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Pathology and Toxicology Rlker Laboratories, Inc. Building 270-3S-05, 3M Center St. Paul, Minnesota 55144-1000 4RW6-0257 I TWO YEAR ORAL (DIET) TOXICITY / CARCINOGENICITY STUDY OF FLUOROCHEMICAL FM-3924 IN RATS (RIKER Experiment No. 0281CR0012) Conducted During April, 1981 - - May, 1983 Volume 1 of 5 RIKER Laboratories, Inc. / 3M Company St. Paul, Minnesota 55144-1000 U.S.A. G0148J2 TWO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FM-3924 IN RATS (RIKER Experiment No. 0281CR0012) TABLE OF CONTENTS PAGE(s) REPORT SUMMARY ..................................................... 1 INTRODUCTION ....................................................... 4 MATERIALS AND METHODS ............................................. 5 R E S U L T S ..............................................................11 DISCUSSION........................................................... 20 C O N C L U S I O N S ......................................................... 24 PRINCIPAL PERSONNEL LIST ........................................... 26 SIGNATURE P A G E ....................................................... 27 REPORT TABLES .................................................... 28-112 TABLE 1 - Analytical Analysis of FM-3924 in the D i e t ......................................... 28 TABLE 2 - Summary of Mean Body Weights M a l e s ............................................... 29 TABLE 3 - Summary of Mean Body Weights F e m a l e s ............................................. 31 TABLE 4 - Summary of Mean Feed Consumption Per Kilogram Body Weight -M a l e s .................... 33 TABLE 5 - Summary of Mean Feed Consumption Per Kilogram Body Weight -F e m a l e s ...................35 TABLE 6 - Summary of Mean Absolute Feed Consumption - Males ................................ 37 TABLE 7 - Summary of Mean Absolute Feed Consumption - Female ................................ 39 TABLE 8 - Estimated Mean FM-3924 Consumption In Milligrams per Kilogram Per D a y ................... 41 001483 TABLE OF CONTENTS - Continued PAGE(s) TABLE 9 - Mortality D a t a ......................... TABLE 10 -Summary of Clinical S i g n s ............................45 TABLE 11 -Summary of Ophthalmologic C h a n g e s ................... 47 TABLE 12 - Mean and Individual Hemogram Values -Males . . . . 49 TABLE 13 -Mean and Individual Hemogram Values - Females . . . 61 TABLE 14 -Mean and Individual Clinical Chemistry Values M a l e s ............................................. 72 TABLE 15 -Mean and Individual Clinical Chemistry Values F e m a l e s ............................................. 84 TABLE 16 -Urinalysis V a l u e s ................................... 96 TABLE 17 -Individual Organ Weight, and AbsoluteMean Organ Weights, Mean Organ Relative Percent To Whole Body Weight, and Organ to Brain Weight Ratios At One Y e a r ............................................. 99 TABLE 18 - Individual Organ Weight, and Absolute Mean Organ Weights, Mean Organ Relative Percent To Whole Body Weight, and Organ to Brain Weight Ratios At Two Y e a r s .......................................... 104 TABLE 19 - Summary of Major Microscopic Findings - Neoplastic Lesions ..................... Ill TABLE 20 - Summary of Major Microscopic Findings - Non-Neoplastic Lesions ................. 112 REPORT FIGURES ................................................... 113-116 FIGURE 1 - Mean Body Weights - M a l e s ........................ 113 FIGURE 2 - Mean Body Weights - F e m a l e s ...................... 114 FIGURE 3 - Mean Feed Consumption Per Kilogram Mean Body Weight - Males ................. 115 FIGURE 4 - Mean Feed Consumption Per Kilogram Mean Body Weight - F e m a l e s ................116 001484 TABLE OF CONTENTS - Continued PAGE(s) APPENDIX ....................................................... 117-1597 ITEM A - Air Monitoring of Animal R o o m s .......................118 ITEM B - Diet Analytical Data S h e e t s ......................... 125 ITEM C - Acceptable Ranges for Clinical Pathology Parameters ............................... 139 ITEM D - Pathology Report by Dr. Robert G. Geil, External Consultant Veterinary Pathologist ........ 142 ITEM E - Biostatistical Analyses Procedures .................. 509 ITEM F - Summary of Mean Body Weights and Individual Animal Body Weight and Feed Jar Weight D a t a ................513 ITEM G - Ophthalmoscopic Evaluation and Data By Dr. Stephen I. Bistner, External Consultant Veterinary Ophthalmologist......................... 1578 ITEM H - Copy of the Study Protocol with Amendments.......... 1581 ITEM I - Quality Assurance Unit Statement.................... 1588 ITEM J - Chemical Analyses of FM-3924 and Stability Analyses of FM-3924 in D i e t ....................... 1589 C01485 TWO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FM-3924 IN RATS (RIKER Experiment No. 0281CR0012) REPORT SUMMARY The purpose of this study was to assess the potential chronic toxicity and oncogenicity of FM-3924, an industrial grade of N-ethyl perfluorooctanesulfonamido ethanol, by mixing in the diet and feeding to 50 rats per sex per dose group for two years. An interim termination and evaluation was performed at one year on 15 additional rats per sex from only the control and high-dose groups. A total of 460 Sprague-Dawley rats (230 of each sex) were equally divided into four groups. The rats were fed diets containing either 0, 10, 30 or 100 ppm of FM-3924 for the duration of the study. In-life observations performed during the course of the study included: daily observations for abnormal clinical signs; periodic physical examinations; periodic recording of body weight and feed consumption; ophthalmoscopic examinations; and clinical pathology determinations including hematology, clinical chemistry and urinalysis. Macroscopic postmortem examinations were performed on all animals including those that died or were terminated prior to the end of scheduled dosing. Selected organ weights were obtained from all of the rats at scheduled necropsy at one year as well as from 15 rats/sex/group, randomly selected from the control and all FM-3924-treated groups, at the termination of the study. Selected tissue specimens were harvested from each animal at necropsy, and preserved for future histopathologic evaluation. Microscopic evaluation was performed on tissues preserved from all of the control and high-dose rats, while a similar evaluation was performed on a limited list of tissues obtained from the low- and mid-dose animals. The major in-life findings associated with FM-3924 administration consisted of a dose related decreased rate of mean body weight gain, an increase in feed consumption per kilogram of mean body weight, a slight 001486 i. 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 highand 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. 60148? 2. The overall incidence of hepatocellular adenomas and carcinomas was low in both control and FM-3924-treated groups with only the high-dose female rats possibly having a tumor incidence outside historical control limits. 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 of tumor appearance, malignancy patterns of tumors and the final mortality values at two years, FM-3924 was not considered to be carcinogenic in the rat under the design and conditions of this study. 001488 3. TWO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL 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., 3M 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 3M Center in St. Paul, Minnesota. 001489 4. MATERIALS AND METHODS p Test System: Four-hundred and sixty Sprague-Dawley rats [CrlrCOBS 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 limits for the suspected fluorochemicals. In addition to the air monitoring, 30 untreated sentinel rats were placed in each of the two animal rooms. From each 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, MO) 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 Item J). 01430 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 animals, 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 FM-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 lid. 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 listed hereinafter. Treatment Groups Dosage Levels (ppm) 1 - Control 2 - High 3 - Mid 4 - Low 0 100 30 10 Group Size & Animal Numbers Males Females (An. Nos.) (An. Nos.) 65 (3516-3580) 65 (3696-3760) 50 (3761-3810) 50 (3811-3860) 65 (4576-4640) 65 (4756-4820) 50 (4821-4870) 50 (4871-4920) 001491 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 6). 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 pH, specific gravity, albumin, glucose, bilirubin, occult 'blood and ketones. Blood samples were collected from the retrobulbar venous plexus of anesthetized rats which had been fasted overnight. Blood was generally collected from the right eye. Urine samples were obtained by placing each rat in an individual metabolism cage for 20-22 hours. The specific methods 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, lung and bone marrow (ie. 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 examined in situ and following removal from the body. Organ weights (ie. wet tissue) were obtained at the interim termination from both the control and high-dose groups, and from the control and all FM-3924-treated groups at the two year necropsy. The weights of the adrenal glands, brain, testes, heart, kidneys, liver, spleen and uterus were recorded for 15 randomly selected rats/sex/group. Body weights were obtained just prior to necropsy from the same rats in order to calculate organ weights relative to whole body weights. Representative samples of the following tissues and organs from each rat were fixed in 10% neutral, buffered formalin for subsequent histologic processing: 001493 8. 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 D). 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 0 0 14 9 4 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 a 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/!esion/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. 601495 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 F). 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 consistent during 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 001496 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 601497 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 low. 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 females developed ocular opacities during this period. The incidence of palpable tissue masses during the in-life phase of the study was not increased in any of the FM-3924-treated groups when compared to the control rats (Table 10). 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. 01498 13. Changes seen in leukocytic 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 low-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 serum 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 15). 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 O O I499 14. 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. These findings 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 low- 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 body weights 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 001300 15. 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 FM-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 FM-3924 treated groups. Details of the histopathologic findings are contained in Appendix Item D and a summary 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 001501 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 male and female groups. Hepatic cystoid degeneration, a condition characterized by areas of multi locular 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 001S02 17. 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 D) had varying incidences either similar to, increased, or decreased from control values; however, essentially all of these findings are commonly associated with either endemic diseases and/or geriatric changes found in this strain of rat. The changes presented hereinafter were not considered test-article related findings, although their incidence varied from that observed in the control rats. 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 lower 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; 001503 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 dose dependent 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 highl and 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-dose groups. 19. DISCUSSION The purpose of this study was to define any long term toxicity and to profile the potential oncogenicity of FM-3924, a periluoroalkylsulfonamido 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 SDA viral infection might have had on body weight gains were considered, but discounted since the FM-3924 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 FM-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 postmortem results confirmed the systemic absorption of the test substance 001305 20. and the 100 ppm dosage level appeared to adequately comply with the concept of a maximum 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 liver 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 001506 21. parameters that were progressive over time. These findings were considered to be associated with the progressive degenerative changes of naturally occurring chronic renal disease commonly found in rats of this strain. The primary test article effect occurred in the liver as increased organ weight (both absolute and relative), as gross findings at necropsy, and as histopathologic alterations. These changes were observed at the one year necropsy, but showed remarkably little progression one year later at the two year necropsy. The high-dose males and females had essentially equal incidences of hepatic findings, while the mid- and low-dose males were more markedly affected than were the females from the corresponding dose groups. Hepatomegalocytosis and hepatocellular vacuolation are characteristic of increased metabolic activity in the rat. It is recognized that these lesions may progress to cystoid degeneration and, ultimately, hepatocellular necrosis. The incidence of hepatic necrosis in this study was slightly increased only in the high-dose males. Since the liver in the rat rarely repairs parenchymal cell loss with fibrosis or scar tissue, a more typical cellular reaction is hepatocellular hyperplasia. In this study, the incidence of hyperplastic nodules were increased only in the high-dose male and female animals (ie., 10% and 18%, respectively) compared to the control groups (ie. 0% and 2%, respectively). It is important to note that no proliferative hepatic lesions (ie. hyperplasia nor neoplasia) were seen in any of the high-dose rats after receiving FM-3924 for one year. Primary liver neoplasms observed in this study after two years consisted of hepatocellular adenomas and carcinomas. The overall incidence of these neoplasms was low, with carcinomas occurring in both the control and FM-3924 treated groups as follows: males 6%, 4%, 2% and 2%; and females 0%, 6% 0% and 0% for the control, high-, mid- and low-dose groups, respectively. Benign hepatic neoplasms (ie. adenomas) were not found in any group except the high-dose females where an incidence of 8% was recorded. Considering the chronic liver stimulation noted in both the high-dose male and female groups during their life span, the incidence of hepatic neoplasia appears to be within reasonable limits with the possible exception of the high-dose female group. Combined malignant and benign incidence values are within reasonable historical control limits for the 001507 22. high-dose males while the high-dose females appear to be slightly outside these limits 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 tumor incidence in the control group (see Table 19). Deviations from 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, lung, 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 accumulation 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. 001508 23. 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 oneyear necropsy, but showed very little 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. 001509 24. 4. 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. 5. The overall incidence of hepatocellular adenomas and carcinomas was low 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. 001310 25. PRINCIPAL PERSONNEL INVOLVED WITH THE CONDUCT AND REPORTING OF RIKER EXPERIMENT NO. 0281CR0012 - TWO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FC-143 IN RATS __________ NAME________ ________ S.I. Bistner, D.V.M. M.T. Case, D.V.M., Ph.[). R.G. Geil, D.V.M. R.W. Hawkinson, Ph.D. J.D. Henderson, D.V.M. , M.S. M.K. Hopp, A.A.S. C.D. King, D.V.M., Ph.lD. 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. G.C. Pecore S.L. Westmark, A.A.S. L.O. Wiseth _______ POSITION/FUNCTION__________ External Consultant/ Veterinary Ophthalmologist Manager, Safety Evaluation External Consultant/ Veterinary Pathologist Supervisor, Statistical Services Manager, Laboratory Animal Medicine and Pathology Senior Laboratory Technician/ Study Assistant External Consultant/Draft Report Preparation Senior Medical Technologist/ Clinical Pathology Determinations Advanced Secretary/ Report Typing Advanced Biostatistician Toxicology Specialist/Sponsor Representative and Project Coordinator Histotechnologist/Microscope Slide Preparation Supervisor, Laboratory Animal Care Laboratory Technician Senior Laboratory Technician/ Assisted With Study Data 001511 26. SIGNATURE PAGE TWO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FN-3924 IN RATS RIKER Experiment No. 0281CR0012 From the Pathology and Toxicology Department RIKER Laboratories, Inc./3M Company St. Paul, Minnesota U.S.A. Study Director: Leonard J. S^inski, B.A. Senior Toxicologist Date Report Reviewed Q-Un James L. Allen, Ph.D. Diplomate, A.B.T. Research Toxicologist V-T'?? Date Report Approved Edward Erickson, Ph.D. Laboratory Manager Date Report Reviewed j-risr Steve V. Elrod, Ph.D. Date Diplomate, A.B.T. Manager, Pathology/Toxicology and Laboratory Animal Medicine 001512 27. Tabi 1 Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FM-3924 in Rats Analytical Analysis of FM-3924S. (% Above/Below De si re d Concentration) Approxima te CCD Analytical Study Month Report Numbers Dosage Levels (ppm) 200 Diet 100 30 Concentrate 0 (Initial) 213 + 7.0% + 7.0% - 4.3% 1 229 + 4.0% + 4.0% _+ 0.0% 4 251 + 7.0% +10.0% + 2.2% 7 290 + 8.5% + 5.0% - 1.0% 10 320 - 1.0% + 5.3% - 6.7% 11 327 - - - 13 341 - 0.5% - 1.3% - 3.3% 16 367 - 3.5% - -19.3% - 4.4% 16 368 - + 3.3% - 19 383 +11.5% + 7.3% +11.0% 22 394 -16.5% - 8.0% -10.0% 24 403 + 4.0% + 1.0% - 2.0% 10 + 0.0% + 9.0% + 7.0% - 3.0% - -21.7% + 0.7% +11.0% + 6.7% +13.0% -17.0% -13.0% Mean Deviation for the study + 2.0% - + 3.4% - 1.8% - + 1.4% & -- Commercial Chemicals Division (CCD) -- Incorrect values given at this level due to instrument malfunction; this dosage level was reanalyzed after new detector was installed. -- Incorrect values given possibly due to a variation in analytical procedure; percentage near lower acceptable limit, this dosage level reanalyzed (two d weeks later). -- Excluding from mean deviation the percentages near + 20% acceptable limit. C01S13 28. Table 2 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Mean Body Weights (g) _+ % Difference f r o m Control MALES Study Week 0 2 4 6 6 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Control 100 ppm Mean Wt. Mean Wt. % Diff. 165.3 270.9 334.0 390.7 429.2 456.2 475.5 493.2 502.9 515.3 526.8 542.3 550.4 561.0 567.5 576.3 580.6 582.9 591.0 599.4 608.4 612.9 619.8 623.5 626.1 639.2 638.6 168.2 253.6 308.7 333.1 369.8 397.2 '417.1 425.5 442.4 452.7 465.0 474.6 483.7 489.0 500.1 510.5 515.9 507.1 518.8 524.9 530.4 536.5 541.7 548.8 552.3 559.9 566.7 + 1 .8 - 6.4 - 7.6 -14.7 -13.8 -12.9 -12.3 -13.7 -12.0 -12.2 -11.7 -12.4 -12.1 -12.8 -11.9 -11.4 -11.1 -13.0 -12.2 -12.4 -12.8 -12.4 -12.6 -12.0 -11.8 -12.4 -1 1.2 30 ppm Mean Wt. % Diff. 169.1 262.8 327.7 361.6 404.8 433.8 454.8 464.7 485.0 495.0 508.9 522.5 532.1 541.4 552.4 561.3 569.2 567.1 576.8 578.2 586.8 592.0 598.8 604.8 611.0 619.1 623.8 +2.3 -3.0 -1 .9 -7.4 -5.7 -4.9 -4.4 -5.8 -3.6 -3.9 -3.4 -3.6 -3.3 -5.5 -2.7 -2.6 -2.0 -2.7 -2.4 -3.5 -3.6 -3.4 -3.4 -3.0 -2.4 -3.1 -2.3 10 ppm Mean Wt. % Diff. 165.6 258.3 321.3 355.3 394.5 428.3 453.2 466.2 484.2 495.0 508.0 521.1 531 .9 541.1 553.0 561.9 570.1 566.3 575.8 578.0 588.7 590.7 595.9 601.3 605.2 614.1 618.1 0 -4.6 -3.8 -9.1 -8.1 -6.1 -4.7 -5.5 -3.7 -3.9 -3.6 -3.9 -3.4 -3.5 -2.6 -2.5 -1.8 -2.8 -2.6 -3.6 -3.2 -3.6 -3.9 -3.6 -3.3 -3.9 -3.2 001514 29 Table 2 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats ( Summary of Mean Body Heights (g) _+ % Difference f r om Control HALES Study Week 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 104 Control 100 ppm Mean Wt. Mean Wt. % Diff. 654.3 661.6 668.0 673.2 674.4 664.5 650.8 656.6 661 .9 658.3 660.8 667.7 668.8 670.6 663.1 668.1 675.6 678.9 690.0 686.0 678.3 677.5 675.7 671.1 665.9 642.0 573.4 579.0 583.6 584.5 589.2 589.5 591.0 592.9 601.2 592.1 588.1 600.2 598.9 607.2 602.6 612.3 610.2 613.4 617.7 610.9 595.3 592.6 594.2 594.7 588.8 568.6 -12.4 -12.5 -12.6 -13.2 -12.6 -11 .3 - 9.2 - 9.7 - 9.2 -10.1 -1 1 .0 -10.1 -10.5 - 9.5 - 9.1 - 8.4 - 9.7 - 9.6 -10.5 -10.9 -12.2 -12.5 -12.1 -11.4 -1 1.6 -11.4 30 ppm Mean Wt. % Diff. 627.3 633.5 634.6 637.3 640.3 641.7 644.7 646.2 650.5 640.5 638.7 651.9 654.8 656.5 657.5 657.3 653.4 648.2 646.9 644.7 634.3 630.9 627.6 630.0 629.0 628.9 -4.1 -4.2 -5.0 -5.3 -5.1 -3.4 -0.9 -1.6 -1 .7 -2.7 -3.3 -2.4 -2.1 -2.1 -0.8 -1.6 -3.3 -4.5 -6.2 -6.0 -6.5 -6.9 -7.1 -6.1 -5.5 -2.0 10 ppm Mean Wt. % Diff. 620.7 625.7 635.2 639.4 641.2 642.8 646.0 650.6 650.5 642.9 641.6 648.3 650.6 652.5 648.8 648.9 653.4 655.9 656.8 655.4 657.3 651.1 649.2 642.1 651.1 645.6 -5.1 -5.4 -4.9 -5.0 -4.9 -3.3 -0.7 -9.1 -1.7 -2.3 -2.9 -2.9 -2.7 -2.7 -2.2 -2.9 -3.3 -3.4 -4.8 -4.5 -3.1 -3.9 -3.9 -4.3 -2.2 +0.6 0l3ls I 30 Tabi 3 Two Yaar Oral (Diat) Toxicity-Oncoganicity Study of Fluorocarbon FM-3924 in Rata Summary of Mean Body Haights (g) jk % Difference f r om C ontrol FEMALES Study Week. 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Control 100 ppm Mean Ht. Mean Ht. t Diff. 136.2 159.2 209.5 238.7 256.9 269.2 279.5 289.7 291.8 306.8 311.6 319.1 324.5 327.3 333.7 338.3 345.? 350.7 355.5 359.3 363.2 371.2 380.1 385.7 392.3 398.6 406.1 138.7 168.5 211.4 224.6 237.7 243.2 241.6 251.1 256.9 263.2 269.4 273.2 278.1 279.9 285.0 282.2 289.8 292.1 300.5 302.1 306.3 311.4 313.9 317.8 321.1 324.6 328.8 + 0.4 + 5.8 + 0.9 - 6.0 - 7.4 - 9.7 -13.6 -13.3 -12.0 -14.2 -13.5 -14.4 -14.3 -14.5 -14.6 -16.6 -16.1 -16.7 -15.4 -15.9 -15.7 -16.1 -17.4 -17.6 -18.1 -18.6 -19.0 30 ppm Mean Ht. % Diff. 135.8 163.3 213.6 234.3 252.0 261.6 264.4 275.0 283.4 292.3 299.3 303.5 310.3 312.9 321.7 318.6 325.7 331.6 337.8 341.5 345.4 353.7 358.3 363.8 368.6 373.9 379.3 -1.7 +2.6 +2.0 -1.8 -2.0 -2.8 -5.4 -5.1 -2.9 -4.7 -3.9 -4.9 -4.4 -4.4 -3.6 -5.8 -5.7 -5.4 -5.0 -5.0 -4.9 -4.7 -6.0 -5.7 -6.0 -6.2 -6.6 10 pp m Mean Ht. Diff. 135.6 158.3 211.0 237.9 256.8 260.8 270.4 283.2 291.7 301.8 308.0 317.0 323.1 327.7 332.5 332.7 337.6 342.1 351.6 358.3 359.6 369.3 376.3 379.6 386.9 391.3 400.5 OK -1.9 -0.6 +0.7 -0.3 0.0 -3.1 -3.3 -2.2 0.0 -1.6 -1.2 -0.7 -0.4 +0.1 -1.7 -2.3 -2.4 -1.1 -0.3 -1.0 -0.5 -1.0 -1.6 -1.4 -1.8 -1.4 001516 31 Table 3 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Mean Body Weights (g) _+ % Difference from Co nt ro l FEMALES Study Week 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 104 Control 100 ppm Mean Wt. Mean Wt. % Diff. 414.1 419.1 420.9 423.6 426.6 426.1 424.9 427.5 431 .4 435.2 446.5 455.2 464.8 474.9 484.0 484.8 492.7 499. 1 500.6 512.5 505.7 506.9 500.0 501.2 503.6 502.0 334.2 340.9 346.9 350.0 351.0 351.8 350.4 357.7 360.8 366.4 371.4 373.4 369.3 378.7 378.2 383.9 378.3 389.7 389.7 392.6 399.1 402.6 402.6 396.9 402.3 397.8 -19.3 -18.7 -17.6 -17.4 -17.7 -17.4 -17.5 -19.5 -16.4 -15.8 -16.8 -18.0 -20.5 -20.3 -21.9 -20.8 -23.2 -21.9 -22.2 -23.4 -21.1 -20.6 -19.5 -20.8 -20.1 -20.8 30 ppm Mean Wt. % Diff. 388.0 396.0 404.1 408.0 41 1 .5 416.5 413.7 422.4 423.5 429.9 435.1 442.1 438.3 444.9 436.4 443.8 443.9 445.5 442.1 448.9 440.1 445.6 444.9 435.5 438.6 425.2 -6.3 -5.5 -4.0 -3.7 -3.5 -2.3 -2.6 -1.2 -1.8 -1.2 -2.6 -2.9 -5.7 -6.3 -9.8 -8.5 -9.9 -10.7 -11.7 -12.4 -13.0 -12.1 -1 1.0 -13.1 -12.9 -15.3 10 pp m Mean Wt. % Diff. 407.6 412.6 421.8 423.9 425.6 429.0 425.5 434.7 440.6 449.9 455.9 458.2 458.7 466.9 467.1 475.7 490.2 486.9 494.6 487.1 486.1 499.3 494.6 492.1 490.4 484.5 -1.6 -1.6 +0.2 0.0 -0.2 +0.7 +0.1 + 1.7 +2.1 +3.4 +2.1 +0.7 -1.3 -1.7 -3.5 -1.9 -0.5 -2.4 -1.2 -5.0 -3.9 -1.5 -1.1 -1.8 -2.6 -3.5 001517 32 Table 4 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Mean Food Consunption Per Kilogram Body Weight (g of diet consumed p e r day) _+ % Di ff er en ce from Co nt ro l MALES Study Week 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Control 100 ppm Mean Wt. Mean Wt. % Diff. 102.0 85.2 76.4 69.4 61.5 53.7 50.7 51.7 48.0 46.8 46.9 44.9 45.0 43.7 42.8 43.2 42.9 41 .8 38.4 40.7 39.5 39.3 38.9 39.0 39.0 38.5 36.5 100.7 89.4 74.5 62.7 65.4 60.2 55.8 51.3 52.3 50.1 50.8 50.1 47.4 45.4 47.3 45.0 43.2 41.4 44.8 44.5 44.3 45.7 45.0 43.4 42.7 42.5 40.6 - 1.3 + 4.9 - 2.5 - 9.7 + 6.3 + 12.1 + 10.1 - 0.8 + 9.0 + 7.1 + 8.3 + 11.6 + 5.3 + 3.9 +10.5 + 4.2 + 0.7 - 1.0 +16.7 + 9.3 + 12.2 + 16.3 + 15.7 + 1 1 .3 + 9.5 + 10.4 + 1 1.2 30 ppm Mean Wt. % Diff. 100.9 90.2 77.4 65.4 65.0 60.2 58.7 51.2 50.1 49.0 49.1 49.5 46.3 44.0 45.0 43.9 42.2 39.8 42.9 42.5 43.1 45.4 42.6 42.3 41.7 40.7 38.2 - 1.1 + 5.9 + 1.3 - 5.8 + 5.7 +12.1 + 15.8 - 1 .0 + 4.4 + 4.7 + 4.7 + 10.2 + 2.9 + 0.7 + 5.1 + 1.6 + 1.6 - 4.8 +1 1 .7 + 4.4 + 9.1 + 15.5 + 9.5 + 8.5 + 6.9 + 5.7 + 4.7 10 ppm Mean Wt. % Diff. 102.4 91.5 77.4 63.3 64.3 60.8 55.7 51.1 50.9 48.9 49.0 48.5 46.3 42.6 43.2 43.1 41.5 38.6 42.4 42.7 42.6 43.9 41.6 40.9 41.3 40.2 32.8 + 0.4 + 7.4 + 1.3 - 8.8 + 4.6 +13.2 + 9.9 - 1.2 + 6.0 + 4.5 + 4.5 + 8.0 + 2.9 - 2.5 + 0.9 + 0.2 - 3.3 - 7.7 + 10.4 + 4.9 + 7.9 +11.7 + 7.5 + 4.9 + 5.9 + 4.4 -10.1 OOisis 33 Table 4 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Mean Food Consumption Per Kilogram Body Height (g of diet consumed pe r day) +_ % Di ff er en ce from Co ntrol MALES Study Week. 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 104 Control 100 ppm Mean Wt. Mean Wt. % Diff. 37.0 36.6 36.1 35.4 35.9 31.0 36.3 32.9 32.6 33.0 34.4 37.1 36.6 34.6 36.3 35.6 35.1 34.6 34.9 35.1 38.5 37.1 37.3 36.7 35.0 33.8 41.9 41.1 41.0 40.4 40.1 41.4 36.2 37.1 40.1 40.9 41 .8 40.7 37.6 39.5 40.2 34.8 40.3 41.1 39.3 39.5 40.7 41.5 41.4 41.9 40.9 39.0 + 13.2 + 12.3 + 13.6 + 14.1 +1 1.7 +33.6 - 0.3 + 12.8 +23.0 +23.9 +21.5 + 9.7 + 2.7 + 14.2 +10.7 - 2.3 +14.8 + 18.1 +12.6 + 12.5 + 5.7 + 1 1.9 +1 1 .0 + 14.2 +16.9 + 15.4 30 ppm Mean Wt. * Diff. 40.2 39.8 39.7 39.1 38.4 39.6 34.3 35.3 37.7 38.7 40.1 39.4 36.5 37.5 36.4 33.3 41.6 39.2 38.5 39.7 40.7 40.6 39.4 40.3 39.9 38.5 + 8.7 + 8.7 + 1.7 + 10.5 + 7.0 +27.7 - 5.5 + 7.3 + 15.6 + 17.3 + 16.6 + 6.2 - 0.3 + 8.4 + 0.3 - 6.5 +18.5 + 12.6 + 10.3 + 13.1 + 5.7 + 9.4 + 5.6 + 9.8 +14.0 + 13.9 10 ppm Mean Wt. % Diff. 39.2 38.4 39.2 38.5 38.7 39.2 34.4 35.7 36.4 38.1 40.7 38.7 37.2 38.2 37.0 33.6 39.6 39.2 39.3 38.6 40.0 37.0 39.4 40.0 40.6 37.8 + 6.0 + 4.9 + 8.6 + 8.8 + 7.8 +26.5 - 5.2 + 8.5 + 11.7 + 15.5 +18.3 + 4.3 + 1.6 + 10.4 + 1.9 - 5.6 + 12.8 + 12.6 + 12.6 + 10.0 + 3.9 - 0.3 + 5.6 + 9.0 +16.0 + 11.8 001S19 34 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 consumed p e r day) _+ % Di ff er en ce from Co ntrol FEMALES Study Week 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Control 100 ppm Mean Wt. Mean Wt. % Diff. 98.8 107.0 97.2 81.0 74.1 72.6 70.2 64.2 57.2 64.3 63.4 58.6 59.5 57.0 61 .7 59.7 58.4 52.9 56.7 56.8 58.4 54.2 54.7 48.5 49.2 51.4 48.3 96.4 101.3 80.3 73.6 74.8 70.9 67.0 64.0 63.1 66.3 64.1 61.9 60.4 58.5 58.6 57.2 58.1 53.1 59.2 58.6 60.1 57.5 55.4 54.1 53.6 49.6 53.2 - 2.4 - 5.3 -17.4 - 9.1 + 0.9 - 2.3 - 4.6 - 0.3 + 10.3 + 3.1 + 1.1 + 5.6 + 1.5 + 2.6 - 5.0 - 4.2 - 0.5 + 0.4 + 4.4 + 3.2 + 2.9 + 6.1 + 1.3 + 11.6 + 8.9 - 3.5 +10.1 30 ppm Mean Wt. % Diff. 98.2 102.9 82.9 79.0 72.3 70.4 67.0 66.7 64.3 65.8 66.2 61.5 60.6 57.4 55.9 53.5 55.4 49.5 56.5 55.6 57.6 53.4 53.0 52.5 55.3 50.8 49.8 - 0.6 - 3.8 -14.7 - 2.5 - 2.4 - 3.0 - 4.6 + 3.9 + 12.4 + 2.3 + 4.4 + 5.0 + 1.9 + 0.7 - 9.4 -10.4 - 5.1 - 6.4 - 0.4 - 2.1 - 1.4 - 1.5 - 3.1 + 8.3 + 12.4 - 1.2 + 3.1 10 p p m Mean Wt. % Diff. 99.6 106.2 93.1 85.3 78.2 81.7 71.4 69.3 63.9 67.0 65.9 61.2 58.5 56.0 57.7 55.2 56.4 50.5 58.9 57.2 59.0 56.3 53.4 50.8 52.0 51.6 49.4 + 0.8 - 0.8 - 4.2 + 5.3 + 5.5 + 12.5 + 1.7 + 7.9 +11.7 + 4.2 + 3.9 + 4.4 - 1.7 - 1.8 - 6.5 - 7.5 - 3.4 - 4.5 + 3.9 + 0.7 + 1.0 + 3.9 - 2.4 + 4.7 + 5.7 + 0.4 + 2.3 001S20 35 Table 5 (concluded) 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 consumed pe r day) _+ % Di ff er en ce from Control FEMALES Study Week 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 104 Control 100 ppm Mean Wt. Mean wt. * Diff. 48.1 51.5 46.3 49.6 47.1 48.4 41 .0 44.9 46.1 45.3 48.4 48.3 44.1 45.7 44.0 43.5 44.3 45.3 46.1 45.9 46.9 42.4 46.8 41.5 42.5 41.6 54.2 53.7 51.3 50.9 51.0 45.5 45.1 52.0 52.7 53.2 51 .4 48.2 55.0 48.3 45.0 47.9 48.4 50.6 48.2 50.4 51.4 53.7 51.7 51.9 48.5 46.8 +12.7 + 4.3 +10.8 + 2.6 + 8.3 - 6.0 + 10.0 +15.8 + 14.3 + 17.4 + 6.2 - 0.2 +24.7 + 5.7 + 2.3 + 10.1 + 9.3 + 1 1.7 + 4.6 + 9.8 + 9.6 +26.7 + 10.5 +25.1 + 14.1 + 12.5 30 ppm Mean Wt. % Diff. 50.0 49.5 46.3 46.8 46.7 41.8 40.1 48.3 49.1 49.3 46.0 45.5 47.2 45.4 42.4 46.6 46.6 48.7 48.9 49.9 51.4 54.1 56.4 56.3 57.5 52.5 + 4.0 - 3.9 0 - 5.7 - 0.9 - 13.6 - 2.2 + 7.8 + 6.5 + 8.8 - 5.0 - 5.8 + 7.0 - 0.7 - 3.6 + 7.1 + 5.2 + 7.5 + 6.1 + 8.7 + 9.6 +27.6 +20.5 +35.7 +35.3 +26.2 10 pp m Mean Wt. % Diff. 50.1 50.4 45.8 46.0 46.1 41.7 38.1 44.2 45.9 51.6 46.5 41.0 44.5 39.6 45.0 43.9 44.9 42.7 43.5 42.5 46.3 47.1 44.5 52.4 46.5 40.5 + 4.2 - 2.1 - 1.1 - 7.3 - 2.1 -13.8 - 7.1 - 1.6 - 0.4 + 13.9 - 3.9 -15.1 + 0.9 -13.4 + 2.3 + 0.9 + 1.4 - 5.7 - 5.6 - 7.4 - 1.3 + 11.1 - 4.9 +26.3 + 9.4 - 2.6 001S21 36 Table 6 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Mean Food Consultation - Absolute (g/rat/day) _+ % Di ff er en ce from C o n t r o l MALES Study Week 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Control 100 ppm Mean Ht. Mean Ht. % Diff. 22.2 23.1 25.5 27.1 26.4 24.5 24.1 25.5 24.1 24.1 24.7 24.3 24.8 24.5 24.3 24.9 24.9 24.3 22.7 24.4 24.0 24.1 24.1 24.3 24.4 24.6 23.3 21.8 22.7 23.0 20.9 24.2 23.9 23.3 21.8 23.2 22.7 23.6 23.8 22.9 22.2 23.6 23.0 22.3 21.0 23.2 23.4 23.5 24.5 24.4 23.7 23.6 23.8 23.0 - 1 .8 - 1.7 - 9.8 -22.9 - 8.3 - 2.5 - 3.3 -14.5 - 3.7 - 5.8 - 4.5 - 2.1 - 7.7 - 9.4 - 2.9 - 7.6 -10.4 -13.6 + 2.2 - 4.1 - 2.1 + 1.7 + 1.2 - 2.1 - 3.3 - 3.3 -1.3 30 ppm Mean Ht. % Diff. 22.4 23.7 25.3 23.6 26.3 26.1 26.7 23.8 24.3 24.2 25.0 25.9 24.7 23.8 24.9 24.6 24.0 22.6 24.8 24.6 25.3 26.9 25.5 25.6 25.5 25.2 23.8 + 0.9 + 2.6 - 0.8 -12.9 - 0.4 + 6.5 + 10.8 - 6.7 + 0.8 + 0.4 + 1.2 + 6.6 - 0.4 - 2.9 + 2.5 - 1.2 - 3.6 - 7.0 + 9.3 + 0.8 + 5.4 + 1 1.6 + 5.8 + 5.4 + 4.5 + 2.4 + 2.2 10 pp m Mean Ht. % Diff. 22.2 23.6 24.9 22.5 25.4 26.0 25.3 23.8 24.7 24.2 24.9 25.3 24.6 23.0 23.9 24.2 23.7 21.9 24.4 24.7 25.1 25.9 24.9 24.6 25.0 24.7 20.3 + 0.0 + 2.2 - 2.4 -17.0 - 3.8 + 6.1 + 5.0 - 6.7 + 2.5 + 0.4 + 0.8 + 4.1 + 0.8 - 6.1 - 1.7 - 2.8 - 4.8 - 9.9 + 7.5 + 1.2 + 4.6 + 7.5 + 3.3 + 1.2 + 2.5 + 0.4 -12.9 0lS2z 37 Table 6 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Mean Food Consuzqption - Absolute (g/rat/day) _+ % Di ff er en ce from C o n t r o l MALES Study Week 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100 102 104 Control 100 ppm Mean Wt. Mean Wt. * Diff. 24.2 24.2 24.1 23.8 24.2 20.6 23.6 21 .6 21.6 21 .7 22.7 24.8 24.5 23.2 24.1 23.8 23.7 23.6 24.1 24.1 26.1 25.1 25.2 24.6 23.3 21.7 24.0 23.8 23.9 23.6 23.6 24.4 21.4 22.0 24.1 24.2 24.6 24.4 22.5 24.0 24.2 21.3 24.6 25.2 24.3 24.1 24.2 24.6 24.6 24.9 24.1 22.2 - 0.8 - 1.7 - 0.8 - 0.8 - 2.5 + 18.4 - 9.3 + 1.9 + 11.6 + 11 .5 + 8.4 - 1.6 - 8.2 + 3.5 + ,0.4 -10.5 + 3.8 + 6.8 + 0.8 + 0.0 - 7.3 - 2.0 - 2.4 + 1.2 + 3.4 + 2.3 30 ppm Mean Wt. % Diff. 25.2 25.2 25.2 24.9 24.6 25.4 22.1 22.8 24.5 24.8 25.6 25.7 23.9 24.6 23.9 21.9 27.2 25.4 24.9 25.6 25.8 25.6 24.7 25.4 25.1 24.2 + 4.1 + 4.1 + 4.6 + 4.6 + 1.7 +23.3 - 6.4 + 5.6 + 13.4 + 14.3 + 12.8 + 3.6 - 2.5 + 6.0 - 0.8 - 8.0 +14.8 + 7.6 + 3.3 + 6.2 - 1.2 + 2.0 - 2.0 + 3.3 + 7.7 . +11.5 10 ppm Mean wt. % Diff. 24.3 24.0 24.9 24.6 24.8 25.2 22.2 23.2 23.7 24.5 26.1 25.1 24.2 24.9 24.0 21.6 25.9 25.7 25.8 25.3 26.3 24.1 25.6 25.7 26.4 24.4 + 0.4 - 0.8 + 3.3 + 3.4 + 2.5 +22.3 - 5.9 + 7.4 + 9.7 + 12.9 +15.0 + 1.2 - 1.2 + 7.3 - 0.4 - 8.4 + 9.3 + 8.9 + 7.1 + 5.0 + 0.8 - 4.0 + 1.6 + 4.5 +13.3 + 12.4 001523 38 Table 7 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Mean Food Consumption - Absolute (g/rat/day) _+ % Difference from Co nt ro l FEMALES Study Week 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Control 100 ppm Mean Wt. Mean Wt. % Diff. 13.5 17.0 20.4 19.3 19.0 19.5 19.6 18.6 16.7 19.7 19.8 18.7 19.3 18.7 20.6 20.2 20.2 18.5 20.2 20.4 21.2 20.1 20.8 18.7 19.3 20.5 19.6 14.0 17.1 17.0 16.5 17.8 17.2 16.2 16.1 16.2 17.4 17.3 16.9 16.8 16.4 16.7 16.2 16.8 15.5 17.8 17.7 18.4 17.9 17.4 17.2 17.2 16.1 17.5 + 3.7 + 0.6 -16.7 -14.5 - 6.3 -11.8 -17.4 -13.4 - 3.0 -11.7 -12.6 - 9.6 -13.0 -12.3 -18.9 -19.8 -16.8 -16.2 -1 1.9 -13.2 -13.2 -1 1.0 -16.4 - 8.0 -10.9 -21.5 -10.7 30 ppm Mean Wt. % Diff. 13.9 16.8 17.7 18.5 18.2 18.4 17.7 18.3 18.2 19.2 19.8 18.7 18.8 18.0 18.0 17.0 18.0 16.4 19.1 19.0 19.9 18.9 19.0 19.1 20.4 19.0 18.9 + 3.0 - 1.2 -13.2 - 4.2 - 4.2 - 5.6 - 9.7 - 1.6 + 9.0 - 2.5 + 0.0 + 0.0 - 2.6 - 3.7 -12.6 -15.8 -10.9 -11.4 - 5.5 - 6.9 - 6.1 - 6.0 - 8.7 + 2.1 + 5.7 - 7.3 - 3.6 10 ppm Mean Wt. % Diff. 13.9 16.8 19.6 20.3 20.1 21.3 19.3 19.6 18.7 20.2 20.3 19.4 18.9 18.3 19.2 18.4 19.0 17.3 20.7 20.5 21.2 20.8 20.1 19.3 20.1 20.2 19.8 + 3.0 - 1.2 - 3.9 + 5.2 + 5.8 + 9.2 - 1.5 + 5.4 + 12.0 + 2.5 + 2.5 + 3.7 - 2.1 - 2.1 - 6.8 - 8.9 - 5.9 - 6.5 + 2.5 + 0.5 + 0.0 + 3.5 - 3.4 + 3.2 + 4.2 - 1.5 + 1.0 001524 39 Table 7 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Mean Food Consumption - Absolute (g/rat/day) _+ % Difference from Co nt ro l FEMALES Study Week 54 56 58 60 62 64 66 68 70 72 74 76 78 80 62 84 86 88 90 92 94 96 98 100 102 104 Control 100 ppm Mean Wt. Mean Wt. % Diff. 19.9 21.6 19.5 21.0 20.1 20.6 17.4 19.2 19.9 19.7 21 .6 22.0 20.5 21.7 21.3 21.1 21 .8 22.6 23.1 23.5 23.7 21.5 23.4 20.8 21.4 20.9 18.1 18.3 17.8 17.8 17.9 16.0 15.8 18.6 19.0 19.5 19.1 18.0 20.3 18.3 17.0 18.4 18.3 19.7 18.8 19.8 20.5 21.6 20.8 20.6 19.5 18.6 - 9.1 -15.3 - 8.7 -15.2 -11.0 -22.3 - 9.2 - 3.1 - 4.5 - 1.0 -11.6 -18.2 - 1.0 -15.7 -20.2 -12.8 -16.1 -12.8 -18.6 -15.7 -13.5 + 0.5 -11.1 - 1.0 - 8.9 -1 1.0 30 ppm Mean Wt. % Diff. 19.4 19.6 18.7 19.1 19.2 17.4 16.6 20.4 20.8 21.2 20.0 20.1 20.7 20.2 18.5 20.7 20.7 21.7 21.6 22.4 22.6 24.1 25.1 24.5 25.2 22.3 - 2.5 - 9.3 - 4.1 - 9.1 - 4.5 -15.5 - 4.6 + 6.3 + 4.5 + 7.6 - 7.4 - 8.6 + 1 .0 - 6.9 -13.2 - 1.9 - 5.1 - 4.0 - 6.5 - 4.7 - 4.6 + 12.1 + 6.8 + 17.8 +17.8 + 6.7 10 pp m Mean Wt. % Diff. 20.4 20.8 19.3 19.5 19.6 17.9 16.2 19.2 20.2 23.2 21.2 18.8 20.4 18.5 21.0 20.9 22.0 20.8 21.5 20.7 22.5 23.5 22.0 25.8 22.8 19.6 + 2.5 - 3.7 - 1.0 - 7.1 - 2.5 -13.1 - 6.9 + 0.0 + 1.5 + 17.8 - 1.9 -14.6 - 0.5 -14.8 - 1.4 - 1.0 + 0.9 - 8.0 - 6.9 -11.9 - 5.1 + 9.3 - 6.0 +24.0 + 6.5 - 6.2 &01S25 40 Table 8 Estimated Mean FM-3924 (mg/kg) Consumption Per Day 100 p p m Male Female 30 p p m Male Female 10 Male 1 10.1 9.6 2 8.9 10.1 4 7.5 8.0 6 6.3 7.4 8 6.5 7.5 10 6.0 7.1 12 5.6 6.7 14 5.1 6.4 16 5.2 6.3 18 5.0 6.6 20 5.1 6.4 22 5.0 6.2 24 4.7 6.0 26 4.5 5.9 28 4.7 5.9 30 4.5 5.7 32 4.3 5.8 34 4.1 5.3 36 4.5 5.9 38 4.5 5.9 40 4.4 6.0 42 4.6 5.8 44 4.5 5.5 46 4.3 5.4 48 4.3 5.4 50 4.3 5.0 52 4.1 5.3 54 4.2 5.4 56 4.1 5.4 58 4.1 5.1 60 4.0 5.1 62 4.0 5.1 64 4.1 4.6 66 3.6 4.5 68 3.7 5.2 70 4.0 5.3 3.0 3.0 2.7 3.1 2.3 2.5 2.0 2.4 2.0 2.2 1.8 2.1 1.8 2.0 1.5 2.0 1.5 1.9 1.5 2.0 1.5 2.0 1.5 1.8 1.4 1.8 1.3 1.7 1.4 1.7 1.3 1.6 1.3 1.7 1.2 1.5 1.3 1.7 1.3 1.7 1.3 1.7 1.4 1.6 1.3 1.6 1.3 1.6 1.3 1.7 1.2 1.5 1.1 1.5 1.2 1.5 1.2 1.5 1.2 1.4 1.2 1.4 1.2 1.4 1.2 1.3 1.0 1.2 1.1 1.5 1.1 1.5 1.0 0.9 0.8 0.6 0.6 0.6 0.6 0.5 0.5 0.5 0.5 0.5 0.5 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.3 0.4 0.4 0.4 0.4 0.4 0.4 0.3 0.4 0.4 001526 Table 8 (concluded) Estimated Mean FM-3924 (mg/kg) Consumption Per Day 100 ppm Male Female 30 ppm Male Female 10 Male 72 4.1 5.3 1.2 1.5 0.4 74 4.2 5.1 1.2 1.4 0.4 76 4.1 4.8 1.2 1.4 0.4 78 3.8 5.5 1.1 1.4 0.4 80 4.0 4.8 1.1 1.4 0.4 82 4.0 4.5 1.1 1.3 0.4 84 3.5 4.8 1.0 1.4 0.3 86 4.0 4.8 1.3 1.4 0.4 86 4.1 5.1 1.2 1.5 0.4 90 3.9 4.8 1.2 1.5 0.4 92 3.9 5.0 1.2 1.5 0.4 94 4.1 5.1 1.2 1.5 0.4 96 4.2 5.4 1.2 1.6 0.4 98 4.1 5.2 1.2 1.7 0.4 100 4.2 5.2 1.2 1.7 0.4 102 4.1 4.9 1.2 1.7 0.4 104 3.9 4.7 1.2 1.6 0.4 001327 I 00152 Table 9 TWO y e a r o h a l t o i e t i TOXICITY -UNCOutNICITY STUDY OF FLUURUCARriON FM- 392* in r a t s MORTAL ITY DATA WEEK OF STUDY QflS&-fifiQUe INITIAL 1- b- 9- 13- 1 1- 21- 25- 29- 33- 37- *1- *5- *9- 53- StiL* ___ 4 _ -- 12 __ La -- a -- 2 4 -- 211 -- 32 _.26 -- 4fl -- 4 4 -- i n -- 2 -- 5b MALES CONTROL 0 PPM HIGH POSE 100 PPM MID DOSE 30 PPM LOW DOSE 10 PPM 50 0 0 0 0 0 0 0 0 1 0 0 0 0 1 50 0 0 0 l ,0 0 0 0 0 0 0 1 1 0 50 0 0 0 0 0 0 0 0 0 0 0 0 0 0 50 0 ' 0 0 0 0 0 0 0 0 0 0 0 0 0 FEMALES CONTROL 0 PPM HIGH DOSE 100 PPM MID DOSE 30 PPM LOW DOSE 10 PPM 50 0 0 0 0 0 0 1 0 0 1 0 0 1 1 50 0 0 0 0 0 0 0 0 0 0 0 0 1 0 50 0 0 0 0 0 0 0 0 0 0 0 0 0 0 50 0 0 0 0 0 0 0 0 0 0 0 0 0 1 -p* CO 62ST00 1 D&SLJiBfiUI! MALES COMTMUL FN MlAM OOSE PPM MIO OOSE 3* F M LON OOSE 10 PPM FEMALES CONTm Ol 0 PPM MlCM OOSL 111 PH* MID OOSE 30 PPM LOn OOSE |0 PPM Table 9 (Concluded) U O yEAM IMALIOUl) TO*ICIT-ONCO&kNIClT STUU OF FLUUMOCAMMON FM-312A IM MATS HO HU Ll IV OAIA Mttft OF STUOT Li. 1 kli* 73- 77- Nl- MS- NO- NT- |0I> 10s- . SSU _ O A __OS -- Oft -- 22 -- 2b -- UH ..111 .jta _ i i ~ 2 o Jill J i t a n OiU units Jl SO 0 10 0 1o 1A 12 12 i 10 32 SO 0 1 1112 300A2 0 i 10 30 so 0 00 12 1 10 12 3A 0 IS 30 so 1 0 01 t 10 13 0 1 12 i 12 2A so 0 3 0 0 1 3 2 2 1 3 S 1 0 so 0 V 1 1 1 3 1 1 A 2 0 2 0 so 10 11003A2S3 50 so 10 102S*22 33 30 Cm I-SOu a m E TtSTS FOH OOSt GHUUP UjFFEMtNCtS FNOM CONTMOL uuSL-utiuut: MALLS Crt|- SUIIAKt P M U H . FEMALES Cut- SOUAME PMOH. I0 A P P M ' it.In 0 .A7H 2 .NS 0.000 10 PPh 0.00 1.000 0 .0 A 0 .M2 3 It P P M 0 .AS 0 .SI2 0 .0 A 0 .M2 J 2S SO 10 32 2? Sa 21 Sa Table 10 Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Clinical Signs Observations Control MF Initial number of rats Survivorg at end of study Mas8(es)-- in various regions (Mass(es) resolved prior to termination) Alopecia in various areas Swollen throat-- Pale (blanched) eyes and/or appears thin (emaciated) Excessive lacrimation Raised ulcerated lesion on hind foot pad(s) Ataxia Convulsions (clonic) Occasional urinary incontinence and/or hematuria Occasional bloody nares 65 34 19 (11) 6 13 9 8 7 4 3 5 3 65 100.0 25 45.4 38 43.8 (7) (13.9) 14 15.4 10 15.4 9 13.9 12 15.4 0 5.4 2 4.6 0 2.3 4 6.9 1 3.0 100 ppm M F % 65 65 100.0 31 34 50.0 13 21 26.2 (6) (3) (6.9) 6 17 17.7 8 3 8.5 8 6 10.8 7 1 6.2 8 1 6.9 8 8 12.3 10 il 8.5 7 6 10.0 10 0.8 30 ppm MF 50 50 100.0 35 23 58.0 12 33 45.0 (7) (3) (10.0) 9 12 21.0 4 3 7.0 13 7 20.0 6 7 13.0 18 2 20.0 8 10 18.0 3 0 3.0 3 3 6.0 2 0 2.0 10 _E5. MF 50 50 100.0 38 22 60.0 13 36 49.0 (9) ( I D (20.0) 5 18 23.0 5 12 17.0 5 9 14.0 5 5 10.0 80 4 7 11.0 4 0 4.0 10 1.0 0 2 2.0 o 00 Goisao a -- (Incidence in males + Incidence in females) /total number of animals in the group x 100 -- To be detailed in the pathology report -- Indication of Sialodacryoadenitis (SDA) viral infection -tpn -- Also had one incidence o tonic convulsions I Observations Occasional bloody feces and/or diarrhea Occasional episode of dyspnea Listing of the head Nodule on ear Circular ulcerated area on shin Swollen (distended) abdomen Swelling in inguinal area Prolapsed uterus Swollen leg and/or foot Paresis of hind legs Swollen ears Table 10 (concluded) Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Less Frequently Observed Clinical Signs Control MF 20 10 10 00 43 02 t1 -0 30 10 00 100 ppm MF 10 00 11 10 20 01 00 -0 21 11 00 30 JEE2L MF 20 00 22 00 10 10 00 -2 21 00 01 10 J2EEL MF 00 11 14 00 22 21 00 -0 20 10 00 001531 o-T>* TABLE 11 Two Year Oral (Diet) Toxicity - Oncogenicity Study Of Fluorocarbon FM-3924 In Rats Summary Of Ophthalmologic Changes ZPSTOO Observations Control - 0 Dorn 100 D D m 30 DDm 10 PDm Eye M F M F M F M F Phthisis Bulbi (Atrophy) Posterior Subcapsular Cataract(s) Corneal (ocular) Opacity (Diffused; ulcerated; with focal iris staphyloma; enlarged; partially collapsed; with microphthalmos; with pannas) Right Left Right Left Bilateral Right Left Bilateral 0 0 2 2 1 0 0 0 112332 10 10 00 00 1000 10 1000 000000 2 11 102 200 100 10000 1 1 0 0 0 0 1 0 0 NOTE: Blood samples were taken via the retro-orbital venus plexus from almost all of the above animals with ophthalmologic abnormalities. CCSTOO i (N) Group MALES (1) Control (1 ) Control (1) Control (1) Control (1) Control (1) High Dose (1) High Dose (1) High Dose FEMALES (1) Control (1) Control (1) Control (1) High Dose (1) Mid Dose 4^ 00 Table 11 (concluded) Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FM-3924 in Rats Summary of Less Frequently Observed Ophthalmologic Changes E y e (s ) Description of Abnormality Right Right Bilateral Bilateral Bilateral Left Right Left Chronic uveitis (secondary to blood sampling) Diffused lens opacity - chronic iritis with microphthalmos Posterior lens opacity Chronic superficial Keratitis Very pale choroidal circulation Diffused hyphema Extensive inflammation (post blood sampling) Chronic superficial Keratitis Right Left Right Left Right Chronic superficial Keratitis Chronic uveitis with secondary exophthalmia Dacryadenitis Chronic uveitis Diffuse lens opacity with iritis I MALE TAbLE 12 T0 Yt Ab URAL (Diti) T U X 1C 1T Y - U N C U u t N 1C H Y STUDY OF F L U O R O C A R B O N Fh -3924 IN RATS MEAN LEUKOCYTE VALUES leukocytes NLUTHORh ILS LYMHh OCVTES MONOCYTES EOSINOPHILS (CELLS X 10**31 (CELLS X 10*31 (CELLS X 10*31 tCELLS X 10**3) (CELLS X 10**31 N MEAN S.DEV. MEAN StUEV. MEAN S.DEV. MEAN S.DEV. MEAN S.DEV. 001534 MONTH 3 0 PPM 100 PPM 30 PPM 10 PPM MONTH O 0 PPM 100 PPM 30 PPM 10 PPM MONTH \2 0 PPM 100 PPM 30 PPM 10 PPM MONTH IB 0 PPM 100 PPM 30 PPM 10 PPM M ONTH 24 0 PPM 100 PPM 30 PPM 10 PPM 15 1 2 ..73 ? .0 74 15 15..15 2.662 15 13..85 2.471 15 13..73 2.430 l.>5 2.20 2.17 2.01 0.656 1.325 1.155 1.33b 10.72 12.42 11.28 11.51 11803 21828 11054 21239 0.18 0 .2 0.26 0 0 * 0.196 0.202 0.212 0.083 0.17 0.24 0.14 0.17 0.13b 0.205 0 .11S 0.140 15 10.74 2.423 15 11.64 2.270 15 13.7(1* 1.941 14 12.41 2.857 1.43 1.48 1.76 0.72 0.727 1.359 1.097 0.543 8.85 9.74 11.40* 11.57* 21416 11958 11840 21707 0.29 0.27 0.36 0.05 0.180 0.253 0.239 0.072 0.17 0.15 0.17 0.06 0.121 0.185 0.169 0.123 14 7.94 1.572 1.10 0.612 14 8.80 1.849 1.65 0.963 15 8.05 1.695 1.29 0.640 15 7.96 2.791 1.71 1 .645 6.35 6.44 6.17 5.82 11256 11252 11138 11872 0.40 0.36 0.25 0.32 0.216 0.236 0.218 0.285 0.10 0.15 0.07 0.11 0.107 0.134 0.126 0.127 15 11.41 7.325 15 8.49 3.303 15 8.98 1.217 15 10.13 4.123 5.06 2.06 2.25 3.35 6.40? 1 .3i6 1.128 3.289 5.61 5.83 6.01 b. 1* 1.-50* 11814 1 1206 11417 0.59 0.49 0.60 0.45 0.405 0.420 0.232 0.2b7 0.16 0.11 o.ia 0.20 0.128 0.144 0.127 0.177 15 10.79 7.529 15 8.91 3.919 15 10.87 A.41 1 15 9.53 3.845 3.72 1.45 3.28 2.96 5.666 1.009 2.754 3.29? 6 .6 b 7.21 7.05 6.28 21140 31718 21916 11844 0.34 0.21 0.66 0.17 0.398 0.159 0.386 0.178 0.08 0.05 0.09 0.12 0.083 0.080 0.115 0.135 : P < .05. TWO TAILED D u n n e t t T UN RAM DATA. : P <s .05. TwU TAILED DUN NETT T UN RAN KE D DATA. MALE TAB LE 12 TwO YEAM OHAL (DIE 1) lOAlClli-ONCooENlCIlY STuUY DE FLU0HUCA880N FM- 3 9 2 4 In h a t s EHY T m H O C YTE S (CELLS A 1 0*6 ) MEAN H E H O G K A M VA1.UES htMOOLOblN (6 /DL) MEMATOChIT 1 PACALO CELLS) NCV (M1Ch ONS3) MCh ( P I C O G H A m S) N MEAN S.DEv. MtAK S.UtV. MEAN S.UEv. m l a n s .DEv . MEAN S.DEV. MCHC (k) MEAN S.OEV. TOO Cfl o in ai o MONTM 3 (1 P P M 100 PPM 30 PPM 10 PPM MONTH 6 0 PPM 100 PPM 30 PPM 10 PPM HOMI 12 0 PPM 100 PPM 30 PPM IO PPM h o m i Ih 0 PPM 100 PPM 3u PPM lo P P M m D N T m 24 0 PPM 100 PPM 30 PPM 1Q PPM 1S 6 . 2 9 0.322 15 B . 10 0 . 3 3 b 15 a . 1 2 0 265 15 a . 27 0.765 16.4 16.1 16.2 16.6 0.39 0.50 0.66 0.b6 15 e . *2 0 . 3 6 4 15 h.21 0.972 15 7 . 3 9 * 0 . 4 1 14 6 . 3 9 0.483 15.1 14.4 15.4 15.2 0.94 1.56 0.79 0.60 14 4<i 14 8 . 2 9 15 a . 40 15 8 .30 0.554 0.42* 0.366 0.435 15.9 14.8 15. 15.7 1.17 0.46 0.67 0.60 15 7 . 4 8 15 8 . 1 9 15 7 . 6 3 15 7.74 2.071 0.615 1.048 U tt*>b 15,.1 15,.9 15,>1 15.,3 3.12 1.08 1.69 1 .59 15 7.64 15 7.77 15 7.88 15 8 . 3 6 1.083 1.303 1.256 0.974 14.5 1* .5 14.6 15.9 1.59 2.21 1 .64 1.75 : P = .05 * 1*0 1A ILIO O u N n ETT t ! P <* .OS, 1*0 1AlLfcO O u N N E i r 1 SA* U ATA . hamalo Da t a . 45.9 45.3 45. 1 *6.1 0.96 1.35 1 .68 2.17 44.5 43.3 45.2 45.5 2.70 4.57 2.31 1.74 46. 7 44.6 46.7 45.5 3.69 2.47 2.31 2.13 40.8 47.2 41.9 41.9 9.14 3.71 5.05 4.66 42.3 42.7 43.3 46.3 5.34 6.83 5.18 6.10 55 1.9 19.a o.ao 35.6 0.47 56 2.4 19. 0.90 35.4 0.63 56 1.6 19.9 0.66 35. 0.52 56 2.9 20.2 0.97 36.0 0.37 53 4.3 53 2.7 61 3.a 54 1.5 17.9 17.6 20.9 18.1 1.41 0.87 1 14 0.63 33.9 33.3 34.2 33.4 0.77 0.70 0.94 O.o7 55 2.2 a.a 0 .4 34.0 0.97 54 2.4 17.8 0.93 33.1 1.38 56 2.4 18. 0.75 33.7 0.84 55 1.9 19.0 0.55 34.5 0.74 56 586 55 54 6.2 3.1 2.7 2.3 21.0 19.4 19.9 19. 3.09 0.99 1.22 O.bO 37.2 33.7 36.0 36.5 1,.53 0..94 0..94 0..71 5* 3.4 1.6 1.27 34.4 0.89 5b 2.6 18.7 1.22 34.0 1.44 55 3.6 19.V 1.11 34.2 0.68 55 3.9 19.0 0.88 34.4 1.56 001536 DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM n ppm 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM n o ppm ANIMAL A1R3518 A1R3527 A1R3532 A1R3S34 A1R3537 AIR3540 A1R3542 A1R3548 A1R3552 A1R3559 A1R3S62 A1R3564 A 1R3565 A1R3567 A1R3569 O1R3701 01R3703 01R3705 D1R3706 01R3711 D1R371* 01R3719 D1R3723 01R3724 D1RJ727 D1R3734 D1R3740 D1R37A8 D1R3749 01R3754 ERYTH 8.10 7.77 8.69 8.15 7.71 8.04 8.70 8.13 B.20 8.63 8.73 8.37 8.41 8.24 8.46 8.44 8.62 8.20 8.19 7.91 7.70 8.03 7.40 8.27 7.79 8.65 7.97 8.03 8.04 8.27 HEMO 16.1 15.5 16.5 16.3 16.3 16.7 16.8 16.5 16.6 16.4 15.6 16.6 16.3 16.8 16.6 16.0 15.4 16.5 15.6 16.3 15.3 16.3 15.6 16.2 15.4 16.4 17.1 16.2 16.1 16.4 TABLE 12 TWO YEAR (JHa L DIET) TOXICITY-ONCOGENICITY Y OF FLUOROCARBON FM-3924 IN MALE RATS INDIVIDUAL HEMOGRAM VALUES ------ ---- M 0 N T H = 3 ----------------------- hema MCV MCH MCHC WBC 45 65.5556 19.8765 35.7778 12.60 44 56.6281 19.9465 35.2273 11.00 46 62.9344 18.9673 35.8696 10.00 45 55.2147 20.0000 36.2222 13.30 45 58.3658 21.1414 36.2222 11.30 46 57.2139 20.7711 36.3043 12.50 47 54.0230 19.3103 35.7447 12.60 47 57.8106 20.2952 35.1064 15.50 46 56.0976 20.2439 36.0670 14.00 46 53.3024 19.0035 35.6522 11.50 45 51.6464 17.8694 34.6667 11.90 47 56.1629 19.8327 35.3191 12.60 46 54*6968 19.3817 35.4348 9.58 47 57.0388 20.3663 35.7447 15.50 47 55.5556 19.6217 35.3191 17.00 47 55.6672 18.9573 34.0426 19.60 43 49.8840 17.8654 35.8140 15.30 46 56.0976 20.1220 35.8696 13.80 45 54.9451 19.0476 34.6667 16.50 47 59.4185 20.6068 34.6809 13.00 44 57.1429 19.8701 34.7727 15.60 46 57.2852 20.2989 35.4348 18.50 44 59**595 21.081l 35.454 11.70 46 55.6227 19.5689 35.2174 17.60 43 66.1990 19.7689 35.8140 18.20 46 63.1792 18.9695 35.6522 16.60 47 58.9711 21.4655 36.3830 11.30 45 56.0399 20.1743 36.0000 12.80 45 55.9701 20.0249 35.7778 12.00 46 55.6227 19.8307 35.6522 14.80 PMNAB 1.3860 1.6500 1.0000 1.3300 2.4860 1.8750 1.3860 2.6350 1.9600 1.0350 2.2610 1.3B60 0.7664 2.7900 0.8500 5.4880 1.3770 1.6560 1.9800 1.6900 1.0920 0.9250 1.0530 2.8160 0.7280 2.8220 4.4070 2.0480 2.8800 2.0720 LYMAB 10.9620 9.0200 8.9000 11.5710 8.8140 9.8750 10.9620 12.0900 11.4800 10.1200 9.4010 10.8360 8.8136 12.5550 15.4700 12.7400 13.3110 11.3160 14.1900 10.6600 14.1960 16.8350 10.5300 14.0800 16.9260 13.4460 6.4410 10.6240 8.6400 12.4320 M0N0A8 0.000 0.110 0.000 0.266 0.000 0.250 0.252 0.620 0.280 0.000 0.119 0.252 0.000 0.000 0.510 0.784 0.153 0.414 0.330 0.390 0.312 0.185 0.117 0.528 0.182 0.166 0.452 0.000 0.120 0.148 EOSAB 0.252 0.220 0.100 0.133 0.000 0.500 0.000 0. 155 0.280 0.345 0.119 0.126 0.000 0.155 0.170 0.588 0.459 0.414 0.000 0.260 0.000 0.555 0.000 0.176 0.364 0.166 0.000 0.128 0.360 0.148 i TABLE 12 TWO YEAR ORAL <OIET> TOXICITY-ONCOOENICITY STUDY OF FLUOROCARBON FM-3924 IN MALE RATS INDIVIDUAL HEMOGRAM VALUES DOSE 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM animal E1R3767 E1R3770 E1R3771 E1P3773 E1R3774 E1R377B E1R37B0 E1R3783 E1R3787 E1R3790 E1R3791 E1R3796 E1R3B00 E1R3B01 E1R3806 F1R3B11 F1R3815 F1R3818 F1R3822 F1R3R24 F1R3B31 F1R3B32 F1R3B3* F1R3836 F1R303B F1R3839 F1R3R40 F1R3R44 F1R3847 F1R3852 ERYTH 8.11 8.25 7.80 8.16 8.23 8.52 7.96 8.41 7.79 8.12 7.84 7.88 8.65 7.91 8.24 8.59 8.17 8.29 8.82 8.63 9.04 8.78 7.92 7.27 7.76 7.63 9.90 7.08 7.43 8.74 HE MO 15.5 16.6 16.1 16.2 17.3 16.3 16.1 16.9 15.8 16.5 15.8 14.5 16.8 15.8 16.2 16.4 16.5 16.6 17.b 16.9 17.4 16.8 16.8 15.1 15.9 16.0 18.4 15.4 16.1 17.2 HERAT 44 46 46 45 47 46 45 47 43 46 44 41 47 44 46 46 46 46 48 47 48 46 46 42 45 45 51 43 45 48 MCV 54.2540 55.7576 58.9744 55.1471 57.1081 53.9906 56.5327 55.8859 55.1990 56.6502 56.1224 52.0305 54.3353 55.6258 55.8252 53.5506 56.3035 55.4885 54.4218 54.4612 53.0973 52.3918 58.0808 57.7717 57,9897 58.9777 51.5152 60.7345 60.5653 54.9199 MCH 19.1122 20.1212 20.6410 19.8529 21.0207 19.1315 20.2261 20.0951 20.2824 20.3202 20.1531 18.4010 19.4220 19.9747 19.6602 19.0920 20.1958 20.0241 19.9546 19.5829 19.2478 19.1344 21.2121 20.7703 20.4897 20.9699 18.5859 21.7514 21.6689 19.6796 MCHC 35.2273 36.0870 35.0000 36.0000 36.8085 35.4348 35.7778 35.9574 36.7442 35.8696 35.9091 35.3659 35.7447 35.9091 35.2174 35.6522 35.8696 36.0870 36.6667 35.9574 36.2500 36.5217 36.5217 35.9524 35.3333 35.5556 36.0784 35.8140 35.7778 35.8333 WBC 16.30 12.70 9.71 12.80 11.20 18.60 14.40 16.10 11.80 12.40 16.40 16.80 12.30 13.00 13.30 11.80 12.80 13.10 16.90 9.80 14.20 14.50 13.50 14.20 11.40 16.90 11.10 18.90 14.40 12.50 PMNAB 3.0970 0.6350 1.4565 2.0480 2.3520 2.6040 1.4400 3.8640 2.1240 1.1160 1.9680 5.0400 2.0910 1.9500 0.7980 1.8880 1.1520 2.4890 5.4080 1.5680 4.5440 2.4650 1.8900 1.4200 0.9120 1.8590 0.9990 1.8900 1.1520 0.5000 LYMAB 12.8770 11.8110 8.1564 10.4960 8.5120 15.6240 12.5280 11.9140 9.3220 11.2840 13.4480 10.9200 9.8400 10.5300 11.9700 9.7940 11.3920 10.2180 11.3230 7.7420 9.6560 11.7450 11.2050 12.3540 10.4880 15.0410 9.8790 16.8210 13.1040 11.8750 MONOAB 0.1630 0.2540 0.0971 0.1280 0.1120 0.3720 0.1440 0.1610 0.1180 0.0000 0.6560 0.6720 0.1230 0.5200 0.3990 0.1180 0.1280 0.2620 0.0000 0.0000 0.0000 0.1450 0.1350 0.0000 0.0000 0.0000 0.1110 0.0000 0.0000 0.0000 EOSAtt 0.163 0.000 0.000 0.128 0.224 0.000 0.288 0.161 0.236 0.000 0.328 0.168 0.246 0.000 0.133 0.000 0.128 0.131 0.169 0.490 0.000 0.145 0.270 0.426 0.000 0.169 0.111 0.189 0.144 0.125 001537 cf\nj I TABLE 12 TWO YEAH ORAL (DItT) TOXICITY-ONCOGENICITY STUOY OF FLUORO CA RB ON FM-3924 IN MALE HATS INDIVIDUAL HEMOGRAM VALUES dose ANIMAL ERYTH MEMO hemat MCV MCH MCHC WBC PMNAB LYMAB MONOAB EOSAB 0 PPM A1R3519 A.24 15.0 46 0 PPM A1R3S24 B.51 14.4 42 0 PPM A1R3529 B.23 14.6 44 0 PPM 0 PPM A1R3533 A1R353T B. 30 8.13 15.7 15.9 45 47 0 PPM A1R3541 8.42 15.9 46 0 PPM 0 PPM 0 PPM A1R3547 A1R3550 A1R3553 7.40 8.38 8.30 14.8 15.4 15.6 44 45 46 0 PPM A1R3S57 8.95 13.0 37 0 PPM A1R3559 9.03 16.2 47 0 PPM A1R3S62 8.58 14.8 45 0 PPM A1R3567 8.69 16.2 47 0 PPM A1R3573 8.70 15.0 45 0 PPM A1R3575 8.44 13.5 41 100 PPM D1R3696 7.63 12.7 37 c 100 PPM D1R3703 8.13 13.8 42 o 100 PPM 100 PPM DIR3707 D1R3710 8.31 8.70 15.0 14.3 44 43 100 PPM D1R3716 8.10 15.3 45 W1 100 PPM D1R372B 8.93 15.8 47 Co 100 PPM D1R3T31 8.32 14.7 43 00 100 PPM D1R3T33 9.10 15.4 47 100 PPM D1R3734 8.37 14.5 44 100 PPM 100 PPM 01R3736 01R3738 8.21 8.99 14.0 16. 1 43 49 100 PPM D1R3743 4.99 9.7 30 100 PPM D1R3746 8.44 15.8 4ft 100 PPM D1R3754 R .20 14.7 44 100 PPM D1R3757 8.70 14.7 45 55.8252 49.3537 53.4629 54.2169 57.8106 64.6318 59.4595 53.6993 55.4217 41.3408 52.0487 52.4476 54.0852 51.7241 46.5782 48.4928 51.6605 52.9483 49.4253 55.5556 52.6316 51.6827 51.6484 52.5687 52.3752 54.5050 60.1202 64.5024 53.6585 51.7241 18.2039 16.9213 17.7400 18.9167 19.5572 18.8836 20.0000 18.3771 18.7952 14.5261 17.9402 17.2494 18.6421 17.2414 15.9953 16.6448 16.9742 18.0505 16.4368 16.8889 17.6932 17.6683 16.9231 17.3238 17.0524 17.9088 19.4369 18.7204 17.9268 16.8966 32.6087 34.2857 33.1818 34.8889 33.8298 34.5652 33.6364 34.2222 33.9130 35.1351 34.4681 32.8889 34.4681 33.3333 32.9268 34.3243 32.8571 34.0909 33.2558 34.0000 33.6170 34.1860 32.7660 32.9545 32.5561 32.8571 32.3333 34.3478 33.4091 32.6667 7.70 8.98 11.70 9.96 9.14 9.83 14.00 7.71 10.90 13.40 8.20 10.70 11.30 11.30 16.30 15.70 11.80 10.50 8.30 14.20 9.41 13.10 12.50 10.70 11.80 10.50 14.80 8.04 10.30 13.00 1.3090 1.2572 1.0530 1.5936 1.6452 0.9830 1.2600 1.6962 3.5970 1.7420 0.5740 1.1770 0.3390 1.5820 1.6300 4.7100 1.0620 1.8900 1.3280 3.2660 0.3764 0.6550 1.3750 0.6420 0.5900 1.8900 0.2960 0.4020 0.2060 3.5100 6.0830 7.6330 10.4130 7.9680 7.0378 8.3555 12.0400 5.6283 6.6490 11.1220 7.0520 8.8810 10.7350 9.0400 14.1810 9.5770 10.5020 8.4000 6.4740 9.7980 8.9395 12.4450 10.8750 9.8440 11.0920 7.8750 14.2080 7.3968 9.6820 8.9700 0.2310 0.0000 0.2340 0.0996 0.1828 0.1966 0.4200 0.3855 0.4360 0.2680 0.2460 0.5350 0.0000 0.5650 0.4890 0.7850 0.0000 0.1050 0.4150 0.7100 0.0941 0.0000 0.0000 0.1070 0.1180 0.5250 0.2960 0.2412 0.4120 0.2600 0.0770 0.0898 0.0000 0.2988 0.2742 0.2949 0.2800 0.0000 0.2180 0.2680 0.3280 0.1070 0.2260 0.1130 0.0000 0.6280 0.2360 0.1050 0.0830 0.4260 0.0000 0.0000 0.2500 0.1070 0.0000 0.2100 0.0000 0.0000 0.0000 0.2600 ccno i TABLE 12 DOSE 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PP" 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM ANIMAL EIR3762 E1R3763 E1R3764 E1R3765 E1R3770 E1R3773 E1R3774 E1R3779 E1R3784 E1R3792 E1R3794 E1R3804 E1R3B06 E1R3808 E1R3H10 F1R3811 F1R3B16 F1R3817 F1R3823 F1R3826 F1R3827 F1R3831 F1R3B33 E1R3834 F1R1837 F1R3839 F1R3BA6 F1R3853 F1R3854 F1R3855 FRYTH 7.92 7.43 7.63 7.67 7.38 6.40 7.11 7.59 7.73 6.99 7.78 7.33 7.44 6.46 8.04 8.65 8.03 8.27 8.11 8.30 9 . IS 8.75 8.48 8.62 8.92 8.46 7.60 8.67 7.40 HEMO 16.6 15.4 15.4 15.5 15.3 13.7 15.3 17.1 16.1 14.8 15.8 15.0 15.4 15.3 14.9 15.2 14.5 15.5 15.4 15.5 15.6 15.5 15.0 15.7 15.5 15.2 13.9 16.0 14.2 TWO YEAR ORAL <DIET) TOXICITY-ONCOGENICITY STUDY OF FLUORO CA RB ON EM-3924 IN MALE MATS INDIVIDUAL HEMOGRAM VALUES ---------------- - M O N T H - 6 ---------- ---- * --- hemat MOV MCH MCHC WBC 49 61.86H7 20.9596 33.8776 14.20 45 60.5653 20.7268 34.2222 12.90 47 61.5990 20.1835 32.7660 14.20 44 57.3664 20.2086 35.2273 14.70 44 59.6206 20.7317 34.7727 13.20 40 62.5000 21.4062 34.2500 11.90 45 63.2911 21.5190 34.0000 11.10 49 64.5586 22.5296 34.8980 13.40 44 56.9211 20.8279 36.5909 8.95 43 61.5165 21.1731 34.4186 17.00 47 60.A 113 20.3085 33.6170 15.10 45 61.3915 20.4638 33.3333 15.00 46 61.8280 20.6989 33.4783 14.00 4b 71.2074 23.6842 33.2609 15.20 44 54.7264 18.5323 33.8636 14.60 45 52.0231 17.5723 33.7778 12.50 45 66.0399 18.0573 32.2222 15.30 46 55.6227 18.7424 33.6957 12.80 45 55.4H71 18.9889 34.2222 13.80 46 55.4217 18.6747 33.6957 8.15 47 51.3661 17.0492 33.1919 14.60 47 53.7143 17.7143 32.9787 18.40 46 54.2453 17.6887 32.6087 11.20 46 53.3643 18.2135 34.1304 11.90 48 53.8117 17.3767 32.2917 11.10 45 53.1915 17.9669 33.7778 14.80 42 55.2632 18.2895 33.0952 8.45 47 54.2099 18.4544 34.0426 11.80 *2 56.7568 19.1892 33.8099 9.00 pmnab 0.8520 1.2900 1.4200 1.9110 1.9800 2.0230 1.6650 2.1440 1.3425 4.5900 1.3590 0.6000 0.4200 3.6480 1.1680 0.7500 0.3060 0.5120 1.6560 0.1630 0.4380 1.1040 0.3360 0.9520 1.8870 0.7400 0.1690 0.9440 0.1800 LYMAH 12.922 11.223 12.212 11.907 10.296 9.520 9.102 10.720 7.339 11.730 12.986 13.950 13.300 10.488 13.286 11.375 14.841 12.160 12.006 7.987 13.870 17.296 10.864 10.948 8.991 13.912 8.112 10.856 8.820 M0N0AB 0.4260 0.2580 0.4260 0.5880 0.7920 0.2380 0.3330 0.1340 0.0895 0.6800 0.1510 0.3000 0.1400 0.7600 0.1460 0.0000 0.1530 0.0000 0.1380 0.0000 0.0000 0.0000 0.0000 0.0000 0.1110 0.1480 0.1690 0.0000 0.0000 EOSAB 0.000 0.129 0.142 0.294 0.132 0.119 0.000 0.402 0.179 0.000 0.604 0.150 0.140 0.304 0.000 0.375 0.000 0.128 0.000 0.000 0.292 0.000 0.000 0.000 0.111 0.000 0.000 0.000 0.000 001539 c-Pn> i DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM animal A1R3516 A 1RJ 517 A1R3520 A1R3522 A1R3527 A1R3535 A1R3543 A1R3546 A1R3550 A1R3551 A1R3554 A1R3566 A1R3570 A1R3575 A1R3580 D1R3696 D1R3699 D1H3711 D1R3714 D1R3715 D1R3720 D1R3721 D1R3722 D1R3727 D1R3732 01R3733 D1R3736 D 1R3737 01H3747 01R3748 ERYTH 8.33 8.07 8.49 8.47 8.84 8.47 8.97 9.47 9.12 8.48 7.88 8.29 7.27 8.04 8.32 7.21 8.41 7.75 8.28 8.54 8.81 8.40 8.37 8.33 8.90 8.48 7.89 8.31 HEMO 15.6 15.7 15.7 16.4 15.7 15.6 16.4 18.1 16.4 15.8 15.8 16.4 12.5 15.9 13.8 14.3 15.1 14.3 15.1 15.2 15.3 14.6 16.1 15.0 14.8 14.2 15.2 14.6 TABLE 12 TWO YEAH ORAL (OIET) TOXICITY-ONCOGENIOITY STUDY OF FL UOHOCAHBON FM-3924 IN MALE BATS INDIVIDUAL HEMOGRAM VALUES -------------------MONTHs 12 ---- ----- ---- -- --- HEMAT MCV MCH MCHC WBC 48 57.6230 18.7275 32.5000 7.9 45 55.7621 19.4548 34.8889 5.2 45 53.0035 18.4923 34.8889 6.8 47 55.4900 19.3625 34.8936 9.2 46 52.0362 17.7602 34.1304 7.4 45 53.1287 18.4179 34.6667 9.1 48 53.5117 18.2832 34.1667 6.9 55 58.0781 19.1130 32.9091 8.2 51 55.9211 17.9825 32.1569 5.7 47 55.4245 18.6321 33.6170 9.2 m m 46 58.3756 20.0508 34.3478 8.0 47 56.6948 19.7829 34.8936 7.0 38 52.2696 17.1939 32.8947 9.9 46 57.2139 19.7761 34.5652 10.7 43 51.6827 16.5865 32.0930 9.5 40 55.4785 19.8336 35.7500 9.7 50 59.4530 17.9548 30.2000 9.2 41 52.9032 18.4516 34.8T80 8.5 44 53.1401 18.2367 34.3182 11.6 45 52.6932 17.7986 33.7T78 6.5 47 53.3485 17.3666 32.5532 11.6 45 53.5714 17.3810 32.4444 8.9 46 54.9582 18.0406 32.8261 7.8 44 52.8211 18.0072 34.0909 8.0 46 51.6854 16.6292 32.1739 8.7 44 51.8868 16.7453 32.2727 4.4 46 58.3016 19.2649 33.0435 9.1 44 52.9483 17.5692 33.1818 9.7 PMNAB 1.817 0.624 0.816 0.736 0.814 2.002 0.828 0.328 0.399 1.564 1.520 1.260 0.495 2.140 2.470 2.231 1.932 2.210 3.712 1.300 3.248 2.136 0.702 0.640 2.001 0.660 1.911 0.679 LYMAB 5.293 4.420 5.440 7.728 6.068 6.097 5.796 7.298 5.073 7.268 6.160 5.600 8.811 7.918 6.460 7.275 6.532 5.440 6.844 4.615 7.308 6.141 6.942 7.280 6.090 3.652 6.916 8.730 MONOAB 0.632 0.156 0.476 0.460 0.518 0.819 0.276 0.574 0.228 0.184 0.240 0.070 0.594 0.428 0.475 0.194 0.368 0.595 0.812 0.325 0.696 0.356 0.156 0.080 0.522 0.000 0.273 0.194 EOSAB 0. 156 0.000 0.068 0.276 0.000 0 . 1S2 0.000 0.062 0.000 0.184 . 0.060 0.070 0.000 0.321 0.095 0.000 0.368 0.255 0.232 0.260 0.348 0.267 0.000 0.000 0.087 0.088 0.000 0.097 001540 ccnn TABLE 12 DOSE 10 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM ANIMAL E1R3769 E1R3775 E1R3776 E1R3779 E1R37B0 E1R3702 F.IR3791 E1R3792 E1R3797 E1H3800 E1R3B02 E1R3803 E1R3805 E1R3B06 E1R380B E1R3812 E1R3813 E1R381A F1R3815 F 1R 3 8 18 F1R3820 F1R3828 E1R3832 E1R3833 F1H3B3S F1H3B39 F1R38A4 F1R3846 F1R3848 F1R38G0 ERYTH 8.51 8.68 8.79 8.50 8.47 8.60 8.70 8.41 8.90 8.15 7.72 7.94 8.67 7.86 8.03 8.33 8.21 8.09 7.79 7.99 8.39 8.21 8.88 8.60 8.13 8.46 7.49 8.00 8.66 9.23 HEMO 15.7 15.9 16.4 17.0 16.1 15.5 15.3 16.0 16.2 16.2 14.2 15.7 15.8 15.5 14.8 15.7 16.3 15.6 15.0 15.4 15.5 15.2 16.7 16.2 15.0 15.8 15.0 15.3 16.6 16.5 T*0 YtAH OHAL (DIET) TOXICITY-ONCOGENICITY STUDY OF FL UOROCAHHON FM-3924 IN MALE HATS INDIVIDUAL HEMOGRAM VALUES ---------------- - m 0NTH=12 ------------------ HEMAT MCV MCH MCMC MAC 49 57.5793 18.4489 32.0408 8.3 47 54.1475 18.3180 33.8298 10.3 50 56.8828 18.6576 32.8000 9.2 50 58.8235 20.0000 34.0000 7.0 46 54.3093 19.0083 35.0000 10.6 46 53.4884 18.0233 33.6957 7.9 45 51.7241 17.5862 34.0000 6.2 47 55.8059 19.0250 34.0426 8.0 49 55.0562 18.2022 33.0612 4.4 46 56.4417 19.8773 35.2174 6.2 42 54.4041 18.3938 33.8095 8.2 48 60.4534 19.7733 32.7083 7.9 47 54.2099 18.2238 33.6170 7.4 46 58.5242 19.7201 33.6957 9.0 43 53.5492 18.4309 34.4186 10.2 46 55.2221 18.8475 34.1304 13.9 48 58.4653 19.8538 33.9583 11.1 45 55.6242 19.2831 34.6667 6.4 43 55.1990 19.2555 34.8837 5.3 45 56.3204 19.2741 34.2222 11.3 44 52.4434 18.4744 35.2273 8.5 44 53.5932 18.6140 34.5455 6.0 50 56.3063 18.8063 33.4000 7.0 45 52.3256 18.8372 36.0000 6.6 44 54.1205 18.4502 34.0909 6.9 47 55 555t> 18.6761 33.6170 8.7 42 56.0748 20.0267 35.7143 11.3 45 56.2500 19.1250 34.0000 7.1 48 55.4273 19.1686 34.5833 4.0 47 50.9209 17.8765 35.1064 5.3 PMNAB 1.494 2.163 2.208 1.960 2.862 0.790 0.248 1.920 0.660 0.620 1.722 1.422 0.444 0.900 0.000 6.950 2.109 0.128 0.795 1.017 1 .955 0.420 1.750 0.528 1.311 2.262 1.921 2.769 1.160 0.530 LYMAB 5.893 7.622 6.348 4.550 7.208 6.873 5.890 5.760 3.564 5.456 6.150 6.399 6.956 7.650 5.421 8.103 6.016 4.187 9.831 6.375 5.460 5.040 5.808 5.451 6.003 8.588 3.976 2.520 4.505 MONOAB 0.830 0.309 0.184 0.490 0.424 0.237 0.062 0.320 0.132 0.124 0.328 0.079 0.000 0.270 0.000 1.251 0.444 0.192 0.159 0.339 0.170 0.120 0.210 0.198 0.138 0.261 0.565 0.355 0.200 0.212 EOSAB 0.083 0.206 0.460 0.000 0.106 0.000 0.000 0.000 0.044 0.000 0.000 0.000 0.000 0.180 0.000 0.278 0.444 0.064 0.159 0.113 0.000 0.000 0.000 0.066 0.000 0.174 0.226 0.000 0.120 0.053 001541 01 I TABLE 12 TWO YEAR ORAL <DIET> TO*IC!TY-ONCOGENICITY STUDY OF FLUORO CA RB ON FM-3924 IN MALE BATS INDIVIDUAL HEMOGRAM VALUES ----------- ------ M O N T H s 18 ---------- --------- DOSE ANIMAL EPYTH HEMO HERAT MC V RCH MCHC WBC PMNAB LYMAB MONOAB E0SA8 0 PPM A1R3519 8.42 15.3 44 52.2565 18.1710 34.7727 10.0 4.400 4.600 1.000 0.000 0 PPM A1R3521 2.48 7.2 18 72.5806 29.0323 40.0000 35.4 26.196 7.080 1.770 0.354 0 PPM A1R352B 8.92 16.5 44 49.3274 18.4978 37.5000 8.7 4.176 4.176 0.261 0.087 0 PPM A1R3531 8.43 16.9 46 54.5670 20.0474 36.7391 9.1 1.729 6.734 0.546 0.091 0 PPM A1R3538 8.23 15.9 45 54.6780 19.3196 35.3353 6.1 1.769 3.904 0.244 0.183 0 PPM A1R3539 8.14 16.4 43 52.8256 20.1474 38.1395 7.3 3.139 3.577 0.438 0.146 0 PPM A1R3542 8.79 16.8 47 53.4699 19.1126 35.74*7 7.8 2.418 4.836 0.468 0.078 0 PPM A1R3552 8.17 16.8 44 53.8556 20.5630 38.1818 9.9 2.574 6.336 0.594 0.396 0 PPM A1R3553 8.32 16.9 45 54.0865 20.3125 37.5556 6.7 2.211 3.953 0.402 0.134 0 PPM A1R3555 7.99 15.8 43 53.8173 19.7747 36.7**2 8.7 1.218 6.960 0.435 0.087 0 PPM A1R3561 9.06 17.6 48 52.9801 19.4260 36.666 7 9.7 3.977 4.850 0.485 0.388 0 PPM A1R3565 4.75 12.3 31 65.2632 25.8947 39.67T4 10.5 4.725 4.725 0.945 0.105 o O 0 PPM 0 PPM 0 PPM A1H3567 A1R357* A1R3S77 8.25 3.59 8.64 16.4 8.9 16.7 46 23 45 55.7576 64.0669 52.0833 19.8788 24.7911 19.3287 35.6522 38.6957 37.1111 12.1 19.4 9.7 3.872 12.028 1.455 8.107 6.790 7.469 0.121 0.388 0.679 0.000 0.194 0.097 H- 100 PPM D1R3697 7.29 14.1 39 53.4979 19.3416 36.1538 7.8 0.936 6.552 0.312 0.000 CH 100 PPM D1R3700 8.47 16.2 47 55.4900 19.1263 34.4681 8.4 1.092 7.056 0.084 0.168 loo pp" D1R3707 7.80 16.4 49 62.8205 21.0256 33.