PA-SR24 100 poe Nicroscopic Ooservations (continued): Lung PPiatruaithtyarroyid Spleen vAalsvceuollaarr mwaicnrroaplhiazgaets,iona,leaild Heetsuosrtrahtagiec, nleopclaalseareas, anterate "ahdtenoenxaanned, mot in plane of section "Heetsaasstiacteirocsinse,oplaaisled TBhreainf,ollSopwiinnagl tCoirsds,aesBowneereMafroruonnd, tSotobneachw,ithSiwnallnorImnatlestLiinneit,s:Large Intestine, Urinary Bladder, hPoarntcar,easT,estSialsi/vEapriydiGdlyaansd, PEryoes.tate, Thyroid, Trachea, Esophagus, Lyaph Node (esenteric), Ffaotei:l (Neaebkeer:108I) RTSer)niml SSaecxrifWiaclee Groups (2) FRITZ 100 pn Macroscopic Observations: Hicrtoiscdonpeiyc Oservations: Liver Lng Trachea ho visible Lesions. , "CPhrreolnoiwcpiprriotgirse,ssiavceuten,ephsreodpaatthey, ald "PPoorrttaall sboivloenudculcetarprcoellilferiantfiiolnt,ratsei,lwild Hegalocytosis, soderate "Wascalar neralization, wild "PCyrsets,sosunb,epiitnhteerlsitailtial, chronic, focal, wild TBhreainf,ollSopniinnagl tCiosrds,uesBowneereNafroruonwd, tSoplbeeen,witHheiarnt,norSmtaolnacLhi,nitSse:all Intestine, Large Intestine, UErsionpahraygusB,ladLdyewr,h fNoordtea,(aTeessetnitse/iEcp)i,diPdaynacsr,easP,rosStaaltiev,arPyitGuliatna,ry,EveA.drenal, Thyroid, Parathyroid, Ffaotiee:alWNeoeskbser:108I) RTeIrminal SSeaxc:rifWiaclee Group: (2) FRITZ 100 pn Maeraseapic Oiservations: Microhsciorpeicd Observations: ho visible Lesions. CSoirntuiscoaildalvaceucotlaastiiao,n,Cofrotceasl,, wsiilndisal PSrpoejceicets:NRuastbr: O2BICROIZ C01792 somcized st pge: 17 508 SIundsiavriidzuaeld MSaicnrgolsecoTpaibculaatndedKidcnrionsaclopRiecpoOrbtse(rcvoanttiionnused) F394 Tu YeaRrikeOrralLaTbooxriactiotriye-sO,ncoIgnec.nici3ty Study in Rats Table: 2 fFaitnea:l (Mbaenedtesr:108()RTTerLainal SSeasc:riMfailcee Group: ( 2) FA-SOZ4 100 poe Nicroscopic Observations (continued): Kidney Liver Lung Lyagh Node (eseateric) Pnuncrteas i Pituitary Trachea ""CHherpoantioccyptreogvraecswsliavteionne,phrmouplittihfyo,cala,inissialld "NVeagsacluolcayrtossiinse,ralwiizladtion, sil Perivascalar sononclear infiltrate, aild "~AHeeisnoarrrhaagter,ophayi,ninwailld -"Nhodteneoxmasined, not in plane of section Cyst, subepithelial The following Brain, Spinal tCoirsds,uesBowneereMafroruonwd, tSoplbeeen,witHheairnt,norSutaoluaclhi,nitSse:all Intestine, Large Intestine, Urinary Bladder, forta, Testis/Epididyais, Prostate, Thyroid, Esophagus, Salivary Gland, Eye. mFaitnea:l (Nsabkesr:171)0-S3a0c2rificeSdexi:n Male Group: extrenis (2) FR-I924 100 ppm Macroscopic Oservations: Skin Liver Nicroscopic Observations: Kidney Liver Lung Lyigh Node (nesenteric) skin "Healing "Wppears ulceration on sosesat ale left and rear fuotpad. sattled; possible area of infarction in right lateral lose, "chronic progressive nephrogathy, ininal Hayipledrplasia, pelvic epithelium, local areas, "NHeecpraotsoicsy,tedivfafcuwslea,tiaoanr,keddiffuse, sarked NNeecgraolsaicsy,tasciesn,trialoodbeurltare, aild "AWlavsecoullaarr msaicnreorpahlaigzeast,ionw,ildwild Heaorrhage, local areas, aild ""Noodtodeexramnaitnietdi,s,aisuslicnegrative, hindleg, wries The folloring Brain, Spinal tissues were found Cord, Bone Marrow, tSoplbeeen,witHheianrt,norSmtaolnacLhi,nitSsu:all Intestine, Large Intestine, UTrriancaheray,BlEasdodpehra,gush,rtPaa,ncrTeeasst,is/SEapliidviadrnyaiGsl,andP,rosEtyaet.e, Pituitary, Arenal, Thyroid, Parathyroid, Psrpoejceicets:NRuabter: O2BICRUIZ 01793 sunrise se pet 10 309 SIanrrizved MScirgoencTpota1tndeMiMcraoslcopRiecpoartarcvaattiiooon P28 To YouRrikeBralLTabooractorieOs,coIgnec.ict2y tay in ats ie: 2 rFile heakret 130 1 SurificedSein elereseo 2 FRI 100 0 fe-- Pititry WicrTolesocswainuciOdoierovnaitisss: rend . ese lie PTMLiitptiode esntric) SFriTossettamitsesiionis uFoeipdlraawaktliaee,, | cndi "aYrotuilcaarlhvuipollaitiiaony,rmtieti,fema,ilalfd, ald rFRaotran,bpltsrorouicvtael,enawirlvedorastsioin,,walldd a"Hteospaetaoackytnesei,vsarcaauloilssaasttsiigoonn,, peiriportal, woderate SlSoeatwwreinairrnoerdt,,isaslidny Tnosti srs, parstseess, iltera, Trianenaf,roylSlpBoinaniandrGtoirsdsryuaeBsyowerTeroforodnu,n BtPoarabt,ehrwiSotrohdiw,nchoTrraScmeusl,inIEtnsstoe:hsatgien,, LFaarcgreestea,tSienlgi,vay Gln, Ep. iFatwe eedres169T) TUrea SSaecrifmilcee frogs (2 FR 10 pn [I Sn -- lteirty Wicrosrceonsct thartions: Heart liigen wy Ruiinseed Sul, aurlapcenr,daterdkinefleanme,d Tein 0.4 ca on right in, Eai. ra Dsion, 4c fa, sedian Cortical vacusation, local ares, soderate F"DwMoryhoorcinaartedmietp,irasr,aenclshdiriovneiccsanolornassuppitpuhtryae,titvseo,wfitds Foopretrpbsiecdauclk eprlifration wild uAsnsalra asiirwoamlaiets,ios,idald SPrcaijoctn Naatbe: oaiiOL2 01794 Suarized STAR Pages 19 310 SIundsiavriidzuaeld MSaicnrgolsecoTpaibculaantdedMiAcnriossaclopRiecpoOrbtse(rcvoanttiionnused) 28: To YeaRrikOerralLaTboorxactiotryi-eGsn,coIgnecn.ici3ty Study in Rats Table: 2 fFnaitsea:l (Neaebekr:10I8R-TSe7rMaiml SSeaxc:riMfailcee Group: (2) PRST24 100 ppm HicrosLcyonpgihcNosdeervaaetsieoantesri(cc)ontinued): PPiatruaitthyarroyid Skin ""HNoott eexxaanniinneedd,, nwoitssiinngplane of section ~"Phoddeondoenrsaatitis, ulcerative, hindles, marked The following brain, Spinal tissues were found Cord, Bone Marrow, Stpolebeen,wiStthoisnacnho,rmaSlelLliniItnst:estine, Large Intestine, Urinary Bladder, forta, Testis/Epididyais, Prostate, Thyroid, Trachea, Escphages, Pancreas, Salivary Bland, Eve. Ffaitnea:l(Neonlbeer: 14I)RFIouSnd DeadSex: Male Group: {20 PASSA 100 ppm MacrHoesacorptic Oservations: SKpildeneeny MicrosTceosptiics/OEbpsiedrivdaytaiiosns: KHiodrnteay LiLvonegr PPaanrcarteahsyroid SpUlreineanry Bladder Possibly slightly enlarged, t ""FFoosssisbille hsyldigrhotnlsyhrsomsailsl.of right kidney. ossibly slightly enlarged, h"Hayttreoxnaenpihoreods,is,aiswsiilnagteral, soderate H"Heegsaclrorchyatgoes,isp,erwiivladscular, soierate a"Ntot eexxsausiinneedd,, aniotssiinngplane of section "~aHtersooprhryh,agew,ildfocal, ild ECpyistthietliis,al ahcyupteer,pl4a1sida, simple, diffuse, wild The following Brain, Spinal tissues vere faund Cord, Bone Narrow, Hteoarbte, wSittohniancho,raSelalLiInntse:stine, Large Intestine, LTyessothisNEopdiedi(dayeasiesn,terPirco)s,tatSea,livPairtyuitGalrayn,d,AErreen.al, Thyroid, Trachea, Esophages, PSrpoejceicets:WoRsabter: 0281CKOIZ CO1795 Snwrized st pge: 10" 311 Snainvriidnuad aScirnogshcTpiactaandsRiicarolscpacrster(vcaattiiovnusnd) P28 Teo YeRrteeaLTeesrcoh iS,oconpem,ici3ty Stay in Rots Tate 2 aFiee tahbeeir00D) TTerwinl SSecrtifailcee Group (2) FIR 100 pa HcrPoitpuiictarOyserations: Wcropic hesrvtions: - Kidney Lng FHaroatthyyroie Tstsipidianis Sul drt esion. "SCyehsprtaoontiiadccypdireosgveraercstasilivoaenio,nne,pahlrsotlpoattcfhlys,,cwlislodstoeeartaete isa weratiation ald SvAoltvyeorluaariwaaec,ropmhoatge1s, p#ainled of ection Thscaar sineratizaion, wile EThienf,olSlwpiansg tCiosrsd,uesBownreNaorrodw, tSoebse,witehuinr,arStaowicLhi,teS:l. Itetin, Lrge Intestine, UFraicnrareys,BaSdaelirv,aroy rSlts,ProEsrtea.te, Adve, Told, Tato, Esphges, rh hse (arsenal, FTaaaeltNkaer:9T) FHond DadSe Wale Grogs (2 PIT 100 pe RcrsicnpaircysBeraveatrions: liver WerLeusrnagep.mc Bserations: foorete ort live -- : Sette -Hyperenic woitehionf pairraprteisnetts hJotthiesnibnieb,,aasisaitgeal, arked Tiietcaardlit,s,wclidanc nspurstive, Seetnrtnsto,tscwontaraItisoLna,, wstiifeatael, ild PLnrgess PPrtosattaatrey Siren STtoeness tis JaMaetgarrloicyntosdsi,iesr,ailmsioindneartgaitoen wild SJaott wwaannoeet,, asiassiinngg SMersospiys,eoanilsd, itd eictrsntsv,omncsTi,tswberate oe of pir rest SPpaegcieets:NRaabte: CBINOL2 01796 Suarized STAR Page: 121 312 SInudsisvairdiuzaeld NSaicnrgolsecoTpaibculaantdedMiMcnriossaclopRiecpoOrhtsecrovnattiinounesd) 398: Too YeaRrikeOrralLaTboosriatcoirtiye-sD,ncoIgnecn.ici3t1y Study in Rats Table: 2 SFaotie:l GNeoeoksr: 69R) SFoTund DeaSdex: Male Grow: ( 2) FR-IT2Y 100 poe Nicroscopic Ooservations (continued): BTrhaeinf,olSlopwiimnlg Ctoirscs,ueBsonveerNearfroouwn,d Ktiodnbeey,wiStmhailnl nIonrtmeasltilnien,itsL:arge Intestine, Urinary Bladder, Thyroid, Parathyroid, Trachea, Esophagus, Lysgh Node (seseteric), Salivary Gland. Fdanties:alWNeaebkesr:75R)IS7a5c0rificedSecitn eMxatlreenisGroup: (20 FAITH 100 ppm WacrLaiscvoepric Observations: NicroHsacorpeicl Observations: Heart KLiidvneery LLyasnsgh Node aesenteric) PrPoarsattahtyeroid Salivary Bland "Raliosbeed,, 1.5 ca dia. nodule in left lateral "CNoordtuilcaarl hvyapecrwpllaatsiioan,, cfoorctaels,, afiolcdal, ail "Asyioncianradlitis, chronic nonseppurative, focal, ""CFhorrotnalic spornoognruecslseiavre cneelplhrionpfaitlhtyr,atea,iniamialld PNoerctraolsisb,ilemldtuicftocparlo,lifaeirladtion, aild Megalacytosis, marked HUepragteocweelllluldairffcearrecnitnioamtaed neoplase. Solid, woderate aitotic activity. t"vaatsceuxlaarnioweidn,erawliiszsaitnigon, wild ""hHaott eexxaasniinneedd,, ariostsiinngplane of section "Hot exaiond, sissing TBhreainf,ollSopwiinnagl