*694 5.9 0.767 4.779 0.354 0.000 inn p p m D1R3713 9.21 17.4 51 55.3746 18.8925 34.1176 9.0 1.980 6.480 0.540 0.000 100 PPM D1R3717 7.72 15.4 47 60.8808 19.9*82 32.7660 5.1 1.173 3.672 0.153 0.102 100 PPM D1R3723 7.42 15.0 44 59.2992 20.2156 34.0909 5.7 1.425 4.104 0.171 0.000 100 PPM D1M372* 7.28 14.0 41 56.3187 19.2308 34.1463 17.9 5.370 10.203 1.790 0.537 100 PPM 01R3730 8.96 15.9 48 53.5714 17.7455 33.1250 8.1 1.782 5.670 0.486 0.162 100 PPM 01R3731 7.82 15.2 45 57.5448 19.4373 33.7778 9.2 2.024 6.716 0.368 0.092 100 PPM D1R373B 8.50 17.0 49 57.6471 20.0000 34.6939 8.3 2.905 4.648 0.581 0.166 100 PPM 01H3740 7.99 16.8 50 62.5782 20.7760 33.2000 7.0 3.080 3.430 0.420 0.070 103 PPM 01R3746 8.54 17.2 52 60.8899 20.1405 33.0769 5.0 0.700 4.050 0.250 0.000 100 PPM D1R3751 8.71 16.8 51 58.5534 19.2882 32.9412 8.1 1.701 5.670 0.648 0.081 100 PPM 01R3755 8.56 14.9 46 53.7383 17.4065 32.3913 13.2 4.224 7.788 0.924 0.264 100 PPM 01M3756 8.61 16.3 49 56.9106 18.9315 33.2693 8.7 1.740 6.699 0.261 0.000 c-nj i OOSE 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM ANIMAL F1R3762 F1H3764 E1R3765 F1R3767 E1R3769 E1H3771 E1R3773 E1R3775 E1R3777 E1R3782 E1R3787 E1R3793 E1R3796 EIR3806 E1R3807 F1R381 1 F1R3813 F1H3B14 F1R3823 F1R3825 F1H3B37 FIR3839 F1H3842 F1H3845 F1R384B F1R3851 F1R3852 F1R3853 F1R3855 F1R3859 ERYTH 7.68 B .54 7.44 8.39 8.06 7.B4 7.1? 8.27 8.15 4.10 7.78 7.81 7.44 7.95 7.95 8.14 8.09 7.57 7.74 8.69 8.3 8.13 7.65 5.08 8.15 7.95 8.38 7.68 7.54 6.89 MEMO 15.4 16.2 16.2 15.6 15.6 15.2 14.0 16.1 15.3 9.4 14.9 15.8 15.5 16.3 14.8 14.9 15.8 15.7 15.1 16.6 16.2 16.0 16.1 10.5 17.2 15.3 16.0 15.3 14.9 13.3 TABLE 12 TWO YEAR OHAL (OIET) TOx ICiTY-ONCOGENICITY STUDY OF FLUORGCAHBON FM-3924 IN MALE HATS INDIVIDUAL HEMOGRAM VALUES ------------ -- MONTHS lB -------------- HEMAT MC V MCH MCHC W8C 45 58.5938 20.0521 34.2222 10.2 46 53.8642 18.9696 35.2174 9.2 44 59.1398 21.7742 36.8182 7.8 44 52.4434 18.6936 35.4545 10.5 45 55.8313 19.3548 34.6667 8.1 43 64.8469 19.3878 35.3488 7.2 39 54.7753 19.6629 35.8974 9.1 45 54.4135 19.4680 35.7778 9.8 4? 51.5337 18.7730 36.4286 10.4 25 60.9756 22.9268 37.6000 10.0 41 52.6992 19.1517 36.3415 7.3 43 55.0576 20.2305 36.7442 8.1 42 56.4516 20.8333 36.904 10.5 44 55.3459 20.5031 37.0465 8.9 41 51.5723 18.6164 36.0976 7.6 41 50.3686 18.3047 36.3415 10.2 44 54.3881 19.5303 35.9091 20.5 4? 55.4822 20.7398 37.3810 9.1 41 52.9716 19.6090 36.8293 10.8 46 52.9344 19.1024 36.0870 8.8 44 52.4434 19.3087 36.8182 5.5 43 52.8905 19.6802 37.2093 11.1 44 57.5163 21.0458 36.5909 8.5 28 56.1181 20.6693 37.5000 5.4 48 58.8957 21.1043 35.8333 6.2 42 52.8302 19.2453 36.4286 9.6 44 52.5060 19.0931 36.3636 8.1 42 54.6875 19.9219 36.4286 9.4 43 57.0292 19.7613 34.6512 10.9 36 52.2496 19.3033 36.9444 17.8 PMNAB 1.224 1.564 2.496 2.415 0.891 1.368 2.002 2.352 2.808 5.000 2.044 1.620 4.410 1.602 1.900 1.836 11.275 2.002 2.700 1.936 1.210 2.220 2.295 0.270 1.302 1.728 1.782 4.512 4.469 10.680 LVMAB 8.466 6.900 4.758 7.245 6.642 5.328 5.915 6.958 6.448 3.600 4.964 5.751 5.565 6.586 5.016 7.854 7.790 6.461 7.560 6.688 4.235 7.881 5.695 4.806 3.906 7.008 6.075 3.854 5.668 6.586 MONOAB 0.510 0.552 0.390 0.735 0.567 0.504 0.910 0.392 1.040 1.000 0.292 0.405 0.420 0.534 0.684 0.408 0.820 0.546 0.324 0.176 0.055 0.555 0.255 0.324 0.682 0.576 0.000 0.846 0.763 0.356 EOSAB 0.000 0.184 0.156 0.105 0.000 0.000 0.273 0.098 0.104 0.400 0.000 0.324 0.105 0.178 0.000 0.102 0.615 0.091 0.216 0.000 0.000 0.444 0.255 0.000 0.310 0.288 0.243 0.188 0.000 0.178 CfrSTOO 00 i DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM ANIMAL A1R3S18 A1R3524 A1M3528 A1R3531 A1H3534 A1H3538 A1R3542 A1R354B A1R3554 A1R3557 A1R3S62 A1R3564 A1R3569 A1R3573 A1H3578 D1R3700 D1R3702 O1H3706 01R3709 D1R3713 D1R3718 01R3725 D1R3730 D1R3739 01R3741 D1R37A6 D1R3752 D1R3755 D1R37S8 D1H3760 ERYTH 7.44 8.08 8.70 8.33 7.96 8.54 8.86 8.09 6.08 9.47 7.74 7.68 5.38 8.52 6.70 8.77 7.44 9.05 8.34 8.76 8.57 7.20 8.12 7.99 6.80 8.40 8.81 6.49 7.91 3.96 HFMO 13.1 14.4 15.5 lb.O 15.3 15.1 16.0 15.6 11.8 16.7 13.2 14.4 12.0 16.1 12.7 15.6 13.9 16.8 14.8 16.1 15.6 13.9 14.4 16.6 12.7 16.8 15.6 11.6 14.1 8.6 TABLE 12 TWO V AR ORAL (DIET) TOXICITY-ONCOGENICITY STUDY OF FL UOROCARBON FM-3924 IN MALE ATS INDIVIDUAL HEMOGRAM VALUES ---- ------ M0NTH=2A -- -------- --------- HEMAT MCV MCH MCHC WRC 37 49.7312 17.6075 35.4054 13.2 43 53.2178 17.8218 33.4884 6.8 45 51.7241 17.6161 34.4444 7.2 47 56.4226 19.2077 34.0426 8.4 46 57.7689 19.2211 33.2609 36.3 45 52.6932 17.6815 33.5556 7.2 46 51.9187 18.0587 34.7826 7.1 46 56.8603 19.2831 33.9130 8.5 34 55.9211 19.4079 34.7059 4.4 50 52.7983 17.6346 33.4000 8.0 37 47.8036 17.0543 35.6757 12.6 42 54.6675 18.7500 34.2857 12.4 33 61.3383 22.3048 36.3636 9.7 47 55.1643 18.8967 34.2553 7.4 37 55.2239 18.9552 34.3243 12.7 47 53.5918 17.7079 33.1915 7.5 43 57.7957 18.b828 32.325b 10.7 49 54.1436 18.5635 34.2857 6.0 42 50.3597 17.7458 35.2381 11.4 49 55.9361 18.3790 32.8571 8.8 46 53.6756 18.2030 33.9130 6.2 40 55.5556 19.3056 34.7500 6.7 42 51.7241 17.7340 34.2837 12.4 48 60.0751 20.7760 34.5833 4.0 40 58.8235 18.6765 31.7500 15.1 47 55.9524 20.0000 35.7447 4.6 47 53.3485 17.7072 33.1915 5.8 34 52.3883 17.8737 34.1176 17.8 43 54.3616 17.8255 32.7907 7.9 23 58.0808 21.7172 37.3913 8.8 PMNAB 3.036 1.632 0.432 1.092 22.506 1.584 0.710 1.445 0.264 1.840 5.922 4.712 0.776 1.554 8.255 0.450 2.568 2.220 1.026 0.440 0.248 0.804 0.744 2.400 2.869 0.230 2.262 2.136 0.632 2.728 LYMA8 9.100 4.760 6.624 6.972 12.342 5.256 6.248 6.885 4.136 6.000 6.300 6.820 8.924 5.328 4.191 7.050 8.132 3.660 10.032 7.920 5.890 5.695 11.532 1.440 11.778 4.232 3.074 15.308 6.952 5.456 M0N0AB 0.924 0.340 0.000 0.336 1.452 0.288 0.071 0.170 0.000 0.080 0.378 0.620 0.000 0.296 0.127 0.000 0.000 0.120 0.114 0.264 0.062 0.201 0.124 0.160 0.453 0.092 0.290 0.356 0.316 0.528 E0SA8 0.132 0.068 0.144 0.000 0.000 0.072 0.071 0.000 0.000 0.080 0.000 0.248 0.000 0.222 0.127 0.000 0.000 0.000 0.228 0.176 0.000 0.000 0.000 0.000 0.000 0.046 0.174 0.000 0.000 0.088 00X544 CvJo1 i TABLE 12 00SE 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM !0 PPM 10 PP" 10 PPM 10 PPM 10 PPM ANIMAL E1R3761 F1R3763 E1R3767 E1R3769 E1R3773 E1R3776 E1R3779 E1R3781 E1R3786 E1R3788 E1R3791 E1R3794 E1R3799 E1R3B03 E1R3807 F1R3811 F1R3815 F1R3817 F1R3822 F1R3826 F1R3029 F1R3832 F 1R3837 E1R3841 F1R3845 F1P3848 F1R3B51 F1R3853 F1R3856 F1R3858 FRYTH 5.46 8.19 8.82 8.56 7.53 5.14 7.82 7.67 8.13 8.88 8.51 9.16 9.14 6.52 8.63 9.26 10.80 6.53 8.46 8.64 7.48 8.51 8.92 7.85 7.65 7.73 8.56 9.03 7.87 8.08 HEMO 11.2 15.5 15.9 16.1 13.9 10.6 15.8 14.2 16.4 15.9 15.9 16.0 16.3 13.3 15.5 16.5 20.6 13.3 16.6 16.5 13.9 16.8 17.0 14.0 14.3 15.9 15.7 16.0 15.3 15.7 TWO YEAR ORAL (DIET) TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FM-3924 IN MALE HATS INDIVIDUAL HEMOGRAM VALUES ---------------- - M0NTH=?4 ------------------ HEMAT MCV MCH MCHC NBC 33 60.4396 20.5128 33.9394 17.1 46 56.1661 18.9255 33.6957 9.0 48 54.4218 18.0272 33.1250 9.3 48 56.0748 18.8084 33.5417 7.0 41 54.4489 18.4595 33.9024 10.9 32 62.2568 20.6226 33.1250 16.2 46 58.0235 20.2046 34.3478 11.3 42 54.7588 18.5137 33.8090 15.7 47 57.8106 20.1722 34.8936 6.5 45 50.6757 17.9054 35.3333 9.1 46 54.0541 18.6839 34.5652 8.2 46 50.2103 17.4672 34.7826 19.7 47 51.4223 17.8337 34.6809 11.6 38 58.2822 20.3908 35.0000 5.3 45 52.1437 17.9606 34.4444 6.2 50 53.9957 17.8186 33.0000 8.2 61 56.4815 19.0741 33.7705 16.6 38 58.1930 20.3675 35.0000 9.6 49 57.9196 19.6217 33.8776 9.1 49 56.7130 19.0972 33.6739 5.7 39 52.1390 18.5829 35.6410 6.2 49 57.5793 19.7415 34.2057 7.3 47 52.6906 19.0583 36.1702 7.5 38 48.4076 17.8344 36.8421 17.6 40 52.2876 18.6928 35.7500 10.1 46 59.5084 20.5692 34.5652 6.0 46 53.7383 18.3411 34.1304 8.3 47 52.0487 17.7187 34.0426 15.3 44 55.9085 19.4409 34.772T 7.0 52 64.3564 19.4307 30.1923 8.5 PMNAB 8.200 3.600 2.697 1.260 1.526 8.262 3.729 8.164 0.650 3.185 1.066 3.152 1.624 0.477 1.550 1.394 11.620 1.824 1.638 0.912 1.674 1.095 1.200 6.608 1.212 2.220 0.913 8.721 2.240 1.105 LYMAB 7.695 4.320 6.324 5.250 8.720 6.480 7.345 6.751 5.655 5.824 6.642 16.154 9.396 4.717 4.464 6.396 4.482 7.392 7.189 4.674 4.154 6.132 6.150 10.384 8.585 3.600 7.138 6.273 4.270 7.310 MONOAB 1.026 0.900 0.279 0.420 0.436 1.296 0.226 0.785 0.130 0.091 0.410 0.000 0.580 0.106 0.186 0.082 0.490 0.384 0.000 0.057 0.186 0.000 0.000 0.176 0.303 0.180 0.249 0.000 0.490 0.000 EOSAB 0.171 0. IflO 0.000 0.070 0.210 0.162 0.000 0.000 0.065 0.000 0.0B2 0.394 0.000 0.000 0.000 0.328 0.000 0.000 0.273 0.057 0.186 0.073 0.150 0.352 0.000 0.000 0.000 0.306 0.000 0.085 001545 cOn 001546 BEST COPY AVAILABLE FEm a LE TwO YtAH OHAL (DIET) TOa ICITY-UNCOGEn ICITY STUDY OK El UUHUCAHBON FH-3924 IN NATS MEAN IIEMGKAM VALUES EHYTHWOCYTES (CELLS A 10**6) MEMOOLOblN (U/OL) h E m a TOCh IT U HACKED CELLS) MCV (MICm ONS**3T m Ch (PICOGm AHS) N MEAN S.DEv . MEAN S.Dtv. MEAN S.DEV. MEAN S.OEv. MEAN S.DEv. month 3 0 PPM 100 PPM 30 PPM 10 PPM muNTH t> 0 PPM 100 PPM 30 Pp m 10 PPM IS 6,91 0.31V IS 6.ol 0.334 14 7.70 0.51b IS 7.b5* .631 lS.h 15.1 IS.7 15.9 o.4b 0.6? 0.4b 0.6b 43.7 41.6 42.V 43.3 i.n 1.72 1.46 1.39 bJ 2.2 61 2.S 56* 3.6 55* 4.3 22.V 22.2 20.4* 20.3* 0.7S 1.00 1.2b 1.60 IS 7.3? 0.413 15 6.8S* 0.2S2 IS 8.02* 0.664 IS 7.73 0.5S1 1S.0 14.0 15.0 1S.1 O.SS 0.53 0.4b 0.64 42.3 41.0 42.? 42.6 l.b4 1.41 1.42 l.bb 5b 2.2 60 2.5 53* 3.5 55 4.2 20.5 20.5 18.7* 19.6 0.95 0.95 1 .29 1.46 H*iTrt 1? 0 PPM loO PP** 3o P p m 10 PPM IS 7.60 0.300 15 7.17* 0.44V 14 7.51 0.4*2 IS 7.38 0.322 15.6 14.2* 15.1 15.3 0.40 0.77 0.69 0.57 44.3 42.5 44.2 43.2 1.39 2.29 2.36 1.74 5b 2.1 2U.6 0.71 59 1.5 19.8* 0.62 5v 1.6 20.1 0.64 59 1.7 20. b 0.61 MuNTH 18 0 PPM 100 PPM 30 PPM 10 PPM IS 7.37 0.66b 15 6.55* 1.055 15 7.29 0.522 15 7.64 0.429 15.4 13.9 14.7 15.5 1.43 1 .b4 1.16 0.b3 MONTH 2A 0 PPM luO 30 P P M 10 P p m 15 7.06 1.129 15 6.10 1.227 15 6 .H 1 1.752 15 6.95 0.736 14.8 12.3* 13.4 1* .7 <T> ; p < S .ON, Two T* ILFD D u n n E T T T On HA d a t a . : p <s .ns, Two t a i l e d O u n n e t t t u n w a n k e d D a t a . 1.60 1.94 3.04 1.37 42.9 40.2 43.7 6 1 4.13 5.72 3.33 2.03 42.3 37.2 39.5 4 2 .0 5.40 6.56 9.17 3.42 5b 1.7 62* 2.7 60 2.4 60* 2.1 21.0 21.3 20.2* 20.3 0.6b 1.20 O.bb 0.72 60 3.5 21.2 1.45 61 3.0 20.3 1.70 64 8.2 22.0 4.41 61 2.4 21.2 0.90 MCh C <) MEAN S.DEv. 36.2 36.3 36.6 36.7 0.44 0.6 0.S9 0.6S 35.4 34.2* 35.4 35.3 1.01 1.34 0.49 0.62 35.3 33.4* 34.2* 35.5 0.48 1.08 0.64 0.56 36.0 34.5* 33.6* 33.6* 0.05 0.09 1.02 0.01 35.1 33.1 34.4 35.0 0.67 1.42 2.64 1.19 i 001547 31S1COPY AVMLABli. FEMALE TABLE 13 T*0 YEAH ORAL (DIET) TO X1C 1TY-ONCUbENICITV STUDY OF FLUOHOCARKON FM-392* IN HATS MEAN LEUKOCYTE VALUES LEUKOCYTES NE UTHOPHILS LYMPHOCYTES MONOCYTES EOSINOPHILS (CELLS X 1(l** 3) (CtLLS X 10*3> (CELLS X i0**3> tCtLLS X 10**3> CELLS X 10**3> N MEAN S.OEV. MEAN S*DtV MEAN S.OEV. MEAN S.OEV MEAN s .d e v . MONTH 3 0 PPM 100 PPM 30 P P M 10 PPM MONTH 6 0 PPM 100 P P M 30 PPM 10 P P M MONTH 12 0 PPM 100 PPM 30 PPM 10 PPM M O N T H 18 0 PPM loo PPM 30 PPM 10 PPM MONTH 2A 0 PPM 100 PPM CrTo> 30 PPM 10 PPM IS 10.90 ?. 690 IS lb.7* A.AOS 1* 12.93* 3#604 IS 15.56 A.HIS 2.57 2.12 1.77 2.23 1A U 6 1.357 1 .OVA 0.9*2 15.73 1A.2S 1 0 .0 0 * 12.70 2i70 3:663 3:393 A;Tb2 0.37 0.17 0 . 1A A 0.36 0.217 0.120 0.097 0.273 0.31 0 .1 0.13 0.27 0.262 0.166 0.199 0.266 IS 7 . 5 ? 2 .SS9 1 .AA 1.506 IS 8.3* 1.020 1.A3 0.572 IS 8.67 2.615 1.16 0.63? IS 6.0 A 1 * 9 2 1.33 0.560 5.87 6. A 1 7.1* 6.26 2:160 liSOfl 2:397 1:256 0.13 0.32* 0.26 0.36* 0.096 0.177 0.152 0.173 0.08 0.20* 0.11 0.09 0.067 0.125 0.090 0.091 15 5.73 2 . 120 1.27 1.562 15 5.73 1.532 0.6A 0.597 1* 5.A9 1.072 1.15 0.576 15 5.A3 1.176 0.69 0.310 A . 13 A. A3 A. 00 A.25 i ;o*9 1 .*19 0:965 1:110 0.21 0.33 0 .2 * 0.22 0.106 0.163 0.138 0.126 0.12 0.13 0.10 0.08 0.125 0.111 0.095 0.073 15 5.75 2.230 1.01 1 .631 15 5.89 1.90* 1.65* 1.038 IS 6.23 2.568 2. 3* 2.271 IS 6.15 1.836 1 . 6 8 a 0.77A A. AH 3.73 3.A8* 3.90 0;973 0:932 0:7*2 K160 0.23 0 AO 0.28 0.A3* 0.2*9 0.198 0.13* 0.267 0.03 0.10 0.13* 0.08 0.057 0.106 0. 1AO 0.07* 15 6.73 A.06A IS 7.2S 2.997 15 10.17 6.661 15 6.76 3.315 2 . til 2.56 5.67 2.00 2.959 2.656 5.651 1.60* 3.6? A .A 1 3.86 A.55 1:329 116*7 11767 K935 0.11 0 .1 0 36 a 0.17 0.151 0 .1A8 0. *85 0.171 0.07 0 .0 V 0.06 0.08 0.07* 0.101 0.061 0 . 1 AA : p <= .OS. TtaO TAILED DUNNETT T ON R AA DATA. * : P <= .OS. ToO TAILED OUNNETT T O n HA Nk ED OATA. i 001548 TABLE 13 DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM ino PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM ANIMAL N1R4576 N1R4578 N1R4582 NIR45B3 NIR4584 N1R4592 N1R4610 N1R4612 N1R4613 N1R4619 N1R4621 N1R4626 N1R4G27 N1R4633 N1R4640 01R4757 Q1R4764 01R4766 01R4772 01R4783 01R478S 01R4790 01R4791 01R4792 01R4793 01R4808 Q1R4B12 Q1R4H14 Q1H4R16 01R4819 ERYTH 6.98 7.72 6.79 6.74 6.31 7.03 6.94 6.88 6.73 7.35 6.60 6.98 6.84 6.84 6.99 6.99 7.05 6.74 6.68 6.64 6.44 7.40 6.91 6.51 7.22 6.65 6.67 6.14 6.85 7.23 HEMO 15.6 16.1 15.7 15.6 14.9 16.2 15.6 15.7 15.0 16.5 15.5 16.0 16.4 16.0 16.4 15.3 15.1 13.9 15.5 14.4 14.9 15.8 15.7 15.5 15.4 15.1 15. tt 14.0 14.6 15.5 TWO YEAR ORAL <OIET) TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FM-3924 In FEMALE RATS INDIVIDUAL HEMOGRAM VALUES ----------------- - M0NTH=3 ------ --- ---- ------ HEMAT MCV MCH MCHC WBC 43 61.6046 22.3496 36.2741 17.5 44 56.9948 20.8549 36.59*9 20.1 43 63.3284 23.1222 36.5116 17.0 43 63.7982 23.1454 36.2791 19.4 42 66.5610 23.6133 35.4762 20.5 45 64.0114 23.0441 36.0000 17.3 44 63.4006 22.4784 35.4545 15.4 44 63.9535 22.8198 35.6818 21.0 42 62.4071 22.2883 35.7143 16.1 45 61.2245 22.4490 36.6667 21.0 42 63.6364 23.4848 36.9048 24.3 44 63.0372 22.9226 36.3636 21.1 45 65.7895 23.9766 36.4444 19.6 44 64.3275 23.3918 36.3636 20.4 45 64.3777 23.4621 36.4444 14.0 40 57.2246 2 1 .8H84 38.2500 15.1 42 59.5745 21.4184 35.9524 15.5 40 59.3472 20.6231 34.7500 22.5 43 64.3713 23.2036 36.0465 26.7 40 60.2410 21.6867 36.0000 12.9 40 62.1118 23.1366 37.2500 12.7 44 59.4595 21.3514 35.9091 12.4 44 63.6758 22.7207 35.6818 11.3 42 64.5161 23.8095 36.9048 14.2 42 58.1717 21.3296 36.6667 20.7 41 61.6541 22.7068 36.8293 14.1 43 64.4678 23.6882 36.7442 20.0 39 63.5179 22.8013 35.8974 19.0 40 58.3942 21.3139 36.5000 19.3 44 60.8575 21.4385 35.2273 14.7 PMNAB 1.925 3.417 2.040 2.134 4.715 5.882 2.156 2.310 2.898 0.630 1.944 4.009 1.176 2.040 1 .260 0.151 2.015 3.825 2.403 3.354 1.016 0.868 1.356 1.278 4.968 0.423 3.000 2.850 2.895 1.470 lymab 14.525 16.080 14.280 17.072 14.555 11.072 12.782 18.480 12.397 19.320 21.384 16.458 18.032 17.544 12.040 14.798 13.175 18.000 23.763 8.901 11.430 11.160 9.831 12.212 15.318 13.677 16.800 15.770 15.826 13.083 MONOAB 0.700 0.402 0.510 0.000 0.410 0.173 0.154 0.210 0.322 0.420 0.243 0.211 0.392 0.816 0.560 0.000 0.155 0.225 0.267 0.129 0.127 0.248 0.000 0.142 0.207 0.000 0.200 0.380 0.386 0.147 EOSAB 0.350 0.201 0.170 0.194 0.820 0.173 0.308 0.000 0.483 0.630 0.729 0.422 0.000 0.000 0.140 0.151 0.155 0.450 0.267 0.516 0.127 0.124 0.113 0.568 0.207 0.000 0.000 0.000 0.193 0.000 CTl CO I TABLE 13 o o Lp Am wl c0 <-pn* DOSE 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM animal R1R4822 R1R4823 R1R4830 R1R4033 R1R4836 R1R4837 R1R4B42 R1R4848 P1R4850 R1R4853 R1R4BS4 R1P4856 R1R4860 R1R4864 R1R4865 S1R4871 S1R4875 S1R4879 S1R4880 S1R4881 S1P4RB4 S1R488S S1R4B86 S1R4889 S1R4896 S1R4897 S1R4901 S1R4902 S1R490S S1R4915 ERYTH 7.20 7.31 8.42 7.83 7.33 7.35 8.12 7.53 7.91 7.53 8.99 7.35 7.23 7.65 7.24 7.87 7.60 7.52 8.29 7.68 7.71 9.96 7.65 7.87 7.49 7.88 7.87 7.60 7.53 HEMO 15.3 15.0 16.6 15.9 16.0 15.4 16.3 15.7 15.3 16.0 15.0 15.4 15.6 16.0 15.1 16.2 15.4 15.3 16.0 15.7 15.0 15.2 15.8 16.6 16.5 16.4 17.5 15.6 15.9 TWO YEAR ORAL (DIET) TOXICITY-ONCOGENICITY STUOY OF FL UOROCARBON FM-3924 IN FEMALE RATS INDIVIDUAL HEMOGRAM VALUES ------------------- MONTHc j ---------------- ----- HEMAT 42 41 45 45 44 41 44 42 42 44 41 * 43 42 44 42 44 43 42 44 43 42 41 42 45 45 44 46 43 43 MCV 58.3333 56.0876 53.4442 57.4713 60.0273 55.7823 54.1872 55.7769 53.0973 58.4329 45.6062 58.5034 58.0913 57.5163 58.0110 55.9085 56.5789 55.8511 53.0760 55.989b 54.4747 41.1647 54.9020 57.1792 60.0801 55.8376 58.4498 56.5789 57.1049 MCH 2 1 .25U0 20.5198 19.7150 20.3065 21.8281 20.9524 20.0739 20.8499 19.342b 21.2483 16.6852 20.9524 21.5768 20.9150 20.8564 20.5845 20.2632 20.3457 19.3004 20.4427 19.4553 15.2610 20.6536 21.0928 22.0294 20.8122 22.2363 20.5263 21.1155 MCHC 36.4286 36.5854 36.8889 35.3333 36.3636 37.5610 37.0455 37.3810 36.4286 36.3b36 36.5854 35.8140 37.1429 36.3636 35.9524 36.8182 35.8140 36.4286 36.3636 36.5116 35.7143 37.0732 37.6190 36.8889 36.6667 37.2727 38.0435 36.2791 36.9767 WBC 8.32 16.90 11.80 13.30 17.50 8.52 14.80 11.10 9.21 11.30 20.80 11.00 13.90 12.60 11.90 14.30 18.40 24.40 14.20 17.50 15.40 14.10 11.90 16.00 10.00 12.20 8.47 25.30 19.40 PMNAB 1.8304 2.8730 0.9440 1.5960 3.3250 0.7668 1.1840 1.6650 0.9210 2.8250 1.0400 0.9900 0.6950 4.1580 2.2610 1.2870 3.8640 1.4640 1.9880 1.7500 2.1560 1.2690 4.1650 2.2400 2.3000 2.4400 1.0164 1.7710 3.4920 lymab 6.4064 13.0130 10.6200 11.5710 14.0000 7.4976 13.4660 9.1020 8.2890 8.4750 19.1360 9.6800 12.9270 8.1900 9.1630 12.4410 14.1680 22.4480 11.6440 15.0500 12.9360 12.4080 7.4970 12.3200 7.3000 8.9060 7.2842 22.7700 14.1620 MONOAB 0.0832 0.1690 0.2360 0.1330 0.1750 0.0000 0.1480 0.3330 0.0000 0.0000 0.2080 0.2200 0.1390 0.1260 0.3570 0.4290 0.1840 0.4880 0.2840 0.3500 0.1540 0.2820 0.0000 1.1200 0.1000 0.4880 0.0847 0.5060 0.5820 E0SAB 0.0000 0.6760 0.00Q0 0.0000 0.0000 0.2556 0.0000 0.1110 0.0000 0.0000 0.4160 0.1100 0.1390 0.1260 0.1190 0.1430 0.1840 0.0000 0.2840 0.3500 0.1540 0.1410 0.2380 0.3200 0.3000 0.3660 0.0847 0.2530 1.1640 TABLE 13 DOSE 0 PPM 0 PPM 0 PPM n ppm 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM (I PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM Ino p p m 100 PPM 100 PPM 100 PPM 100 PPM ANIMAL N1R4582 N1R4SB* N1R45B6 N1R4590 N1R4598 N1R4603 N1R4607 N1R4616 N1R4619 N1R4621 N1R4622 N1R4629 N1R4631 N1R4632 N1R4639 01R4759 01R4760 G1R4764 01R4771 Q1R4773 01R4774 01R4776 01R4785 01R4786 Q1R4794 01R479B 01R4B03 01R4808 Q1H4812 Q1R4814 ERYTH 7.32 7.85 8.81 7.19 7.31 8.60 7.88 8.03 7.70 6.80 7.23 7.32 7.36 7.28 7.05 6.51 6.71 6.87 6.80 6.33 6.94 6.71 6.55 7.22 7.03 6.91 7.14 6.87 7.14 7.00 MEMO 15.0 15.8 13.8 IS.3 15.1 14.7 lb.8 14.6 15.3 14.3 14.4 lb. 1 14.8 lb. 1 15.4 13.4 13.2 14.9 13.6 14.3 13.7 13.8 14.1 13.9 14.3 14.1 13.7 13.8 14.8 14.9 TWO YtAH OHAL iOItT) TOXICITY-ONCOGENICITY STUOY OF FL U0R0CAH80N FM-3924 IN FEMALE RATS INDIVIDUAL HEMOGRAM VALUES - M0NTH=6 - HERAT MCV MCH MCHC WBC 43 58.7432 20.4918 34.8837 8.59 46 58.5987 20.1274 34.3478 6.45 39 57.2687 20.2643 35.3846 6.24 43 59.8053 21.2796 35.5814 7.95 42 57.4555 20.6566 35.9524 7.43 40 60.6061 22.2727 36.7500 7.69 44 55.8376 20.0508 35.9091 6.43 4* 54.79#5 18.1818 33.1818 6.95 44 57.1429 19.8701 34.7727 5.98 42 61.7647 21.0294 34.0476 6.61 41 56.7082 19.9170 35.1220 4.59 42 57.3770 20.6284 35.9524 14.90 40 54.3478 20.1087 37.0000 11 .00 42 57.6923 20.7418 35.9524 4.76 43 60.9929 21.8440 35.8140 7.28 38 58.3717 20.5837 35.2632 8.60 42 62.5931 19.6721 31.4286 7.57 40 58.2242 21.6885 37.2500 4.64 39 57.3529 20.0000 34.8718 10.30 41 64.7709 22.5908 34.8780 9.96 42 60.5187 19.7406 32.6190 8.26 40 59.6125 20.5663 34.5000 6.71 42 64.1221 2 1 ,52b7 33.5714 7.45 41 56.7867 19.2521 33.9024 8.64 43 61.1664 20.3414 33.2558 9.08 41 69.3343 20.4052 34.3902 7.17 41 57.4230 19.1877 33.4146 8.53 40 58.2242 20.0873 34.5000 7.32 42 58.8235 20.7283 35.2381 12.70 43 61.4286 21.2857 34.6512 8.20 PMNAB 0.6872 0.5160 1.9344 1.1925 0.9659 0.4614 0.5787 0.4170 0.5382 1.2559 0.4131 4.7680 1.2100 1.0948 5.6056 1.4620 1.8168 0.5104 1.2360 1.4940 0.9912 0.9394 1.7135 0.8640 1.5436 1.5057 2.3884 0.9516 2.6670 1.3120 LYMAB 7.5592 5.8695 4.0560 6.5190 6.3155 7.0748 5.7227 6.3940 5.3222 5.2219 4.0392 9.8340 9.2400 3.5224 1.3832 6.8800 5.4504 3.9904 8.5490 7.8684 7.1036 5.3009 5.1405 7.0848 6.9916 4.9473 5.1180 5.7096 9.5250 6.4780 MONOAS 0.2577 0.0000 0.0624 0.2385 0.0000 0.0769 0.1286 0.1390 0.0598 0.0661 0.0918 0.1490 0.3300 0.0952 0.2184 0.1720 0.1514 0.0464 0.4120 0.3984 0.0826 0.1342 0.3725 0.3456 0.4540 0.2868 0.6824 0.4392 0.5080 0.2460 E0SA8 0.0859 0.0645 0.1872 0.0000 0.1486 0.0769 0.0000 0.0000 0.0598 0.0661 0.0459 0.1490 0.2200 0.0476 0.0728 0.0860 0.1514 0.0928 0.1030 0.1992 C .0826 0.3J55 0.2235 0.3456 0.0908 0.4302 0.3412 0.2196 0.0000 0.2460 COIS Otin i 001551 TABLE 13 DOSE animal 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM R1R4822 R1R4826 R1R4829 R1R4832 R1R4835 R1R4838 R1R4850 R1R4853 R1R4854 R1R4856 R1R4858 R1R4860 R1R4867 R1R4868 R1R4870 S1R4873 S1R4876 S1R4877 S1R4878 S1R4881 S1R4887 S1R4890 S1R4891 S1R4898 S1R4901 S1R4907 S1R4912 S1R4913 S1H4915 S1R4918 oCT>l ERYTH 7.320 7.490 7.790 7.710 7.430 8.730 7.560 9.270 7.900 8.030 7.520 7.360 9.190 8.750 8.190 7.640 7.760 7.640 7.640 8.240 9.230 7.510 7.440 8.24) 7.120 7.260 7.190 7.580 8.150 7.240 MEMO 14.9 15.5 14.6 14.8 15.0 15.1 14.7 15.5 14.8 15.4 14.6 13.8 15.6 14.6 15.4 14.0 14.9 14.3 15.6 15.7 15.7 15.1 15.3 14.0 15.7 14.3 14.8 15.8 15.3 15.3 TWO YEAH O K a L (OIET TOXIC1TY-ONCOOfNIC ITY STUDY OF FL UOHOCAHbON FM-3924 In FEMALE HATS INDIVIDUAL HEMOGHAM VALUES MONT H=6 henat MCV MCH MCHC WBC 42 57.3770 20.3552 35.4762 5.96 43 57.4099 20.6943 36.0465 11.50 42 53.9153 18.7420 34.7619 11.90 42 54.4747 19.1958 35.2381 11.60 42 56.5276 20.1884 35.7143 8.54 42 48.1100 17.2967 35.9524 11.10 41 54.2328 19.4444 35.8537 5.47 44 47.4649 16.7206 35.2273 6.27 43 54.4304 18.7342 34.4186 13.10 43 53.5492 19.1781 35.8140 6.69 41 54.5213 19.4149 35.6098 5.61 39 52.9891 18.7500 35.3846 7.67 45 48.9663 lh.9750 34.6667 6.91 41 46.8571 16.6857 35.6098 9.97 43 52.5031 18.8034 35.8140 7.81 41 53.6649 18.3246 34.1463 9.00 43 55.4124 19.2010 34.6512 6.85 40 52.3560 18.7173 35.7500 9.50 43 56.2827 20.4188 36.2791 9.13 45 54.6117 19.0534 34.8889 8.38 44 47.6706 17.0098 35.6818 6.91 42 55.9254 20.1065 35.9524 8.26 43 57.7957 20.5645 35.5814 7.41 39 47.3244 16.9882 35.8974 8.52 45 63.2022 22.0506 34.8889 4.88 41 56.4738 19.6970 34.8780 8.11 41 57.0236 20.5841 36.0976 6.65 45 59.3668 20.8443 35.1111 10.70 44 53.9877 18.7730 34.7727 9,63 43 59.3923 21.1326 35.5814 6.65 PMNAB 0.9536 2.3000 0.9520 0.8120 0.3416 1.4430 0.3282 0.7524 1.5720 2.2746 0.3927 1.6107 0.8292 1.3958 1.4839 1.0800 0.6850 1.7100 1.3695 1.4246 1.3820 1.1564 0.5928 1.9596 0.9760 0.8921 1.7290 2.8890 1.1556 0.9310 LYMAB 4.7680 8.5100 10.7100 10.4400 7.7714 8.9910 4.9230 5.2668 11.1350 3.8133 5.0490 5.9059 5.7353 8.0757 6.0137 7.4700 5.8225 7.6000 7.5779 6.3688 4.9061 6.4428 6.7431 6.0492 3.5624 6.6502 4.3890 7.2760 7.7040 5.3865 MONOAB 0.1788 0.5750 0.1190 0.1160 0.4270 0.4440 0.1641 0.1881 0.1310 0.3345 0.1122 0.0767 0.2764 0.3988 0.3124 0.4500 0.3425 0.1900 0.0913 0.5028 0.4146 0.6608 0.0741 0.3408 0.1952 0.4866 0.3990 0.5350 0.4815 0.1995 E0SAB 0.059b 0.1150 0.1190 0.2320 0.0000 0.2220 0.0547 0.0627 0.2620 0.2676 0.0561 0.0767 0.0691 0.0997 0.0000 0.0000 0.0000 0.0000 0.0913 0.0838 0.2073 0.0000 0.0000 0.1704 0.1464 0.0811 0.1330 0.0000 0.2889 0.1330 i &SSTOO TABLE 13 DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 1 00 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM ANIMAL N1R4578 N1R45B2 N1R45B5 N1R458B N1R4589 N1R4590 N1R4601 N1R4608 N1R4610 N1R4620 N1R4629 N1R4630 N1R463I N1R4632 N1R4640 Q1R4757 Q1R4760 01R4761 Q1R4763 01R4775 (J1R4779 O1R4780 (J1R4782 Q1R4783 Q1H47B5 Q1R47B7 Q1R4788 Q1R4793 01R4806 01R4816 ERYTH 7.55 7.57 7.84 7.23 7.94 7.44 7.17 8.26 7.32 7.80 7.84 7.44 7.68 7.55 7.30 7.40 7.26 7.11 6.77 6.58 7.53 7.78 7.29 6.76 7.21 7.33 7.41 7.86 7.08 6.17 HFMO 15.7 15.7 15.9 15.2 15.1 15.8 15.2 16.3 15.1 15.3 16.0 15.6 15.8 16.3 15.6 14.7 14.5 13.8 13.7 13.9 15.1 14.4 14.0 13.2 14.5 14.2 15.1 15.6 13.8 12.6 TWO YEAR ORAL DIET) TOXICITY-ONCOQENICITY STUDY OF FLUOROCARBON FM-3924 IN FEMALE RATS INDIVIDUAL HFMOGRAM v a l u e s MONTH=12 HEMAT MCV MCH MCHC WBC 44 58.2781 20.7947 35.6818 3.5 44 50.1242 20.7390 35.6818 6.9 45 57.3980 20.2806 35.3333 4.1 43 59.4744 21.0235 35.3488 3.9 43 54.1562 19.0176 35.1163 6.8 44 59.1390 21.2366 35.9091 5.4 43 59.9721 21*1994 35.3488 4.6 46 55.6901 19.7337 35.4348 7.1 42 57.3770 20.6284 35.9524 3.8 43 55.1282 19.6154 35.5814 5.2 47 59.9490 20.4082 34.0426 12.1 44 59.1398 20.9677 35.4545 6.5 45 58.5938 20.5729 35.1111 5.9 46 60.9272 21.5894 35.4348 4.9 45 61.6438 21.3699 34.6667 5.2 44 59.4595 19.8649 33.4091 5.0 43 59.2287 19.9725 33.7209 6.0 42 59.0717 19.4093 32.8971 5.4 41 60.5613 20.2363 33.4146 5.0 41 62.3100 21.1246 33.9024 5.2 44 58.4329 20.0531 34.3182 5.8 44 56.5553 18.5090 32.7273 8.9 45 61.7284 19.2044 31.1111 5.0 41 60.6509 19.5266 32.1951 3.4 42 58.2524 20.1110 34.5238 4.6 44 60.0273 19.3724 32.2727 6.4 44 59.3792 20.3779 34.3182 5.6 45 57.2519 19.8473 34.6667 4.5 42 59.3220 19.4915 32.8971 9.2 36 58.3468 20.4214 35.0000 5.9 PMNAB 0.840 0.621 0.451 0.390 3.264 0.648 0.598 0.710 0.152 0.156 6.171 1.365 1.239 1.666 0.728 0.500 0.840 1.566 1.150 0.416 2.262 1.513 0.700 0.238 0.874 1.024 0.168 0.045 0.552 0.767 lymab 2.450 5.865 3.280 3.276 3.468 4.482 3.542 5.822 3.534 4.888 5.324 4.810 4.189 2.891 4.056 4.200 4.740 3.132 3.650 4.420 3.016 6.764 4.200 2.958 3.220 4.544 5.040 4.185 8.188 4.248 MONOAB 0.140 0.207 0.287 0.156 0.068 0.162 0.276 0.355 0.038 0.156 0.121 0.325 0.413 0.294 0.208 0.250 0.180 0.486 0.200 0.364 0.464 0.534 0.100 0.170 0.322 0.57b 0.224 0.270 0.184 0.590 EOSAB 0.070 0.207 0.082 0.078 0.000 0.108 0.184 0.213 0.076 0.000 0.484 0.000 0.059 0.049 0.208 0.100 0.240 0.216 0.000 0.000 0.058 0.089 0.000 0.034 0.184 0.256 0.168 0.000 0.276 0.295 <--TlI i 001553 TABLE 13 DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM ANIMAL N1R4581 N1R4583 N1R4586 N1R4592 N1R4595 N1H4S98 N1R4599 N1R4602 N1R4604 N1R4606 N1R4609 N1H4611 N1R4612 N1R4627 N1R4638 G1R4762 01R4765 Q1R4772 Q1R4776 01R4778 Q1R4789 01R4794 01R4801 01R4803 Q1R4H07 01R4808 Q1R4B11 Q1R4813 01R4814 01R4817 ERYTH 6.16 7.52 7.08 8.04 7.52 7.44 7.80 7.72 7.97 5.85 7.07 6.95 8.27 7.36 7.76 6.81 7.54 7.11 7.07 7.10 6.81 6.73 6.89 6.94 3.15 6.76 6.11 6.87 5.44 6.94 HEMO 12.3 15.6 14.5 16.8 15.3 16.4 16.1 16.6 16.4 12.4 15.5 14.7 16.5 16.2 16.4 14.4 14.7 14.7 15.1 14.7 14.5 14.4 14.0 14.3 7.6 14.1 13.8 15.1 12.5 13.9 TWO YEAR ORAL DIET) TOXICITY-ONCOGENICITY STUOY OF FLUOROCARBON FM-3924 IN FEMALE RATS INDIVIDUAL HEMOGRAM VALUES ----------------- - M O N T H s l B --------- --- ------ HEMAT 34 44 41 46 44 45 44 45 47 34 41 41 47 46 45 41 43 43 42 43 43 42 40 42 21 42 40 44 35 42 MCV 55.194b 58.5106 57.9096 57.2139 58.5106 60.4839 56.4103 58.2902 58.9711 58.1197 57.9915 58.9928 56.8319 62.5000 57.9897 60.2056 57.0292 60.4782 59.4059 60.5634 63.1424 62.4071 58.0552 60.5187 66.6667 62.1302 65.4664 64.0466 64.3382 60.5187 MCH 19.9675 20.7447 20.4802 20.8955 20.3457 22.0430 20.6410 21.5026 20.5772 21.1966 21.9236 21.1511 19.9516 22.0109 21.1340 21.1454 19.4960 20.6751 21.3579 20.7042 21.2922 21.3967 20.3193 20.6052 24.1270 20.8580 22.5859 21.9796 22.9779 20.0288 MCHC 36.1765 35.4545 35.3659 36.5217 34.7727 36.4444 36.5909 36.8889 34.8936 36.4706 37.8049 35.8537 35.1064 35.2174 36.4444 35.1220 34.1860 34.1860 35.9524 34.1860 33.7209 34.2857 35.0000 34.0476 36.1905 33.5714 34.5000 34.3182 35.7143 33.0952 WBC PMNAB 13.2 5.2 4.7 6.5 4.3 5.0 4.8 6.5 4.9 5.1 4.9 5.3 7.0 5.0 3.8 9.0 3.5 5.0 4.5 5.4 5.8 6.1 2.8 5.7 10.1 5.0 5.2 5.9 6.6 7.7 6.600 0.208 0.517 1.690 1.075 0.200 0.384 0.195 0.441 1.632 0.931 0.371 0.840 0.050 0.076 2.070 ' 0.735 1.050 0.945 1.404 1.392 1.281 0.504 1.596 4.949 1.550 1.404 1.711 1.716 2.464 lymab 5.544 4.836 3.854 4.680 2.967 4.650 4.128 6.305 4.410 3.060 3.675 4.664 5.950 4.900 3.610 6.030 2.590 3.700 3.150 3.726 3.944 4.453 2.072 3.363 4.141 3.000 3.328 3.717 4.422 4.389 MONOAB 1.056 0.156 0.188 0.130 0.129 0.150 0.144 0.065 0.049 0.408 0.294 0.265 0.210 0.050 0.114 0.720 0.140 0.200 0.405 0.270 0.406 0.305 0.196 0.342 0.808 0.300 0.468 0.354 0.396 0.693 E0SA8 0.000 0.000 0.141 0.000 0.129 0.000 0.144 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.180 0.035 0.050 0.000 0.000 0.058 0.061 0.028 0.399 0.202 0.150 0.000 0.118 0.066 0.154 Oi 00 i 001534 TABLE 13 DOSE 3 p p p 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 30 PPP 10 PPP 10 PPP 10 PPP 10 PPP 10 PPP 10 PPP 10 PPP 10 PPP 10 PPP 10 PPP 10 PPP 10 PPP 10 PPP |0 PPP 10 PPP <(n> AN1HAL B1MAB2A R1RA825 R1RA832 R1RA836 RIRAS39 R1RA8AA R|RA8a 5 RlHAtA PIRABA? R1RASA9 R1RA0SS R1RA61 R1RAB62 R1RAB63 RIRAbA S1RA872 S1MA873 S1RA876 S1RAB7B S1RA8B1 S1RA892 S1RAB93 S1RA903 S1RA90A S1RA907 S1RA909 S1HA910 S1RA915 S1RA916 S1RA919 ERYIH 6.87 7.A7 7.32 7.AA 7.65 7.03 7.09 5.95 7.95 7.68 7.AA 7.27 6.87 7.16 8.15 7.33 7.3A 7.86 7.93 7.62 7.60 7.38 7.71 8.59 8.03 7.7? 7.37 7.22 6.82 8.08 MC PO 13.8 1A.9 1A.3 1A 9 15.8 15.A 1A.3 11.7 17.0 1A.5 15.1 13.9 1A.3 15.1 15.5 1A.7 15.1 16.1 15.5 15.A 15.1 16.1 15.6 16.2 15.6 16.0 1A.8 15.1 lA .A 16.6 THO YtAP OH*L lOItTl T0*IC1TY-0NC06ENICITV STUY UF FL UOHOCAHHON FM-392A IN FEMALE PATS INDIVIDUAL HEMOKAM VALUES M O N T H 18 - MENAT MC V MCh MCHC MRC A3 62.S910 20.0873 32.0930 5.0 a5 6 0 2a 10 19.9A65 33.1111 5.6 A2 57.3770 19.5355 3A.0A76 5.A AA 59.1398 20.0269 33.8636 5.A A6 60.1307 20.6516 3A.3A78 3.1 A6 65.A339 21.9061 33.A 783 6.3 A2 59.23RA 20.1693 3A.0A76 5.3 35 58.8235 19.6639 33.A286 7.A A9 61.6352 21.3836 3A.6939 6.6 A7 61.1979 1H .8802 30.8511 5.9 A5 60.A839 20.2957 33.5556 7.0 Al 56.3961 19.1197 33.902A 1A.8 Al 59.6798 20.8151 3A.H780 5.A AA 61.A525 21.089a 3A.J182 A.A a6 5 b . a a 17 19.018A 33.6957 5.9 AA 60.0273 20.05A6 33.A091 7.6 A5 61.3079 20.5722 33.5556 7.0 AR 61.0687 20.AH35 33.5A17 3.7 A6 58.0076 19.5A60 33.6957 6.2 AA 5 7 . 7a ?H 20.2100 35.0000 6.0 A6 60.5263 19.H6RA 32.8261 10.6 A7 63.6856 21.8157 IA.2553 6.1 A7 60.9598 20.2335 33.1915 3.5 A9 57.0A31 1R.H591 33.0612 5.2 Ah 57.2H52 19.A271 33.9130 5.7 AR 61.7761 20.5920 33.3333 6.A AT 63.7720 20.0H1A 3 1 .A89A 3.3 AA 60 9a 1H 20.91A 1 3A.3182 7.2 A? 61.5836 2 1 . 1 1 AA 3A.28S7 7.1 A9 60 .6a 36 20.5AA6 33.8776 6.6 PMNAB 1.800 1.512 1.836 1.9AA 0.992 0.9AS 1.537 3.A0A 2.57A 1.AT5 2.380 10.212 1.296 1.232 1.888 1.368 2.730 O.7A0 1.2A0 1.260 3.286 1.830 0.560 1.66A 0.855 1.98 A 1.155 2.592 2.059 1.91A LVMA8 3.050 3.S8A 3.078 2.916 1.736 A.977 3.657 3.700 3.56A A . 130 A.200 3.A0A 3.780 2.728 3.717 5.700 3.150 2.553 A.6S0 A.260 6.360 3.90A 2.660 3.120 A.61? 3.776 1.980 3.672 3.976 A . 158 MOMOAB 0.100 0.336 0.378 0.32A 0.310 0.315 0.053 0.1A8 0.330 0.236 0.A20 0.592 0.270 0.26A 0.177 0.AS6 0.A20 0.370 0.186 0.2A0 0.95A 0.305 0.280 0.A16 0 11A 0.AA8 0.099 0.792 0.923 0.A62 EOSAB 0.050 0.168 0.108 0.216 0.062 0.063 0.053 0.1A8 0.132 0.059 0.000 0.592 0.05a 0.176 0.118 0.076 0.000 0.037 0.12A 0.2AQ 0.000 0.061 0.000 0.000 0.11A 0.192 0.066 0. 1AA 0.1A2 0.066 i '01555 TABLE 13 DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 P>M 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM ANIMAL N1R4583 N1R4586 N1R4591 N1RA59S N1R4S98 N1R4603 N1R4606 N1R4611 N1R4614 N1H4616 N1R4626 N1R4628 N1R4634 N1R4636 N1R4638 01R47S9 01H4764 01R4767 01R4769 01H4773 01R4778 Q1R4794 01R4796 01R4800 Q1R4803 01R4809 Q1R4811 01R4814 01R4817 01R4819 ERYTH 7.48 7.22 7.91 7.97 7.43 7.07 7.78 4.21 7.34 7.24 7.31 6.21 4.86 7.90 7.99 6.30 5.87 4.68 5.32 6.49 7.82 7.04 7.62 3.62 6.97 5.49 5.61 6.25 4.75 7.74 HEMO 15.3 14.3 15.7 15.9 16.4 14.9 15.9 10.3 16.0 15.2 14.5 13.4 11.7 16.1 16.8 12.7 11.7 10.3 11.3 12.* 15.4 14.5 13.9 8.9 13.7 10.4 11.9 11.2 10.4 15.1 TWO YEAH ORAL (OItT) TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FM-3924 IN FEMALE RATS INDIVIDUAL HEMOGRAM VALUES ---------- --- --- -- MONT H=2 A --------- ---- ----- HEMAT 42 42 45 46 47 44 46 29 44 43 42 38 32 47 47 39 35 30 33 38 47 45 43 25 42 32 35 38 30 46 MCV 56.1497 58.1717 56.8900 57.7164 63.2571 62.2348 59.1260 68.8836 59.9455 59.3923 57.4555 61.1916 65.8436 59.4937 58.8235 61.9048 59.6252 64.1026 62.0301 58.5516 60.1023 63.9205 56.4304 69.0b08 60.2582 58.2878 62.3886 60.8000 63.1579 59.4315 MCH 20.<545 19.8061 19.483 19.9498 22.0727 21.0750 20.4370 24.4656 21.7984 20.9945 19.8358 21.5781 24.0741 20.3797 21.0263 20.1587 19.9319 22.0085 21.2406 19.1063 19.6931 20.5966 18.2415 24.5856 19.6557 18.9435 21.2121 17.9200 21.8947 19.5090 MCHC 36.4286 34.0476 34.8889 34.5652 34.8936 33.8636 34.5652 35.5172 36.3636 35.3488 34.523 35.2632 36.5625 34.2553 35.7447 32.5641 33.4286 34.3333 34.2424 32.6316 32.7660 32.2222 32.3256 35.6000 32.6190 32.5000 34.0000 29.4737 34.6667 32.8261 WBC 18.7 4.1 4.9 4.6 6.2 4.2 4.7 9.2 5.1 4.5 5.4 8.6 12.2 5.0 3.5 7.7 5.6 5.8 14.9 6.2 4.3 4.9 4.9 12.8 6.1 7.9 5.7 6.3 9.4 6.3 PMNAB 12.529 1.148 0.735 2.714 2.232 1.092 1.081 3.496 1.989 2.115 2.592 3.870 5.246 1.650 0.630 2.541 0.784 2.146 11.622 1.488 0.989 2.058 1.470 4.352 2.135 1.343 2.907 1.575 1.410 1.575 LYMAB 5.984 2.952 4.018 1.702 3.844 3.066 3.525 5.428 3.060 2.340 2.646 4.386 6.222 3.250 2.695 4.774 4.704 3.364 2.980 4.526 3.225 2.646 3.332 7.680 3.782 6.241 2.565 4.032 7.708 4.662 MONOAB 0.187 0.000 0.000 0.092 0.062 0.000 0.094 0.184 0.051 0.000 0.108 0.086 0.610 0.100 0.140 0.308 0.112 0.174 0.298 0.062 0.000 0.147 0.049 0.384 0.000 0.237 0.171 0.504 0.282 0.063 EOSAB 0.000 0.000 0.147 0.138 0.062 0.042 0.000 0.092 0.000 0.045 0.054 0.258 0.122 0.000 0.035 0.077 0.000 0.116 0.000 0.124 0.086 0.049 0.049 0.384 0.183 0.079 0.057 0.189 0.000 0.000 o i TABLE 13 001556 DOSE 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM ANIMAL R1H4822 R1R4826 R1R4827 R1R4832 R1R4B34 R1R4836 R1R4839 R1R4644 R1R4B47 R1R4851 R1R48S4 R1R485B R1R4B59 R1R4864 R1R4869 S1R4872 S1R4873 S1R4876 S1R4881 S1R4882 S1R4884 S1R48B5 S1R4892 S1R4894 S1R4897 S1R4903 S1R4914 S1R4916 S1R4918 S1R4919 ERYTH 3.29 6.39 6.75 7.3B 6.05 7.07 7.33 6 . B0 8.10 1.52 6.40 6.87 6.95 8.11 7.09 6.53 7.11 6.96 7.7B 6.68 6.11 7.64 6.39 7.73 7.47 8.04 6.71 6.02 5.61 7.54 HEMO 8.1 13.5 13.4 13.9 12.7 14.6 15.0 15.2 18.5 5.6 13.0 14.6 14.9 15.0 13.7 13.2 14.7 14.6 15.1 14. A 13.3 16.1 13.0 17.0 15.7 16.3 14. B 13.2 12.7 16.1 TWO YEAR ORAL <DIET) TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FM-3924 IN FEMALE RATS INDIVIDUAL HEMOGRAM VALUES ---------- --- --- M 0 N T H = 2 * ----------------- ------ HEMAT MCV MCH MCHC NBC 26 79.0274 24.6201 31.1538 15.5 39 61.0329 21.1268 34.6154 7.2 40 59.2593 19.8519 33.5000 8.5 43 58.2656 18.8347 32.3256 6.9 38 62.8099 20.9917 33.4211 3.9 42 59.4059 20.6506 34.7619 5.8 . 45 61.3915 20.4638 33.3333 3.9 44 64.7059 22.3529 34.5455 12.3 53 65*4321 22.8395 34.9057 17.4 13 85.5263 36.8421 43.0769 28.4 40 62.5000 20.3125 32.5000 10.1 42 61*1354 21.2518 34.7619 4.2 43 61.8705 21.4388 34.6512 5.5 44 54.2540 18.4957 34.0909 7.8 40 56.4175 19.3230 34.2500 15.1 38 58.1930 20.2144 34.7368 5.4 43 60.4782 20.6751 34.1H60 3.9 42 60.3448 20.9770 34.7619 5.0 44 56.5553 19.4087 34.3182 4.9 41 61.3772 22.1557 36.0976 9.3 39 63.8298 21.7676 34.1026 12.1 45 58.9005 21.0733 35.7778 5.0 39 61.0329 20.3443 33.3333 14.1 45 58.2147 21.9922 37.7778 4.1 47 62.9183 21.0174 33.4043 7.4 47 58.4577 20.2736 34.6809 2.8 42 62.5931 22.0566 35.2381 7.6 38 63.1229 21.9269 34.7368 10.3 36 64.1711 22.6381 35.2778 5.9 44 58.3554 21.3528 36.5909 3.9 PMNAB 11.625 3.16b 1.445 1.863 1.482 1.856 0.897 8.364 15.486 19.028 5.454 2.520 2.860 2.964 9.060 1.080 0.897 1.200 0.833 4.650 6.897 1.100 2.820 0.779 2.146 0.280 2.280 3.296 1.062 0.624 LYMAB 3.100 3.816 6.885 4.830 2.379 3.712 2.808 3.567 1.392 7.384 4.040 1.554 2.475 4.446 5.738 4.158 2.808 3.650 3.969 4.464 4.719 3.750 10.575 3.321 4.884 2.520 5.016 6.386 4.779 3.237 MONOAB 0.620 0.144 0.170 0.069 0.039 0.116 0.156 0.369 0.522 1.988 0.505 0.084 0.110 0.234 0.302 0.108 0.156 0.150 0.098 0.093 0.484 0.100 0.564 0.000 0.074 0.000 0.304 0.309 0.059 0.039 EOSAB 0.155 0.072 0.000 0.138 0.000 0.116 0.039 0.000 0.000 0.000 0.101 0.042 0,055 0.156 0.000 0.054 0.039 0.050 0.000 0.093 0.000 0.050 0.141 0.000 0.296 0.000 0.000 0.515 0.000 0.000 ^EST COPY AVAILABLE TABLE 14 male T10 YEAH UHAL (OUT) TOXICITY'-UNCObEN 1CITY STUDY OF ELUOKUCAHBON FM-3924 IN NATS MEAN BLOOD C H E M IS T R Y VALUES o l u C o SE IMG/DL) HL000 UHtA NITHObE N (Mb/DU ALT (1U / L ) AST (10/L) N MEAN S.DtV. MEAN S.DEV. MtAN S.DEV. MEAN S.DEV. 001557 MONTH 3 0 PPM 100 PPM 30 P p m 10 PPM month 6 0 PPM 100 PPM 30 PPM 10 P p m MONTH J? 0 PPM 100 PPM 30 PPM 10 PPM MONTh 16 0 PPM 100 Pp m 30 PFM 10 PPM MONTH A 0 PPM 100 PPM 30 PPM 10 PPM IS 1 2 0 . 6 IS 1 2 V.S IS 126.A IS 1 2 0 . 1 13.74 11.70 14.17 9.26 16.3 lb.5* iV. 1 16.2 1.64 1.36 1.92 2.01 21.4 2 V .1A 27.1# 30.4# 2.67 5.47 5.92 9.66 45.3 52.2 51.2 57.9 7.26 9.96 16.33 21.90 IS 1 1 V . 0 13.2v IS 110.3 6 .2 v IS 135.1* 14.20 14 12v.3* 9.42 17.5 17.3 17.3 16. 1.36 2.0V 1.62 1.47 24.1 42.1# 30.7 32.0 3.75 25.44 12.30 11.68 49.7 74.7 53.3 59.5 14.98 31.24 21.65 27.46 14 1S4.3 14 137.5 15 140. V IS 1S7.3 26.17 17.07 17.VM 27.6V 16 .4 17.1 17.7 17.V 2 . SO 1.44 2.02 1.26 33.5 65.2* 39.6 43.9 19.45 31.20 12.52 23.37 79.1 63.2 71.1 76.7 44.61 29.06 13.49 31.21 IS 123.4 26.3V IS 131.1 19.61 IS 144.9 16.54 IS 146.1* 21.34 16.1 15.4 15.7* 17.3 3.38 1.S9 1.63 3.24 34.1 46.1 56.0* 45.8 10.68 25.40 23.51 13.33 99.1 63.1 75.6 63.4 66.14 17.39 3b.83 16.27 IS 122.5 IS 1 1 0 . 1 IS 122.3 IS 1? b .6 23.07 2 0 . V7 25.12 26.52 lb.5 IS. 6 IS.9 1b .4 3.1b 2.04 5.30 9.19 33.4 67.1# 31.2 30.2 6.10 42.10 14.62 7.83 64.9 95.8 * 67.9 74.3 25.76 35.86 31.99 30.21 * : P <= os. ini! t a i l e d d u n n e t t t o n r a w d a t a . : 0 <= os. Tm O TAILED Dl'NNtTT T ON HANKED DATA 1ST COPY AVAILAB MALE TwO y E a h Oh AL IU1E.T To a ICITy MEAN oLOOD CntMlSTHY VALUES (TblLl TOTAL ttlLlMUBlN (MO/OU ALBUMIN (OM/DLI N ME AN S.OE V MEAN s.utv month 3 0 PPM 100 PPM 30 PPM 10 PPM MONTH 6 0 PPM oe 100 PPM 30 PPM 10 PPM k tn c n MONTH 1? o o 0 PPM loo PMM 30 PPM 10 PPM HUNT 1* 0 PPM 100 PPM 3o P h m lu Pp m HUNT 0 PPM 100 PPM 30 PPM CO 10 Pp m IS 0 . 6 0.16 * .* 0.3* 15 0.9 0 . 2 2 *. 9 0.27 15 1 .0 0 .2 b 4 .b . 1 H 15 0.9 0 .2 * <*.3 0 . 2 0 15 0 . 6 0.19 4 .b 0 . 2 0 15 1 .2 * 0. *5 b.s* 0.19 15 0 . 6 0.16 *.7 0.39 1A 0.9 0 . 2 2 h *b 0 . 2 0 1A 0.7 0 . 2 0 3.7 0 .2 0 Is 0.7 0.23 * . 0 0.30 15 0.7 0 . 1 6 3.6 0 .2 * 15 0 . 6 0.17 3.7 0 . 2 0 15 0.9 0.35 3.2 0.36 15 0 .6 0 .1* 3.6* 0.31 15 O.sw 0 . 1 0 3*4 0 .1* 15 0.5* 0 . 1 2 3.* 0 .2 0 15 o.s 0.25 2 . 6 0.23 15 0 .* 0.09 3.3* 0.27 15 0.3 0 . 1 2 2.9 0.31 15 0 ,* 0 . 2 2 2.9 0.32 : P <= .05. TwO TAILED D u n n e TT T ON HAw DATA. : P <* .05 TwQ TAILED D u n n e t t T ON HANKED OAT A. TAULE 14 UNCUbENICITV STuUr OF FLUOHUCAk BUN FM-3924 IN KATS ALb, TPKOT. ALKPHOS. CPA, CA) aITH STANAHD DEVIATIONS TOTAL PKUTEIN UM/DLt ALKALINE phosphatase (10/L) CHEATINE PrtOSPHOMNASE 11U/L) CALCIUM CMO/DU MEAN S.OEV MEAN S.OEV MEAN S.OEV MEAN S.OEV b. 8 0.34 b. V 0 .2 b b .b 0 . 1 0 b.b 0.24 VI.1 2 b . 22 133.V* 44.6V 130.7* 40.24 138.b* 24.0b 100.7 7V.4 111.4 1OS.b 2b ,4b 29.87 9b.63 32.90 11.1 10.8 10.9 11.2 0.68 0.34 0.34 0.2S 7.0 0.36 97.1 40.41 89.9 41.32 7.3 0.23 1 2 1 .2 97.39 111.7 60.53 7.0 0.26 117.7 93.0b 52.1 20.56 b.9 0.24 1 1 2 .1 23.32 99.5 53.49 11.5 11.4 11.5 11.6 0.40 0.19 0 .2 a 0.23 b .b b.7 b.7 6.5* 0.27 0.25 0.27 0.27 105.6 133.1 1 2 1 .b 105.7 43.94 9 9 . la 99.46 25.62 79.7 56.2 59.3 112.6 47.61 15.39 18.79 134.42 10.5 1 0 .5 10.5 10.5. 0.30 0.25 0.24 0.23 7.1 O.bl 05.2 93.7b 7.1 0.40 206.2 396.6b 7.4 0.45 79.5 91.43 7.3 0.27 77.5 19.61 79.9 74.52 47.5 12.69 2 6 .84 12.45 42.1b 28.66 11.1 1 0 .1* 11.4 11.3 0.93 0.90 0.52 0.70 6 .V 0.44 70.1 25.53 1 1 1 .1 66.04 7.1 0.42 103.5* 96.16 101.9 52.19 b 6 0.40 62.7 91.63 75.0 23.35 b.7 0.62 89.1 40.13 84.9 23.56 10.9 11.1 10.9 11.1 0.43 0.31 0 .4 1 0.69 TABLE 14 TWO YE AW OW*L (DIET! TUX I C l T Y - O N C O G E N 1 0 1TY S T U D Y OK E L U O W O C A W H O M E M - 3 9 2 4 JN M A L E H A T S INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE animal GLU HUN 0 PPM A1R3518 112 17 0 PPM A1R3527 140 21 0 PPM A1R3532 13 17 0 PPM A1R3534 112 17 0 PPM A1R3537 129 15 0 PPM A1R3540 102 17 0 PPM A1R3542 111 14 0 PPM A1R354B 98 14 0 PPM A1R3552 141 16 0 PPM A1R3559 108 17 0 PpM A1R3562 130 16 0 PPM A 1R3564 125 18 0 PPM A 13505 129 17 0 PPM A 13507 114 15 0 PPM A 13509 120 14 100 PPM P1R3701 147 1 100 PPM 01R3703 112 17 100 PPM 01W3705 152 19 100 PPM O1W3706 130 18 100 PPM 0 1 R 3 7 1 1 11 19 100 PPM D 1 3 7 14 11 1 100 PPM 01R3719 145 17 100 PPM D1W3723 124 2 0 100 PPM D1R3724 134 19 100 PPM D1H3727 135 16 100 PPM 01R3734 120 20 100 PPM D1W3740 127 1 9 100 PPM D1B3748 135 17 100 PPM 01 3749 123 19 100 PPM D1R3754 123 21 ALT A S T 20 3 22 42 20 36 22 50 28 59 21 42 22 43 21 40 18 38 18 4 4 21 51 24 50 20 47 1 9 30 2 5 58 32 54 2 2 38 2 9 52 2 6 49 2 9 49 34 57 24 37 20 30 40 07 2 5 47 37 5 5 30 64 30 53 20 b7 32 58 THIL! 0 .6 0.5 0.9 0.8 0.8 0.5 0.7 0.5 0.5 0.5 0.4 0.8 0.9 0.6 0.7 0.9 0.6 0.9 0.7 1.3 1.1 0.9 1.0 1.2 0.7 0.6 0.9 0.8 1.2 0.8 ALH TPROT ALKPHOS 4.2 6 . 8 4.4 6 * 6 4.4 7.1 5.1 7.8 4.4 6 . 6 4.1 6.5 4.4 6.7 3.9 6.5 4.2 6 . 8 4.4 6 .6 4.1 6.5 5.1 6 *h 4.6 6 . 4.2 6.5 4.3 7.0 5.4 7.5 4.6 6.7 5.1 6.9 5.0 6.9 4.9 7.0 5.2 7.0 4.5 6.9 4.5 6.5 5.0 7.1 4.6 6 . 6 4.8 6 ft 5.1 6 . 8 4.6 6.9 4 . 6.9 5.0 6 . 6 107 106 58 105 100 no 60 125 71 52 73 125 128 69 108 177 59 132 158 114 62 185 76 160 170 186 123 184 113 109 CPK CA 115 11.5 104 11.3 69 1 1 .2 140 12.4 144 1 0 . 8 120 1 0 .8 60 1 0 . 8 80 1 1 . 2 74 1 1 . 1 109 1 1 . 6 85 9.3 72 1 2 . 0 113 1 1 .0 72 1 1 . 2 134 1 1 .0 179 11.3 65 1 0 .8 77 1 0 . 6 71 10.9 86 11.3 75 10.4 75 1 0 . 6 71 10.3 79 1 1 .1 59 1 1 .2 55 1 1 .0 57 10.3 81 10.9 98 1 0 .6 63 1 0 .8 GSSXoo -P* 09ST00 i tn TARI,E 14 TWO YEAR OHAL (DIET) T O X I C I TY -O NC OO ENIC ITY STUDY OF FLUUMOCAHRON FM-3V24 N MALE WATS INDIVIDUAL PLASMA CHEMISTRY VALUES -------------------MON TH =.T ---------------- ---- DOSE ANIMAL GLU HUN ALT AST TRILI ALH TPROT ALKPHOS CPK CA 30 PWM F1R3767 156 18 19 44 1 . 1 4.6 6.5 30 PPM E1H3770 109 18 35 98 1 . 6 4.8 6 . 8 30 PPM E1R3771 152 21 32 62 0 . 6 4.5 6.7 30 PPM E1R3773 120 22 23 36 0 . 8 4.3 6.5 30 PPM E1R3774 119 21 36 70 1 .1 4.7 6.9 30 PPM E1R3778 119 16 32 47 0 . 8 4.4 6.5 30 PPM E1R3780 141 21 30 52 1 .2 4.4 6.5 30 PPM E1R37R3 125 19 34 62 1 . 2 4.4 6.5 30 PPM E1R37B7 120 17 26 41 0.7 4.6 6.5 30 PPM E1R3790 142 20 20 39 0 . 8 4.6 7.0 30 PPM E1R3791 126 20 24 44 1 .1 4.3 6.5 30 PPM E1R3796 124 19 24 36 0 . 6 4.6 6.5 30 PPM F1R300 137 16 23 44 0 . 8 4.3 6 4 30 PPM E1R3801 110 21 24 50 1 .1 4.8 6 . 8 30 PPM F1H3806 126 16 22 43 0.9 4.8 6.7 10 PPM F1R3H11 111 20 24 40 0.9 4.7 6 . 8 10 PPM F1R3815 126 15 27 43 0 . 6 4.5 6.7 10 PPM FIR381B 125 20 25 47 1 . 1 4.2 6 . 8 10 PPM F1R3822 126 16 32 63 0.7 4.4 6.7 10 PPM F1R3824 133 16 25 50 0.7 4.3 6 . 6 10 PPM FIR3R31 130 16 32 62 0 . 8 4.6 7.0 10 PPM F1R3H32 120 18 33 58 0.9 4.3 6.4 10 PPM F 1H 3834 114 19 29 64 1 .2 4.6 6 . 8 10 PPM F1R3R36 112 17 63 128 0.7 4.1 6 . 6 10 PPM FIR3838 108 20 23 36 0.7 4.1 6 . 1 10 PPM F1H3839 128 2 ? 26 40 0.7 4.4 6.3 10 PPM F1R3R40 120 17 23 53 1.5 4.3 6 . 6 10 PPM F1R3844 121 20 30 58 0 . 6 4.5 6 . 6 10 PPM F1R3847 127 18 29 71 0.9 4.1 6.5 10 PPM F1R3852 100 15 33 56 0 . 8 4.1 6.3 107 75 1 0 .3 125 3*5 1 0 .A 168 93 1 0 .9 124 92 1 0 .7 117 137 1 1 .0 172 64 1 1 .1 160 67 1 1 .0 180 338 1 0 .7 123 56 1 0 .5 78 69 1 1 .2 170 59 1 1 .1 188 85 1 1 .3 92 64 1 0 .,4 99 69 1 1 .2 58 58 1 1 .2 151 129 1 1 .2 133 78 1 1 . I 105 86 1 1 .3 110 73 1 1 .0 138 63 1 1 .0 176 140 1 1 .7 169 106 1 1 .0 122 154 1 1 .2 183 13* 1 1 .S 13* 55 1 1 .3 107 73 1 1 .4 13* 108 1 0 .9 135 125 1 1 .4 128 153 1 0 .9 15* 105 1 0 .S i TABI,E 14 TWO YEAR ORAL (DIET) TO*ICt TY -ONCOGENICITY STUDY OF FLUOROCARRON FM-392A IN MALE MATS INDIVIDUAL PLASMA CHEMISTRY VALUES 001561 DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM animal A1R3519 A1R352A A1R3529 A1R533 A1R3S37 A1R3SA1 A1R35A7 A1R3550 A1R3553 A1R3557 A1M1559 A1R3S62 A1R3S67 A1R3573 A1R3575 01R3696 (11P3703 D1R3707 D1R3710 Ol37l6 D1R372R 01R3731 D1H3733 D1R373A D1R3736 D1R3730 D1R37A3 D1R37A6 D1R37SA 01R37S7 GUI 133 139 130 12A 109 12A 115 12 99 109 100 133 129 102 111 106 105 115 111 10A 103 10 HA no 113 10 li ili 103 126 UN 19 17 16 19 16 1 19 15 20 17 17 1 1 17 17 15 1A 19 16 1 16 1 1 19 22 17 17 1A 1 1 ALT AST 1 39 21 SA 20 25 20 Al 27 5 19 35 29 28 25 A3 29 S3 22 7A 21 51 2 55 23 A9 26 7A 25 67 22 37 A3 0 121 153 A9 7A 29 5A 31 58 3A 0 A3 100 37 1 76 126 27 A9 2 55 29 60 31 6 A 31 A9 THILT 0.6 O.H 0.6 O.H 1.1 0.7 1.1 0 . 0.7 1.1 0.9 0 .6 0 . 1.0 0.7 2.1 0.7 1.2 1.1 1.7 1.2 O.H 1.1 1.0 1.7 1.5 O.A 1.0 0.9 1.6 ALH A.3 A.A A.7 A. 8 A.9 4.S A.H A.7 A. 6 A.7 A.5 A.7 A. 6 5.0 A.A 5.1 5.A 5.3 5.5 5.7 5.3 5.A 5.0 5.3 5.2 5.A 5.6 5.A S .6 5.A TPROT 6 .A 7.3 6.7 7.5 7.0 7.2 7.5 7.0 7.1 7.3 6.7 6 .6 6 . 7.5 6.7 7.3 7.A 7.2 7.2 7.6 7.5 7.3 6.9 6.7 7.A 7.A 7.2 7.1 7.3 7.3 ALKPMOS 123 109 72 05 no 65 HA 213 62 120 50 69 69 11 78 121 62 171 100 133 1A5 106 1A9 176 121 172 57 HA 103 118 CPK 70 82 51 119 20A 58 62 b7 57 119 85 79 5 1*A 77 62 79 13A 1A3 HH 1A3 159 269 69 190 62 63 7 67 69 CA 1 0 .6 1 1 .6 1 1 .3 1 1 .7 1 1 .6 1 1 .3 1 2 .2 1 1 .6 1 1 .9 1 1 .6 1 1 .A 1 0 .9 1 1 .,A 1 1 .,7 1 1 .0 1 1 .,3 1 1 .5 1 1 .,A 1 1 .0 1 1 .5 1 1 .,5 1 1 .7 11 .3 11.1 1 1 .,5 1 1 .6 1 1 .,5 1 1 .2 1 1 .3 1 1 .3 TARLE 14 T W O YEAR ORAL < 0 IETI t o x i c i t y -o n c o g e n i c i t y STUDY OF FLUOROCARBON FM - 392* IN MALE HATS INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE ANIMAL OLII HUN ALT AST THIH ALH TPROT ALKPHOS CPK CA 30 PPH F1R3762 111 17 33 52 0 .6 4.9 6.9 30 PPM F 1R3763 116 19 *3 7* 0.5 4.7 7.3 30 PPM F1R3764 1*3 16 *2 6 * 0.5 4.7 7.2 30 PPM F1R3765 138 18 26 *9 0.5 *.* 6.7 30 PPM E1P3770 130 19 2* 53 0 . 8 4.8 6.7 30 PPM E1R3773 131 17 15 21 0 .6 4.0 30 PPM E1R377* 12* 20 *1 80 0.7 5.0 7.3 30 PPM f 1R3779 1*2 19 21 *3 0 . 6 4.6 6.7 30 PPM E1R3784 1*1 16 17 32 0 . 8 4.9 7.2 30 PPM E1R3792 116 15 59 102 0.5 4.4 7.0 30 PPM F1R379* 158 16 19 32 0.7 5.0 7.1 30 PPM EIR380* 158 16 27 33 0.H 4.1 6.5 30 PPM E1R3806 137 15 2* *7 1 . 0 5.3 7.1 30 PPM E1R3808 1*7 17 28 * 6 0 .* 4.1 6.9 30 PPM F1R3810 135 19 *2 72 0 . 6 5.0 7.1 10 PPM F1R3811 118 17 20 *5 1 .2 5.0 7.2 10 PPM F1R3B16 126 1* 23 39 O.H 4.8 7.2 10 PPM F1R3817 131 15 22 35 0.7 4.8 6.9 10 PPM F1R3B23 118 18 *0 52 0.7 4.3 6 . 8 10 PPM F1R3B26 1*6 15 30 59 0.9 4.5 6 . 8 10 PPM F1R3B27 122 18 23 *0 0.9 4.9 10 PPM F1R3831 1.33 17 33 49 0.9 4.9 7.2 10 PPM F1R3833 135 19 28 35 0.5 4.8 6.7 10 PPM F1R3834 125 17 *1 73 1 . 2 4.9 7.3 10 PPM F1H3837 13) 16 32 6 * 1 .0 5.0 6.9 10 PPM F1R3B39 132 19 60 85 0 . 8 4.8 6.7 10 PPM F1R3B46 133 17 23 * 9 1 . 2 4.7 7.1 10 PPM F1R3853 112 16 2* 39 0 . 8 4.6 6 . 8 10 PPM F1R3854 132 16 52 13* 0.9 4.9 7.1 10 PPM F1R3B55 1*5 18 29 95 0.5 4.6 6 * 6 118 47 11.3 183 40 11.9 118 39 1 1 . 6 118 49 1 1 .2 125 88 11.3 82 52 1 1 . 6 111 n o 1 2 .0 126 44 1 1 .1 131 43 11.7 175 35 1 1 .1 122 54 1 1 . 6 127 51 1 1 . 6 52 * 2 11.7 89 33 11.3 88 55 11.3 107 219 1 1 . 8 134 74 11.3 91 46 11.3 76 75 11.7 150 170 1 1 . 2 110 57 11.7 151 108 1 1 . 8 94 66 11.4 129 121 1 2 . 0 n o 58 1 1 .6 101 97 1 1 . 6 75 153 11.7 122 42 11.3 125 155 11.7 107 52 11.5 89ST00 i --J 00 TARI,E 14 TWO YEAH OH a L (DIET) TOXICITY-ONCOGENICITY STUDY OF FLUOH0CAHBON FM-3924 IN MALE ATS INDIVIDUAL PLASMA CHEMISTRY VALUES ---------. . . --- -- HONTHalZ ---------------- -- DOSE ANIMAL GLU RUN ALT AST TBILI ALB TPROT ALKPHOS CPK CA 0 PPM A1R3516 147 18 22 56 0.9 3.6 6.9 0 PPM A1R3517 150 16 16 40 0.5 3.8 7.1 0 PPM A1R3520 124 16 15 43 0.4 3.8 6 . 6 0 PPM A1R3522 134 15 65 123 0 . 6 3.7 6.7 0 PPM A1R3527 155 18 37 67 0 . 6 3.9 6 . 8 0 PPM A1R3535 141 17 23 56 0 . 6 3.8 6 . 8 0 PPM A1R3S43 183 17 33 85 1 . 0 3.9 7.0 0 PPM A1R3546 178 17 0 PPM A1R3550 185 18 37 1 1 0.9 4.0 6.9 32 79 1 . 0 3.9 6.9 0 PPM A1R3551 165 20 41 88 0 . 6 3.9 6.7 0 PPM A1R35S4 214 18 87 21 2 0 . 6 3.5 6.3 0 PPM A1R3S68 123 14 18 43 0.7 3.3 6 . 2 0 PPM A1R3S70 125 9 23 54 0.5 3.6 6.5 0 PPM A1R3S75 143 16 23 63 0.4 3.5 6.9 0 PPM A1R3580 148 17 31 59 0.7 3.9 7.1 100 PPM D1R3696 118 19 79 92 0.7 4.0 7.0 100 PPM 01R3699 125 19 6 6 78 0.7 4.0 6 . 8 100 PPM D1R3711 132 16 94 96 0 . 6 4.2 7.0 100 PPM D1R3714 130 16 62 95 0 . 6 4.5 7.0 100 PPM D1R3715 133 15 84 90 0 . 6 3.7 6.3 100 PPM D1R3720 118 18 32 53 0 . 8 4.5 7.0 100 PPM D1R3721 136 16 100 PPM 01R3722 145 17 40 74 0.7 3.7 6.7 34 52 0.7 3.5 64 100 PPM 01R3727 141 17 40 69 0 . 6 4.0 6 . 6 100 PPM 01R3732 115 16 31 50 0.9 3.8 6.3 100 PPM 01R3733 165 20 63 73 0.7 4.0 6.7 100 PPM D1R3736 165 18 43 60 1.5 4.0 6.7 100 PPM 01R3737 140 16 83 80 0 . 6 4.5 6 . 6 100 PPM 01R3747 132 17 147 155 0.7 3.9 6 .6 100 PPM 01R3748 168 16 80 131 0 . 6 3.9 7.0 139 72 1 1 .0 104 43 1 0 . 49 42 1 0 .5 108 61 1 0 .4 102 80 1 0 .8 113 103 1 0 .6 115 88 1 0 .7 107 234 1 0 .4 225 89 1 0 .5 95 65 1 0 .2 88 105 1 0 .3 48 50 1 0 .4 72 39 9. 8 70 58 1 0 .,4 152 66 1 0 .9 159 39 1 0 .7 16S 56 1 0 .5 1 1 75 1 0 .5 79 39 1 0 .5 129 46 1 0 .1 192 57 1 0 .5 91 67 1 0 .4 71 55 1 0 .4 144 52 1 0 .4 152 70 1 0 .5 158 79 1 1 .2 86 48 1 0 .2 150 37 1 0 .6 115 66 1 0 .7 192 87 1 0 .7 001563 i 'vl ix> TABLE 14 TWO YEAH OHAL DIET* TOXICITY-ONCOOENICITY STUDY OF FLUOMOCARHON FM-3H24 IN MALE HATS INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE animal GLU HUN ALT AST THILI ALH TPROT ALKPHOS CPK CA 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM 10 PPM F1R3769 E1R3775 F1R3776 E1R3779 F1R37B0 E1R3782 E1R3791 E1R379? E1R3797 E1R3800 E1R3802 ElR3ft03 E1R3805 E 1R3806 F1R3R08 F1P3R12 F1R3A13 F1R3814 F1R3815 F 1 R 3 8 1ft F1R3R20 F1R3A2B F1M3832 F1R3833 F1R3B35 F1R3R39 F1R3844 F1R3846 F1R3B4A F1R3860 137 135 118 133 125 123 176 123 141 152 152 147 124 172 156 152 134 163 157 222 141 216 131 154 160 139 135 133 161 172 24 16 15 17 IB 17 18 17 16 1 18 IB 19 17 17 1 ft 15 20 IB 17 1 19 17 1 20 18 19 17 17 1H 28 48 36 79 41 B 2 44 72 25 64 46 ftft 35 8 66 87 57 76 29 57 58 76 30 60 36 69 26 47 41 73 41 85 34 49 44 87 112 147 26 60 71 135 29 HH 55 67 26 47 26 6 ft 40 44 33 51 35 69 26 53 61 100 0.5 0.6 0.8 0.6 0.6 0.8 1.0 0.8 0.9 0.7 0.5 0.6 0.6 0.6 0.4 0.6 0.5 0.6 0.5 0.7 0.6 0.7 0.4 0.4 0.6 0.4 0.6 0.6 0.6 1.1 3 . ft 3.8 4.1 4.0 3.5 3.6 3.8 3.8 4.0 3.7 3.4 3.9 3*6 4.3 3.6 3.3 3.8 3.7 3.6 3.5 3 #fi 3.5 3.9 3.9 3.3 3.5 3.8 3.7 3.8 3.9 6*6 6.7 7.2 7.0 7.0 6.3 6.5 6.9 6 .8 6.5 6.3 6.4 6.4 6.7 6.7 6 .8 6.5 6*4 6 .2 6 .6 6.9 6 .0 6.4 6 .6 6.3 6.1 6.7 6.7 6.3 6.7 167 46 1 0 .9 68 5 1 0 .6 80 89 1 0 .ft 134 41 1 0 .7 144 46 1 0 .0 113 84 1 0 .2 174 57 1 0 .,3 181 55 1 0 .6 154 54 1 0 .8 76 10 2 1 0 .,* 120 59 1 0 .iA 136 67 1 0 .,5 109 35 1 0 .,4 54 47 1 0 .5 11* 50 1 0 .5 109 50 1 0 .>6 105 42 1 0 .5 140 54 1 0 .3 133 86 1 0 .3 64 2 0 0 1 0 .5 104 71 1 1 .>0 94 577 1 0 .1 151 75 1 0 .b 80 64 1 0 .,7 124 81 1 0 .,3 90 103 1 0 .,4 120 38 1 0 .7 68 59 1 0 .7 116 73 1 0 .7 87 116 1 0 .5 001564 i 00 O TABLE 14 TWO YEAH OWAL <OIET) TOXICITY-ONCOGENICITY STUDY OF FLUOWOCAKBON FM-3v?* IN MALE BATS INDIVIDUAL PLASMA CHEMISTRY VALUES --------- -------- MONTM= lH ----------- -- -- ---- DOSE ANIMAL RLU PUN ALT AST THIL! ALP TPROT ALKPHOS CPK CA 0 PPM A1R3519 1*1 19 *1 9* 0.7 3.2 6 . 0 0 PPM AIR3521 125 29 59 317 0.2 2.1 5.5 0 PPM A1R3528 UR 19 2 * 55 0 . 6 3.2 7.0 0 PPM A1H3531 1*3 1 * 2 98 l.o 3.* 7.* 0 PPM A1R3530 129 15 38 93 0.7 3.3 6 . 8 0 PPM A1P3S39 132 16 2 * 5* 0.9 3.7 8 . 1 0 PPM AlP35*2 107 18 30 61 1 . 1 3.* 7.2 0 PPM A1R3552 117 21 23 5* 1 .1 3.3 7.* 0 PPM A1R3553 127 17 ** 7* 0.9 3.* 7.5 0 PPM A1R3555 1*0 17 35 8 * 1 .1 3.3 7.3 0 PPM A1H3S61 135 17 26 61 0.9 3.* 7.6 0 PPM AIR3565 126 l* 23 62 0.9 3.3 6 . 6 0 PPM A1R3567 13* 17 0 PPM A1R357* 91 17 3* 133 0.9 3.2 7.7 2 * 79 0 . 2 2 . 6 6.7 0 PPM A1R3577 * 6 17 *5 168 1 . 6 3.* 7.3 100 PPM D1H3A97 120 1* 21 * 2 0 . 6 3.8 6.9 100 PPM D1R3700 115 15 91 78 0.5 3.5 6.9 100 PPM niH3707 1 2 R 16 101 85 0.5 3.9 7.1 100 PPM D1R3713 1*9 1* 50 63 0 . 6 3.5 7.3 100 PPM 01R3717 170 17 56 68 0 .* 3.8 7.5 100 PPM 01H3723 139 19 17 3* 0.5 3.5 6.7 100 PPM D1H372* 160 1* 22 71 0.5 3.0 6 . 1 100 PPM O1R3730 130 15 30 * 6 0.5 * . 0 7.0 100 PPM D1R3731 87 15 28 * 8 0.5 3.6 7.2 100 PPM D1R373B 118 18 38 86 0 . 8 3.7 7.2 100 PPM D1R3740 13* 16 *5 bH 0 . 6 * . 0 7.3 100 PPM DIR37A6 125 1* 30 61 0.5 3.5 6.9 100 PPM D1R37S1 130 1* 87 91 0.5 3.2 6.9 100 PPM 01H3755 12* 1* t>3 60 0 .* 3.1 6.9 100 PPM D1H3756 138 16 32 * 6 0.9 3.7 7.9 120 16* 57 56 113 82 *1 55 65 12* 90 87 66 82 68 6* 119 136 90 1*3 63 16** 101 9* 130 90 7* 1** 87 11* 37 1 0 . 6 79 10.5 39 11.9 3* 1 2 . 0 96 10.9 35 1 1 . 0 *9 11.5 *1 12.0 83 11.9 108 1 1 .1 59 1 0 .2 *1 9.0 77 10.9 87 1 0 .1 33* 1 2 .* 39 1 0 . 1 33 1 0 . 0 66 9.8 78 1 0 . 0 * 6 9.7 35 9.2 52 8.3 58 10.7 38 9.2 59 9.9 *3 10.5 39 1 0 . 6 *1 11.3 ** 1 0 . 0 *1 12.1 001565 I oo TABLE 14 TWO YEAR ORAL (DIET) TOXIC1TY- ONCOGENICITY STUDY OF FLUOROCAHHON FM-392* IN MALE MATS INDIVIDUAL PLASMA CHEnlSTKY values DOSE animal GL II PUN ALT AST THIL! ALH TPROT ALKPHOS CPK CA 30 PPM F1R3762 160 16 39 65 0 . 6 3.6 7.2 30 PPM E1R376* 180 15 66 11* 0 .6 3.6 8.0 30 PPM E1R3765 112 13 50 79 0.3 3.5 7.A 30 PPM E1R3767 197 17 52 57 0 .* 3.5 7.* 30 PPM E1R3769 1*9 15 *7 57 0.5 3.* A.O 30 PPM E1R3771 161 15 6 * 76 0.5 3.5 7.6 30 PPM E1R3773 1 * 2 20 29 3B 0 .* 3.1 7.1 30 PPM E1R3775 129 17 3* 3H 0 .* 3.3 7.5 30 PPM E1R3777 1*5 16 *7 *7 0 .* 3.* 8 . 1 30 PPM E1R37B2 125 1* 11 177 0.3 3.5 6 . 6 30 PPM E1R37R7 160 1 5* 66 0.3 3.5 6.9 30 PPM E1R3793 1* 15 5* 79 0.5 3.5 7.5 30 PPM E1P3796 1*0 1* 50 6 * 0.3 3.3 7.1 30 PPM F1R3A06 135 1* 39 * 2 0.5 3.6 7.5 30 PPM E 1R3B07 1** 17 97 135 0 .* 3.3 6.9 10 PPM F1R3B11 162 1* 50 62 0.5 3.5 7.* 10 PPM F1R3B13 1*6 16 66 79 0 .* 3.3 7.3 10 PPM F1R3A1* 169 19 3* 57 0.5 3.6 7.3 10 PPM F1R3A23 S3 20 33 37 0.5 2.9 7.3 ]0 PPM F1R3A25 1*0 16 3* 50 0.5 3.5 7.3 10 PPM F1R3A37 155 16 * 1 67 0 . 6 3.* 7.1 10 PPM F1R3A39 1*6 17 56 77 0.5 3.2 6.9 10 PPM F1R38A2 139 16 4b 7* 0.5 3.5 7.3 10 PPM F1R3A*S 150 1 31 50 0 .* 3.* 7.2 10 PPM F1R3A*8 160 16 36 *7 0.7 3.6 7.8 10 PPM F1R351 1*7 16 36 52 0 . 6 3.3 7.6 10 PPM F1R3852 130 16 35 55 0 . 6 3.5 7.1 10 PPM F1R38S3 177 19 65 91 0.3 3.5 7.8 10 PPM F1R3A55 1*7 16 56 92 0.3 3.1 6.9 10 PPM F1R3A59 1*1 16 68 61 0.3 3.2 7.3 93 68 1 1 .* A5 37 1 1 . 0 9 28 1 1 .0 76 33 11.3 9* 15 12.9 9H 2 * 1 1 . 6 51 26 1 1 . 0 52 26 1 1 . 6 106 27 1 1 . 6 3* 29 11.5 93 16 1 0 . 6 57 20 11.3 139 30 1 1 . 0 *1 21 1 1 .6 125 32 1 1 . 2 82 26 10.7 79 61 11.3 107 31 1 1 . 8 33 19 11.3 72 32 11.5 81 21 12.3 75 30 1 2 . 6 65 32 1 1 . 6 *9 123 11.5 7* 2 * 1 0 . 0 A3 23 1 0 .0 A7 35 1 1 .1 115 55 1 1 .1 75 86 11*3 85 3* 11.3 99ST00 i 0r0o TABLE 14 TWO YEAH OHAL IOIET) TOXICtTY-ONCOOENICITY STUDY OF f l u o r o c a h r o n FM-3924 IN MALE MATS INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE animal 6 LU RUN ALT AST THILI ALR TPROT ALKPHOS CPK CA 0 PPM A 1 R 3 M 8 130 14 26 52 0 . 2 2 . 6 6 . 6 0 PPM A1R3524 138 23 29 42 0 . 6 2.7 7.1 0 PPM A1R3528 141 15 28 47 0 . 2 3.0 6 . 8 0 PPM A1R3531 109 14 36 60 0.3 3.1 7.1 0 PPM A1R3534 67 20 21 142 0.3 2.7 5.9 0 PPM A1H3538 147 12 38 69 0 . 2 2 . 8 6.4 0 PPM A1R3S42 96 15 35 50 0 . 6 3.0 7.0 0 PPM A1H3S48 12 2 15 32 48 0.4 2.9 7.0 0 PPM A1R3554 158 17 43 74 0 . 2 3.0 6 . 6 0 PPM A1R3557 117 16 42 66 0 . 6 3.0 7.3 0 PPM A1R3562 134 17 33 53 0 . 1 2.4 6 . 8 0 PPM A1R3564 116 19 27 50 0.5 2.5 6.9 0 PPM A1R3569 143 22 29 74 1 . 0 2.7 7.4 0 PPM A1R3573 105 14 29 50 0.7 3.1 7.7 0 PPM A1R3S78 115 15 53 97 0.4 2 . 6 7.3 100 PPM 01R3700 109 18 58 72 0.3 3.2 6.9 100 PPM 01R3702 123 18 117 110 0.4 3.1 6.9 100 PPM D1R3706 123 14 123 119 0.5 3.3 7.6 100 PPM O1R3709 107 14 40 56 0.3 3.2 6 . 6 100 PPM D1R3713 112 13 39 67 0.3 3.1 7.2 100 PPM D1R3718 112 16 41 57 0.3 3.7 7.5 100 PPM D1R3725 132 17 42 70 0.3 3.5 7.2 100 PPM 01R3730 132 18 48 97 0.4 3.5 7.6 100 PPM D1R3739 84 13 6 2 154 0.5 3.4 7.1 100 PPM D1R3741 116 17 70 133 0.4 3.3 7.9 100 PPM D1R3746 119 15 41 70 0.5 3.3 7.1 100 PPM 01R3752 50 19 50 107 0*3 3.7 6.9 100 PPM 01R3755 94 14 41 79 0 . 2 2 . 6 7.5 100 PPM D1R3758 120 17 185 172 0.4 3.4 6.9 100 PPM D1R3760 119 14 49 74 0.3 3.1 6.3 118 87 1 0 .5 74 51 1 1 .5 39 63 1 0 .8 55 72 1 1 .0 61 190 1 1 . 1 6 6 69 1 0 .5 37 54 1 1 .6 97 108 1 0 .9 29 73 1 1 .0 109 90 1 1 .2 68 76 1 0 .1 77 187 1 0 .5 58 299 1 0 .3 86 101 1 1 .3 77 146 1 0 .9 108 99 1 0 .7 140 55 1 0 .8 169 58 1 1 .5 82 117 1 1 .,0 77 105 1 1 .2 109 86 1 1 .1 94 63 1 0 .9 70 2 1 2 1 1 .A 51 8 8 1 1 .3 161 215 1 1 . 1 62 54 1 1 .5 76 111 1 0 .6 113 136 1 0 .6 160 48 1 0 .8 81 81 1 1 .3 001567 i 00 CO TABLE 14 TWO YtAH OHAL <UItT> TOAICITY-ONCOOENICITV STUDY OF FLUOHOCAHRON FM-392A IN MALE HATS INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE animal GUI PUN ALT AST TRIL! ALA TPROT ALKPHOS CPK CA 30 PPM E1R3761 103 15 22 55 0.2 2 .A 6.1 30 PPM E1R3763 1A0 19 31 59 O.A 2 . 6 6.9 30 PPM E1R3767 135 16 33 66 0.5 2.9 6.5 30 PPM E1R3769 116 13 27 68 O.A 3.0 6.9 30 PPM E1R3773 139 32 23 A3 0 . 6 2 . 8 6.3 30 PPM F1R3776 93 11 20 52 O.A 2 . 6 7.0 30 PPM E1R3779 112 18 21 55 0 . 2 3.1 6.3 30 PPM E1R3781 7A 16 29 7A O.A 2.9 7.A 30 PPM E1R3786 158 17 25 59 0.3 3.3 6 . 8 30 PPM F1R3788 13? 15 2A 56 0 . 2 2.7 6 .1 30 PPM E1R3791 160 15 26 57 0.3 3.3 6.5 30 PPM E1R379A 109 15 21 AA 0 . 2 3.0 6.3 30 PPM E1R3799 133 1A 37 59 0*3 2.9 6.7 30 PPM E1R3B03 91 7 57 173 O.A 3.6 7.1 30 PPM E1R3807 1A 0 16 72 99 0 . 2 2.9 6 . 2 10 PPM FIR3811 1A6 13 22 Al O.A 3.0 6 . 6 10 PPM F1R3815 86 A8 25 163 0.6 2.3 5.3 10 PPM F1R3817 138 10 20 61 0 . 2 2 . 8 5.9 10 PPM F1R3822 135 17 35 80 0.3 3.1 7.5 10 PPM F1R3R26 173 13 36 57 0.3 3.1 6 * 6 10 PPM F1R3829 86 13 38 107 0.6 3.5 6.9 10 PPM F 1R 38 32 113 1* 10 PPM F1R3A37 1A6 16 10 PPM F1R3BA1 128 17 A9 33 20 81 0 .) 3.1 6 . 6 55 0.5 2.9 6 .A 6A 0.2 2 .A 6 .2 10 PPM F1R3RAS 119 18 2A 5A 0 . 2 2 . 8 6.7 10 PPM F1R3RA8 130 15 27 57 O.A 2.9 6.7 10 PPM F1R3851 162 15 28 56 0.5 2.9 6.7 10 PPM F 1R3853 129 1A 33 76 0 . 2 3.0 7.A 10 PPM F1R3R56 69 7 3A 98 1 .0 3.5 7.8 10 PPM F1R385B 139 16 29 65 0.3 2 . 6 . 8 58 71 1 0 .7 10A 7A 1 1 .2 88 9A 1 1 .A 89 100 1 1 .A 71 53 1 1 .3 5A 77 1 0 .A 81 A 6 1 1 .0 57 109 1 0 .5 103 65 1 0 .8 58 96 9. 9 10A 51 1 0 .7 91 55 1 1 . 1 15A Al 1 0 .A 20 113 1 1 .2 109 80 1 0 .9 83 85 1 0 .8 175 91 9. 9 A7 81 1 0 .5 88 57 1 0 .9 108 85 1 1 .3 63 122 1 1 . 1 12A 9A 1 0 .9 75 A7 1 1 .6 1AO 83 1 0 .5 50 112 1 2 .1 79 125 1 1 .3 92 85 11.3 126 A6 1 0 .9 20 89 1 2 .8 66 72 1 1 .0 001568 i 00 -P* TABLE 15 Itall y E AH KAL lOltT TU a ICITY-u n Cu O E M C U Y SlUOY OF FLUUHOCAKbQN Fm -3924 IN HAT S MEAN BLOOD CHEM ISTR Y VALUES OLUCUSE IM6 /DLI BLOOD UHtA NITHOOtN (Mo/UL) ALT (I u / L ) AST (IU/L) FEMALE N Ht AN S.DLV MtAN 5.DEV. MEAN S.DEV. MEAN S.DEV* m ONTh 3 0 PPM 100 PPM 30 PPM 10 PPM MONTn b 0 PPM 100 PPM 30 Pr M 10 PPM m ONTh 12 0 PPM 100 PPM 30 PPM 10 PPM MONTH 10 0 PPM 100 PPM 30 PPM 10 PPM MONTH 24 0 PPM 100 PPM 30 PP m 10 PPM IS 136.9 5.7* IS 125.1 0 .0 / 1* 130.3 1 1 . 0 15 13o.l 1 0 . u 19.7 2 2 .Vo 24.1 22.0 1.02 4.10 S.lo 2.33 2 2 .6 2 0 .b 19.9 20.5 4.67 3.29 4.27 6.10 40.0 43.0 43.0 47.5 9.20 5.92 7.04 10.64 IS 1S'*.8 14.96 IS 127.1* 13.45 15 151.0 1 0 . * 0 IS 130.1 9.52 2 1 .6 23.5 20.9 21.0 3.22 2.59 2.09 2.31 23.5 24.1* 26.9 22.7 17.20 2.25 6.62 14.40 69.7 72.7 52.6 6b. 1 30.56 11.50 13.99 34.8 2 15 134.9 15 127.9 14 120.9 15 13o.7 10.51 2 0 .2 H 11.02 0 .*/ 19.0 20.3 10.5 lb.9 2.14 1.95 2.20 2.70 24.1 61.2 92.0 26.6 15.17 74.60 9.41 15.73 66.1 87.9 61.7 64.5 36.77 113.65 14.67 21.13 IS 123.5 IS 127.5 15 120.7 15 133.1 15.51 14.77 12.20 17.70 16.1 20.3 16.6 1 6 .1 2.49 2.34 2.07 3.23 40.7 60.5 41.9 23.9 11.60 25.24 11.63 7.45 70.1 76.3 66.2 56.7 2'.0 39.00 16.01 11.13 15 1 2 2 . 2 IS 1 1 2 . 2 IS 113.1 15 124.0 13.75 O.o7 10.57 14.45 17.9 16.3 21.9 16.0 4.10 3.27 19.13 4.b0 40.0 60.5 Jo. 1* 25.7 10.11 0.72 31.20 0.29 67.0 64.0 194.9 61.1 30.03 24.34 400.95 21.09 : P <= .05. T0 1AJLLD D u Nn ETT T UN HA DATA. * : P <= .05. TwU TAILED DUNNETT T ON HANKED DATA. f tMALE MONTH 3 0 PPM 100 PPM 3u PPM 10 PPM MUNTn b 0 PPM 100 PPM 30 PPM 10 Pp m MUNTH 12 0 PPM 100 PPM 30 PPM 10 PPM MUNTH ip 0 PPM loo PPM 30 PPM 10 PPM MUNTH 24 0 PPM 100 PPM 3o PPM 10 PPM TW YEAH UHAL (DIET) t o x i c i t y MEAN BLOOD C h EMISTPY VALUES ITo IL1 TOTAL BILI Hub]N (H G / L ) ALBUMIN (UM/Ul ) N MEAN S.DEV m e a n S.EV 15 0 . 6 0.18 S. 3 0.45 IS o.s 0 . 1 1 S.4 0.30 14 O.b 0 . 1 1 S. 3 0.33 IS 0.7 o . 2v S.2 0.44 IS O.b 0.1 4 S.V U.6 S IS O.S 0.1S 6 . 0 0.28 IS 0.S o.oo 5.7 0.41 IS 0 . 6 0 . 2 2 S.7 0.51 IS 0 . 8 0.38 4.3 0 .2 b IS O.S# 0.17 4.5 0.38 14 o.s# 0 . 1 0 0.13 IS 0 . 6 0 . 2 1 4.2 0.25 IS O.b 0 .2 b 3. V 0.23 IS O.S 0 . 1 1 4.* 0.37 IS O.S 0 . 2 0 3.B 0 . 2 2 IS O.S* 0 . 1 1 3.7 0.13 IS 0 ,o 0.31 3.* 0 .2 1 IS 0.3 0.1 4 3.S 0.34 IS 0 .*. 0.13 3.2 0.43 is O.o 0.71 J.4 0 .2 V 001S69 : H <= .05 T0 t a i l e d D u n n e TT T N HA UATA. : H <s 0 b * T0 t a i l e d D u n n e TT T O n PANNED DATA. TABLE 15 UNCbtNlClY SlUDY OF FLUHUCAHBON FM-3924 IN HATS AL6 . TPHOI. ALKHHOSt CMK * CAI bITM STANOa HD DEVlATlUNb TOTAL FKTEI N IG M / U ALKALINE MHOSHHATASE (1U/LI Ch Ea TINE Fh OSHHOk JNASE IIU/L) CALCIUM (MO/OL) HLAN S.Otv MEAN S.OEV HEAN S.OEO MEAN S.OEV 7.2 0 A 1 7.2 0.25 7.1 0.33 7.1 0.47 3.7 2.4 1.0 7. 3 32.29 29.97 27.97 5.00 93.9 65.3 125.3 96.2 51.44 25.29 101.23 4o*b7 11.0 10.7 11.4 11.7* 0.55 0.50 0.49 0.45 7.4 0 b4 7.3 0.30 7.2 0.35 7.1 0.47 77.6 61.1 95.1 69.0 30.56 24.2b 25.07 32.51 56.5 70.9 51.5 54.3 14.79 32.34 13.62 10.3 11.7 11.3* 11.4 11.7 0.53 0.31 0.32 0.39 7.3 0.52 7.3 0.4b 7.3 0.29 7.2 0.35 76.5 96.3 91.3 72.6 30.01 37.34 36.61 23.66 54.6 2 0 .0 2 105.9 112.41 47.3 15.09 37.3# 7.59 11.2 10.9 10.9 10.9 0.60 0.35 0.22 0.26 7.9 0.57 6 . 2 0 6 1 6.3 0.67 7.6 0.46 65.5 32.10 67.1 20.46 37.1* 11.3 41.9* 17.4 37.3 9.61 26.3# 15.85 31.1# 17.81 36.7* 34.72 11.4 12.0 10.9* 11.0 0.53 0.41 1.00 0.50 7.6 0.69 7.6 0.46 7.3 0.69 7.5 0.93 68.7 33.39 97.9 40.93 6.3 116.63 56.7 26.4 7 66.4 32.23 55.7 19.04 125.5 66.91 101.1 42.27 11.5 11.3 11.0 11.6 0.64 0.57 0.61 0.9b 001570 i 0CT0> TABLE 15 TWO YEAR ORAL <01ET) TOXIC1TY-ONCOOF.NICITY STUDY o f FLUOROCARBON FM-3R2A IN FEMALE RATS INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE animal GLU FIUN ALT AST THIL1 ALH TPROT ALKPHOS CPK CA 0 PPM N1R4576 143 22 20 47 n p p m N1R4578 150 22 1A 49 0.5 4.B ftoft 0 . 8 5.1 7.0 0 PPM N1R4582 129 20 17 55 0 . 8 5.9 7.8 0 PPM N1R45B3 147 1A 19 41 0.5 4.9 7.1 0 PPM N1R45A4 129 19 29 6 ft 0.5 4.8 7.1 0 PPM N1R4592 134 17 25 62 0 .6 5.2 7.0 0 PPM N1R4610 143 21 32 57 0.7 5.9 7.8 0 PPM N1R4612 147 20 19 39 0.5 4.8 6 . 6 0 PPM N1R4613 129 19 19 41 0.5 4.9 7.0 0 PPM N1R4619 139 1A 22 51 1.0 5.3 6.9 0 PPM N1R4A21 131 19 23 49 0.5 4.9 7.1 0 PPM N1R4626 163 20 28 *8 0.4 5.3 7.1 0 PPM N1R4627 133 1A 16 43 0.5 5.7 7.0 0 PPM N1R4633 134 22 25 32 0 .8 5.9 8 .0 0 PPM N1R4640 133 21 27 40 0.9 5.9 7.6 100 PPM 100 PPM 01R4757 Q1R4764 130 1ft 122 22 20 24 32 42 0.4 5.5 7.4 0.4 5.8 7.4 100 PPM 01R4766 107 20 20 45 0.5 5.0 6.9 100 PPM 01R4772 120 19 20 43 0 . 6 5.3 7.0 100 PPM 01R473 11A 25 25 47 0.4 5.2 7.0 100 PPM 01R4785 128 23 18 38 0 5 5.3 7.1 100 PPM 01R4790 130 16 22 44 0.5 5.5 7.4 100 PPM 01R4791 131 20 18 51 0.5 5.5 7.4 100 PPM 01R4792 143 30 17 4 4 0 .6 5.6 7.4 100 PPM Q1R4793 131 28 29 55 0 . 6 5.2 7.4 100 PPM 01R4A08 1 IB 25 22 46 0.7 5.3 6.9 100 PPM Q1R4A12 135 23 19 42 0 . 6 5.3 7.1 100 PPM 01R4A14 1 2 ? 21 18 35 0.5 5.1 6.9 100 PPM 01R4A16 126 26 19 50 . 0.7 6 . 2 7.9 100 PPM Q1R4A19 11 IS 26 18 43 0.7 5.4 6.9 120 71 1 0 .I 61 95 1 0 .T 152 150 1 1 .T 61 58 1 0 .6 95 234 1 1 .2 128 168 1 1 .3 6 8 60 1 2 .2 89 58 1 0 .8 61 50 1 0 .6 65 94 1 1 .2 67 80 1 0 .7 120 58 1 0 .6 40 66 1 0 .9 70 90 1 1 .4 58 76 1 1 .7 103 64 1 0 .1 49 125 1 0 .1 100 6 6 1 0 .5 n o 6 6 1 0 .9 135 78 1 0 .8 76 79 1 0 .7 98 71 1 0 .8 9 9 91 1 1 .0 73 128 1 1 .2 138 133 1 1 .4 48 75 9. 7 52 103 1 1 .1 91 56 1 0 .7 79 64 1 1 .3 135 81 1 0 .1 001571 i 0'04 TABLE 15 TWO YEAH ORAL DIET) TOXICITY-ONCOGENIC lTV STUDY OF FLUOROCARBON FM-3924 IN FEMALE HATS INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE ANtMAL GLU HUN ALT AST THIL1 ALB TPHOT ALKPHOS CPK CA 30 PPM R1R4A22 IIP 34 15 36 30 PPM R1R4A23 1AF> 30 24 68 30 PPM R1R4R30 13fc 20 19 36 30 PPM R1RAR33 129 17 22 39 30 PPM R1R4836 146 31 18 36 30 PPM R1RAR37 132 20 21 42 30 PPM R 1R4842 130 28 13 62 30 PPM R1RAAAS 123 27 23 52 30 PPM R1RAR50 157 23 31 43 30 PPM R1R4853 13A 23 18 38 30 PPM R1RARSA 133 2 2 18 38 30 PPM R1RAR56 131 16 22 51 30 PPM R1R4860 139 22 17 40 30 PPM R1R4864 129 22 18 45 30 PPM R1RAA65 159 26 19 39 10 PPM S1R4871 163 18 17 43 10 PPM S1R4875 135 22 15 32 10 PPM S1R4R79 140 21 16 42 10 PPM S1R48A0 125 21 18 46 10 PPM S1RARH1 130 19 37 82 10 PPM 51R48A4 136 25 17 41 10 PPM S1R4RA5 13ft 27 16 36 10 PPM S1RAAR6 153 24 19 2 10 PPM S1R48R9 133 21 24 45 10 PPM S1RAR96 130 21 31 76 10 PPM S1RAP97 134 22 19 51 10 PPM S1R4901 139 22 18 46 10 PPM S1R4902 126 24 22 67 10 PPM S1RA905 130 23 20 61 10 PPM S1R4915 129 20 19 63 0.5 5.3 6.9 O.H 5.6 7.3 0 . 6 5.7 7.3 0.7 5.0 6 . 6 0 . 6 4.7 6 * 6 0 . 6 5.4 7.0 0 . 6 5.2 7.1 0.7 5.8 7.5 0 . 6 5.1 7.1 0 . 6 5.0 7.1 0.4 5.2 7.3 0.5 5.1 6.9 0.4 6 . 1 6.7 0.7 5.2 6.9 0.7 5.9 7.8 0.5 6 . 6 7.4 0.4 5.1 6 . 6 0.4 5.3 7.1 0 . 6 5.9 7.9 0.5 5.3 7.3 0.5 5.0 7.2 0.5 5.2 7.1 1.2 6.2 8.0 0.7 5.2 7.2 0 . 8 5.5 7.5 0.7 4.9 7.0 0 . 6 5.2 7.0 1.4 4.7 6.7 0.9 4.7 6 * 6 0.7 4.6 6.3 97 67 1 0 .A 79 92 1 0 .5 91 60 1 1 .A 46 92 1 1 .5 59 111 1 1 .5 76 461 1 1 .9 135 142 1 0 .9 121 164 1 1 .a 116 75 1 1 .2 78 106 1 1 .6 67 117 1 1 .2 125 6 8 1 1 .a 112 72 1 1 .o 54 196 1 2 .l 109 56 1 1 .5 85 46 1 1 .,7 88 32 1 1 .5 69 48 1 1 .a 54 79 1 2 .o 68 148 1 1 .A 96 115 1 2 .2 88 49 1 1 .,7 56 78 1 2 .6 86 76 1 1 .6 96 128 1 1 .6 59 174 1 1 .0 69 81 1 1 .2 74 119 1 2 .0 91 179 1 1 .8 96 121 1 0 .9 i TABLE 15 001572 TWO YEAR OHAl IOIET) TOXICJTY-ONCObENIOITY STUDY OF FLUOROCARHON FM-392A IN FEMALE RATS INDIVIDUAL PLASMA CHEMISTRY VALUES ---------- ------ -- M 0 N T H = 6 -------- --- --------- DOSE animal ALU HUN ALT AST THILI ALH TPROT ALKPHOS CPK CA 0 PPM 0 PPM n ppm 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM N1RAS82 N1RA5AA N1RASA6 N1PAS90 N1RA59B N1RA603 N1RA607 N1RA616 N1RA619 N1RA621 N1RA622 N1RA629 N1RA631 N1RA632 N1RA639 01RA759 Q1RA760 01RA76A 01RA771 Q1RA773 01RA77A 01RA776 01RA7A5 (11RA786 01RA79A 01RA798 01RAA03 OIRAAOA 01RAA12 Q1RAA1A 178 17? 159 183 1A 1 161 1A7 ISO 1AO ISA IbO 130 137 ISA 1S6 121 122 167 12A 118 116 129 119 120 123 121 1A6 119 13S 126 21 22 23 22 20 22 23 18 18 20 1A 20 22 2A 31 2S 23 22 21 2A 20 29 ?A 25 23 26 21 27 20 23 21 5S 88 26 20 32 35 25 26 26 3A 33 25 27 30 26 25 26 23 25 20 21 2A 23 25 22 28 27 22 2A 3 7 0.9 7.2 7.7 118 0 . 6 5.8 8.9 183 0.5 6.5 7.9 A8 0 .6 5.6 7.2 AH 0 . 6 5.8 7.2 71 O.A 6 . 1 7.5 96 0.5 5.5 7.0 56 O.A 5.2 6.9 57 0 . 6 6 . 0 7.2 a 7 0.7 6.9 8 . 1 79 0.5 5.6 7.2 58 O.A A.9 6.3 55 O.A 5.2 6.7 30 0.7 6 .A 8 . 0 62 0 . 6 6 .A 7.6 68 0.7 6 . 1 7.5 80 0 . 8 5.7 7.3 5A 0.3 6 . 1 7.A 6 A 0.5 5.9 7.3 70 0.5 6 . 6 7.7 7A O.A 5.7 6 . 8 78 0.3 6 . 1 7.2 92 O.A 5.8 7.2 73 O.A 5.6 6.9 59 0.5 5.8 6.9 85 0.5 5.9 7.3 60 O.A 6 .A 7.5 9A O.A 6 . 0 7.A 70 0.3 5.7 7.2 70 0.7 6 . 2 7.9 137 71 1 2 .9 125 55 1 1 .2 85 Al 1 2 .2 101 69 1 1 .8 51 33 1 1 .6 39 85 1 1 .6 61 A9 1 1 .A 55 52 1 1 .0 57 66 1 1 .8 51 73 1 2 .2 108 50 1 1 .0 98 55 1 1 .A 90 32 1 1 .3 50 59 1 2 .,3 59 57 1 1 .,8 10A 70 1 2 .0 99 77 1 1 .,5 AO 73 1 1 .3 91 55 1 1 .,7 106 65 1 1 .A 67 50 1 1 .0 52 59 1 0 .9 71 53 1 1 .A 85 67 1 1 . 1 98 35 1 1 .0 53 161 1 1 . 1 110 6 8 1 1 .5 9A A5 1 1 .2 A5 58 1 1 .3 1 0 2 127 1 1 .7 001573 i CO <~o TABLE 15 TWO YEAR OHAl (DIET) TUXICITY-ONCOQENICITY STUDY OF FLUOROCARBON FM-3924 IN FEMALE RATS INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE ANIMAL GLU BUN ALT AST THIL1 ALB TPHOT ALKPHOS CPK CA 30 PPM RIH4822 14? 23 25 52 0.7 6 . 2 7.6 30 PPM R1R4826 140 19 26 44 0.5 5.7 7.8 30 PPM R1R4829 141 19 24 49 0.5 6.5 7.4 30 PPM R1R4832 152 22 27 46 0.4 5.8 7.2 30 PPM R1R4835 152 20 23 40 0.4 5.1 6.7 30 PPM R1R4838 149 24 45 76 0.5 6 . 0 7.6 30 PPM R1R4850 180 23 29 71 0.7 5.7 7.2 30 PPM R1R48S3 154 2 2 23 42 0.5 5.2 7.0 30 PPM R1R4854 144 21 26 45 0.5 5.8 7.3 30 PPM R1R4856 145 17 37 78 0 . 6 5.6 7.4 30 PPM R1R4858 160 19 19 54 0 . 5 5.5 6 . 8 30 PPM RlR48b0 147 20 31 6 9 0.5 6 . 0 7.2 30 PPM R1R4867 145 23 24 45 0 . 6 5.0 7.2 30 PPM R1R4868 161 23 22 44 0.4 5.4 6.7 30 PPM R1R4870 165 19 22 34 0.5 5.4 6.7 10 PPM S1R4873 157 22 22 40 0.7 4.6 6.4 10 PPM S1R4876 132 22 24 53 0.5 5.7 7.3 10 PPM S1R4877 128 21 29 40 0 . 8 6 . 1 7.8 10 PPM S1R4878 129 24 3? 53 0 . 6 6 . 0 7.1 10 PPM S1R4881 134 20 33 67 0 .* 5.6 7.3 10 PPM S1R4887 151 21 33 71 1 . 2 5.6 7.0 10 PPM S1R4890 126 25 26 4H 0 . 6 5.4 7.0 10 PPM S1R48P1 155 23 79 181 1.0 6.3 8 .1 10 PPM S1R4898 139 19 44 87 0.5 6 .1 7.6 10 PPM S1R4901 136 2 0 33 72 0.7 5.9 7.0 10 PPM S1R4907 135 25 26 43 0 . 6 5.3 6 * 6 10 PPM S1R4912 136 24 24 47 0.5 6 . 6 7.6 10 PPM S1R4913 132 18 39 77 0.4 5.5 6 . 8 10 PPM S1R4915 141 19 19 53 0.5 5.4 6.7 10 PPM S1R4918 141 24 27 59 0 . 6 5.0 6.9 94 57 1 1 . 8 113 60 11.5 88 53 1 1 .6 115 35 11.4 133 44 1 0 . 8 97 37 11.5 117 81 1 1 . 2 76 57 11.3 70 53 1 1 .1 119 67 11.9 82 47 11.4 112 67 1 1 . 6 77 41 1 1 . 2 34 34 1 0 . 8 100 40 11.3 113 52 1 1 .1 73 41 11.3 111 47 1 2 . 1 43 50 11.4 64 46 11.7 85 65 11.7 123 44 1 2 . 2 110 76 1 2 .1 84 48 1 1 . 6 98 56 11.5 126 4 b 1 1 . 8 54 56 12.4 20 52 11.5 104 68 1 1 . 1 127 6 8 11.5 DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM animal N1R4578 N1R4582 N1R4585 N1R4588 N1R45B9 N1R4590 N1R460 1 N1R4608 N1R4610 N1R4620 N1R4629 N1R4630 N1R4631 N1R4632 N1R4640 01R4757 DIR4760 01R47M 01R4763 Q1R4775 01R4779 O1R47P0 Q1R47P2 Q1R4783 01R4785 01R4787 Q1R4788 01R4793 Q1R4806 Q1R4816 TAP.LE ] r) TWO YEAR ORAL (DIET) TOXICITY-ONCOOENICITY STUDY Of FLUOROCARMON FM-3924 IN FEMALE RATS INDIVIDUAL PLASMA CHEMISTRY VALUES ----------------- - h ONTH= 12 ----------- --- ---- GLU BUN ALT AST T8 ILI ALB TPROT 146 24 27 48 1 . 2 4.1 7.3 124 18 22 42 1.5 4.7 8 . 6 132 24 33 60 0 . 8 4.5 7.6 137 20 23 47 0.5 4.4 7.0 132 19 67 183 0.7 4.6 7.7 136 19 24 46 0 . 6 4.5 7.3 143 20 40 59 0 . 6 4.1 7.3 131 18 2 * 51 1 . 1 4.2 7.2 127 21 25 62 1 . 0 4.1 7.1 146 19 31 51 0 . 6 4.1 7.0 136 18 67 119 0.4 3.9 6.7 157 22 42 79 0.5 3.8 6 . 6 128 20 41 94 0.5 4.4 7.4 113 1 19 33 1.4 4.3 8 . 2 135 17 26 47 0 . 2 4.4 7.2 128 21 20 39 0 . 6 4.7 7.7 125 21 21 47 0.5 4.6 7.3 123 19 25 50 0.4 5.0 8 . 2 133 21 117 20 36 65 0.4 4.6 7.6 27 56 0.4 4.7 7.4 128 19 24 38 0.4 4.8 7.5 115 19 30 56 0.4 5.0 7.0 123 21 30 54 0.4 3.8 6.4 111 18 46 74 0.4 4.1 6.7 128 21 25 50 0.3 4.1 6 . 8 120 19 39 54 0.4 4.2 7.4 198 21 318 492 1 .0 4.6 7.3 129 18 64 124 0.7 4.3 7.3 121 26 37 66 0.4 4.2 7.5 119 21 26 51 0.5 5.0 7.8 alkphos 71 13* 8* 44 104 84 127 39 72 71 80 54 99 43 42 119 82 45 51 41 101 151 132 120 71 144 73 104 141 70 CPK 62 82 42 56 50 38 41 60 104 55 40 37 29 76 47 55 462 78 128 32 45 45 119 51 70 64 249 89 61 40 CA 11.7 12.5 11.5 10.8 11.7 11.3 10.8 11.1 10.7 10.9 10.9 10.5 10.8 12.4 11.1 11.0 10.9 11.2 10.6 11.0 11.1 10.8 10.2 10.4 10.5 10.9 10.9 11.2 11.2 11.6 001574 Ol> i i TADLE 15 TWO YEAR ORAL <OIET) TO *IC ITY-ONCOGENICITV STUOY Of ELUOROCARHON FM-3924 IN FEMALE HATS INDIVIDUAL PLASMA CHEMISTRY VALUES --------------------MONTH*]? ------ --- ---- -- --- DOSE animal GLU HUN ALT AST THILI ALH TPROT ALKPHOS CPK CA 30 PPM R1R4822 120 17 2H 46 0.4 4.5 6.9 30 PPM R1R4824 138 18 23 50 0.5 4.6 7.4 30 PPM R1R483B 112 19 54 68 0 . 6 4.5 7.7 30 PPM R1R4839 127 23 30 68 0.4 4.3 6.9 30 PPM R1R4840 135 18 38 70 0.5 4.5 7.6 30 PPM R1R48A2 132 20 46 87 0.5 4.5 7.2 30 PPM R1R4R48 113 20 3* 62 0.5 4.4 7.5 30 PPM R1R4R49 131 17 28 48 0.4 4.1 6.9 30 PPM R1R48S0 151 18 35 73 0 . 6 4.2 7.4 30 PPM R1R4RS? 124 20 26 55 0.7 4.3 7.5 30 PPM R1R4855 120 17 39 86 0.4 4.4 7.3 30 PPM R1R4R57 132 20 20 42 0.4 4.3 7.1 30 PPM R1R4R6? 131 19 33 74 0.4 4 . 4 7.4 30 PPM R 1R4868 122 13 22 47 0.3 4.4 7.5 30 PPM R1R4870 148 18 24 50 0.5 4.4 6 . 8 10 PPM S1H4874 139 17 62 86 0.7 4.1 7.0 10 PPM S1R4885 140 24 25 57 0.5 4.4 7.6 10 PPM S1R4RH6 114 21 24 43 0.9 4.0 7.1 10 PPM S1R4894 132 20 26 4H 1 . 2 4.5 7.8 10 PPM S1R4897 14 1 17 37 58 0.4 4.0 6.7 10 PPM S1R4899 137 21 31 48 0.5 4.3 7.2 10 PPM S1R4902 142 17 26 52 0 . 6 4.2 7.0 10 PPM S1R4903 121 20 78 125 0.4 4.5 7.6 10 PPM S1R4907 140 17 36 6 ? 0.5 4.1 6.7 10 PPM S1R4909 131 15 37 62 0 . 6 4.2 7.1 10 PPM S 1 R4 912 133 23 28 63 0.5 4.6 7.3 10 PPM S1R4916 145 16 50 78 0.5 4.3 7.0 10 PPM S1R4917 143 20 24 42 0.7 4.2 7.3 10 PPM S1R4918 138 19 42 77 0 . 6 4.4 7.3 10 PPM S1R4920 139 16 26 67 0.4 3.6 6 * 6 86 57 1 1 .2 60 36 1 1 .0 102 51 1 0 .8 104 46 1 0 .7 134 42 1 0 .8 145 63 1 0 .9 121 51 1 1 .i 49 24 1 0 .7 110 84 1 0 .9 88 42 1 0 .8 92 32 1 1 .2 91 41 1 0 .8 44 55 1 1 .0 13 29 1 0 .A 131 56 1 0 .6 83 36 1 0 .8 91 34 1 1 .2 59 35 1 1 . 1 78 32 1 1 .1 48 56 1 0 .3 63 32 1 0 .7 6 6 43 1 0 .7 76 42 1 1 .0 87 40 1 0 .6 47 33 1 1 .1 49 49 1 1 .1 102 38 1 0 .7 83 29 1 1 .0 123 29 1 1 .0 34 32 1 0 .6 001575 i TABLE 15 TWO YtAH OWAt COlfcT1 TOXIC ITY-ONCOUENICITY STUDY OK fLUOWOCARHON FM-3<^4 IN FEMALE RATS INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE ANIMAL GLU BUN ALT AST TBIL1 ALB TPHOT ALKPHOS CPK CA 0 PPM N1R4581 128 2 ? 37 50 0.3 3.3 6.4 0 PPM N1R4583 120 17 40 64 0 . 8 3.9 8.4 0 PPM N1R45P6 98 19 59 93 0.3 3.7 7.8 0 PPM N1P4S92 107 23 35 53 O.b 4.2 8.4 0 PPM N1R4595 116 18 71 132 0.4 4.0 8 . 6 0 PPM N1R4598 123 17 65 79 0 m b 4.0 7.8 0 PPM N1R4599 133 16 69 106 0.5 4.0 7.7 0 PPM N1R4602 103 21 43 58 0 . 8 4.0 8 . 2 0 PPM N1R4604 ISO 14 38 44 0.5 3.8 7.4 0 PPM N1R4606 126 18 SH 79 0.7 3.8 7.8 0 PPM N1R4609 110 15 48 65 1 .0 4.2 8 . 6 0 PPM N1H461 1 143 19 40 49 O.b 4.0 7.5 0 PPM N1B4612 138 18 42 49 1 . 2 3.8 7.9 0 PPM N1R4627 116 16 42 66 O.b 3.7 7.8 0 PPM N1R4638 141 18 64 65 0.9 4.0 ft3 100 PPM 01R4762 110 17 107 185 0.7 3.3 8.4 100 PPM Q1R4765 136 22 41 65 0.5 4.3 8 . 0 100 PPM Q1R4772 118 21 4b 73 0 . 6 4.4 8 . 2 100 PPM 01R4776 136 19 23 49 0.5 4.7 8.7 100 PPM 01R4778 163 15 35 57 0 . 6 4.2 8 . 1 100 PPM 01R4789 124 21 34 50 0 . 6 4.6 9.0 100 PPM 01R4794 139 21 28 48 0.5 4.4 8 . 1 100 PPM Q1R4801 139 21 58 80 0.5 4.1 7.6 100 PPM Q1R4803 138 20 4b 67 0.5 4.5 8 . 8 100 PPM Q1R4807 108 17 32 62 0.3 3.7 6.7 100 PPM Q1R4808 130 22 82 13b 0.5 4.3 8 . 8 100 PPM Q 1 R 4 8 1 1 116 20 8 50 0.4 4.1 8.3 100 PPM Q1R4813 123 23 89 112 0.3 4.0 7.9 100 PPM Q1R4814 110 23 28 4H 0*5 4.4 8 . 8 100 PPM 01R4817 123 22 50 b3 0.5 3.8 7.6 88 33 1 1 . 8 51 39 11.7 152 27 11.3 91 42 11.7 63 37 11.5 40 32 11.7 53 47 11.3 55 37 1 2 . 1 62 27 1 1 . 0 88 27 1 1 . 6 56 33 11.3 IT 36 1 1 . 2 60 66 1 0 . 0 27 41 1 2 . 2 79 35 1 1 . 0 65 5 1 2 .1 99 19 1 2 . 1 93 33 1 1 . 6 35 19 12.3 47 20 11.4 57 13 1 1 . 8 54 21 1 1 .8 6 6 31 11.5 63 29 1 2 . 6 72 18 1 2 . 6 54 73 1 2 . 2 38 22 11.9 87 25 11.4 80 45 12.5 96 22 1 2 .0 001576 VrOo I e C/I At "Si vo CO TABLE 15 TWO YtAR ORAL O U T ) TOX ICIT Y-ONCOGENICI TV STUDY OF FLUOROCARBON FM-3924 IN FEMALE RATS INDIVIDUAL PLASMA CHEMISTRY VALUES DOSE ANIMAL GLU BUN ALT AST t h i l i 30 PPM R1R4A24 132 23 42 42 0 . 8 30 PPM R1R4B25 112 21 45 72 0.5 30 PPM R1R4R32 14R 16 51 62 0.7 30 PPM R1R4A36 135 16 53 75 0.3 30 PPM R1R4R39 13A 20 30 PPM R1R4R44 120 16 27 44 55 0.4 b5 0.4 30 PPM R1R4R45 129 16 39 95 0.4 30 PPM R1R4R46 103 17 28 72 0.5 30 PPM R1R4A47 131 18 43 71 0 . 6 30 PPM R1R4A49 124 1H 29 47 0.3 30 PPM R1R4R55 119 15 3? 55 0.4 30 PPM R1R4861 132 20 44 57 0.5 30 PPM R1R4A62 125 1H 39 80 0.3 30 PPM R1R4R63 149 25 74 105 1 . 0 30 PPM R1R4R64 134 20 39 70 0.5 10 PPM S1R4R72 109 18 37 65 0.5 10 PPM S1R4R73 180 20 2 fl 56 0.4 10 PPM S1R4R76 148 20 29 47 0.5 10 PPM S1R4A78 132 15 26 48 0*5 10 PPM SIR4RA0 136 17 34 49 0.5 10 PPM S1R4R92 148 1 48 78 0*5 10 PPM S1P4RR3 120 11 33 74 0.4 10 PPM S1R4903 1?fl 21 40 61 0.7 10 PPM S1R4904 130 17 2H 55 0.5 10 PPM S1R4907 127 18 36 55 0 . 6 10 PPM S1R4909 120 12 27 59 0.4 10 PPM S1R4910 116 14 28 53 0.5 10 PPM S1R491S 117 16 50 81 0 . 6 10 PPM S1R4916 145 11 29 48 0 . 2 10 PPM S1R4919 143 14 36 51 0.5 ALH TPROT 3.9 8.4 3.9 9.1 3.9 9.1 3.7 8 . 0 3.7 7.5 4.0 8.7 4.1 8.3 3.9 8 .2 3.4 8 * 6 3.6 7.8 3.8 7.8 3.3 7.0 3.8 8 .1 3.9 9.6 3.7 7.9 3.7 7.9 3.6 7.7 3.8 7.6 3.8 7.8 3.8 8 .0 3.7 8 . 2 3.6 7.4 3.7 8 . 2 3.8 7.6 3.9 8 . 2 3.5 7.4 3.8 8 .1 3.7 8 . 8 3.4 6 . 8 3.7 7.4 ALKPHOS 21 33 30 21 60 44 52 31 50 26 41 34 34 50 30 47 60 54 25 28 66 26 39 74 62 25 18 34 33 37 CPK 6 32 85 32 26 22 36 26 48 22 26 15 23 36 31 24 26 21 36 22 35 20 30 27 29 161 32 27 30 30 CA 1 0 .0 11.i 1 0 .2 1 1 .A 1 0 .8 1 1 .6 1 1 .,9 1 1 .,7 1 0 .2 n. 3 u. 5 9. 0 u. 9 8 .8 1 1 .,4 1 1 ..4 11.1 1 0 .5 1 1 .2 1 1 .2 1 1 .3 1 1 .0 1 0 .6 1 1 .5 1 0 .9 1 1 .3 1 1 .4 9. 6 1 0 .9 1 1 .5 001578 i V-PO> TABLE 15 DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM ANIMAL N1H4SR3 N1R45B6 N1R4S91 N1R4595 N1R4598 N1R4603 N1R4606 N1R461 1 N1R4614 N1R4616 N1R4626 N1R4628 N1R4634 N1R4636 N1R4638 R1R4759 Q1R4764 Q1R4767 Q1R4769 Q1R4773 01R4778 (11R4794 01R4798 O1R4R00 01R4803 01R4809 01R481 1 Q1R4814 01R4817 (11R4819 TWO YEAR OHAL (DIET) TOXICITY-ONCOGENICITY STUOY OF FLUOROCARBON FM-3924 IN FEMALE RATS INDIVIDUAL PLASMA CHEMISTRY VALUES --------------- - m ONTH=2* ------------ ----- GLU HUN ALT AST THILI ALB TPROT 135 17 36 52 1 . 0 3.3 8 . 1 121 18 52 88 0.3 3.4 7.3 11" 20 32 58 1 . 2 3.5 7.8 123 17 6 6 158 0.5 3.6 8.5 140 16 37 52 0.4 3.4 7.2 138 26 34 56 0.4 3.4 7.2 120 17 36 52 0.7 3.3 7.9 148 21 42 81 0.5 3.2 6.5 115 17 37 42 0 . 6 3.7 7.6 118 16 42 73 0.4 3.3 7.5 112 10 27 52 0 . 2 3.7 8 . 6 107 15 36 4H 0.4 3.2 7.5 97 26 42 98 0 . 2 2.9 6 . 1 130 15 29 42 0 . 6 3.4 7.5 111 17 52 65 1.1 3.5 8.4 109 16 41 75 0 . 2 3.3 6 . 6 97 13 41 57 0 . 2 3.2 7.6 99 IS 30 52 0.3 3.6 7.8 120 14 30 44 0.3 3.2 7.3 121 18 52 79 0.4 3.5 7.4 128 12 3H 60 0 . 2 3.4 7.8 110 15 37 46 0.4 4.2 8 . 2 123 19 32 48 0 .2 3.6 7.3 102 20 52 84 0.3 3.8 8 . 1 1 14 16 40 55 0.3 4.0 8 .1 1 14 19 45 71 0 . 6 3.2 6 . 8 1 1" IS 33 39 0.3 3.6 7.6 111 24 35 42 0.5 3.3 7.9 110 17 41 73 0 . 2 2.9 8 . 1 107 12 60 135 0 . 6 3.2 7.4 ALKPHOS 49 149 127 53 38 35 78 70 76 46 39 39 87 61 84 94 117 71 42 83 68 73 80 188 82 97 52 112 148 161 CPK 76 45 109 57 34 59 119 50 36 80 52 75 35 58 141 3S 66 53 34 64 45 32 63 39 72 36 56 67 98 76 CA 1 2 .* 1 1 .2 1 2 .4 1 2 .0 1 1 .,5 1 1 .0 1 1 .,4 1 1 .3 1 1 .3 1 1 .0 11.I 1 1 .0 1 0 .,5 1 1 .,6 1 2 .e 1 0 .8 1 0 .2 1 1 .8 1 0 .8 1 0 .8 1 1 .0 1 1 .3 11.1 1 1 .8 1 1 .9 1 1 .2 1 1 .,9 1 1 .,4 1 1 . 1 2 .,4 TWO STUDY DOSF ANIMAL GLU BUN 30 PPM 1B4822 115 27 30 PPM R1B4B26 103 14 30 PPM H1R4B27 121 IB 30 PPM R1R4832 127 15 30 PPM R1R4834 138 16 30 PPM R1R4R36 119 IB 30 PPM R1R4B39 115 18 30 PPM R1FUR44 98 18 30 PPM R 1R*B47 105 15 30 PPM R|R4B51 57 90 30 PPM RlRR54 113 19 30 PPM P 1R*85H 127 17 30 PPM RiR*fl<>9 125 14 30 PPM R1R4864 117 15 30 PPM R1R4869 117 14 10 PPM S 1R4R72 112 19 10 PPM S1R4B73 136 2 0 10 PPM S1R*B76 128 17 10 PPM S1R4RB1 141 17 10 PPM S1RW882 139 21 10 PPM S1R4884 116 26 10 PPM S1R48R5 132 20 10 PPM S1R4892 141 16 10 PPM S1R4894 138 20 10 PPM S1R4897 110 9 10 PPM S1R4903 93 10 10 PPM S1R4914 126 16 10 PPM S1R4916 133 16 10 PPM S 1R 4 9 18 118 15 10 PPM S1R4919 109 10 001579 VO CJl TABLE 15 YEAR OHAL MIETI TOa ICITY-ONCOGENICITY 01 FLUOHOCARHON EM-3924 IN IEMALE RATS INDIVIDUAL PLASMA CHEMISTRY VALUES ALT AST THILI ALU TPROT ALKPHOS CPK CA 25 22 0 . 2 3.4 6.3 29 55 0.3 3.2 7.6 A2 66 0.4 3.4 7.8 3 64 0.5 3.5 8 . 2 22 49 0 . 6 3.3 7.3 33 62 0.4 3.0 6 . 0 25 55 0.4 3.6 7.9 31 70 0.3 3.4 8.4 25 120 0 . 6 2.5 6.7 1960 0.5 2 . 2 5.5 39 109 0.3 3.4 8.5 26 6 H 0.4 3.9 R.O 20 56 0 . 2 2.9 7.6 21 105 0.5 3.4 7.5 20 62 0.3 3.4 6.9 25 57 0.5 3.5 7.7 26 51 0 . 6 3.4 7.5 21 47 0.3 3.2 6.4 30 50 0 . 6 3*b 7.8 29 76 1.7 3.3 8 . 1 17 53 0 . 2 2 . 8 6 . 0 25 52 1.5 3.4 8 . 8 26 63 0.3 3.4 7.1 *0 60 2 . 8 3.8 9.4 1* 49 0.4 3.6 7.2 14 56 0.7 3.9 8.4 27 48 0 . 6 3.4 7.3 31 66 0.3 2.9 6 . 2 lri 132 0.3 3.3 7.1 42 57 0 . 6 3.6 7.4 39 85 42 59 63 26 88 64 81 511 78 71 4S 30 43 100 82 58 34 71 38 68 98 65 21 7 70 52 42 44 67 11.3 71 1 0 . 8 70 1 1 . 1 118 11.5 87 10.9 101 10.5 51 1 1 . 0 73 10.7 157 9.6 223 1 0 .6 159 1 1 . 2 195 11.9 68 10.8 382 1 0 .8 41 1 2 . 2 82 10.5 94 1 1 . 6 76 10.4 151 1 1 . 1 175 12.3 129 10.7 169 13.3 76 1 0 . 6 83 13.6 42 1 1 . 6 99 1 1 .8 101 1 1 .1 66 11.2 39 1 1 . 6 134 1 2 . 2 I Table 16 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats 0281CR0012 Urinalysis Values Dose Group Specific Gravity PH Albumin Bilirubin Glucose Occult Blood Ketone8 3 Mo. Male Control 100 PPM 30 PPM 10 PPM 1.025-1.062 1.033-1.060 1.012-1.058 1.027-1.056 7-9 6-7 6-7 7-8 N-Tr N-2+ N-1 + N-N N-N N-N N-N N-N N-N N-4+ N-N N-N N-2+ N-N N-N N-N N-N N-N N-1 + N-N 001580 3 Mo. Female Control 100 PPM 30 PPM 10 PPM 1.011-1.052 1.009-1.064 1.028-1.064 1.023-1.070 7-8 6-8 CO rC*1O* N-1 + N-Tr N-Tr N-1 + N-N N-N N-N N-N zz1 N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N 6 Mo. Male Control 100 PPM 30 PPM 10 PPM 1.021-1.066 1.028-1.068 1.030-1.058 1.030-1.064 6-8 6-8 6-8 CO N-3 + N-2+ N-4 + N-3+ N-N N-N N-N N-N N-N N-3+ N-N N-N N-3+ N-1 + N-N N-N N-1 + N-N N-N N-N 6 Mo. Female Control 100 PPM 30 PPM 10 PPM 1.028-1.072 1.016-1.053 1 .022-1 .046 1.020-1.058 6-7 6-8 6-8 c<r>> CVO01 N-3+ N-N N-Tr N-1 + N-N N-N N-N N-N N-N N-1 + N-1 + N-N N-N N-N N-N N-N N-N N-N N-N N-N Code: N - negative Tr - trace 1+ - slight 2+ - slight to moderate 3+ - moderate to marked 4+ - marked Table 16 (continued) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 In Rats 0281CR0012 Urinalysis Values zz1 001581 Dose Group Specific Gravity pH Albumin Bilirubin Glucose Occult Blood Ketones 12 Mo. Male Control 100 PPM 30 PPM 10 PPM 1.040-1.093 1.020-1.056 1.034-1.060 1.026-1.058 7.0-8.5 7.0-7.5 7.0-8.0 N-4+ N-2+ N-2+ N-2+ N-N N-N N-N N-N N-N N-3 + N-Tr N-N N-N N-Tr N-N N-Tr N-Tr N-N N-3 + N-Tr 01 CD o tz+1o 12 Mo. Female Control 100 PPM 30 PPM 10 PPM 1.023-1.070 1.017-1.062 1.020-1.044 1.015-1.071 6.5-7.5 6.5-8.0 7.0-8.5 6.5-8.0 N-3+ N-4+ N-4+ N-4+ N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-2+ N-N 18 Mo. Male Control 100 PPM 30 PPM 10 PPM 1.016-1.064 1.044-1.088 1.030-1.090 1.008-1.075 6.5-8.0 6.5-7.5 6.5-8.0 6.5-8.0 N-3+ N-4+ N-4+ N-4+ N-N N-N N-N N-N N-N N-N N-N N-Tr N-N N-N N-1 + N-N N-N N-2+ N-N 18 Mo. Female Control 1.016-1.058 7.0-7.5 N-3+ 100 PPM 1.017-1.056 6.5-8.5 N-1 + 30 PPM 1.018-1.058 6.0-8.0 N-4+ 10 PPM 1.016-1.056 6.0-8.0 N-3+ I-Xo) N-N N-N N-N N-N N-N N-N N-Tr N-Tr N-N N-N N-Tr N-N N-N N-N N-N Code: N - negative Tr - trace 1+ - slight 2+ - slight to moderate 3+ - moderate to marked 4+ - marked I Dose Group TABLE 16 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats 0281CR0012 Urinalysis Values Specific Gravity pH Albumin Bilirubin Glucose Occult Blood 24 Mo. Male Control 100 PPM 30 PPM 10 PPM 24 Mo. Female Control 100 PPM 30 PPM 10 PPM 1.018-1.054 1.017-1.071 1.007-1.096 1.019-1.080 1.012-1.034 1.011-1.033 1.008-1.034 1.010-1.037 6.5-8.5 6.0-8.0 6.0-7.5 6.0-8.5 7.0-8.5 6.5-8.0 5.0-8.0 6.5-8.0 N-4+ N-4+ N-4+ N-4+ N-2+ N-2+ N-4+ N-3+ N-N N-N N-Tr N-N N-N N-N N-N N-N N-N N-4+ N-N N-4+ N-N N-4+ N-N N-4+ N-N N-N N-N N-4+ N-N N-3+ N-N N-N Ketones N-N N-N N-N N-Tr N-N N-N N-N N-N Code: N - negative Tr - trace 1+ - slight 2+ - slight to moderate 3+ - moderate to marked 4+ - marked 001582 to 00 001583 i 3 ID TABLE 17 TWO YEA R ORAL (DIET) TOXICI T Y - O N C O G EN I C I T Y STUDY OF F L U O R O C A R B O N FM-3924 IN RATS ABSOLUTE AND RELATIVE MEAN ORGAN WEIGHTS ONE YEAR INTERIM ABSOLUTE ORGAN WEIGHT (GRAMS) 0 PPM 100 PPM MALE N = 15 N = IS ORGAN WT SD WT SD BODY LIVER HEART SPLEEN KIDNEYS AORENALS TESTES BRAIN PITUITARY 6 2 5 . 5 * - 65..905 1 9 . 1 5 * - 3..212 1 . 6 2 9 * - 0..157 0 . 8 9 4 * - 0.. 144 3.054*- 0 .507 .0679*- 0 .013 3.553*- 0 .419 2 . 1 1 3 * - 0..111 . 0 2 0 5 * - 0..006 5 5 5 . 3 + - 40. 6 1 9 2 6 . 1 1 * - 2..691 1 . 4 4 9 * - 0..1 3 0 0 . 7 3 4 * - 0..1 1 2 3 . 0 0 0 * - 0..295 .0532*- 0 .006 3 . 5 6 0 * - 0..409 2 . 0 4 9 + - 0.. 059 . 0 1 0 5 * - 0..00 2 FEMALE ORGAN BODY LIVER HEART SPLEEN KIDNEYS AORENALS UTERUS BRAIN PITUITARY N = 15 WT SD 4 0 1 . 1 * - 77. 172 1 2 . 2 0 * - 1..904 1. 1 1 7 * - 0..134 0 . 6 6 3 * - 0. 123 2 . 5 3 3 * - 0. 3 6 3 . 0 7 6 1 * - 0. 0 1 2 0 . 7 7 5 * - 0..247 1 . 9 6 3 + - 0. 120 . 0 2 2 7 + - 0. 0 0 6 N = 15 WT SD 3 3 5 . 7 + - 57. 7 2 1 1 7 . 7 2 + - 2..416 0 . 9 9 0 * - 0..1 13 0 . 5 3 5 + - 0..1 03 2 . 7 1 5 * - 0. 2 7 5 . 0 0 2 4 * - 0..006 0 . 0 6 1 * - 0. 165 1 . 9 5 4 + - 0. 0 9 3 . 0 2 1 5 + - 0. 0 0 7 : P < = .OS, TW O T A I L E D D U N N E T T T O N R A W DATA. : P <= .OS, T W O T A I L E D D U N N E T T T O N R A N K E D DATA. 001584 l oo TABLE 17 TWO YEA R OR A L (DIET) TO X I C I T Y - O N C O G EN I C I T Y STUDY OF F L U O R O C A R B O N FM-3924 IN RATS ABSOLUTE AND RELATIVE MEAN ORGAN WEIGHTS ONE YEAR INTERIM O R G A N W E I G H T / B O D Y W E I G H T (X) 0 PPM 100 PPM MALE N = 15 N = 15 ORGAN X SD X SD LIVER HEART SPLEEN KIDNEYS ADRENALS TESTES BRAIN PITUITARY 3.0 5 3 + - 0 .318 0 . 2 6 2 + - 0 .021 0 . 144+-0.025 0.617*-0.057 0.011+-0.002 0 . 5 7 0 * - 0 .057 0 . 3 4 0 * - 0 .026 0 . 0 0 3 + - 0 .001 4. 7 3 2 + - 0 .664 0.261+-0.022 0. 1 3 2 + - 0 .019 0.7 0 2 + - 0 .057 0.010+-0.001 0 .646+-0.084 0.371+-0.032 0.0 0 2 + - 0 .000 FEMALE ORGAN LIVER HEART SPLEEN KIDNEYS ADRENALS UTERUS BRAIN PITUITARY N = 15 X SO 3.090^-0.293 0 . 2 8 4 + - 0 .038 0 . 1 6 0 * - O .031 0 . 6 4 2 * - 0 .091 0.020f-0.005 0 . 2 0 1 + - 0 .077 0 . 5 0 7 + - 0 . 105 0.006^-0.002 N = 15 X SD S.343+-0.652 0 . 2 9 9 + - 0 .032 0 . 160+-0.026 O . 0 2 3 + - O . 107 0.0 2 5 + - 0 .006 0 . 2 6 5 + - 0 . 073 0.598^-0.100 0.0 0 6 + - 0 .002 : P < = .05. TWO T A I L E D D U N N E T T T O N R A W DATA. 1 : P <= .05. TW O T A I L E D D U N N E T T T O N R A N K E D DATA TABLE 17 0015 TWO YEAR ORAL (OIET) TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FM-3924 IN RATS ABSOLUTE AND RELATIVE MEAN ORGAN WEIGHTS ONE YEAR INTERIM ORGAN WEIGHT/BRAIN WEIGHT (RATIO ) 0 PPM 100 PPM MALE N = 15 N = 15 ORGAN LIVER HEART SPLEEN KIDNEYS ADRENALS TESTES PITUITARY RATIO SO 9 . 0 4 9 + - 1 .321 0.772 +- 0 .07 1 0. 424 +- 0 .070 1 . 8 2 1 + - 0 . 192 0.0 3 2+-0.006 1 . 6 7 8 * - 0 . 150 0 . 0 10+-0.003 RATIO so 12.75-*--- 1.452* 0.7 0 7+-0.067 * 0 . 3 5 9 + - 0 .056 1 . 8 9 9 + - 0 . 155 0.026+-0.004* 1.7 4 3 + - 0 .213 0.005 +- 0 .001 * FEMALE ORGAN LIVER HEART SPLEEN KIDNEYS ADRENALS UTERUS PITUITARY N = 15 RATIO so 6 . 2 7 3 + - 1 .001 0.571+ - 0 .073 0 . 3 3 7 + - 0 .056 1 . 2 9 4 + - 0 . 197 0.0 3 9 + - 0 .006 0 . 397+-0.130 0.012+-0.004 N = 15 RATIO SD 9 . 0 7 4 + - 1 .208* 0 . 5 0 7 + - 0 .055* 0.273 +- 0 .049* 1 . 3 0 9 + - O . 122 0.0 4 2 + - 0 .004 0.4 3 9 + - 0 .083 0 . 0 1 1+-0.004 * : P <= .05, TWO TAILED DUNNETT T ON RAW DATA. * : P < = .05, TWO TAILED DUNNETT T ON RANKED DATA I TABLE 17 TtfO t AH OHAl (DIET) TOXlCITY-ONCOUENICITY STUDY UF TLUOMOCAHHON FM-392* IN M|.t HATS ONE Yt AH 1 N U H I H INDIVIDUAL ORGAN HK IGNIS 98ST00 DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM ANIMAL AIR-3516 AIR-3517 AIR-3520 A 1P-352? AIR-3527 AIR-3535 AlR-35*3 A1R-3S*6 AIR-3550 AIR-3551 AIR-3550 A1R-356B AIR-3570 AIR-3575 AIR-3580 R1R-3696 R1R-3699 B1R-3711 R1R-371* RIP-3715 RIB-3720 R1R-3721 R1R-3722 RIB-3727 P1R-3732 P1R-3733 H1R-3736 RIB-3737 RlR-37*7 R1R-37AR BOOY 720 651 655 627 63* 5** 7*7 656 566 *9* 627 6 HR 575 551 598 566 521 5*1 515 625 530 515 508 610 *67 561 5*3 557 535 585 LIVER 23.88 21 .7* 20.87 16.18 18.71 18.12 2 *.96 17.61 15.19 13.96 19.53 22.31 16.55 19.88 19.77 29.3* 26.*3 27.51 30.80 21 .R9 23.88 23.2* 25.17 26.06 22.51 25.53 29.*8 30.27 26.38 23.18 HEAHT 1.786 1.565 1.719 1.675 1.517 1.65* 1.783 2.018 1.*76 1.361 1.536 1.629 1.526 1.636 1.556 1.516 1.318 1 .*31 l.*91 1.*98 1 .360 1.825 1 .*28 1.518 1.307 l.5*9 1.269 1.350 1.360 1.512 SPLFFN 1.079 0.87* 0.772 0.776 0.658 0.895 0.90* 0.905 0.70* 0.751 0.872 1.091 0.991 1.113 1.028 0.795 0.633 0.779 0.7*7 0.8*5 0.575 0.7*3 0.70* 0.715 0.615 0.502 0.815 0.781 0.872 0.893 MONEYS J.970 *.0*3 *.352 <..281 3.356 3.*7* *.365 J.9SR 3.656 2.657 3.5*8 <..679 3.525 3.781 *.170 3.*8* J.66* 3.856 3.996 3.95* 3.823 *. TR* * .3 |3 3.869 J.688 3.*69 3.603 3.9*7 3.872 *.39* adhenals- 9* 66 62 67 57 H7 59 77 *1 59 78 6* 6* 67 76 5? *8 *9 SI 61 50 52 56 51 50 51 7J *M 51 55 TESTES 3.727 *.1*7 3.967 3.79* 3.316 3.238 3.70* 3. *60 3.911 ?.SM| 3.331 3.8 To 3.503 2.9*4 3.805 3.367 3.3 75 3.609 3.720 3.1** 3.76? 3.450 3.415 4.661 3.402 3.0*5 3.98* 3. 780 3.727 3.076 HHA IN 2.3 30 2.111 2.2(1* 2 .22 T 2.086 1 .953 2.19* 2.0 79 2.150 1 .9<*0 2,0 7* 2.20? 2.11 1.971 2.071 2.09 2 2. 19* 1.'<1 2.060 2.026 1.9X9 2.083 2.022 ?. 0* 2.0*1 2.025 1.951 2.05* 2. M l 2.027 8 1TUT A Y-- ** 16 19 20 31 27 16 26 15 26 23 l'< 25 15 15 12 i / 10 10 H 13 1* 12 11 1 10 12 12 9 NOTES: BODY WEIGHTS AND ORGAN WEIGHTS ARE IN G. rOo - I N D I C A T E S A D R E N A L A N D P I T U I T A R Y W E I G H T S IN MG. i 001587 TABLE 17 T0 ytAO OHa L <!IE T TOKICITY-On COOFNICITY STu o y of f l u o h o Ca w h o n e m -3924 in f e m a l e h a t s ONE YtAR INTERIM INDIVIDUAL ORGAN WEIGHTS DOSE ANIMAL BODY LIVER HEART SPLEEN MONEYS ADRENALS^ UTERUS HMA IN P|TUTARY- 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM N1R-A576 N|R-A52 N1R-A5R5 N|R*A5 NIR>459 NiR-4840 N1R-4A01 N1R-46Q NIR-AMO n i r -a a ?o N1R-A6?9 N1R-A630 N1R-4631 MlR-4632 NlR-4640 OIR-47S7 01R-4760 01R-A76I 0lR-A7ftJ 01R-A77S 0 IR-4 770 01R-47AO 01R-A7A2 01R-A7B1 0|R-475 01P-4787 01R-A7RA 01R-A703 01R-4R06 0lR-416 540 305 353 306 378 373 470 429 345 320 401 466 240 5 11 395 377 305 326 294 36 315 259 3 72 251 400 401 279 433 277 3 7 15.34 12.26 12.90 11.99 13.19 10.52 13.39 13.00 11.31 11.45 11.33 13.03 7.37 14.70 11.69 19.34 17.93 16.93 10.2H 20.04 16.62 14.36 17.14 12.31 17.35 19.54 16.05 19.0 10.14 21.96 1.390 1.1 5 1.035 1.117 1.095 1.037 1.164 1.021 0.902 1.176 1 .004 1 .2 0 0 0 .0 1 0 1.12 1.230 1.140 0.969 0.991 0.992 1.13 0.997 0.753 0.926 0.H25 1 .001 1.039 0.960 1 .099 0.885 1.134 0.751 0.4|H 0.626 0.679 0.651 0.571 0.06 0.64 0.6! 0 7B9 0.663 0.725 0.414 0.723 0.731 0.623 0.408 0.507 0.562 0.482 0.467 0.2H1 0.888 0.462 0.656 0.672 0.609 0.64 0.477 0.572 3.279 2.40S 2.223 2.838 3.106 2.10 3.115 2.356 e.435 2.470 2.176 2.616 1.A44 2.620 2.512 3.013 3.036 2.561 2.70? 2.70 2 .6 8 2.227 2.610 2.139 2.612 2.930 2.6? 2. 43 2.704 3.0 7 HO n .696 2.044 2? 1 0.R70 1.674 27 56 0.674 1.912 18 A? 0.654 2.073 1 7 1.032 1 .963 25 7 0.H33 1.8/5 17 62 0.40 7 1.9 ? 25 5 0.963 2.124 18 7 1.371 1.9*9 30 9 0.H46 2. 135 16 65 0.523 1.96 7 19 HO 0.520 2.184 17 62 0.820 1 .3 8 3 20 59 0.H90 1 .8 * 6 4 II 92 0 . 33 1. 9 J ?6 76 0.700 1.580 20 5 0.907 2 .0 9 4 15 HA 0.964 1.975 ?1 91 1 .1 9 5 ?. 1 | H 16 7 0.672 1 .6 4 4 26 HH 1.125 1.971 20 6 0.R30 1.6 3 19 76 0.535 1.904 1l 97 0.7 35 1.323 14 7 0.73H 1,9?5 17 HA 1.0 7? 2.0*1 39 76 0.744 1 . 9 `<3 22 rs 0.338 1 .968 32 2 0.837 | .H I* 21 0 1 .030 1 .979 2i NOTES: BODY HEI GHTS AND ORGAN HEI GHTS ARE IN G. S - INDICATES ADRENAL AND PITUITARY HEIGHTS IN HG. TABLE 18 IT COPY AVAILABLE TWO YEAR ORAL DIET) TOXICI T Y - O N C O G E N I C I TY STUDY OF F L U O R O C A R B O N F M - 3 9 2 4 IN RATS ABSOLUTE ANO RELATIVE MEAN ORGAN WEIGHTS a b s o l u t e ORGAN WEIGHT (GRAMS) 0 PPM 100 PPM 30 PPM 10 P P M z II Jl male N x 15 N x 15 N x :IS OPOAN WT SO WT SO WT SO WT SO BODY LIVFM ME APT SPLEEN KIDNEYS ADRENALS TESTES BRAIN 666.7-99.76l 18.15*- 3.074 1,720*- $ .225 .217*- 0.339 t.*05- 0.7*5 .o r o l- o.oie 3.*78*- 0.701 2.10b- 0.133 S81.24-80.93b* 2 2 k 10*- 3*362* 1.0954- 0.212 0.T5A4- 0.182* 4.*034- 0.443 .08054- 0.018A 3.5*44. 0.530 2.075- 0.093 E,*fi.7*-8T.* 8 * 2 0 . 89-. 2 . 2 * 6 1k793- *.18b O.9A04- 0.126* .5194- 0.372 .1026- 0.0*0 3 * 0 1 - 0.616 2.141- 0.124 653.64-493.615 18.304* 2.811 1.794.4 0.2*2 1.0264 0.273 .3*94 0.38b .098644 0.033B 3.7124 0.590 2.1624* 0.101 G0ib88 FEMALE ORGAN BODY LIVFH HEART SPLEEN KIDNEYS adrenals UTERUS BRAIN N x 15 WT SU 512.5- 82.58b 15.11- 9.752 1.366- 0.199 0.797- 0.1*0 3.129- 0.287 .1030- 0.O46P 0.81*- 0.290 2.03*4- 0.102 N x 15 T SD 413.4- 83.150* 2 0 k 18- 5.013* 1.2*1- 0.195 0.731- 0.178 3.193- 0.404 .1085- 0.036 1.002- 0.328 1.997- 0.119 N x if WT SO 451.94-69,577 16.59- 9.170 1229*4 0.188 Ok7*74- 0.208 3.143- 0.337 .1193. 0.0*3 0.836*- 0.271 1*938- 0.179 N x 15 WT SO 504)9**128.23 17.02** 5.96* 1.375*4 0.282 0.776*4 0.228 3.093* 0.593B .1*33*4 0.052A 0.860*4 0.324B 1.965*4 0.13* 104. * : P x .05 . TWO TAItFD DUNNETT T ON RAW OATA. # J P <X 05 TWO TAILED DUNNETT T ON r a n k e d d a t a ; ( ! N i 13 ANfHLS. B : N x l* A N I M A L S . BEST COPY AVAILABLE BESTCOPYtv TABLE 18 TWO Y E A R ORAL (OIET) T O X l C m - O N C O O E N l C T T Y ST U D Y OF F L U O R O C A R B O N F M - 3 9 2 4 IN RATS ABSOLUTE AND RELATIVE MEAN ORGAN WEIGHTS o r g a n w e i g w t / b o d y W E I G H T <<*> 0 PPM 10* PPM 30 PPM 10 P P M MALE N = 15 N s 15 N = 15 N = 15 organ ft S O ft S O ft S D % SD LI VER HEART SPLEEN KIDNEYS ADRENALS TESTES BRAIN 2.733+-0.339 0.261 +-0 03 7 0 187 +-0 05V 0.6 6 6 + - 0 . 101 0.012+-0.003 0.53+-0*l44 0.322+-0.049 3.836+-0.595* 0.297+-0.058 0.130+-0.025* 0.T74+-0.166* 0.014+-0.003A 0.618+-0.114 0 . 9 6 4 + - 0 060 3i2l6+-0s344* O.2B0+-O.O42 0 + 1 5 4 +-*0it34 0.706+-0.095 0.016+-0.008 0*528+^0*092 0.339+-0.040 2 . 8 1 2 * ,40 . 3 0 1 0 . 2 7 8 +<*0.041 0.156 +M . 0 3 3 0 . 6 7 7 +.*0.104 0.015+^0.0048 0.579+W0.126 0.337+-0.051 001589 FEMALE organ liver HEART SPLEEN KIDNEYS ADRENALS UTFRUS r ra tn N = 15 ft S D 2.941+-0S465 0.269+-0*U36 0 . 158+-04033 0.62+ - 0 . 080 0.020+-0.008B 0.161+-0.059 0.408+-0.077 N * 15 ft S D 4.903+-0.959* 0.908+-0.070 0.478+-0.028 0.093+-0.152* 0.027+-0.010 0 . 2 5 3 + - 0 . 105* 0.499+-0.095* N * IS ft S D 3i679+0i523* 0+275+-0.041 0* 167 +- 0 . 0 4 7 0 + 7 0 6 + - 0 < 110 0*027+^0*011 0 + 18ft*-0 *064 0*437+-0*065 N s 15 ft S D 3.335*-<#.773 0.279*^0.047 0.154+^0.023 0 .6 2 1 + w o . 1118 0.030 +>*0.012A* 0.177+^0.0768 0.410+^0.094 : P <= .05, TWO TAI L ED D U NNETT T ON RAW DATA. con : P <= .05, TWO TA I L E D d u n n e t t T ON r a n k e d d a t a ; A : N a 13 ANIMALS. R : N * 14 ANIMALS. 001590 i cor> TABLE 18 ^AVAILABLE T W O Y E A H O H A L (DIET) TOX IC 1T Y - O N C U U E N I C I T Y S T U D Y OF F L U O R O C A H H O N F M - 3 9 ? 4 IN H A T S ABSOLUTt ANO RELATIVE Mt AN ORGAN WEIGHTS ORGAN w EIGHT/UHAIN WEIGHT (RATIO) 0 PPM IVO PPM 30 HRM 10 P P M hale N = lb N = IS N * 15 N a 15 ORGAN RATIO SO ratio so RATIO SO ratio sd LIVER heart SPLEEN kidneys adrenals TESTES 8 . 6 4 8 * - l .587 0.819.-0.103 0.570.-0.155 2.099.-0.377 0.038*-0.0lo 1.650.-O.33b 10.65.-1.52?* 0 * 8 1 8 0 105 Uk36<..-0.0?2* 2.127.-0.246 0k019.-0.0094 17l4.-0.2H4 9 . 6 8 6 . - 1 . 107 0.H41*-0.109 0.460.-0.076* 2 . 1 19.-0.242 0.0404-0.021 1.590*-0.283 8.470**1.253 0 . H 3 2 * * 0 . 122 0.47S.0.127 * 2.017.-0.218 0 . 0 4 6 . * 0 . 0 1 7H 1 .721**0.2R1 FEMALE ORGAN LIVER HEART spleen kidneys adrenals UTERUS N r 15 RATIO SO 7 . 4 5 6 . - 1 .918 0 . 6 T 3 * - 0 . 100 0.394 - O .078 1 .543*-fl.lbb 0.050.-0.022R 0 . 4 4 . - 0 . lbb N s 15 ratio so It.15*-?.755* 0 k b 2 3 . - 0 . 100 0.367.-0.091 U599.-0.172 0k054.-0.018 0k502.-0.lGl N IS RATIO SO 0.6514-2.060 0.635.-0.087 0386.-0107 1.637.-0.25? 0.063*-0.026 0 . 4 3 5 . - 0 . 145 P <s . 0 5 . T W O T A I L E D u u n n f t t T U N R A W D A T A . W P <= .05. TWO TAILED DUNNETT T UN RANKED OATA. A N = 13 ANIMALS. 8 N 3 14 ANIMALS. N s 15 RATIO SU 0.58?.*?.682 0.6994*0.125 0.3914-0.098 1.569.*0.2388 0.0734-0.024A* 0.4364*0.1548 i BEST COPY AVAILABLE 001591 TABLE 18 two YEAR ORAL n u n lOXlClTV-ONOUii-NICITv S T U D Y OF F L U O M O C A M H O N 7 M - 3924 i n MAL: N A T S TN<) Y A R INDIVinilAL O h (iA N m M i.h t s (G) hose 0 PPM o ppm n ppm 0 PPM 0 PPM 0 PPM n ppm 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM n ppm 0 PPM n ppm 100 p p m mo p p m m o PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM mo p p m mo p p m too p p m 100 PPM loo p p m ANIMAL A|R351H A1R3524 A1H3S2B A1P1S3I A1R3*33 A1R353* A1R1SA2 A1R354 A1H3SS4 A1M355T A1M3562 A 1R356 4 A1R3569 A1R3S73 A1R3ST8 *31 H 3 700 H1M1702 H1R3706 1R3709 1R3713 H1H3718 H1M3725 R1M1730 H1R3739 h 1P 3741 1R3746 P1H37S2 H1R37SS M|M 37S8 M 1R 3 78 0 MOOV 556 638 HI2 733 76S 788 733 706 *17 M2 S8H 576 696 7S9 521 643 663 624 576 625 624 544 619 369 568 660 437 587 602 592 LIVFR 15.12 23.45 19.67 17.5? 18.07 21.72 17.60 18.44 14.19 17.71 15.14 16.20 21.44 22.41 13.52 23.31 22.90 24.82 22.29 21 .25 29.97 26.08 20.84 18.57 20.?3 19.33 15.43 22.70 22.01 21.7 HK ART 1 .623 1.511 1.784 I .871 1.575 2.251 1.586 1 .667 1.547 1.786 1.616 1.679 2.172 1.625 1.538 1.921 1.437 1.701 1.820 1.998 1.645 2.037 1 .576 1.651 1.455 l.629 1.361 1.975 1.590 1.629 splfln 1.318 1.415 1.111 0.870 0.991 1.M9J 0. 728 1.146 1. 135 1.106 1. 754 1 . 396 1.586 0.90 7 0.900 0.829 1.180 0 .6 7 0.876 0.79O 0.625 0.927 0.729 0.500 0.789 0.548 0.481 0.63 7 0.731 0.792 K 1DN YS 3.913 4.805 4.924 3.842 4.128 4 . 5 35 4.233 4.670 3.467 4.718 3.98 3.7o5 6.41 5.011 3.641 4.280 4.415 4.985 *.561 5.084 4.307 5.094 4.356 0.754 4.32 7 4.026 3.555 4.350 3.800 4.149 AIIPF N AL 5 -- 60 57 87 76 1 no 90 54 73 88 70 61 93 1 no 113 77 62 69 132 `"--Db 67 78 9 ,-hD 76 75 76 78 7? 75 T M S 4.523 3 9 19 4.082 3.574 2.996 3. 7 78 1 .4 H 3.526 3.628 4.123 3.475 3.326 3.20 3 3.561 3.018 4.05 3 4.3011 3.309 4. | 99 3 . 5 in 3.018 4.448 3 7o 7 2.40 3.39 7 3.69H 1 5 14 2.727 3.284 3.096 P 9 A 1'1 2. m o 2.086 2.0 76 2.127 2.080 2.19 3 2.200 2. 329 1.990 2.282 2.061 2.223 2.086 1.861 1.850 2.199 2 . 0 36 2. 106 2.014 2.186 2.244 1.9S9 2.054 1 .919 2.104 2.036 2.128 2.162 1.983 2.08M _ i ADRENAL WEIGHTS ARE IN MG. o - ADRENAL WEIGHTS NOT TAKEN, ONE ADRENAL INVOLVED WITH A MASS. i BEST COPY AVAILABLE TABLE 18 S6GT00 T*<> Yf.ftp OH At. U H F T 1 TO* 11'.I T Y -ONCIH3. N |C I T Y STIJl'Y OF F L U O w G C A H H O N F M- 19?4 IN *ALF H A T S T *1) T E A M I N D I V I D U A L O M H A N W t l D H T S ( G ) OOSF animal HODY LIVE HFftRT SLFFN KlONf vs AOMF NAL s TF.STFS MAIN 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 P P M 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 10 PP M 10 PP M 10 PP M 10 PP M 10 P P M 10 P P M in P P M 10 P P M 10 PP M 10 PP M 10 P P M 10 P P M 10 P P M 10 P P M 10 P P M C1M3761 C 1 R 3763 C1R3767 C1R3769 C1R3773 C1R3776 C1H3779 C1M3781 C1M37H6 C1R3788 C1R3791 C1M379* C1R3799 C1M3H03 C1R3807 91R3811 D1RJ8I4 D1R3817 01R3?3 D1R38?6 01R3?9 01R3A3? D1R3837 ni3*i D1R1845 01R 384 01R3Sl OI B I A S 3 niMis6 OIMIASA 6?3 64? 786 7?A S48 ssi 634 S96 69A 601 71? AO 3 700 SOI 60A 7A3 607 68? 7SA 61? S78 7S7 696 S71 S6B 8?S 679 S?A 606 SS4 19.69 ?l.b* ? 1.0 3 ?4.0S ?0.?4 ? 1 37 19.?9 IA. 89 ?0.?6 19.07 ?3.J ?s .o j ? 0 .44 18.07 1 7 . OJ ?4.67 16.66 1H.O? 16.?A 16.HH 17.09 ?0. JO ? 1 . 18 16.17 18.09 ?1.1H ?1.1? IS.0 1 14.4? 17. J9 1.789 1.18 1.H7S 1.711 l .976 ?.0J? 1.666 1 .s/o |.6M0 1 .65 1.69J ?.?79 1.787 1.641 1.7SJ ?. 170 1.60? 1 7?0 1.34* 1.67 1 1.S/9 ? 0 70 1.784 ?.0l 3 1.706 ?.??n l.663 1.64* 1.9*3 1.7M1 0.68* 1.0 3* 0.968 1.0*6 1.?79 1.OSS 0.9*7 0.976 0.913 1 .0?S 1.003 n.A?6 1.00? 0.9S? 0.999 1 .s?i 0.9S7 0.A3S 1 ? 7 3 1.413 0.681 1.093 1 ? S R 1.034 0.809 1 ? 8 ? 0.916 0.860 0.S9S O.A70 4.463 4 . 4 1* *.907 4.6?? 4 . 6 17 S.?S0 4.390 4.176 4.408 3.978 4.S96 5.031 4.797 4.098 4.017 4.SIS 3.81* 3.93S 3.6S6 *.?A8 *.798 * .6H* * *50 *.6?3 *.09 S .0S6 *.**9 *.SS4 *.?0 1 *. 10* 7* 110 A* 88 79 ?10 1 7A 109 89 70 80 97 68 10 95 88 l?l 1?? 86 70 |08 8* 77 73 7* 1 9 8 --u 93 97 89 1.6S? ? 69(| 3*896 3*100 1.488 ?.5S0 3.78 1 3*390 4.396 3.988 ? 768 3.919 3.3? ?.?* 1 3 .A?8 3.489 3.739 3.38? 3.69? 4.8S4 3.* 3S 4 . 3?6 4.079 3.7 35 3.666 3.886 ? .46 1 3.637 ?.H7? 4.*?7 ? 080 3.098 3.044 ?. ISO 1.978 1.89 3. n o 3.13? 3 . IS? 3.11? 3.333 3.304 3.338 ?.l 18 ?.l 17 3. 30 3.34 3.096 3.176 3.0S 1 3.060 3.3? 3.111 ?.! 3. 1S9 3.037 3 ? 3 3.30 3 ? .008 ?. |9S _ i ADRENAL WEIGHTS ARE IN MG. o ADRENAL WEIGHTS NOT TAKEN, ONE ADRENAL INVOLVED WITH A MASS. TABLE 18 T W O Y h A W U K A L 4<IK T T O X I C I T Y s t i i d y f l u o m o c a m m o n m - 3 9 ? 4 i two ycam individual omuan 001593 oose animal ROOT . LIVhP Hh AMT SPLf.hN 0 PPM 0 PPM 1) P P M 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM (I P P M A PPM 0 PPM 0 PPM 0 PPM 0 PPM n ppm 100 PPM too PPM 100 PPM m o ppm 100 PPM 100 PPM 100 PPM ion p p m 100 PPM 100 PPM 100 PPM 100 PPM 100 PPM ion p p m ion p p m N|R4SA3 N|W4SRh NlfUSVl N1R4S9S N1P4S9R N|R4601 N1R4606 N 1P 4 6 11 N |R 4 6 14 N |U46?6 N1R4628 N]R4634 N1R4636 6)9463 01R47S9 0)94764 01R47N7 0 1P 4 7 6 9 01R4 773 01R477H 0 1 R4 7*74 0194796 0 |R 4 0 0 0 01R4AOJ 01R4AAV 0)94)| 0 l R 4 H 14 0|R4P|7 01R4R|9 404 400 S16 4S5 *71 4P1 so? 604 SI .1 7 3S1 S3S S6 7 S60 67S 47S 3?6 30? 3 7 3?3 4?? 423 *10 34 477 30R 4S7 441 Ml 2? IS.99 1 1 .6 14.21 1 1 08 13.*S 14.37 14.09 2 * . MR 1*.*0 11.77 10.?H 13.14 10.?3 10.S7 16. 2B 22.M 1 11.M3 16.?0 10.01 lO.Sl 16. HH 21 .60 17.31 IS.SO 23.60 30.21 21.01 23.03 27.SR 14.SR 1 .1 74 1 .21S 1.32? 1 .4 IS 1.SJM 1 ,*6S 1 .601 1 .S7 1.400 1 .2S4 0.049 1. 1H? 1 .S?3 1. |M0 1. M ? 1.104 0.002 0.026 1 .2SS 1 .233 1 .321 1.?1S 1.114 1 .21R 1 .?S6 1.170 1 .449 1 . I0H 1 .661 1 .463 1.032 0.9H 1 0.740 II. 740 0.9 1 0.6S7 0.7S7 0.721 0.69 7 .717 0.6) 0.930 0.66S 0.913 0. 79H 0.794 0.606 0.6S9 0.6S 0.639 1.064 O.SHH 0.670 0.672 0.690 0.776 0 .ROO 0.701 1.176 0.S69 ADRENAL HEIGHTS ARE IN MG. - ADRENAL HEIGHT NOT TAKEN, ONE ADRENAL GREATLY ENLARGED. BEST COPY AVAILABLE -ONOWNICITV IN M- M A Lf Mar; wt.I<>Hls(G) KIMNt VS *I)MFN*LS- 1.388 2.H2* 3.M l 2.78H 3 *88 3 ? 1H 3.37* 3.31H 1.3S6 3 . III? 2.*8* 3.082 2.H78 3.281 3.390 3.1 JS 2 fth7 3. O N ? 3.31* 3.HM* 3.S73 3. a OS 2.809 2.8*7 3. * 0 8 2.78S 3.889 3.389 3.*9| 2.8 82 98 83 8* |OH .b H* 11* ?S3 91 12? 7H 79 1OH HS 7S 189 90 88 H8 1 38 193 H* 88 12* 82 113 IIS 118 93 9* (IlNUS 0.8*1 1 .08S 0*88* 0.729 1.M S 0.72S 1.S91 0.S88 0.S7O 0.80 3 0. IS* 0.8|? 0.7 38 0.7*8 0 . 8 38 1.097 0.7 OH 0.700 0.972 1.700 0.798 1. 18S 0.SI9 1.137 0.7 MS 1.283 1 S8S 0.789 0.88S 0.928 (39 *|N 2.03S 2.089 1 .980 2.0"9 1.928 2.17* 1.9?7 2.1 IS 2 .oss 2.1*0 2 . 0 32 1.971 1.919 1.H7* 2.218 1.988 2.00 3 1.8S2 2 . 0 33 2.0*9 2.017 2.M2 1.978 1 .-*1 | .HMH 1.771 2. 1 31 2.217 2.00* 1.9|9 I 001594 BEST COPY AVAILABLE T W O Yh AW O R A L 4IJ11- T ) TDK 11 ! TV - O N C O G F N 1C I T Y S T U D Y UF F L U O R O C A R M O N M u W ^ 4 |N l-FMAl> H A T S T MO YF A h |N|il j I O U A L wMOhr^(G) OSF *N|MAL ROPY LIVE* HF ART 5PLFFN K IDN1. YS 30 PPM 30 PPM 30 PO M 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PP M 30 PPM 30 PPM 10 P M 10 P P M 10 P P M in P P M in P P M 10 P P M in P P M 10 PPM 10 P P M 10 P P M 10 P P M 10 PPM 10 P P M in PP M 10 PP M P1R4A23 P1R4A26 P1R4A27 PlfURl? PIR4A34 P1R4A36 P1R4AJ9 P1R4A44 P1R4A4Q P 1R 4 A 5 4 PIR4A5S P1R4A54 P1R4A54 P1R4A44 P1R4A4Q 01R4A72 Q1R4A7 1 Q1R4A74 01P4RA1 01R4AA? 01P4AA4 U1R4AAS 01R4R9? 01R4AR4 01R4A97 U1R4903 Q1R4914 Q1R4916 0 IRAQ 1H Q1R4919 413 374 307 54? 473 50? 404 337 403 A? 7 400 443 A01 4A7 514 35A 51? Al? 54 3 444 AOS 550 740 AS 1 4A9 37 A 445 47? 294 4 74 20.40 14.A3 14.54 1V.47 ?0.53 15. 3 14.74 13.21 12 4 A lb.O 1 ?1.5H 14.14 11.5V 17.44 I V . 35 13.47 13.V4 13.4 ?0.V4 IV.45 ?l .44 17.44 ?V .2? 14.17 13.A4 11.21 2 0 . 4H 25.24 5.51 14.SM 1.0 74 1.038 1.131 1.4H7 1.21V 1.307 1.425 1.075 0.445 1.1H2 1.21V 1 .? 14 1.311 1.174 1.307 1 .? JV 1.505 1.04 1.25 V 1.444 1.054 l.5 7V 2.141 1. 17H 1.310 1. TV? 1.440 1 .5h'l 1.44 1 . 134 0.445 1.071 0.5V3 0.5V1 0.43? 0.42H 0.74V 0.44H 0.54H 0.H4I 0.441 0.74M 0.40V 0.427 1.210 0 55 5 0.455 A.44H 0.414 0.994 0.77V 0.7.17 1.244 0.H20 0.424 0.50 7 0 .MAT 1.057 0.349 O . A 11 HEIGHTS ARE IN MG - KIDNEY ANO UTERUS HEIGHTS NOT TAKEN DUE TO CONGENITAL ABNORMALITY. - ADRENAL HEIGHTS NOT TAKEN DUE TO INVOLVEMENT UITH MASS. 1. 1 34 3.244 2.5V4 1.447 2.V31 3.515 2.7VH 3. 142 2.734 3.144 1.535 2.4H0 3.0|1 3.314 3.413 2.4V 2.515 2.542 3.000 3. 1?4 . !> 3.513 4.017 2.HH 1 3.34*. 2.412 14 M 1 3.044 2.0.14 4.0?5 ADRKNALC - 20V 1VO 44 94 V? 1A? V4 101 l?o 1SV 154 4A V4 99 74 100 94 11V AS 1A 1 220 119 193 207 19H 154 125 C _ ** c -- UTFRUS 0.500 0.744 1.151 1.544 0.474 0.495 0,594 1.014 0 .A 34 0.474 0.74* 0.747 0.422 0.544 1.OlH 1.2? 0.51 7 0.531 1 .** 0.475 .b 0.44 1 0.440 0.994 0.444 0.514 1.3M4 0.473 <1.737 1.014 H R A 141 I.47H 2.029 2.O0H 1.445 2.057 2.044 2.209 1.457 I.A4 1 1 .450 1.414 1 '1? 1 1 . 4 15 2.1?5 2.111 1.049 1 .A41 1.444 2.004 2.044 1.447 1 .A 4 4 2.113 1.V9S 2.04 7 1.444 2.0V4 2.121 1.44? 2.04M no. TABLE 19 Two Year Oral (D1tt) Toxicity - Oncogenicity Study of Fluorochemlcal FM-3924 1n Rats Summary of Major Microscopic Findings - Percent Incidence at Two Years Oraan/Findinas MEOP-LASIlg IESU?N$- Controls Male Femal 50- 50 Hiqh Male Female 50 50 ADRENAL Pheochromocytoma, Benign Pheochromocytoma, Maiignant 4402 0000 LIVER Hepatocellular 6046 Carcinoma Hepatocellular Adenoma 0 0 0 8 MAMMARY GLAND Adenocarcinoma Adenoma Carcinoma Fibroadenoma 15 -7 -2 - - 22 . 21 -0 -0 - 13 PITUITARY Adenoma 35 72 43 71 THYROID C-cell Adenoma C-cell Carcinoma 0 222 5024 UTERUS Polyp 22 Mid Male Female 50 50 80 02 20 00 . 24 -0 -0 - 33 60 82 43 23 9 Low Male Female 50 50 82 20 20 00 13 -0 -0 - 36 47 76 72 02 8 a No statistically significant differences (a 0.05) were found between rats fed diets with FM-3924 and control group animals. b 50 rats/sex/group were at risk; % values derived from actual tissues examined. 001595 m. i m i L ia Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorochemlcal FM-3924 1n Rats Summary of Major Microscopic Findings - Percent Incidence at Two Years MOM-NEOPLASTIC LESIONS Oraan/Findinas Controls Male Female 50? 50 Hiah Male Female 50 50 ADRENAL Nodular Hyperplasia Sinusoidal Ectasia Cortical Vacuolation HEART Myocardial Fibrosis Myocarditis, Chronic KIDNEY Nephropathy, Chronic Pelvic Mineralization LIVER Cystoid Degeneration Hepatocellular Alt.Vac. Hepatocellular Vac. Hyperplastic Nodule Megalocytosis Necrosis LUNG Alveolar Macrophages Perivas, Mono.Infil. Vascular Mineralization Pneumonia, Interstitial TESTIS/EPIDIDYMIS Polyarteritis Vascular Mineralization OVARY Tubular Hyperplasia THYROID C-cell Hyperplasia URINARY BLADDER Epithelial Hyperplasia UTERUS Cystic Glands 4 22 48 10 28 88 8 8 20 44 0 0 6 20 42 86 32 12 0 - 2 7 0 84 10 4 32 60 60 0 26 60 -2 0 10 28 26 44 14 - 0 0 14 14 22* 2 30 68 36 22 10 2 30 4* 86 36 0 66 30* 8 18 12 78* 82 10 18* 84* 88* 20 8 46* 54* 14* 38 96 78* 12 18 412 - - 31* 99 44 29 Mid Male Female 50 50 04 40 78 30 14 12 10 50 14 80 52 16 48 16 0 32 12 38 50 20 56* 2 0 12 30 30 40 20 88 84* 14 12 44- - 23* 6 11 13 5 13 Low Male 1Female 50 50 10 0 10 72 20* 10 20 6 40 18 88 44 16 46 12 0 24 12 24 54 00 54* 0 4 10 36 28 30 18 90 80* 8* 20 814* - - 13* 40 2 0* 17 - - 50 rats/sex/group were at risk; % values derived from actual tissues examined * - Statistically significant difference ( - 0.05) from controls. 001596 112. I Figure 1 Two Y e a r O r a l ( D ie t) T o x i c i t y - O n c o g e n i c i t y S tu d y o f F lu o r o c a r b o n FM-3924 i n R a ts Mean Body W e ig h ts (g) M a le s e o H* C/l CO Ni OJ STUDY WEEK LEGEND* GROUP *-**CONTROL *-*100 PPM -*-+ 30 PPM 10 PPM I Fig u re 2 Two Y e ar O r a l ( D ie t ) T o x i c i t y - O n c o g e n i c i t y S tu dy o f F lu o r o c a r b o n FM-3924 in R a ts Mean Body W e ig h ts (g) Fem ales o cn CO & -p LEGEND* GROUP CONTROL -- 100 PPM 30 PPM -- 10 PPM Figure 3 i Two Vear O r a l ( D ie t) T o x i c i t y - O n c o g e n i c i t y S tu dy o f F lu o r o c a r b o n FM-3924 i n R a ts Mean Food C o n su m p tion P e r K ilo g r a m Mean Body W e ig h t - M a le s u-ooa o o z o o a L h . o z i c q o q v - asF-^no- LEGEND. GROUP -CONTROL 100 PPM 30 PPM 10 PPM i Fig u re 4 Two Y e a r O r a l ( D ie t) T o x i c i t y - O n c o g e n i c i t y S tu d y o f F lu o r o c a r b o n FM-3924 i n R a ts Mean Food C onsum ption P e r K ilo g ra m Mean Body W eight - Fem ales - < o o o o x \ o i z o - H T J C c w z o n o o o "n LEGEND. GROUP **-m CONTROL 100 PPM +- 30 PPM 10 PPM TWO YEAR ORAL (DIET) TOXICITY / CARCINOGENICITY STUDY OF FLUOROCHEMICAL FM-3924 IN RATS APPENDIX ITEMS 001601 Internal Correspondence cc: Appendix Item A F. D. Griffith - 220-2E-02 W o McCormick - 220-2E-02 re : J. K. Sugg - 220-2E-02 F . A . Ubei, M.D. - 220-2E-02 To -M. T. CASE F'orr. S . D . S0REN Su&ec: Air Monitoring, Project 89003107 Da-e August 27, 1981 3M Summary Air monitoring has been conducted in three animal treatment room used in fluorochemical studies. The purpose of the mo n i t o r i n g was to evaluate possible ai rborne contaminants. The sample results indicate that fluorochemical exposures, if any, were below detectable amounts. Detail Air sampling was conducted in the three animal treatment rooms used in the two year animal feeding study of FM-392*! and FC-1M3. The study has been in progress since April 21, 1981. Area samples were collected in each of the several treatment rooms by means of either lmplngers with methanol media or SKC* silica gel sampling tubes. With one exception, samples were located on top of the animal racks. The one exception was an air sampler located near the room air exhaust near the floor. The periods sampled are Judged representative of "usual" or steady state conditions. The flow rate of the sample pumps was checked approximately every 30 minutes throughout the sampling period. The samples were analyzed by the Analtyical Section of the 3M Central Research Laboratory. This laboratory has full accreditation as an Industrial Hygiene Laboratory by the American Industrial Hygiene Association. 001602 Appendix Item A M. T. Case 2- August 27, 1981 The sample results Indicate that airborne concentrations of the test fluorochemlcals, if any, were below detectable limits. On this basis, it is Judged that cross contamination potential by airborne means is unlikely. Please call of there are any questions. S D S :cr 001^03 1 19 M. T. Case Appendix Item A 3- Sample Data Building 218-3 Project. #89003107 August 7, 1981 Sample Number CCL81-20 CCLB1-23 CCL81-21 CCL81-25 CCL81-22 CCL81-24 Description D-340. Control Roam, top of rack. Same as above D-332. FM-3924, dose Roam. Sampler on top of high dose rack. D-332. Sampler at rear room air exhaust about 18 inches above floor. D-338. FC-143, dose Room. Sampler on top of high dose rack. Same as CCL81-22, duplicate sample using silica gel tube. Time 922-1225 922-1225 926-1236 1055-1236 925-1228 931-1228 August 27, 1981 Compound FM-3924 FC-143 FM-3924 Concentration, mg/m^ < 0.003 G . Z r f ' e <{.0.001 <0.003 FM-3924 <0.025 FC-143 FC-143 <0.001 < 0.002 Z . o. //-^ * -r>b SAMPLING METHOD: FM-3924 SXC silica gel sampling tubes. FC-143 Impinger - methanol. ANALYTICAL METHOD: FM-3924 - gas chromatography, electron capture detector. FC-143 - derivativetien; gas chromatography, electron capture detector. ANALYTICAL REQUEST: A80248. 001G04 InternalCorrespondence APPENDIX ITEM A To: From: Subject: Date: L. J. Sibinski J. D. Johnson Analysis of Plasma Samples from Sentinal Rats Housed in Room w i th Two Y e ar T o x Study-Rats (Riker St ud y No. 0281C R O 0 12) O c t o b e r 7, 1985 I have attached the one page protocol attachment for the use of sentlnal rats in Riker Study No. 0281CR0012. These samples were collected as described. O n July 15, 1981, forty plasma samples (see attached) were transferred to V. Pothapragada (Dr. V) in Commercial Chemicals for analysis of organic fluorine. The results were sent back by Dr. V 8/24/81. All samples were less than one part per million. From this, it can be concluded that there was no airborne fluorine present that was interfering with this study. These data are in SJG Notebook 56531, p 53. James D. Johnson Research Specialist Riker Laboratories, Inc. G01G05 121 InternalCorrespondence Appendix Item A cc: M.T. Case i-'.O. Griffith R.E. Ober w.il. Pear Ison R.A. Prokop 3o i l s ' -- To: v. Pothapragada From: j .d . Johnson * Subject Analysis of Plasma Samples from Sentinal Rats Housed in Room with Two Year Tox Study Rats (Riker Study No. 0281 CR 0012). Dale: July 15, 1981* Forty plasma samples from sentinal rats are submitted for fluorine analysis. These samples include 5 male (IR 3861, IR 3862, ZR 3863, IR 3864, and IR 3865) and 5 female (ZR 4921, ZR 4922, ZR 4923, ZR 4924, and IR 4925) which were sacrificed before dosing was initiated. The other thirty plasma samples were collected at 30 days after dosing started. There are 5 rats of each sex from the control room, from the room in which study rats are receiving FC-143, and from the room in which study r a t s ^ r e receiving FM-3924. The numbers for these, rats are as follows: * 5 male Control Room (IR 3866, ZR 3867, IR 3868, IR 3869, IR 3870) 5 female Control Room (ZR 4926, ZR 4927, IR 4928, IR 4929, IR 4930) 5 male FC-143 Room (IR 3876, IR 3877, IR 3878, IR 3879, IR 3880) 5 female FC-143 Room (IR 4936, IR 4937, IR 3838, IR 3839, IR 3840) 5 male FM-3924 Room (ZR 3886, IR 3887, IR 3888, IR 3889, IR 3890) 5 female FM-3924 Room (ZR 4946, ZR 4947, IR 4948, ZR 4949, IR 4950) Please get back to us with the data. It may be that interpretation of the results will lead to specific analysis or to analysis of tissue. i/mho G01G06 122 BEST COPY AVAILABLE - A l Ccjo tlttv * lM > 1 3 yj A * 16 6T /<k t*n *9* m H 2oo Aof J o 2- ;R 3S4I (K 3S6x 1C JTfcb *#v 3 * 4 m; 3 * 4 i f M M M M M Mi 1 IT < <6 3.2- F m 1- Ms F /is <6 x S' r- . 2o3 m 'x 2oU IK' ST Mi qp------- 3*64 3 * 4 '! i?6 * ./? '3 7c- M tA n l N Appendix Item A 2. < V . , t . ' > * *4 4.V k*\ Ssfl-T-'*'. * ' <" ft'* * . 1 -f 1 t #\ 1 iJi-jjtr.<I (tA ***( J # | I1 * K | ** 1 : *V * J *S- i ** * 1 ** *3 I u*zuw 6 a *f/ F a ff / V-a.V-1 / V -*f7 ' 5,- !!/ *7V H I M l s i? if still P ( r Vi | v T 1 I 1 . X/ V -j i<vJ-v,'' X x \ iv 4L| " a*" -3 . s-a a -ii saa-?l cjq * i * / 5 23 ?/ 5-23 8/ 2ot 2 of 2 to 2l t J /3 - i.x 4 ' / l t Ms *fO Mi V I / / i if M2-5 h ^ lc F r i r- r > */ *5 # S" a /3 a /y -2 /r a /6 2 '7 1 K 3*74 \K i 2>*7 7 IK 3'7*S iK 3 * 7 ? Ul 1 I M M /C - '%3 wros* **/ 4a *3 */ *r U s SI S 'S | U'S-ti u s 81 ^ T / .*7327/ s-a i-tt -1/ / f o u. <V . - > 1 _ . . ir j 4 1 1 /2 tt u Jnt 1/ y ./ 001G07 *. 123 Appendix Item A cep () /Is m , a /s 2 /1 22 222- R i h u * /il *<r3b i* * 1 31 I*. 3 * 3 S if 3 S > f 3e* P P _P F BEST COPY AVAILABLE p C - f b ^ /2ww) * / *i IS " C s tl b ' S 'SI * T I| 4 -S -8 ) S '!! >K 4 22322* 2VS" 2 -2 4 227 / 3 2 * l& g * 7 l\ 3? & / f \ 3 ZK -, 37 Vk M F * i- 3^ m (? i w * 7 ^fa. <KJ 22* 2 2 -1 230 a ji 2S 2- li< * 1 / <= K '" i IK. P / } 4<? $T c- F -*/ *2 1 *r St/ *<r xaa& i sail saz* i s-aa-ti S-az-11 *st> iisu 6TH (,* % Sc. 001G08 ifr/u 124 A p p en d ix Item B Two Year Oral (Diet) Toxicity - Oncogenicity Study of Flurorcarbon FM-3924 in Rats \ Blending Procedure o f FM-3924 Diet Concentrate 1. F M - 3 9 2 4 (0.24 g/kg of diet to be mixed) was d i s s ol ve d in ethanol-- (approximately 6 - 1 0 ml) in a 10 ml graduated cylinder. 2. This solution was "sprinkled" in layers of no n- tr ea te d ground d i e t to be mixed. The graduated cylinder was also worked with an additional 5 ml of ethanol and this also was "sprinkled" into the diet. 3. The treated diet was ph ys ic al ly mixed for appr ox im at ly 20 minutes using a Hobart blender. 4. After mixing, the FM-3924 d i e t concentrate was spread out in stainless steel pans (66.5 cm long x 40.7 cm wide x 3.0 cm deep) and placed into a fume cabinet for approximately 72 hours to evaporate the ethanol-- * This procedure was done on a weekly basis to yield a FM-3924 concentration of 200 ppn in diet. -- u.S. Industrial Chemicals Co., Div. of National Distillers . Ch e m i c a l s Corp., Chicago, IL; 190 proof,* Lo t #480316. -- CCD Analytical Report #213 revealed the level of ethanol (ETOH) in the FM-3924 diet concentrate after drying to be less than 1 ppm. G01G09 125 BEST COPY AVAILABLE A p p en d ix Item B CCD ANALYTICAL REPORT #213 From: p. J. Colbert - 236-2B GLC Analysis of FM-3924 (T-2999CoC) FC-143 (T-2998CoC) Blended `jecl into Ground Lab Chow. (Riker Study #0281CR0012) Date: April 29, 1981 Reference: Commercial Chemicals Analytical Laboratory Requests #17079, 17080, 17096 Commercial Chemicals Analytical Laboratory Method #'s G30-0481, G31-0481 The samples of FM-3924 (W.R. EtFOSE) blended into Ground Lab Chow, along with four blank Ground Lab Chow samples, were received from L. J. Siblnski on 4-20-81 for analysis. All samples were run in triplicate. The results are: Compound Theoretical ppm Actual ppm uq/q FM-3924 Blank for concentrate 0 0 FM-3924 Concentrate (blended 4-17-81) 200 214 * FM-3924 Top Sample 100 105 V ^ M1d Sample 100 105 U Bottom Sample 100 111 ' FM-3924 Top Sample M1d Sample 30 30 29 \ 27 W Bottom Sample 30 30 / FM-3924 Top Sample Mid Sample Bottom Sample 10 10 10 11 \ 9\^ 1 0 />1 00110 126 APPENDIX ITEM B L. J. Sibinski CCD Analytical Report April 29, 1981 Page 2 #213 Compound Theoretical ppm oiimwiiUBLE Actual ppm (ug/g)FM-3924 Blank for 100 ppm level 0 0 Blank for 30 ppm level 0 0 Blank for 10 ppm level 0 0 The level of ethanol in FM3924 Concentrate (blended 4-17-78) was also checked and found to be less than 1 ppm (ug/g). 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. The results are: Theoretical pp.n (ctual ppm (uq/g)FC-143 FC-14: 300 v' 326 Mid' Bottom Blank for 300 ppm li FC-143 Top Sample Mid Sample 300 300 30 30 282 * 297 0 24 t 23 / Bottom Sample .30 . 28'V Blank for 30 ppm OV .0 Because two le three 30 ppm level sampl were low, another' set of sami es were received from L. J. Sibil jl on 4/27/81 for ar . The results are: t / GOlull 127 de: M. T. Case . G. Lamprecht J. D. LaZerte W. C. McCormick V. Pothapragada R. A. Prokop L. D. Winter 218-2 218-3 236-1 220-2E-02 236-3A 236-28 236-2B Commercial Chemicals Analytical Report 11229 Appendix Item B To: From: P. J. Colbert 236-28 Subject: Date: GLC Analysis of FM-3924 (T-2999 CoC) FC-143 (T-2998 CoC) Blended Into Ground Lab Chow (Riker Study #Q281CR0012) June 15, 1981 BEST COPY AVAILABLE Reference: Commercial Chemicals Analytical Laboratory Requests #17172, 17173. Commercial Chemicals Analytical Laboratory Method # 1s G30-0481, G31-0481. Ten samples of FM-3924 (W.R. E+FOSE) blended fnto Ground Lab Chow, along with three blank Ground Lab Chow samples, were received from L. J. Sibinski on 5-18-81 for analysis. All samples were run in triplicate. The results are: Sample Theoretical ppm Actual ppm m l 9 FM-3S FM-3924 Concentrate (Blended 5/15/81) Blank for 100 ppm 200 0 4 T: 208 0 FM-3924 Top Mid Bottom Blank for 30 ppm 100 100 100 0 , I" 109 /108 \ 96 0 FM-3924 Top Mid Bottom Blank for 10 ppm 30 30 30 0 33 * , i 10 J 31 27 0 FM-3924 Top Mid Bottom 10 10 10 11.3 /'' ( n-5 \ 10.0 01G12 128 uc . E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E-02 V. Pothapraqada - 236-3A R. A. Prokop - 236-2B L. D. Winter - 236-2B G. W. Kirscn - 23b-.jm Appendix Item B COMERCIAL CHEMICALS ANALYTICAL REPORT #251 To t. J. S8WSJ - 218-3-3 From: P. J. COLBERT - 236-2B Subject: Date GLC ANALYSIS OF FM-3924 (T-2999 CoC) BLENDED INTO GROUND RODENT CHOW (RIKER STUDY #0281CR0012) September 8, 1981 Reference: Commercial Chemical Analytical Laboratory and CCD Method 630-0481. Ten samples of FM-3924 (W. R. EtFOSE) blended into ground rat show along with four blank ground rat chow samples, were received from L. J. Sibinski on August 17, 1981, for analysis. All samples were run in triplicate. The results are: Actual ppm Sample Theoretical ppm q/q FM-3924 Blank for 200 ppm 200 ppm Concentrate 00 200 214 *It. Blank for 100 ppm 100 ppm Top 100 ppm Mid 100 ppm Bottom 00 100 100 no n o / 108 + '^ 100 W \ 1 1 2 Blank for 30 ppm 30 ppm Top 30 ppm Mid 30 ppm Bottom 00 30 30 / 31 S ' % U r 31 / 30 Blank for 10 ppm 10 ppm Top 10 ppm Mid 10 ppm Bottom 00 10 >11.5 10 W <10.6 10 yo.o PJC/hc TSTCOPYAYAIUBIE 001G13 129 Appendix Item B COMMERCIAL CHEMICALS ANALYTICAL REPORT 290 T From: Subject: Date: R. M. P A Y F E R - 2 3 6 - 2 B G L C A N A L Y S I S OF F M - 3 9 2 4 (T - 2 9 9 9 C o C )B L E N D E D IN TO G R O U N D RODENT CHOW (RIKER STUDY #0281 CR0012) D e c e m b e r 1, 1981 Reference: Commercial Chemicals Analytical Laboratory Request #17780 Ten samples of FM-3924 (W.R. EtFOSE) blended into ground rat chow, along with three blank ground rat chow samples, were r e c e i v e d f r o m L. J. S i b i n s k i on N o v e m b e r 16, 1981, for analysis. All samples were run in triplicate with the following results: Sample Theoretical PPM Actual PPM ug/9 FM-392^ 200 PPM Concentrate Blank for 100 PPM 100 PPM Top 100 PPM Middle 100 PPM Bottom Blank for 30 PPM 30 PPM Top 30 PPM Middle 30 PPM Bottom B l a n k for 10 PPM 10 PPM Top 10 PPM M i dd le 10 PPM Bottom 200 0 100 100 100 0 30 30 30 0 10 10 10 217 0 108 y ,, 103 104 0 29 s . - 29 V 31 0 ' -i 9.5 G. W. Kirsch - 236-3A E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E-02 V. Pothapragada - 236-3A R. A. Prokop - 236-2B L. D. Winter - 236-2B (2 copies) -f COPY AVAILABLE G01G14 130 de: M.T. Case - 218-2 G.W. Kirsch - 236-3A E.G. Lamprecht - 218-3 J.D. LaZerte - 236-1 W.C. McCormick - 223-2E-02 V. Pothapragada - 235-3A L.D. Winter - 236-2B Appendix Item B COMMERCIAL CHEMICALS ANALYTICAL REPORT #320 To: L. J. SIBINSKI - 218-3-3 From: R. M. PAYFER - 236-2B Subject GLC ANALYSIS OF FM-3924 (T2999 CoC) BLENDED INTO GROUND RODENT CHOW (RIKER STUDY #0281 CR 0012) Date: MARCH 5, 1982 Reference: Commercial Chemicals Analytical Laboratory Request #18072 Ten samples of FM-3924 (W.R. EtFOSE) blended into ground rat chow, along with three blank ground rat chow samples, were received from L. J. Sibinski on February 15, 1982. All samples were analyzed in triplicate for FM-3924 with the following results: Sample Theoretical PPM Actual PPM ug/g FM-3924 200 PPM concentrate Blank for 100 PPM 100 PPM Top 100 PPM Middle 100 PPM Bottom Blank for 30 PPM 30 PPM Top 30 PPM Middle 30 PPM Bottom Blank for 10 PPM 10 PPM Top 10 PPM Middle 10 PPM Bottom 200 0 100 100 100 0 30 30 30 0 10 10 10 198 * 0 107 106 103 0 31 29 24 0 8.8 9.0 & - L- r* G01G15 :f AVAILABLE 131 cc: M.T. Case - 218-2 G.W. Kirsch - 236-3A E.G. Lamprecht - 218-3 J.D. LaZerte - 236-1 W.C. McCormick - 220-2E-02 V. Pothapragada - 236-2B L.D. Winter - 236-2B Appendix Item B COMMERCIAL CHEMICALS ANALYTICAL REPORT #327 Rcttv Subject Date: R. M. PAYFER - 236-2B GLC ANALYSIS OF FM-3924 (T-2999 CoC) BLENDED INTO GROUND RODENT CHOW (RIKER STUDY #0281 CR 0012) MARCH 22, 1982 Reference: Commercial Chemicals Analytical Laboratory Request #18101 Three samples of FM-3924 (W.R. EtFOSE) 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 Theoretical PPM Actual PPM Uq/q FM-3924 Blank for 10 PPM 10 PPM Top 10 PPM Middle 10 PPM Bottom 0 10 10 10 0 10.6 \ 1C 9.7 9.9 P'ic BEST COPY AVAILABLE 001G16 132 Appendix Item B COMMERCIAL CHEMICALS ANALYTICAL REPORT #341 Fror, Sdtxuci Dale R. M. PAYFER - 236-2B GLC ANALYSIS OF FM-3924 (T-2999 CoC) BLENDED INTO GROUND RODENT CHOW (RIKER STUDY #0281 CR0012) May 28, 1982 Reference: Commercial Chemicals Analytical Laboratory Request #18320 Ten samples of FM-3924 (W.R. EtFOSE) blended into ground rat chow, along with four blank ground rat chow samples, were received from L. J. Sibinski on May 17, 1982. All samples were analyzed in triplicate for FM-3924 with the following results: Sample Theoretical PP Actual PPM ug/g FM-3924 200 PPM Concentrate Blank for 200 PPM Blank for 100 PPM 100 PPM Top 100 PPM Middle 100 PPM Bottom Blank for 30 PPM 30 PPM Top 30 PPM Middle 30 PPM Bottom Blank for 10 PPM 10 PPM Top 10 PPM Middle 10 PPM Bottom 200 0 0 100 100 100 0 30 30 30 0 10 10 10 199 - - ' 0 0 100 , loi > y 95 0 30 . .. 29 ' ' 4O- OKJ 0 10.5v 11.9 f"'- 10.9 - /' de: M. T. Case - 218-2 G. W. Kirsch - 236-GB E. G. Lamp recht - 218-3 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E-02 V. Pothapragada - 236-GB L. D. Winter - 236-2B BEST COPY AVAILABLE 001G17 133 Appendix Item B COMMERCIAL CHEMICALS ANALYTICAL REPORT #367 To From Subject: Date: R. M. PAYFER - 236-28 GLC ANALYSIS OF FM-3924 (T-2999 CoC) BLENDED INTO GROUND RODENT CHOU (R1KEE STUDY #0281 CR0012) Sept. 13. 1982 Reference: Commercial Chemicals Analytical Laboratory Request #18608 Ten samples of FM-3924 (W.R. EtFOSE) blended into ground rat chow, along with four blank ground rat chow samples, were received from L. J. S1b1nsk1 on Aug. 16. 