tCoirsds,uesBowneereNarfroouwn,d tSoplebeen,witShtionnacnho,rmaSlallliniItnst:estine, Urinary Bladder, ort, TestisEpididyuis, Pituitary, Large Intestine, Thyroid, Trachea, Esophagus, Pancreas, Eve. fFnaitse:al MNeoesbkesrz106I)RTTTeSrLninal SSeaxc:riMfailcee Group: (2) PR-STZA 100 gpm Macroscopic Observations: NicroEsscaoppiacguOsbservations: Xo visible Lesions. "Kot exanined, aissing SPpreocjieecst: NRuastber: 02810R0012 01797 Soourined ST Pge: 12 313 SInudsimvairdiuzaeld MSaicnrgolsecoTpaibclaatneddMiAcnirooaslcopRiecpoCrhtee(rcvoanttiionnused) F394: Too YeaRrikerralLaTboorraitcoirtiye-sD,ncTongee.nci3t1y Stady in Rats. Table: 2 nFaitsea:l (NMoesebkesr:106I)R-TTTeSr1aimal SSeacctriMfailcee Group: ( 2) FK-I924 100 pou Nicroscopic Observations (continued): heart Kidney Liver Lung PiPtauraitthayrryoid TShpyireorid Trachea "Mlyooccalardairteiss,, cahirlodnic nonsuppurative, ""CPhorrotnailc spornoognrcelsesairve cneellphrionpfaitlhtyr,ates,odearialtde Portal bile duct proliferation, ld Hepatocyte vacolation, multifocal, soderate Crstoid drgenration, sultifocal, aild Negalocytosis, aild : "Pvearsicvualsacrulsairnesroanloimzuactlieoanr, ainlfdiltrate, aild Not exasined, nissing -~bHeesnoosnisderosis, aild "Hot exanined, wissing "Not exavined, aissing The following rin, Spinal tissues were found Cord, Sone arrow, tSotobweachw,ithSienal]sorIenatlesltiinniet,s:Large Intestine, Urinary Bladder, arta, Testis/Epididyais, Adrenal, Lysgh Node (eseteric), Pancreas, Salivary Gland, Eve, Prostate. Ffaitnea:l (Nloenekbser:1081)8-T3e9r5a2inal SSaecxtrifMiaclee Groups ( 2) FEIT 100 ppm Macroscopic Observations: Liver Nicroscopic Observations: Heart Kidney Liner Lung Pancreas "Pale, raised lesion, 0.7 co dia. in right Lateral Tobe, "Msyioncianradlitis, chronic nonsuppurative, focal, ""PCohrrtoanlicsopnroongurcelsesairvecenlelphirnofpialtthryate, wild PHoerptaatloceblillueladrucctaprrcoilniofneration, ald Regalocytosis, wininil VHaesscourlrahragei,nelroaclailzaatrieosn,, saoidledrate "Aimar atrophy, waked IRsoledteractelellycpalrecoirnoorsnhic, encapsulated, with infiltration of capsule by tur cells. Vascular invasion. SPpreocjieecst:aRbaetr: 0281CR0012 01798 Susarized STAR Page: 123 314 SInudsimvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMiMcnirsoaslcopRiecpoOrbtse(rcvoanttiionnused) FA-IF24: Too YeaRrikeOrralLabToorxaitcoirtiye-sG,ncoIpnec.nici9t0y Stady in Rats Table: 2 fFaitnea:l ONlabeekr:1081)0-3T7e5r2ainal SSeaxc:rifMiaclee Groups (2) PA-SR20 100 ppm WicrosPcaorpaitchysroeirdvations (continued): Spleen "~Hheiseorsoindserosis, ild The following rain, Spinal Ctoirsds,ueBsoneerearfroouwn,d Sttoosbsechw,ithSeianl]norImnatlestLiinsei,ts:Large Intestine, Urinary Bladder, fLoyrstgah,NoTdeesti(se/sEepnitdeirdiycn)i,s,SaPlriovsatratye,ElaPnidt,uitEarre.y, Adrenal, Thyraid, Trachea, Esophagus, SFaotei:l (Neoskbeer:90()6-S3a7cr5ificedSexi:n eMxatlreenisGroup: (2) FRIR24 100 poe Macroscopic Observations: LSipvleeren TTheysmtusis/Epididnais RicroHsacroepniacl Observations: rain HKeiadnrety Liver Long Lyssh Node tneseteric) Pancreas Salivary Bland TSeosltoisnEpididyais ""EEnnllaarrggeedd and wottled vith a circular raised LLeosbieona,nd1.a7ncctahedriac.i,rcoanlaroneLeaseidoina,n0.8 ca dia. "iognhttheteostthiesrwsaeldli.an lobe. "Bark henorrhagic lesion, 1.5 x 1 cn, "Nalignant alignant ysphona, Iywhona, IIyysspphhooccyttiicc Large, hesorrhagic lesion with aalacia in "HaclariegbnealnltunL.ymphoma, Iysphacytic ""NhaelpiagtnoacnytteIyvsapchuoonlaa,tioIny,spcheancttriiclobular, marked Naligunt Iysphoss, ephocytic NMeecsraalsoicsy,tocseinst,risltorbaltare, scderate "HHeaslairgrnhaargte,ysmpuhlotniaf,ocaLly,mpmhiolcdytic "MHaelsiagrnrahnagte,Iysspohdoenraa,teIraphocytic hhiennoansatrophy, soderate "hKaatliegxnaannitneIdy,sghwoinsas,ingLymphocytic ""THuabluilgenaanttroypshpyh,onaas,perLsyamtpohgoecnyetsiics, wnilateral, arked SPrpoejceicets:MaRsabter: 0281CR012 01799 Suaarized STAR Pages 124 - 315 Sumarized Single Taulated Animal Report (continued) Individual Macroscopic and Wicroscopic Observations F398: Tuo YeaRrikerralLabToorraitcoirtiye-sD,acIongce,nci3t0y Study in Rats Table: 2 Ffnaitoea:l (NMaeaebkesr:90R)-TSIaScSrificeSdexi:n Male Grow: extrenis ( 2) PRI924 100 pha MicrosTchoypmiscs Ghservations (continued): "MaTlhiyganaasntwaTrkyesdolnyse,nlIayrmgpehdocbyytinceoplastic infiltrate and hesorrhage. The follosing tissues vere found to be within normal limits: Spinal Card, Sone Narrow, Stosach, Seal] Intestine, Large Intestine, Urinary Bladder, horta, Prostate, Pituitary, Thyroid, Parathyroid, Traches, Esophagus, Eye. Ffantien:al (Nhueaebke=r:1061)R-TTTeSr0siml Sex: Male Sacrifice Group: ( 2) FN-I924 100pa Macroscopic Observations: Pituitary HicrTohsycorpoiicdObservations: Adrenal Kidney LLiavregre Intestine Lung Lyogh Kode (sesenteric) Pancreas Pituitary TestisEpididyais "Raised mass, 0.5 co dia. "Possibly slightly enlarged. "Sinusoidal ectasia, "Chronic progressive corte, soderate nephropathy, soderate ""NPeosratatlodisaosniosn,uccloealroncell infiltrate, ald Portal bile duct proliferation, sild Hepatacyte vacuolation, sultifocal, soderate Necrosis, focal, aininal Kegalacytosis, ald ""Nvoatsceuxlaasrinmeidn,eraailsisziantigon, aild "Hyperplasia islet cell, ild -"bPdoelnyoanrateritis, aild The following Brain, Spinal tissues vere found Cord, Bone Marrow, Stoplbeeen,witHheairnt,norSmtaolnaclhi,mitSsa:all Intestine, Urinary Bladder, forta, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Salivary Gland, Eye. Ffraitoea:l (NHuessbkeer:106R)-TTIeSrSainal Sex: Male Sacrifice Grow: ( 2) FN-IS24 100 pps Macroscopic Observations: Stin Thyroid PTietsutiitsa/rEypididynis "CiarncdulLaerftrahiinsdedfaiantfplaatsse.ed lesions on right ""Spuoaslslibdlayrkslliegshitolny. enlarged. "Right testis small. PSrpoejceicets:MaRsahter: 0281080012 01300 Snrizeg STR Pes 15 316 SInudsiavairiuzaeld NSicRinrkgoelsrecTLoaaibbcourlaaatntdoerdiMeiAscn,irnoasIlcco.pRiecpo3Or0tser(ncoanttiionnused) P24: Tao Year Oral Tosicity-Ocsgencity Stud in Rats Tale: 2 nFaitel: hbeelres106()07T5er5anal SSaeccriMfailcee rou (2) FITZ 10 pp HicroHsciarpeinc Ooserations (continued): Hert Liivteerr ung PPiatruaitthayrryoid Skin Testis pide oSritniucsoaildalvaeccstluastiiao,n,cawratelrt,ifaaiclld, wild HNoocdaurladrithiysp,erpclrasaina,i csonrstpe,urfaotcailv,ewild Cwhirotniifcocpr,ogwrielsesive nepropathy, wild "Foerrtaall sbiolaencdlucetarprcoellilferiantfiiolnt,ratwei,ldwild sNetaaldotdoesesn,ratwiilodn, focal, wild sAcvaelsatar ssaicnerrpahlaigzeast,iona,ildwild "oHtenexsasined, sat in pane of section "boidlaotderraalt,itwsak,edulcerative ists, "wTiuerlaeteatrophy, aspermtagenesis, wilatenal, Trhaeinf,olSlpoiwnianlg toirsts,ueBsonweerMearfroounn,d tgolebee,wiStthoisnacoh,rmSmallliniItnst:estine, Large Intestine, PUaricnraersys,BlSaaddleirv,aryfoErlta,nd,PrEorset.ate, Throld, Traches, Esphaus, Lygh ode (aesentericl, fFaotea:leNeobker:1055) S%acrificedSexi:n Mtalreesrout (2) FSR 100 pp RacrFoisicptiacrByrsernaions: Wicrorseanpacl Observations: heart idry Liver TM Lyah Note (aeseateric) "alarged, 0.8 ca in dante "oSrintuiscoaildalaceocltaatsiioan,cofratel,, fwoiall, wile "Hwpictairfdeictails,, wcihronic ronuppurative, C"horrotnailc sporaognrcelsseiave ceelglhroinpfaitlhtyr,ates,ildwild PHoerptaatlocbyitlee vdaccstlaptrioolni,fersalttiiofno,caall,d ald aHsescolrarargea,inmelrtailfiozcaatli,o,wialiel Sinusedal teas, woberte PSrpoejceicets:aRsahte: O21CK012 01801 Summarized STAR Pages 126 . 317 Sumarized Single Tabulated Mnimal Report (continued) Individual acroscopic and Wicroscopic Observations FI-3928: Teo Riker Laboratories, Inc, 1 Year ral Toxicity-Dncogenicity Study in Rats Table: 2 Ffnaitoea:l (NMuesebkesr:105B)-TS7aScErificeSdexi:n Male Group: extrenis ( 2) PN-I924 100 pa MicrPosictoupiitcarOybservations (continued): Splem Urinary Bladder ~bdnona "Hesosiderosis, aild "Epithelial hyperplasia, single, diffuse, aild The follosing Brain, Spinal tissues were found Cord, Bone Marrow, to be within normal linits: Stosach, Seall Intestine, Large Intestine, Aorta, Testis/Epididais, Prostate, Thyroid, Parathyroid, Traches, Esophagus, Pancreas, Salivary Gland, Ee. AFantiem:al lNeoesktser:991)6-S5a7c5r7ificedSeixn: Male Groups extrenis (20 PA-ISZA 100 pp Macroscopic Observations: [ NicrPoisctaupiitcarOybservations: Ere Kidney Liver Lung Pituitary Spleen Thyroid "Opacity of right eye. "Hesorehagic aass, 1 x 0.8 cu dia. ~Phthsis "Chronic bulbi, wilateral progressive nephropathy, wild "PPoorrttaall bsoinloenudculcetarprcoellilferiantfiiolnt,ratiel,daild Hepatocyte vacuslation, multifocal, ail Negalactosis, sinisal VAalsvceaollaarr aacirneorpahlaigzeast,iona,ildsild "~Hheiweonsoimdaerosis, ile - cell carcinoma TBhreainf,ollSopviinnagl tCiosrsd,uesBowseereNafroruonwd, Htoeabret,wiStthoisnachn,ormSaelalllimIinttse:stine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Parathyroid, Trachea, Esophagus, Lysoh