1982. All samples were analyzed 1n triplicate for FM-3924 with the following results: Sample Theoretical PPM Actual PPM ug/g FM-3924 200 PPM Concentrate Blank for 200 PPM Blank for 100 PPM 100 PPM Top .100 PPM Middle 100 PPM Bottom Blank for 30 PPM 30 PPM Top 30 PPM Middle 30 PPM Bottom Blank for 10 PPM 10 PPM Top 10 PPM Middle 10 PPM Bottom 200 0 0 100 100 100 0 ^mCm **- 30 30 30 0 10 10 10 193 0 0 91 %d i t i -- 28 29 ; 29 0 10 -t? 11 11 de: M. T. Case - 218-2 G. U. Kirsch - 236-GB E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E-02 V. Pothapragada - 236-GB L. D. Winter - 236-2B m MPYmnm 001G18 134 Appendix Item B Commercial Chemicals Analytical Report #368 To Ftcrr, Subject Date R. M. Payfer - 236-2B GLC Re-analysis of FM-3924 (T-2999CoC) blended into ground rat chow (Riker Study No. 0281 CR0012) September 14, 1982 Reference: Commercial Chemicals Analytical Laboratory Request #18610 Three samples of FM-3924 (W.R. Et-Fose) blended into ground rat chow, along with a blank ground rat chow sample, were received from L. J. Sibinski on August 27, 1982. These samples were analyzed in triplicate for FM-3924 with the following results. Actual PPM Sample Theoretical PPM ug/g FM-3924 Blank for 100 PPM 100 PPM top 100 PPM middle 100 PPM bottom 0 100 100 100 0 105 100 85 G01G19 135 , `U Appendix Item B To m From G. W. Kirsch - 236-2B Commercial Chemicals Analytical Report #383 SuDject GLC Analysis o f FM-3924 (T-2999 CoC) Blended into Ground Rodent Chow (Riker Study #0281-CR0012) Date. December 8, 1982 Reference: Commercial Chemicals Analytical Laboratory Request #18854. ! Ten samples of FM-3924 (W.R. EtFOSE) blended into ground rat chow, along with four blank ground rat chow samples, were received from L. J. Sibinski on November 15, 1982. All samples were analyzed in tr ipI Icate for FM-3924 with the following results: ! i Actual ppm Samp Ie Theoretical ppm pg/g FM-3924 200 ppm Concentrate Blank for 200 ppm Blank for 100 ppm 100 ppm Top 100 ppm Middle 100 ppm Bottom Blank for 30 ppm 30 ppm Top 30 ppm Middle 30 ppm Bottom Blank for 10 ppm 10 ppm Top 10 ppm Middle 10 ppm Bottom 200 0 0 100 100 100 0 30 30 30 0 10 10 10 QiW\ GWK:ch de: M. T. Case - 218-2 E. G. Lamprecht - 218-3 J. D. LaZerte - 216-1L W. C. McCormick - 220-2E R. M. Payfer - 236-2B V. Prothapragada - 236-GB L. D. Winter - 236-2B BEST COPY AVAILABLE 001620 136 best copy available Appendix Item B To from Subtect Date Commercial Chemicals Analytical Report #394 L. J. SIBINSKI - 218-3 G. W. KIRSCH - 236-2B GLC ANALYSIS OF FM-3924 (T-2999 CoC) BLENDED INTO GROUND RODENT CHOW (RIKER STUDY #0281-CR0012) MARCH 1, 1983 3M Reference: Commercial Chemicals Analytical Laboratory Request #18854 Ten samples of FM-3924 (W.R. EtFOSE) blended into ground rat chow, along with four blank ground rat chow samples, were received from L. J. Sibinski on February 16, 1983. All samples were analyzed in triplicate for FM-3924 with the following results: Sample 200 ppm Concentrate Blank for 200 ppm Blank for 100 ppm 100 ppm Top 100 ppm Middle 100 ppm Bottom Blank for 30 ppm o u Op 30 ppm Middle 30 ppm Bottom Blank for 10 ppm 10 ppm Top 10 ppm Middle 10 ppm Bottom Theoretical ppm 200 0 0 100 100 100 0 30 30 30 0 10 10 10 Actual ppm ug/g FM-3924 ifi7 0 0 / 92 V u - \ 104 X 80 0 -/7 ' r ' r t- / 27 r7~ \ 25 \ 29 - A '' 0 /9 V- < 8 "`A 8 -__ -M GWK/hc de: M. T. Case - 218-2 E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E R. M. Payfer - 236-2B W. H. Pearl son - 223-6SE L. D. Winter - 236-2B i AVAILABLE BEST COPY AVAILABLE 00121 137 best copy available Appendix Item B Commercial Chemicals Analytical Report #403 To: From Subject Date G. W. KIRSCH - 236-2B GLC ANALYSIS OF FM-3924 (T-2999 CoC) BLENDED INTO GROUND RODENT CHOW (RIKER STUDY #0281-CR0012) APRIL 19, 1983 Reference: Commercial Chemicals Analytical Laboratory Request #19332 Ten samples of FM-3924 (W.R. EtFOSE) blended into ground rat chow, along with four blank ground rat chow samples, were received from L. J. Sibinski on April 13, 1983. All samples were analyzed in triplicate for FM-3924 with the following results: Sample Theoretical ppm Actual ppm ug/g FM-3924 200 ppm Concentrate Blank for 200 ppm Blank for 100 ppm 100 ppm Top 100 ppm Middle 100 ppm Bottom B1ank for 30 ppm 30 ppm Top 30 ppm Middle 30 ppm Bottom B1ank for 10 ppm 10 ppm Top 10 ppm Middle 10 ppm Bottom 200 0 0 100 100 100 0 30 30 30 0 10 10 10 207 ^Mc'' 0 0 101 V. 99 M - 103 (-* 0 31 . 29' 28 y 0 9, , 9 -13 8^ GWK/hc .V{\n<M de: M. T. Case - 218-2 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E R. M. Payfer - 236-2B W. H. Pearl son - 223-6SE L. D. Winter - 236-2B wcopM Hm m *1 001G Z Z 138 Appendix Item C Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FM-3924 in Rats Normal Ranges for Hematologic and Blood Chemistry Values of Rats at Ri k e r Laboratories, Inc., St. Paul, MN Erythrocytes Hemoglobin Hematocrit Mean Corpuscular Volume (MCV) Mean Corpuscular Hemoglobin (MCH) Mean Corpuscular Hemoglobin Concentration (MCHC) Leukocytes Neutrophils 2-22% Lymphocytes 65-95% Monocytes 0-5% Eosinophils 0-6% Blood Urea Nitrogen (BUN) Glucose Total Bilirubin Total Protein Albumin Calcium Al an in e Aminotransferase (ALT) Aspartate Aminotransferase (AST) Alkaline Phosphatase Creatine Phosphokinase (CPK) 5,000,000-8,000,000 cells/cu mm 11-17 g/dl 36-52% 57-77 microns^ 18-24 picograms 30-34% 6,000-15,000 cells/cu mm 500-4,000 cells/cu mm 5,000-14,000 cells/cu mm 0-500 cells/cu mm 0-500 cells/cu mm 10-30 mg/dl 120-160 mg/dl 0.1-1.0 mg/dl 5.5-7.5 g/dl 3.5-5.5 g/dl 10.2-12.5 mg/dl 10-40 International Units/1 20-60 International Units/1 50-200 International Units/1 50-150 International Units/1 G01G23 139 Appendix Item C Methods Used for Hematology On Bleedings at 3 and 6 Months Parameters Units Methods Hematology Total Erythrocytes > Leukocytes Hemoglobin Hematocrit Differential cells/cubic mm g/dl % packed cells %/100 WBC Coulter Counter Model FN Coulter Electronics Hemoglobinometer, Model 231, Instrumentation Laboratories Microhematocrit Centrifuge, Model MB International Equipment Co. Microscope slide G01G24 14 APPENDIX ITEM C METHODS USED FOR HEMATOLOGY DETERMINATIONS FOR 12, 18 AND 24 MONTHS METHODS USED FOR CLINICAL CHEMISTRY DETERMINATIONS FOR 3, 6, 12, 18 AND 24 MONTHS Parameters Hematology Erythrocytes Leukocytes Hemoglobin Hematocrit Differential Chemi stry Total Bilirubin, Glucose Blood Urea Nitrogen Albumin, Total Protein Alkaline Phosphatase AST, ALT, CPK Urinalysi s Specific Gravity pH, Albumin, Bilirubin, Glucose, Occult Blood and Ketones Units______ cells(10^6/mm3) cel 1s(10/%n; g/dl % X/100 WBC Methods and Techniques UltraLogic 800 Hematology Analyzer Clay Adams, Division of Becton, Dickinson & Co. Microscope slide mg/dl g/dl International Units/1 Rotochem 36 11A Travenol Laborataories,Inc, TS Meter, AO Instrument Co. BiliLabstix Ames Company 001625 141 APPENDIX ITEM D PATHOLOGY REPORT OF RATS RECEIVING FLUOROCHEMICAL FM-3924 IN DIET FOR TWO YEARS 60X626 142 METHODS Gross Pathology All rats which were sacrificed at the 1 year interim or the 2 year terminal sacrifice or which died or were sacrificed in extremis during the course of study were necropsied. 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 examined in situ and after removal from the carcass. Representative tissues and organs from each rat were 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, 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 other gross lesions Microscopic examination of tissues from the 30 and 10 ppm groups included all the above listed tissues except aorta, brain, eyes, small and large intestine, lymph node and spinal cord/bone marrow. 0281CR0012 (FM-3924) G01G27 143 RESULTS Gross Pathology At the 1 year interim sacrifice, an increased incidence of pale/tan color livers described in male rats from the 100 ppm group was considered possibly compound related. There were no necropsy findings suggestive of a compound effect in female rats from the 100 ppm group which were sacrificed at 1 year. In rats which were sacrificed at study termination or which died or were sacrificed in extremis during the course of study (TS/DOS), an increased incidence was noted for liver masses, nodules and raised lesions, mottled livers and yellow or pale live?- foci and lesions at the 100 ppm level in males and females. No gross findings suggestive of a compound effect were seen in any TS/DOS rats from the 3G or 10 ppm groups. Other gross pathologic findings were typical of findings in ageing rats of this strain. These included mammary masses, pituitary masses and foci, ulcers on the hind footpads, pale livers and pale, pitted and enlarged kidneys. Organ Weights There were several statistically significant (p ^ C.05) variations in absolute and relative organ weights (organrbody, organ:brain weight ratios) in male and females rats from the 100 ppm group which were sacrificed at 1 year. Increases in absolute liver weight and in liver:brain weight ratios in males and females from the 100 ppm group correlated with compound related morphologic changes and were considered toxicologically significant. A significant decrease in group mean body weight in male and female rats from the 100 ppm group at 1 year also was considered toxicologically significant. None of the other organ weight variations in 100 ppm rats at the 1 year interim was considered of toxicologic significance. At the terminal sacrifice, statistically significant increases occurred in absolute liver weight and in liver:body and liver:brain weight ratios in males and females at the 100 ppm level. A significant increase in liver:body weight ratio also occurred in 30 ppm males and females. These increases in liver weight correlated with morphologic liver changes and were considered toxico logically significant. A statistically significant decrease in body weight in males and females at 100 ppm also was considered toxicologically significant. No morphologic correlates were observed for other statistically significant organ weight variations and they were not considered toxicologically significant. 0281CR0012 (FM-3924) -2- 001G28 144 Histopathology Compound related microscopic changes were observed in the livers of male and female rats from the 100 ppm group at the 1 year interim sacrifice, in male and female TS/DOS rats from the 100 and 30 ppm groups and in male TS/DOS rats from the 10 ppm group. The principal compound related liver change was megalocytosis, which was characterized by an increase in size of liver parenchymal cells due to an increase in cytoplasmic volume. The increased cytoplasm was of a finely granular "ground glass" appearance. The coarser cytoplasmic organelles were relatively decreased and were displaced to the cell membrane. The nucle us: cytoplasm ratio was decreased by the increase in cytoplasmic volume in affected cells. Most or all lobules in affected livers were involved and the centrilobular cells were more severely affected. At the 1 year interim, megalocytosis occurred to a mild to marked degree in 15/15 males and to a minimal to moderate degree in 14/15 females from the 100 ppm group. The lesion was accompanied by mild to moderate hepatocyte vacuolation, probably fatty, in 14/15 males and by minimal to mild necrosis in 6/15. In females, minimal to mild hepatocyte vacuolation occurred in 5/15 controls and 15/15 100 ppm rats but necrosis was not seen. Association of hepatocyte vacuolation and necrosis with megalocytosis suggests that the progression of lesions is megalocytosis to fatty degeneration to necrosis. In TS/DOS rats, megalocytosis occurred in males from the 100, 30 and 10 ppm groups with a dose response evident in incidence and severity. In female TS/DOS rats, megalocytosis occurred only at the 100 and 30 ppm levels; the 10 ppm level was free of compound related microscopic lesions in females. The incidence of megalocytosis in TS/DOS males was 0/50, 42/50, 28/50 and 27/50 at the 0, 100, 30 and 10 ppm levels, respectively. In females, the incidence was 44/50 and 1/50 at the 100 and 30 ppm levels. The incidence of megalocytosis was 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 100 ppm TS/DOS males; the increased incidence of these lesions was statistically significant at this level. Five hyperplastic nodules occurred in males at the 100 ppm level and 1 was seen at the 30 ppm level. Presence of hyperplastic nodules indicated regeneration was occurring in these livers. There were 9 hyperplastic nodules in 100 ppm females and 1 in a control female; this increase was statistically significant. Cystoid degener ation, characterized by areas of multilocular microcysts in the liver parenchyma, 0281CR0012 (FM-3924) -3- 001&29 145 also was increased in male rats from the 100 and 30 ppm groups and in females from the 100 ppm group. Incidence of this lesion in males was 4/50, 15/50, 8/50 and 6/50 at 0, 100, 30 and 10 ppm, respectively. The increased incidence at the 100 ppm level was statistically significant. In females, the incidence of cystoid degeneration was 4/50 in the 100 ppm group and 0/50 in all other groups. Occurrence of these liver histomorphologic changes correlated with elevations in alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase levels observed in 100 ppm male rats. The markedly reduced incidence and severity of histomorphologic liver changes in female rats parallels the absence of change in liver specific serum biochemical values in females. There was no direct or indirect compound effect in tissues other than liver at the 1 year interim sacrifice. In TS/DOS rats, changes which were considered secondarily compound related, probably through FM-3924 altered liver metabolism of endogenous steroids, were observed in the adrenals and ovaries. In the adrenals, a statistically significant increased incidence of nodular hyperplasia of the cortex occurred in males at the 100 ppm level. Incidence of this lesion was 2/49, 11/50, 0/49 and 5/50 at the 0, 100, 30 and 10 ppm levels, respectively. In females, there was a dose related occurrence of tubular hyperplasia of the ovarian stroma. Tubular hyperplasia is a non-neoplastic diffuse increase in tubular elements of the ovarian stroma which was usually bilateral and associated with absent or markedly reduced follicular development. The incidence of this condition, which was statistically significant at all dose levels, was 0/48, 15/48, 11/48 and 6/47 at the 0, 100, 30 and 10 ppm levels, respectively. An increased incidence of accumulations of foamy alveolar macro phages in the lung, which was probably compound related, was statistically significant in males and females at the 100 ppm level. The incidence of this condition at the 0, 100, 30 and 10 ppm levels, respectively, was 10/50, 23/50, 15/50 and 18/50 in males and 14/50, 27/50, 15/50 and 14/50 in females. There was no increased incidence of neoplasia suggestive of a compound effect in male rats. Incidence of primary liver tumors (hepatocellular carcinomas) in males was 3/50, 2/50, 1/50 and 1/50 at 0, 100, 30 and 10 ppm, respectively. In females, the only occurrence of primary liver tumors was at the 100 ppm level where there were 3 hepatocellular carcinomas and 4 hepatocellular adenomas. This increased incidence of these primary liver tumors in high dose female rats was not statistically significant. There was no other incidence of neoplasia 0281CR0012 (FM-3924) -4- G01fi30 146 suggestive of a compound effect in female rats. Other microscopic lesions in tissues from FM-3924 treated rats were typical of naturally occurring inflammatory, degenerative and neoplastic lesions in an ageing population of Charles River CD rats. Commonly occurring inflammatory lesions included chronic nonsuppurative myocarditis with associated myocardial fibrosis, mononuclear inflammatory cell infiltrate into the portal triads of the liver which was frequently associated with portal bile duct proliferation and perivascular mononuclear inflammatory cell infiltrate and multifocal chronic interstitial pneumonia in the lung. There were a number of non-neoplastic lesions which, although they had a statistically significant variation in incidence compared to control group levels, were not considered to be of toxico logical significance. These included decreased incidence of chronic myocarditis in 100 ppm females, decreased incidence of perivascular mononuclear cell infiltrate in the lung of 100 ppm males, increased incidence of vascular mineralization in the lung of 100, 30 and 10 ppm females, decreased incidence of interstitial pneumonia in 10 ppm males, increased incidence of vascular mineralization in the testes of 10 ppm males and decreased incidence of epithelial hyperplasia of the urinary bladder epithelium of 10 ppm females. Some of the more commonly occurring degenerative lesions in this study included adrenal cortical vacuolation and sinusoidal ectasia, focal mineralization in large pulmonary artery branches in the lung, focal acinar atrophy in the pancreas and chronic progressive nephropathy. Pituitary adenomas were the most common neoplasm in male and female rats. Mammary adenocarcinomas and fibroadenomas also were frequently observed in female rats. Overall, the health of the rats in this study was excellent, with organs free of lesions of common infectious diseases which would have had an impact upon survival or the validity of the study. Robert G. Geil, D.V.M. Diplomate, American College of Veterinary Pathologists 0281CR0012 (FM-3924) -5- 147 TABLE OF CONTENTS Table Number Page 1 Macroscopic Incidence for Males - 1Year In te ri m.................. 1 2 Macroscopic Incidence for Females - 1Year In t e r i m................ 2 3 Macroscopic Incidence for M a l e s .................................... 3-3 4 Macroscopic Incidence for F e m a l e s.................................. 3-S 5 Non-ncoplastic Incidence for Males - 1 Year I n te ri m............. u-12 3 Nnn-neoplastic Incidence for Females - 1 Year I n te ri m........... 13-- 1 *3 7 Non-neoplastic Incidence for M a l e s ............ ................... 17-2* 7 Mon-neoplastic Incidence for F e m a l e s ............................... 27-33 'J Neoplastic Incidence for Males - 1Year I n t e r i m.................... 37 13 Neoplastic Incidence for Females - 1 Year I n t e r i m ............... 3.- 11 Neoplastic Incidence for M a l e s ......................................3-^") 12 Neoplastic Incidence for F e m a l e s ................................... 41-32 Appendix Table Number Page 1 Single Tabulated Animal Report - 1 Year I n t e r i m ..................1-2- 2 Single Tabulated Animal R e p o r t ......................................?"-2~l 3 Tissue Inventory - 1 Year I n t e r i m .................................. 232-233 ; Tissue I n ve nt or y.......................................................236-317 148 Macroscopic Incidence for Males Rlker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Project Number: 0231CR0012 Species: Rat Site/ Description Group 1 Group 2 No visible lesions Eye opacity atrophy Liver pale/tan color Mesentary fat necrosis Kidney hydronephrosis cystic lesion Skin hair loss Soft Tissue (thorax) mass Soft Tissue (leg) swollen foot 97 1 1 25 1 1 1 1 1 1 Table 1 Titles: Group 1 CONTROL Group 2 FM-3924 0 ppm 100 ppm 001G33 Macroscopic Incidence Page: 1 149 Macroscopic Incidence for Females Rlker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Stu<(y 1n Rats - One Year Interim Table: 2 Project Number: 0281CR3012 Species: Rat Site/ Description Group I Group 2 No visible lesions Eye atrophy Pituitary enlarged Adrenal enlarged Liver pale/tan* herniated lobe Mesentary mass Kidney hydronephrosis Uterus cystic lesion enlarged dilated, fluid filled Maimary SIand mass Skin hair loss mass 59 1 3 1 11 1 11 1 1 1 I 1 21 1 Titles: Group 1 CONTROL Group 2 FM-3924 0 ppm 100 ppm G01G34 * includes "possibly" Macroscopic Incidence Page: 2 1 Macroscopic Incidence for Males R1ker Laboratories, Inc. 3M FM-3924: Two Year Oral Tox1c1ty-0ncogen1c1ty Study In Rats Table 3 Project Number: 0281CR0012 Species: Rat Site/ Description Group 1 Group 2 Group 3 Group No visible lesions Brain dark area Eye opacity/cloudy ulcer/lesion atropny Pituitary nass/enlarged/raised lesion dark/hemorrhagic/red foci Thyroid enlarged Adrenal enlarged/mass cyst Throax (internal) fluid filled Thymus enlarged* hemorrhagic/hamorrhagic lesion Lung mottled frothy tracheal exudate consolidation* mass/raised lesion hyperemi c Heart flaccid/flabbly enlarged* pale Abdomen (internal) gas, gastrointestinal tract stomach empty of food mass, omentum fluid filled Esophagus enl arged'.thickened wall Stomach edema/thlckened wall enlarged rugae erosi ons/ulcerations* Small Intestine mass hemorrhage 11 7 8 16 11 112 211 1 7 13 18 10 4431 1 1 1 2333 1 11 11 1 1 1 1 1 1 1 1 1 1 1 11 1 11 1 1 11 11 1111 Titles: Group 1 Group 2 Group 3 Group 4 CONTROL FM-3924 FM-3924 FM-3924 0 ppm 100 ppm 30 ppm 10 ppm GG1G3S Includes "possibly" Macroscopic Incidence Page: 3 151 Macroscopic Incidence for Males Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Tox1c1ty-0ncogen1c1ty Study 1n Rats Table 3 Project Number: 0281CRQ012 Species: Rat Site/ Description Large Intestine hemorrhagic Pancreas mass/nodule Liver pale/pale lobes* mass/nodul/raised lesion mottled* yellow/pale foci/lesion enlarged Infarct dark lesion shrunken lobes irregular surface Spl een enlarged raised lesion pale foci pale, depressed area dark small* Lymph node (mesenteric/abdominal) enlarged hemorrhagic mass Mesentery nodular/enlarged/thlckened vessels bloody cystic lesion Kidney enlarged, pale, pitted pale, pitted pitted/rough surface pale, enlarged* pale pale area hydronephrosis, pelvic dilatation cystlc/polycystic ulcerated area mass Group 1 Group 2 Group 3 Group 1 21 10 6 4 5 362 1 9 13 18 1 13 1 1 1 1 3321 12 2 1 1 21 22 2 1 11 1 3232 2 11 1 1 111 23 3 32 1 2 Titles: Group 1 Group 2 Group 3 Group 4 CONTROL FM-3924 FM-3924 FM-3924 0 ppm 100 ppm 30 ppm 10 ppm G0153G * includes "possibly" Macroscopic Incidence Page: 4 152 Macroscopic Incidence for Males Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table 3 Project Humber: C231CRQQ12 Species: Rat Site/ Description Urinary Bladder distended hematuria/filled with reddish/dark fluid hemorrhagic wall calculi Testis/Epididymis smal 1 enlarged* Prostate enlarged/thickened/mass edematous small Mammary Gland mass Skin ulcers/i nflamed/ci rcular/rai sed lesions, hind footpads dermati tis/ulcer/lesion/ inflamed area* moist area hair loss mass/thickening abscess Soft Tissue (neck) mass Soft Tissue (thorax) mass Soft Tissue (leg) swollen paws/feet Bone swollen joints Group 1 Group 2 Group 3 Group 4 11 2 1 11 4353 11 11 1 1 11 743 5 1 31 1 11 44 12 1 2 1 11 11 Titles: Group I Group 2 Group 3 Group 4 COMTROL FM-3924 FM-3924 FM-3924 0 ppm 100 ppm 30 ppm 10 ppm G01G37 * includes "possibly" Macroscopic Incidence Page: 5 153 Macroscopic Incidence for Females Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table 4 Project Humber: 0281CR0012 Species: Rat Si te/ Description Group 1 Group 2 Group 3 Group No visible lesions Eye opacity/cloudy inf1animation atrophy Pituitary mass/enlarged/raised lesion hemorrhagic/darlc lesion cyst Thyroid enlarged Adrenal enlarged mass/raised lesion pale Thorax (internal) fluid filled mass Thymus enlarged Lung mottled consol idation nodule pale hemorrhagic filled with red fluid Lymph Node (bronchial) enlarged Heart pericarditis* Stomach ulcerati ons/erosi ons enlarged rugae red mucosal areas/reddened blackish, yellowish fluid contents Small Intestine 1nf1amed thickened walls Large Intestine impaction mass 4644 321 11 1 25 23 30 33 11 1 1 8335 41 1 1 1 1 1 2 1 1 1 1 1 1 1 11 1 2 1 Titles: Group 1 Group 2 Group 3 Group 4 CONTROL FM-3924 FM-3924 FM-3924 0 ppm 100 ppm 30 ppm 10 ppm G01G38 includes "possibly" Macroscopic Incidence Page: 6 154 Macroscopic Incidence for Females Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table 4 Project Number: 0231CR0012 Species: Rat Si te/ Description Group 1 Group 2 Group 3 Group 4 Pancreas mass/nodule Liver pale* mass/nodule/raised lesion mottled circular lesion/pale foci/pale lesion/ yellowish lesion enlarged* dark red area/lobe rough/irregular surface dark color/dark brown Spleen enlarged* smal 1 Lymph node (mesenteric/abdominal) enlarged reddened Kidney enlarged, pale, pitted enlarged* pale, pitted pitted mottl ed cyst congenital absence, left Urinary Bladder enlarged calculi mass thickened walls Ovary mass cyst Uterus enlarged filled with dark/bloody fluid mass cystic lesion dark area/lesion prolapsed congenital absence of left horn, ovary Vagina mass 11 10 6 8 10 28 1 4923 913 2111 1 12 2 5 52 1 2 21 1 21 1 11 12 21 11 32 1 1 1 1 1 11 1 2 2 1 21 111 22 1 ] 1 Titles: Group 1 Group 2 Group 3 Group 4 CONTROL FM-3924 FM-3924 FM-3924 0 ppm 100 ppm 30 ppm 10 ppm C-01G39 * includes "possibly Macroscopic Incidence Page: 155 Macroscopic Incidence for Females Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table 4 Project Number: 0Z81CRO012 Species: Rat Site/ Description Group 1 Group 2 Group 3 Group 4 Mammary Gland mass/nodule milk cyst Skin raised/inflamed/ulcerated lesion, footpad mass raised lesion hair loss/thinning circular lesion Tissues (neck) reddened, gland-like structures Tissues (leg) swollen foot mass 27 14 24 19 122 11 12 2 4 1 2123 1 1 1 Titles: Group 1 Group 2 Group 3 Group 4 CONTROL 0 ppm FM-3924 100 ppm FM-3924 30 ppm FM-3924 10 ppm 001^40 Macroscopic Incidence Page: 8 156 Non-Neoplastic Incidence for Hales Riker Laboratories, Inc. 3H FM-3524: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 5 Project Number: 0281CR00I2 Species: Rat Tissue/ Diagnosi s/ Modi fier Adrenal Within normal limits Cortical vacuolation mild Nodular hyperplasia, cortex moderate Sinusoidal ectasia, cortex moderate Aorta Within normal limits Bone Marrow Within normal limits Brai n Within normal limits Esophagus Within normal limits Eye Within normal limits Keratitis, acute marked Heart Within normal limits Myocarditis, chronic nonsuppurative mild Ki dney Within normal limits Calculus Chronic progressive nephropathy minimal mild Cyst Hydronephrosi s moderate Nephritis, interstitial, chronic mi 1d Pyelitis, acute minimal Large Intestine Within normal limits Liver Within normal limits Group 1 Group ( 15) 12 1 1 1 1 1 1 ( 15) 15 '( 14) 14 ( 15) 15 ( 15) 15 ( 15) 15 0 0 ( 15) 14 1 1 ( 15) 5 1 8 5 3 1 1 1 1 1 1 1 ( 15) 15 ( 15) 7 ( 15) 15 0 0 0 0 0 0 ( 15) 15 ( 15) 15 ( 15) 15 ( 15) 15 ( 15) 14 1 1 ( 15) 15 0 0 ( 15) 7 0 8 5 2 0 0 0 0 0 0 0 ( 14) 14 ( 15) 0 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm (1 * Total Examined 001G41 Microscopic Incidence Page: 9 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Tox1c1ty-0ncogen1c1ty Study 1n Rats - One Year Interim Table: 5 Project Number: 0281CR0012 Species: Rat Tissue/ Diagnosis/ Modifier Liver (continued) Hepatocyte alteration, vacuolated minimal mi 1d Hepatocyte vacuolation mild moderate Megalocytosis mild moderate marked Necrosis minimal mild Portal bile duct proliferation minimal mild Portal mononuclear cell infiltrate minimal mild Lung Within normal limits Alveolar macrophages mild Atelectasi s mild Hemorrhage mild moderate marked Hyperplasia, septal cell mild Perivascular mononuclear infiltrate minimal mild Pneumonia, interstitial, chronic minimal mild Vascular mineralization minimal mild Group 1 Group 2 ---------- ---------- 2 1 1 0 0 0 0 0 0 0 0 0 0 5 1 4 7 1 6 ( 15) 1 3 3 1 1 6 6 0 0 1 1 2 0 2 3 1 2 7 4 3 0 0 0 14 8 6 15 5 5 5 6 1 5 8 2 6 14 1 13 ( 15) 1 3 3 1 1 6 3 2 1 0 0 5 1 4 3 0 3 9 1 8 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm () * Total Examined Microscopic Incidence Page: 10 158 Non-Neoplast1c Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table Project Number: 0281CR0012 Species: Rat 5 Tissue/ Diagnosis/ Modifier Lymph Node (mesenteric) Within normal limits Hemorrhage mild Hemosiderosis mild Mannary Gland Within normal limits Mesentery Necrosis, fat marked Steatitis, chronic moderate Pancreas Within normal limits Acinar atrophy mild moderate Pancreatitis, chronic mild Parathyroid Within normal limits Pituitary Within normal limits Cyst Prostate Within normal limits Salivary Gland Within normal limits Small Intestine Within normal limits Spinal Cord Within normal limits Spleen Within normal limits Hemosiderosis mild Stomach Within normal limits Testis/Epididymis Within normal limits Group 1 Group 2 ( 13) 13 0 0 0 0 ( 3) 3 ( 1) 1 1 1 1 ( 15) 11 3 2 1 3 3 ( 7) 7 ( 14) 13 1 ( 15) 15 ( 15) 15 ( 15) 15 ( 14) 14 ( 15) 15 0 0 ( 14) 14 ( 15) 15 ( 14) 13 1 1 1 1 ( 1) 0 ( 0) 0 0 0 0 ( 14) 14 0 0 0 0 0 ( 5) 5 ( 13) 11 1 ( 15) 15 ( 13) 13 ( 15) 15 ( 14) 14 ( 15) 14 1 1 ( 14) 14 ( 15) 13 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm 0 * Total Examined 001G 43 Microscopic Incidence Page: 11 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 5 Project Number: 0231CR0012 Species: Rat Tissue/ Diagnosis/ Modi fier Testi s/Epi didymi s (conti nued) Tubule atrophy, aspermatogenesis mild Vascular mineralization mild Thyroid Within normal limits Follicular hyperplasia, cystic moderate Trachea Within normal limits Urinary Bladder Within normal limits Group 1 Group 2 ---------- ---------- 0 G 0 ( 11) 11 0 0 ( 15) 15 ( 15) 15 1 1 1 1 ( 12) 11 1 1 ( 15) 15 ( 14) 14 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm () = Total Examined 160 G01G44 Microscopic Incidence Page: 1 Non-Neoplastic Incidence for Females Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 5 Project Number: 02S1CR0012 Species: Rat Tissue/ Diagnosis/ Modi fier Adrenal Within normal limits Cortical degeneration mild Sinusoidal ectasia, cortex mild marked Aorta Within normal limits Bone Marrow Within normal limits Brain Within normal limits Esophagus Within normal limits Eye Within normal limits Atrophy marked Panophthalmitis . marked Heart Within normal limits Myocarditis, chronic nonsuppurative minimal Kidney Within normal limits Calculus mild moderate Chronic progressive nephropathy mild Cyst mild Hydronephrosi s moderate Hyperplasia, pelvic epithelium mild Pelvic mineralization mi nimal mild moderate Group 1 Group ( 15) 10 2 2 4 3 1 ( 14) 14 ( 15) 15 ( 15) 15 ( 15) 15 ( 15) 14 1 1 1 1 { 15) 14 1 1 ( 15) 5 4 1 1 1 1 1 1 1 1 1 1 4 4 0 0 ( 15) 13 1 1 1 1 0 ( 15) 15 ( 15) 15 ( 15) 15 ( 12) 12 ( 15) 15 0 0 0 0 ( 15) 15 0 0 ( 15) 12 1 0 0 c 2 0 0 0 0 0 0 2 0 1 1 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm () * Total Examined G 01 G45 Microscopic Incidence Page: 13 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 5 Project Number: 0231CR0012 Species: Rat Tissue/ Diagnosis/ Modifier Large Intestine Within normal limits Nematodiasis Liver Within normal limits Hepatocyte alteration, vacuolated mild Hepatocyte vacuolation minimal mild Megalocytosis minimal mild moderate Pigment, Kupfer cell mild Portal bile duct proliferation mild Portal mononuclear cell infiltrate minimal mild Telangiectasis moderate Lung Within normal limits Alveolar macrophages mild Bronchiectasi s mild Hemorrhage mild moderate Perivascular mononuclear infiltrate mild Pneumonia, interstitial, chronic mild Vascular mineralization mild Lymph Node (mesenteric) Within normal limits Group 1 Group 2 14) ( 15) 12 14 21 15) ( 15) 50 10 10 5 15 37 b5 8 0 14 04 07 03 01 01 23 23 2n 10 13 01 01 15) ( 15) 31 13 13 01 01 11 10 97 23 13 13 12 12 13 13 12) ( 14) 12 14 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm () = Total Examined 001G46 I 62 Microscopic Incidence Page: 14 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 6 Project Number: 0281CR0012 Species: Rat Tissue/ Diagnosis/ Modi fier Mammary Gland Within normal limits Galactocele Mesentery Necrosis, fat moderate Steatitis, chronic moderate Ovary Within normal limits Cyst Pancreas Within normal limits Pancreatitis, chronic mild Parathyroid Within normal limits Pituitary Within normal limits Salivary Gland Within normal limits Skin Within normal limits Small Intestine Within normal limits Spinal Cord Within normal limits Spleen Within normal limits Hemosiderosis mil d moderate Stomach Within normal limits Thyroid Within normal limits Trachea Within normal limits Urinary Bladder Within normal limits Group 1 Group 2 ( 15) 13 2 ( 1) 1 1 1 1 ( 15) 14 1 ( 15) 14 1 1 ( 6) 6 ( 15) 14 ( 15) 15 ( 2) 2 ( 15) 15 ( 14) 14 ( 15) 14 1 1 0 ( 15) 15 ( 14) 14 ( 15) 15 ( 12) 12 ( 15) 13 1 ( 1) 1 1 1 1 ( 14) 14 0 ( 15) 15 0 0 ( 4) 4 ( 15) 13 ( 14) 14 ( 1) 1 ( 15) 15 ( 15) 15 ( 15) 12 2 2 1 ( 15) 15 ( 13) 13 ( 14) 14 ( 14) 14 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm () * Total Examined C01G47 Microscopic Incidence Page: 15 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: S Project Number: 0231CRQ012 Species: Rat Tissue/ Diagnosis/ Modi fier Uterus Within normal limits Cystic glands marked Endometritis, chronic mild Hydrometra moderate Hyperplasia, glandular epithelium mil d moderate Metaplasia, squamous mi nimal mild moderate Group 1 Group ( 15) 12 1 1 0 0 0 0 2 2 0 2 0 2 0 ( 15) 7 0 0 1 1 2 2 1 0 1 6 1 4 1 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm () Total Examined G01G48 164 Microscopic Incidence Page: 15 Non-Neoplastic Incidence for Hales Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modifier Adrenal Within normal limits Atrophy mild marked Cortical degeneration mild Cortical vacuolation mi nimal mild moderate Hemorrhage marked Medullary cell hyperplasia minimal mild moderate marked Nodular hyperplasia, cortex minimal mild moderate marked Sinusoidal ectasia, cortex minimal mild moderate marked Aorta Within normal limits Mineralization mild Necrosi s Bone moderate Arthritis, synovitis; joints mild moderate marked Bone Marrow Within normal limits Group 1 Group 2 Group 3 Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 15) 1[ 34) 6 13 00 00 00 00 00 7 17 02 4 13 32 00 00 26 00 14 12 00 02 00 01 01 00 7p T 02 23 22 00 ( 15) ( 34) 13 34 10 10 10 10 ( 0) ( 2) 02 00 00 02 ( 15) ( 32) 15 32 ( 19) ( 31) 9 10 11 10 01 00 00 6 12 11 55 06 01 01 03 03 02 00 01 47 11 33 02 00 5 10 13 44 03 00 ( 15) ( 31) 15 31 00 00 00 00 ( 1) ( 1) 01 00 01 a0 ( 19) ( 31) 19 31 ( 14) ( 35) 48 00 00 00 02 02 3 12 01 23 13 00 00 05 01 03 01 00 00 00 00 00 00 7 13 00 43 14 21 ( 0) ( 0) 00 00 00 00 00 ( 0) ( 0) 00 00 00 00 ( 0) ( 0) 00 ( 12) ( 33) 7 19 00 00 00 04 04 19 o' 0 18 01 00 00 11 00 10 00 00 05 00 03 01 01 32 00 31 01 o0 ( 0) ( 0) 00 00 00 0 00 { 1) ( 0) 19 10 0 00 ( 0) ( 0) 00 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm C01G49 () = Total Examined DOS* Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) |65 Microscopic Incidence Page: 17 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modifier Brain Within normal limits Abscess mild Hemorrhage moderate Esophagus Within normal limits Eye Within normal limits Cataract Keratitis, acute narked Keratitis, chronic mild marked Panophthalmitis marked Phthsis bulbi marked Retinal atrophy Heart mild Within normal limits Endocarditis, chronic moderate Epicarditis, chronic mil d Myocardial fibrosis minimal mil d moderate Myocarditis, chronic nonsuppurative minimal mil d moderate Kidney Within normal limits Calculus minimal moderate marked Group 1 Group 2 G r o u p *J> Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 16) ( 34) 14 33 10 10 10 10 ( 15) ( 33) 15 33 ( 12) ( 33) 12 32 00 00 00 00 00 00 00 00 00 00 01 01 ( 15) ( 34) 8 23 00 00 00 00 32 00 32 00 4 10 02 47 01 ( 16) ( 34) 40 01 01 00 00 ( 13) ( 31) 17 30 00 00 00 00 ( 17) ( 28) 17 2S ( 17) ( 31) 14 29 00 00 00 00 00 00 02 02 20 10 00 00 ( 19) ( 31) 12 19 00 00 00 00 14 00 14 00 5 10 12 48 00 ( 13) ( 31) 10 10 00 00 00 ( 0) ( 0) 00 0n 00 00 00 ( 9) ( 15) 9 15 ( 1) ( 1) 01 00 10 10 00 00 00 00 00 00 00 00 00 ( 15) ( 35) 3 11 00 00 00 00 15 02 12 01 5 20 00 4 19 11 ( 15) ( 35) 4*5 V 06 00 02 02 ( 0) ( 0) 00 00 00 00 00 ( 9) ( 35) 3 36 { 1) ( 4) 01 01 00 00 11 10 01 00 00 00 00 01 01 ( 13) ( 33) 9 15 01 01 10 10 10 0 -> SJ 16 03 2 13 01 2 15 01 ( 12) ( 38) 13 02 00 00 00 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 166 GOlsso Microscopic Incidence Page: 10 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project (lumber: 0281CR0Q12 Species: Rat Table: 7 Tissue/ Diagnosis/ Modi fier Kidney (continued) Chronic progressive nephropathy minimal mild moderate marked Cyst moderate narked Hydronephrosi s mild moderate Hyperplasia, pelvic epithelium mild Mineralization mild Nephrosi s moderate Papillary necrosis moderate Pelvic mineralization minimal mild moderate Pigment, conv. tub. epithelium moderate Protein resorption droplets mild marked Pyelitis, acute minimal mild moderate Pyelonephritis, acute mil d moderate Large Intestine Within normal limits Nematodiasis Liver Within normal limits Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 10 34 14 5 15 2 11 23 13 01 12 12 10 02 00 00 00 00 10 10 10 10 13 01 1 u0 00 00 00 00 00 00 00 00 00 00 10 10 00 ( 14) ( 34) 14 23 05 ( 16) ( 31) 20 12 31 45 8 15 05 04 00 00 00 31 00 31 10 10 10 10 20 20 00 00 00 00 00 00 10 10 00 00 00 00 00 00 00 22 01 21 ( 17) ( 31) 17 27 04 ( 19) ( 31) 00 11 29 17 6 14 07 41 00 00 00 00 00 00 00 00 00 00 00 00 00 00 03 02 04 02 00 00 10 10 00 02 00 01 01 01 00 01 ( 0) ( 1) 01 00 ( 15) ( 35) 02 10 34 26 7 19 15 04 11 00 00 02 00 00 11 11 10 10 00 00 00 00 26 00 2 00 00 00 10 00 10 02 01 01 00 00 00 0 ( 0) ( 0) 00 00 ( 12) ( 33) 30 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm OOlf,51 {) * Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrifice(s) 167 Microscopic Incidence Page: 19 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modi fier Liver (continued) Atrophy marked Cystoid degeneration mi nimal mild moderate Fibrosis mild marked Hematopoiesis, extramedullary mild Hepatocyte alteration, basophilic mild moderate Hepatocyte alteration, vacuolated minimal mild moderate Hepatocyte vacuolation minimal mild moderate marked Hyperplastic nodule Megalocytosis minimal mild moderate marked Mitotic activity, increased mild Necrosis minimal mild moderate marked Pigment mi nimal mild Portal bile duct proliferation minimal Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 00 00 04 01 02 01 00 00 00 00 0 02 01 01 19 00 17 02 8 14 01 4 13 20 20 00 00 00 rj\ 0 00 00 00 00 21 00 10 11 00 00 00 00 6 21 00 00 00 2 13 02 2 10 01 00 00 00 10 10 03 01 02 09 00 06 03 15 24 01 90 3 14 31 05 14 23 21 4 10 5 10 37 00 00 73 01 32 20 20 12 01 11 8 21 20 00 00 17 00 17 00 00 00 00 00 00 03 03 00 3 13 00 39 04 7 12 01 67 14 00 01 4 24 3 12 13 04 00 00 00 00 00 00 00 00 00 00 00 5 16 13 10 10 15 01 14 00 11 01 10 00 00 00 00 00 0 12 01 0 10 01 39 02 25 10 01 00 1 26 1 21 05 00 00 10 10 02 01 01 00 00 00 0 00 3 25 11 Titles: Group I CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm c o ir ,52 () = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 168 Microscopic Incidence Page: 20 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modifier Liver (continued) Portal bile duct proliferation mild moderate Portal mononuclear cell infiltrate minimal mild moderate Telangiectasis mild Lung Within normal limits Alveolar macrophages minimal mild moderate Atelectasis marked Edema mild moderate marked Fibrosi s mild Granuloma mild Hemorrhage mild moderate marked Hyperplasia, septal cell mild moderate Mineralization mild Necrosi s marked Peribronchial lymphoid hyperplasia mild Perivascular mononuclear infiltrate minimal mild Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 5 21 10 7 30 02 7 28 00 00 00 ( 16) ( 34) 01 55 12 42 01 00 00 30 10 10 10 10 10 00 00 64 21 12 31 00 00 00 00 00 10 10 01 01 2 19 0n 2 14 6 21 00 7 23 10 5 23 00 00 00 ( 19) ( 31) 00 6 17 00 6 16 01 00 00 00 00 00 00 00 00 00 00 10 6 72 33 01 00 00 00 00 00 00 00 00 00 16 00 16 3 13 10 9 20 15 7 15 10 10 10 ( 15) { 35) 13 5 10 00 58 02 00 00 00 00 00 00 00 00 10 10 4 10 15 34 01 02 01 01 01 01 00 00 00 00 6 14 01 6 12 2 25 00 6 35 12 4 33 10 00 00 ( 12) ( 38) 01 2 16 00 2 15 01 10 10 10 10 00 00 00 0G 00 00 26 13 13 00 00 00 00 00 00 00 00 00 00 1 14 00 1 14 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm 001^53 () = Total Exami ned DOS* Unscheduled Death!s) SAC* Protocol Scheduled Sacrifice(s) 169 Microscopic Incidence Page: 21 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: Q281CR0012 Species: Rat Table: 7 Tissue/ Diagnosi s/ Modifier Lung (continued) Perivascular mononuclear infiltrate moderate Pneumonia, foreign body moderate Pneumonia, interstitial, chronic minimal mild moderate Thrombus Vascular mineralization minimal mild moderate Lymph Node Sinusoidal ectasia moderate Lymph Node (abdominal) Hemorrhage mi 1d Sinusoidal ectasia marked Lymph Node (mesenteric) Within normal limits Hemorrhage minimal mild moderate Pigment mild Sinusoidal ectasia moderate Mesentary Cyst Polyarteri ti s marked Pancreas Within normal limits Acinar atrophy minimal mild moderate Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 03 00 00 2 14 00 1 11 13 10 10 33 02 10 31 00 ( 0) ( 0) 00 00 ( 0) ( 0) 00 00 00 00 ( 12) ( 33) 10 29 24 12 11 00 00 00 00 00 ( 0) ( 2) 00 02 c L. ( 13) ( 33) 10 24 24 00 12 11 00 01 00 00 00 00 05 25 01 00 05 25 00 00 00 00 17 31 13 31 01 01 17 29 12 23 01 01 ( 0) ( 0) ( 0) ( 0) 00 00 00 00 ( 0) ( 0) ( 0) ( 1) 00 01 00 01 00 01 00 01 ( 13) ( 29) ( 1) ( 1) 10 25 00 23 01 02 00 10 00 11 0l 31 01 00 0Q 10 90 1 0 0 0 ( 0) ( 1) ( 1) ( 0) 01 00 00 10 00 10 ( 13) ( 29) ( 14) ( 35) 11 21 7 26 35 44 10 10 03 22 21 12 00 10 10 04 00 04 00 00 11 34 17 10 27 00 ( 0) ( 1) 01 01 ( 0) ( 0) 00 00 00 00 ( 0) ( 1) 00 00 00 00 00 00 A0 0 0 ro> 00 ( 0) ( 0) 00 00 00 ( 11) ( 37) 10 23 16 10 05 01 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm 0 = Total Examined D0S= Unscheduled Death(s) 170 SAC= Protocol Scheduled Sacrifice(s)1 00ir,54 Microscopic Incidence Page: 22 Mon-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR3312 Species: Rat Table: 7 Tissue/ Diagnosi s/ Modifier Pancreas (continued) Acinar atrophy marked Hyperplasia, acinar cell moderate Hyperplasia, islet cell mild moderate Pancreatitis, chronic marked Polyarteri tis mild moderate marked Parathyroid Within normal limits Fibrosi s moderate Hyperpl asia mild moderate marked Pituitary Within normal limits Cyst Hyperplasia mild Preputial Gland Preputial adenitis, acute moderate marked Prostate Within normal limits Edema moderate Hyperpl asia moderate Prostatitis, acute minimal mild moderate marked Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 01 00 00 02 00 02 00 00 04 00 02 02 ( 6) ( 15) 6 15 00 00 30 00 00 00 ( 15) ( 33) 7 13 22 02 02 ( 0) ( 0) 30 00 00 ( 13) ( 33) 10 27 13 10 3 nw 33 3G 00 12 13 11 01 00 00 03 01 0 OC 00 00 00 00 00 00 ( 13) ( 16) 12 13 00 00 12 11 01 00 ( 17) ( 33) 13 12 02 00 00 { 1) ( 3) 10 00 10 ( 15) ( 31) 13 29 03 30 01 01 21 01 10 00 10 n3 00 00 12 00 12 01 01 10 10 00 00 ( 9) ( IS) G 17 13 10 23 00 10 10 ( 15) ( 33) *T 14 01 03 00 ( 0) ( 1) 01 01 00 ( 12) ( 35) 9 25 00 u 0 30 00 38 01 11 13 13 00 01 01 00 00 03 00 30 02 00 02 00 ( 9) ( 25) 5 25 03 00 03 03 03 33 ( 11) ( 35) 4 13 1 iu 02 2 ( 3) ( 0) 03 30 00 ( I D ( 33) 9 34 r- 0 03 2 02 22 G0 31 01 20 Titles: Group 1 CONTROL 3 ppn Group 2 FM-3924 190 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 13 ppm () = Total Examined D0S= Unscheduled 0e3th(s) SAC= Protocol Scheduled Sacrifice(s) 171 G01G55 Microscopic Incidence Page: 23 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR3012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modi fier Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC Prostate (continued) Prostatitis, chronic marked Salivary Gland Within normal limits Atrophy Sialadenitis, chronic minimal Skin Atrophy moderate Cyst, dermal inclusion Dermatitis, chronic mild Pododermatitis, ulcerative marked Ulcer marked Small Intestine Within normal limits Polyarteritis moderate marked Spinal Cord Within normal limits Spleen Within normal limits Atrophy mild moderate Fibrosi s moderate Hematopoiesis, extramedullary, increased mild moderate marked Hemosiderosis mi nimal mild moderate Necrosi s moderate 00 00 ( 12) ( 32) 12 31 00 01 01 ( 3) ( 7) 00 00 00 00 03 35 35 10 10 ( 14) ( 34) 13 32 02 0 11 01 ( 15) ( 32) 15 32 ( 15) ( 34) 6 23 00 00 00 01 01 40 20 10 10 5 11 g0 5 11 00 01 01 00 00 ( 15) ( 33) 14 30 00 00 00 ( 3) ( 3) 00 00 00 00 0c 22 22 00 03 ( 17) ( 31) 17 31 Q0 00 00 ( 19) ( 31) 19 31 ( 19) ( 31) 5 13 30 20 10 33 30 0 20 00 1a 13 13 00 9 13 10 g0 00 01 01 ( 13) ( 33) 12 33 10 00 00 ( 6) ( 10) 10 10 30 10 10 49 49 00 00 ( 0) ( 1) 01 00 00 30 ( 3) ( 0) 30 ( 15) ( 35) 9 23 03 30 00 00 0Q 02 01 01 00 54 01 43 10 00 00 rJ\ 0 0Q ( 10) ( 32) 13 32 00 00 00 ( 1) ( 5) 00 00 01 00 00 14 14 00 00 ( 0) ( 0) 00 ou 0 00 nu 0 ( 0) ( 3) 0n ( 12) ( 33) 7 35 00 30 n0 00 00 2 10 10 03 33 00 13 23 00 00 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm 001G5G () * Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 172 Microscopic Incidence Page: 24 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 3281CRQ012 Species: Rat Table: 7 Tissue/ Diagnosi s/ Modi fier Stomach Within normal limits Edema moderate marked Gastritis, acute moderate Mineralization mild Necrosis modera te Ulcer moderate marked Testis/Epididymis Within normal limits Leydig cell hyperplasia minimal Mineralization mi 1d Polyarteri ti s minimal mil d moderate marked Tubule atrophy, aspermatogenesis minimal mil d moderate marked Vascular mineralization minimal mild moderate Thyroid Within normal limits Cyst, colloid mild FoTlicular hyperplasia, cystic mild moderate marked Group 1 Group 2 Group 3 Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 16) 11 3 2 1 ( 33) 33 0 0 0 00 00 00 00 00 00 10 00 10 ( 15) ( 33) 13 25 00 00 01 01 15 00 11 01 03 34 00 11 11 12 00 00 00 00 ( 12) ( 31) 11 25 01 01 01 00 01 00 ( 19) ( 31) 15 31 20 20 00 00 00 00 00 20 20 00 00 00 ( 19) ( 31) 13 23 10 10 01 01 02 00 01 00 01 33 10 01 c2 20 33 21 12 00 ( 13) ( 27) 12 22 11 00 02 1 A0 01 ( 15) ( 35) 12 33 10 10 D0 01 01 10 10 00 00 11 10 00 { 14) ( 35) 9 31 00 00 00 00 20 00 10 10 00 42 00 10 21 11 0z 00 02 03 ( 15) ( 33) 13 24 03 00 10 10 00 00 ( 11) (: 37) 13 35 00 00 00 00 00 00 00 00 00 11 00 10 ( 12) ( 33) 10 24 00 00 03 00 04 01 02 0i 00 13 03 00 10 03 16 02 13 01 ( 13) ( 35 ) 8 29 03 03 01 00 00 01 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3S24 30 ppm Group 4 FM-3924 10 ppm () = Total Examined D0S= Unscheduled Oeath(s) SAC= Protocol Scheduled Sacrifice(s) 173 001S57 Microscopic Incidence Page: 25 Non-Neoplastic Incidence for Hales (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Humber: 0231CR0Q12 Species: Rat Table: 7 Tissue/ Modifier Thyroid (continued) Hyperplasia, C cell mild moderate Hyperplasia, follicular cell mild Ultimobranchi4l cyst Trachea Within normal limits Cyst Tracheitis, acute mild Tracheitis, chronic mild moderate Urinary Bladder Within normal limits Calculus Cystitis, acute mil d moderate marked Cystitis, chronic mild Epithelial hyperplasia, papillary marked Epithelial hyperplasia, simple mild moderate marked Hemorrhage mild marked Ulcer Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 01 01 00 00 00 11 ( 15) ( 34) 15 34 00 00 00 00 00 00 ( 13) ( 33) 10 32 00 10 00 10 00 00 00 00 00 21 21 00 00 10 c0 10 00 22 22 00 00 00 11 ( 18) ( 29) 13 24 03 00 00 02 02 00 ( 13) ( 30) 14 30 00 20 10 0n y* 10 00 00 10 10 20 20 00 00 10 i0 00 00 03 03 00 00 00 24 ( 15) ( 35) 15 27 01 01 01 05 05 01 ( 13) ( 34) 11 30 01 12 nV' 1 10 01 01 01 00 00 24 11 12 01 00 00 00 01 02 01 01 10 10 11 ( 11) ( 37) 11 30 00 00 00 07 05 2J ( 11) ( 38) 9 37 10 00 00 00 00 00 00 00 00 1 r> 10 00 00 00 0A u 00 0A u Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 174 0015S Microscopic Incidence Page: Zi Non-Neoplastic Incidence for Females Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: 0 Tissue/ Diagnosis/ Modifier Adrenal Within normal limits Cortical atrophy moderate marked Cortical degeneration mild moderate marked Cortical vacuolation minimal mild moderate marked Hematopoiesis, extramedullary minimal mild moderate Medullary cell hyperplasia mild Necrosi s moderate marked Nodular hyperplasia, cortex mild moderate Pigment, brown mild Sinusoidal ectasia, cortex minimal mild moderate marked Aorta Within normal limits Mineral ization mild Bone Arthritis, synovitis; joints moderate Group 1 Group 2 Group 3 Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 25) ( 25) 20 00 00 00 25 10 13 02 32 00 21 11 00 40 00 30 10 i2 12 30 i0 20 0U 00 00 00 00 19 23 01 84 58 59 ( 21) ( 23) 17 23 20 20 ( 0) ( 0 ) 00 00 ( 15) ( 34) 46 11 11 00 00 00 00 00 55 00 45 10 01 00 00 00 00 01 01 00 00 00 10 10 00 01 01 ft 25 11 2 12 44 19 ( 14) ( 33) 14 33 00 00 ( 0) ( 1) 01 01 ( 25) ( 23) 22 10 00 10 36 1 y1j 23 00 52 10 21 21 00 20 3 0 10 10 01 01 10 00 10 11 10 01 00 00 20 19 21 54 a5 59 ( 0) { 0) 00 00 00 ( 0) ( 0) 00 0c ( 27) ( 22) 31 00 00 00 22 10 11 01 41 r\ 0 31 10 0 r) 10 10 00 00 00 00 00 00 00 00 -v '<-j1 00 0n 00 15 21 00 5G 75 39 ( 0) ( 0) 00 00 00 ( 0) ( 0) 00 00 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm 0 = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice!s) 001G59 Microscopic Incidence Page: 27 175 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0Q12 Species: Rat Table: 8 Ti ssue/ Diagnosi s/ Modi fier Bone Marrow Within normal limits Brain Within normal limits Clitoral Gland Cyst moderate Inflammation, chronic moderate Esophagus Within normal limits Eye Within normal limits Cataract Keratitis, acute marked Keratitis, chronic mi 1d Panophthalmitis marked Phthsis bulbi moderate Retinal atrophy mild moderate marked Heart Within normal limits Endocarditis, chronic mild Myocardial fibrosis mild moderate Myocarditis, chronic nonsuppurative minimal mild moderate Pericarditis, chronic moderate Kidney Within normal limits Group 1 Group 2 Group 3 Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 25) ( 25) 23 25 ( 25) ( 25) 25 24 ( 0) ( 0) 00 00 00 00 ( 15) ( 21) 14 21 ( 20) ( 23) 17 21 10 10 10 00 00 01 01 01 01 00 00 00 00 ( 25) ( 25) 19 14 00 n0 02 02 00 5 10 00 4 10 20 00 00 ( 25) ( 25) 33 ( 16) ( 34) 16 34 ( 15) ( 34) 16 34 ( 0) ( 0) 00 00 00 00 ( 13) ( 30) 13 30 ( 12) ( 34) 11 30 01 00 00 00 00 01 01 10 00 03 01 01 rJ\ 1 ( 16) ( 3) 15 31 00 00 01 00 nj> 1 02 32 00 00 00 00 ( 16) { 34) 44 ( 0) ( 0) 00 ( 3) ( 0) 30 ( 0) ( 0) 00 00 00 00 ( 25) ( 20) 25 20 ( 2) ( 2) 21 01 00 00 00 00 00 00 00 00 01 00 n0 G1 ( 27) ( 23) 22 17 01 01 23 23 00 2 rj 1i 14 00 l0 10 ( 27) ( 23) 53 ( 0) ( 0) 00 ( 1) ( 1) 11 ( 1) ( 1) 11 01 01 01 ( 24) ( 21) 24 21 ( 2) ( 2) 12 00 00 ru\ 0 l0 l0 00 00 00 00 00 03 c0 00 ( 20) { 22) 22 15 00 00 12 11 01 T5 9n 93 00 03 00 ( 23) ( 22) 65 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s)' 176 OOlu Microscopic Incidence Page: 73 Non-Neoplastic Incidence for Females (continued) Ri'<er Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR3Q12 Species: Rat Table: 3 Tissue/ Diagnosis/ Modifier Kidney (continued) Calculus moderate Chronic progressive nephropathy minimal mild moderate marked Cyst moderate Hematopoiesis, extramedullary mild moderate Hydronephrosi s moderate Hyperplasia, pelvic epithelium mild moderate Mineralization mild Nephritis, acute mild Nephrosi s mild moderate marked Pelvic mineralization minimal mild moderate marked Pigment, conv. tub. epithelium minimal mild Polyarteritis moderate Protein resorption droplets mild moderate marked Pyelitis, acute minimal Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 00 00 12 13 34 5 10 23 21 21 20 00 00 00 10 10 41 41 00 20 20 00 0c 70 10 30 2n 14 15 45 38 12 10 00 00 00 00 0Q 00 00 00 00 00 00 10 0 1 17 o4 0 12 01 10 00 00 03 00 00 00 03 01 01 00 0Q 00 00 00 00 00 00 Q J 10 23 3 10 19 12 02 05 0i 04 01 01 10 00 10 00 10 00 00 00 14 12 75 55 21 01 03 30 O L 0 10 10 03 03 21 11 10 00 00 00 30 2l i0 i 0i 12 12 5A 56 i2 03 00 00 Q 0o 0 "i 'j 00 00 00 30 11 10 01 01 10 12 '4 4 5f 01 31 0n 0Q 10 10 00 01 30 33 30 00 r\j 0 3n 10 10 11 0 1 01 13 13 50 57 11 13 10 00 13 00 00 43 1 r\ 00 3o 1i 00 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 130 ppm Group 3 FM-3924 33 ppm Group 4 FM-3924 10 ppm 0 = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 177 001G61 Microscopic Incidence Page: 29 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR3012 Species: Rat Table: 3 Ti ssue/ u 1a^iiub 1> / Modi fier Kidney (continued) Pyelitis, acute mild Pyelonephritis, acute moderate marked Vacuolation, conv. tub. epitheium minimal mild moderate Large Intestine Within normal limits Nematodiasis Liver Within normal limits Cystoid degeneration mild Hematopoiesis, extramedullary minimal mild moderate Hepatocyte alteration, basophilic mi nimal mild moderate Hepatocyte alteration, eosinophilic mild moderate Hepatocyte alteration, vacuolated mild Hepatocyte vacuolation mi nimal mild moderate marked Hyperplastic nodule Megalocytosis mi nimal mild moderate marked Group 1 --- -- DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 ----- DOS SAC Q0 l0 l0 00 l0 00 00 10 ( 24) ( 23) 22 22 11 ( 25) ( 25) 10 00 0 30 00 30 00 17 00 15 2 12 2 10 2 11 2 11 15 15 11 9 13 31 23 01 0 00 00 00 00 10 03 00 00 53 23 20 13 ( 14) ( 34) 13 31 03 ( 15) ( 34) 00 04 04 12 00 1o 03 32 00 02 00 00 00 00 05 0G 12 29 10 4 18 6 10 11 27 11 33 31 0 17 3 13 02 01 10 00 10 3 Cl 00 00 00 ( 1) ( 0) 10 00 ( 27) ( 23) 42 00 0 82 42 30 10 01 01 03 00 30 00 33 05 05 11 14 25 73 11 10 00 01 0 0l 00 00 11 03 03 00 10 33 13 30 ( 3) ( 0) 20 00 ( 23) ( 22) 41 00 00 13 03 00 30 35 2 20 11 33 03 00 05 06 15 12 31 or> 10 51 20 03 03 00 00 30 0 ru* Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () * Total Examined 00S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrificc(s) 178 G01G62 Microscopic Incidence Page: 30 Non-Kooplastic Incidence for Females (continued) Rimer Laboratories, Inc. 3M FM-332t: Two Year Oral Toxicity-Oncogenicity Study in Rats Project lumber: 32'51CR'J012 Species: Rat Table: Tl 5SU0./ Diagnosis/ Modi f ic r L iv e r (continued) M ito tic a c tiv ity , increased moderate Kecr jsi 3 minimal m ild noderote Marked Pigment, brown mi nir.ial m ild Pigment, hapatucyto ;3`i m'r.ir;] n i 1d Portal b ile duct pro! i feracion minimal m ild I'.KJGOrMtC r , i r ;jd P o rta l noriuni'.clcar c e ll i n f i l t r a t e minimal m ild nod^ra 12 i 01c.10"I ji, ud-j 1c m ild 1u."*.-'n*Jn W ithin normal lim it s Abscass A1 veol ar ri-icrophejes mi .li.mel m ild moderate Atel ectasi s mi 1c Cyst Edema mi 1d moderate Granelcma mi nim-al m ild Group 1 DOS SAC Group DOS SAC Group 3 DOS SAC Group DOS SAC 1J 10 Tl 00 1 X1 1; 2w JJ r> 0 0Q o' 'i 0J IZ V^ 0 J 12 1' X 1J 10 J 10 n 1J 1J 1 j ( 35) ( 25) C3 1J cJ 1c 0 r Wj 0 n J J 'J J2 J Jj m0 0j 20 0J 0 03 0 2 J1 *> 1 j r> 1 z1 zK 01 J 13 o J'i 03 1 13 1 ft 1 12 J U J0 ! 15) ( 35) 2 'J 15 17 1J 7 12 OC ** 0J > 'j JJ 03 0J J0 j 2 nj jj 0 Z 51 X J 11 20 10 1 /> J 0j 1J 0 J0 0 'j 00 7 1 oJ 2 11 0L. 'J J 9 J L) J r\ ,, ( 27) ( 23) z r) j0 5 X:J Xy j 03 J r\ 'J J 12 1j L3 2 o iX 01 J3 j _ 52 i 2j 2j e) 0Z 00 00 rU* r< cz 2 U7 0 f_ JJ 1 ,) JJ X2 Q3 J2 C 'J J Ti 3 ( 2 -) ( 22) X1 1 u2 2 P J 3 0 10 X1 w 1 "1 'j J 2 X i ') 11 Titles: Group 1 CONTROL a ppm Group 2 FM-3324 155 ppm Group 2 FM-39'M 33 ppm Group Mn f m -s?:* 13 ppm () = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice's) 179 001G63 Microscopic Incidence Page: 31 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 3 Tissue/ uidynoiii/ Modifier Lung (continued) Hemorrhage mild moderate marked Hyperplasia, septal cell mild Mi neral ization mild Pelvic mineralization mild Perivascular mononuclear infiltrate minimal mild moderate Pigment moderate Pleuritis, chronic moderate Pneumonia, acute exudative mild moderate Pneumonia, bronchopneumonia moderate Pneumonia, interstitial, chronic minimal mi 1d moderate Thrombus moderate Vascular mineral ization minimal mild Lymph Node (mesenteric) Within normal limits Hemorrhage mild moderate Polyarteritis mild moderate Group 1 ------------ DOS SAC Group 2 ---- DOS SAC Group 3 DOS SAC Group 4 ------ DOS SAC 95 33 11 01 00 00 00 00 00 03 49 01 47 01 01 01 00 n0 1a 00 10 00 00 43 0 43 00 00 00 12 10 00 12 10 ( 19) ( 23) 14 22 21 11 10 00 00 00 59 47 02 10 00 00 00 00 10 10 4 15 11 3 13 01 00 00 00 00 20 20 00 00 00 27 01 26 0 00 00 13 25 0w 13 25 ( 9) ( 29) r> 24 13 11 02 02 01 01 95 64 2a 1i 10 10 01 01 00 00 55 01 54 00 00 00 10 10 10 13 00 00 00 24 00 24 00 0 00 23 19 22 21 17 ( 3) ( 3) 72 00 00 00 00 00 00 83 50 23 10 01 01 00 00 00 00 63 01 vC 2 l0 00 00 00 00 00 30 00 10 10 37 00 27 13 10 1a 23 17 21 21 16 ( 1) ( 0) 00 00 00 00 00 00 0 ,1J*> Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () * Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) ]oU C_ -_01C64 Microscopic Incidence Page: 32 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: 3 Ti ssue/ Modi fier Lymph Node (mesenteric) (continued) Sinusoidal ectasia moderate Mammary Gland Within normal limits Galactocele Lobular hyperplasia moderate Ovary Within normal limits Cyst Tubular hyperplasia mild moderate marked Pancreas Within normal limits Acinar atrophy minimal mild moderate marked Cyst Hyperplasia, islet cell mi 1d Polyarteri ti s marked Parathyroid Within normal limits Hyperpl asia mild Sinusoidal ectasia moderate Pituitary Within normal limits Hemorrhage marked Necrosis moderate Pigment, brown moderate Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 10 10 ( 23) ( 23) 49 54 43 10 ( 25) ( 23) 19 17 33 00 00 00 00 ( 24) ( 25) 22 15 00 01 0? 03 00 01 00 00 03 00 ( 5) ( 0) 50 00 00 00 00 ( 22) ( 24) 57 10 13 13 13 00 90 00 0o ( 14) ( 33) 10 19 03 01 00 ( 14) ( 34) 12 14 05 2 12 25 07 Q0 ( 14) ( 34) 12 33 13 30 0 0n 10 00 00 13 10 30 00 ( 3) { 23) G 20 Q1 31 01 31 ( 15) ( 34) JO 13 03 30 03 nu 0 01 31 31 C1 ( 23) ( 23) 13 10 3 21 00 ( 25) ( 23) 19 12 23 47 43 02 02 ( 17) ( 17) 15 13 13 30 12 33 31 30 0n 00 r\ 3 03 ( 15) ( 15) 16 15 03 30 03 00 ( 23) { 21) 34 3 r\ 33 30 03 00 00 39 33 ( 25) ( 22) 14 9 J< 3 22 03 ( 25) ( 21) 23 13 15 15 33 12 30 ( 21) ( 23) 19 15 0? 03 00 32 J 3 90 01 31 31 31 ( 19) ( 13) 19 13 03 -a 3 03 30 ( 25) ( 21) 56 33 30 33 3O wn 0 03 Titles: Group 1 CONTROL 3 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) " 181 G01G65 Microscopic Incidence Page: 33 Mon-Neoplastic Incidence for Females (continued) Rlker Laboratories, Inc. 3M FH-3924: Two Year Oral Toxicity-Oncogenicity Study In Rats Project Number: 0281CR00I2 Species: Rat Table: 8 Tissue/ Diagnosis/ Modifier Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC CM L<SMI Sal1vary 61and Within normal limits Hemorrhage Sialadenitis, chronic mild moderate Skin Within normal limits Acanthosis mild Pododermatitis, ulcerative marked Ulcer moderate marked Small Intestine Within normal limits Ulcer Spinal Cord Within normal limits Malacia moderate Spleen Within normal limits Hematopoiesis, extramedullary, Increased minimal mild moderate marked Hemosiderosis mild moderate marked Stomach Within normal limits Edema moderate Gastritis, acute moderate Granuloma minimal ( 19) ( 24) 18 24 00 10 00 10 ( 3) ( 3) 00 01 01 00 00 20 10 10 ( 24) ( 25) 24 25 00 ( 25) ( 23) 23 23 10 10 ( 25) ( 4 11 72 00 11 41 20 12 13 3 13 40 00 ( 25) ( 25) 20 25 00 0n 3 0 J 00 00 ( 13) ( 33) 13 32 00 01 00 01 ( 0) ( 2) 01 00 00 01 01 00 00 00 ( 14) ( 34) 14 33 01 ( 15) ( 34) 15 34 00 00 ( 16) ( 34) 8 20 20 00 00 20 00 6 14 2 11 33 10 { 16) ( 34) 13 34 00 00 00 20 '0 00 ( 19) ( 20) 18 19 10 01 01 00 ( 5) ( 4) 02 00 00 11 11 00 00 00 { 1) ( 0) 10 00 ( 0) ( 0) 00 00 00 ( 27) ( 23) 9 20 10 1 00 11 30 b0 32 32 50 00 ( 26) ( 23) 21 23 20 20 10 1 r* 10 10 ( ( 20) 20 20 00 00 00 00 { 5) ( 1) 31 00 00 00 00 00 00 00 ( 1) ( 0) 00 00 ( 0) ( 0) 00 00 00 ( 28) ( 22) 7 17 44 01 12 1 10 15 1 S1 60 10 ( 28) { 22) 2G 21 00 00 10 0 : 00 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrifice(s) 18Z 001666 Microscopic Incidence Page: 3 Non-Neoplastlc Incidence for Females (continued) Riker Laboratories, Inc. 3M FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Humber: Q2S1CR0012 Species: Rat Table: 3 Tissue/ Diagnosis/ Modifier Stomach (continued) Hemorrhage moderate Mineralization mild Necrosis mild moderate Ulcer marked Thyroid Within normal limits Follicular hyperplasia, cystic mild marked Hyperplasia, C cell minimal mild moderate U1 timobranchial cyst Trachea Within normal limits Urinary Bladder Within normal limits Calculus Cystitis, chronic marked Epithelial hyperplasia, papillary marked Epithelial hyperplasia, simple mild moderate Uterus Within normal limits Cystic glands minimal mild moderate marked Exudate, lumenal moderate Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 10 10 10 10 20 10 10 10 00 ( 25) ( 25) 20 23 10 10 00 00 00 00 00 21 ( 25) ( 25) 25 25 ( 25) ( 25) 17 25 10 00 00 10 10 70 60 10 ( 25) { 25) 21 17 25 00 01 21 03 00 00 0 '0 00 00 00 10 00 10 00 00 ( 13) ( 33) 12 27 01 00 01 13 00 02 11 00 ( 14) ( 34) 14 34 ( 13) ( 34) 12 33 00 00 00 00 00 11 11 00 ( 14) ( 34) 11 20 2 12 01 15 14 01 10 10 00 00 00 00 10 10 00 20 00 ( 20) ( 18) 18 12 00 00 00 13 01 12 00 11 ( 25) ( 21) 25 21 ( 23) ( 21) 20 21 00 00 00 00 00 20 20 00 ( 24) ( 23) 17 18 33 00 10 22 01 00 00 00 00 00 00 00 00 00 01 01 ( 23) ( 22) 19 17 00 00 00 00 00 00 00 34 ( 24) ( 22) 24 22 ( 25) ( 22) 21 22 00 10 10 10 10 00 00 00 ( 26) ( 22) 22 11 35 00 02 02 31 00 00 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm 0 * Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrifice(s) 1 001667 Microscopic Incidence Page: 35 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CRQ012 Species: Rat Table: 8 Tissue/ Diagnosis/ Modifier Uterus (continued) Hydrometra moderate marked Hyperplasia, endometrial moderate Inflammation, acute marked Metritis, acute mild Polyarteritis moderate Group 1 DOS SAC Group 2 DOS SAC Group 3 DOS SAC Group 4 DOS SAC 01 00 01 00 00 00 00 00 00 00 00 01 01 00 00 00 00 00 00 00 00 00 00 00 00 00 00 10 10 00 00 00 00 11 00 11 01 01 00 00 01 01 01 01 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () * Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrlfice(s) 184 001G6S Microscopic Incidence Page: 36 Neoplastic Incidence for Males Rlker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study In Rats - One Year Interim Table: 9 Project Nunber: 0281CR0012 Species: Rat Tissue/ Diagnosis/ Modifier Mannary Gland Adenocarcinoma Pituitary Adenoma Group 1 Group 2 (3) 0 ( 14) 0 (1) 1 ( 13) 1 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm () Total Examined 001669 185 Microscopic Incidence Page: 37 Neoplastic Incidence for Females Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 10 Project Number: 0281CR0012 Species: Rat Tissue/ Diagnosis/ Modifier Mammary Gland Adenocarcinoma Pituitary Adenoma Group 1 Group 2 { 15) 0 { 15) 1 { 15) 1 ( 15) 2 Titles : Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm () = Total Examined w 186 Microscopic Incidence Page: 33 Neoplastic Incidence for Males Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study 1n Rats Project Number: 0281CR0012 Species: Rat Table: 11 Tissue/ Diagnosis/ Modifier Adrenal Carcinoma, cortical Pheochronocytoma, benign Pheochromocytoma, malignant Hemolymphoreticular neoplasm present Bone Osteosarcoma Brain Astrocytoma, benign Oligodendroglioma, benign Hemolymphoreticular neoplasm present Eye Hemolymphoreticular neoplasm present Heart Hemolymphoreticular neoplasm present Ki dney Adenoma Hemolymphoreticular neoplasm present Liver Hepatocellular carcinoma Hemolymphoreticular neoplasm present Lung Adenoma Hemolymphoreticular neoplasm present Lymph Mode (abdominal) Hemolymphoreticular neoplasm present Lymph Mode (mesenteric) Hemangiosarcoma Hemolymphoreticular neoplasm present Pancreas Adenoma Islet cell adenoma Islet cell carcinoma Hemolymphoreticular neoplasm present Parathyroid Adenoma Pituitary Adenoma Salivary Gland Hemolymphoreticular neoplasm present Group 1 Group 2 Group 3 Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 15) ( 34) 01 11 00 00 ( 0) ( 2) 00 ( 15) ( 34) 01 10 00 ( 12) ( 33) 00 ( 16) ( 34) 10 ( 16) ( 34) 00 10 ( 15) ( 34) 21 21 ( 15) ( 34) 00 31 ( 0) ( 0) 00 ( 12) ( 33) 00 10 ( 13) ( 33) 00 01 00 10 ( 6) ( 16) 00 ( 15) ( 33) 6 11 ( 12) ( 32) 00 ( 19) ( 31) 01 00 00 10 ( 1) ( 1) 10 ( 18) ( 31) 01 00 10 ( 17) ( 31) 10 ( 19) ( 31) 20 ( 19) ( 31) 00 10 ( 19) ( 31) 11 20 ( 19) ( 31) 01 20 ( 0) ( 0) 00 ( 13) ( 29) 00 10 ( 15) ( 29) 10 11 01 10 ( 13) ( 16) 01 ( 17) ( 30) 4 16 ( 15) ( 30) 10 ( 14) ( 35) 00 13 00 00 ( 0) ( 0) 00 ( 0) ( 0) 00 00 00 ( 1) ( 1) 00 ( 15) ( 35) 10 ( 15) ( 35) 00 10 ( 15) ( 35) 01 11 ( 15) ( 35) 00 11 ( 0) ( 1) 01 ( 1) ( 1) 00 10 ( 14) ( 35) 00 12 00 10 ( 9) ( 13) 01 ( 15) ( 33) 11 18 ( 13) ( 33) 00 ( 12) ( 33) 00 13 01 00 ( 1) ( 0) 00 ( 0) ( 0) 00 00 00 ( 1) ( 4) 00 ( 12) ( 33) 00 ( 12) ( 38) 01 10 ( 12) ( 38) 10 10 ( 12) ( 38) 00 10 ( 0) ( 0) 00 ( 0) ( 1) 01 00 ( 11) ( 37) 00 01 00 00 ( 9) ( 26) 00 ( 11) ( 36) 6 16 ( 10) ( 32) 00 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm G01G71 () * Total Examined D0Ss Unscheduled Death(s) SAC= Protocol Scheduled Sacrificeis) 187 Microscopic Incidence Page: 32 Neoplastic Incidence for Males (continued) Rlker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: 11 Tissue/ U! dyflOb 15/ Modi fier Skin Basal cell tumor, benign Fibroma Fibrosarcoma Keratoacanthoma Liposarcoma Papilloma Squamous cell carcinoma Hemolymphoreticular neoplasm present Small Intestine Hemolymphoreticular neoplasm present Soft Tissues (head) Hemangiosarcoma Zymbal gland carcinoma Soft Tissues (neck) Fibroma Fibrosarcoma Soft Tissues (thorax) Liposarcoma Spl een Hemangiosarcoma Hemolymphoreticular neoplasm present Stomach Hemolymphoreticular neoplasm present Testi s/Epi didymi s Mesothelioma, benign Thymus Hemolymphoreticular neoplasm present Thyroid C cell adenoma C cell carcinoma Follicular adenoma Urinary Bladder Papilloma Hemolymphoreticular neoplasm present Hemolymphoreticular System [# affected] Malignant lymphoma, lymphocytic Malignant lymphoma, histiocytic Malignant lymphoma, mixed Group 1 Group 2 Group '3 Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 8) ( 7) 00 10 10 12 10 01 00 10 ( 14) ( 34) 10 ( 0) ( 0) 00 00 ( 0) ( 0) 00 00 ( 0) ( 0) 00 ( 16) ( 34) 01 11 ( 16) ( 33) 10 ( 15) ( 33) 00 ( 1) ( 0) 10 ( 12) ( 31) 00 02 00 ( 13) ( 33) 00 10 [ 3] c 1] 00 31 00 ( 3) ( 3) 00 01 10 00 00 00 00 00 ( 17) ( 31) 00 ( 2) ( 0) 10 10 ( 0) ( 0) 00 00 ( 0) ( 0) 00 ( 19) ( 31) 00 10 ( 19) ( 31) 00 ( 19) ( 31) 00 ( 1) ( 0) 10 ( 13) ( 27) 10 10 00 ( 18) ( 30) 00 00 C 3] c 0] 20 10 00 ( 6) ( 10) 01 01 00 00 00 00 10 00 ( 0) ( 1) 00 ( 0) ( 0) 00 00 ( 0) ( 0) 00 00 ( 0) ( 0) 00 ( 15) ( 35) 00 11 ( 15) ( 35) 00 ( 14) ( 35) 00 ( 0) ( 0) 00 ( 15) ( 33) 02 01 01 ( 13) ( 34) 00 00 [ 1] [ 1] 00 01 10 ( 1) ( S) 00 01 00 00 00 00 00 10 ( 0) ( 0) 00 ( 0) { 0) 00 00 { 1) ( 1) 01 10 ( 1) ( 0) 10 ( 12) ( 33) 00 00 ( 11) ( 37) 00 ( 12) ( 33) 01 ( 0) ( 0) 00 ( 10) ( 36) 03 00 00 ( 11) ( 33) 01 00 [ 1] [ 0] 00 10 00 Ti ties: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 188 001G72 Microscopic Incidence Page: 40 Neoplastic Incidence for Females R1ker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study In Rats Project Number: 0281CR0012 Species: Rat Table: 12 Tissue/ Diagnosis/ Modifier Adrenal Adenoma Adenoma, cortical Carcinoma, cortical Pheochromocytoma, benign Pheochromocytoma, malignant Hemolymphoreticular neoplasm present Aorta Hemolymphoreticular neoplasm present Bone Marrow Hemolymphoreticular neoplasm present Brain Oligodendroglioma, benign Esophagus Hemolymphoreticular neoplasm present Eye Hemolymphoreticular neoplasm present Heart Hemolymphoreticular neoplasm present Kidney Hemolymphoreticular neoplasm present Large Intestine Leiomyosarcoma Hemolymphoreticular neoplasm present Liver Hepatocellular adenoma Hepatocellular carcinoma Hemolymphoreticular neoplasm present Lung Hemolymphoreticular neoplasm present Lymph Node (mesenteric) Hemolymphoreticular neoplasm present Lymph Node (thoracic) Hemolymphoreticular neoplasm present Manmary Gland Adenocarcinoma Adenoma Carcinoma Fibroadenoma Hemolymphoreticular neoplasm present Group 1 Group 2 Group -3 Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 25) ( 25) 00 00 00 02 00 20 ( 21) ( 23) 20 ( 25) ( 25) 20 ( 25) ( 25) 01 ! 