ode estoteric), Pancreas, Salivary Gland. Ffantieo:al (Nbueaekbser:1081)R-TIeTrSn8inal Sew: Male Sacrifice Grog: ( 2 FR-ITZH 100 pe Macroscopic Observations: Microscopic Observations: hirenal "Ho visible lesions. "CNoordtuilcaarl hyvpaecuropllaatsiioan,, colorctaels,arfeoacsa,l,soadielrdate SPrpoejceicets:MaRsahter: 0281080012 01302 Sunrized st page: 7 318 SInudairviidzueald MSaicnrgolsecoTpaibculaantdedNiMcnirwoaslcopRiecpoOrbtse(rcvoanttiionnused) Riker Laboratories, Inc, 3 F398 Tuo Year Oral Toricity-Dncogenicity Stuy in Rats Table: 2 fFnaitoea:l (NMuesebkesr:1061)R-TT7eSr0ninal SSeaxc:riMfailcee Grow: ( 2) PN-IR2A 100 pga WicroKsicdonpiecy servations (continued): Liver Lung TLeysstshis/KEopdiediedsyeanitseric) Trachea "CHhyrdornoincephprroosgirse,ssiBvielatneersahlr,opistohdye,rawtield "PPoorrttaall sboinloenudculcetarprcoellilferiantfiiolnt,ratsei,ldaild Hepatocyte nacwolation, multifocal, sild NReecgraolsoicsy,tsmilst,ifaoocdaelr,ateald Piguent, "vascular wmailnteirfaalciazla,tioln,dald Alveolar sacrophages, wild "--WHaesscourlrahragea,isesriaaliinzaaltion, aild "Tracheitis, chronic, aild The following Brain, Spinal iCosrsdu,esBowneerearfroousn,d tSoplbeeen,witHheianrt,norSmtaoluaclhi,sitSse:all Intestine, Large Intestine, Urinary Bladder, forta, Prostate, Pituitary, Thyroid, Parathyroid, Esophagus, Pancreas, Salivary Bland, Eye. Fmaitnea:l (Nhuesebkesr:1081)R-TTeTrSa)imal SSeaxc:rifMiaclee Group: (2) FNI924 100 ppm Macroscopic Observations: MicrPoistcuopiitcarOybservations: Kidney Liver Lung Pituitary SpTleesetins/Epididyais "Circular mass, 0.5 cu dia. ""CPhorrotnalic spornoognruecslseiavrecenlelphrionpfaitlhtyr,atea,odearialtde PCoyrsttaolidbidleegendeucrtatipoena,liffeorcaatli,oni, daild HKeegpaaltooccyyttoesiasl,tersaotdieorna,tevacuolated, aild Hepatocyte vacuslation, miltifocal, saderate "PVrasecuuolnaira,wiinnetrearlsitziattiiaoln,, cahirlodnic, multifocal, aAllvdeolar sacrophages, soderate Perivascalar sononuclear infiltrate, ald Heorrhage, local areas, marked "AHdeesnoosmiaderasis, aild "Tubule atrophy, asperaatogenesis, wilateral, ail SPpreocjieecst: NRuastber: G21CR00I2 01303 Sonics si pg 0 319 Saudnaiiaeed NSianTgolescTpauilaatneddWMicirsoasaRpecposrter(vcaotnitionnuses) PHI2H Teo YerteealLToeosrcshorBiceapnnei,ci3ty Stayi Ras Tate 2 iFane haebie:106S) TTerwinal SSiefiWaclee ou {2 F410 30 NcrosecipmircyBMeartaetrions (canine): rpm--_-- TrShoaesitoniltlSeopviiHnniagretCnios,rstueTshBrownoeirteM,aorauosdnthtHroeaabrde,swiStTthnaiintceha,,rSmEuaxlhliantetesst,:inrea,hLoidree Iansteenstteinrei,chh,orPt,aes, Shar lan, Eve. Foirtees eedret1661 ) Tesi uSeraitfimclee Brows (2) F920 10 an [---- Werescraepaitc stration: rt avneery wn FPaanrcsrtaosid Towoid Ho vise Lesions. ASaotslclaradriyaciflirrassp, sfoa,l, fwoicladl, aid Twiatridsials,, icleron snsppntive, ruroanl sreermeseinvecpelrofpiars,ti,lald seactroocsrit,esaiketliatoi,on,almditifocl, soerate eYPeavsoaunoilcay,ownotsa,wrtssitnitteiitoaen,, vitaec, witifecl, wie apAtlrvpeosaliasrniseanc,rolpahesakgseiscg,olw,ildsoferate Jat eine, sisson The follonng tissis wre found to be within normal Linits: BrLrioamieanr,yNSeBpeianaealrs,CtoredK,orrBstoe,neTNSeaasrlritoviwas,ryoSiplilaeaentn,,s,SEtero.moascthi,teS,waliltiItntieyst,iner,acLearsg,e EInstoeasgtiense,, SPpreocpieest: NRaabter: OIRO 01304 sanrizes sti pges 1" 320 STaanrviizaead RSiancgtleocTpaila1te8dMlcroslcniRcprutacttiiovnnt PRE To YeaererraLTiesctoSncoqniecity Std is Bats Table: 2 Fairtnet eYealr,0B) SAarTifiScd:a esmtirson -- wary -- Bnd Pfreietalty crpoass)Oservtisss tienr i Wane stand jHit--s Siem (2) FEN 10 Baarhtewditihataalelasskss, $3251 1 ch LHe3et0n1sriar,eerairgth,eit0r,i0]b1 0dwhe,dnin roy of lit Sbniestndulis,tawtaatcorete, wilitera, SAcennrtcoopnae,essmtrsa,ilimtntoitonMr,iltw,ild itd SeeTtehsrmteartcaiiccttiwoononsnlofetur pest, WL of 4 eaturltaaisfeesraedsnieisstretss0ocbptriaimleyc.elaog with etSwaetvuovaanirisainst,twitrnushaalearyof, citciroensst, irae rUThraeiinaa,rylyoBnaagdeLtaisdrs,utehseovneWrrearfsns,aOKtreiaybne,Twicuthhtirn,,soSTmtaHolEacSah,,tsES:ablite,stiLngh, Lhitrhge WIentsensteirn,cl Pures, Sli Sl: Fortal Neesre 9B0Fo8und badSe: Femie Sr (2) ART 10 on Wcroesctnrc yaration: WrBeroenmntaanration: oKeey Lrg Itt Rused beri is, 1511 cn. SJJairtnnuise,actsaisaicorte, ile "EBetbicc ,iwaetiviinction, dete So noe, sasog rSpaegcieess:eaet: C2IOLZ 01305 Sunnarized 5TH Page: 110-321 ISnudnimvairdiuzaeld aScinrgolsecoTpaibculaatneddicMrnioosaclopRiecpohrtser(vcoanttiionnused) FA-I924: Too YeaRrikeOrralLaTbooxriactiotriye-sD,ecoIgnecn.ici3t0y Study in Rats Table: 2 final Nanber: IR-ATSE Sex: Female Group (2) FH-I924 100 ppm Fates (eet 9) Found Dead NicrLoiscvoepric Observations (continued): Lung NLaysmpahryNodEelantdeseateric) Ptaanrcryeas. FiPatruaitthayrryoid SSaulilvarIyntelsatnidne TShpylereonid Uterus. "PHoerptaatlocbyitleevdauccutolaptrioolni,ferdaitfifouns,e,sislodderate "PHlrveesulsasr,maaccruotpehaegexsu,datailvde, local areas, ail "VNaotscuelxaarninseidn,eraaliiszsaitnigon, aild "Kot Not eeaanniinneedd,, wissing issing ""KHoytperepxlaansiinae,d,issliestsicnegll, ild ""Nhoetreoxnainnd, ising ""NHoetsoesxiadneirnoesdi,s,aissosdienrgate "Not "Not eexaanmiinneedd,, wissing aissing TShpeinaflollCoowrid,ngBtoinssuHeasrrowwe,reHefaorutn,d tSotonbaechw,ithUirninnaorrymaBlladldiesri,ts:forts, Trachea, Brain. FJaatei:sa(lMemeeksr:1051)R-TAeTSr0sima SSaexc:rifFiecmeale Group: (2) FE-IT24 100 pon MacroWsacsopaiacryOGslearnvdations: NicrosLciovpeirc Observations: hirenal Kidney Liner Lung Nasaary Gland PaBnucrreyas Pituitary theres BTrhaeinf,ollSopwiinnagl tCiosrsd,uesBoenereNafroruonwd, asrsig,ht4ixng3uicnna,l alerfeta.alla bx Sx Zen, "tgpears wottled ""Spiinguuseanitd,alcoencvt.astiuab,, ceoprittehxe,liowna,kewdild "HHeepgaatlooccyytteosivsa,cuoalialtdion, periportal, soderate ~VHaesscourlrahragei,nelroaclailzaatrieoans,, sailld "FFiibbrraoaaddeenroonn ""hTeuibnualrarathryoppehryp,lalsiad, bilateral, soderate ""Chysetriocmglands, wild tSoplbeeen,witHheianrt,orSmtolmaclhin,itSsw:ill Intestine, Large Intestine, Psrpoejceicets:WaRsabter: 0261080012 01306 Sunsarized STAR Pages 131 322 Susmarized Individual MSaicnrgolsecoTpaibculaantdedMiMcnriowsalcopRiecpoOrbtse(rcvoanttiionnused) 3924; Tuo YeaRrikOerralLaTboorriactoirtiye-sO,ncoIgnec.nicity Study in Rats Table: 2 fFiatnea:l WMeueadkesr:105R)-4T7e5r0simal SSeaxc:riFfeimcaele Groopt ( 2) FR-IT24 100 phe . Wieroscapic Observations (continund): The follosing tissues were found Urinary Bladder, Aorta, Trachea, tThowrbaeidw,itPhairnatnhoyrrmoaild,liEnsictosha(gcuosn,tinLyusepdh):Node (aeseteric), Salivary Gland, Eye. Ffantien:al (Mbaenedtesr:1051)R-T7e6r2ainal Sex: Female Sacrifice Group (2) FA-I924 100 pp MacroPsictoupiitcarOybservations: Liver MicroAscroepniacl Diservations: Kidney Liver Lung [ Fituitary STphlyereonid ""BHaerskorrihnagcioclorasssr,ai0s.e8d cc irdciual.ar lesion, 1.5 co dia., aedian lobe circular Lesion, 1 ca dia., right anterior Lobes circalar lesion, 0.9 ca dia., caudate lobe. "Sinusoidal ctasia, cortes, ild "Chronic progressive nephropathy, ild Piguet, conv. tub. epitheliua, ile "Portal ononuclear cell infiltrate, aild . Portal bile duct proliferation, ild HHeeppaattooccyyttee avlatceuroaltaitoino,n,vadciufofluastee,d,ansdielrdate FNeygpaelropclyatsotsiics,nosdoudleerate ~Hesorrhage, sitidfocal, ld Vascular simeralization, aild Preuaonia, ald interstitial, chronic, mitifocal, Hiveslar macrophages, oderate "TPaebruilvaarscuhlyaperrpsloansoinai,clbeialratienrfaill,trsatoed,erawtoederate ""HAeesarsoinderosis, nile < cell adenons BTrhaeinf,ollSopuiinanlg tCiosrsd,uesBovneereNafroruonwd, Htoearbte,wiStthoimnachn,ormSaelalllisIinttse:stine, Large Intestine, LUryisnharyNodBelad(dneers,entAeorritca,),UtPearnucsr,easK,aaSsaarlyivalrayndG,lanTdr,achEevse,. Parathyroid, Esophagus, SPpreocjieecst: NRaastber: 0281CR0012 01307 Susnarized STAR Page: 132 323 Suaaarized Single Tabulated Mniwal Report (continued) Individual Macroscopic and Microscopic Observations iter Laboratories, Inc. 31 FI-3924: Tuo Year Oral Tosicity-Oncogencity Study in Rats Table: 2 Animal Mader: 1R-4760 Sex: Fesale Group: (2 FR-IT2A 100 gpa Fate: (Weeks 105) Teraiml Sacrifice MacrPoistcuopiitcarOybservations: Nicrohsacroepincl Oiservations: KiEdsonpehyagus Large Intestine Liner ng Lysgh Node (seseateric) tury Pituitary Spleen "Large hesorrhagic mss, 1.2 ca i. "Sinusoidal ectasia, cortes, wild ""CHhortoneixcaspirnoedg,reswsiisvseinngephropathy, aild Pelvic aineralization, ald "Nesatodiasis, colon "Hepatocyte vacwlation, multifocal, wild "Nveagsaclualcayrtowsiinse,ralaiizladtion, ald Alveolar sacrophages, 11d "Hesorrhage, soderate "Tubular hyperplasia, bilateral, wild henna ~Hesosiderosis, nild The following rain, Spinal tissues ere found Gord, Sone Narrow, to be within Heart, Swall normal linits: Intestine, Urinary Bladder, dorta, Uterus, Nanaary Gland, Trachea, Thyraid, Parathyroid, Pancreas, Salivary Gland, Ere, Stosach. iFantea:l (Neaebser:1051)8-T4e7r6s5inal Sex: Fewale Sacrifice Group: (2) FH-S924 100 pou MacrPoistcuopiitcarDyiservations: Liver WicroLsicvoepric Observations: Lung Parathyroid Thyroid "Clear fluid Filled cyt, 0.5 ca dia. "Hopears mottled "Fortal snonuclear cell infiltrate, aild Portal bile duct proliferation, sild Hepatocyte vacuslation, local ares, wild "VNaesgcaulloacrrtoasiinse,ralaiizladtion, sild ""HHopteresxlaaisniead,,Coctelli,n psloadneeraotfe section The following tissues were found to be within morsal liits: Brain, Spinal Cord, Bone Narrow, Kidowy, Heart, Stosach, Seal] Intestine, Large Intestine, Urinary Bladder, Aorta, Werus, Dury, Trachea, Esophagus, Lysph Noce (sesenteric], Pancreas, Salivary Gland, Naasary Bland, Pituitary, Adrenal, Eve, Spleen. Species: Rat Project aber: OZ81CRUOLZ 01308 Sunearized STAR Page 133 324 Suaarized Individual MSaicnrgolsecoTpaibculaantdedMidcisrmoaslcopRiecpoOrbtse(rcvoanttiionnused) F-39024: Teo YeaRrikearlLaTboorraitcoirtiye-sD,ncIongce.nci0ty Study in Rats Table: 2 MFaitne:d (NMaeaebkesr:1031)6-4T7e6r6ainal Sex: Female Sacrifice Groups (2) PA-IS24 100 pou Macroscopic Observations: Nicroscapic Observations: Adrenal Kidney Liver Lung Xo visible lesions. ""Spienluvsiocidsailnerecatlaisziaat,ionc,orstien,ieaalild Pigeent, conv. tub. epitheliue, aild "HNeegpaaltooccyyttoesivsa,cusooldaetriaotne, multifocal, wild Piguet, hepatocyte, wild "HAelsvoerorlhaargea,acrwolpthiafgoecsa,l,wialdld The following rain, Spinal tCoirsds,ueBsonveerNearfroouwn,d Stpolebeen,wiHtehairnt,noSrtmoanlaclhi,niStwsa:ll Intestine, Large Intestine, EUsroipnhaargyusB,ladLdyeorp,h Nfoodrets,(sUetseernutse,ricO)v,aryP,ancRraesaesa,rySallainvda,ryPlitaunidt,aryE,ye.Trachea, Thyraid, Parathyroie, nial Fate: hMuaasbter:10(5)R-4T7e6r7sinal SSeaxc:riFfeimcaele Grow: ( 2) PR-JS24 100 pon MacrPoistcuopiitcarOybservations: Microscopic Observations: hgrenal idee Liver Lung ory PiPtauraitthayrryoid SpUlteereuns. "Raised wass, 1 cn dia. ""SPienluvsiociadianlereacltazsaitai,onc,ort4e1x1,d ail "HCeypsattooicdytdeegvenaecraattiiono,n,midtiifffoucsael,, soadledrate MHeegmaaltaocpyotiaessiiss,, aeoxdterraasteedullary, il "Avlavsecoullaarr awaicnreorpahlaigzeast,iona,ilald "CTyusbtu,lawrilhyapteerrpallasia, wilateral, ail "Kot exanined, not in plane of section -"hHdeewncosnisderosis, aild "Eystic glands, wild TBrhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonveerNearfroouwn,d tHoearbte, wSittohmianchn,orSmwaalllLiIsnttse:stine, Large Intestine, UParnicnraerays,BlSaaddleirv,aryAorEtlaa,nd,NaEnvwea.ry Gland, Trachea, Thyroid, Esophagus, Lysph Mode (aesenteric), SPpreocjieecst: NRuastber: 0261080012 01309 Suanarized STAR Page: 134 325 SInudwiavriidzuaeld RSaincgrlaescTpaiuclsatneddNnicirmolceRpecpoOrbtse(rcvoanttiionnused P3924: To YairteOrralLTioovrayt-aOiecsa,geTie.cit0y Study in Rats Te: 2 fFlaera eNaebeer:105A17T8e0raiol SSecirifFiecdee Group: (20 PST 100 pn Hcrooseapc Brvations: Litveatu Heraroesa) Baervations: Bideney Liver fabsutrhyyreid FSiptlueietniry Thyroid ""ihgshst, e0y.e7 ichnfilaas.ed ad cldy. Slightly pale nd mettle. "CSoirntsicoaildlacsucltaatsiiao,n,Colrotcea,l airleds, irked --"paureapihchalparigteiess,ivweilnaetpehrrsolp,ithmya,rkeidl Zieatucye vicwlation, periportal, asterate "oMTtegaaleroacsyitboosdei,sr,osta.il,di bpillanaeteorfalsescdtieornate HSeiwesriodneronis wild Frolileicdular hperplsia, esti, wilateral, STaheinf,olplioianlg Ctoirsds,ueBs nwreAafroounn,d etoarbe, Urinary Blader, ora, Uerus, Nasa wLituhgi,n Elin, sStroiwc,LiSimtasll: Intestine, Lure Trche, Esshges, Lop No Ianetseestnitneer,ic, Pacres, Salivary Slant. Foitie:e eNeabeer:10150-T0e6r0inl SScer:ifFecmeale Groups { 2) POA 100 po RcrssHoapaicr BSslenrtions: Wcrssroepniacl Oservations: Kivaenrey ang Naar Gland Ftiuuriytary "sas,, i6nxle4itxi2ngcuianianl daerfeta.mith bx 4x2 S"ivmasnoeidplroagcrteasssiiav,e ceoprhtreo,patwhiyl,d aild JHeKpeeapatltoaacccyyttteeossaili,tceerwlaitaliidoonn,, bmasiotpihfilaitcl,, wiallde "Aasvcelasr aicnerrpahluigzeast,ion1,1d14 FHietorrorhtatgreo,nTocal ars, ld "MTnuobcaaarrcihynpoenrsplasia, Bilateral, soderate Jaton PSrpoejceiecst:NaRabter: CBICHOT2 01310 sunrint sarge 15" 326 Sumarized Single Tabulated Mnimal Report (continua) Individual Macroscopic and Microscopic Observations F308: Teo Riker Laboratories, Inc. 30 Year ral Toricity-Dncogenicity Study in Rats. Table: 2 AFnaitnea:l (Nbaesbtesr:1051)6-4T7e6r9ainal SSeaxc:riFfeimcaele Groopt (2) FR-IF26 100 pou Nicroscopic Observations (continued): Uterus "Hronetra, soderate The follosing Brain, Spinal tissues were found Cord, Bone Narrow, to be within normal linits: Spleen, Heart, Stosach, Seall Intestine, Large Intestine, UPrainncarreyas,BlaSdadleirv,arfyarGtlsa,nd,TraEcyhee.a, Thyroid, Parathyroid, Esophagus, Lyaph Node (sesenteric), Anil Muster: 16-4770 Sex: Fesale Grow: ( 21 PA-ITZ4 100 pha Fate: (Heeks 105) Terninal Sacrifice NacroNsacsoapaicryOiEslaenrdvations: Liver Nicroscopic Observations: LAirveenral Lung NPaanncarreyas Eland Pituitary Spleen Hass, 43 4x1 cay in throat area, ~Hopears aottled ""SHienpuastooicdyatle evcatcawsliaat,iocno,rtepse,rispoodretrala,tesoderate Negalocytosis, aoderate Pigamnt, hepatocyte, sininal "vascular mineralization, ild APlevreiovlaasrculsaarcrospohnaggheusc,lesaordeirnaftieltrate, wild "~hFciibmraorateandcennacen ~hienom "Heassiderosis, aild BTrhaeinf,olSlopwiimnlg Ctoirsds,ueBsorweerNearfroouwn,d Ktiodnbeey,wiHtehairnt,norSmtaolmaclhi,sitSsea:l] Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Parathyroid, Esophagus, Lysgh Rote (esenteric), Salivary Gland, Eve. fninal Masher: 18-4771 Sex: Fesale Grow: ( 20 PA-IS24 100 phe Fate: eek 91) Sacrificed in extrenis MacrPoistcuopiitcarOybservations: Liver Microhsicroepniacl Observations: "Heaarrhagic aass, 0.8 cb dia. "dgpears dark brown in color with sultiple pale foci on all lobes. "CSoirntuiscoaildalvicesctlaastiiao,n,cowritleds, ald SPpreocjieecst:uRsahter: GZA1CR0012 01311 Suanarized STAR Page: 136 - 327 Snugsinvariidzueld MSaicnrgolsecoTpaibcalaantdedMiicnroaslcopRiecpoOrbtse(rcvoanttiionnused) Fak: To YouireBralLaTboarvactiotriye-sd,ncTorge,ici3t8y Stdy in ats Tale: 2 iFantae:l eNsotaeh:911)47S7ac1rificeSdeni:n FexatlreenisGrog 2) FRSA 160 pn Nicrosicoepirc Observations (continued): Liver Log Pituitary "pVealcvuisclastiinoenr,alciozma.tiotnb,.seinpiiatlhe, wild "oPorrttaall sbimlaendccltewprcoellilferiantfiiolnt,rataei,idwild sHecpaatarcyeaivnieaolliaztaitoino,n,pearlidportal, sedeate HPhevreisvtsacrulsacrrosphoangoemsc,learildinfiltrate, aild "HHeetroornhsage, diffuse, warked TBhreainf,ollSopviinaag tCiosrds,uesBoenereMafroruonnd, rina later, erta, Weris, tSoplebeen,witahrint,sorSmtaolmaclhi,mitSsw:ill Ovary, Namsry Eland, Traches, TIhnrtoeiset,in,PaLaatrhgneroIindt,esEtsionpeh,agus, Leh Node esata), Facress, Salivary Eland, Eve. nFatie:lhoetheers105R)ATTerTninal SSeuxe:ifFiecneale Grou: (2) PISA 100 pa WacrLoiwvaepric Dbsrvations: WicroHsaarpiecl Obsrvations: itney Liner TM NLayswahryNoGtlean(daesenteric) TPhayrraotihdyroid ircalar sass, 25 1.2 cy in right Jeter. "CSoirntuiscoailtalvaceocltaatiiao,n,Coartleds, marked "PQerlavinccsperrolgriezsastiiveonn,ephsrionpiaatlhy, sininal eWgpielrosclaysttoincs,roolfeerte HLeapragteoctelulurlawritahdmaorness of necrosis, Toto ccaellls Lasrgnee,ratliazyatviiocno,laatledd. Plrdeusnia, interstitial, chronic, mltifocal, ""atolticetnocneilnee, sissing "Shpyeperrlpalassiisa meilnti,fecawli,tiafialdcl, aild STeheanf,olSopwiinanlg Ctoirsds,ueBsoaoreMarfroouen,d Stpolebeen,wibtheirnt,noSrmtaolmacLhi,stSse:al atest, Large Intestine, PSrpoejceiecst:ufsahter: O2ICRL2 Luuiidgi Sanarined STH Page: 157 328 `TSoudsisvairidzuend aSikonsegclreopTLiaabcurlaastdeodMniAc,nriossancleo,pRiecpo3srter(vcaotnitionnused) P28 Tao Yer Gal Tscrtr-Gncopeicty tay in Rats Tate 2 iFitee eWeavee:109A) TTeTniol SSaecsriFfiocee Gro 2 E70 10 pn FThievfioecltrioosssatcgpeitrcssORssoeetsreawtihieornfesosn(dcGntatoribyneuPnsiisathiitnarsyo,reTsracLhiesn,tsE(scponat,inS:alivary Sad, Ere, Pucres. fouiereaNsokve1057 ) Terainal SSiecrrifFiocuels Grows 2) ALA 10 0 Wacrsocarpiyc GSsearnations: ter PIreat -- Kare arg Intestine Liver wy FJ our San-- d Fiotruiytary "SSuel.ulcerated ms, 2c din, a right "liei,nsiglohbtel,y raised ass, 152 co in SSiimgsmeai,tlcosmteastiash,, cpatrotemsi,onir,kebdrow, Saewitaltasis, colon ~Hetyppeaetrpalcarseticaltneordautlieon, vcusated, mltifoul, [essraysovcsl--ati--on, tifa, wild sHaelaar svianrrtgineat,ionw,itailadcl, ald HPeerwirvahcgatearisdonncien infiltrate, aisial eHmoecamrtmineon,, icctall tushsghrearsaeis.os mre ateacrcinons. ne "Syhse,nfoil, wilateral Shfaoeirnto,,tSWvarirasn,CtTiorsrssd6ueeBsa,nwrTeNraroornouw,d, StPoluaebteeh,ywiohtrhadi,rn,ssuoSrboawaligcsLh,,inSrs:aelsI,tetSianliev,arUyriGnlaroy,SlEraet.er, SPpaegcess:Naatar: UBIEROLE 01813 Sunaized SHR age: 118 . 