15) ( 21) 10 ( 20) ( 23) I0 ! 25) ( 25) 10 ( 25) ! 25) 30 ( 24) ( 23) 00 10 ( 25) ( 25) 00 C0 50 ( 25) ! 25) 50 ( 19) ( 23) 30 ( 0) ( 0) 00 ( 23) ( 23) 43 21 01 64 20 ( 15) ( 34) 00 00 00 01 00 10 ! 14) ( 33) 00 ( 16) ( 34) 00 ( 16) ( 34) 00 ( 13) ! 30) 00 ( 12) ( 34) 00 ( 16) ! 34) 10 ( 16) ( 34) 10 ( 14) ( 34) 10 00 ( 16) ( 34) 04 12 10 ( 16) ( 34) 10 ( 9) ( 29) 00 ( 0) ( 0) 00 ( 14) ( 33) 46 00 00 15 00 ( 26) ( 23) 00 10 10 00 01 10 ( 0) ( 0) 00 ( 0) ( 0) 00 ( 3) ( 0) 00 ( 25) ( 20) 00 ( 2) ( 2) 00 ( 27) ( 23) 00 ( 27) ( 23) 00 ( 1) ! 0) 00 00 ( 27) ( 23) 00 00 00 ! 27) ( 23) 00 ( 8) ( 3) 10 ( 1) ( 0) 10 ( 23) ! 23) 56 00 00 78 00 ( 27) ! 22) 01 00 00 10 00 20 ( 0) ( 0) 00 ( 0) ( 0) 00 ( 1) ! 1) 00 ! 24) ( 21) 00 ( 2) ( 2) 00 ( 28) ( 22) 10 ( 28) ( 22) 20 ( 3) ( 0) 00 10 ( 23) ( 22) 00 00 40 ( 28) ( 22) 30 ( 1) ! 0) 10 ( 0) ( 0) 00 ( 25) ( 22) 33 00 00 6 11 10 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () Total Examined DOS Unscheduled Death!s) SAC Protocol Scheduled Sacrifice!s) 18S 001673 Microscopic Incidence Page: 41 Neoplastic Incidence for Females (continued) R1ker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 12 Tissue/ Modifier Mesentary Leiomyosarcoma Ovary Leiomyoma Tubular adenoma Hemolymphoreticular neoplasm present Pancreas Acinar adenoma Islet cell adenoma Islet cell carcinoma Hemolymphoreticular neoplasm present Parathyroid Adenoma Pituitary Adenocarcinoma Adenoma Skin Fibroma Fibrosarcoma Lipoma Hemolymphoreticular neoplasm present Small Intestine Hemolymphoreticular neoplasm present Soft Tissues (leg) Hemolymphoreticular neoplasm present Spinal Cord Hemolymphoreticular neoplasm present Spleen Hemolymphoreticular neoplasm present Stomach Hemolymphoreticular neoplasm present Thymus Hemolymphoreticular neoplasm present Thyroid Adenocarcinoma C cell adenoma C cell carcinoma Hemolymphoreticular neoplasm present Urinary Bladder Transitional cell carcinoma Hemolymphoreticular neoplasm present Group 1 Group 2 Group 3 Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 0) ( 0) 00 ( 25) ( 23) 10 04 20 ( 24) ( 25) 00 01 01 20 ( 5) ( 0) 00 ( 22) ( 24) 00 15 17 ( 3) ( 3) 12 00 00 00 ( 24) ( 25) 00 ( 0) ( 0) 00 ( 25) ( 23) 10 ( 25) ( 25) 30 ( 25) ( 25) 10 ( 0) ( 0) 00 ( 25) ( 25) 00 01 00 20 ( 25) ( 25) 00 10 ( 0) ( 0) 00 ( 14) ( 34) 00 03 00 ( 14) { 34) 01 00 00 00 ( 6) ( 23) 01 ( 15) ( 34) 00 12 23 ( 0) ( 2) 00 00 00 0 0. { 14) ( 34) 00 ( 1) ( 0) 10 ( 15) ( 34) 00 ( 16) ( 34) 00 ( 16) ( 34) 00 ( 0) ( 0) 00 ( 13) ( 33) 00 01 11 00 { 13) ( 34) 00 00 ( 0) ( 1) 01 ( 25) ( 23) 00 02 00 ( 17) ( 17) 00 02 00 10 ( 16) ( 15) 00 ( 23) ( 21) 01 20 16 ( 5) ( 4) 30 10 11 00 t 1) ( 0) 00 ( 0) ( 0) 00 ( 0) ( 0) 00 ( 27) ( 23) 00 ( 26) ( 23) 10 ( 1) ( 0) 10 ( 20) ( IS) 01 01 01 00 ( 23) ( 21) 00 10 ( 0) { 0) 00 ( 26) ( 21) 00 00 10 ( 21) { 20) 00 00 00 20 ( 19) ( 18) 00 ( 25) ( 21) 00 20 15 ( 5) ( 1) 00 00 00 20 ( 1) ( 0) 10 ( 0) ( 0) 00 ( 0) { 0) 00 ( 23) ( 22) 20 ( 28) ( 22) 10 ( 0) ( 0) 00 ( 23) ( 22) 00 10 01 00 { 25) ( 22) 10 20 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () = Total Examined DOS* Unscheduled Oeath(s) SAC* Protocol Scheduled Sacrifice(s) 190 001674 Microscopic Incidence Page: 4 Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FM-3924: Two Year Oral. Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 12 Tissue/ Diagnosis/ Modifier Uterus Adenoma Hemangioma Leiomyoma Polyp Hemolymphoretlcular neoplasm present Hemolymphoreticular System [# affected] Malignant lymphoma, histiocytic Malignant lymphoma, lymphocytic Lymphosarcoma Group 1 Group 2 Group '3 Group 4 DOS SAC DOS SAC DOS SAC DOS SAC ( 25) { 25) 01 00 00 01 20 [ 5] [ 03 20 30 00 ( 14) ( 34) 00 00 00 01 00 [ 13 c 0] 10 00 00 ( 24) ( 23) 00 10 00 22 10 [ 3] [ 0 ] 10 00 20 ( 26) ( 22) 00 00 01 13 00 C 4] [ 0] 40 00 00 Titles: Group 1 CONTROL 0 ppm Group 2 FM-3924 100 ppm Group 3 FM-3924 30 ppm Group 4 FM-3924 10 ppm () Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrifice(s) G01G7S Microscopic Incidence Page: 43 Suuarized Single Tabulated Aniaal Report Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3516 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Meek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Lung Lyaph Node (aesenteric) Pancreas Parathyroid Saall Intestine Thyroid -No visible lesions. -Chronic progressive nephropathy, aild -Vascular aineralization, ainiaal -Not exaained, aissing -Acinar atrophy, aild -Not exaained, aissing -Within noraal liaits Fewer than protocol nuaber -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, Heart, Stoaach, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Naaaary Bland, Pituitary, Adrenal, Trachea, Esophagus, Salivary Bland, Eye. Aniaal Nuaber: 1R-3517 Sex: Hale Broup: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Lung Parathyroid Thyroid -No visible lesions. -Chronic progressive nephropathy, ainiaal -Vascular aineralization, aild -Not exaained, aissing -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Haaaary Gland, Pituitary, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3520 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate! (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Kidney -No visible lesions. -Sinusoidal ectasia, cortex, bilateral, aoderate -Chronic progressive nephropathy, ainiaal Species: Rat Project Nuaber: 0281CR0012 001G76 Suaaarized STAR Page: 1 192 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3520 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Week- 53) 1 Year Interia Sacrifice Microscopic Observations (continued): Liver Lung Lyaph Node (aesenteric) Parathyroid Pituitary -Hepatocyte alteration, vacuolated, Focal, ainiaal -Vascular aineralization, ainiaal -Not exaained, aissing -Not exaained, not in plane of section -Not exaained, aissing The following tissues were found to be within noraal limits: Grain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Gladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3522 Sex: Male 6roup: ( 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Parathyroid Thyroid -Light (pale) tan in color. -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, ainiaal -Vascular aineralization, aild Heaorrhage, aultifocal, aild Perivascular aononudear infiltrate, aild -Not exaained, aissing -Not exaained, aissing The fol1owing tissues were found to be within noraal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Maaaary Gland, Pituitary, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3527 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Liver Lung -No visible lesions. -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild -Heaorrhage, aultifocal, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Species: Rat Project Nuaber: 02B1CR0012 G01G77 Suaaarized STAR Page: 2 193 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Tmo Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3527 Sex: Hale Sroup: ( 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Microscopic Observations (continued): The following tissues were Found to be within noraal liaits (continued): Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3535 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Hesentary Microscopic Observations: Lung Hesentary Parathyroid Thyroid -Area of fat necrosis, 2 x 3 x 0.5 ca. -Alveolar aacrophages, aultifocal, aild Atellectasis, focal, aild -Necrosis, fat, aarked Steatitis, chronic, aoderate -Not exaained, aissing -Not exaained, aissing The following tissues Mere found to be within noraal liaits: Brain, Spinal Cord, Bone Narrou, Liver, Kidney, Heart, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Spleen. Aniaal Nuaber: 1R-3543 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Liver Lung -No visible lesions. -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, focal, ainiaal -Vascular Mineralization, ainiaal The following tissues Mere found to be within noraal liaits: Brain, Spinal Cord, Bone Harrou, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Species: Rat Project Nuaber: 281CR0012 G01C78 Suaaarized STAR Page: 3 194 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3546 Sex! Male Sroup: ( 1) CONTROL 0 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Liver Lung Stocach -No visible lesions. -Nodular hyperplasia, cortex, unilateral, aoderate -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aultifocal, aild -Perivascular aononudear infiltrate, aild -Not exaained, aissing The foilowing tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3550 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Macroscopic Observations: Kidney Microscopic Observations: Heart Kidney Liver Lung Pancreas -Bilateral hydronephrosis -Myocarditis, chronic nonsuppurative, focal, aild -Hydronephrosis, bilateral, aoderate Calculus, pelvic -Portal aononudear cell infiltrate, aild -Vascular aineralization, aild -Acinar atrophy, focal, aoderate Pancreatitis, chronic, focal, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary 61and, Eye. Species: Rat Project Nuaber: 0281CR0012 C-01G79 Suaaarized STAR Page: 4 195 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interi* Table: 1 Aniaal Nuaber: 1R-35S1 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Week= S3) I Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Liver Lung -Pale tan -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild -Pneuaonia, interstitial, chronic, focai, aild Heaorrhage, aultifocal, aild Hyperplasia, septal cell, focal, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3559 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: <Week= S3) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Liver Lung -No visible lesions. -Pyelitis, acute, bilateral, ainiaal Nephritis, interstitial, chronic, focal, unilateral, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild -Heaorrhage, aultifocal, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3568 Sex: Male 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Pancreas Parathyroid -No visible lesions. -Chronic progressive nephropathy, aild -Pancreatitis, chronic, focal, aild Acinar atrophy, focal, aild -Not exaained, not in plane of section Species: Rat Project Nuaber: 0281CR0012 OOIGSO Suaaarized STAR Page: 5 96 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3568 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) t Year Interia Sacrifice Microscopic Observations (continued): The follotting tissues were found to be within noraal liaits: Grain, Spinal Cord, Bone Narrow, Spleen, Liver, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3570 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Lung Parathyroid -No visible lesions. -Cortical vacuolation, aultifocal, aild -Pneuaonia, interstitial, chronic, focal, ainiaal Heaorrhage, aultifocal, aild -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3575 Sex: Hale Group:.! 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Soft Tissues (leg) Microscopic Observations: Kidney Lung Pituitary -Swollen left hind foot at the hock joint. -Chronic progressive nephropathy, ainiaal -Vascular aineralization, ainiaal Alveolar aacrophages, aultifocal, aild Heaorrhage, focal, aild -Cyst, pars distalis The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Liver, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 0281CR012 001681 Suaaarized STAR Page: 6 197 I Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-35B0 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Kidney Microscopic Observations: Bone Harrow Kidney Lung Pancreas Parathyroid Spinal Cord -Dark cystic lesion, 0.4 ca dia., left. -Not exaained, aissing -Chronic progressive nephropathy, aiId Cyst, cortical, unilateral -Alveolar aacrophages, aultifocal, aiId Pneuaonia, interstitial, chronic, aultifocal, aild -Pancreatitis, chronic, focal, aild -Not exaained, not in plane of section -Not exaained, aissing The following tissues were found to be within noraal lints: Brain, Spleen, Liver, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-4578 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations! Kidney Lyaph Node (aesenteric) Parathyroid -No visible lesions. -Pelvic aineralization, ainiaal -Not exaained, aissing -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus,, Ovary, Maaaary Gland, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4582 Sex: Feaale 6roup: 1( 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Hesentary Microscopic Observations: Heart Kidney -Yellow nodular aass, 1 x 0.5 ca. -Myocarditis, chronic nonsuppurative, focal, ainiaal -Calculus, pelvic, unilateral Species: Rat Project Nuaber: 0261CROC12 001S82 Suaaarized STAR Page: 7 198 Suaaarized Single Tabulated Aniaal Report (continued) Individual Nacroscopic and Microscopic Observations Rifcer Laboratories, Inc. 3N FM-3924: Two Tear Oral Toxicity-Oncogenicity Study in Rats - One Year Interii Table: 1 Aniaal Nuaber: 1R-4582 Sex! Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year Interi* Sacrifice Microscopic Observations (continued): Large Intestine Lung Hesentary Parathyroid Urinary Bladder Uterus -Not exaained, aissing -Pneuaonia, interstitial, chronic, aultifocal aild Heaorrhage, local areas, aild Perivascular aononudear infiltrate, aild -Necrosis, fat, nodular, aoderate Steatitis, chronic, aoderate -Not exaained, not in plane of section -Not exaained, aissing -Hyperplasia, glandular epitheliua, aild Metaplasia, squaaous, glandular, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, Stoaach, Saall Intestine, Aorta, Ovary, Maaaary Gland, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-45B5 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid -No visible lesions. -Sinusoidal ectasia, cortex, focal, unilateral, aild -Pelvic aineralization, ainiaal -Portal aononudear cell infiltrate, ainiaal -Vascular aineralization, aild Heaorrhage, aultifocal, aild -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Gland, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Species: Rat Project Nuaber: 0261CR0012 001683 Suaaarized STAR Page: B 199 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4S8B Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Skin Adrenal Microscopic Observations: Adrenal Kidney Liver Lung Spinal Cord Spleen -Hair loss, neck. -Left enlarged -Sinusoidal ectasia, cortex, unilateral, aarked Cortical degeneration, unilateral, aild -Hyperplasia, pelvic epitheliua, aild Calculus, pelvic, unilateral Cyst, aedullary, aild -Hepatocyte vacuolation, aultifocal, aild -Heaorrhage, diffuse, aoderate -Not exaained, aissing -Heaosiderosis, aild The following tissues were found to be within noraal liaits: Brain, Bone Marrow, Heart, Stoaach, Saall intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Skin. Aniaal Nuaber: 1R-4589 Sex: Feaale Group: < 1) CONTROL 0 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Liver Haaaary Bland Parathyroid -Slightly enlarged -Portal eononuclear cell infiltrate, aild Portal bile duct proliferation, aild -6alactocele -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, 5pleen, Kidney, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node laesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 001G84 Suaaarized STAR Page: ? 200 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interie Table: 1 Anieal Nuaber: 1R-4590 Sex: Feeale Group: ( 1) CONTROL 0 ppi Fate: (Heek= S3) 1 Year Interie Sacrifice Macroscopic Observations: Microscopic Observations: Lung -No visible lesions. -Heeorrhage, local areas, eoderate The fallotting tissues Mere found to be within noreal lieits: Grain, Spinal Cord, Bone Harrow, Spleen, Liver, Kidney, Heart, Stoeach, Seal1 Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary 61and, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (eesenteric), Pancreas, Salivary Gland, Eye. Anieal Nueber: 1R-4601 Sex: Feeale Group: ( 1) CONTROL 0 ppe Fate: (Week= 53) 1 Year Interie Sacrifice Macroscopic Observations: Kidney Microscopic Observations: Kidney Liver Lung -Hydronephrosis, unilateral -Hydronephrosis, unilateral, eoderate Calculus, unilateral, eild -Hepatocyte vacuolation, eultifocal, einiaal -Heeorrhage, eultifocal, eild The fallowing tissues were found to be within noreal lieits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoeach, Seall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyeph Node (eesenteric), Pancreas, Salivary Gland, Eye. Anieal Nueber: 1R-4608 Sex: Feeale Group: ( 1) CONTROL 0 ppe Fate: (Heek= 53) 1 Year Interie Sacrifice Macroscopic Observations: Uterus Microscopic Observations: Liver Lung Lyeph Node (eesenteric) Uterus -Left horn cystic looking lesion, 1 x 0.6 ce. -Hepatocyte vacuolation, eultifocal, sinieal -Heeorrhage, eultifocal, eild -Not exaeined, eissing -Cystic glands, focal, earked The foilowing tissues were found to be within noreal lieits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoeach, Seall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Haeeary Gland, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nueber: 0281CR012 001685 Sueearized STAR Page: 10 201 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Rileer Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4610 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: !Week= 53) 1 Year Interia Sacrifice Macroscopic Observations: Pituitary Uterus Microscopic Observations: Adrenal Large Intestine Lung Pancreas Parathyroid Uterus -Slightly enlarged -Slightly enlarged -Sinusoidal ectasia, cortex, aild -Neaatodiasis -Alveolar aacrophages, aultifocal, aild -Pancreatitis, chronic, focal, aild -Not exaained, not in plane of section -Hyperplasia, glandular epitheliua, aild Metaplasia, squaaous, glandular, aild The following tissues were found to be within noraal Units: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, Kidney, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Ovary, Maaaary Bland, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-4620 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Macroscopic Observations: Eye Microscopic Observations: Eye Kidney Lung Urinary Bladder -Atrophy, right eye. -Panophthalaitis, unilateral, narked Atrophy, unilateral, narked -Pelvic aineralization, ainiaal -Heaorrhage, aultifocal, aild -Not exaained, aissing The following tissues were found to be within noraal 1iaits: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, Heart, Stoaach, Saall Intestine, Large intestine, Aorta, Uterus, Ovary, Maaaary Gland, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-4629 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Macroscopic Observations: Skin Microscopic Observations: Adrenal -Hair loss, head, neck, face. -Cortical degeneration, focal, unilateral, aild Species: Rat Project Nuaber: 0281CR0012 G01G86 Suaaarized STAR Page: 11 202 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4629 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Microscopic Observations (continued): Aorta Large Intestine Liver Parathyroid -Not exaained, aissing -Neaatodiasis -Portal bile duct proliferation, aild -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Lung, Stoaach, Saall Intestine, Urinary Bladder, Uterus, Ovary, Naaaary Gland, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye, Skin. Aniaal Nuaber: 1R-4630 Sex: Feaale Group: < 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Parathyroid Thyroid -Possibly slightly pale in color. -Calculus, pelvic, unilateral, aoderate -Hepatocyte alteration, vacuolated, aultifocal, aild -Heaorrhage, aultifocal, aild -Not exaained, aissing -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary 61and, Pituitary, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-4631 Sex! Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Lung Lyaph Node (aesenteric) Parathyroid Urinary Bladder -No visible lesions. -Pelvic aineralization, ainiaal -Heaorrhage, local areas, aild -Not exaained, aissing -Not exaained, not in plane of section -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, Heart, Stoaach, Saall Intestine, Species: Rat Project Nuaber: 02B1CR0012 001G87 Suaaarized STAR Page: 12 203 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4G31 Sex! Feaale Sroup: ( 1) CONTROL 0 ppa Fate: (Week- 53) 1 Year Interia Sacrifice Microscopic Observations (continued): The folloaing tissues Here found to be Mithin noraal liaits (continued): Large Intestine, Aorta, Uterus, Ovary, Maaaary 61and, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4632 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Pituitary Maaaary Gland Microscopic Observations: Adrenal Kidney Liver Lung Maaaary Gland Ovary Pituitary -Slightly enlarged with a dark red focus on surface. -Saall spherical aass, 1.2 ca dia., containing dark red fluid, left inguinal. -Sinusoidal ectasia, cortex, focal, unilateral, aild -Chronic progressive nephropathy, aild -Hepatocyte vacuolation, aultifocal, aild -Heaorrhage, aultifocal, aild -Galactocele Chronic inflaaaation and heaorrhage in cysts, -Cyst, unilateral -Adenoaa The folloHing tissues Here found to be uithin noraal liaits: Brain, Spinal Cord, Bone MarroH, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and. Eye. Aniaal Nuaber: 1R-4640 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Liver Lung Parathyroid -No visible lesions. -Hepatocyte vacuolation, aultifocal, ainiaal -Heaorrhage, aild -Not exaained, not in plane of section The folloHing tissues Here found to be Hi thin noraal lia its : Brain, Spinal Cord, Bone MarroH, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Gland, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 001688 Suaaarized STAR Page: 13 204 Suaaarized Single Tabulated Aniaal Report Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3N FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interi 1 Table: 1 Aniaal Nuaber: 1R-3696 Sex: Hale Sroup: ( 2) FH-3924 100 ppa Fate: (Neek= 53) 1 Year Interi Sacrifice Hacroscopic Observations: Hicroscopic Observations: Liver Parathyroid Stoaach -No visible lesions. -Portal aononudear cell infiltrate, ainiaal Portal bile duct proliferation, ainiaal Hepatocyte vacuolation, local areas, aoderate Hegalocytosis, Barked Host lobules filled with aarkedly enlarged hepatocytes. Cells enlarged by increase in voluae of finely granular cytoplasa which displaces coarser organalles to cell aeabrane. In soae lobules there is a gradient of decreased swelling froa central to peripheral. Hany enlarged cells have aultiple vacuoles. -Not exaained, not in plane of section -Not exaained, aissing The following tissues were found to be within noraal Halts: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Lung, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3699 Sex: Hale 6roup: 1 2) FH-3924 100 ppa Fate: (Week= 531 1 Year Interia Sacrifice Hacroscopic Observations: Hicroscopic Observations: Kidney Liver Lung Parathyroid Pituitary Spleen Thyroid -No visible lesions. -Chronic progressive nephropathy, ainiaal -Hepatocyte vacuolation, aultifocal, aild Hegalocytosis, aarked -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aild Perivascular aononudear infiltrate, aild -Not exaained, aissing -Cyst, pars distalis -Heaosiderosis, aild -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: 0281CR0012 001689 Suaaarized STAR Page: 14 205 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3699 Sex: Male Broup: ( 2) FH-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Microscopic Observations (continued): The following tissues were found to be within noraal liaits (continued): Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber! 1R-3711 Sex: Male Group! ( 2) FH-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Large Intestine Liver Lung -No visible lesions. -Not exaained, aissing -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aild Hegalocytosis, narked -Perivascular aononudear infiltrate, ainiaal The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber! 1R-3714 Sex: Male Group: ( 2) FH-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations'. Liver Microscopic Observations: Liver Lung Parathyroid Thyroid -Slightly pale, tanish-yellow color. -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aoderate Hegalocytosis, Barked Necrosis, aultifocal, aild -Vascular aineralization, aild -Not exaained, aissing -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 00:1690 Suaaarized STAR Page: 15 206 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber! 1R-3715 Sex: Male Group: ( 2) FH-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Liver Lung Pituitary Salivary Gland -No visible lesions. -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Megalocytosis, aoderate Necrosis, aultifocal, aild -Vascular aineralization, aild Heaorrhage, diffuse, aarked -Not exaained, aissing -Not exaained, aissing The following tissues Mere found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-3720 Sex: Male Group: ( 2) FH-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Hacroscopic Observations: Eye Microscopic Observations: Kidney Liver Lung Parathyroid Pituitary -Slight atrophy of right eye due to eye bleeding. -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aild Megalocytosis, aild Necrosis, aultifocal, aild -Vascular aineralization, aild Alveolar aacrophages, aultifocal, aild -Not exaained, aissing -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 001G91 Suaiarized STAR Page: 16 207 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3721 Sex: Male Group: ( 2) FM-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Eye Skin Liver Microscopic Observations: Eye Liver Lung Pancreas Parathyroid Thyroid Urinary Bladder -Focal corneal opacity of right eye due to eye bleeding. -Bilateral hair thinning, ventral abdoaen and thigh. -Pale tan in color. -Keratitis, acute, unilateral, aarked -Portal aononuclear cell infiltrate, siId Portal bile duct proliferation, aild Hepatocyte vacuolation, diffuse, aoderate Megalocytosis, aarked Necrosis, aultifocal, aild -Vascular aineralization, aild -Not exaained, aissing -Not exaained, not in plane of section -Follicular hyperplasia, cystic, unilateral, aoderate -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary 61and. Aniaal Nuaber: 1R-3722 Sex: Hale 6roup: 1 2) FM-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Lyaph Node (aesenteric) -Pale tan in color. -Chronic progressive nephropathy, aild -Portal aononuclear cell infiltrate, aild Portal bile duct proliferation, ainiaal Hepatocyte vacuolation, centrilobular, aoderate Megalocytosis, aild -Vascular aineralization, ainiaal Heaorrhage, local areas, aoderate -Heaorrhage, aild Heaosiderosis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: 0281CR0012 001G92 Suaaarized STAR Page: 17 208 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3722 Sex: Male 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Microscopic Observations (continued): The following tissues were found to be within noraal liaits (continued): Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3727 Sex: Male Broup: ( 2) FH-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Parathyroid Testis/Epididyais -Pale tan in color. -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Megalocytosis, aild -Heaorrhage, local areas, aild -Not exaained, not in plane of section -Tubule atrophy, asperaatogenesis, local areas, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3732 Sex: Male Sroup! ( 2) FH-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Hacroscopic Observations: Microscopic Observations: Liver Lung Parathyroid Thyroid -No visible lesions. -Portal aononudear cell infiltrate, aild Megalocytosis, aoderate -Alveolar aacrophages, aultifocal, aild Pneuaonia, interstitial, chronic, aultifocal, aild Heaorrhage, aultifocal, aild Perivascular aononudear infiltrate, aild Atellectasis, focal, aild -Not exaained, aissing -Not exaained, aissing Species: Rat Project Nuaber: 0281CR0012 001693 Suaaarized STAR Page: 18 209 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3732 Sex: Hale Sroup: ( 2) FM-3924 100 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Microscopic Observations (continued): The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3733 Sex: Hale 6roup: ( 2) FM-3924 100 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Hacroscopic Observations: Microscopic Observations: Kidney Liver Lung Lyaph Node (aesenteric) Salivary Gland -No visible lesions. -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Hegalocytosis, aild -Heaorrhage, local areas, aoderate -Not exaained, aissing -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Eye. Aniaal Nuaber: 1R-373& Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Macroscopic Observations: Soft Tissues (thorax) Microscopic Observations: Liver Lung Haaaary 61and -Subcutaneous aass at thoracic inlet, 1.2 ca dia. -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Hegalocytosis, aoderate -Vascular aineralization, aild Alveolar aacrophages, aultifocal, aild -Adenocarcinoaa Large tuaor froa area of thoracic inlet. Highly anaplastic, aost tuaor cells in sheets, soae areas of abortive duct foraation. High aitotic activity. Local invasion. Species: Rat Project Nuaber: 0281CR0012 001694 Suaaarized STAR Page: 19 210 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FN-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3736 Sex! Male Group: ( 2) FM-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Microscopic Observations (continued): Parathyroid Pituitary -Not exaained, not in plane of section -Adenoaa The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Saall Intestine. Aniaal Nuaber: 1R-3737 Sex: Hale Group: ( 2) FM-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Spinal Cord -Slightly tan in color. -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aoderate Megalocytosis, aoderate -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3747 Sex: Male 6roup: ( 2) FM-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Parathyroid Testis/Epididyais -No visible lesions. -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aild Megalocytosis, aoderate Necrosis, aultifocal, aild -Heaorrhage, local areas, aild -Not exaained, not in plane of section -Vascular aineralization, aild Species: Rat Project Nuaber: 0281CR0012 001G95 Suaaarized 5TAR Page: 20 21 1 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3747 Sex: Male Group: I 2) FM-3924 100 ppa Fate: (Meek5 53) 1 Year Interia Sacrifice Microscopic Observations (continued): The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3748 Sex: Male Group! ( 2) FM-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Parathyroid -Pale tan in color. -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aiId Hepatocyte vacuolation, centrilobular, aoderate Negaiocytosis, aiId Necrosis, focal, ainiaal -Vascular aineralization, aild Pneuaonia, interstitial, chronic, local areas, aild Perivascular aononudear infiltrate, aild -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4757 Sex: Feaale Group: ( 2) FM-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Parathyroid Uterus -No visible lesions. -Chronic progressive nephropathy, aild -Hepatocyte vacuolation, aultifocal, aild Megalocytosis, aild -Heaorrhage, local areas, aoderate -Not exaained, not in plane of section -Metaplasia, squaaous, glandular, aild Species: Rat Project Nuaber: 0281CR0012 001G96 Suaaarized 5TAR Page: 21 212 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 The foilowing tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Naaaary Gland, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4760 Sex: Feaale Group: ( 2) FM-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Liver Lung Spleen -No visible lesions. -Hepatocyte vacuolation, aultifocal, ainiaal Negalocytosis, aild -Alveolar aacrophages, aultifocal, aild Perivascular aononudear infiltrate, aild -Heaosiderosis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Naaaary Gland, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-4761 Sex! Feaale Group: ( 2) FM-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Large Intestine Liver Lung Parathyroid Urinary Bladder Uterus -No visible lsions. -Neaatodiasis -Hpatocyte vacuolation, aultifocal, ainiaal Negalocytosis, ainiaal -Vascular aineralization, aild Alveolar aacrophages, aultifocal, aild Heaorrhage, aultifocal, aild -Not exaained, not in plane of section -Not exaained, aissing -Metaplasia, squaaous, glandular, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Aorta, Ovary, Naaaary 61and, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001G97 Suaaarized STAR Page: 22 213 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4763 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Skin Microscopic Observations: Liver Lung Ovary Parathyroid Spleen Uterus -Hair loss, head, neck area. -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, ainiaal Megalocytosis, aoderate -Heaorrhage, local areas, aoderate -No diagnosis, inadequate section -Not exaained, not in plane of section -Heaosiderosis, aild -Hydroaetra, aoderate The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Maaaary Gland, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Skin. Aniaal Nuaber: 1R-4775 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Keek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Liver Lung Maaaary 61and Parathyroid Uterus -No visible lesions. -Hepatocyte vacuolation, aultifocal, ainiaal Megalocytosis, aoderate Portal bile duct proliferation, aild -Alveolar aacrophages, aultifocal, aild -Galactocele -Not exaained, not in plane of section -Metaplasia, squaaous, glandular, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Species: Rat Project Nuaber: 0281CR0012 G01G98 Suaaarized STAR Page: 23 214 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4779 Sex: Feaale Group: (2) FM-3924 100 ppa Fate! (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Uterus Microscopic Observations: Liver Lung Lyiph Node (aesenteric) Uterus -Dilated, filled with a cloudy fluid. -Hepatocyte vacuolation, aultifocal, aild Megalocytosis, ainiaal -Pneuaonia, interstitial, chronic, aultifocal, aild Heaorrhage, aultifocal, aild Perivascular aononudear infiltrate, aild -No diagnosis, inadequate section -Hydroaetra, aoderate Endoaetritis, chronic, aild The follotting tissues Here found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Naaaary Gland, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nusber: 1R-4780 Sex: Feeale Group: < 2) FM-3924 100 ppi Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Liver Lung Parathyroid Thyroid -No visible lesions. -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, ainiaal Megalocytosis, aild -Heaorrhage, local areas, aoderate -Not exaained, not in plane of section -No diagnosis, inadequate section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Bland, Pituitary, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Species: Rat Project Nuaber: 02B1CR0012 001G99 Suaaarized STAR Page: 24 215 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4782 Sex: Feaale Group: ( 2) FM-3924 100 ppa Fate: (Neek= S3) 1 Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Liver Spleen -Right lateral lobe herniated through the diaphraga into the right thoracic cavity. The lobe within the thorax is aottied dark red. -Hepatocyte vacuolation, aultifocal, aild Telangiectasis, aoderate Telangiectasis in herniated liver lobe. -Heaosiderosis, aoderate The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Kidney, Heart, Lung, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Naaaary Gland, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-47B3 Sex: Feaale Group: ( 2) FM-3924 100 ppa Fate: (Heek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Skin Microscopic Observations: Adrenal Liver Lung Naaaary 61and Parathyroid -Saall subcutaneous aass, 1 ca dia., behind right shoulder. -Sinusoidal ectasia, cortex, focal, aild -Hagaiocytosi5, aild Pigaent, Kupfer cell, brown, aild Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild Heaorrhage, local areas, aild -Adenocarcinoaa -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001700 Suaaarized STAR Page: 25 216 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4785 Sex: Feaale Broup: < 2) FH-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Liver Microscopic Observations: Esophagus Liver Lung Parathyroid -Slightly pale -Not exaained, aissing -Hepatocyte vacuolation, aultifocal, aild Megalocytosis, ainiial -Bronchiectasis, focal, aild -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Seal1 Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Bland, Pituitary, Adrenal, Thyroid, Trachea, Lyaph Node (aesenteric), Pancreas, Salivary G1and, Eye. Aniaal Nuaber: 1R-4787 Sex: Feaale 6roup: (2) FH-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Kidney Liver Lung Pituitary Uterus -No visible lesions. -Cortical degeneration, focal, unilateral, aild -Chronic progressive nephropathy, aild Pelvic aineralization, aoderate Calculus, pelvic -Hepatocyte vacuolation, aultifocal, aild Megalocytosis, aild -Vascular aineralization, aild -Adenoaa -Metaplasia, squaaous, glandular, aoderate Hyperplasia, glandular epitheliua, aoderate The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Haaaary Gland, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 0281CR0012 601701 Suaaarized STAR Page: 26 217 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-478B Sex: Fetale Group: (2) FH-3924 100 ppa Fate: (Week: 53) 1 Year Interia Sacrifice Hacroscopic Observations: Hicroscopic Observations: Esophagus Kidney Liver Lung Parathyroid Pituitary Thyroid Trachea Uterus -No visible lesions. -Not exaained, aissing -Pelvic aineralization, aiid -Hepatocyte vacuolation, aultifocal, ainiaal Hegalocytosis, aoderate -Heaorrhage, aultifocal, aild Perivascular aononuclear infiltrate, aild Pneuaonia, interstitial, chronic, aultifocal, aild -Not exaained, aissing -AdenDta -Not exaained, aissing -No diagnosis, inadequate section -Metaplasia, squaaous, glandular, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harron, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Haaaary Gland, Adrenal, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4793 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Week= 53) 1 Year Interia Sacrifice Hacroscopic Observations: Hesentary Hicroscopic Observations: Esophagus Liver Lung Hesentary Parathyroid Salivary Gland -Saall nodular aass 1 x 1.5 ca, next to the right ovary. -Not exaained, aissing -Portal aononuclear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, ainiaal Hegalocytosis, ainiaal -Heaorrhage, local areas, aild -Necrosis, fat, nodular, aoderate Steatitis, chronic, aoderate -Not exaained, not in plane of section -Not exaained, aissing The following tissues Here found to be within noraal liaits: Brain, Spinal Cord, Bone HarroH, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, Pituitary, Adrenal, Species: Rat Project Nuaber: 0281CR0012 001702 Suaaarized STAR Page: 27 218 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4793 Sex: Feaale Group: ( 2) FM-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Microscopic Observations (continued): The following tissues were found to be within noraal liaits (continued): Thyroid, Trachea, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-4806 Sex: Feaale Group: (2) FM-3924 100 ppa Fate: (Neek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Liver Lung Parathyroid Uterus -No visible lsions. -Hpatocyte vacuolation, aultifocal, aild Megalocytosis, aild -Heaorrhage, local areas, aild -Not exaained, not in plane of section -Hetaplasia, squaaous, glandular, sinisai The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Maaaary Bland, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-48U Sex: Feaale Group: ( 2) FM-3924 100 ppa Fate: (tieek= 53) 1 Year Interia Sacrifice Macroscopic Observations: Microscopic Observations: Liver Lung Parathyroid -No visible lesions. -Hepatocyte vacuolation, aultifocal, aild Hegalocytosis, aild -Heaorrhage, aultifocal, aild -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Bland, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Adrenal. Species: Rat Project Nuaber: 0281CR0012 001703 Suaaarized STAR Page: 28 219 Suaaarized Single Tabulated Aniaal Raport Individual Macroscopic and Microscopic Observations Rileer Laboratories, Inc. 3M FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nutter: 1R-3518 Sex: Male Broup: ( 1) CONTROL 0 ppa Fate: (Heek= 106) Terainal Sacrifice Macroscopic Observations: & Skin Microscopic Observations: Adrenal Heart Kidney Liver Lung Parathyroid Pituitary Skin Thyroid -Raised inflaaaed lesion oa right rear footpad. -Cortical vacuolation, aultifocal, aild Medullary cell hyperplasia, oultifocal, aild -Myocarditis, chronic nonsuppurative, local areas, eoderate -Chronic progressive nephropathy, ainiaal Pelvic aineralization, ainiaal -Portal aononudear cell infiltrate, ainiaal Portal bile duct proliferation, aild -Vascular aineralizatioo, ainiaal Pneuaonia, interstitial, chronic, aultifocal, aild Perivascular aononudear infiltrate, eoderate -Not exaained, aissing -Adenoaa -Pododeraatitis, ulcerative, hindleg, narked -Not exaained, aissing The following tissues tere found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3519 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Keel= 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Esophagus Heart Kidney Liver -No visible lesions. -Sinusoidal ectasia, cortex, aultifocal, aild Cortical vacuolation, aultifocal, aild -Not exaained, aissing -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aultifocal aild ^ A c o i n OKIMHC*** ,-M nasLLe. m * s/d. ; 7SP/4 A ^ \s/V U iV O fM C O '//'< /* Sru.y iftjtero * . Species: Rat Project Nueber: 02B1CR0012 001704 Suaaarized STAR Page: 29 220 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3519 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Keek- 106) Terainal Sacrifice Microscopic Observations (continued): Lung -Vascular aineralization, aild Perivascular aononudear infiltrate, aoderate Pneuaonia, interstitial, chronic, aultifocal, aoderate The following tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Narro, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Lysph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3S21 Sex: Male Broup: ( 1) CONTROL 0 ppa Fate: (Neek= 92) Sacrificed in extreais Macroscopic Observations: Skin Liver Spleen Microscopic Observations: Adrenal Heart Kidney Liver Lung Parathyroid Skin Spleen Stoaach -Both hind footpads ulcerated. -Pale -Enlarged -Cortical vacuolation, local areas, aild Medullary cell hyperplasia, aultifocal, aild -Myocardial fibrosis, aultifocal, aild -Chronic progressive nephropathy, aoderate -Hepatocyte vacuolation, centrilobular, aoderate -Vascular sineralization, aild Pneuaonia, interstitial, chronic, local areas, aild Edeaa, local areas, aild Fibrosis, pleural, aild Throabus -Not exaained, aissing -Pododeraatitis, ulcerative, hindleg, aarked -Heaatopoiesis, extraaedullary, increased, aoderate -Edeaa, subaucosal, aarked The following tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0412 001705 Suaaarized STAR Page: 30 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tho Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3523 Sex: Rale 6roup: ( 1) CONTROL 0 ppa Fate: (Heek= 95) Sacrificed in extreais Macroscopic Observations: Soft Tissues (thorax) Stosach Microscopic Observations: Adrenal Heart Kidney Liver Lung Prostate Skin Stoaach -Hass, 10 x 9 x 4 ca in left axilla involving ausde and rib, extending into left thoracic cavity, collapsing left lung. Mass soft and fatty. -Hall edeaatous uith possible ulceration in cardia. -Cortical vacuolation, aultifocal, aild Sinusoidal ectasia, cortex, diffuse, aild -Myocardial fibrosis, aultifocal, aild -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aild -Vascular aineralization, aild Heaorrhage, focal, aild Alveolar aacrophages, aild -Prostatitis, acute, suppurative, narked -Fibrosarcoaa, thorax Hell differentiated, highly cellular uith aoderate collagen foraation. -Ulcer, narked The following tissues aere found to be within nomai Units: Brain, Spinal Cord, Bone Marrou, Spleen, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuiber: 1R-3S24 Sex: Male 6roup: ( 1) CONTROL 0 ppa Fate: (Ueeks 106) Teriinal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Kidney Large Intestine Liver -Saall red lesion. -Medullary cell hyperplasia, aultifocal, aild -Chronic progressive nephropathy, aoderate Pelvic aineralization, aild -Neaatodiasis, colon -Hepatocyte alteration, vacuolated, aoderate Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Species: Rat Project Muaber: 0281CR0012 001706 Suaaarized STAR Page: 31 222 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3524 Sex: Male 6roup: ( 1) CONTROL 0 ppe Fate: (Neek* 106) Terainal Sacrifice Microscopic Observations (continued): Lung Lyaph Node (aesenteric) Parathyroid Pituitary Thyroid -Vascular aineraliiation, aild -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa -Follicular hyperplasia, cystic, unilateral, aoderate Large cystic lesion occupying auch of one thyroid lobe. The follotting tissues eere found to be aithin noraal 1iaits: Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Trachea, Esophagus, Pancreas, Salivary 61and, Eye. Aniaal Nuaber: IR-3525 Sex.* Hale Sroup: ( 1) CONTROL 0 ppa Fate: (Week- 106) Terainal Sacrifice Macroscopic Observations: Bone Liver Microscopic Observations: Adrenal Bone Heart Kidney Liver Lung Parathyroid Spleen Testis/Epididyais -Joints of right foreliab and right hindliab seollen. -Raised pale circular lesion, 2 ca dia., in aedial lobe. -Cortical vacuolation, local areas, aoderate -Arthritis, synovitis; joints, foreleg, hindleg, narked -Myocarditis, chronic nonsuppurative, local areas, aild -Chronic progressive nephropathy, aoderate -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocellular carcinoaa Large, poorly differentiated, anaplastic, infiltrative. Adenoid areas. Multiple tuaor eaboli in lung. -Vascular aineralization, aild Metastatic neoplasa -Not exaained, not in plane of section -Heaosiderosis, aild -Tubule atrophy, asperaatogenesis, aild The folloaing tissues mre found to be within noraal Units: Brain, Spinal Cord, Bone Harroa, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Species: Rat Project Nuaber: 02B1CR0012 001707 Suaaarized STAR Page: 32 223 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tea Veer Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3S25 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Week- 106) Terminal Sacrifice Microscopic Observations (continued): The following tissues nere found to be eithin noraal lieits (continued): Aorta, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3S26 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Liver Lung -No visible lesions. -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Cystoid degeneration, focal, aild Hepatocyte alteration, vacuolated, aild -Vascular aineralization, aild The folloning tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nusber: 1R-3S28 Sex: Male Group: ( i) CONTROL 0 ppa Fate: (Heek= 106) Terainal Sacrifice Macroscopic Observations: Kidney Microscopic Observations: Adrenal Kidney Liver Lung Pituitary -Hydronephrosis -Cortical vacuolation, focal, aild -Chronic progressive nephropathy, noderate Hydronephrosis, unilateral, aoderate -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aild -Hyperplasia, focal, pars distalis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Species: Rat Project Nuaber: 02B1CR0012 001708 Sumerized STAR Page: 33 224 Swearized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FN-3924: Tho Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aninal Nuaber: 1R-3S28 Sex: Male 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Microscopic Observations (continued): The following tissues were found to be within noraal liaits (continued): Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3S29 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Week- 96) Sacrificed in extreais Macroscopic Observations: Skin Liver Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid Prostate Salivary Gland Skin Urinary Bladder -Areas of deraatitis with hair loss, soae scabbed; back, side, abdoaen. -Raised pale aass, 1.2 ca dia. in left lateral lobe. -Cortical vacuolation, aultifocal, aild -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Hepatocellular carcinoaa Trabecular pattern, fairly well differentiated. -Vascular aineralization, aild Edeaa, subpleural, aoderate -Not exaained, not in plane of section -Not exaained, aissing -Not exaained, aissing -Ulcer, back, abdoaen, aarked -Epithelial hyperplasia, siaple, diffuse, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Testis/Epididyais, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-3530 Sex: Male Bmp: ( 1) CONTROL 0 ppa Fate: (Neek* 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Heart Kidney Liver -No visible lesions. -Myocarditis, chronic nonsuppurative, focal, ainiaal -Chronic progressive nephropathy, aild -Portal aononudear call infiltrate, aild Portal bile duct proliferation, aild Cystoid degeneration, focal, aoderate Hepatocyte alteration, vacuolated, aild Species: Rat Project Nuaber: 0281CR0012 001709 Suaaarized STAR Page: 34 225 Suaaarized Single Tabulated flniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FN-3924: Tho Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anisal Nuiber: 1R-3530 Sex: Hale Oroup: ( 1) CONTROL 0 ppa Fate: (Week- 106) Teriinal Sacrifice Microscopic Observations (continued): Lung Spleen -Vascular aineralization, aild Peribronchial lyaphoid hyperplasia, aild -Heaosiderosis, aild The following tissues Here found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3531 Sex: Hale Broup: I 1) CONTROL 0 ppa Fate: (Heeks 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Liver Lung -No visible lesions. -Chronic progressive nephropathy, aild -Hepatocyte vacuolation, eultifocal, aild Portal aononudear cell infiltrate, ainiaal -Vascular aineralization, aild Pneuaonia, interstitial, chronic, local areas, aoderate The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrou, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3532 Sex! Male 6roup! ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Pituitary Kidney Microscopic Observations: Eye Heart Kidney Liver Lung -Raised red aass, 0.4 ca dia. -Fluid filled cyst, 1 ca dia., in right kidney -Retinal atrophy, focal, aild -Myocardial fibrosis, focal, aild -Chronic progressive nephropathy, aoderate Cyst, cortical, narked -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aild Heaorrhage, local areas, aild Perivascular aononudear infiltrate, aild Species: Rat Project Nuaber: 02B1CR0012 001710 Suaaarized STAR Page: 35 226 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tno Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3532 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Heek 106) Tereinal Sacrifice Microscopic Observations (continued): Lyeph Node (eesenteric) Pituitary Spleen -Heeorrbage, eild -Adenoea -Heeosiderosis, eild The following tissues ere found to be within noreal lieits: Brain, Spinal ConT, Bone Harrow, Stoeach, Seall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyeis, Prostate, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary 61and. Anieal Nuaber: 1R-3533 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Heek= 106) Tereinal Sacrifice Macroscopic Observations: Spleen Microscopic Observations: Eye Heart Kidney Liver Lung Prostate Spleen -Pale circular depressed area, 0.4 co dia. -No diagnosis, inadequate section -Myocarditis, chronic nonsuppurative, aultifocal, wild -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aild Perivascular aononudear infiltrate, aild -Prostatitis, acute, suppurative, aild -Heeosiderosis, aild Fibrosis, local areas, aoderate The following tissues were found to be within nomai liaits: Brain, Spinal Cord, Bone Harrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyeis, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lysph Node (eesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-3534 Sex*. Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Sacrificed in extreais Macroscopic Observations: Thyaus Pancreas -Enlarged -Massive beige colored aass, 7.5 x 3 ca in area of pancreas coapletely surrounding spleen and adhering to posterior areas of right and left lateral Species: Rat Project Nuaber: 02B1CR0012 001711 Suaaarized STAR Page: 36 227 Summed Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-3534 Sex! Hale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Sacrificed in extreeis Macroscopic Observations (continued): Pancreas (continued) Kidney Testis/Epididynis Liver Microscopic Observations: Adrenal Kidney Liver Lung Lynph Node (sesenteric) Pancreas Parathyroid Pituitary Saall Intestine Spleen Stoaach Testis/Epididynis Thynus Thyroid Urinary Bladder -liver lobes. -Pale and pitted. -Right testis saall. -Pale with yellowish circular lesion 0.3 ca diaaeter in right anterior lobe -Cortical vacuolation, diffuse, aoderate Medullary cell hyperplasia, local areas, aoderate -Chronic progressive nephropathy, aoderate Malignant lyaphosa, histiocytic -Hepatocyte vacuolation, diffuse, narked -Heaorrhage, diffuse, narked Malignant lyaphosa, histiocytic -Heaorrhage, aiId Malignant lyaphoaa, histiocytic -Malignant lyaphoaa, histiocytic -Not exaained, aissing -Adenoaa -Malignant lyaphoaa, histiocytic -Malignant lyaphoaa, histiocytic -Malignant lyaphoaa, histiocytic -Tubule atrophy, asperaatogenesis, unilateral, narked -Malignant lyaphoaa, histiocytic Multiple sections of tuaor froa thyaic and aediastinal areas. -Not exaained, aissing -Malignant lyaphoaa, histiocytic The following tissues were found to be within noraal Units: Brain, Spinal Cord, Bone Harrow, Heart, Trachea, Esophagus, Salivary Gland, Eye, Large Intestine, Aorta, Prostate. Species: Rat Project Nuaber: 02B1CR0012 001712 Suaaarized STAR Page: 37 228 Suaaarized Single Tabulated Aninal Report (continued) Individual Nacroacopic and Hicroscopic Observations Riker Laboratories, Inc. 3M FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3536 Sex: Hale Broup: ( 1) CONTROL 0 ppa Fate: (Week- 106) Terminal Sacrifice Hacroscopic Observations: Skin Hicroscopic Observations: Adrenal Kidney Large Intestine Liver Lung Skin -Raised lesion, 1.5 c> dia., appears to be abscess. -Cortical vacuolation, focal, aild Sinusoidal ectasia, cortex, focal, aoderate -Chronic progressive nephropathy, ainiaal -Neaatodiasis, colon -Portal bile duct proliferation, aultifocal, aild Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, ainiaal -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Keratoacanthoaa Raised lesion froa back. The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye, Urinary Bladder. Aniaal Nuaber: 1R-3537 Sex: Hale Sroup: ( 1) CONTROL 0 ppa Fate: (Heek* 73) Found Dead Hacroscopic Observations: Liver Lyaph Node (abdoainal) Abdoaen (internal) Pituitary Hicroscopic Observations: Eye Heart Liver Lung Lyaph Node (aesenteric) Pancreas Parathyroid -Very pale -Renal lyaph nodes enlarged. -Multilobular, fleshy aass, 4 x 3.5 x 3.5 attached to oaentua, left inguinal area. -Heaorrhagic aass, 0.7 ca dia. -Not exaained, aissing -Halignant lyaphoaa, histiocytic -Hepatocyte vacuolation, diffuse, narked Halignant lyaphoaa, histiocytic -Halignant lyaphoaa, histiocytic Heaorrhage, local areas, aoderate -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing Species: Rat Project Nuaber: 0281CR0012 001713 Suaaarized STAR Page: 3B 229 Suaaarized Singlt Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aninal Nuaber: 1R-3537 Sex: dale Broup: ( 1) CONTROL 0 ppn Fate: (Heek= 73) Found Dead Hicroscopic Observations (continued): Pituitary Skin Spleen Thyroid -Adenona -Halignant lyophona, histiocytic Hass iron inguinal area nas salignant lyaphona. There was extensive necrosis in tunor. -Henosiderosis, nild -Not exanined, eissing The Following tissues eere Found to be within norsal linits: Brain, Spinal Cord, Bone Harrow, Kidney, Stonach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Trachea, Esophagus, Salivary 61and. Aniaal Nuaber: 1R-353B Sex! Hale Sroup: ( 1) CONTROL 0 ppa Fate: (Meek- 106) Terainal Sacrifice Hacroscopic Observations: Pituitary Liver Spleen Hicroscopic Observations: Adrenal Kidney Liver Lung Lyaph Node (aesenteric) Parathyroid Prostate Spleen Urinary Bladder -Saall heaorrhagic area, 0.2 ca dia. -Multiple pale Foci, all lobes. -Enlarged -Cortical vacuolation, Focal, aild -Chronic progressive nephropathy, aild -Halignant lyaphoaa, histiocytic -Vascular aineralization, aild Alveolar aacrophages, aild Halignant lyaphoaa, histiocytic Perivascular aononuclear infiltrate, aild -Heaorrhage, ainiaal -Not exaained, not in plane oF section -Prostatitis, acute, suppurative, aarked -Halignant lyaphoaa, histiocytic -Epithelial hyperplasia, siaple, diffuse, aild The Following tissues were Found to be within noraal Units: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Testis/Epididyais, Pituitary, Thyroid, Trachea, Esophagus, Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 0281CR0012 001714 Suaaarized STAR Page: 39 230 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3539 Sex: Male Group: ( 1) CONTROL 0 ppe Fate: (Meek- 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Large Intestine Liver Lung Parathyroid Pituitary Spleen Thyroid No visible lesions. -Chronic progressive nephropathy, aild -Neaatodiasis, colon -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal aild Perivascular aononudear infiltrate, aild -Not exaained, not in plane of section -Cyst, pars distalis -Heaosiderosis, aild -Ultiaobranchial cyst The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber! 1R-3S40 Sex: Hale 6roup: I 1) CONTROL 0 ppa Fate: (Week? 64) Found Dead Macroscopic Observations: Microscopic Observations: Bone Harrow Liver Lung Prostate Spinal Cord Thyroid Urinary Bladder -No visible lesions. -Not exaained, aissing -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild -Vascular aineralization, aild Alveolar aacrophages, aild -Not exaained, aissing -Not exaained, aissing -Ultiaobranchial cyst -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Testis/Epididyais, Pituitary, Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 40 Suaaarized Single Tabulated flnieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniial Nueber: 1R-3541 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek* 106) Terainal Sacrifice Macroscopic Observations: Skin Microscopic Observations: Adrenal Kidney Liver Lung Prostate Skin Testis/Epididyeis Urinary Bladder -Raised lesion on left rear footpad. -Cortical vacuolation, focal, eild Sinusoidal ectasia, cortex, ainioal -Chronic progressive nephropathy, ainiaal -Portal aononuclear cell infiltrate, aild Portal bile duct proliferation, aild -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aild Heaorrhage, diffuse, narked Perivascular aononuclear infiltrate, aild -Not exaained, aissing -Pododeraatitis, ulcerative, hindleg, narked -Not exaained, aissing -Not exaained, aissing The follouing tissues acre found to be within noraal liaits: Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3542 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Heek 106) Terainal Sacrifice Macroscopic Observations: Testis/Epididyais Microscopic Observations: Kidney Liver Lung Lyaph Node (aesenteric) Pancreas Testis/Epididyais Thyroid -Both testes saall. -Chronic progressive nephropathy, aoderato -Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, ainiaal -Heaorrhage, ainiaal -Hyperplasia, islet cell, aoderate -Tubule atrophy, asperaatogenesis, bilateral, narked Polyarteritis, aild -Not exaained, aissing The follouing tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harro, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Adrenal, Parathyroid, Trachea, Salivary Gland, Eye, Esophagus. Species: Rat Project Nuaber: 02B1CR0012 001716 Suaaarized STAR Page: 41 232 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3544 Sex: Hale 6roup: ( i) CONTROL 0 ppe Fate: (Heek 106) Tereinal Sacrifice Macroscopic Observations: Pituitary Kidney Testis/Epididyeis Microscopic Observations: Adrenal Kidney Liver Lung Pancreas Parathyroid Pituitary Spleen Testis/Epididyeis -Heeorrhagic lesion, 0.7 ca dia. -Both enlarged, pale and pitted. -Left testis snail. -Cortical vacuolation, aultifocal, eoderate Sinusoidal ectasia, cortex, aoderate -Chronic progressive nephropathy, narked -Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild Alveolar aacrophages, aild -Acinar atrophy, aild Polyarteritis, aoderate -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, aild -Tubule atrophy, asperaatogenesis, unilateral, narked Polyarteritis, aarked The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary 61and, Eye, Heart. Aniaal Nuaber: 1R-3545 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Week- 104) Found Dead Macroscopic Observations: Skin Liver Microscopic Observations: Adrenal Eye Heart Kidney Lung Pancreas Pituitary -Circular lesions, 2.S ca dia. on both hind footpads. -Slightly pale -Sinusoidal ectasia, cortex, aoderate Cortical vacuolation, aultifocal, aoderate -Not exaained, aissing -Myocardial fibrosis, local areas, aild -Chronic progressive nephropathy, aild -Vascular aineralization, aild Alveolar aacrophages, aild -Acinar atrophy, aoderate -Adenoaa Species: Rat Project Nuaber: 02B1CR0012 001717 Suaaarized STAR Page: 42 233 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: To Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3545 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Meek- 104) Found Dead Microscopic Observations (continued): Skin Spleen -Pododcraatitis, ulcerative, hindleg, bilateral, aarked -Heaatopoiesis, extraaedullary, increased, aild The following tissues sere found to be aithin noraal liaits: Brain, Spinal Cord, Bone Narroa, Liver, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Bland. Aniaal Nuaber: 1R-3S47 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 85) Sacrificed in extreais Hacroscopic Observations: Pituitary Liver Microscopic Observations: Adrenal Brain Kidney Liver Lung Pituitary Stoaach -Hass, 0.4 ca dia. -Pale -Sinusoidal ectasia, cortex, aoderate -Oligodendroglioaa, benign Large neoplasa coaposed of large, fairly unifora polyhedral cells in cerebral cortex. -Chronic progressive nephropathy, ainiaal Pyelonephritis, acute, aild -Portal aononuclear cell infiltrate, aild Hepatocyte vacuolation, periportal, aoderate -Vascular aineralization, aild -Adenoaa -Edeaa, subaucosal, aoderate The following tissues were found to be within noraal liaits: Spinal Cord, Bone Harrow, Spleen, Heart, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3548 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Meek* 106) Terainal Sacrifice Hacroscopic Observations: Microscopic Observations: Adrenal -No visible lesions. -Cortical vacuolation, aultifocal, aild Species: Rat Project Nuaber: 0281CR0012 001718 Suaaarized STAR Page: 43 234 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-J924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-354B Sex: Hale Sroup: ( 1) CONTROL 0 ppa Fate: INeek= 106) Terainal Sacrifice Microscopic Observations (continued): Kidney Liver Lung Lyaph Node (aesenteric) Parathyroid Pituitary Thyroid -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, periportal, aild Hepatocyte vacuolation liaited to one area of liver. -Vascular aineralization, aild Alveolar aacrophages, ainiaal Perivascular aononudear infiltrate, aild -Heaorrhage, aild -Not exaained, not in plane of section -Cyst, pars distalis -C cell carcinosa The fallowing tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harro, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Trachea, Esophagus, Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3549 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Week B6) Sacrificed in extreais Macroscopic Observations: Pituitary Liver Hicroscopic Observations: Heart Liver Lung Parathyroid Pituitary Spleen Thyroid -Heaorrhagic aass, 1.4 x 0.8 ca. -Slightly pale -Myocarditis, chronic nonsuppurative, aultifocal, aild -Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild Alveolar aacrophages, ainiaal -Not exaained, aissing -Adenoaa -Heaosiderosis, aild -Not exaained, aissing The following tissues were found to be within noraal Halts: Brain, Spinal Cord, Bone Harrou, Kidney, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 0281CR0012 001719 Suaearized STAR Page: 44 235 Suiaarizcd Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3552 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: <Neek= 104) Tereinal Sacrifice Macroscopic Observations: Spleen Microscopic Observations: Adrenal Kidney Liver Lung Pancreas Parathyroid Pituitary Prostate Spleen -Circular raised lesion, 1.2 ca dia. -Cortical vacuolation, aultifocal, aild Medullary cell hyperplasia, local areas, aoderate -Chronic progressive nephropathy, aoderate -Portal eononudear cell infiltrate, aild Portal bile duct proliferation, aild -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal aild -Acinar atrophy, aild -Not exaained, not in plane of section -Adenoaa -Prostatitis, acute, suppurative, aild -Heaangiosarcoaa The folloing tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harro, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyeis, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Anieal Nuaber: 1R-3553 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= BB) Found Dead Macroscopic Observations: Adrenal Microscopic Observations: Adrenal Eye Heart Kidney Large Intestine Liver Lung Lyaph Node (aesenteric) -Left enlarged by a 1 ca dia. aass. -Sinusoidal ectasia, cortex, aild Pheochroaocytoaa, benign, unilateral -Not exaained, aissing -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aild -Not exaained, aissing -Portal eononudear cell infiltrate, aild Portal bile duct proliferation, aoderate Hepatocyte vacuolation, aultifocal, aild Necrosis, aultifocal, aild -Vascular aineralization, aild -Not exaained, aissing Species: Rat Project Nuaber: 02B1CR0012 001720 Sueearized 5TAR Page: 4S 236 Suaurizcd Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Wiservations Riker Laboratories, Inc. 3H FH-3924: Too Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3553 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Meek 88) Found Dead Hicroscopic Observations (continued): Pancreas Pituitary Salivary Gland Snail Intestine -Not exaained, aissing -Cyst, pars distaiis -Not exaained, aissing -Nat exaained, aissing The fallotting tissues acre Found to be eithin noraal Units: Brain, Spinal Cord, Bone Harroa, Spleen, Stoaach, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus. Aniaal Nuaber: 1R-3554 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Keek- 106) Terainal Sacrifice Hacroscopic Observations: Hicroscopic Observations: Kidney Liver Lung Parathyroid Prostate -No visible lesions. -Chronic progressive nephropathy, aoderate -Portal aononuclear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aild -Alveolar aacrophages, aultifocal, aoderate Perivascular aononuclear infiltrate, aoderate Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aoderate -Not exaained, not in plane of section -Prostatitis, acute, suppurative, aoderate The folloaing tissues aere found to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3555 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Week- 102) Sacrificed in extreais Hacroscopic Observations: Kidney Urinary Bladder Hicroscopic Observations: Adrenal -Pale, enlarged; aild hydronephrosis. -Enlarged, fluid filled, all appears heaorrhagic. Cortical vacuolation, local areas, aoderate Species: Rat Project Nuaber: 02B1CR0012 001721 Suaaarized STAR Page: 46 237 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Too Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3555 Sex'. Hale Broup: ( 1) CONTROL 0 ppa Fate: (Heek- 102) Sacrificed in extreais Hicroscopic Observations (continued): Aorta Heart Kidney Liver Lung Parathyroid Prostate Saall Intestine Spleen Stoaach Urinary Bladder -Hineralization, aild -Myocarditis, chronic nonsuppurative, aultifocal, aild -Nephrosis, tubular, aoderate Papillary necrosis, aoderate Hydronephrosis, aild Tubules dilated with lou, basophilic epitheliua, scattered aineralized tubules. -Portal bile duct proliferation, aild Hepatocyte vacuolation, eultifocal, aild -Vascular aineralization, aild Alveolar aacrophages, aild Heaorrhage, focal, aild -Not exaained, not in plane of section -Prostatitis, acute, suppurative, aild Edeaa, intersititial, aoderate -Hithin noraal Units Fever than protocol nuaber -Heaosiderosis, aild -Edeaa, subaucosal, aoderate -Heaorrhage, aarked Epithelial hyperplasia, siaple, diffuse, aild Cystitis, acute, aoderate The following tissues were found to be within noreal lioits: Brain, Spinal Cord, Bone Harrov, Large Intestine, Testis/Epididyais, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3556 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 10b) Terainal Sacrifice Hacroscopic Observations: Adrenal Hicroscopic Observations: Adrenal Kidney Liver -Right enlarged by aass, 2 x 1 ci. -Carcinoaa, cortical, unilateral Large neoplasa, aostly necrotic. Cells foaay, polyhedral arranged in cords and sheets. High aitotic activity. Multiple lung aetastases. -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Species: Rat Project Nuaber: 02B1CR0012 001722 Suaaarized STAR Page: 47 238 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic (Miservations Riker Laboratories, Inc. 3H FN-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anisal Nuaber: 1R-3556 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Microscopic Observations (continued): Lung Parathyroid -Pneuaonia, interstitial, chronic, eultifocal, aild Metastatic neoplasa Perivascular aononudear infiltrate, aild Vascular aineralization, aild -Not exaained, not in plane of section The following tissues nere found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3557 Sex! Hale 6roup`. ( 1) CONTROL 0 ppa Fate: (Neeks 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Thyroid -No visible lesions. -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Hepatocyte alteration, vacuolated, aild -Vascular aineralization, aild Pneuaonia, interstitial, chronic, eultifocal, aild -Hyperplasia, C cell, aild The following tissues were found to be within noreal liaits: Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3558 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 106) Terainal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Kidney Liver -Raised aass, 0.9 ce dia. -Sinusoidal ectasia, cortex, aild -Chronic progressive nephropathy, aild Calculus, pelvic, ainiaal -Cystoid degeneration, focal, ainiaal Species: Rat Project Nuaber: 02B1CR0012 001723 Sueaarized STAR Page: 48 239 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3558 Sex: Hale Group: ( 1) CONTROL 0 ppe Fate: (Week- 106) Terainal Sacrifice Hicroscopic Observations (continued): Parathyroid Pituitary Spleen -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Eland, Eye. Aniaal Nuaber: 1R-3560 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Week= 35) Sacrificed in extreais Hacroscopic Observations'. Brain Lung Spleen Lyaph Node (abdoainal) Liver Hicroscopic Observations: Brain Liver Lung Lyaph Node (aesenteric) Saall Intestine Spleen -Focal circuascribed dark area, dorsal surface, left cerebral heaisphere (0.2 ca dia.) and lateral surface of right cerebral heaisphere (0.2 ca dia.) -Dark red diffuse Bottling, all lobes) red frothy exudate at trachea. -Enlarged -Hepatic and renal nodes enlarged. -Pale, appears enlarged. -Abscess, aild Heaorrhage, aultifocal, aoderate -Halignant lyaphoaa, histiocytic -Halignant lyaphoaa, histiocytic Heaorrhage, diffuse, aarked Necrosis, local areas, aarked -Heaorrhage, ainiaal -Nithin noraal liaits Fewer than protocol nuaber -Heaatopoiesis, extraaedullary, increased, aarked The following tissues were found to be within noraal liaits: Spinal Cord, Bone Harrow, Kidney, Heart, Stoaach, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 001724 Suaaarized STAR Page*. 49 240 i Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Rifcer Laboratories, Inc. 3H FH-3924: Tno Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3561 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Neek* 106) Terainal Sacrifice Macroscopic Observations: Soft Tissues (leg) Kidney Microscopic Observations: Adrenal Bone Bone Marrow Kidney Large Intestine Liver Lung Parathyroid Pituitary Spinal Cord Spleen Testis/Epididyais Thyroid -Right and left hindpaw and right forepan swollen. -Right kidney polycystic. -Cortical vacuolation, aultifocal, aild Medullary cell hyperplasia, aultifocal, aild -Arthritis, synovitis! joints, hindleg, foreleg, aarked -Not exaained, aissing -Chronic progressive nephropathy, aild Pelvic aineralization, aild Cyst, cortical, unilateral, narked -Neaatodiasis, colon -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild -Perivascular aononudear infiltrate, aild Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aild Heaorrhage, local areas, aoderate -Not exaained, aissing -Adenoaa -Not exaained, aissing -Heaosiderosis, aild -Tubule atrophy, asperaatogenesis, aoderate Polyarteritis, aarked -Not exaained, aissing The following tissues were found to be uithin noraal lieits: Brain, Heart, Stoeach, Snail Intestine, Urinary Bladder, Aorta, Prostate, Trachea, Esophagus, Lynph Node (nesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3562 Sex: Hale 6roup*. ( 1) CONTROL 0 ppa Fate: (Heek= 106) Terainal Sacrifice Macroscopic Observations: Skin Spleen Microscopic Observations: Adrenal -Raised ulcerated inflaaaed lesion, right rear footpad. -Several pale foci. -Nodular hyperplasia, cortex, unilateral, aoderate Species: Rat Project Nuaber: 0281CR0012 001725 Suaaarized STAR Page: 50 241 Sunaarized Single Tabulated flnieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tw Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniual Nueber: 1R-3542 Sex: Hale Group: ( 1) CONTROL 0 ppe Fate: (Heek 104) Terainal Sacrifice Microscopic Observations (continued): Heart Kidney Large Intestine Liver Lung Parathyroid Pituitary Salivary 61and Skin -Myocarditis, chronic nonsuppurative, eultifocal, aild -Chronic progressive nephropathy, aild -Neaatodiasis, colon -Portal aononudear cell infiltrate, aild -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aild Perivascular aononudear infiltrate, aild -Not exaained, not in plane of section -Adenoaa -Not exaained, aissing -Pododeraatitis, ulcerative, hindleg, narked The following tissues vere found to be Mithin noreal lieits: Brain, Spinal Cord, Bone Marrou, Spleen, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Epididyeis, Prostate, Thyroid, Trachea, Esophagus, Lyeph Node (aesenteric), Pancreas, Eye, Anieal Nueber: 1R-3543 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Week 104) Terainal Sacrifice Macroscopic Observations: Thyroid Skin Microscopic Observations: Adrenal Brain Heart Kidney Liver Lung Pancreas Pituitary Prostate -One side enlarged, 1 x 0.6 ca. -Mass, 1.7 x 1.4 ca, dorsal area. -Cortical vacuolation, eultifocal, aild Sinusoidal ectasia, cortex, ainiaal -Astrocytoaa, benign Poorly defined lesion in basal area of cerebrua. Tueor cells spindelate. -Myocarditis, chronic nonsuppurative, eultifocal, aild -Chronic progressive nephropathy, aoderate -Hepatocyte alteration, basophilic, aoderate Portal aononudear cell infiltrate, aild Hepatocyte alteration, vacuolated, aoderate Necrosis, local areas, aoderate -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Acinar atrophy, narked -Adenoaa -Prostatitis, acute, suppurative, aoderate Species: Rat Project Nuaber: 0281CR0012 001726 Suanarized STAR Page: SI 242 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924*. Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3563 Sex: Hale firoup: ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Microscopic Observations (continued): Skin Thyroid -Keratoacanthoaa, back -C cell carcinoaa The follotting tissues ere found to be uithin noraal liaits: Spinal Cord, Bone Harroa, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenterid, Salivary Bland, Eye. Aniaal Nuaber: 1R-3564 Sex: Male Broup: ( 1) CONTROL 0 ppa Fate: Week* 106) Terainal Sacrifice Macroscopic Observations: Kidney Microscopic Observations: Adrenal Bone Narro Heart Kidney Liver Lung Pancreas Parathyroid Pituitary Salivary Bland Spinal Cord Testis/Epididyais -Pale area in cortex of one kidney. -Cortical vacuolation, aultifocal, aild Medullary cell hyperplasia, aultifocal, aoderate -Not exaained, aissing -Myocarditis, chronic nonsuppurative, aultifocal, aild Myocardial fibrosis, aultifocal, aild -Chronic progressive nephropathy, aoderate Cyst, unilateral, aoderate Area of aultilocular cysts in cortex with lipid change in surrounding parenchyaa. -Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Portal aanonudear cell infiltrate, aild -Vascular aineralization, aild -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa -Not exaained, aissing -Not exaained, aissing -Mineralization, focal, aild The folloing tissues ere found to be within noraal liaits: Brain, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Eye. Species: Rat Project Nuaber: 0281CR0012 001727 Suaaarized STAR Page: 52 243 Suaaarized Singli Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3824: Too Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nusber: 1R-3565 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Meek* 84) Found Dead Hacroscopic Observations: Skin Liver Microscopic Observations: Adrenal Aorta Esophagus Eye Kidney Large Intestine Liver Lung Lyaph Node (aesenteric) Pancreas Parathyroid Pituitary Prostate Salivary Gland Skin Saall Intestine Spleen Thyroid Trachea Urinary Bladder -Large aass, 7 x 7 ca, scrotal area. -Pale -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -No diagnosis, inadequate section -Chronic progressive nephropathy, aild -No diagnosis, inadequate section -Hepatocyte vacuolation, suitifocal, aild Necrosis, aultifocal, aoderate -Vascular aineralization, aild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Liposarcoaa The scrotal aass uas coaposed of large, vacuolated aononudear cells. The degree of autolysis Bade diagnosis soaewhat uncertain. -Not exaained, aissing -Hesatopoiesis, extraaedullary, increased, aild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing The folloaing tissues aere found to be within noraal liaits: Brain, Spinal Cord, Bone Harroa, Heart, Stoaach, Testis/Epididyais. Aniaal Nuaber: 1R-3566 Sex'. Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Kidney -Saall dark lesion. -Nithin noraal liaits One of pair present -Chronic progressive nephropathy, aild Species: Rat Project Nuaber: 0281CR0012 001728 Suaaarized STAR Page: 53 244 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Tot Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber*. 1R-3564 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: <Neek= 106) Terainal Sacrifice Microscopic Observations (continued): Liver Lung Pancreas Parathyroid Spleen -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Polyarteritis, aoderate -Not exaained, not in plane of section -Heaosiderosis, aild The following tissues were found to be within noraal liaits*. Brain, Spinal Cord, Bone Harrow, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Trachea, Lyaph Node (aesenteric), Salivary Gland, Stoaach, Seal1 Intestine, Heart, Eye, Esophagus. Aniaal Nuaber: 1R-3S67 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Meek- 106) Terainal Sacrifice Macroscopic Observations: Skin Spleen Microscopic Observations: Adrenal kidney Liver Lung Skin Spleen -Raised papilloaa type aass on back; raised inflaaaed lesion, right rear footpad. -Two pale foci. -Cortical vacuolation, aultifocal, aild Nodular hyperplasia, cortex, focal, aild -Chronic progressive nephropathy, aoderate -Portal aononudear cell infiltrate, aild -Vascular aineralization, aild Alveolar aacrophages, ainiaal Perivascular aononudear infiltrate, ainiaal -Papilloaa, back Pododeraatitis, ulcerative, hindleg, aarked -Necrosis, local areas, aoderate The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001729 Suaaarized STAR Page: 5f 245 Suuarized Single Tabulated flniial Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tno Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3569 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Week 106) Terainal Sacrifice Macroscopic Observations: Kidney Microscopic Observations: Adrenal Heart Kidney Liver Lung Pituitary Testis/Epididyais -Bilaterally enlarged) pale, pitted. -Cortical vacuolation, focal, ainiaal Sinusoidal ectasia, cortex, aiId Medullary cell hyperplasia, aultifocal, aiId -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aarked -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Hyperplasia, focal, pars distalis, aild -Polyarteritis, aoderate The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3571 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 106) Terainal Sacrifice Macroscopic Observations: Liver Kidney Mesentery Microscopic Observations: Adrenal Heart Kidney Liver Lung Mesentery Pancreas Parathyroid Pituitary -Pale -Pale, pitted, enlarged. -Mesenteric vessels thickened -Cortical vacuolation, focal, ainiaal -Myocarditis, chronic nonsuppurative, aultifocal, ainiaal -Chronic progressive nephropathy, aarked -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild Perivascular aononudear infiltrate, ainiaal -Polyarteritis, aarked -Polyarteritis, aarked -Not exaained, not in plane of section -Not exaained, aissing Species: Rat Project Nuaber: 0281CR0012 001730 Suaaarized STAR Page: 55 246 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3S71 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: INeek= 10b) Terainal Sacrifice Hicroscopic Observations (continued): Saall Intestine Spleen Testis/Epididyais -Polyarteritis, aesentery, aarked -Heaosiderosis, aild -Polyarteritis, aarked The following tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harro, Stoaach, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary 61and, Eye. Aniaal Nuaber: iR-3572 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Hacroscopic Observations: Hicroscopic Observations: Kidney Liver Lung Pancreas Parathyroid Stoaach -No visible lesions. -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild -Vascular oineralization, aild -Hyperplasia, islet cell, aoderate -Not exaained, not in plane of section -Not exaained, aissing The following tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harro, Spleen, Heart, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3573 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Ueek= 106) Terainal Sacrifice Hacroscopic Observations: Pancreas Hicroscopic Observations: Adrenal Kidney Large Intestine Liver -Saall circular pale aass, 0.5 ca dia. -Cortical vacuolation, aultifocal, aild Pheochroaocytoaa, benign, unilateral Chronic progressive nephropathy, aild -Neaatodiasis, colon -Hepatocyte alteration, vacuolated, aild Hepatocyte alteration, basophilic, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Portal aononudear cell infiltrate, aild Species: Rat Project Nuaber: 0281CR0012 001731 Suaaarized STAR Page: 56 24 7 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3573 Sex: Hale Sroup: ( 1) CONTROL 0 ppa Fate: (Meek- 106) Terainal Sacrifice Microscopic Observations (continued): Lung Pancreas Parathyroid -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Acinar atrophy, aoderate Islet cell adenoaa -Not exaained, not in plane of section The folloaing tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Snail Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3574 Sex'. Male 6roup: ( 1) CONTROL 0 ppa Fate: (Heek= 99) Sacrificed in extreais Macroscopic Observations: Skin Thorax (internal) Heart Liver Kidney Testis/Epididyais Microscopic Observations: Adrenal Aorta Heart Kidney Liver Lung Lyaph Node (aesenteric) Pancreas Parathyroid -Ulcerated right and left hind footpads; circular white subcutaneous aass, 1.5 ca dia., in right inguinal area. -Filled with fluid. -Slightly pale and flaccid. -Slightly pale -Pale and pitted; 1.5 ca cyst in right kidney. -Testes saall -Cortical vacuolation, aultifocal, aild -Necrosis, local areas, aoderate Unifora intiaal necrosis with reactive cellular infiltrate. -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aarked Cyst, unilateral, aarked -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild -Pneuaonia, interstitial, chronic, diffuse, aoderate Perivascular aononudear infiltrate, aild Edeaa, local areas, aarked -Not exaained, aissing -Acinar atrophy, aild -Not exaained, not in plane of section Species: Rat Project Nuaber: 0281CR0012 001732 Suaaarized STAR Page: 57 248 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3574 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Meek2 99) Sacrificed in extreais Microscopic Observations (continued): Pituitary Prostate Salivary Gland Skin Te5tis/Epididyais -Cyst, pars interaedia -Prostatitis, acute, suppurative, soderete -Not exaained, aissing -Fibrosa, subcutaneous, inguinal Pododeraatitis, ulcerative, hindleg, narked -Tubule atrophy, asperaatogenesis, bilateral, aoderate The follouing tissues aere found to be aithin noraal Units: Brain, Spinal Cord, Bone Narroa, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Thyroid, Trachea, Esophagus, Eye. Aniaal Nuaber: 1R-3576 Sex: Hale Group: I 1) CONTROL 0 ppa Fate: (Neek= 55) Sacrificed in extreais Macroscopic Observations: Skin Abdoaen (internal) Microscopic Observations: Kidney Lung Parathyroid Spleen Urinary Bladder -Hoist area around genital papilla. -Large aaount of gas in gastrointestinal tract! no food in stoaach. -Pelvic aineralization, aild -Heaorrhage, diffuse, Barked -Not exaained, not in plane of section -Heaosiderosis, aild -Not exaained, aissing The follouing tissues Here found to be uithin noraal liaits: Brain, Spinal Cord, Bone Harrou, Liver, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Testis/EpididyBis, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (sesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3577 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Kidney Liver No visible lesions. Chronic progressive nephropathy, aoderate Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Cystoid degeneration, aultifocal, aild Hepatocyte alteration, vacuolated, aild Species: Rat Project Nuaber: 02B1CR0012 001733 Suaaarized STAR Page: 58 249 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3577 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Microscopic Observations (continued): Lung Mesentery Pancreas Saall Intestine Spleen Thyroid -Vascular aineralization, aild -Polyarteritis, aarked -Polyarteritis, aarked -Polyarteritis, aesentery, aoderate -Heoosiderosis, aild -Cyst, colloid, aild The folloaing tissues aere found to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Heart, Stoaach, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Bland, Eye. Aniaal Nuaber: 1R-3576 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Pituitary Skin Microscopic Observations: Kidney Liver Lung Pituitary Prostate Salivary 61and Skin -Heaorrhagic aass, 0.7 ca dia. -Raised ulcerated inflaaaed lesion, 1.3 ca dia., left hind footpad. -Chronic progressive nephropathy, aild Hydronephrosis, unilateral, aoderate Calculi present in ureter of hydronephrotic kidney. -Portal aononuclear cell infiltrate, aild Portal bile duct proliferation, aild -Vascular aineralization, aild Heaorrhage, local areas, aoderate -Adenoaa -Prostatitis, acute, suppurative, aoderate -Sialadenitis, chronic, ainiaal Very ainiaal lesion, only one duct affected. -Pododeraatitis, ulcerative, hindleg, aarked The folloaing tissues aere found to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Species: Rat Project Nuaber: 02B1CR0012 001734 Suaaarized STAR Page: 39" 250 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3579 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Heek- 86) Sacrificed in extreais Macroscopic Observations: Pituitary Liver Skin Microscopic Observations: Kidney Liver Lung Parathyroid Pituitary Skin Snail Intestine Spleen Testis/Epididyais -Raised aass, O.B ca dia. -Raised pale 2 ca dia. aass in right lateral lobe. -Mass seen clinically on right side appears to be healed lesion. -Chronic progressive nephropathy, narked -Portal bile duct proliferation, aild Hepatocellular carcinoaa Portal aononudear cell infiltrate, aild -Perivascular aononudear infiltrate, aild -Not exaained, not in plane of section -Adenoaa -Keratoacanthoaa Skin lesion froa right side. -Nithin noraal liaits ^ Fewer than protocol nuaber -Heaosiderosis, aild -Tubule atrophy, asperaatogenesis, unilateral, aild Polyarteritis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Large Intestine, Urinary Bladder, Aorta, Prostate, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4576 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 25) Sacrificed in extreais Hacroscopic Observations: Liver Lyaph Node (bronchial) Lung Spleen Stoaach Lyaph Node (aesenteric) Microscopic Observations: Adrenal Bone Marron Kidney -Enlarged; Bottled yellou color. -Enlarged -Pale -Enlarged -Red patchy areas on aucosa. -Enlarged and reddened. -Sinusoidal ectasia, cortex, aild -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic Mineralization, cortical, aild Species: Rat Project Nuaber: 02B1CR0012 001735 Suaaarized STAR Page: 60 251 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FM-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4576 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 25) Sacrificed in extreais Microscopic Observations (continued): Liver Lung Lyaph Node (aesenteric) Pancreas Salivary Gland Spinal Cord Spleen Stoaach Urinary Bladder -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic Heaorrhage, aultifocal, aild -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Not exaained, aissing -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Ulcer -Epithelial hyperplasia, siaple, diffuse, aild The following tissues ere found to be within noraal liaits: Brain, Heart, Saall Intestine, Large Intestine, Aorta, Uterus, Ovary, Haaaary Gland, Pituitary, Trachea, Thyroid, Parathyroid, Esophagus, Eye. Aniaal Nuaber*. 1R-4577 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 99) Found Dead Macroscopic Observations: Pituitary Haaaary 61and Microscopic Observations: Adrenal Kidney Liver Lyaph Node (aesenteric) Haaaary Gland Pituitary Spleen Uterus -Heaorrhagic aass, 0.8 ca dia. -Multilobular aass, 4.5 x 3.5 x 2 ca, in right axilla. -Sinusoidal ectasia, cortex, aoderate -Pelvic aineralization, aild Nephrosis, tubular, aarked -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild -Not exaained, aissing -Lobular hyperplasia -Heaorrhage, aarked Necrosis, aoderate -Heaosiderosis, aild -Cystic glands, aoderate The following tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Narro, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Thyroid, Parathyroid, Esophagus, Pancreas, 5alivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 001736 Suaaarized STAR Page: 61 252 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anisal Nuaber: 1R-4579 Sex: Feeale Group: ( 1) CONTROL 0 ppn Fate: (Heefc- 84) Sacrificed in extreais Macroscopic Observations: Pituitary Skin Liver Stoaach Kidney Microscopic Observations: Adrenal Aorta Heart Kidney Liver Lung Lyaph Mode (aesenteric) Parathyroid Pituitary Skin Spleen Stoaach -Raised aass, 0.5 ca dia. -Raised thickened lesion with scab on right side. -Slightly pale -Soaeahat reddened -Fluid filled cyst in left kidney. -Sinusoidal ectasia, cortex, aiId -Mineralization, aultifocal, aiId -Myocarditis, chronic nonsuppurative, aultifocal, aoderate -Nephrosis, tubular Pelvic aineralization, aarked Cyst, cortical, aoderate Hyperplasia, pelvic epitheliua, diffuse, aild -Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa -Ulcer, aarked Skin lesion froa side. -Heaosiderosis, aild -Mineralization, aucosal, aild The follouing tissues aere found to be within noraal liaits: Brain, Spinal Cord, Bone Harrou, Saall Intestine, Large Intestine, Urinary Bladder, Uterus, Ovary, Haasary Gland, Trachea, Thyroid, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4580 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 52) Sacrificed in extreais Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Aorta Esophagus Lyaph Node (aesenteric) Maaaary 61and Parathyroid -Enlarged; dark red aass, 0.5 ca dia. -Sinusoidal ectasia, cortex, aild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -6alactocele -Not exaained, not in plane of section Species: Rat Project Nuaber: 0281CR0012 001737 Suaaarized STAR Page: if 253 Suaaarized Single Tabulated Anieal Report (continued) Individual Nacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-45B0 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 52) Sacrificed in extreais Hicroscopic Observations (continued): Pituitary Spleen -Adenoaa -Heaosiderosis, eoderate The follouing tissues were found to be within noreal liaits: Brain, Spinal Cord, Bone Harrow, Liver, Kidney, Heart, Lung, Stoaach, Seall Intestine, Large Intestine, Urinary Bladder, Uterus, Ovary, Trachea, Thyroid, Pancreas, Salivary Gland, Eye. Anieal Nuaber: 1R-45B1 Sex*. Feaale 6roup: ( 1) CONTROL 0 ppa Fate: fHeek- 85) Sacrificed in extreais Nacroscopic Observations: Haaaary 61and Liver Spleen Hicroscopic Observations: Adrenal Liver Lung Haaaary 61and Parathyroid Spleen -Ulcerated aass, 6 x 6 x 3 ca behind right shoulder. -Possibly slightly pale and saollen. -Enlarged -Sinusoidal ectasia, cortex -Portal aononudear cell infiltrate, aiId Hepatocyte vacuolation, aultifocal, aild Hepatocyte alteration, basophilic, aild Heaatopoiesis, extraaedullary, aild -Vascular aineralization, aild Pneueonia, interstitial, chronic, aultifocal, aild -Adenocarcinoaa -Not exaained, not in plane of section -Heaatopoiesis, extraaedullary, increased, aarked The follouing tissues acre found to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Pituitary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-45B3 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek- 105) Terainal Sacrifice Nacroscopic Observations: Eye Haaaary 61and -Extensive post bleeding inflaaaation of right eye. -Fira nodular aass, & x 5 x 3 ca, left inguinal. Species: Rat Project Nuaber: 0281CR0012 001738 Suaaarized STAR Page: 3' 254 Suaaarized Single Tabulated Aniul Report (continued) Individual Hacroscopic and Microscopie Observations Riker Laboratories, Inc. 3N FH-3Y24: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4583 Sex: Feaale Broup: ( 1) CONTROL 0 ppa Fate: (Weeks 105) Terainal Sacrifice Microscopic Observations (continued): Adrenal Eye Kidney Liver Lung Haasary Gland Ovary Parathyroid Spleen Uterus -Sinusoidal ectasia, cortex, aarked -Panophthalaitis, unilateral, aarked -Pelvic aineralization, aild Chronic progressive nephropathy, ainiaal -Hepatocyte vacuolation, aultifocal, aild Necrosis, focal, aild -Alveolar aacrophages, aild Perivascular aononuclear infiltrate, aild -Fibroadenosa -Tubular adenoaa, unilateral -Not exaained, not in plane of section -Heaatopoiesis, extraaedullary, increased, aoderate -Cystic glands, aarked The folloaing tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Pituitary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-45B4 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Meek 105) Terainal Sacrifice Hacroscopic Observations: Eye Pituitary Adrenal Microscopic Observations: Adrenal Eye Heart Kidney Liver Lung Parathyroid -Slight atrophy with corneal opacity, right eye. -Enlarged -Left adrenal enlarged. -Sinusoidal ectasia, cortex -Phthsis bulbi, aoderate -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aild -Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild -Pneuaonia, interstitial, chronic, aultifocal, aild Perivascular aononuclear infiltrate, aild Heaorrhage, local areas, aild -Not exaained, not in plane of section Species: Rat Project Nuaber: 0281CR0012 001739 Susaarized STAR Page: A4 255 Suaaarized Singli Tabulated Anieal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-4584 Sex: Feeale Group: ( 1) CONTROL 0 ppe Fate: (Neek= 105) Terainal Sacrifice Hicroscopic Observations (continued): Pituitary Spleen -Adenoea -Heaosiderosis, aild The following tissues were found to be within noraal Units: Brain, Spinal Cord, Bone Harrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haasary Gland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-4586 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal Sacrifice Hacroscopic Observations: Pituitary Uterus Hicroscopic Observations: Adrenal Kidney Liver Lung Ovary Pancreas Parathyroid Pituitary Uterus -Raised dark aass, 0.3 ca dia. -Dark area, 0.5 x 0.5 ca, in left horn near cervix. -Sinusoidal ectasia, cortex, aild -Chronic progressive nephropathy, aild Pelvic aineralization, aild -Portal aononuclear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aild -Perivascular aononuclear infiltrate, ainiaal -Not exaained, aissing -Acinar atrophy, aoderate -Not exaained, not in plane of section -Adenoaa -Cystic glands, narked The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Hasaary Bland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-4587 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Weeks 105) Terainal Sacrifice Hacroscopic Observations: Haaaary Gland -Saall nodular aass, 3 x 2 ca, axillary; large aass, 8 x 8 x 3 ca, throat area. Species: Rat Project Nuaber: 0281CR0012 0 0 1 740 Suaaarized STAR Page: 65 ' 256 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Biker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-45B7 Sex! Feaale Broup: ( il CONTROL 0 ppa Fate: (Keeks 105) Terainal Sacrifice Hicroscopic Observations (continued): Adrenal Heart Kidney Liver Haaaary 61and Parathyroid Salivary Gland Skin Spleen Uterus -Sinusoidal ectasia, cortex, narked -Hyocarditis, chronic nonsuppurative, aultifocal, ai1d -Chronic progressive nephropathy, aild Pelvic aineralization, ainiaal -Hepatocyte vacuolation, aultifocal, ainiaal -Lobular hyperplasia -Not exaained, not in plane of section -Not exaained, aissing -Fibrosa, subcutaneous -Heaosiderosis, aild -Kithin noraal Units Fewer than protocol nuaber The following tissues were found to be within noraal Units: Brain, Spinal Cord, Bone Harrow, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Pituitary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-4591 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Keek 105) Terainal Sacrifice Hacroscopic Observations: Hicroscopic Observations: Adrenal Kidney Liver Lung Lyaph Node (aesenteric) Pancreas Parathyroid Pituitary -No visible lesions. -Cortical vacuolation, local areas, eoderate Sinusoidal ectasia, cortex, ainiaal -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Hepatocyte alteration, vacuolated, aild -Vascular aineralization, aild -Not exaained, aissing -Acinar atrophy, focal, ainiaal -Not exaained, not in plane of section -Adenoaa The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, Trachea, Thyroid, Esophagus, Salivary Gland, Eye. % Species: Rat Project Nuaber: 02B1CR0012 001741 Suaaarized STAR Page: 64 257 Summed Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-4592 Sex: Feeale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 88) Found Dead Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Kidney Liver Lung Lyeph Node (eesenteric) Maaeary 61and Parathyroid Pituitary Spleen -Enlarged, 0.9 x i ce. -Sinusoidal ectasia, cortex, eoderate -Chronic progressive nephropathy, ainieal -Hepatocyte vacuolation, eultifocal, eild -Vascular aineralization, eild Perivascular eononudear infiltrate, eild -Not exaeined, eissing -Lobular hyperplasia, eoderate -Not exaeined, not in plane of section -Adenoaa -Heao5iderosis, eild The following tissues were found to be within noreal Units: Brain, Spinal Cord, Bone Marrow, Heart, Stoeach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Esophagus, Pancreas, Salivary 61and, Eye. Anieal Nueber: 1R-4593 Sex: Feeale Broup: ( 1) CONTROL 0 ppe Fate: (Neek= 105) Tereinal Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Liver Lung Parathyroid -No visible lesions. -Sinusoidal ectasia, cortex, narked -Hepatocyte alteration, vacuolated, eild Hepatocyte alteration, basophilic, eild -Vascular eineralization, eild -Not exaeined, not in plane of section The following tissues were found to be within noreal Units: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoeach, Seall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaeary Bland, Pituitary, Trachea, Thyroid, Esophagus, Lyeph Node (eesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nueber: 0281CR0012 001742 Suaearized STAR Page: 67 258 Suaearized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4594 Sex: Feaale Group: I11) CONTROL 0 ppa Fate: (Neele- 79) Found Dead Macroscopic Observations: Kidney Urinary Bladder Pituitary Microscopic Observations: Adrenal Aorta Kidney Liver Lung Lyaph Node (aesenteric) Ovary Pancreas Parathyroid Pituitary Saall Intestine Spleen Urinary Bladder -Right kidney appears slightly enlarged; filled with yellon ailky fluid. -Enlarged, 4.5 x 2 ce; filled with large, hard calculi. -Heaorrhagic aass, 0.9 x 0.6 ca -Sinusoidal ectasia, cortex, aoderate One of pair present -Not exaained, aissing -Pyelonephritis, acute, bilateral, aoderate Hydronephrosis, bilateral, aoderate Nephrosis, tubular, bilateral, aoderate -Hepatocyte alteration, vacuolated, aild -Vascular aineralization, aild -Not exaained, aissing -Within noraal liaits One of pair present -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa -Not exaained, aissing -Heaosiderosis, aoderate -Epithelial hyperplasia, papillary, diffuse, aarked Calculus The following tissues were found to be Mithin noraal liaits: Brain, Spinal Cord, Bone Marron, Heart, Stoaach, Large Intestine, Uterus, Maaaary Bland, Trachea, Thyroid, Esophagus, Salivary Gland, Eye. Aniaal Nuaber: 1R-4595 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Meek- 105) Terainal Sacrifice Macroscopic Observations: Pituitary Maaaary Bland Pancreas Microscopic Observations: Adrenal -Heaorrhagic aass, O.B ca dia. -Saall lobular aass, 2.7 x 1.5 x 1.8 ca, left axilla. -Saall lobular aass, 1 x 0.7 ca, in area of pancreas. -Sinusoidal ectasia, cortex, aoderate Species: Rat Project Nuaber: 0281CR0012 001743 Susaarized STAR Page: 8 259 Suaaarized Single Tabulated flniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. SI FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4595 Sex*. Feaale 6roup: ( 1) CONTROL 0 ppa Fate: {Heek 105) Terainal Sacrifice Hicroscopic Observations (continued): Kidney Liver Lung Haaaary 61and Pancreas Parathyroid Pituitary Uterus -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aild -Alveolar aacrophages, aild -Lobular hyperplasia -Islet cell carcinoaa Partially encapsulated with invasion of capsule. Hell differentiated. -Not exaained, not in plane of section -Adenoaa -Adenoaa Snail circuascribed papillary lesion. The -following tissues were found to be within noroal lieits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Seal1 Intestine, Large Intestine, Urinary Bladder, Aorta, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye, Ovary. Aniaal Nuaber: 1R-4596 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 78) Sacrificed in extreais Hacroscopic Observations: Pituitary Haaaary 61and Liver Kidney Adrenal Hicroscopic Observations: Adrenal Aorta Kidney Liver -Hass, O.B x 0.6 ca. -Hass, 2.5 x 2 x 1.5 ca, in left axilla. -Very pale -Bilaterally pale and pitted; slightly enlarged; 0.4 ca dia. cyst in right. -Pale, bilaterally -Cortical vacuolation, focal, aoderate Sinusoidal ectasia, cortex, aoderate Hedullary cell hyperplasia, aultifocal, aild Cortical degeneration, local areas, aoderate -Hineralization, aild Hineralization also in aedia of an elastic artery in section of aesentery subaitted for aesenteric lyaph node. -Chronic progressive nephropathy, narked Cyst, cortical, aoderate -Hepatocyte vacuolation, diffuse, narked Species: Rat Project Nuaber: 0281CR0012 001744 Suaaarized STAR Page: 69 260 Sueaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3R FB-3924: Too Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-4596 Sex*. Feeale Group: ( 1) CONTROL 0 ppi Fate: (Neek= 70) Sacrificed in extreeis Microscopic Observations (continued): Lung Lyeph Node (eesenteric) Haeeary 61and Parathyroid Pituitary Salivary 61and Spleen Urinary Bladder -Vascular eineralization, eild Alveolar eacrophages, einieal -Not exaeined, eissing -Fibroadenoea -Not exaeined, not in plane of section -Adenoea -Not exaeined, eissing -Heeosiderosis, eoderate -Epithelial hyperplasia, sieple, diffuse, eild The following tissues were found to be within noreal Units: Brain, Spinal Cord, Bone Narrow, Heart, Stoeach, Snail Intestine, Large Intestine, Uterus, Ovary, Trachea, Thyroid, Esophagus, Pancreas, Eye. Anieal Nueber: 1R-4597 Sex: Feeale 6roup: ( 1) CONTROL 0 ppe Fate: (Neek* 105) Tereinal Sacrifice Macroscopic Observations: Adrenal Microscopic Observations: Adrenal Kidney Liver Lung Lyeph Node (eesenteric) Ovary Pancreas Parathyroid Spleen Uterus -Right adrenal enlarged. -Sinusoidal ectasia, cortex, narked Medullary cell hyperplasia, focal, eild -Chronic progressive nephropathy, einieal Pelvic eineralization, eild -Portal eononudear cell infiltrate, eild Portal bile duct proliferation, eild -Alveolar eacrophages, eild Perivascular eononudear infiltrate, eild -No diagnosis, inadequate section -Tubular adenoea, unilateral -Cyst -Not exaeined, not in plane of section -Heeosiderosis, eild -Nithin noreal lieits Fewer than protocol nueber The following tissues were found to be within noreal Units: Brain, Spinal Cord, Bone Harrow, Heart, Stoeach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Maaeary Gland, Pituitary, Trachea, Thyroid, Esophagus, Salivary Gland, Eye. Species: Rat Project Nueber: 0281CR0012 601745 Suaearized STAR Page: 70 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4598 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 105) Terainal Sacrifice Macroscopic Observations: Pituitary Adrenal Microscopic Observations: Adrenal Brain Heart Kidney Liver Lung Ovary Pancreas Parathyroid Pituitary Uterus -Hass, 0.7 ca dia. -Left adrenal greatly enlarged. -Sinusoidal ectasia, cortex, narked -Oligodendroglioaa, benign -Myocarditis, chronic nonsuppurative, aultifocal, aiId -Chronic progressive nephropathy, aoderate Pelvic aineralization, aild Hyperplasia, pelvic epitheliua, local areas, aild -Hepatocyte vacuolation, aultifocal, aild Hepatocyte alteration, basophilic, aild -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Tubular adenoaa -Acinar atrophy, aoderate -Not exaained, not in plane of section -Adenoaa -Cystic glands, aoderate The following tissues Here found to be within noraal liaits: Spinal Cord, Bone Harrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Haaaary Gland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Salivary Bland, Eye. Aniaal Nuaber: 1R-4599 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Heek= 102) Found Dead Macroscopic Observations: Haaaary 61and Liver Stoaach Urinary Bladder Eye Microscopic Observations: Adrenal Aorta Esophagus Eye -Subcutaneous aass, 2.5 x 2 x 1 ca, in perineal area. -Appears aottled -Areas of enlongated ulceration. -Thickened walls; aass 1.5 x 1 ca, with adhesions to abdoainal wall. -No tissue taken due to postaortea changes -Sinusoidal ectasia, cortex, narked -Malignant lyaphoaa, histiocytic -Malignant lyaphoaa, histiocytic -Not exaained, aissing Species: Rat Project Nuaber: 0281CR0012 001746 Suaaarized STAR Page: 71 262 Suaaarized Single Tabulated Anieal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories) Inc. 3H FH-3924: Tbo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: JR-4599 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week- 102) Found Dead Hicroscopic Observations (continued): Heart Kidney Large Intestine Liver Lung Lyaph Node (aesenteric) Haaaary Gland Ovary Pancreas Parathyroid Pituitary Spleen Stoaach Thyroid Urinary Bladder Uterus -Hyocarditis, chronic nonsuppurative, aultifocal, aiId -Halignant lyaphoaa, histiocytic Pelvic aineralization, aild Hyperplasia, pelvic epitheliua, local areas, aild Nephrosis, tubular, aild -Halignant lyaphoaa, histiocytic -Halignant lyaphoaa, histiocytic Necrosis, local areas, aarked -Halignant lyaphoaa, histiocytic Heaorrhage, aultifocal, aild -Halignant lyaphoaa, histiocytic -Halignant lyaphoaa, histiocytic -Halignant lyaphoaa, histiocytic -Halignant lyaphoaa, histiocytic -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, aild -Necrosis, aucosal, aoderate -Halignant lyaphoaa, histiocytic -Halignant lyaphoaa, histiocytic Epithelial hyperplasia, siaple, diffuse, aild -Halignant lyaphoaa, histiocytic The folloNing tissues Mere found to be uithin noraal liaits: Brain, Spinal Cord, Bone HarroM, Saall Intestine, Trachea, Salivary 61and. Aniaal Nuaber: 1R-4600 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 99) Found Dead Hacroscopic Observations: Haaaary 61and Liver Hicroscopic Observations: Adrenal Eye Heart -Subcutaneous cystic aass, 4 x 3.5 x 2 ca, in region of throat; subcutaneous aultilobular aass, 5 x 4 x 2 ca, in right axilla. -Appears Bottled -Necrosis, unilateral, narked -Not exaained, aissing -Hyocarditis, chronic nonsuppurative, aultifocal, aild Species: Rat Project Nuaber: 02B1CR0012 001747 Sueaarized STAR Page: 7? 263 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anisal Nuaber: 1R-4SOO Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek* 99) Found Dead Microscopic Observations (continued): Kidney Liver Lung Haaaary 61and Ovary Parathyroid Pituitary Spleen -Chronic progressive nephropathy, aild Pelvic aineralization, aild Nephrosis, tubular, aoderate -Portal aononudear cell infiltrate, aoderate Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Hepatocyte alteration, eosinophilic, aoderate Telangiectasis, aild -Vascular aineralization, aild -Adenoaa, papillary Lobular hyperplasia -Cyst, unilateral -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, aild The follouing tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and. Aniaal Nuaber: 1R-4602 Sex: Feaale Group ( 1) CONTROL 0 ppa Fate: (Week- 105) Terainal Sacrifice Macroscopic Observations: Eye Pituitary Adrenal Kidney Microscopic Observations: Adrenal Eye Heart Kidney Liver Lung Parathyroid Pituitary -Cornea appears cloudy. -Raised aass, 1 ca dia. -Right adrenal enlarged. -Pale and pitted. -Sinusoidal ectasia, cortex, aarked Cortical degeneration, diffuse, aarked -No diagnosis, inadequate section -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aarked Pelvic aineralization, aild Cyst, cortical -Hepatocyte alteration, basophilic, aild -Heaorrhage, local areas, aoderate -Not exaained, not in plane of section -Adenoaa Species: Rat Project Nuaber: 02B1CR0012 001748 Suaaarized STAR Page: 73 264 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Piker Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4602 Sex: Feaale Group: ( l) CONTROL 0 ppa Fate: (Neek= 105) Terainal Sacrifice Microscopic Observations (continued): Spleen Uterus -Heaosiderosis, aild -Nithin noraal liaits Fewer than protocol nuaber The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Haaaary Gland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-4603 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Meek* 105) Terainal Sacrifice Macroscopic Observations: Liver Skin Microscopic Observations: Adrenal Heart Kidney Liver Lung Haaaary Gland Parathyroid Pituitary Skin Spleen -Circular raised lesion, 0.6 ca dia., left lateral lobe. -Hair loss on foreliabs. -Sinusoidal ectasia, cortex, aoderate Cortical degeneration, diffuse, aoderate -Myocarditis, chronic nonsuppurative, aultifocal, aild -Pelvic aineralization, aild -Portal aononuclear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aild -Perivascular aononuclear infiltrate, aild -Galactocele -Not exaained, not in plane of section -Adenoaa -Acanthosis, aild -Heaosiderosis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 001749 Suaaarized STAR Page: 74 Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. SH FM-3924: Tho Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anisal Musber*. 1R-4604 Sex: Fesale Group: ( 1) CONTROL 0 pps Fate: (Neek= 10S) Tersinal Sacrifice Macroscopic Observations: Adrenal Microscopic Observations: Adrenal Aorta Esophagus Kidney Large Intestine Liver Ovary Parathyroid Uterus -Left adrenal enlarged. -Sinusoidal ectasia, cortex, marked -Not examined, missing -Not examined, missing -Chronic progressive nephropathy, mild Pelvic mineralization, mild -Not examined, missing -Portal bile duct proliferation, mild Hepatocyte vacuolation, multifocal, mild Hyperplastic nodule -Cyst, unilateral -Not examined, not in plane of section -Nithin normal limits Fewer than protocol number The following tissues aere found to be aithin noreal lieits: Brain, Spinal Cord, Bone Marron, Spleen, Heart, Lung, Stomach, Small Intestine, Urinary Bladder, Massary Gland, Pituitary, Trachea, Thyroid, Lyaph Node (sesenteric), Pancreas, Salivary Gland, Eye. Aniaal Number: 1R-4605 Sex: Feaale Group: ( 1) CONTROL 0 ppm Fate: (Week- 77) Sacrificed in extremis Macroscopic Observations: Kidney Lung Microscopic Observations: Adrenal Heart Kidney Liver Lung -Slightly pitted -Right apical lobe consolidated and somewhat enlarged; possibly tumor, mass, chronic pneumonia. -Necrosis, local areas, moderate Hematopoiesis, extramedullary, multifocal, mild -Myocarditis, chronic nonsuppurative, multifocal, moderate Malignant lymphoma, lymphocytic -Chronic progressive nephropathy, moderate Pelvic mineralization, minimal -Hepatocyte vacuolation, aidzonal, moderate Malignant lymphoma, lymphocytic -Vascular mineralization, mild Malignant lymphoma, lymphocytic Large circumscribed sass with extensive necrosis. Species: Rat Project Nusber: 281CR0012 001750 Summarized STAR Page: 75 266 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Miservations Riker Laboratories, Inc. 3M FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4605 Sex: Feaale Broup: ( 1) CONTROL 0 ppa Fate: (Meek: 77) Sacrificed in extreais Microscopic Observations (continued): Ovary Parathyroid Pituitary Spinal Cord Spleen Urinary Bladder -Cyst, unilateral -Not exaained, not in plane of section -Adenoaa -Halacia, local areas, aoderate -Heeosiderosis, aiId -Epithelial hyperplasia, siaple, diffuse, aoderate The follouing tissues aere found to be aithin noraal liaits: Brain, Bone Marroa, Stoaach, Saall Intestine, Large Intestine, Aorta, Uterus, Maaaary Bland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-4606 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Meek: 105) Terainal Sacrifice Macroscopic Observations: Maaaary Bland Pituitary Uterus Microscopic Observations: Adrenal Heart Kidney Liver Lung Lyaph Node (aesenteric) Maaaary 61and Ovary Parathyroid Pituitary Uterus -Saall aass, 1.4 ca dia., left lateral area. -Enlarged; circular dark lesion, 0.4 ca dia. -Dark fluid filled lesion, 0.5 x 0.6 ca, right horn. -Sinusoidal ectasia, cortex, aiId Cortical degeneration, bilateral, aoderate Pheochroaocytoaa, benign, unilateral -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aild Pelvic aineralization, aild -Hepatocyte vacuolation, aultifocal, aild Hepatocyte alteration, vacuolated, aild -Pigaent, aoderate Scattered saall foci of dark broun pigaent-laden aacrophages aithin alveoli. -Heaorrhage, aild -Adenocarcinoaa -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa -Hydroaetra, aarked The -following tissues aere found to be aithin noraal liaits: Brain, Spinal Cord, Bone Marroa, Spleen, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: 0281CR0012 001/si Suaaarized STAR Page: 76" 267 Summed Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Tho Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4606 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week- 105) Terainal Sacrifice Microscopic Observations (continued): The following tissues were found to be within noraal liaits (continued): Urinary Bladder, Aorta, Trachea, Thyroid, Esophagus, Pancreas, Salivary Sland, Eye. Aniaal Nuaber: 1R-4607 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week 40) Sacrificed in extreais Macroscopic Observations: Soft Tissues (neck) Lyaph Node Liver Spleen Microscopic Observations'. Adrenal Aorta Bone Harrow Esophagus Eye Kidney Liver Lung Lyaph Node (aesenteric) Naaaary 61and Ovary Parathyroid Salivary Gland Spleen Stoaach Thyroid Uterus -Reddened gland like structures, possibly enlarged lyaph nodes or salivary glands. -Enlarged axillary, hepatic, aesenteric and internal iliac lyaph nodes. -Possibly slightly pale. -Considerably enlarged. -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -No diagnosis, inadequate section -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic Heaorrhage, local areas, aild Abscess -Heaorrhage, aoderate Malignant lyaphoaa, lyaphocytic Massive enlargaent of node by aature appearing lyaphocytes. All other nodes exaained were siailarily involved. -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Not exaained, not in plane of section -Not exaained, aissing -Malignant lyaphoaa, lyaphocytic -Heaorrhage, subaucosal, aoderate Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Heart, Saall Intestine, Large Intestine, Urinary Bladder, Pituitary, Species: Rat Project Nuaber: Q281CR0012 001752 Suaaarized STAR Page: 77 268 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FN-3924: T*o Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 ftniaal Nueber: 1R-4607 Sex: Feaale 6roup: ( 1) CONTROL 0 ppe Fate: (Heek 40) Sacrificed in extreais Microscopic Observations (continued): The fallowing tissues were found to be within nomai liaits (continued): Trachea, Pancreas. Aniaal Nuaber: 1R-4609 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Meek* 105) Terainal Sacrifice Macroscopic Observations: Pituitary Naaaary Gland Microscopic Observations: Adrenal Heart Kidney Large Intestine Liver Lung Naaaary Gland Pancreas Parathyroid Pituitary Spleen Thyroid Uterus -Raised aass, 1 ca dia. -Hass, 5 x 4 ca, throat area; 3 ca dia., left axilla. -Sinusoidal ectasia, cortex, aoderate -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aild Pelvic aineralization, aoderate -Not exaained, aissing -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild -Pneuaonia, interstitial, chronic, aultifocal, aild -Carcinoaa Highly cellular very undifferentiated tuaor. -Acinar atrophy, aoderate -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, aild -C cell adenoaa -Nithin noraal liaits Fewer than protocol nuaber The following tissues were found to be within noraal Units: Brain, Spinal Cord, Bone Harrow, Stoaach, Snail Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001753 Suaaarized STAR Page: 78 269 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4611 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week- 105) Terainal Sacrifice Hacroscopic Observations: Haaaary Gland Hicroscopic Observations: Adrenal Liver Lung Haaaary Gland Parathyroid Pituitary -Large lobular aass, 10 x 7.5 x 5 ca. -Sinusoidal ectasia, cortex, narked Cortical degeneration, local areas, aoderate -Hpatocyte vacuolation, aultifocal, aiId Hepatocyte alteration, eosinophilic, aild -Heaorrhage, aultifocal, aild Alveolar aacrophages, aultifocal, aild -Fibroadenoaa -Not exaained, not in plane of section -Adenona The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4612 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Meek* 105) Terainal Sacrifice Hacroscopic Observations: Pituitary Haaaary 61and Hicroscopic Observations: Adrenal Eye Liver Lung Haaaary 61and Parathyroid Pituitary Uterus -Raised aass, 0.7 ca dia. -Hass, 3 ca dia., left axilla) 4 ca dia., right axilla) 7 x 6 x 2 ca, right side. -Sinusoidal ectasia, cortex, aoderate -No diagnosis, inadequate section -Hepatocyte vacuolation, aultifocal, aild -Heaorrhage, diffuse, aarked Alveolar aacrophages, aild -6alactocele Fibroadenoaa Fibroadenoaa Two tuaors present. -Not exaained, not in plane of section -Adenoaa -Nithin noraal liaits Fewer than protocol nuaber The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Species: Rat Project Nuaber: 0281CR0012 001754 SuMiriit, STAR Pi,.: 71 270 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Hicroacopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4612 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week- 105) Terainal Sacrifice Microscopic Observations (continued): The -following tissues aere found to be within noraal liaits (continued): Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-4613 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Heek= 89) Sacrificed in extreais Macroscopic Observations: Pituitary Haaaary Gland Liver Microscopic Observations: Adrenal Esophagus Kidney Large Intestine Liver Lung Haaaary 61and Parathyroid Pituitary Spleen Urinary Bladder Uterus -Soaeahat enlarged -Hass, 10 x G x 5 ca, inguinal area; surface ulcerated. -Appears pale -Heaatopoiesis, extraaedullary, aild Sinusoidal ectasia, cortex, aild Cortical vacuolation, focal, aild -Not exaained, aissing -Pelvic eineralization, aild Hyperplasia, pelvic epitheliua, local areas, aild -Not exaained, aissing -Hepatocyte vacuolation, periportal, aild Necrosis, aultifocal, aild Heaatopoiesis, extraaedullary, aild -Heaorrhage, aultifocal, aild Pneuaonia, interstitial, chronic, aultifocal, aild -Lobular hyperplasia -Not exaained, not in plane of section -Adenoaa -Heaatopoiesis, extraaedullary, increased, aoderate -Epithelial hyperplasia, siaple, diffuse, aild -Nithin noraal liaits Fewer than protocol nuaber The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Aorta, Ovary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. 