329 SIunmdiavriidzueadl SNiancgrloescToapbiuclaatneddMAincirmoaslcopRiecporOtbse(rcvoanttiinounesd) F392 Tuo YeRarikeOrralLabToorractiotryi-eOs,ncoIgnec,nici31ty Study in Rats Table: 2 Arial Fate: (NMuessbkeer: 921)6-4S7a7c0rificeSdexi:n Fesale Group: extrenis (2) FA-IS24 100 poe Macroscopic Observations: Pituitary MicrosLciovpeirc Observations: Adrenal Kidney Liver PLaurnagthyroid PiUrtiuniatrayryBladder ""RaSiesead thespoarlrehaagnidcsmoatstsl,ed.1.1 ca dia. ""Cpoerltviiccalsivnaecrwaolliaztaitoino,n,foscianli,nalwiliteral, aild PVraecluiotliast,iona,cutceo,nv.ailtdub. epitheiun, ild "PPoorrttaall sboinloenudculcetarprcoellilferiantfiiolnt,rataei,ldsininal Hepatocyte vacuolation, diffuse, marked Negalocytosis, aoderate Necrosis, "Vascular sfioncearla,liazialtdion, sild "Not exanined, not in plane of section E-pbietnhoenlsial hyperplasia, simple, diffuse, aild BTrhaeinf,olSlpoiwnianlg Ctoirses,ueBsonveerNearfroouwn,d Stpolebeen,wiHtehairnt,norSmtaolmaclhi,nitSse:ll Intestine, Large Intestine, Horta, Uterus, Ovary, Nambry Gland, Trachea, Thyroid, Esophagus, Lyeph Node (nesenteric, Pancreas, Salivary Gland, Eye. Ffantien:al(Mhaeaekbser:105()R-TAeTr7a6inal SSeaxc:rifFiecneale Grow: ( 2) FR-ISZH 100 pha Macroscopic Oservations: Ni[cros3copic Observations: Adrenal KEisdonpehyagus Liver Lung oury Splewn TBhreainf,ollSopwiinnagl tCiosrds,uesBowneereMafrroouwn,d "Hesorrhagic cyst, 1 ca dia., right owry. "Sinusoidal ectasia, cortex, unilateral, "Hrokteedxanined, wissing ""PCohrrtoanlic spornoognruecslseiarvecenlelshrionpfaitlhtyr,atew,ildwininal Hepatocyte vacuolation, mltifocal, aild NHeygpaelrapclyatsotsiics,nodauilled "Vascular wineralization, wild ""OHyeswtc,sifdoelrloisciusl,ara,ldbilateral tHoeabret,wiStthosiinchn,oraSamlalllisIinttse:stine, Large Intestine, PSrpoejceicets:MaRsabter: 0261080012 01812 Sunrized sh Page: 197 330 Susmarized Individual NSaicnrgolsecoTpaibculaantdedHiAcnriossaclopRiecpoOrbtse(rcvoanttiionnused) Riker Laboratories, Inc. 31 F-39242 Tuo Year Oral Toricity-Oncogenicity Study in Rats Table: 2 Aninal ushers 18-4776 Sexi Female Sroupt { 2) FN-3924 100 pps Fate: (Vests 105) Ternima Sacrifice Microscopic Observations (continued): The following tissues were found to be within normal Urinary Bladder, Aorta, Pituitary, Trachea, Thyroid, lisits (continued): Parathyroid, Lys Node (sesenteric), Pancreas, Salivary Gland, Eye, Mamary Bland, Uterus. fninal Masher: IR-4777 Sex: Female Group: (2) FI3924 100 pp. Fate: (Heek= 62) Found Dead Macroscopic Observations: Pituitary Microscopic Observations: Ere Liver Lung Pancreas Pituitary "Hesorrhagic mass, 0.6 1 0.9 ca. "Hot exasined, aissing "Hepatocyte vacuolation, saltifocal, sil Wegalocytosis, ail ~Prevsonia, acute exudative, local areas, wild Hesorrhage, miltifocal, ail cin atrophy, local areas, soderate -Adenona The fallosing Brain, Spinal tissues were found Cord, Bone arrow, to be within normal lisits: Spleen, Kidney, Heart, Stomach, Seal] Intestine, LThayrrgoeidI,ntPeasrtaitnhe,yroUirdi,naErsyopBhlaagdudse,r,LyAsoprhta,NodUeter(usse,senOtvearriyc,),NaSmaslairvyarBylaGnlda,ndT.rachea, Adrenil, Aninal Nusber: 1R-4778 Sex: Female Group: (2) FA-3924 100 pou Fate: (Heh 105) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Kidney Large Intestine Liver Lung Ha visible lesions. "Sinusoidal ectasia, cortes, unilateral, wrked "Chronic progressive nephropathy, aild Pelvic sineralization, ainisal Newatodiasis, colon "Portal sononuclear cell infiltrate, sininal Negalocytosis, ild Hepatocyte vacuolation, multifocal, saderate Portal bile duct proliferation, sild "Alveolar sacrophages, focal, aild Perivascalar sononuclear infiltrate, focal, ald SPrpoejceicets:Nufsabter: 0281CR0012 01815 Sussarized STAR Page: 140 - 33] SInutainvairdiuzaeld RSaicnrgolsecoTpaibculaatndedMiAcnrionsalcopRiecpoOrbtse(rcvoanttiionnused) F-39242 Tuo YeaRrikOerralLaTboorxaitcoirtiye-sD,ncIongce.nci3t0y Stady in Rats Table: 2 dFnaitaea:l (Keokbeer:1051)RATTeIrEsinal SSeacc:riFfeincaele Group: (2) FR-ST24 100poe Nicroscopic Observations (continued): TBrhaeinf,olSlpoirniaalg Ctoirsds,ueSsonweerHearfroouwn,d Stpolebeen,witHheairnt,noSrtmoaacLhi,stSse:al Intestine, Urinary Bladder, Lfyoarptsh,NoUdteeru(sa,eseanrtyer,ic)K,asPaanycreGalsa,nd,SalPiivtauriytarGyl,andT,racEhree.a, Thyroid, Parathyroid, Esophagus, fFaitnea:l GNeanlbser: SII)R-ASTa8c1rificeSdexi:n FeexmtarleesisGroup: ( 20 FAIA 100 ppm Macroscopic Oservations: LSipvleeren Large Intestine WicrHoisrceopniacl Observations: Large Intestine Liver Lang Lyssh Node taeseteric) ""iSpapaelarspasleulfloci, wprorimately 0.2 ca dia, in Left lateral lobe. "Beginning with the rectus, the colon, cecun afnidlleidleawnitahrefeecanllarmgaetderiaanld. Section of rectus appears enlarged and thickened. ""SLieniucsaoyiodaslarceoctnasia, cortex, wininal Lnaurcgleeawrelplledoisfofrpehriesnst.iateIdnvtadoers,cosNoad.erate "NHeecgraolsoicsr,tusmilst,ifsoocdaelr,ataeild ""HAelsovrerahrages,acrwoiplhdages, focal, ald Trhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonweerNearfroousn,d Stpolebeen,witKihdinneyn,orHmeaarti,iSsto:mach, Seal Intestine, EUsroipnhaargyusB,laPdadnecrr,eafso,rtsS,aliUvtaerryus,GlaOnvda,ry,BreK.ammary lan, Pituitary, Trachea, Thyroid, Parathyroid, fFantiee:al(aHebseker:105()R-TAeTrBaHinal SSaexc:rifFiecmeale Group: { 2) FA-IT2A 100 poe Macroscopic Observations: Nasaary Bland "Lobular mss, 21 1x 1 ca, dn Deft inguinal KicrLoiscvoepric Observations: Kidney "Haltigle pale foci in Left lateral lobe, "pNeeltvaisctaatiincernaeloipzlaatsison, sininal PSrpoejceicets:bReatr: O28ICHOIZ C0136 Summarized STAR Page: 141 332 Summarized Individual aScirngolsecoTpaibculaantdedMiMcirwoaslcopRiecpoOrbtse(rcvoanttiionnused) F398 Tuo YeaRrikeOrralLabToorxactiotryi-eDsn,coIgnecn.ici3t0y Study in Rats Table: 2 feinal Fate: (Mhaetskesr:105()R-4TTeBr0sinal SSeaxc:riFfeincaele Group: ( 2) PA-ISZ4 100 pom NicroLsicvaepric Observations (continued): Lung LWaysaiaryNoldean(desesteric) Paorvaartyhyroid PiStaluiivtaarryyBland Spleen "HNeepgaatlooccyyttoesivsa,cuonlialtdion, saltifocal, aild sPcraeslsoanria,sinienrtaerlsitziattiiaoln,, cshirlodnic, mltifocal, sAilnvienoallar sacrophages, sultifocal, wild Perivascular sononuclear infiltrate, wild ""Hbodt.eneoxcaavricniend,onwissing Hiingvhalsyionc.elluRleatra,stactysitcictoarceaapss.ularLysspuhraftaicce of one Kidney. "Tubular hyperplasia, bilateral, soderate Not exanined, not in plane of section "bSidalsadmenitis, chronic, soderate "Heaosiderosis, aild The following Brain, Spinal iCosrsdu,esBovneereMafroruonwd, tHoeabret,wiStthoinnachn,ormSaelalllimIinttse:stine, Large Intestine, Urinary Bladder, Aarts, Uterus, Traches, Adrenal, Thyroid, Esophagus, Pancreas, Eye. fFnaitnea:l (NMuesebkesr:1021)R-4S7a8c6rificeSdexi:n Female" Group: extrenis ( 2) FA-TO24 100 pp Macroscopic Observations: PiRtauswiatrayrySlant Liver Microscopic Observations: Adrenal hort Kidney Liver "-DLaorbkulraatiesdedwashse,sor1crhaagidcia.a,assi,n | cn dia. right axilla; sinilar sass in left inguinal area. "Raised wass, 3 x 1.5 ca, in right lateral lobe. ""SHiontuseoxiadnailnede,ctaissiai,ngcortex, moderate ""PHeelpvaitceeayitneervaalciuzoaltaitoino,n,inpeirniaplortal, soderate NHeegpaaltooccyetlolsuilsa,r ald carcinosa VAerlelasdiofffenreecnrtoisaitse.d, Mtordaebreactuelasritpoattitcern. activity. SPpreocjieecst:MuRsatter: 0201080012 013817 Suanarized STAR Pages 192 333 Sauniaiitaaeld RSirngnlecpTaiulaatnedrMiassa pRepoertra(ctoinotonusst) P28 Tho YehreGrraLTaoovrcsrorti-eB,no1pce,iit3y Stay in Rats Tae: 2 iFantael eWeaeve1000) 7S5ericaSenitn Fxtereiwser (2 E410 on Nerscpaic Osernticns (cantons: "vsecallaarr ssrinorpahtaiezsti,ons,taeladl, ald f--p-- Paratroid MFeinrscdceirtonon Not tained ot 0 plane of sein SiFraetne SSeeweitsersss, waterate Hers Tai shade wie TaihiennfsolSlSivaiknnerCt,oirsesDyuaerBsrewrTeMrasrforoeosun,n Wthoarrbee,swiStohEwiinschhe,ramSa,allLHieTnthtest:oidnee,esLerngterInitle,stiPnae,nes, Silivry San, Er. aFistel eNabtsr:7)ATSu)crificesSe1 Feerlessrot (2) PROTA 100 on WcrsWcpnictyOserations: tw H"eSvatrtrehraegdicseaasl,pl0e1fcoaciiain, wut Lobes. WerosrtaopctBervations: "CSoritiscaallvaacsthaastiioan,Cofrotsc,, fwoiclals,tesrnalla,teirlald, wdiatrshpesasi, corte, foc, ttnreey "wciulltaetriaotny, acloem. tub, eptarte walation, ppeirtihpeoritua,l,sian1iasl YNeecarlooscips,esatsl, twdoe,ateale wip sFarotnat,seerlsintataio,n, acrladic, mitifecal, Awvieesta wcrophge, focal, ald LFyuathNroatsed esateric) "JJoett esnainned,, saagi1n0gplane of section Pitti aero Stosach. ~Bastritis, acute, soderate TSWahiinnef,oylyoBnoiamneg rtCoirstsrsuetBseonweeiraerarfnra,,deStrpolseb,een,waibtvheirant,sSeShraanadl, iInnttses:tin, Large Traches, Thyrrd, tseshtiantg,, Parra, SPpreocjieest:hRaabter: 08ICROL2 01818 Sanrized ST ge 16 334 SIunnrdizud tShiogrneiTLbcolar4tnieddeco,rlonec.psor3BtaerCvoatnitonisn F#-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats tie 2 oFrlt tvhres9I ) Surn fed in FwroeensGrow: (2) FH 10 on SheirfiosclriaSositgp,iicbsae.ruatwrieonFo(nco0nti8nuewdi:thin oral iit (cntinels Foiier haavkr4TSaisr ie FsoiurlesnsGr: (BFR 10 hrssapwircy uSardtions: urrgeemscsr,at7xe,8xe2i5ncoirnsrig0ht inn Hrssanrienct Basrtions: ttStwicianr,enasso surface. Upon incision, sass found to contain KiEtomomra SJSaaetpcatianemt,ircsaaatiineg,n,smiisies, id us aHAlacsaianssn,reseiitdeionf,la,614 LovharyaSt dsteric StPaeerwavcativieonrm,ss,eocnilgco wile, lg PJPuorers t llltat swwaaiinnndd,,, asenngyg PSStaiiltnianryatorsttant lClottt wwwiiannnsd,,, asLoniknnfygaring rcesing Trroams . i lltttaiwmaaninnseesd,,, asanisnniyga hrBereisfnlbBoooegtrios,u waree foeunrd,toSbeowci,thinSrlonanl eiistt:ing tating inary Bld, rSeoaccitaetr: ARO 01819 Suvi sg . 330 SInudminvairdiuzaeld MSaicnrgolsecoTpaibculaantdedWiAcnriowaslcopRiecporOtbse(rcvoanttiionnused) F324 To YeRairkeOrralLubToorxaitcoirtiye-sO,ncoIngce.nic9i%ty Study in Rats Table: 2 fFartie:) (Nbuesebtesr: 65B)-4STa9c1rificeSdexi:n Female Group: extreais ( 2) FN-3924 100 pps Macroscopic Observations: NicrPoistcuopiitcarOybservations: Kidney Liver Lung PSpilteueintary Reddish mass, 1x 0.8 cn ""VHaecpuaotloactyitoen,vaccounovl.attiuobn., eppeirtihpeoirutna,l,misniilmdal NHeygpaelropclyatsatsiics,noadiullde "Pvealsvciuclarwinweirnaelriazlaitziaotni,on,aladld ~bHeesossiaderosis, ald The allowing Brain, Spinal tissues were found Core, Bone Narrow, to be Heart, wSittohnianchn,ormSeaall]liIsnittse:stine, Large Intestine, UEsroipnhaargyusB,laLdydsesrh, Nfoudreta,seUsteenrtuesr,icOlv,aryP,ancNraemaas,rySaGlliavnadr,yTSrlaacnhee,a,EyAed.renal, Thyroid, Parathyroid, AFantie:l (MWuesebkesr:1051)6-0T1e9r2winal SSeaxc:riFfeimcaele Groupt (2) PA-3F26 100 poe MacroWscaoapircyOEblsaenrdvations: WicroAscroepniacl servations: Kidney Liver Lung Nasuury Gland PiPatnuciretaasr.y "Hawslst,il2obcualadri,assi,n r4i1gh3t axxi2lclaa,; in perineal La ""Spienluvsiocidaailneercatlaisziaat,ionc,ortaeisl, sodrate "Hepatocyte vacuolation, sultifocal, wild PNieggaaelnotc,ytborsoiwsn,, ahieldpatocytes, sininal Hperplastic nodule "vascular Alveolar ssaicnreorpahlaigzeast,ionl,ocasliladreas, soderate ""Fhiebirroataetnrcopahy, focal, ald "hdtnons The following Brain, Spinal tissues were found Cord, Bone Narrow, to be within normal lisits: Spleen, Heart, Stosach, Small Intestine, Large Intestine, ULryisngahryNoBdlead(daeers,enftaerrtiac,),UtSearluisv,arDyrGyla,nd,TraEcvhe.ea, Thyroid, Parathyroid, Esophagus, SPrpoejceicets:MuRsabter: 0281CR0012 01820 Sunrined 588 Puget 165" 336 SIunnriizad tSoiogapeiTLaiclcan4taerdirera,iconie,RcporBtaercvoantitoinns) PA To er Bl Tor conc tty fo ats wie 2 F Ft skR 10) Teresa R SiFce E WWrrsFsooniniicrnOmrroon:: Hewerhgic wes, 0.5 cn fs, Kiiwes HSTeermseeasoiteasniaascttioiolonsin,o,n,Twmlieitrteon,4aig WiSeepslctysoisa,raetrioant,e ics a, mie, nHusithnress ioHwetnpoatnocoytne ,alteertati1on,lbeasoophilsicc,iofnocal, he i UrThiernenlSpBoinanale,iarsryseoyrveDrayfo,onndontyaerbnye,ilhennrtTrrnalcge,LSiAtnortw:ne,,STlyrdn,esEtsinp,nsL,uge Intestine, ih va eka, Press Sivas Bn, Er. Fita:ltatrs1079 T5oren SSeir cFhela Ge: (2 PH 10 po [Tr---- Sfeond. ale ae, 2 en in in Tit ter Hwy ion NeIarrriaia,an rfreassmsewdeanlt312ctcs,huc ad Wrsarpeica Sarton: GSitnsanitlwcatlsa,,arftecea,l, wldd iianrnts FA"Ftetbdnesbiyalre,suskatiiaongt,aarldi, aie wn Apenlnetctarolsssy,riesdon, wid [er dAKeotsrmlhaagr,ioonaeC,iweesc, lileree, soderste sarin cFeiesRtatter: CAIR0L2 01821 Soviet sn 957 Sumarized Individul MSaicnrgolsecoTpaibclaatneddMiMcnriomslcopRiecpoOrbtse(rcvoanttiionnused) F392: Tuo YeRarikeOrralLabToorxactiotryi-eDs,ncoIgnec.nici30ty Stuy in ats Table: 2 MFiatnea:l (Nbaesebtesr:105()6-T4e7r5ainal SSeanc:riFfeiscaele Groust (2) FA-I924 100 gpa Nicroscapic Observations (continued): vary Spleen Uterus ""Hceyssto,sidfeorlolsiicsu,larsoterate "Cystic glands, ile The folloning Brain, Spinal tissues were found Cord, Bone Narrow, tHoeabret,wiStthonianchn,ormSaulalllisIinttse:stine, Large Intestine, Urinary Bladder, forts, Pituitary, Traches, Thyraid, Parathyroid, Lyaph Node (seseateric), Pancreas, Salivary Bland, Eye. Ffantiea:al WKeoeskhser:1051)8-T4e7rs9inal SSaecx:rifFiecneale Group: (2) FR-3924 100 pn Macroscopic Observations: Microscopic Observations: Kidney Liver [ Xo visible lesions. * ""pHeelpvaitcocsyitneervaalciwzoaltaitoino,n,wisnuilntailfocal, aoderate Negalocytsis, soderate "PVearsicvualsacrulmairnermaolnioznautciloena,r ianlfdiltrate, wild The following Brain, Spinal Ctoirsds,ueBsonveerNearfroouwn,d tSpolebeen,wiHtehairnt,noSrtmoanlaclhi,niStesa:l] Intestine, Large Intestine, UParriantahryyroBilda,ddeErs,ophAaogrutsa,, ULytseprhus,NodOevar(ys,eseNnatmearricy),GlPaannd,crePaist,uitSaarlyi,varTyracGhlaenad,, hEyree.nal, Thyroid, nFaitsea:l OMhuessbke=r:1051)6-4T7e9r7sinal SSeaxc:riFfeimcaele Group: ( 2) PA-ISZN 100 ppm Macroscopic Observations: MicroLsicvoepric Osservations: harenal Kidney Liver Lung Lyaph Node (sesenteric) Pituitary Thyroid "Aopears pale and mottled. ""SPienluvsiacidaailneercatlaisziaat,ionc,ortseisn,isasloferate HeNepgaatlooccyytteosivsa,cuoslaartkieodn, diffuse, aaderate "pVearsicvualsacrulaairnesroanlainzuactlieoanr, isniflidltrate, wild ""PMoelnyaornteritis, aoderate "Hyperplasia, cell, focal, ail SPpreocjieecst:NuRmabter: 0281CRO012 0413852 Sonar TH ges wT. 338 Sdoimvairdiunaeld MSaicnrgolsecoTpaibcla4tneddKiiearolscoRpecpoDrtsecrvoattiinoanesd) FATE Tao YukreGralLaTboariactirtiye-sB,coTpce,ici3t8y Stdy in Rats Tae:2 fFaitnea:l tNhaebeer101907T9er7anal SSeasc:riFfiocaels raw (2) FIR 100 pn Wcrsscpic Oarvations (continued): rTUahreiinnaf,raylSvpSiianndagietC,oirsdsH,uierDsto,nweerUMerarosruo,nn,dOSvtpaolryeb,een,wRiaHtwheaiarnry,noGrlSmatanoldm,acLhTi,rnacSshm:eaal,l IPnatreastthiynreo,id,LiErseohIantness,tinFea,cress, Salivary Sid, Ere. rFaiteasl aNsakbser:1051)0T7e9r8inal SSaenctrifFiecmeale rau (2) PSTN 100 0 Nacrsscpic Oiservations: Wicrolsicvpeirc Oorvations: Lng LHyawthaNoSdleanansateric) FSaurlalthIynrtoedstine Ho visible Lesions. "PFoarrttaall sbiolneemfculteaprcoellilferiantfiiolnt,ratwei,ldwild HBeapaltoacyttoe nv,acastniieoant,e mltifecal, wild "Ssicveaallaarr sacivreorpaalgienst,ionf,ocaali,lwild HPeriovrarshcgael,armsltoivfnocciaola,rwiilndfiltrate, ald oeatorercaagsein,e,sosdeirsastey "Jocterexsine, nat in plan of ction TBUrrhaieinnaf,roylSlBiolnnandagdertC,iosrsrduetBs,onwereearrfrsoou,en,dOSvtaporlybe,em,wPiiKttiuhdiintneayrs,yo,rsHaeTlarratci,hnestS,st:oAidcre,nalL,irTehyrIonitde,stiEnse,ghas, Pancreas, Salivary Slant, Eve. nFatie:l ONeostteen:10B)ASTcrSificedSei:n tFormelsesrou ( 21 PRSEZH 100 oo WaroPsictoupiitcarsyervations: Hiroshcoorpoinacl servations: tLiivdey ung "Elurge, 0.8 a dia. "eClovrtiiccalaianrcaslliaztaitoino,n,{aaicnlialwild JiFeepplaatcaycoenivsi,cwalialtion, perigortl, sadeate eFaeorriraisucglea,rssiotniofnoaccalle,esfligltrate, wild SPpreocjieecst:Naubter: CAICROIZ C0183 Surin tra 18 537 SInudsiavriidzueald NSaicnrgolsecoTpaibculaantdedMiMcirwoaslcopRiecporOtbse(rcvoanttiionnused) PH-324: Too YeaRrikeOrralLabToornaitcoirtiye-sO,ncoIgnec.nicity Study in Rats Table: 2 AFoaitnea:l (Mbaesebtesr: 701)-7Sa9c9rificeSdexi:n FtermealneisGroups ( 2) PA-3924 100 pp MicrosLcyosphic NOobdseer(veasteisotnesri(cc)ontinued): Parathyroid PiSatluiivtaarryyGland Urinary Bladder ""HNoott eexxaansiinneedd,, naoitssiinngplane of section ~hdenons ""HNoott eexxaansiinneedd,, waiissssiinngg The following Brain, Spinal iCosrsdu,esBowneereNafroruonwd, tSoplbeeen,witHheiarnt,norSmtaolaaclhi,sitSse:all Intestine, Large Intestine, forta, Uterus, Ovary, Namary Gland, Trachea, Thyroid, Esophagus, Pancreas, Ere. fFnaitnea:l ONhuesebkesr:1051)R-4TGe0r0minal SSeaxc:rifFeincaele Grow: ( 2) PN-I924 100 pa Macroscopic Observations: skin Namary Gland Nicroscopic Observations: harenal Kidney Liver Lung Nawary Bland Poavraartyhyroid Pituitary "Hair "Mass lionssriognhtabadxoislelna., 1ca dia; wass in leit willy, 3x 2c, "Sinusoidal ctasia, corter, wilateral, wirked "Chronic progressive nephropathy, ild Pelvic aineralization, sild "HNyepgearlpolcaystioas,is,pelaviilcd epithelive, wild "Previn, interstitial, chronic, sultifocal, "hadlednocarcinons "hTduebnuolcaarrchiynpoesrsplasia, bilateral, soderate "Not exanined, not in plane of section ~hdenona The following Brain, Spinal tissues were found Cord, Sone Narrow, tSoplebeen,witHheianrt,norSmtaolmaclhi,mitSse:all Intestine, Lirge Intestine, Urinary Bladder, Aorta, Uterus, Trachea, Thyroid, Esophagus, Lyaph Node (sesenteric), Pancreas, Salivary Gland, Ere. PSrpoejceicets:NoRsatter: G2810R0012 c01824 Suanarized STAR Pages 149 - 340 Sduimvmiadriuzaeld MSaicnrgolsecoTpaibculaantdedMihcariosncopRiecporDtbse(rcnoanttiionnuse) PRIA Too YuTriteGralLibTuorsaitcoirtiyes-,DcoTogce,nciStUy Study in Rats Tale: 2 fFaotael eNsasteer: 99A)8S0a1crificeSdecitn FeesmtarleesisGrow: (2) FSEZE 100 pon KacroPsictoupiictarsyervations: NicroLsicvaepric Bhserations: Lng PlLsyigthaNraye Gsenteric) --haised red mass, 1 ca dia, "Hepatocyte vacwlation, local ares, soderate "AMpieagvaesllaoacrrytoassiiicnsre,orpahlsaiigzleadst,ionl,ocaaliladreas, oderate Hesorrage, mtifocs, aild "ohtereoxnanined, wissing BTrhaeinf,olSlopwiinnag Ctoirsds,ueTsownerMearfroouw,n tSpolebeen,witKhidihneyn,orhaeaarti,niSttso:wach, Seal Intestine, LTahrogied,IntPeasrtaitnhe,yroUirdi,narEysoBmlaagdedse,r,Pfaacrrtesa,s,UtSearlusi,varOyuarSya,ndR,awEwvaer.y Shan, Trache, renal, fFiotael ONeastteo:109() ATeZrainal SSaecxrifFiocaels Grog: ( 2) FSE24 100 poe MacrPoisctoupiitcarDyhsertions: Liver Wicroscapic Doservations: \ Ereent Liivee Lg FiNtasnintyryBland thSeplresesn "Thaeinsrerdhapgailce wcisr,cul0a.r7Lceasidoina,. 