5pecies: Rat Project Nuaber: 0281CR0012 001755 Suaaarized STAR Page: BO 271 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-4614 Sex: Feeale Group: ( 1) CONTROL 0 ppe Fate: <Neek= 105) Tereinal Sacrifice Macroscopic Observations: Maeaary 61and Uterus Microscopic Observations: Adrenal Kidney Liver Maeeary 61and Pancreas Parathyroid Pituitary Spinal Cord Spleen Thyroid Uterus -Mass in perineal area; possible eilk cyst. -Large gelatinous cervical eass, 2 ce dia. -Sinusoidal ectasia, cortex, eoderate -Pelvic aineralization, einiaal Chronic progressive nephropathy, aild -Hepatocyte vacuolation, aultifocal, aild -Adenocarcinoaa -Acinar atrophy, aild -Not exaained, not in plane of section -Adenoea -No diagnosis, inadequate section -Heeosiderosis, aild -Ultieobranchial cyst -Polyp This was the eass at cervix noted at necropsy. The following tissues were found to be within noraal liaits; Brain, Bone Narrow, Heart, Lung, Stoeach, Seal1 Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Esophagus, Lyeph Node (eesenteric), Salivary 61and, Eye. Anieal Nueber: 1R-4615 Sex: Feeale 6roup: ( 1) CONTROL 0 ppe Fate: (Heek= 105) Tereinal Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Aorta Kidney Liver Lung Maeeary Gland Parathyroid Spleen Uterus -No visible lesions. -Sinusoidal ectasia, cortex, earked -Not exaained, eissing -Pelvic aineralization, einiaal -Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aild Hepatocyte alteration, basophilic, aild -Pneuaonia, interstitial, chronic, aild Alveolar aacrophages, aild -6alactocele -Not exaained, not in plane of section -Heaosiderosis, aild -Nithin noraal liaits Fewer than protocol nueber Species: Rat Project Nueber: 0281CR0012 001756 Suaaarized STAR Page: B1 272 Suaaarized Single Tabulated Anita! Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4A15 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 105) Terainal Sacrifice Microscopic Observations (continued): The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Stall Intestine, Large Intestine, Urinary Bladder, Ovary, Pituitary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-4A1A Sex: Fetale 6roup: ( 1) CONTROL 0 ppa Fate: (Week3 105) Terainal Sacrifice Hacroscopic Observations: Microscopic Observations: Adrenal Heart Kidney Liver Lung Haaaary Bland Ovary Parathyroid Spleen -No visible lesions. -Cortical degeneration, unilateral, aarked -Myocardial fibrosis, focal, aild Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aild Pelvic aineralization, ainiaal -Portal aononudear ceil infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Hepatocyte alteration, vacuolated, aild -Perivascular aononudear infiltrate, aoderate Vascular aineralization, aild Alveolar aacrophages, aild -Not exaained, aissing -Cyst, unilateral -Not exaained, not in plane of section -Heaosiderosis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Pituitary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 02B1CR0012 0 0 1 75*7 Suaaarized STAR Page: 82 273 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Tvo Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4617 Sex: Feaale Group: ( 1) CONTROL 0 ppi Fate: (Meek* 73) Sacrificed in extreais Macroscopic Observations: Ovary Liver Microscopic Observations'. Adrenal Liver Lung Maaaary 61and Ovary Parathyroid Pituitary -Heaorrhagic aass, 5 ca dia., left ovary. -Pale; left lateral lobe dark red. -Sinusoidal ectasia, cortex, aild One of pair present -Portal aononudear cell infiltrate, aild Necrosis, diffuse, aarked Massive necrosis of one lobe uith coapensatory increase in aitoses in another lobe. -Vascular aineralization, aild -Not exaained, aissing -Leioayoaa Large well differentiated neoplasa, aostly necrotic, probably arises froa an oviduct. -Not exaained, not in plane of section -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4618 Sex: Feaale Broup: ( 1) CONTROL 0 ppa Fate: (Meek* 93) Sacrificed in extreais Macroscopic Observations: Pituitary Maaaary 61and Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Maaaary 61and Parathyroid Pituitary -Raised aass, 1.1 cn dia. -Large ulcerated aass, 10 x 7 x 9 ca, right axillary area. -Sinusoidal ectasia, cortex, aild -Not exaained, aissing -Pelvic aineralization, ainiaal -Portal aononudear cell infiltrate, aild -Vascular aineralization, aild Alveolar aacrophages, aild Perivascular aononudear infiltrate, aild -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa Species: Rat Project Nuaber: 02B1CR0012 001758 Suaaarized STAR Page: 83 274 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations ftiker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniial Nuaber: 1R-461B Sex: Feaale Group: < 1) CONTROL 0 ppi Fate: (Neek= 93) Sacrificed in extreais Microscopic Observations (continued): Skin Thyroid Urinary Bladder -Fibroaa, subcutaneous Large neoplasa aith extensive collagen foraation, large portion necrotic. Described as aaaaary lesion but no aaaaary tissue present in section. -Ultiaobranchial cyst -Epithelial hyperplasia, siaple, diffuse, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Stall Intestine, Large Intestine, Aorta, Ovary, Trachea, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Uterus. Aniaal Nuaber: 1R-4619 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 64) Found Dead Hacroscopic Observations: Spleen Liver Pituitary Microscopic Observations: Adrenal Esophagus Eye Kidney Liver Lung Lyaph Node (aesenteric) Naaaary Gland Parathyroid Pituitary Salivary 61and Spleen Stoaach Urinary Bladder -Slightly enlarged -Pale aith an irregular surface on all lobes. -Enlarged aith heaorrhagic foci. -Necrosis, diffuse, aarked Malignant lyaphoaa, histiocytic -Not exaained, aissing -Not exaained, aissing -Nephrosis, tubular, aarked -Portal bile duct proliferation, aarked Necrosis, local areas, aoderate Malignant lyaphoaa, histiocytic -Vascular aineralization, aild Malignant lyaphoaa, histiocytic -Heaorrhage, aild -Galactocele -Not exaained, not in plane of section -Adenoaa -Sialadenitis, chronic, aoderate -Malignant lyaphoaa, histiocytic Heaatopoiesis, extraaedullary, increased, aoderate -Necrosis, aucosal, aild -Epithelial hyperplasia, siaple, diffuse, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Saall Intestine, Large Intestine, Aorta, Uterus, Ovary, Species: Rat Project Nuaber: 0281CR0012 001759 Suaaarized STAR Page: 84 275 Suaaariied Single Tabulated Anieal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Too Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4619 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week- 64) Found Dead Microscopic Observations (continued): The Folloaing tissues aere Found to be aithin noraal liaits (continued): Trachea, Thyroid, Pancreas. Aniaal Nuaber: 1R-4621 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 99) Sacri-ficed in extreais Hacroscopic Observations: Pituitary Haaaary Gland Liver Adrenal Microscopic Observations: Adrenal Esophagus Heart Kidney Liver Lung Haaaary 61and Parathyroid Pituitary Spleen -Slightly enlarged -Subcutaneous ulcerated aass, 5 x 4 x 1.5 ca, in right axilla. -Appears aottled. -Slightly enlarged. -Cortical vacuolation, Focal, aild Sinusoidal ectasia, cortex, aarked -Not exaained, aissing -Myocarditis, chronic nonsuppurative, aultiFocal, aild -Chronic progressive nephropathy, aild Pelvic aineralization, aild Nephrosis, tubular, aoderate -Portal aononudear cell inFiltrate, ainiaal Hepatocyte vacuolation, periportal, aild -Alveolar aacrophages, aild Perivascular aononuclear inFiltrate, aild Heaorrhage, local areas, aild -Fibroadenoaa Galactocele -Not exaained, not in plane oF section -Adenoaa -Heaatopoiesis, extraaedullary, increased, aild The Folloaing tissues aere Found to be Mithin noraal liaits: Brain, Spinal Cord, Bone Harros, Stoaach, Saal1 Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001700 Suonarized STAR Page: 85 276 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4622 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek* 62) Found Dead Macroscopic Observations: Skin Naaaary Gland Kidney Pituitary Lung Microscopic Observations*. Adrenal Aorta Kidney Liver Lung Haaaary Gland Parathyroid Pituitary Skin -Saall circular lesion on back; slight hair loss on left lateral side. -Mass, 2 ca dia., right axillary area; l.S ca dia., left inguinal area. -Raised area, 0.3 ca dia., on surface of right kidney; appears fluid filled. -Dark red gelatinous aass. -Slightly aottled -Sinusoidal ectasia, cortex, aarked -Not exaained, aissing -Chronic progressive nephropathy, aoderate Pelvic aineralization, aoderate Hyperplasia, pelvic epitheliua, local areas, aild -Hepatocyte vacuolation, periportal, aoderate -Alveolar aacrophages, aild -Galactocele -Not exaained, not in plane of section -Not exaained, aissing -Ulcer, focal, aoderate The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Uterus, Ovary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4623 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 96) Sacrificed in extreais Macroscopic Observations: Eye Haaaary Gland Adrenal Microscopic Observations: Adrenal Esophagus Eye Kidney Liver -Opacity, right eye. -Multilobular aass, 11 x 12 x 3 ca, right axilla. -Appear enlarged -Sinusoidal ectasia, cortex, aarked -Not exaained, aissing -Cataract, unilateral -Pelvic aineralization, ainiaal -Portal aononudear cell infiltrate, aild Hepatocyte alteration, vacuolated, aild Species: Rat Project Nuaber: 02B1CR0012 bOl 7& Suaaarized STAR Page*. 86' 277 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aninal Nuaber: 1R-4623 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 96) Sacrificed in extrenis Microscopic Observations (continued): Lung Lyaph Node (nesenteric) Haanary 61and Pituitary Thyroid Uterus -Pneuaonia, interstitial, chronic, aultifocal, aild Alveolar aacrophages, aild Perivascular aononuclear-infiltrate, aild -Sinusoidal ectasia, aoderate -Fibroadenoaa -Adenoaa -Follicular hyperplasia, cystic, unilateral, aild -Within noraal liaits Fever than protocol nuaber The following tissues Mere found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Parathyroid, Pancreas, Salivary 61and. Anioal Nuaber: 1R-4624 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 100) Sacrificed in extreais Hacroscopic Observations: Pituitary Haaaary Gland Lung Microscopic Observations: Adrenal Kidney Liver Lung Haaaary 61and Ovary -Heaorrhagic aass, 0.6 ca dia. -Ulcerated, cystic aass, 4 x 4 x 3.5 ca, in left axilla-throat area; aultilobular aass, 8.5 x 5.5 x 3 ca, in right inguinal area. -Raised circular nodule, 0.6 ca dia., in left lobe. -Sinusoidal ectasia, cortex, aoderate -Chronic progressive nephropathy, ainiaal Pelvic aineralization, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild -Pneuaonia, interstitial, chronic, aultifocal, aild Metastatic neoplasa Large aetastasis of aaaaary adenocarcinoaa. -Fibroadenoaa Adenocarcinoaa -Cyst, unilateral Species; Rat Project Nuaber: 0281CR0012 001762 Suaaarized STAR Page: 8f 278 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 311 FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4624 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Heek- 100) Sacrificed in extreais Microscopic Observations (continued): Parathyroid Pituitary Spleen -Not exaained, not in plane of section -Adenoaa -Heaatopoiesis, extraaedullary, increased, aoderate The following tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Trachea, Thyroid, Esophagus, Lyeph Node iaesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-4625 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek- 100) Sacrificed in extreais Macroscopic Observations: Pituitary Maaaary Bland Adrenal Kidney Microscopic Observations: Adrenal Esophagus Eye Heart Kidney Liver Lung Maaaary 61and Parathyroid Pituitary Spleen -Enlarged due to raised Bass, 1.2 ca dia. -Cystic aass, 2 ca dia., left axilla. -Both appear enlarged. -Soaewhat pitted -Sinusoidal ectasia, cortex, aarked Cortical degeneration, local areas, aild -Not exaained, aissing -No diagnosis, inadequate section -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aarked -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, ainiaal -Heaorrhage, local areas, aoderate -Fibroadenoaa -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary 61and. Species: Rat Project Nuaber: 02B1CR0012 001763 Suaaarized STAR Page: BB 279 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nueber: 1R-4626 Sex: Fecale 6roup: ( 1) CONTROL 0 ppe Fate: (Meek: 105) Tereinal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid Pituitary Spinal Cord Spleen -Raised eass, 0.9 ca dia. -Pheochroaocytoea, benign, unilateral -Chronic progressive nephropathy, aoderate Pelvic aineralization, aoderate -Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild -Not exaained, not in plane of section -Adenoaa -Not exaained, aissing -Heaosiderosis, aild The following tissues were found to be within noraal liaits: Brain, Bone Narrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary SIand, Eye. Aniaal Nuaber: 1R-4627 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Week= 105) Terainal Sacrifice Macroscopic Observations: Pituitary Haaaary 61and Microscopic Observations: Adrenal Heart Kidney Liver Lung Haaaary Bland Ovary -Hass, 1 x 0.6 ca. -Fira aass, 5.5 x 4 x 3.5 ca, right lateral area; lobular aass, 7 x 6 x 5 ca, left axilla. -Sinusoidal ectasia, cortex, aoderate Medullary cell hyperplasia, aultifocal, aild -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aoderate -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aoderate Hepatocyte alteration, basophilic, aoderate -Vascular aineralization, aild Alveolar aacrophages, aild Perivascular aononudear infiltrate, aild -Adenocarcinoaa Neoplasa arises in several places in a fibroadenoaa. -Tubular adenoaa, unilateral Cyst, bilateral Species: Rat Project Nuaber: 0261CR0012 001764 Suaaarized STAR Page: B9 280 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4627 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Weeks 105) Terainal Sacrifice Microscopic Observations (continued): Pancreas Parathyroid Pituitary Skin Uterus -Islet cell adenoaa -Not exaained, not in plane of section -Adenoaa -Fibroaa, subcutaneous -Cystic glands, aild The folloaing tissues uere found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-4628 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal Sacrifice Hacroscopic Observations: Pituitary Maaaary Gland Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Maaaary Gland Parathyroid Pituitary -Mass, 1.2 ca dia. -Saall nodule, 1.5 ca dia., right axilla; possible ilk cyst. -Sinusoidal ectasia, cortex, aoderate -Not exaained, aissing -Pelvic aineralization, ainiaal -Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aild Hepatocyte vacuolation, aultifocai, aild -Vascular aineralization, aild -Balactocele Adenoaa, papillary Saall highly cellular neoplasa lying adjacent to several large galactocoels. -Not exaained, not in plane of section -Adenoaa The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuiber: 0281CR0012 001765 Sueiarized STAR Page: 90 281 Suaaarized Single Tabulated flniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4433 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 43) Sacrificed in extreais Macroscopic Observations: Liver Spleen Haaaary Gland Microscopic Observations: Adrenal Aorta Esophagus Kidney Liver Lung Haaaary 61and Parathyroid Salivary Bland Spleen -Very pale -Slightly enlarged -Large subcutaneous aass, 4 x 10 x 2.5 ca, aith necrotic areas, containing dark brow fluid, ventral abdoaen. -Heaatopoiesis, extraaedullary, cortical, aild Sinusoidal ectasia, cortex, aild -Not exaained, aissing -Not exaained, aissing -Chronic progressive nephropathy, ainiaal Vacuolation, conv. tub. epitheiua, aoderate -Hepatocyte vacuolation, centrilobular, aarked -Vascular aineralization, aild Heaorrhage, aultifocal, aild -Adenocarcinoaa Nell differentiated, ductular pattern, areas of aoderate aitotic activity, large areas of necrosis. -Not exaained, not in plane of section -Not exaained, aissing -Heaatopoiesis, extraaedullary, increased, aoderate The folloaing tissues aere Found to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Uterus, Ovary, Pituitary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-4434 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Meek* 105) Terainal Sacrifice Hacroscopic Observations: Pituitary Haaaary Gland Microscopic Observations: Adrenal Esophagus Heart -Hass, 0.7 ca dia. -Lobular aass, 8 x 6 x 4 ca, right axilla! lobular aass, 9 x 7 x 3.5 ca, left inguinal. -Sinusoidal ectasia, cortex, aoderate -Not exaained, aissing -Myocarditis, chronic nonsuppurative, aultifocal, aild Species: Rat Project Nuaber: 02B1CR0012 001766 Suaaarized STAR Page: 91 282 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Too Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-4434 Sex: Feaale Group: ( 1) CONTROL 0 ppe Fate: (Keeks 105) Tereinal Sacrifice Microscopic Observations (continued): Kidney Liver Lung Naaaary Gland Parathyroid Pituitary Spleen -Pelvic aineralization, einiaal -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte alteration, vacuolated, aild Hepatocyte alteration, basophilic, aoderate Hepatocyte alteration, eosinophilic, aild -Vascular aineralization, aild Perivascular aononudear infiltrate, aild Heaorrhage, aultifocal, aild -Fibroadenoea Fibroadenoaa Both aasses aere fibroadenoaas. Areas of necrosis and cystic areas in tuaors. -Not exaained, not in plane of section -Adenoaa -Heaatopoiesis, extraaedullary, increased, aild Heaosiderosis, aild The following tissues aere found to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4635 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 94) Found Dead Macroscopic Observations: Saall Intestine Naaaary Gland Microscopic Observations: Adrenal Esophagus Eye Kidney -Jejunua appears inflaaaed with reddish fluid; ileua appears inflaaaed near cecua. -Hass, 7 x 7.5 x 2 ca, aultilobular and ulcerated, right inguinal; aass, light beige in color, spherical, 2 ca dia., in left axilla. -Sinusoidal ectasia, cortex, aild Heaatopoiesis, extraaedullary, cortical, aoderate -Not exaained, aissing -Not exaained, aissing -Chronic progressive nephropathy, aild Pelvic aineralization, ainiaal Species: Rat Project Nuaber: 0281CR0012 001767 Suaaarized STAR Page: 92 283 Suaaarized Single Tabulated Anital Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4635 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week2 74) Found Dead Microscopic Observations (continued): Liver Lung Naaaary Gland Parathyroid Pituitary Salivary Gland Spleen Thyroid -Hepatocyte vacuolation, diffuse, aild Heaatopoiesis, extraaedullary, aild Mitotic activity, increased, aoderate -Vascular aineralization, aild Metastatic neoplasa -Adenoaa Adenocarcinoaa Extensive necrosis. -Not exaained, not in plane of section -Not exaained, aissing -Not exaained, aissing -Heaatopoiesis, extraaedullary, increased, aarked -Ultiaobranchial cyst The folloaing tissues ere found to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Lyaph Node (aesenteric), Pancreas. Aniaal Nuaber: 1R-4636 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal Sacrifice Macroscopic Observations: Haaaary 61and Liver Microscopic Observations: Adrenal Heart Kidney Large Intestine Liver Lung Haaaary Gland Pancreas Parathyroid Pituitary -Hass in right axilla appears to be ailk cyst. -Slightly raised dark aass, 0.6 ca dia., left lateral lobe. -Cortical vacuolation, focal, aild Sinusoidal ectasia, cortex, aild -Myocardial fibrosis, aultifocal, aild -Chronic progressive nephropathy, aild -Neaatodiasis, colon -Hepatocyte vacuolation, aultifocal, aild Hepatocyte alteration, vacuolated, aild Hepatocyte alteration, basophilic, aild -Vascular aineralization, aild Alveolar aacrophages, aild -Lobular hyperplasia -Acinar atrophy, aild -Not exaained, not in plane of section -Adenoaa Species: Rat Project Nuaber: 0281CR0012 001768 Suaaarized STAR Page: 93 284 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Rifcer Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4636 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Meek* 10S) Terainal Sacrifice Microscopic Observations (continued): Spleen -Heaosiderosis, aild The follouing tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-4&37 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 82) Sacrificed in extreais Macroscopic Observations: Pituitary Lung Liver Microscopic Observations: Eye Kidney Liver Lung Haaaary61and Pituitary Spleen Uterus -Reddened aass, 1 ca dia. -Focal areas of consolidation in anterior part of right and left lung. -Possibly pale -Keratitis, acute, narked -Pelvic aineralization, aild Mineralization, cortical, aild Chronic progressive nephropathy, aild -Hepatocyte vacuolation, periportal, aoderate -Pneuaonia, acute exudative, local areas, aoderate Neaorrhage, aultifocal, aild -6alactocele -Adenoaa -Heaosiderosis, aoderate -Cystic glands, aoderate The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Adrenal, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-4&38 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Ueek^ 105) Terainal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations'. Adrenal Esophagus -Hass, 0.5 ca dia. -Sinusoidal ectasia, cortex, aild -Not exaained, aissing Species: Rat Project Nuaber: 02B1CR0012 001763 Suaaarized STAR Page: 94 285 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4638 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Meek- 105) Terainal Sacrifice Hicroscopic Observations (continued): Kidney Liver Lung Haaaary 61and Parathyroid Pituitary Spleen Uterus -Chronic progressive nephropathy, aild -Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aoderate -Vascular aineralization, aild -Not exaained, aissing -Not exaained, not in plane of section -No diagnosis, inadequate section -Heaosiderosis, aild -Cystic glands, aarked The following tissues Mere found to be within noraal liaits: Brain, Spinal Cord, Bone Karros, Heart, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye, Ovary. Aniaal Nuaber: 1R-4639 Sex'. Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek= 56) Sacrificed in extreais Hacroscopic Observations: Skin Liver Hicroscopic Observations: Kidney Large Intestine Liver Lung Haaaary 61and Salivary 61and Spleen Uterus -Hidsternal subcutaneous aass, B x B x 3 ca. -Slightly pale -Pelvic aineralization, aild Chronic progressive nephropathy, aild -Neaatodiasis, colon -Portal aononudear cell infiltrate, aild -Heaorrhage, aultifocal, aild -Fibroadenoaa -Not exaained, aissing -Heaosiderosis, aild -Nithin noraal liaits Fewer than protocol nuaber The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Ovary, Pituitary, Trachea, Adrenal, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Species: Rat Project Nuaber: 0261CR0012 001770 Suaaarized STAR Page: 95 286 Suanarized Single Tabulated Aniaal Report Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3697 Sex: Hale Sroup: < 2) FH-3924 100 ppa Fate: (Meek* 94) Found Dead Hacroscopic Observations: Skin Spleen Liver Microscopic Observations: Adrenal Aorta Esophagus Kidney Liver Lung Lyaph Mode (aesenteric) Pancreas Parathyroid Pituitary Prostate Salivary 61and Saall Intestine Soft Tissues (head) Spleen Thyroid Trachea Urinary Bladder -Hass, 5 x 4 ca, left side of head. -Dark and enlarged. -Mottled -Cortical vacuolation, aild One of pair present -Not exaained, aissing -Not exaained, aissing -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, ainiaal Portal bile duct proliferation, ainiaal Hepatocyte vacuolation, diffuse, aoderate Hegalocytosis, aarked -Vascular aineralization, aild Alveolar aacrophages, aild -Heaorrhage, aild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Hithin noraal Units Fewer than protocol nuaber -Heaangiosarcoaa Large neoplasa in connective tissue and eusde froa side of head. Solid areas and large cavernous vascular spaces. Infiltrative into surrounding ausde. -Heaatopoiesis, extraaedullary, increased, aild Heaosiderosis, aild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing The following tissues were found to be within noraal Units: Brain, Spinal Cord, Bone Harrow, Large Intestine, Testis/Epididyais, Eye, Heart, Stoaach. Species: Rat Project Nuaber: 0281CR0012 001771 S u H i r i : ! STM P a ,.: 96 287 Summarized Single Tabulated Anital Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nutber: 1R-369B Sex: Hale 6roup: ( 2) FH-3924 100 ppt Fate: (Keek- 68) Found Dead Macroscopic Observations: Skin Liver Urinary Bladder Prostate Microscopic Observations: Heart Kidney Liver Lung Prostate Skin Urinary Bladder -Ulcerated Footpads -Possibly slightly pale and tottled. -Distended into abdoten and Filled uith reddish Fluid. -Slightly enlarged and thickened. -Myocarditis, chronic nonsuppurative, ultiFocal, aild -Chronic progressive nephropathy, aild -Portal aononudear cell inFiltrate, aild Hepatocyte vacuolation, ultiFocal, aild Cystoid degeneration, aultiFocal, aild -Vascular aineralization, aild -Prostatitis, acute, suppurative, aarked -Pododeraatitis, ulcerative, aarked -Cystitis, acute, diFFuse, aarked The Following tissues were Found to be within noraal liaits: Brain, Spinal Cord, Bone Narrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Aorta, Testis/Epididyais, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyiph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3700 Sex: Male Broup: ( 2) FH-3924 100 ppa Fate: Week3 106) Terainal SacriFice Macroscopic Observations: Brain Microscopic Observations: Adrenal Brain Heart Kidney Large Intestine Liver -Dark area, possibly old heaorrhage, on anterior right cerebral hemisphere. -Cortical vacuolation, ultifocal, aoderate -Astrocytoaa, benign Large neoplast with central cavitation. Nunerous gitter cells in cavity. -Myocardial Fibrosis, ultiFocal, aild -Chronic progressive nephropathy, aild -Neaatodiasis, colon -Portal aononudear cell inFiltrate, aild Portal bile duct proliFeration, aild Hepatocyte vacuolation, aultiFocal, ainiaal Cystoid degeneration, aultiFocal, aild Hepatocyte alteration, vacuolated, aild Negaiocytosis, aarked Species: Rat Project Nuaber: 02B1CR0012 OOJL 7 V 2 Summarized STAR Page: 97 288 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3700 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Hicroscopic Observations (continued): Lung Parathyroid Prostate Thyroid -Vascular aineralization, aild Alveolar aacrophages, aild -Not exaained, not in plane of section -Prostatitis, acute, suppurative, ainiaal -Cyst, colloid The following tissues were found to be within noraal liaits: Spinal Cord, Bone Harrow, Spleen, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Pituitary, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber! 1R-3701 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Hacroscopic Observations: Haaaary 61and Adrenal Kidney Liver Hicroscopic Observations: Heart Kidney Liver Lung Parathyroid Pituitary Prostate Skin -Subcutaneous aass, 5 x 3 x S ca. -Enlarged -Enlarged, pale and pitted. -Pale raised circular lesion, 1.1 ca dia., aedian lobe. -Hyocardial fibrosis, focal, aild -Chronic progressive nephropathy, aarked -Hepatocyte vacuolation, diffuse, aoderate Hepatocyte alteration, vacuolated, aild Hegalocytosis, aoderate Hyperplastic nodule -Vascular aineralization, aoderate Pneuaonia, interstitial, chronic, aultifocal, aild Alveolar aacrophages, aild -Hyperplasia, aoderate -Adenoaa -Hyperplasia, focal, aoderate -Fibroaa, subcutaneous Large solid neoplasa with abundant collagen foraation. The following tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harro, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Species: Rat Project Nuaber: 0281CR0012 C'Ol 773 Suaaarized STAR Page: 98 289 Suaaarized Single Tabulated flnieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3702 Sex: Hale 6roup: (2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Eye Liver Hicroscopic Observations: Adrenal Eye Kidney Liver Lung Pituitary Spleen -Extensive inflaaaation in right eye post blood saapling. -Bottled -Sinusoidal ectasia, cortex, aild -Panophthalaitis, unilateral, aarked -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, diffuse, aoderate Hegalocytosis, aarked -Vascular aineralization, aild Alveolar aacrophages, aild Perivascular aononudear infiltrate, aild -Cyst, pars distalis -Heaosiderosis, aild The following tissues were found to be Mithin noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-3703 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 79) Sacrificed in extreais Macroscopic Observations: Pituitary Hicroscopic Observations: Adrenal Kidney Liver Lung Pancreas Pituitary -Red aass, 1 xl ca. -Cortical vacuolation, focal, einisal Sinusoidal ectasia, cortex, ainiaal -Chronic progressive nephropathy, aild Pyelonephritis, acute, aoderate -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Hegalocytosis, ainiaal -Vascular aineralization, aild Alveolar aacrophages, aild Heaorrhage, aultifocal, aild -Acinar atrophy, focal, ainiaal -Adenoaa Species: Rat Project Nuaber: 0281CR0012 001774 Suaaarized STAR Page: 99 290 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: To Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3703 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 79) Sacrificed in extreais Hicroscopic Observations (continued): Prostate Spleen Stoaach Testis/Epididyais Thyroid -Prostatitis, acute, suppurative, aild -Heaosiderosis, aild -Edeaa, subaucosal, aoderate -Tubule atrophy, asperaatogenesis, unilateral, ainiaal -Hyperplasia, C cell, aild The folloning tissues Here found to be within noraal liaits: Brain, Spinal Cord, Bone Harron, Heart, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3704 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Ueek= 106) Terainal Sacrifice Hacroscopic Observations: Pituitary Kidney Hicroscopic Observations: Adrenal Heart Kidney Large Intestine Liver Lung Parathyroid Pituitary Spleen Testis/Epididyais -Raised aass, 0.9 x 0.7 ca dia. -Enlarged, pale, pitted. -Sinusoidal ectasia, cortex, aoderate -Hyocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aarked -Neaatodiasis, colon -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Cystoid degeneration, focal, aild -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aild -Hyperplasia, aild -Adenoaa -Heaosiderosis, aild -Tubule atrophy, asperaatogenesis, bilateral, aoderate Polyarteritis, aarked The following tissues Here found to be Hithin noraal li a i t s : Brain, Spinal Cord, Bone Harroa, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001775 Suaaarized STAR Page: 100 291 Sueearized Single Tabulated Anieal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tmo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-3705 Sex: Hale Group: ( 2) FH-3924 100 ppe Fate: (Week= 106) Tereinal Sacrifice Hacroscopic Observations: Hesentery Hicroscopic Observations: Adrenal Kidney Liver Lung Hesentery Parathyroid Salivary Gland Thyroid Trachea -Bloody cystic lesion, 4 x 3 ce dia., possibly tueor or heeatoea. -Cortical vacuolation, focal, eoderate Sinusoidal ectasia, cortex, eoderate Nodular hyperplasia, cortex, focal, eoderate -Chronic progressive nephropathy, eild -Portal eononudear cell infiltrate, eild Portal bile duct proliferation, eild Hepatocyte alteration, vacuolated, eild Hegalocytosis, eoderate Hyperplastic nodule -Vascular eineralization, eild -Cyst Gross lesion was large cystic structure with eany heeosiderin laden eacrophages and eononudear inflaeeatory cells within the wall. -Not exaeined, eissing -Not exaeined, eissing -Not exaeined, eissing -No diagnosis, inadequate section The -following tissues nere found to be within noreal Units: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoeach, Seal! Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyeis, Prostate, Pituitary, Esophagus, Lyaph Node (eesenteric), Pancreas, Eye. Anieal Nueber: 1R-3706 Sex: Hale 6roup: ( 2) FH-3924 100 ppe Fate: (Week- 106) Tereinal Sacrifice Hacroscopic Observations: Liver Hicroscopic Observations: Adrenal Esophagus Heart Kidney Liver -Slightly pale -Cortical vacuolation, eultifocal, eild -Not exaeined, eissing -Hyocarditis, chronic nonsuppurative, eultifocal, einieal -Chronic progressive nephropathy, earked -Portal eononudear cell infiltrate, eild Hepatocyte vacuolation, centrilobular, earked Cystoid degeneration, eultifocal, eild Hegalocytosis, earked Species: Rat Project Nueber: 0281CR0012 001776 Sueearized STAR Page: 101 292 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3706 Sex: Hale Group: ( 2) FH-3924 100 ppe Fate: (Neek= 106) Tereinal Sacrifice Microscopic Observations (continued): Lung Pancreas Pituitary -Vascular eineralization, aild -Not exaained, aissing -Cyst, pars distalis The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harron, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Parathyroid, Trachea, Lyaph Node (aesenteric), Salivary Bland, Eye. Aniaal Nuaber: 1R-3707 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Week- 106) Terainal Sacrifice Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Lyaph Node (aesenteric) Parathyroid Spleen -Scattered pale foci and pink raised aass, 1 ca dia., in left lateral lobe. -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aoderate Cystoid degeneration, focal, ainiaal Hepatocyte alteration, vacuolated, aoderate Hegalocytosis, aarked Hyperplastic nodule -Vascular eineralization, aild Alveolar aacrophages, aild Heaorrhage, focal, aild -Heaorrbage, aoderate -Not exaained, not in plane of section -Heaosiderosis, aild The following tissues Here found to be within noraal liaits: Brain, Spinal Cord, Bone MarroH, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001777 Suaaarized STAR Page: 102 ~ 293 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopie and Hicroscopic Observations Riker Laboratories, Inc. 91 FH-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3708 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Week- 100) Sacrificed in extreais Hacroscopie Observations: Lung Hicroscopic Observations: Adrenal Esophagus Eye Heart Kidney Liver Lung Lyaph Node (aesenteric) Salivary 61and Spleen -Left lobe coapletely consolidated; partial consolidation of right lung. -Cortical vacuolation, local areas, aild Nodular hyperplasia, cortex, focal, aild -Not exaained, aissing -Halignant lyaphoaa, histiocytic -Myocarditis, chronic nonsuppurative, aultifocal, aild Halignant lyaphoaa, histiocytic -Chronic progressive nephropathy, aild -Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Hegalocytosis, aild -Vascular aineralization, aild Heaorrhage, aultifocal, aild Halignant lyaphoaa, histiocytic Cross appearance of consolidation due to aassive infiltration of neoplastic histiocytic type lyaphocytes. -Not exaained, aissing -Halignant lyaphoaa, histiocytic -Heaosiderosis, aild The folloNing tissues were found to be within noreal liaits: Brain, Spinal Cord, Bone Harrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Pancreas. Aniaal Nuaber: 1R-3709 Sex: Hale Croup: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Hacroscopie Observations: Liver Hicroscopic Observations: Adrenal Kidney Liver -Scattered yellowish foci. -Nodular hyperplasia, cortex -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, diffuse, aoderate Hegalocytosis, aild Hepatocyte alteration, basophilic, aild Species: Rat Project Nuaber: 02B1CR0Q12 001778 Suaaarized STAR Page: 10? 294 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FM-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3709 Sex: Hale Broup: (2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Hicroscopic Observations (continued): Lung Parathyroid -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Not exaained, not in plane of section The follouing tissues ere found to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3710 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Hacroscopic Observations: Pituitary Hicroscopic Observations: Adrenal Kidney Liver Lung Pituitary Thyroid -Raised nass, 0.9 ca dia. -Cortical vacuolation, focal, aoderate -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Hepatocyte alteration, vacuolated, aild Hegalocytosis, aild -Vascular aineralization, aild Alveolar aacrophages, aild Perivascular aononudear infiltrate, aild -Adenoaa -Hyperplasia, C cell, aild Ultiaobranchial cyst The follONing tissues ere found,to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3712 Sex: Hale Broup: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Hacroscopic Observations: Liver Hicroscopic Observations: Adrenal -Appears enlarged and aottled. -Cortical vacuolation, aultifocal, aild Nodular hyperplasia, cortex, focal, aild Species: Rat Project Nuaber: 0281CR0012 001779 Suaaarized STAR Page: 104- 295 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3712 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Microscopic Observations (continued): Kidney Large Intestine Liver Lung Pancreas Parathyroid Spleen -Chronic progressive nephropathy, aild -Neaatodiasis, colon -Hepatocyte vacuolation, diffuse, aoderate Cystoid degeneration, focal, ainiaal Hegalocytosis, aarked -Vascular aineralization, aild Alveolar aacrophages, aild -Acinar atrophy, aild -Not exaained, not in plane of section -Heaosiderosis, aild The folloHing tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3713 Sex: Hale 6roup; ( 2) FH-3924 100 ppa Fate: <Neeks 106) Terainal Sacrifice Macroscopic Observations: Adrenal Hicroscopic Observations: Adrenal Kidney Liver Lung Pancreas Parathyroid -Enlarged involving heaorrhagic aass, 2 x 1 ca dia. -Sinusoidal ectasia, cortex, aild Medullary cell hyperplasia, unilateral, aarked Heaorrhage, unilateral, narked Grossly abnoraal adrenal coapletely replaced by encapsulated area of organizing heaorrhage. -Chronic progressive nephropathy, aild -Hepatocyte vacuolation, diffuse, aoderate Cystoid degeneration, focal, aild Hegalocytosis, aoderate -Vascular aineralization, aild Alveolar aacrophages, aild -Acinar atrophy, aild Hyperplasia, islet cell, aoderate -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: 0281CR0012 001780 Suaaarized STAR Page: 105 296 Suaaarized Single Tabulated Anieal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3713 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Weeks 106) Terainal Sacrifice Hicroscopic Observations (continued): The following tissues were found to be within noraal liaits (continued): Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3716 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Week= 83) Sacrificed in extreais Hacroscopic Observations: Liver Skin Hicroscopic Observations: Adrenal Brain Kidney Liver Lung Pancreas Soft Tissues (head) Stoaach Testis/Epididyais Thyroid -Pale -Ulcerated aass, 5 x 4 x 3 ca, containing large areas of necrosis involving subcutaneous and ausde tissue in area, possibly tuaor or chronic abscess. -Sinusoidal ectasia, cortex, aild Nodular hyperplasia, cortex, focal, ainiaal -Hetastatic neoplasa Hutiple saall eaboli of Zyabal gland carcinosa in aeningeal vessels. -Chronic progressive nephropathy, aild -Portal bile duct proliferation, ainiaal Hepatocyte vacuolation, diffuse, aarked Hegalocytosis, aoderate -Vascular aineralization, aild Alveolar aacrophages, aild Perivascular aononudear infiltrate, aild -Acinar atrophy, aoderate -Zyabal gland carcinoaa Large neoplasa, infiltrative, with extensive necrosis. Squaaous aetaplasia. Origin froa Zyabal gland clearly evident. -Edeaa, subaucosal, aoderate -Vascular aineralization, focal, ainiaal Leydig cell hyperplasia, focal, ainiaal -Cyst, colloid The following tissues uere found to be within noroal lieits: Spinal Cord, Bone Harrow, Spleen, Heart, Stall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 001781 Suaaarized STAR Page: 106 297 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Nicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3717 Sex: Hale Broup: ( 2) FH-3924 100 ppa Fate: (Heek= 106) Terainal Sacrifice Hacroscopic Observations: Pituitary Hicroscopic Observations: Kidney Liver Lung Pituitary Spleen Testis/Epididyais Thyroid -Raised aass, 0.5 ca dia. -Chronic progressive nephropathy, aiId -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hegalocytosis, aild -Vascular aineralization, aild Alveolar aacrophages, aild -Adenoaa -Heaosiderosis, aild -Hineralization, tubular, aild -Hyperplasia, C cell, aild The following tissues aere found to be within noraal liaits: Brain, Spinal Cord, Bone Harroa, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3718 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Heek= 106) Terainal Sacrifice Hacroscopic Observations: Pituitary Liver Nicroscopic Observations: Kidney Liver Lung Pancreas Pituitary Thyroid -Heaorrhagic lesion, 0.3 ca dia. -Nottied -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, diffuse, aoderate Hegalocytosis, aarked Hepatocyte alteration, basophilic, aoderate -Vascular aineralization, aild Pneuaonia, interstitial, chronic, focal, ainiaal -Islet cell adenoaa -Adenoaa -Follicular hyperplasia, cystic, unilateral, aild The following tissues aere found to be within noraal liaits: Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 ooi Suaaarized STAR Page: 107 298 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tno Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3719 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: <Neek= 62) Sacrificed in extreais Macroscopic Observations: Skin Liver Abdoaen (internal) kidney Microscopic Observations: kidney Liver Lung Skin Spleen Thyroid -Large subcutaneous aass in ventral cervical area, 5 x 6 x 6 ca; aultiple cysts containing dark red fluid within aass. -Slightly pale -Stoaach and saall intestine gas filled. -Rough surface with patchy pale areas. -Pigaent, conv. tub. epitheliua, aoderate Nephrosis, tubular, aoderate -Hepatocyte vacuo!ation, aultifocal, aild Necrosis, focal, aild Heaatopoiesis, extraaedullary, aild -Vascular aineralization, aild Heaorrhage, local areas, aoderate Metastatic neoplasa -Fibrosarcoaa, subcutaneous Hell differentiated neoplasa with aoderate collagen foraation. Large areas of necrosis. -Heaatopoiesis, extraaedullary, increased, aarked -Ultiaobranchial cyst The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3723 Sex! Male 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Liver Microscopic Observations: Adrenal Kidney Liver -Entlarged with scattered pale foci. -Cortical vacuolation, focal, aild -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aoderate Hepatocyte alteration, vacuolated, aild Negalocytosis, aarked Species: Rat Project Nuaber: 02B1CR0012 GOl <*83 Suaaarized STAR Page*. 10B 299 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic (ftservations Riker Laboratories, Inc. 3H FH-3924: To Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anisal Nueber: 1R-3723 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Microscopic Observations (continued): Lung Spleen Trachea -Vascular aineralization, aild -Heaosiderosis, aild -Tracheitis, chronic, aild The follotting tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Marro, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3724 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 82) Sacrificed in extreais Macroscopic Observations: Skin Lung Spleen Abdoaen (internal) Kidney Liver Microscopic Observations: Aorta Bone Heart Kidney Liver -Large, subcutaneous aass, 7 x 6 x 5 ca, in left inguinal area; coapletely surrounding left hindliab. Hass very firs, hard and gritty upon cutting, boney in appearance. -Raised, whitish, circular aass, 0.6 ca dia., left lobe; raised circular lesion, 0.3 ca dia., in right diaphragaatic lobe. -Enlarged -Hard, boney, aultilobular aass, 2.5 x 2 x 2 ca, in oaentua. -Hydronephrosis, left -Saall whitish lesion, 0.2 ca dia., aedian lobe! saall pale yellowish lesion, 0.4 ca dia., left lateral lobe. -Not exaained, aissing -Osteosarcoaa, hindleg Large neoplasa with abundant new osteoid and bone foraation. -Myocardial fibrosis, focal, aild -Chronic progressive nephropathy, aild Hydronephrosis, unilateral, aoderate Nephrosis, tubular, aoderate -Hepatocyte vacuolation, centrilobular, aoderate Hegalocytosis, aild Malignant lyaphoaa, lyaphocytic Tno grossly described nodules coaposed of large lyaphoblastic cells with vesicular nuclei and high aitotic activity. Different froa osteosarcoaa cells. Species: Rat Project Nuaber: 0261CR0012 ooi ; Suaaarized STAR Page*. 109 300 Sunaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tno Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Muaber: 1R-3724 Sex: Male Broup: ( 2) FH-3924 100 ppa Fate: (Meek 82) Sacrificed in extreais Microscopic Observations (continued): Lung Parathyroid Spleen Thyroid -Vascular aineralization, aild Henorrhage, local areas, aoderate Metastatic neoplasa Multiple aetastases of osteosarcoaa throughout lung. -Hyperplasia, aild -Heaatopoiesis, extraaedullary, increased, aild -C cell adenoaa The following tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Testis/Epididyais, Prostate, Pituitary, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3725 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Heek= 106) Terainal Sacrifice Macroscopic Observations: Eye Bone Microscopic Observations: Bone Eye Heart Kidney Liver Lung Parathyroid -Extensive inflaaaation of right eye afer blood saapling. -Left rear aetatarsal joint swollen. -Arthritis, synovitis; joints, hindleg, aoderate -Panophthalaitis, unilateral, narked -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Cystoid degeneration, focal, aild Negalocytosis, aoderate -Vascular aineralization, ainiaal Alveolar aacrophages, aild Fewer than protocol nuaber -Not exaained, not in plane of section The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Species: Rat Project Nuaber: 0281CR0012 001785 Suaaarized STAR Page: 110 301 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Piker Laboratories, Inc. 3M FM-3924: Tno Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3725 Sex: Male Group: ( 2) FM-3924 100 ppe Fate: (Neel- 106) Terainal Sacrifice Microscopic Observations (continued): The following tissues were found to be within noreal lieits (continued): Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Anieal Nuaber: 1R-3726 Sex: Male Group: ( 2) FM-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Pituitary Liver Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Pituitary Spleen Testis/Epididyais -Raised heeorrhagic lesion, 0.4 ca dia. -Saall scattered pale foci. -Sinusoidal ectasia, cortex, ainiaal -Not exaained, aissing -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aild Hepatocyte alteration, vacuolated, aoderate Hegalocytosis, aoderate -Vascular aineralization, aild Heaorrhage, aultifocal, aild Adenoaa Saall papillary neoplasa near hilus. Hell differentiated. -Adenoaa -Heaosiderosis, aild -Vascular aineralization, ainiaal The -following tissues were found to be within noraal lieits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Parathyroid, Trachea, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3728 Sex! Male Group: ( 2) FM-3924 100 ppa Fate: (Heek- 106) Terainal Sacrifice Macroscopic Observations: Liver Microscopic Observations: Adrenal -Pale raised aass, 1.3 x 0.8 ca, anterior right lateral lobe. -Cortical vacuolation, local areas, aoderate Nodular hyperplasia, cortex, aultifocal, aoderate Medullary cell hyperplasia, focal, aild Species: Rat Project Nuaber: 0281CR0012 001786 Suaaarized STAR Page: 111 302 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-372B Sex: Male Group: ( 2) FH-3924 100 ppa Fate: (Keek- 100) Tereinal Sacrifice Microscopic Observations (continued): Kidney Liver Lung Pancreas Pituitary Spleen Thyroid -Chronic progressive nephropathy, oderate -Portal aononuclear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, centrilobular, aoderate Cystoid degeneration, focal, aild Negaiocytosis, aoderate Hyperplastic nodule Large lesion with good preservation of lobular structure. Most cells of nodule vacuolated. -Vascular aineralization, aild Heaorrhage, diffuse, aoderate Feuer than protocol nuaber -Acinar atrophy, aoderate -Mot exaained, aissing -Heaosiderosis, aild -Follicular hyperplasia, cystic, unilateral, aarked The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Parathyroid, Trachea, Esophagus, Lyaph Mode (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3729 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Meek= B4) Sacrificed in extreais Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Parathyroid Spleen -No visible lesions. -Chronic progressive nephropathy, ainiaal -Portal aononuclear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aild Necrosis, aultifocal, aild Negaiocytosis, aarked Pigaent, portal, aild -Vascular aineralization, aild Heaorrhage, local areas, aild -Not exaained, not in plane of section -Heaosiderosis, aild Species: Rat Project Nuaber: 02B1CR0012 001787 Suaaarized STAR Page: 112 303 Sueaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tho Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-3729 Sex: Hale 6roup: (2) FH-3924 100 ppa Fate: (Neek= 84) Sacrificed in extreeis Microscopic Observations (continued): Testis/Epididyeis -Vascular aineralization, eild The following tissues Mere found to be within noreal lieits: Brain, Spinal Cord, Bone Harrou, Heart, Stoeach, Seal1 Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyeph Node (aesenteric), Pancreas, Salivary Gland, Eye. Anieal Nueber: 1R-3730 Sex: Male Group: ( 2) FH-3924 100 ppa Fate: (kfeek= 106) Tereinal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Adrenal kidney Liver Lung Lyeph Node (aesenteric) Pancreas Pituitary Spleen -Raised eass, 0.6 ce dia. -Cortical vacuolation, focal, eild Sinusoidal ectasia, cortex, einieal -Chronic progressive nephropathy, eoderate -Portal bile duct proliferation, eild Hpatocyte vacuolation, eultifocal, eild Hegalocytosis, eild Pigeent, parenchyaal, einieal -Vascular aineralization, eild -Pigeent, eild -Not exaained, eissing -Adenoaa -Heeosiderosis, eild The folloMing tissues Mere found to be within noreal Units: Brain, Spinal Cord, Bone Harrou, Heart, Stoeach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Salivary Gland, Eye. Anieal Nueber: 1R-3731 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Week- 106) Sacrificed in extreeis Macroscopic Observations: Saall Intestine Stoeach Microscopic Observations: Adrenal -Spherical eass, dark, 0.5 ce dia., near beginning of jejunua, attached to outside nail. -Enlarged gastric rugae uith erosions. Sinusoidal ectasia, cortex, eultifocal, eild Species: Rat Project Nueber: 02B1CR0012 001788 Sueearized STAR Page: 113 304 Sueearized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and HicroKopic Observations Riker Laboratories, Inc. 3H FH-3924: Tno Year Oral Toxicity-Oncogenicity 5tudy in Rats Table: 2 Anieal Nueber: 1R-3731 Sex: Hale Group: ( 2) FH-3924 100 ppe Fate: (Week- 106) Sacrificed in extreeis Microscopic Observations (continued): Kidney Liver Lung Pancreas Parathyroid Spleen Stoeach Thyroid -Calculus, pelvic -Hepatocyte vacuolation, eultifocal, eiId Cystoid degeneration, nultifocal, eild Hegalocytosis, eoderate -Vascular eineralization, eild Heeorrhage, nultifocal, eild -Islet cell adenoea Encapsulated, well differentiated tueor. (Gross lesion.) -Not exaeined, not in plane of section -Heeosiderosis, eild -Necrosis, eucosal, eoderate -Hyperplasia, C cell, eild The following tissues were found to be within noreal lieits: Brain, Spinal Cord, Bone Harrow, Heart, Seall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididysis, Prostate, Pituitary, Trachea, Esophagus, Lyoph Node (eesenteric), Salivary Gland, Eye. Anieal Nueber: 1R-3734 Sex.* Hale 6roup: ( 2) FH-3924 100 ppe Fate: (Week- 45) Found Dead Macroscopic Observations: Kidney Spleen Urinary Bladder Microscopic Observations: Adrenal Eye Kidney Large Intestine Liver Lung Lyeph Node (eesenteric) Pancreas Preputial Bland Salivary Gland Seall Intestine -Bilateral narked hydronephrosis. -Appears ssaller -Expanded with hard calculi eeasuring about 0.B ce dia. -Sinusoidal ectasia, cortex, focal, eild -Not exaeined, eissing -Pyelonephritis, acute, eoderate Hydronephrosis, bilateral, eoderate -Not exaeined, eissing -Hegalocytosis, eild -Vascular eineralization, eild Alveolar eacrophages, eild -Not exaeined, eissing -Not exaeined, eissing -Preputial adenitis, acute, narked -Not exaeined, eissing -Not exaeined, eissing MF r f o o iT~ior>iA-L. /Ha AJO c o p t e O & J K R V * T * e + J S H a /A, - UJ& T9+so A tA -TrO O A A vtU JD p * A i * j e A u H a m a . / h jo A o u A t o m o u t h - C f i o u i * f i 3 U /a/ C o a o * . ' P & m . j + U L t 4 n & r -m o AH A S S 7wc p e jo \ s . Species: Rat Project Nueber: 02B1CR0012 G ) ifiXriKiKHAt. tS A - & & U O y/y/srsr G iM M tsn * M>14* A M A * 0017S9 Sueearized STAR Page: 114 305 Suaaarized Single Tabulated Anieal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3M FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-3734 Sex: Hale Group: ( 2) FH-3924 100 ppe Fate: (Heek= 45) Found Dead Hicroscopic Observations (continued): Spleen Urinary Bladder -Heaosiderosis, eoderate Atrophy, eoderate -Epithelial hyperplasia, papillary, diffuse, earked The foIloHing tissues were found to be within noreal lieits: Brain, Spinal Cord, Bone Harrow, Heart, Stoeach, Aorta, Testis/Epididyeis, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus. Anieal Nueber: 1R-3735 Sex: Hale 6roup: ( 2) FH-3924 100 ppe Fate: (Ueeks 52) Found Dead Hacroscopic Observations: Hicroscopic Observations: Eye Kidney Large Intestine Liver Lung Lyaph Node (eesenteric) Parathyroid Seall Intestine Testis/Epididyeis -No visible lesions. -Not exaained, aissing -Mineralization, tubular, aild -Not exaained, aissing -Necrosis, centrilobular, narked -Vascular eineralization, aild -Not exaained, aissing -Not exaained, not in plane of section -Not exaained, aissing -Vascular eineralization, ainiaal The following tissues were found to be within noraal lieits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Urinary Bladder, Aorta, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Pancreas, Salivary Gland. Aniaal Nueber: 1R-373G Sex: Hale Group: { 2) FH-3924 100 ppa Fate: (Neek3 106) Terainal Sacrifice Hacroscopic Observations: Thyroid Pituitary Liver Hicroscopic Observations: Adrenal Heart -Possibly slightly enlarged. -Heaorrhagic lesion, 0.4 ca dia. -Scattered pale foci. -Sinusoidal ectasia, cortex, ainiaal Nodular hyperplasia, cortex, focal, ainiaal -Myocarditis, chronic nonsuppurative, aultifocal, aild Species: Rat Project Nuaber: 0281CR0012 001 Suaaarized STAR Page: 115 306 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3739 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Week- 106) Terainal Sacrifice Hicroscopic Observations (continued): Kidney Liver Lung Parathyroid Pituitary Thyroid Trachea -Chronic progressive nephropathy, ainiaal Pyelonephritis, acute, aiId -Hepatocyte vacuolation, aultifocal, aild Cystoid degeneration, aultifocal, aild Hepatocyte alteration, vacuolated, aoderate Hepatocyte alteration, basophilic, aoderate Hegalocytosis, aild -Vascular aineralization, aild Alveolar aacrophages, aild -Not exaained, aissing -Adenoaa -Not exaained, aissing -Cyst, subepithelial The following tissues ere found to be uithin noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3739 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Heek= 106) Terainal Sacrifice Hacroscopic Observations: Pituitary Liver Adrenal Hicroscopic Observations: Adrenal Heart Kidney Liver -Raised aass, 0.5 ca dia. -Scattered pale foci. -Right adrenal greatly enlarged due to 2 ca dia. aass. -Atrophy, cortical, aarked Carcinoaa, cortical, unilateral Large, well differentiated, high aitotic activity, extensive necrosis. Harked secondary atrophy of cortex in contralateral gland. Hultiple aetastases. -Hyocardial fibrosis, local areas, aild Hyocarditis, chronic nonsuppurative, local areas, aild -Chronic progressive nephropathy, aarked -Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Hegalocytosis, aild Hetastatic neoplasa Species: Rat Project Nuaber: 0201CR0012 001791 Suaaarized STAR Page: 116 307 Suaaarized Single Tabulated Anieal Report (continued) Individual Nacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: IR-3739 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Tereinal Sacrifice Hicroscopic Observations (continued): Lung Parathyroid Pituitary Spleen -Vascular aineralization, eild Alveolar eacrophages, eild Hetastatic neoplase Heeorrhage, local areas, eoderate -Not exaeined, not in plane of section -Adenoaa Hetastatic neoplasa -Heaosiderosis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3740 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Week- 106) Terainal Sacrifice Hacroscopic Observations: Hicroscopic Observations: Kidney Liver Lung Trachea -No visible lesions. -Chronic progressive nephropathy, aild Pyelonephritis, acute, aoderate -Portal aononuclear cell infiltrate, aild Portal bile duct proliferation, aild Hegalocytosis, aoderate -Vascular aineralization, aild Pneuaonia, interstitial, chronic, focal, aild -Cyst, subepithelial The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3741 Sex: Hale 6roup: ( 2) FH-3924 1D0 ppa Fate: (Neek* 106) Terainal Sacrifice Hacroscopic Observations: Hicroscopic Observations: Adrenal -No visible lesions. -Cortical vacuolation, focal, ainiaal Sinusoidal ectasia, cortex, aild Species: Rat Project Nuaber: 02B1CR0012 001792 Suaaarized STAR Page: 117 308 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Rileer Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3741 Sex: Male 6roup: ( 2) FH-3924 100 ppa Fate: (Ueek= 106) Terainal Sacrifice Microscopic Observations (continued): Kidney Liver Lung Lyaph Node (aesenteric) Pancreas Parathyroid Pituitary Trachea -Chronic progressive nephropathy, ainiaal -Hpatocyte vacuolation, aultifocal, aiId Hegalocytosis, aild -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Heaorrhage, ainiaal -Acinar atrophy, aild -Not exaained, not in plane of section -Adenoaa -Cyst, subepithelial The following tissues Mere found to be within noraal liaits: Brain, Spinal Cord, Bone Marrou, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Esophagus, Salivary 61and, Eye. Aniaal Nuaber: 1R-3742 Sex: Hale Sroup: ( 2) FH-3924 100 ppa Fate: (Heek= 77) Sacrificed in extreais Macroscopic Observations: Skin Liver Microscopic Observations: Kidney Liver Lung Lyaph Node (aesenteric) Skin -Healing ulceration on left rear footpad. -Appears soaeMhat pale and Bottled; possible area of infarction in right lateral lobe. -Chronic progressive nephropathy, ainiaal Hyperplasia, pelvic epitheliua, local areas, aild -Hepatocyte vacuolation, diffuse, aarked Necrosis, diffuse, aarked Necrosis, centrilobular, aild Hegalocytosis, aoderate -Vascular aineralization, aild Alveolar aacrophages, aild Heaorrhage, local areas, aild -Not exaained, aissing -Pododeraatitis, ulcerative, hindleg, aarked The following tissues sere found to be within noraal liaits: Brain, Spinal Cord, Bone Marrou, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001793 Suaaarized STAR Page: 116 309 Summed Single Tabulated Anieal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniial Nuaber: 1R-3743 Sex: Hale Group! ( 2) FH-3924 100 ppe Fate: (Neek= 95) Sacrificed in extreeis Hacroscopic Observations: Pituitary Liver Testis/Epididyais Hicroscopic Observations*. Adrenal Kidney Liver Lung Lyaph Node (aesenteric) Pituitary Prostate Spleen Testis/Epididyais -Raised dark aass, 1 ca dia. -Pale and Bottled. -Appear saall -Cortical vacuolation, aultifocal, aild Nodular hyperplasia, cortex, aultifocal, aild Atrophy, cortical, aild -Chronic progressive nephropathy, aild -Portal bile duct proliferation, aild Hepatocyte vacuolation, periportal, aoderate -Vascular aineralization, aild -Not exaained, aissing -Adenoaa -Not exaained, aissing -Heaosiderosis, aild -Tubule atrophy, asperaatogenesis, bilateral, aarked The follotting tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harroe, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3744 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Heek= 106) Terainal Sacrifice Hacroscopic Observations: Skin Pituitary Liver Hicroscopic Observations: Adrenal Heart Kidney Liver Lung -Raised ulcerated inflaaaed lesion on right hind footpad. -Saall, raised dark lesion, 0.4 ca dia. -Circular pale lesion, 0.4 ca dia., aedian lobe. -Cortical vacuolation, local areas, aoderate -Hyocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aoderate -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hyperplastic nodule -Vascular aineralization, aild Alveolar aacrophages, aild Species: Rat Project Nuaber: 0281CR0012 001794 Suaaarized STAR Page: 119 310 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3744 Sex: Male Group: ( 2) FH-3924 100 ppe Fate: (Heek: 106) Tereinal Sacrifice Microscopic Observations (continued): lyaph Node (aesenteric) Parathyroid Pituitary Skin -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa -Pododeraatitis, ulcerative, hindleg, narked The following tissues aere found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Thyroid, Trachea, Esophagus, Pancreas, Salivary Sland, Eye. Aniaal Nuaber! 