0.7 ca dia, in sBaelienlesliaovne;s,a0l.5ti1 rcabiseidn left lateral Toe. "RSeitmisnoaildaaltroepchays,iaw,itciofrotcear,l,wialidl r"oerltiacl aaisnmeornaclliezawtriocne,laiilnfiltrate, sild PHoerptaatlocbyitlee vdaccstolpartoiloinf,ermalttiiofno,caali,d aild NHeegpaatloocceyltlauslsa,r aaidlmons "Hteapsactloacrellauilnaeralaidzeaotinosn, wild Perivascular sononcleat infiltrate, wild ""Ghailracetraeele "HCeyasctsicigelraonidss,, wsoeddeerraattee BTrhaeinf,olSlpowiimnlg Ctoirsds,ueBsonveerMearfroounn,d Hteoarbte,wiSttohmianchn,ormSeaall]LiIninttse:stin, Large Intestine, SPproejceicet: Mfaasther: O2ICKL2 01325 Suanwized STH Page: 150 - 34 Snduinvaiidausnld NSiHanirgeolrsecTpLaiiucslaaattdueidWeMesri,ossIacnco.Rpecpo1Brter(vcaotnitonnusnt)-- FI: To ter Gal Toicity-Bncogenicity Stuy in Rats Tle: 2 nFaatels taebsr:105()4RT0er2inal SSaecriFfiecmele Grp (2) PSR 160 pn iThnearfNlyclrBooivsdaodgpeirtc,isQsHuasreetsra,awtrDieuornfyso,n(dTtrioancuebsee,d)wTi:htyhrionidn,orPaaratLhiynriotisd,(cEonptihnu,e: Ch Note esnteric, usreas, Salivary Eland. oFitae:n Goether:1091)0T4e0r5aiml SSaec:rifFiecmele Group (2 FET 100 pre Ncresopc Bertions: Ae visible Lesions. HcroHseompac Bsertionst Kitney S"innoiictaplroegrcetsssiv,e ceaprrtasp,thiys,insinial liver SCepptaatiodcydepeveircawtliatoino,n,miutiitfiacfaalc,l,wlmdld Hislaetoyte alteration, vacate, focal, ag TReossalaoy,toiinstewrislteitial, ironic, local ares, aHPvleresliarvaaarsophngeis,onwltiinffeialtlr,atei,lsie taserryss T"uobslacrgWlipnedrss,laisla, Bilateral, aild ihBaneianrf,oylSlBpoilnnaaadglertC,iosrsdo,uersBtownerPeaarfaoryn,dShtSaolndeb,ee,wPiittHuheiirtnta,rnyo,rSmtaTolwriacTchei,st,sS:aThlyroIinet,esPtairna,thyLraorigde, IEntxepsthignee,, Ligh Yost. eseataich, Pancras, Salivary Glad, Eve. TFiatea:l Gaeberk:105A) RTeOrinal SSicerifFiecmeale regi (20 ROR 100 in NcrosScoofpticTisOssueersatlieogn)s: LPiitvueirtary HerosArceonpacl Bernations: sLefot brinafowtass,ul0le.n.ct Witiple ale foc in all diLs.es Lure pale aListe,ral45Is3e.12 ca, dn Let Swinruissotidal ects, carter, wilaterl, PSrpoejceiecst:NaRabt.er: BIC C0132 1520 . `Sussarized STAR Page: 151 342 , SInodnivriiduzael aSirgolwoopTiouclaatnadNiicnraolsaRicpGtha(rcanttiioonuse) ke Lowratorin, a, 3 . FH-3924: Twa Year Oral Toricity-Oncogenicity Study in Rats Tae 2 iFavteha eYeeer:1015 T0ersiml SSaecsriFfiocee Grows 21 ALITA 10 pn Wcrscrpeic Osrntions (cantina: ine Liver Awetivlistiosn,,ssyfveiattsei joints, inden, oFenniic oreergapesaitvieonb,rS1a6t, siniml pFoartwarlt,socvonieclteawh ceaplilthienlfiiolnt,ratber,oww,idwild Pertal ite uc protifration, aid ny FiStiuirtary Wars WeHepapsadttoceceyrtiesavh,arcuaoallracdtiinoonn,smultifocal, sild "Faesaaltagrsssiie,rteitnrtaimobnu,iaanlyd, ald PFeertirvtahsatgael,arLcallaeess, isofdletrrtaete, ails Sfeovsitltresis, wild Covi shade were TShreif,ollSoininadg iCosrstu,esowereMafrroounn,t Htoarbte,wiStohniinchsyorSmlelLiottet:ine, Large Intestine, LrionhryNoBdeladeesr,otKeorrtiecDPrsye,esas,mSaalivShaarnytyBlTanrda,coEme,.Tootd, Paratha, Espa, FeatiesstNaaskbe80A) FSound DeadSer Fels Geo 2 FLEA 10 pn WcroFsicapiitcarByserntions: Wcrosltopwic servations: oieoe Soenprrhgic as, 1250.7 ch p Seivic-- simrah-- aation, site Vciolation, caw. th e5theion, arate Liver [ Loyry Noe Caster) Parsioid HuWesspualatooyrctyotessiovsea,rcauiotlliaeattioino,,pewriildportal, soderate Aevrthaargs,criTpohlageasr,ses,oewriaete TWoittsaerussawis,senbilateral, wild Jt ensined, wt in plan of ection FSpaegcieets:NRaet s UBIRO1Z 0132 1827 Sunricet STR Pg: 152 343 Susmarized Incividul MSaicnrgolsecoTpaibculaantdedMidcnriossaclopRiecpoOrbtse(rcvoanttiionnused) Riker Laboratories, Inc. 38 3924 Tuo Year Gral Toricity-Dncogenicity Study in Rats Table: 2 Fnaitea:l (Mlueaekbser:87()G-FAoBu0nSd Sex: Dead Fesale Group: ( 2) PR-IT2N 100 phe Microscopic Observations (continued): Pituitary Suall Intestine SpUlrienmanry Bladder Uterus. ""HAietrhionnnormal lisits Fewer than protocol usher "-HHoetsoesxiadneirnoesdi,s,wissasriknegd "Euutate, lueml, soderate The following Brain, Spinal tissues were found Cord, Bone Narrow, tSotobsaechw,ithLianrgneorImnatlesltiisniet,s:Aorta, Rassary Gland, Trachea, Adrenal, Thyroid, Esophagus, Pancreas, Salivary Gland, Heart. final Rusber: R-ABO7 Sex: Female Group: ( 2) PA-IT2A 100 ppm Fate: (ex 79) Sacrificed in extrenis Macroscopic Observations: Skin Liver Nicroscopic Observations: Adrenal KiEdsonpehyagus Liver Lung Raswary Slant Parathyroid Spleen Thyroid Trachea "Ulcerated necrotic muss, 5x 35x 2 cr, right axilla. "suall gale lesion, 0.4 ca dia. right anterior lobe. "Sinusoidal ectasia, cortes, soderate ""PHeoltviecxasniinneerda,liwziastsiionng, sinisal "HNyepgearlpolcaysttoiscis,nodaullde "PVrasecwusloanra,ainienrtaerlsitziattiiaoln,, cwhirlodnic, multifocal, Awlivledolar sacrophages, waltifocal, wild "~Hhodtemeoxcaanricniendo,ns,sisdsuicntgal "Hetopaiesis, extrasedullary, increased, wierate "Not exanined, issing "Not exanined, wissing The following Brain, Spinal tissues were found Cord, Bone arrow, to be Heart, wSittohmianchn,ormSeaalllliIsnittse:stine, Large Intestine, Urinary Bladder, forta, Uterus, Ovary, Pituitary, Lysph Node (sessateric), Pancreas, Salivary Gland, Eye. SPrpoejceicets:MaRsahter: 0781080012 01328 Suarized STAR Page: 153 - 344 STaodwivriidzule MSaicnrgolsecoTpaincl1tedHirciraalscoRpeccetra(tciaonniss) PSE Tao Yeir wralaeTraastcorr-sSc,apInci,ci3ty Stay in Rat Tate 2 iFantel tYhaert:16T5 TAenial aSecxidFiocl Gro: { 2) FAS4 10 30 WarosHcpiitc Ossrations: Kawry Sond aSoitsuearhseeshr,ha4gi3c2wcsh, e1tcasdiidae.. Wcrosrimnic Damnation: Kine oitrosnioanrg,reasiivnesinephropathy, ile ler peolrrtiacl aserraetieonc,elwrfiislttrate, ild PHoerptaatlocByitlee vdauccatlaptrioolsi,ferfaitifouns,,ssidleate Hweipeatocyte alteration, vacated, eel, I nesaslotcyonsgsr,atiitadtion, ald etrrhage, cl aes, sderte FLaykeodSehanGdesntric) aJbolsaeipnls aissing Fbartyary aTeuolnas hpplasia, bilateral, ald Urinary Hater Estonia persia, sie, focal, sila Uterus. "Cystic glands, woderate STTahaeitnf,ao,lSliweinrnaegsGatoi,rsdsyuTeysbrnworseNaPrfrrooadwoyStoloeibwe,,wiEhtshasihrng,rusS,mtowFiacihcn,etsSsa,:l,SaIltevtiinGel,nL,rEgr.Intestine Fnaitneal hNoustbser:1051)R-T48e0w9ial SSeexi:fiFecmeale Group: (2) FN-3924 100 ppa MacrolsFicvaoepwricrObSslearnvtations: Wcrocrpeicl Oseraian: ine Live SSoovtaa pwalse L5ei5c4s5a42a1a,Tbrea.t wes tTeui ringeuhin 6ar.e5s5. 551 1.5 cy S"inmsiecitrlorcwtssiiav,e csosrhtoep,atwoar,kedile fearttiacl ssenroanlilaataionc,elsfiislatlrate, ile TPoretallcioles,ictsopworlaitferaion, wile JHepoesrttaacsetliaclrswteesomtiple elation of Mpaectes in soe oul. SPpreocjieecst:hRaabter: CBICHOLZ 01329 Sunrise 1" 345 Sadoinvriitzuld BSiTnoglsecTpatislaatnedWnriEaslopRecporet.ra(ctaitionnun) Riker Lavortoris, lnc, FN-3924: Two Year Oral Toricity-Oncogenicity Study in Rats Tae: 2 fFiotael hoaakr:1615)45T0ew0imal SSaecriFfiocnee ropt { 2 LITZ 160 sot Werescnoepic Brion (ctinue): Nau Bland Pbiuturiytary ars ihvreilaasralcaerphsaognecsi,omnltfifialcle,ti,tdald FLrrg aires of cross in tar. aSbileam pra, laterals slg "wie shuns, sobre SThaeifnelSoinviag CtiosrstusBworeRtfreound Uinay Saber ey Traoen, 0Slebee,witHhuirnt,saStaovicLhiyitws:ll Ttestin, Lrg Intestine, Trods Purarass, Fgh, Lh a (asker), Fares, Salivary las, Ere, FraeteltNhasbte:160 9 Terninal SSeix dFoeuls Grows 2) FA 10 pn WcrsHceiitc Osaration: Werorpailc hstrations: ner wr "aise dark was, 0. ca ti. J onic wroaresiAve sbropa-- thy inal pearttiacl ssioeaanticilaetwionce,lsiinsfailltrate, aininl epaacte welation, wltifcal aid ung LPoratyNootres Castaic) Rtutary aFMerlgaolaoncy,toisniispt,eariwsratrtiktieiodanl,, ewlndc, sltifacl, Sieesrrhge, acl aes, ala SJiatowsaaiailnti,tiissingsere Savon TShaeinf,olSlyoinneg tCiosrstuesBwnreNafrroouwn, tSolebee,witahrinsnorSmtaolwscihwy iS:eal Ttestine, Large Intestine, iSinlkivyayBGalkaendr,y Bre.ey easy Ory, vary lady Traches, Thad Espa, Frees PSrcoijoent:Haetrs OBIGOLZ 01330 [I . LL Suswarized Single Tabulated Mnioal Report continued) Individual Macroscopic and Microscopic Observations Riker Lioratories, Inc. 3 FI4: Too Year Oral Tonicity-Dncogenicity Study in Rats Table: 2 fFaotien:al (Mbuesetke=r:1051)R-4T8e1r1ainal Sex: Fesale Sacrifice Group: ( 20 PA-ISZ4 100 ppm MacroEsceopic Ohservations: Liver NicroAscroepniaclOservations: Esophages fre Kidney Liver DLuunrgy Spleen Uterus. "Opacity, Left eye. "Pale and mottled. "Sinusoidal ectasia, cortes, aild Nedullary cell hyperplasia, unilateral, ail Pheachrosccytos, benign, unilateral "Not exavined, sissing "Retinal atrophy, unilateral, soderate "CChartoanriacct,prougnrielsastievrealnephropathy, wild Pelvic aineralization, soderate ~Fortal sononuclear cell infiltrate, aild Portal bile duct proliferation, ile Hepatocyte vacwalation, periportal, soderate PNieggeaelnotc,ytbosriosw,,sohdaetroactyetes, sild "vTausbcuullararasdienneroa,liuznaitliaotne,rawlild "Hesosiderosis, aild "Dystic glands, ald The folloring tissues were found to be within sora linits: Brain, Spiral Cord, Bone Marrs, Heart, Stomach, Sell Intestine, Large Intestine, Urinary Bladder, Kota, Naanary Gland, Pituitary, Traches, Thyroid, Parathyroid, Pancreas, Salivary Gland, Lyaph Node (sesenteric). Anisal onber: 1R-1612 Sexi Female Group: ( 2) FR-IS24 100 gon Fate: (eke 105) Terminal Sacrifice MacrSokscionpic Observations: Fituitary Nicrohsicropeimcl Observations: Kidney Liver Lung Poaurrathyroid Hair loss, head to neck. "Raised heorrhagic ass, 1 co dia. "Sinusoidal ectasia, cortex, ald "Pelvic sineralization, sininal "Hepatocyte vacuolation, autifocal, sild Negalocytosis, aoderate "Vascular sineralization, ald "ATlavbeuollaarrpsearcprlopahsaigae,s, wliolcaatleraarle,as,wialidld "Not exasined, not in plane of section SPpreocjieecst:NRaabter: 0281080012 01331 Sumwarized STR Pages 156 347 ISnudsiavairdiuzaeld MSaicnrgolsecoTpaibculaantdedRiMcnriansaclopRiecpoOrbtse(rcvoanttiionnused) S924: Tuo YeaRrikOerralLaTboorxactiotryi-eOsn,coIgnecn.ici3t0y Stady in Rats Table: 2 mFaitnea:l WNeoesbkesr:1051)6-4T8e1r2ainal SSeaxc:riFfeimcaele Group: (2) FR-IT24 100 ppm WicraPsictopuiictaOrbyservations (continued): SpUlteereusn ""HHedseorsiodmerosts, soderate "Cystic glands, animal The following Brain, Spinal tissues were found Cord, Bon arrow, to be within noraal linits: Heart, Stosach, Small Intestine, Large Intestine, UPrainncarreays,BlaSdadleirv,aroytBala,nd,RamEnyae,rySGkliann.d, Trachea, Thyroid, Esophagis, Lyesh Node (aesenteric), Ffanties:al (NHeacbkeer:1051)8-T0e8r1a3imal SSaecx:rifFiecmeale Groups ( 20 FHI920 100 pga Macroscopic Observations: NicrLoiscvoepric Observations: hirenal Lifveer LuOunagry PiPtaruaitthayrryoid Spleen "ale an wottied. "tCiorntaiclal avtarcoupohly,atiiornk,edlocal areas, aild "FPoorrttaall snonuclear cell infiltrate, aild bile duct proliferation, aild HHeeppaattuoccyyttee vaalctweorlaattiioon,n,vtaciufsolactaedl,, waaitlifocal, ail Negalocytosis, ail ""Tsacbaullaarradienneoraml,izwaitliaotne,ra#lild ""HHoitereoxnained, fat in plane of section "Hencsiderosts, wild The following Brain, Spinal tissues were found Cord, Bone Narrow, tKoidbneey,witHheairnt,noSrtmoanacLhi,itSsw:all Intestine, Large Intestine, ULryisnsahryNoBdlead(daeers,enRtoerrtiac,),UtPearnucsr,easN,annSaarlyivGalrayndG,laTndr.achea, Thyroid, Esophagus, Fmaitnea:l(Neaebker:1051)8-T1e8r1m4inal SSaeccrtifFiecweale Group: ( 2) FRITH 100 pon Macroscopic Oiservations: Nicrohsacroepniacl Observations: Xo visible lesions. "Simsoidal ectasa, corte, wild SPpreocjieecst:NRoaatber: 0281CR0012 01832 Sunarived sit ge: 1577 548 TSaunrdizoed RSiagteonTuiataedMiicnrolsepmiratracattiioend) ~ P28 To YouireGrraLTaroactoarierconqei,cit3y Std in at Table: 2 Fiintel tNeaer16F5 AToOrsion SSeis tFile ro (2) PRN 10 0 Nersctooprc serio (cation: Dhrioecnsprwograeasastivieonb,ralods, aid jr AePaapraaatlaabtieemaducettrooctanelraftitilitntr,aetiel,soaintee TM AeWesuatuslao,tsotalsrsiatitidtsia,, filraon, wife, Paths AMweeeoalsaostc,rgshgtes10,Laicnl oafrcest,ioanrte HSelitaeyr tng Siew "Sleeeeveneanronn,, iasding Tore Se eanoet, st 0 lan f action rrThaaeirfnyolSoHiinangsatiirsssrueseBwnerWeBaafrrrooynnd,Setrorytb,e,awiStathwiynihsyLruSnwdu,tariinsceh:ei,n,EpLbragesnotin, Uh oie wsstaric, Pures, re oFuit:e eYtaear10T5ATBoSrso SSeerFioee rout (2 FR 100 pn Wesresl terion: Weroesstsn erations: fr rt Po ine - ASetiurTeetaonur15e,8 di, 100 bor, [TnreitcPa aIrty,Rwilapterl,--er--e DAwrrcoianrfedi,tprsi,gsrBearsiiavlseessmmopstnhtyI,vsSfeate PPelbretcristtias,ticoant,iaidsete pNeeaprsialcswtsoeiv,araanirtiincoon)l, lmlttitfc,l, aalsein nbAvaeettraasuscmrlgsihngteois,oans,lliinefcii,raew,ild64 PSpaegcieets:Naabter: 081012 01833 Sussarized STAR Page: 158 349 PSSTuKsesairTiznoedYeSMaisrnrgeoGleseacTLoTapbleuila4ctaedWtArniscsanoclemoeRiepptoCrytssS(crtoanytiisniunnedR)ats Foirtel tNeaaer,10I5 TSerk SSe aseiwe Gras (2) FRITN 10 pe . Tae 2 WerscIopicoakersattiorn i(c tions our -- Sei mows, ilteal, erate PHoirtess eFiat,setogn arisd iss, otrate ers Fain rtThaeenfsolSotpiinoognass ssisroeeweoraesrfeosunsaptnoldbeye,wriotShmoisns,syrTlSeuliintnPse:rsather,eiLyargSe pItastsineS,alivary lst, Be FJ e te 15) Terao Stier pry [ Sin -- Hhituy Arusmnd apleerlterdesiiyond, Left ru fotpd, I aole.ated irae ws, 2 co din, etn Mersroon tsarutians: Ggarutinca,l sbaolm,ticoonrt,icaalc,laialres wild rt itor A"wrBaricidciitr,ian agamemlsesremspERtr,tiva,id jr FFeaeritaiahcl esilrenlfcucmkhtrlanifenrratttioesn, ,ilwld ptaarttergimraationo,n,tfcilsta,lrksd - ApPuarteiarrseclsalmtrasasainrncacltioionnn wlidtt, ald TyoourNosink(asst jos SGaahtcetiacmrteesnt PBreaihtrsrid Sin Se"theiewematits, slartive, indie, mied hreaoalSoynnneg Giovstuoeverre foond StopbeeewittheinacshoaSalLitt:te, Lire ntsioe, sPapgieets Naatber: caiorz 01534 FE -- _ 350 SInudsisvairsiuzaeld NSkainregolrsecoTLpaiibocualtnaatredicnArsn,oissaTclcs,Riecpo0Grtha(rcvotnitisnnused) FI: Teo Yer Bal Toicity-Dncogeicity Stay in Rats Tae: 2 Fiatu: teheris10U5 TTeraioal SSaeccriFfiocuels roups ( 2) FET 100 on The fI olowing tissues werep found t-- o be within ermal Lists (continued: Winay Bader, forts, Wars, Trchs, Thro, Esophagus, Pisces, Salivary Bland, Ee. eFaae:l eNaebler:101)46Si1c8rificeSdenis Fexotarlesnisrapt 2) FR 100 an NroPsictpuiitcarsyervations: Mdaerey Hc"rhosrceospiact Oharvtions: Biagihste awdarse,s 0p.eecarstie.nlarged. ale, pitted md ged, "ortical vacation, saerate tity hLiover Fadaatrhyyreid FiStlueietiey STthyarcoihd enss "CSroirnatuinscoeaildaplartorgeorcpethasyss,iiav,seniecolprarttoeepra,alt,shoysd,oereairtraekteed HPeeplavtioccyatievrvailciazlataitoino,n,sdniifafaulse, sisial ZHnvsecsutlaarr smcirnoepahlaignetsi,onf,awci,ldainisal "FTaebruilvasrchuplerrpsloansonic,iebairlatienrfaill,traatlee, aininl J"onoenetsiety at In ee of ection eSsuscrsiitdirso,sssc,kes,itesferate "hCyeplerlplacsairac,ioCnscal, local ares, waterate Drtic glas, serste The folowing tissues wre found to be within morsl Limits: Brain, Spinal Cord, Bone Marrow, Heart, Seall Intestine, Large Intestine, Urinary Bladder, Aorta, Massary Gland, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. rFaitaesl ONasbter:10I5RATReIrYinal SScerdifFiocmele oust (2) FSFE 00 pn NrosictpuiitcarByreration: Panry Sln ""bDarlLaesiaosnk,,0.351ca1.d3i1n. 1 ca, Left inp] Liver alToee.tircla lesion, 1.4 cn dis, seisn SPpreocjieecst:Naatbe: CAICROLZ 01835 Suanaized STH Pag: 140 . 351 Seuirde cioleie CtDaittedrrbiinnsaeBs3Br o(cantiosst PT Te Yeu al Torrcy Sty i Rte nie 2 Fiiee toeer8TTSrae SnriFcle rg 2) PRT 190 0 rsaopidc Bertie ctinat: SSortiictalaalwaitins,tItsl r1e0a, wild iaSvireon iTToidt asraeHtanisoatTasaflsaenteestariets ewatlrtieeocskslprreea, B14 booognryy Sd TFpierttiaoasnlesnw,mnielteytiniltte aid JToortrieie lFeieraerdinwh of section os Sati sis iihenv,eySlBoyeieGssovetb,sreeeweTerrfreend eSoeoesmietSiesLnshnrlBSile.]iissti:tnre,cLuereent,etioSea,ve St, a FSeeewer0ToEnt 3 Se Foie ro 7 IE 100 7 Narspaeic setion: Aarreaamniteetssm,n8e14n315 [sLSeiovruet-- PFroinofgcin, yo i, fNpeienm ltfoitonwtrosiIonwni,tnbististic Kirets FlTeaiieptanneoraaonttio,o,n,smiatisl st iLgee Ttstine Tateliidaragtiwnooesteicstiwcert tateehrotaatwiti.fn alifoaton forge Species: Rat 0133 R `Sussarized STAR Page: 161 352 STandnvriidauae RialtoescTpai t8sNrciraslcnBsoratracotnitoinnu) PIA To YurveBalLoTwcrhireG,cgnei.ict9y Stay in ats Tales 2 Fiitae easees01F0ound BodSes Fale Gg (DFR 10 . [TIn ------ incaaltiIvrolni,tioins,isirteic TLohaotleodestar) Fairs llJtot wvvaiasnsndee,,, asaoaesnsingsy SSohllTIantnesatinee p J"rKolipnitonyion, hstiotic Ttconssloanrgatiicnaind asiermtleisr.nt Ssttoeutms eHresstt,emretsseaotas ares, atrte rine ater Jo nin, wssing Ehreimnaf,neSl,oovSnliaivdws,yuSBwetretrfeoant tBorabes,witDhirnysoPilstLai,s:Traces, Toro, Patho, SHpoeecooaste: OBL co1837 Saiz ST Pg 127 B 993