1R-3745 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Heek= 14) Found Dead Macroscopic Observations: Heart Spleen Kidney Testis/Epididyais Microscopic Observations: Aorta Kidney Liver Lung Pancreas Parathyroid Spleen Urinary Bladder -Possibly slightly enlarged. -Possibly slightly saall. -Possible hydronephrosis of right kidney. -Possibly slightly enlarged. -Not exaained, aissing -Hydronephrosis, unilateral, aoderate -Hegalocytosis, aild -Heaorrhage, perivascular, aoderate -Not exaained, aissing -Not exaained, not in plane of section -Atrophy, aild -Heaorrhage, focal, aild Epithelial hyperplasia, siaple, diffuse, aild Cystitis, acute, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Testis/Epididyais, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001705 Suaaarized STAR Page: 120 31 I Suaaarized Single Tabulated Anisal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anisal Nuaber: 1R-3746 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: Week* 104) Teriinal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Kidney Liver Lung Parathyroid Pituitary Testis/Epididyais -Saall dark lesion. -Chronic progressive nephropathy, aild -Hepatocyte vacuolation, aultifocal, aoderate Cystoid degeneration, aultifocal, aoderate -Vascular aineralization, aild Alveolar aacrophages, aild -Not exaained, not in plane of section -Adenoaa -Vascular aineralization, aild The follOMing tissues Mere found to be Mithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Stall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3749 Sex: Hale Fate: (Neek= 69) Found Dead Macroscopic Observations: Urinary Bladder Liver Lung Microscopic Observations: Adrenal Aorta Eye Heart Liver Lung Pancreas Pituitary Prostate Spleen Stoaach Testis/Epididyais 6roup: ( 2) FH-3924 100 ppa -Heaaturia -Mottled -Hypereaic -Within noraal liaits One of pair present -Not exaained, aissing -Phthsis bulbi, unilateral, aarked -Myocarditis, chronic nonsuppurative, aultifocal, aild -Hepatocyte vacuolation, aultifocal, aild Necrosis, centrilobular, aoderate Hegalocytosis, aoderate -Vascular aineralization, aild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Heaosiderosis, aild Atrophy, aild -Necrosis, aucosal, aoderate -Within noraal liaits One of pair present Species: Rat Project Nuaber: 0281CR0012 001796 Suaaarized STAR Page: 121 312 Suaaarized Single Tabulated flnieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: To Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniial Nuaber: 1R-3749 Sex: Male Broup: ( 2) FH-3924 100 ppa Fate: (Heek= 9) Found Dead Microscopic Observations (continued): The -following tissues ere Found to be within noraal liaits: Brain, Spinal Cord, Bone Harro, Kidney, Saall Intestine, Large Intestine, Urinary Bladder, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary 61and. Aniaal Nuaber: 1R-37S0 Sex'. Hale Group: ( 2) FH-3924 100 ppe Fate: (Neek= 75) Sacrificed in extreais Macroscopic Observations: Liver Microscopic Observations: Adrenal Heart Kidney Liver Lung Lyaph Node (aesenteric) Parathyroid Prostate Salivary 61and -Raised, 1.5 ca dia. nodule in left lateral lobe. -Cortical vacuolation, Focal, aild Nodular hyperplasia, cortex, Focal, aild -Myocarditis, chronic nonsuppurative, Focal, ainiaal -Chronic progressive nephropathy, ainiaal -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Necrosis, aultifocal, aild Hegalocytosis, aarked Hepatocellular carcinoaa Large ell differentiated neoplasa. Solid, aoderate aitotic activity. -Vascular aineralization, aild -Not exaained, aissing -Not exaained, not in plane of section -Not exaained, aissing -Not exaained, aissing The following tissues ere found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Pituitary, Large Intestine, Thyroid, Trachea, Esophagus, Pancreas, Eye. Aniaal Nuaber: 1R-3751 Sex: Male Group: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Esophagus -No visible lesions. -Not exaained, aissing Species: Rat Project Nuaber: 0281CR0012 001797 Suaaarized STAR Page: 122 313 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FR-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3751 Sex: Male Group: (2) FH-3924 100 ppa Fate: (Heeks 106) Terainal Sacrifice Microscopic Observations (continued): Heart Kidney Liver Lung Parathyroid Pituitary Spleen Thyroid Trachea -Myocarditis, chronic nonsuppurative, local areas, aild -Chronic progressive nephropathy, aoderate -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aoderate Cystoid degeneration, aultifocal, aild Megalocytosis, aild -Vascular aineralization, aild Perivascular aononudear infiltrate, aild -Not exaained, aissing -Adenoaa -Heaosiderosis, aild -Not exaained, aissing -Not exaained, aissing The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Adrenal, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Prostate. Aniaal Nuaber: 1R-3752 Sex: Male Group: ( 2) FH-3924 100 ppa Fate: INeek= 106) Terainal Sacrifice Macroscopic Observations: Liver Microscopic Observations: Heart Kidney Liver Lung Pancreas -Pale, raised lesion, 0.7 ca dia., in right lateral lobe. -Myocarditis, chronic nonsuppurative, focal, ainiaal -Chronic progressive nephropathy -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocellular carcinoaa Megalocytosis, ainiaal -Vascular aineralization, aild Heaorrhage, local areas, aoderate -Acinar atrophy, aarked Islet cell carcinoaa Moderately pleoeorphic, encapsulated, with infiltration of capsule by tuaor cells. Vascular invasion. Species: Rat Project Nuaber: 0281CR0012 001798 Suaaarized STAR Page: 123 314 Summed Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anisal Nusber: 1R-3752 Sex! Male 6roup: ( 2) FH-3924 100 pps Fate: (Heek= 106) Tersinal Sacrifice Microscopic Observations (continued): Parathyroid Spleen -Adenoaa -Hesosiderosis, si1d The following tissues were found to be within norsal lisits*. Brain, Spinal Cord, Bone Marrow, Stosach, Seal1 Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididysis, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3753 Sex: Hale 6roup: < 2) FH-3924 100 ppa Fate: (Week- 94) Sacrificed in extreais Macroscopic Observations: Spleen Liver Testis/Epididyais Thyaus Microscopic Observations: Adrenal Brain Heart Kidney Liver Lung Lyaph Node (aesenteric) Pancreas Salivary 61and Spleen Testis/Epididyais -Enlarged -Enlarged and aottled with a circular raised lesion, 1.7 ca dia., on one aedian lobe and another circular lesion, 0.8 ca dia. on the other aedian lobe. -Right testis saall. -Dark heaorrhagic lesion, 1.5 x 1 ca. -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic Large, heaorrhagic lesion with aalacia in cerebellua. -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Hepatocyte vacuolation, centrilobular, aarked Malignant lyaphoaa, lyaphocytic Megalocytosis, noderate Necrosis, centrilobular, aoderate -Malignant lyaphoaa, lyaphocytic Heaorrhage, aultifocal, aiId -Heaorrhage, aoderate Malignant lyaphoaa, lyaphocytic -Acinar atrophy, aoderate Adenoaa Malignant lyaphoaa, lyaphocytic -Nat exaained, aissing -Malignant lyaphoaa, lyaphocytic -Tubule atrophy, asperaatogenesis, unilateral, " narked Species: Rat Project Nuaber: 0281CR0012 601793 Suaaarized STAR Page: 124 Suaaarized Single Tabulated flniial Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nutber: 1R-3753 Sex*. Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Week: 94) Sacrificed in extreeis Microscopic Observations (continued): Thyeus -Malignant lyephosa, lyaphocytic Thyaus aarkedly enlarged by neoplastic infiltrate and heaorrhage. The following tissues were found to be within noraal liaits: Spinal Cord, Bone Harrow, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Eye. Aniaal Nuaber: 1R-3754 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Week- 104) Terainal Sacrifice Hacroscopic Observations: Pituitary Thyroid Hicroscopic Observations: Adrenal Kidney Large Intestine Liver Lung Lyaph Node (aesenteric) Pancreas Pituitary Testis/Epididyais -Raised nass, 0.5 ca dia. -Possibly slightly enlarged. -Sinusoidal ectasia, cortex, aoderate -Chronic progressive nephropathy, aoderate -Neaatodiasis, colon -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aoderate Necrosis, focal, ainiaal Hegalocytosis, aild -Vascular aineralization, aild -Not exaained, aissing -Hyperplasia, islet cell, aild -Adenoaa -Polyarteritis, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Salivary Gland, Eye. Aniaal Nuaber: 1R-3755 Sex: Hale Group: < 2) FH-3924 100 ppa Fate: (Week: 106) Terainal Sacrifice Hacroscopic Observations: Skin Thyroid Pituitary Testis/Epididyais -Circular raised inflaaaed lesions on right and left hind footpads. -Possibly slightly enlarged. -Saall dark lesion. -Right testis saall. Species: Rat Project Nuaber: 0281CR0012 001300 Suaaarized STAR Page*. 125 316 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tea Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nueber: 1R-3755 Sex: Hale 6roup: ( 2) FH-3924 100 ppt Fate: (Neek= 106) Tereinal Sacrifice Microscopic Observations (continued): Adrenal Heart Kidney Liver Lung Parathyroid Pituitary Skin Testis/Epididyais -Cortical vacuolation, aulti-focal, aild Sinusoidal ectasia, cortex, aild Nodular hyperplasia, cortex, focal, aild -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Cystoid degeneration, focal, aild Megalocytosis, aild -Vascular aineralization, aild Alveolar aacrophages, aild -Not exaained, not in plane of section -Adenoaa -Pododeraatitis, ulcerative, hindleg, bilateral, narked -Tubule atrophy, asperaatogenesis, unilateral, aoderate The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Eland, Eye. Aniaal Nuaber: 1R-3756 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Sacrificed in extreais Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Heart Kidney Liver Lung Lyaph Node (aesenteric) -Enlarged, 0.B cn in diaaeter -Cortical vacuolation, focal, aild Sinusoidal ectasia, cortex, focal, aild -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild -Vascular aineralization, aild Heaorrhage, aultifocal, aild -Sinusoidal ectasia, aoderate Species: Rat Project Nuaber: 0281CR0012 001801 Suaaarized STAR Page: 126 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 91 FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3756 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Heek= 105) Sacrificed in extreais Microscopic Observations (continued): Pituitary Spleen Urinary Bladder -Adenoaa -Heaosiderosis, aiId -Epithelial hyperplasia, siaple, diffuse, aild The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Harroa, Stoaach, Saall Intestine, Large Intestine, Aorta, Testis/Epididyais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3757 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Ueek= 98) Sacrificed in extreais Macroscopic Observations: Eye Pituitary Microscopic Observations: Eye Kidney Liver Lung Pituitary Spleen Thyroid -Opacity of right eye. -Heaorrhagic aass, 1 x 0.8 ca dia. -Phthsis bulbi, unilateral -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Megalocytosis, ainiaal -Vascular aineralization, aild Alveolar aacrophages, aild -Adenoaa -Heaosiderosis, aild -C cell carcinoaa The following tissues were found to be within noraal liaits: Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and. Aniaal Nuaber: 1R-3758 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Keek- 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal -No visible lesions. -Cortical vacuolation, local areas, aoderate Nodular hyperplasia, cortex, focal, aild Species: Rat Project Nuaber: 02B1CR0012 001802 Suaaarized STAR Page: 127 318 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Too Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-37SB Sex: Hale Broup: ( 2) FH-3924 100 ppa Fate: (Neek- 106) Terainal Sacrifice Microscopic Observations (continued): Kidney Liver Lung Lyaph Node (aesenteric! Testis/Epididyais Trachea -Chronic progressive nephropathy, aild Hydronephrosis, bilateral, aoderate -Portal sononudear cell infiltrate, aild Portal bile duct proliferation, aild Hepatocyte vacuolation, aultifocal, aild Necrosis, aultifocal, aild Hegalocytosis, aoderate Pigaent, aultifocal, aild -Vascular Bineraiization, aild Alveolar aacrophages, aild -Heaorrhage, ainiaal -Vascular aineralization, aild -Tracheitis, chronic, aild The follouing tissues Here found to be within noraal liaits: Brain, Spinal Cord, Bone Harrou, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Thyroid, Parathyroid, Esophagus, Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3759 Sex: Hale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 106) Terainal Sacrifice Macroscopic Observations: Pituitary Hicroscopic Observations! Kidney Liver Lung Pituitary Spleen Testis/Epididyais -Circular aass, 0.5 ca dia. -Chronic progressive nephropathy, aoderate -Portal aononudear cell infiltrate, aild Portal bile duct proliferation, aild Cystoid degeneration, focal, aild Hepatocyte alteration, vacuolated, aild Hegalocytosis, aoderate Hepatocyte vacuolation, aultifocal, aoderate -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aild Alveolar aacrophages, aoderate Perivascular aononudear infiltrate, aild Heaorrhage, local areas, aarked -Adenoaa -Heaosiderosis, aild -Tubule atrophy, asperaatogenesis, unilateral, aild Species: Rat Project Nuaber: 0281CR0012 001803 Suaaarized STAR Page: 128 319 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3759 Sex: Male 6roup: ( 2) FH-3924 100 ppa Fate: (Heek- 106) Terainal Sacrifice Microscopic Observations (continued): Urinary Bladder -Not examined, aissing The folloaing tissues were found to be aithin noraal liaits: Brain, Spinal Cord, Bone Harroa, Heart, Stoaach, Stall Intestine, Large Intestine, Aorta, Prostate, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3760 Sex: Hale Group: ( 2) FH-3924 100 ppa Fate: (Week- 106) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Heart Kidney Liver Lung Pancreas Parathyroid Thyroid -No visible lesions. -Medullary cell hyperplasia, focal, aild -Myocardial fibrosis, focal, aild Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aild -Portal aononudear cell infiltrate, aild Hepatocyte vacuolation, aultifocal, aoderate Necrosis, aultifocal, aild Negaiocytosis, aoderate -Vascular aineralization, aild Pneuaonia, interstitial, chronic, aultifocal, aild Alveolar aacrophages, aild -Hyperplasia, islet cell, aoderate -Not exaained, aissing -Not exaained, aissing The folloaing tissues aere found to be within noraal liaits: Brain, Spinal Cord, Bone Harroa, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, Pituitary, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Bland, Eye. Species: Rat Project Nuaber: 0281CR0012 60304 Suaaarized STAR Page: 129 320 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4756 Sex: Feaale Broup: (2) FM-3924 100 ppa Fate: (Neek= 80) Sacrificed in extreais Macroscopic Observations: Haasary Bland Pituitary Adrenal Eye Microscopic Observations: Adrenal Eye Liver Lung Maaaary 61and Parathyroid Pituitary Spleen -Ulcerated aultilobular sass, 5 x 2.5 x 1 ca, right axilla; pale aass, 2 x 1 ca, right inguinal area. -Heaorrhagic aass, 0.7 ca dia. -Left adrenal enlarged, 1 ca dia. -Atrophy of left eye -Sinusoidal ectasia, cortex, unilateral, aarked -Phthsis bulbi, unilateral -Heaatopoiesis, extraaedullary, aild Necrosis, aultifocal, aild -Vascular aineralization, aild Metastatic neoplasa -Adenocarcinoaa Three sections of tuaor present. All of a veil differentiated ductular neoplasa with necrosis and vascular invasion. Lung aetastases siailar to priaary. -Not exaained, not in plane of section -Adenoaa -Heaatopoiesis, extraaedullary, increased, aoderate The following tissues Here found to be within noraal liaits: Brain, Spinal Cord, Bone Harroa, Kidney, Heart, Stoaach, SealI Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-4758 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 89) Found Dead Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Esophagus Eye Kidney Large Intestine -Raised heaorrhagic aass, l.S x 1 ca. -Sinusoidal ectasia, cortex, aild -Not exaained, Hissing -Not exaained, aissing -Pelvic aineralization, aoderate Calculus, pelvic -Not exaained, aissing Species: Rat Project Nuaber: 02B1CR0012 001,505 Suaaarized STAR Page: 130 321 Suuarized Single Tabulated Aniaal Report (continued) Individual ttacroscopic and Hicroscopic Observation* Riker Laboratories, Inc. 3H FH-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4758 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 89) Found Dead Hicroscopic Observations (continued): Liver Lung Lyaph Node (aesenteric) Haasary Eland Ovary Pancreas Parathyroid Pituitary Salivary Gland SealI Intestine Spleen Thyroid Uterus -Portal bile duct proliferation, aild Hepatocyte vacuolation, diffuse, aoderate -Alveolar aacrophages, aild Pneuaonia, acute exudative, local areas, aild Vascular aineralization, aild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Hyperplasia, islet cell, aild -Not exaained, aissing -Adenoaa -Not exaained, aissing -Not exaained, aissing -Heaosiderosis, aoderate -Not exaained, aissing -Not exaained, aissing The following tissues aere Found to be within noraal liaits: Spinal Cord, Bone Harrow, Heart, Stoaach, Urinary Bladder, Aorta, Trachea, Brain. Aniaal Nuaber: 1R-47S9 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Heek= 105) Terainal Sacrifice Hacroscopic Observations: Haaaary Gland Liver Hicroscopic Observations: Adrenal Kidney Liver Lung Haaaary Gland Ovary Pancreas Pituitary Uterus -Hass, 4 x 3 ca, left axilla* 6 x 5 x 2 ca, right inguinal area. -Appears aottled -Sinusoidal ectasia, cortex, narked -Pigaent, conv. tub. epitheliua, aild -Hepatocyte vacuolation, periportal, aoderate Hegalocytosis, aild -Heaorrhage, local areas, aild Vascular aineralization, aild -Fibroadenoaa Fibroadenoaa -Tubular hyperplasia, bilateral, aoderate -Acinar atrophy, aild -Adenoaa -Cystic glands, aild The following tissues were Found to be within noraal liaits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: 02B1CR0012 001806 Suaaarized STAR Page: 131 322 Suaaarized Single Tabulated ftnieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Too Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4759 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Week 105) Terainal Sacrifice Microscopic Observations (continued): The following tissues aere found to be within noraal lia its (continued): Urinary Gladder, Aorta, Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-4762 Sex: Feaale Group! ( 2) FH-3924 100 ppa Fate: (Heek= 105) Terainal Sacrifice Macroscopic Observations: Pituitary Liver Microscopic Observations: Adrenal Kidney Liver Lung Ovary Pituitary Spleen Thyroid -Keaorrhagic aass, 0.8 ca dia. -Dark in color; raised circular lesion, 1.5 ca d ia ., aedian lobe; circular lesion, 1 ca d ia ., right anterior lobe; circular lesion, 0.9 ca d ia ., caudate lobe. -Sinusoidal ectasia, cortex, aild -Chronic progressive nephropathy, aild Pigaent, conv. tub. epitheliua, aild -Portal aononudear cell in filt r a t e , aild Portal bile duct p rolifera tion , aild Hepatocyte vacuolation, d iffuse, aoderate Hepatocyte a lteration, vacuolated, aild Hyperplastic nodule Negalocytosis, aoderate -Heaorrhage, a u ltifo c a l, aild Vascular aineralization, aild Pneuaonia, in te r s titia l, chronic, a u ltifo c a l, aild Alveolar aacrophages, aoderate Perivascular aononudear in filt r a t e , aoderate -Tubular hyperplasia, b ila te ra l, aoderate -Adenoaa -Heaosiderosis, aild -C cell adenoaa The following tissues ere found to be Mithin noraal lia it s : Brain, Spinal Cord, Bone Harro, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Naaaary Gland, Trachea, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 001807 Suaaarized STAR Page: 132 323 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. SM FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: IR-4764 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Esophagus Kidney Large Intestine Liver Lung Lyaph Node (aesenteric) Ovary Pituitary Spleen -Large heaorrhagic aass, 1.2 ca dia. -Sinusoidal ectasia, cortex, aild -Not exaained, aissing -Chronic progressive nephropathy, aild Pelvic aineralization, aild -Neaatodiasis, colon -Hepatocyte vacuolation, a u ltifo c a l, aild Hegalocytosis, aild -Vascular aineralization, aild Alveolar aacrophages, aild -Heaorrhage, aoderate -Tubular hyperplasia, b ila te ra l, aild -Adenoaa -Heaosiderosis, aild The folloiiing tissues aere found to be aithin noraal 1ia its : Brain, Spinal Cord, Bone Harroa, Heart, Saall Intestine, Urinary Bladder, Aorta, Uterus, Maaaary Bland, Trachea, Thyroid, Parathyroid, Pancreas, Salivary Gland, Eye, Stoaach. Aniaal Nuaber: 1R-4765 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Macroscopic Observations: Pituitary Liver Microscopic Observations: Liver Lung Parathyroid Thyroid -Clear flu id fille d cyst, 0.5 ca dia. -Appears aottled -Portal aononudear cell in filtr a te , aild Portal b ile duct prolifera tion , aild Hepatocyte vacuolation, local areas, aild Hegalocytosis, aild -Vascular aineralization, aild -Not exaained, not in plane of section -Hyperplasia, C c e ll, aoderate The following tissues were found to be aithin noraal lia it s : Brain, Spinal Cord, Bone Harroa, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61 and, Maaaary Gland, P itu ita ry , Adrenal, Eye, Spleen. Species: Rat Project Nuaber: 0281CR0012 ooiaos Suaaarized STAR Page: 133 324 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4766 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Macroscopic Observations: Microscopic Observations'. Adrenal Kidney Liver Lung -No visible lsions. -Sinusoidal ectasia, cortex, aild -Pelvic aineralization, ainiaal Pigaent, ccnv. tub. epitheliua, aild -Hpatocyte vacuolation, aultifocal, aild Hegalocytosis, aoderate Pigaent, hpatocyte, aild -Alveolar aacrophages, aild Heaorrhage, a u ltifo c a l, aild The following tissues ere found to be within norail 1ia its : Grain, Spinal Cord, Gone Harrou, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Gland, P itu ita ry , Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4767 Sex: Feaale Group: ( 2) FH-3924 100 pps Fate: (Heek= 105) Terainal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Kidney Liver Lung Ovary Parathyroid Pituitary Spleen Uterus -Raised aass, 1 ci dia. -Sinusoidal ectasia, cortex, wild -Pelvic aineralization, aild -Hepatocyte vacuolation, d iffuse, aoderate Cystoid degeneration, a u ltifo ca l, aild Hegalocytosis, derate Heiatopoiesis, extracedullary, aild -Vascular aineralization, aild Alveolar aacrophages, aild -Tubular hyperplasia, unilateral, aild Cyst, unilateral -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, aild -Cystic glands, aild The following tissues aere found to be within noraal U n it s : Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Maaaary Gland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001,309 Suaaarized STAR Page: 134 325 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4768 Sex! Feaale Group: ( 2) FH-3924 100 ppa Fate: (Heek- 105) Terainal Sacrifice Macroscopic Observations: Eye Pituitary Liver Microscopic Observations: Adrenal Eye Kidney Liver Ovary Parathyroid Pituitary Spleen Thyroid -Right eye inflaaaed and cloudy. -Hass, 0 .7 ca dia. -S lig h tly pale and nottled. -Cortical vacuolation, local areas, narked Sinusoidal ectasia, cortex, aild -Panophthalaitis, unilateral, narked -Chronic progressive nephropathy, aild -Hepatocyte vacuolation, periportal, aoderate Negalocytosis, aild -Tubular hyperplasia, b ila te ra l, aoderate -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, aild -Follicular hyperplasia, cystic, unilateral, narked The -following tissues were found to be within noraal lia its : Brain, Spinal Cord, Bone Harroa, Heart, Lung, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Maaaary 61 and, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-4769 Sex: Fenale Group: < 2) FH-3924 100 ppa Fate: INeek= 105) Terainal Sacrifice Macroscopic Observations: Maaaary Gland Microscopic Observations: Adrenal Kidney Liver Lung Maaaary Gland Ovary Pituitary -Mass, 6 x 4 x 2 ca in le ft a x illa ; 6 x 4 x 2 ca, in le ft inguinal area. -Sinusoidal ectasia, cortex, aild -Chronic progressive nephropathy, aild -Hepatocyte vacuolation, a u ltifo c a l, aild Negalocytosis, aild Hepatocyte alteration, basophilic, aild -Vascular aineralization, aild Alveolar aacrophages, aild Heaorrhage, local areas, aild -Fibroadenoaa Adenocarcinoaa -Tubular hyperplasia, b ila te ra l, aoderate -Adenoaa Species: Rat Project Nuaber: 02B1CR0012 001310 Suaaarized STAR Page: 135 326 Suasarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nutber: 1R-4769 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Heek= 105) Terainal Sacrifice Microscopic Observations (continued): Uterus -Hydroaetra, aoderate The folloNing tissues Here found to be within noraal lia it s : Brain, Spinal Cord, Bone Harron, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4770 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Macroscopic Observations: Maaaary Gland Liver Microscopic Observations: Adrenal Liver Lung Maaaary Gland Pancreas Pituitary Spleen -Mass, 4 x 4 x 1 ca, in throat area. -Appears aottled -Sinusoidal ectasia, cortex, aoderate -Hepatocyte vacuolation, periportal, aoderate Megalocytosis, aoderate Pigaent, hepatocyte, ainiaal -Vascular aineralization, aild Alveolar aacrophages, aoderate Perivascular aononudear in filtr a te , aild -Fibroadenoaa -Acinar adenoaa -Adenoaa -Heaosiderosis, aild The following tissues Here found to be Hi thin noraal li a i t s : Brain, Spinal Cord, Bone Marrou, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Salivary Bland, Eye. Aniaal Nuaber: 1R-4771 Sex: Feaale 6roup*. ( 2) FH-3924 100 ppa Fate: (Heek= 91) Sacrificed in extreais Hacroscopic Observations: Pituitary Liver Microscopic Observations: Adrenal -Heaorrhagic aass, 0.8 ca dia. -Appears dark bronn in color aith aultiple pale foci on all lobes. -Cortical vacuolation, aild Sinusoidal ectasia, cortex, aild Species: Rat Project Nuaber: 0281CR0012 001811 Suaaarized STAR Page: 13b 32 7 Suaaarized Single Tabulated flniial Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3R FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4771 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 91) Sacrificed in extreais Hicroscopic Observations (continued): Kidney Liver Lung Pituitary -Pelvic aineralization, ainiaal Vacuolation, conv. tub. epitheiua, aild -Portal aononudear cell in filt r a t e , aild Portal b ile duct prolifera tion , aild Hepatocyte vacuolation, periportal, aoderate -Vascular aineralization, aild Alveolar aacrophages, aild Perivascular aononudear in filt r a t e , aild Heaorrhage, d iffuse, aarked -Adenoaa The folloaing tissues were found to be within noraal U n it s : Brain, Spinal Cord, Bone Harrou, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4772 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Hacroscopic Observations: Liver Hicroscopic Observations: Adrenal Kidney Liver Lung Lyaph Node (aesenteric) Haaaary Gland Parathyroid Thyroid -Circular aass, 2 x 1.2 ca, in right posterior. -Cortical vacuolation, aild Sinusoidal ectasia, cortex, narked -Chronic progressive nephropathy, ainiaal Pelvic aineralization, ainiaal -Hegalocytosis, aoderate Hyperplastic nodule Hepatocellular adenoaa Large tuaor with areas of necrosis. Tuaor cells large, aany vacuolated. -Vascular aineralization, aild Pneuaonia, in te r s titia l, chronic, a u ltifo c a l, aild -Not exaained, aissing -Galactocele -Hyperplasia, aultifocal, aild -Hyperplasia, C c e ll, aultifocal, aild The following tissues were found to be within noraal li a i t s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Snail Intestine, Large Intestine, Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 137 328 Suaaari2ed Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4772 Sex: Feaale Sroup: ( 2) FM-3924 100 ppa Fate: (Meek 105) Terainal Sacrifice Microscopic Observations (continued): The following tissues Mere found to be within noraal lia its (continued): Urinary Bladder, Aorta, Uterus, Ovary, P itu ita ry , Trachea, Esophagus, Salivary Bland, Eye, Pancreas. Aniaal Nuaber: 1R-4773 Sex: Feaale Group: ( 2) FM-3924 100 ppa Fate: (Meek 105) Terainal Sacrifice Macroscopic Observations: Naaaary Bland Liver Microscopic Observations: Adrenal Kidney Large Intestine Liver Lung Lyaph Node (aesenteric) Maaaary 61 and Ovary Pituitary -Saall ulcerated aass, 2 ca d ia ., on right side. -Pale, s lig h tly raised aass, 3 x 2 ca, in aedian lobe. -Sinusoidal ectasia, cortex, narked -Pigaent, conv. tub. epitheliua, brown, ainiaal -Neaatodiasis, colon -Hyperplastic nodule Hepatocyte alteration, vacuolated, Multifocal, aild Hegalocytosis, Moderate Hepatocyte vacuolation, a u ltifo c a l, aild -Vascular Mineralization, aild Alveolar Macrophages, a u ltifo c a l, aild Perivascular aononudear in filtr a te , ainiaal -Heaorrhage, aild -Adenocarcinoaa, ductal Adenocarcinoaa, ductal Both gross lesions were adenocarcinoaas. One was ulcerated. -Cyst, fo llic u la r, unilateral -Adenoaa The following tissues were found to be within noraal lia its : Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Uterus, Trachea, Thyroid, Parathyroid, Esophagus, Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 138 329 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: IR-4774 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek* 92) Sacrificed in extreais Macroscopic Observations: Pituitary Liver Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid Pituitary Urinary Bladder -Raised heaorrhagic aass, 1 .1 ca dia. -Soaewhat pale and aottled. -Cortical vacuolation, focal, unilateral, ai Id -Pelvic aineralization, ainiaal P y e litis , acute, aild Vacuolation, conv. tub. epitheiua, aild -Portal aononudear cell in filt r a t e , ainiaal Portal bile duct p rolifera tion , aild Hepatocyte vacuolation, d iffuse, aarked Negalocytosis, aoderate Necrosis, focal, aild -Vascular aineralization, aild -Not exaained, not in plane of section -Adenoaa -Epithelial hyperplasia, siaple, diffuse, aild The following tissues were found to be within noraal lia its : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Uterus, Ovary, Haaaary Gland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4776 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Nacroscopic Observations: Ovary Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Ovary Spleen -Heaorrhagic cyst, 1 ca d ia ., right ovary. -Sinusoidal ectasia, cortex, unilateral, aarked -Not exaained, aissing -Chronic progressive nephropathy, aild -Portal aononudear cell in filt r a t e , ainiaal Hepatocyte vacuolation, a u ltifo c a l, aild Negalocytosis, aild Hyperplastic nodule -Vascular aineralization, aild -Cyst, fo llicu lar, bilateral -Heaosiderosis, aild The following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: 02B1CR0012 001814 Suaaarized STAR Page: 139 ~ 330 S u m m e d Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nueber: 1R-4776 Sex! Fesale Broup: ( 2) FH-3924 100 ppe Fate: (Neek= 105) Terminal Sacrifice Microscopic Observations (continued): The follouing tissues eere found to be uithin norail lia its (continued): Urinary Bladder, Aorta, P itu ita ry , Trachea, Thyroid, Parathyroid, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Hasaary Bland, Uterus. Aniaal Nuaber! 1R-4777 Sex: Feaale Broup: ( 2) FH-3924 100 ppa Fate: (Neek= 82) Found Dead Macroscopic Observations: Pituitary Microscopic Observations: Eye Liver Lung Pancreas Pituitary -Heaorrhagic aass, 0.6 x 0.9 ca. -Not exaained, ai ssi ng -Kepatocyte vacuolation, a u ltifo ca l, aild Negalocytosis, aild -Pneuaonia, acute exudative, local areas, aild Heaorrhage, a u ltifo c a l, aild -Acinar atrophy, local areas, aoderate -Adenoaa The following tissues Mere found to be uithin noraal lia it s : Brain, Spinal Cord, Bone Marrou, Spleen, Kidney, Heart, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Bland, Trachea, Adrenal, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Salivary 61and. Aniaal Nuaber: 1R-4778 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Meek= 105) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Kidney Large Intestine Liver Lung -No visible lesions. -Sinusoidal ectasia, cortex, unilateral, narked -Chronic progressive nephropathy, aild Pelvic aineralization, ainiaal -Neaatodiasis, colon -Portal aononudear cell in filt r a t e , ainiaal Negalocytosis, aild Hepatocyte vacuolation, a u ltifo c a l, aoderate Portal bile duct prolifera tion , aild -Alveolar aacrophages, focal, aild Perivascular aononudear in filt r a t e , focal, aild Species: Rat Project Nuaber: 0281CR0012 001815 Suaaarized STAR Page: 140 331 Suaaarized Single Tabulated Anieal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4778 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Heek= 105) Terainal Sacrifice Hicroscopic Observations (continued): The following tissues were found to be within noraal lia its : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, P itu ita ry , Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4781 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 51) Sacrificed in extreais Hacroscopic Observations: Spleen Liver Large Intestine Hicroscopic Observations: Adrenal Large Intestine Liver Lung Lyaph Node (aesenteric) -Appears saall -Saall pale fo c i, approxiaately 0.2 ca d ia ., in le ft lateral lobe. -Beginning with the rectua, the colon, cecua and ileua are enlarged and fille d with fecal a a te ria l. Section of rectua appears enlarged and thickened. -Sinusoidal ectasia, cortex, ainiaal -Leioayosarcoaa Large well differentiated tuaor. Hoderate nuclear pleoaorphisa. Invades aucosa. -Hegalocytosis, aoderate Necrosis, aultifocal, aild -Alveolar aacrophages, focal, aild -Heaorrhage, aild The following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, P itu ita ry , Trachea, Thyroid, Parathyroid, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4784 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Hacroscopic Observations: Haaaary Gland Liver Hicroscopic Observations: Kidney -Lobular aass, 2 x 1 x 1 ca, in le ft inguinal area. -Multiple pale foci in le ft lateral lobe. -Pelvic aineralization, ainiaal Hetastatic neoplasa Species: Rat Project Nuaber: 0281CR0012 COiXS Suaaarized STAR Page: 141 332 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tvo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4784 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Hicroscopic Observations (continued): Liver Lung Lyaph Node (aesenteric) Haaaary Gland Ovary Parathyroid Pituitary Salivary Gland Spleen -Hepatocyte vacuolation, a u ltifo c a l, aild Hegalocytosis, aild -Vascular aineralization, aild Pneuaonia, in te r s titia l, chronic, a u ltifo c a l, ainiaal Alveolar aacrophages, a u ltifo c a l, aild Perivascular aononudear in filt r a t e , aild -Not exaained, aissing -Adenocarcinoaa Highly cellu la r, cystic areas. Lyaphatic invasion. Hetastatic to capsular surface of one kidney. -Tubular hyperplasia, b ila te ra l, aoderate -Not exaained, not in plane of section -Adenoaa -Sia la d en itis, chronic, aoderate -Heaosiderosis, aild The following tissues Here found to be within noraal lia it s : Brain, Spinal Cord, Bone Karroa, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Trachea, Adrenal, Thyroid, Esophagus, Pancreas, Eye. Aniaal Nuaber: 1R-47B6 Sex: Feaale- Group: ( 2) FH-3924 100 ppa Fate: (Ueek= 102) Sacrificed in extreais Hacroscopic Observations: Pituitary Haaaary Gland Liver Hicroscopic Observations: Adrenal Aorta Kidney Liver -Dark raised heaorrhagic aass, 1 ca dia. -Lobulated aass, 1 ca d ia ., in right a x illa ; sia ila r aass in le ft inguinal area. -Raised aass, 3 x 1.5 ca, in right lateral lobe. -Sinusoidal ectasia, cortex, aoderate -Not exaained, aissing -Pelvic aineralization, ainiaal -Hepatocyte vacuolation, periportal, aoderate Hegalocytosis, aild Hepatocellular carcinosa Nell differentiated, trabecular pattern. Areas of necrosis. Hoderate a itotic activity. Species: Rat Project Nuaber: 0281CR0012 G01S17 Suaaarized STAR Page: 142 333 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FM-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-47B6 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 102) Sacrificed in extreais Microscopic Observations (continued): Lung Haaaary Gland Parathyroid Pituitary Spleen Uterus -Vascular aineralization, aild Alveolar aacrophages, a u ltifo c a l, aild -Adenocarcinoaa Fibroadenoaa -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, aoderate -Cystic glands, aild The folloaing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Narrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Ovary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4789 Sex! Feaale Group: ( 2) FH-3924 100 ppa Fate: (Week= 93) Sacrificed in extreais Macroscopic Observations: Pituitary Liver Microscopic Observations: Adrenal Kidney Liver Lung Lyaph Node (aesenteric) Parathyroid Pituitary Stoaach -Heaorrhagic aass, 0 .7 ca dia. -Scattered saall pale foci in aost lobes. -Cortical vacuolation, focal, unilateral, aild Sinusoidal ectasia, cortex, focal, unilateral, aoderate Nodular hyperplasia, cortex, focal, unilateral, aild -Vacuolation, conv. tub. epitheiua, ainiaal -Hepatocyte vacuolation, periportal, aild Hegalocytosis, aoderate Necrosis, aultifocal, aild -Vascular aineralization, aild Pneuaonia, in te r s titia l, chronic, a u ltifo c a l, aild Alveolar aacrophages, focal, aild -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa -G a s tritis , acute, aoderate The following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, Trachea, Thyroid, Esophagus, Pancreas, Species: Rat Project Nuaber: 0281CR0012 001818 Suaaarized STAR Page: 143 ' 334 Sueearized Single Tabulated flnieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-4789 Sex: Feeale Group: ( 2) FM-3924 100 ppe Fate: <Neek= 93) Sacrificed in extreeis Microscopic Observations (continued): The following tissues were found to be within noreal lis its (continued): Salivary 61 and, Eye. Anieal Nueber: 1R-4790 Sex: Feeale Group: < 2) FM-3924 100 ppe Fate: (Neek= 76) Sacrificed in extreeis Macroscopic Observations: Haeeary 61 and Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Lyeph Node (eesenteric) Haeeary 61 and Ovary Pancreas Parathyroid Pituitary Salivary Gland Spinal Cord Thyroid Trachea Uterus -Large eass, 7 x B x 2.5 ce in right inguinal area! ulcerated, bleeding area on surface. Upon incision, eass found to contain cystic areas. -Not exaeined, eissing -Not exaeined, eissing -Pelvic eineralization, einieal -Hepatocyte vacuolation, eultifocal, eiId Megalocytosis, eild -Vascular eineralization, eild Alveolar eacrophages, focal, eild Perivascular eononudear in filt r a t e , eild -Not exaeined, eissing -Adenocarcinoea, cystic -Not exaeined, eissing -Not exaeined, eissing -Not exaeined, eissing -Not exaeined, eissing -Not exaeined, eissing -Not exaeined, lost during processing -Not exaeined, eissing -Not exaeined, eissing -Not exaeined, eissing The following tissues were found to be within noreal lia it s : Brain, Bone Marrow, Spleen, Heart, Stoeach, Sea11 Intestine, Large Intestine, Urinary Bladder, Aorta, Eye. Species: Rat Project Nueber: 02B1CR0012 001319 Sueearized STAR Page: 144 335 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4791 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Meek- 65) Sacrificed in extreais Macroscopic Observations: Pituitary Microscopic Observations: kidney Liver Lung Pituitary Spleen -Reddish aass, 1 x O.B ca. -Vacuolation, conv. tub. epitbeiua, ainiaal -Hepatocyte vacuolation, periportal, aild Hegalocytosis, aild Hyperplastic nodule -Vascular aineralization, aild Pelvic aineralization, aild -Adenoaa -Heaosiderosis, aild The following tissues were found to be within noraal lia its : Grain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Gladder, Aorta, Uterus, Ovary, Haaaary Gland, Trachea, Adrenal, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-4792 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Macroscopic Observations: Haaaary Gland Microscopic Observations: Adrenal kidney Liver Lung Maaaary Bland Pancreas Pituitary -Mass, 2 ca d ia ., in right a xilla ! aultilobular aass, 4 x 3 x 2 ca, in perineal area. -Sinusoidal ectasia, cortex, aoderate -Pelvic aineralization, aild -Hepatocyte vacuolation, a u ltifocal, aild Hegalocytosis, aild Pigaent, brown, hepatocytes, ainiaal Hyperplastic nodule -Vascular aineralization, aild Alveolar aacrophages, local areas, aoderate -Fibroadenoaa -Acinar atrophy, focal, aild -Adenoaa The following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Gladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 G01S20 Suaaarized STAR Page: 145 336 S u m m e d Single Tabulated Aniial Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniial Nueber: 1R-4794 Sex! Feiale Group: ( 2) FH-3924 100 ppi Fate: (Heek= 105) Teriinal Sacrifice Macroscopic Observations: Pituitary Microscopic Observations: Kidney Liver Parathyroid Pituitary Uterus -Heiorrhagic eass, 0.3 ce dia. -Pelvic in e ra liza tio n , larked -Nepatocyte vacuolation, a u ltifo c a l, ai Id Cystoid degeneration, local areas, aild Hepatocyte alteration, vacuolated, a u ltifo c a l, i id Megalocytosis, eoderate Hepatocyte alteration, basophilic, focal, ild -Not exaiined, not in plane of section -Adenoia -Cystic glands, larked The following tissues ere found to be within norial l i i i t s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Lung, Stoiach, Stall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Hauary Gland, Trachea, Adrenal, Thyroid, Esophagus, Lyiph Node (eesenteric), Pancreas, Salivary Gland, Eye. Aniial Nuiber: 1R-4795 Sex: Fetale Group: ( 2) FH-3924 100 ppi Fate: (Heek= 105) Teriinal Sacrifice Macroscopic Observations: Liver Hauary Gland Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Hauary 61 and -Raised pale lass, 2 c i, d ia ., in le ft lateral lobe. -Necrotic, in fla u e d a ilk cysts, neck and perineal areas; lass, 3 x 2 c i, inguinal area. -Cortical vacuolation, focal, lild Sinusoidal ectasia, cortex, iiId -Not exaiined, lissing -Pelvic lineralization, lild -Portal bile duct p ro life ra tio n , lild Megalocytosis, lild Hepatocellular adenoia -Vascular lin e ra lizatio n , lild Alveolar tacrophages, local areas, aoderate Heiorrhage, local areas, lild -Adenocarcinoia, cystic Adenocarcinoia Species: Rat Project Nuiber: 0281CR0012 001821 Suuarized STAR Page: 146 337 Sueaarized Single Tabulated Anieal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-4795 Sex'. Feeale Group: ( 2) FH-3924 100 ppe Fate: (Neek= 105) Tereinal Sacrifice Microscopic Observations (continued): Ovary Spleen Uterus ~Cyst, follicular -Heeosiderosis, aoderate -Cystic glands, eild The following tissues were found to be within noreal lie it s : Brain, Spinal Cord, Bone Harrow, Heart, Stoeach, Seal! Intestine, Large Intestine, Urinary Bladder, Aorta, P itu ita ry , Trachea, Thyroid, Parathyroid, Lyiph Node (eesenteric), Pancreas, Salivary 61 and, Eye. Anieal Nueber: 1R-4796 Sex: Feeale Group: ( 2) FM-3924 100 ppe Fate! (Heek= 105) Tereinal Sacrifice Hacroscopic Observations: Microscopic Observations: Kidney Liver Lung -No visib le lesions. / -Pelvic aineralization, ainiaal -Hepatocyte vacuolation, e u ltifo c a l, aoderate Megalocytosis, aoderate -Vascular aineralization, eild Perivascular eononudear in filt r a t e , eild The following tissues were found to be within noreal lie it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoeach, Seal1 Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Naeeary Gland, P itu ita ry , Trachea, Adrenal, Thyroid, Parathyroid, Esophagus, Lyeph Node (eesenteric), Pancreas, Salivary Gland, Eye. Anieal Nueber: 1R-4797 Sex: Feeale 6roup: ( 2) FM-3924 100 ppe Fate: (Week? 105) Tereinal Sacrifice Macroscopic Observations: Liver Microscopic Observations: Adrenal Kidney Liver Lung Lyeph Node (eesenteric) Pituitary Thyroid -Appears pale and eottled. -Sinusoidal ectasia, cortex, aoderate -Pelvic aineralization, ainiaal -Hepatocyte vacuolation, d iffuse, aoderate Megalocytosis, aarked -Vascular eineralization, eild Perivascular eononudear in filt r a t e , eild -P o ly a rte ritis , aoderate -Adenoea -Hyperplasia, C c e ll, focal, eild Species: Rat Project Nueber: 0281CR0012 001323 Sueearized STAR Page: 147 338 I Suaaarized Single Tabulited Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4797 Sex! Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Microscopic Observations (continued): The following tissues were found to be within noraal H a lt s : Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Naaaary Bland, Trachea, Parathyroid, Esophagus, Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-4798 Sex: Feaale Group: I 2) FH-3924 100 ppa Fate: (Ueek= 105) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Liver Lung Lyaph Node (aesenteric) Naaaary Gland Parathyroid Saall Intestine -No visible lesions. -Portal aononudear cell in filt r a t e , aild Portal bile duct prolifera tion , aild Hepatocyte vacuolation, a u ltifo c a l, aild Megalocytosis, aoderate -Vascular aineralization, aild Alveolar aacrophages, focal, aild Perivascular aononudear in filtr a te , aild Heaorrhage, a u ltifo c a l, aild -Heaorrhage, aoderate -Not exaained, aissing -Not exaained, not in plane of section -Ulcer The following tissues ere found to be within noraal lia its : Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, P itu ita ry , Trachea, Adrenal, Thyroid, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: IB-4799 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Heek= 70) Sacrificed in extreais Macroscopic Observations: Pituitary Microscopic Observations: Adrenal Kidney Liver Lung -Enlarged, 0.8 ca dia. -Cortical vacuolation, focal, aild -Pelvic aineralization, ainiaal -Hepatocyte vacuolation, periportal, aoderate Megalocytosis, aild -Heaorrhage, a u ltifo c a l, aild Perivascular aononudear in filt r a t e , aild Species: Rat Project Nuaber: 02B1CR0012 0 0 1 ooro* a Suaaarized STAR Page: 14B 339 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4799 Sex: Feaale Group: ( 2) FN-3924 100 ppa Fate: (Week= 70) Sacrificed in extreais Microscopic Observations (continued): Lyaph Node (aesenteric) Parathyroid Pituitary Salivary Gland Urinary Bladder -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa -Not exaained, aissing -Not exaained, aissing The following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Uterus, Ovary, Haaaary Gland, Trachea, Thyroid, Esophagus, Pancreas, Eye. Aniaal Nuaber: 1R-4800 Sex: Feaale Group: ( 2) FN-3924 100 ppa Fate: (Week= 105) Terainal Sacrifice Macroscopic Observations: Skin Haaaary 61 and Microscopic Observations: Adrenal Kidney Liver Lung Haaaary Gland Ovary Parathyroid Pituitary -Hair loss on abdoaen. -Mass in right a x illa , 1 ca d ia .; aass in le ft a x illa , 3 x 2 ca. -Sinusoidal ectasia, cortex, unilateral, narked -Chronic progressive nephropathy, aild Pelvic aineralization, aild Hyperplasia, pelvic epitheliua, aild -Hegalocytosis, aild -Pneuaonia, in te r s titia l, chronic, a u ltifocal, aild -Adenocarcinoaa Adenocarcinoaa -Tubular hyperplasia, b ila te ra l, aoderate -Not exaained, not in plane of section -Adenoaa The following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Species: Rat Project Nuaber: 02B1CR0012 001824 Suaaarized STAR Page: 149 340 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4801 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Week* 94) Sacrificed in extreais Macroscopic Observations: Pituitary Microscopic Observations: Liver Lung Lyaph Node (aesenteric) Pituitary -Raised red aass, 1 ca dia. -Hpatocyte vacuolation, local areas, aoderate Megalocytosis, aild -Vascular aineralization, aild Alveolar aacrophages, local areas, aoderate Heaorrhage, a u ltifo c a l, aild -Not exaained, aissing -Adenoaa The following tissues were found to be within noraal lia it s : Grain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Gladder, Aorta, Uterus, Ovary, Maaaary Bland, Trachea, Adrenal, Thyroid, Parathyroid, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4802 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: <Week= 105) Terainal Sacrifice Macroscopic Observations: Pituitary Liver Microscopic Observations: Adrenal Eye Ki.dney Liver Lung Haasary Gland Pituitary Spleen Uterus -Heaorrhagic aass, 0 .7 ca dia. -Raised pale circular lesion, 0 .7 ca d ia ., in aedian lobe; aultiple raised pale lesions, 0.5 - 1 ca, in le ft lateral lobe. -Sinusoidal ectasia, cortex, aild -Retinal atrophy, aultifocal, aild -Pelvic aineralization, aild -Portal aononudear cell in filtr a te , aild Portal bile duct prolifera tion, aild Hepatocyte vacuolation, a u ltifo c a l, aild Megalocytosis, aild Hepatocellular adenoaa Hepatocellular adenoaa -Vascular aineralization, aild Perivascular aononudear in filt r a t e , aild -6alactocele -Adenoaa -Heaosiderosis, aoderate -Cystic glands, aoderate The following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: 0281CR0012 001325 Suaaarized STAR Page: 150 341 Suaaarized Single Tabulated Aniaal Report (continued)-' Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-4802 Sex: Fesale Group: < 2) FH-3924 100 ppe Fate: (Neek= 105) Tersinal Sacrifice Microscopic Observations (continued): The following tissues ere found to be within noreal lie its (continued): Urinary Bladder, Aorta, Ovary, Trachea, Thyroid, Parathyroid, Esophagus, Lyeph Node (aesenteric), Pancreas, Salivary Bland. Aniaal Nuaber: 1R-4803 Sex! Fesale Group: ( 2) FH-3924 100 ppa Fate: !Heek= 105) Terainal Sacrifice Macroscopic Observations: Microscopic Observations: Adrenal Kidney Liver Lung Ovary Uterus -No visible lesions. -Sinusoidal ectasia, cortex, ainiaal -Chronic progressive nephropathy, ainiaal -Hepatocyte vacuolation, a u ltifo ca l, aild Cystoid degeneration, a u ltifo c a l, aild Hepatocyte alteration, vacuolated, focal, aild Hegalocytosis, aild -Pneuaonia, in te r s titia l, chronic, local areas, aild Alveolar aacrophages, a u ltifo c a l, aild Perivascular aononuclear in filt r a t e , aild -Tubular hyperplasia, b ila te ra l, aild -Cystic glands, aild The following tissues ere found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Naaaary Gland, P itu ita ry , Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61 and, Eye. Aniaal Nuaber: 1R-4804 Sex'. Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal Sacrifice Macroscopic Observations: Soft Tissues (leg) Pituitary Liver Microscopic Observations: Adrenal -L e ft hind foot swollen. -Heaorrhagic aass, 0.8 ca dia. -Multiple pale foci in a ll lobes; large pale aass, 4 x 3 x 2 ca, in le ft lateral lobe. -Sinusoidal ectasia, cortex, unilateral, aarked Species: Rat Project Nuaber: 0281CR0012 00182S Suaaarized STAR Page: 151 342 S u m m e d Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tea Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nueber: 1R-4B04 Sex: Feeale Group: ( 2) FH-3924 100 ppe Fate: (Neek= 105) Tereinal Sacrifice Microscopic Observations (continued): Bone Kidney Liver Lung Pituitary Spleen Uterus -A rth ritis , synovitis; joints, hindleg, unilateral, soderete -Chronic progressive nephropathy, ainiaal Pelvic aineralization, aild Pigaent, conv. tub. epitheliua, broen, aild -Portal aononudear cell in filtr a te , aild Portal bile duct prolifera tion , aild Hepatocyte vacuolation, a u ltifo c a l, aild Hegalocytosis, aild Hepatocellular carcinoaa Heaatopoiesis, extraaedullary, aild -Vascular aineralization, aild Perivascular aononudear in filt r a t e , aild Heaorrhage, local areas, aoderate -Adenoaa -Heaosiderosis, aild -Cystic glands, aoderate The fallowing tissues sere found to be within noraal li a i t s : Brain, Spinal Cord, Bone Harroa, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Haaaary Gland, Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenterid, Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-4B05 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Week- 67) Found Dead Macroscopic Observations: Pituitary Liver Microscopic Observations: Eye Kidney Liver Lung Lyaph Node (aesenteric) Ovary Parathyroid -Heaorrhagic ass, 1.2 x 0 .7 ca. -Pale -Not exaained, aissing -Pelvic aineralization, ainiaal Vacuolation, conv. tub. epitheiua, aoderate -Hepatocyte vacuolation, periportal, aoderate Hegalocytosis, aild -Vascular aineralization, aild Alveolar aacrophages, aoderate Heaorrhage, local areas, aild -Not exaained, aissing -Tubular hyperplasia, b ila te ra l, aild -Not exaained, not in plane of section Species: Rat Project Nuaber: 02B1CR0012 001827 Suaaarized STAR Page: 152 343 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Too Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4805 Sex: Feaale 6roup: I 2) FH-3924 100 ppa Fate: (Meek- B7) Found Dead Microscopic Observations (continued): Pituitary Saall Intestine Spleen Urinary Bladder Uterus -Adenoaa -Mithin noraal lia its Fewer than protocol nuaber -Heaosiderosis, aarked -Not exaained, aissing -Exudate, luaenal, aoderate The -following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Stoaach, Large Intestine, Aorta, Maaaary Gland, Trachea, Adrenal, Thyroid, Esophagus, Pancreas, Salivary Bland, Heart. Aniaal Nuaber: 1R-487 Sex: Feaale Group*. ( 2) FH-3924 100 ppa Fate: (Week- 79) Sacrificed in extreais Macroscopic Observations: Skin Liver Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Maaaary Bland Parathyroid Spleen Thyroid Trachea -Ulcerated necrotic aass, 5 x 3.5 x 2 c i, right axilla. -Saall pale lesion, 0.4 ca d ia ., right anterior lobe. -Sinusoidal ectasia, cortex, aoderate -Not exaained, aissing -Pelvic aineralization, ainiaal -Megalocytosis, aild Hyperplastic nodule -Vascular aineralization, aild Pneuaonia, in te r s titia l, chronic, a u ltifo c a l, aild Alveolar aacrophages, a u ltifo c a l, aild -Adenocarcinoaa, ductal -Not exaained, aissing -Heaatopoiesis, extraaedullary, increased, aoderate -Not exaained, aissing -Not exaained, aissing The following tissues were found to be within noraal li a i t s : Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, P itu ita ry , Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 0281CR0012 6 0 1 328 Suaaarized STAR Page: 153 344 Suatarized Single Tabulated flnieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-480B Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Week: 105) Terainal S a crific e Macroscopic Observations: P itu ita ry Haaaary Gland Microscopic Observations: Aorta Kidney Liver Lung Lyaph Node (aesenteric) Haaaary 61 and Ovary P itu ita ry Urinary Bladder Uterus -Raised heaorrhagic aass, 1 ca dia. -Nodular aass, 4 x 2 ca, le f t side. -Not exaained, aissing -Chronic progressive nephropathy, a ild P elvic ain eralizatio n , aarked -Portal aononudear c e ll in filt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolation, d iffu se, aoderate Nepatocyte alteration , vacuolated, focal, aild Negalocytosis, a ild -Vascular ain eralization , a ild Heaorrhage, local areas, aoderate -Not exaained, aissing -Lobular hyperplasia -Tubular hyperplasia, b ila te ra l, a ild -Adenoaa -E p ith elial hyperplasia, siaple, focal, a ild -C ystic glands, aoderate The follouing tissues Mere found to be within noraal lia it s : Brain, Spinal Cord, Bone Marroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Trachea, Adrenal, Thyroid, Parathyroid, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4B09 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Week^ 105) Terainal S a crifice Macroscopic Observations: Liver Maaaary Gland Microscopic Observations: Adrenal Kidney Liver -Several pale lesions in a ll lobes. -Nodular aass, 5.5 x 5 x 2 ca, throat area; nodular aass, 6.5 x 5.5 x 2.5 ca, le f t inguinal area. -Sinusoidal ectasia, cortex, aarked -Chronic progressive nephropathy, a ild Pelvic aineralization, ainiaal -Portal aononudear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Negalocytosis, aoderate Hepatocellular adenoaa Hyperplastic nodule, a u ltip le Vacuolation of hepatocytes in soae nodules. Species: Rat Project Nuaber: 0281CR0012 00i29 Suaaarized STAR Page: 154 345 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4B09 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal S a crific e Microscopic Observations (continued): Lung Naaaary Gland Ovary P itu ita ry Uterus -Alveolar aacrophages, a u ltifo c a l, a ild Perivascular aononudear in filt r a t e , a ild -Fibroadenoaa Large areas of necrosis in tuaor. -Tubular hyperplasia, b ila te ra l, a ild -Adenoaa -C ystic glands, aoderate The fallowing tissues Here found to be within noraal lia it s : Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Trachea, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4B10 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal S a crifice Macroscopic Observations: P itu ita ry Microscopic Observations: Adrenal Kidney Liver Lung Lyaph Node (aesenteric) Parathyroid P itu ita ry -Raised dark aass, 0.8 ca dia. -Sinusoidal ectasia, cortex, aoderate -Chronic progressive nephropathy, ainiaal Pelvic aineralization, ainiaal -Portal aononudear c e ll in f ilt r a t e , ainiaal Hepatocyte vacuolation, a u ltifo c a l, a ild Hegalocytosis, aarked -Vascular ain eralization , a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, aild Heaorrhage, local areas, a ild -Not exaained, aissing -Sinusoidal ectasia, aoderate -Adenoaa The following tissues Here found to be within noraal lia it s : Brain, Spinal Cord, Bone MarroH, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Naaaary Gland, Trachea, Thyroid, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 001830 Suaaarized STAR Page: 155 346 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FM-3924: Teo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anisal Nuaber: 1R-48U Sex: Feaale Group: ( 2) FN-3924 100 ppa Fate: (Heek= 105) Terainal S a crifice Macroscopic Observations: Eye Liver Microscopic Observations: Adrenal Esophagus Eye Kidney Liver Lung Ovary Spleen Uterus -Opacity, le f t eye. -Pale and Bottled. -Sinusoidal ectasia, cortex, a ild Medullary c e ll hyperplasia, u n ila te ra l, a ild Pheochroaocytoaa, benign, u n ila te ral -Not exaained, sissing -Retinal atrophy, u n ila te ra l, aoderate Cataract, unilateral -Chronic progressive nephropathy, a ild P elvic ain e ra liza tio n , aoderate -Portal aonanuclear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolati on, p erip ortal, aoderate Negalocytosis, aoderate Pigaent, broun, hepatocytes, a ild -Vascular ain eralization , a ild -Tubular adenoaa, u n ila te ral -Heaosiderosis, a ild -Cystic glands, a ild The folloHing tissues ere found to be Mithin noraal lia it s : Brain, Spinal Cord, Bone Marrou, Heart, Stoaach , Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Haaaary Gland, P itu ita ry , Trachea, Thyroid, Parathyroid, Pancreas, Salivary 61and, Lyaph Node (aesenteric). Aniaal Nuaber: 1R-4812 Sex: Feaale Group: I 2) FM-3924 100 ppa Fate: (Neek= 105) Terainal S a crifice Macroscopic Observations: Skin P itu ita ry Microscopic Observations: Adrenal Kidney Liver Lung Ovary Parathyroid -Hair loss, head to neck. -Raised heaorrhagic aass, 1 ca dia. -Sinusoidal ectasia, cortex, aild -Pelvic aineralization, ainiaal -Hepatocyte vacuolation, a u ltifo c a l, a ild Negalocytosis, aoderate -Vascular ain eralization , a ild Alveolar aacrophages, local areas, a ild -Tubular hyperplasia, u n ila te ra l, a ild -Mot exaained, not in plane of section Species: Rat Project Nueber: 02B1CR0012 001831 Suaaarized STAR Page: 156 347 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4812 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal S a crifice Microscopic Observations (continued): P itu ita ry Spleen Uterus -Adenoaa -Heaosiderosis, aoderate -Cystic glands, ainiaal The follotting tissues Mere found to be within noraal lia it s : Brain, Spinal Cord, Bone Marron, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Haaaary Bland, Trachea, Thyroid, Esophagus, Lyaph Mode (aesenteric), Pancreas, Salivary Bland, Eye, Skin. Aniaal Nuaber: 1R-4813 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal S a crifice Hacroscopic Observations: Liver Microscopic Observations: Adrenal Eye Liver Lung Ovary Parathyroid P itu ita ry Spleen -Pale and aottled. -Cortical vacuolation, local areas, a ild -Retinal atrophy, aarked -Portal aononudear c e ll in filt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolation, a u ltifo c a l, a ild Hepatocyte alteration , vacuolated, a u ltifo c a l, aild Hegalocytosis, a ild -Vascular ain eralization , a ild -Tubular adenoaa, u n ilateral -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, a ild The following tissues sere found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrou, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Haaaary Gland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and. Aniaal Nuaber: 1R-4814 Sex: Feaale Group*. ( 2) FH-3924 100 ppa Fate: (Keeks 105) Terainal S a crific e Hacroscopic Observations: Microscopic Observations: Adrenal -No v is ib le lesions. -Sinusoidal ectasia, cortex, a ild Species: Rat Project Nuaber: 0261CR0012 001832 Suaaarized STAR Page: 157 348 Suaaarized Single Tabulated Aniaal Report (continued) ' Individual Microscopic end Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-4814 Sex: Feeale Group: ( 2) FH-3924 100 ppe Fate: (Neek 10S) Terainal S a crific e Microscopic Observations (continued): Kidney Liver Lung Parathyroid P itu ita ry Salivary Bland Spleen Thyroid -Chronic progressive nephropathy, a ild Pelvic Bineraiization, a ild -Portal aononudear c e ll in filt r a t e , a ild Portal b ile duct p ro life ra tio n , ainiaal Hepatocyte vacuala t i on, a u ltifo c a l, a ild Hegalocytosis, a ild -Vascular Bineraiization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, aild Alveolar aacrophages, local areas, aoderate -Not exaained, not in plane of section -Adenoaa -Not exaained, aissing -Heaosiderosis, a ild -Not exaained, not in plane of section The follou in g tissues uere found to be u ith in noraal lia it s : Grain, Spinal Cord, Gone Harrou, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Gladder, Aorta, Uterus, Ovary, Haasary Bland, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-4B15 Sex: Feaale Group: < 2) FM-3924 100 ppa Fate: (Neek= 105) Terainal S a crifice Macroscopic Observations: Adrenal Uterus Microscopic Observations: Adrenal Heart Kidney Liver Lung -Left adrenal enlarged. -C ystic lesion, 1.5 ca d ia ., le f t horn. -Sinusoidal ectasia, cortex, unilateral, aarked C ortical atrophy, u n ila te ra l, aoderate -M yocarditis, chronic nonsuppurative, aultifocal, ainiaal -Chronic progressive nephropathy, aoderate Pelvic aineralization, aild P o ly a rte ritis , c o rtic a l, aoderate -Portal aononudear c e ll in f ilt r a t e , ain iaal Hepatocyte vacuolation, a u ltifo c a l, a ild Hegalocytosis, ainiaal -Vascular ain eralization , a ild Alveolar aacrophages, a u ltifo c a l, a ild Perivascular aononudear in filt r a t e , a ild Species: Rat Project Nuaber: 0281CR0012 001833 Suaaarized STAR Page: 158 349 S u m m e d Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Too Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4815 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Week- 105) Terainal S a crifice Microscopic Observations (continued): Lyaph Mode (aesenteric) Ovary Pancreas P itu ita ry Uterus -Polyarteritis, aild -Tubular hyperplasia, b ila te ra l, aoderate -Acinar atrophy, a ild -Pigaent, brown, pars d is t a lis , aoderate -Polyp The following tissues were found to be within noraal U n its : Brain, Spinal Cord, Bone Harrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Haaaary Gland, Trachea, Thyroid, Parathyroid, Esophagus, Salivary Gland, Eye. Aniaal Nuaber: 1R-4G17 Sex! Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Ueek= 105) Terainal S a crifice Macroscopic Observations: Skin P itu ita ry Liver Microscopic Observations: Adrenal Heart Kidney Liver Lung Lyaph Node (aesenteric) Haaaary 61and Ovary Parathyroid P itu ita ry Skin -Raised ulcerated lesion , le f t rear footpad. -Raised nass, 0.7 ca dia. -Pale raised circu la r aass, 2 ca d ia ., aedian lobe. -C ortical vacuolation, local areas, aild Pigaent, brown, c o rtic a l, a ild -M yocarditis, chronic nonsuppurative, au ltifoca l, ainiaal -Chronic progressive nephropathy, a ild P elvic a in e ra liza tio n , aoderate -Portal aononudear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolation, d iffu se, aarked Cystoid degeneration, focal, a ild Hepatocellular carcinoaa -Vascular aineralization, a ild Perivascular aononudear in f ilt r a t e , a ild -Not exaained, aissing -Galactocele -Cyst, bilateral -Adenoaa -Adenoaa -Pododeraatitis, ulcerative, hindleg, aarked The following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Narrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: 0281CR0012 001334 Suaaarized STAR Page: 159 350 Suaaarized Single Tabulated Aniaal Report (continued)' Individual Nacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4B17 Sex: Feaale Broup: ( 2) FH-3924 100 ppa Fate: (Neek= 105) Terainal S a crifice Hicroscopic Observations (continued): The following tissues ere found to be within noraal l i a i t s (continued): Urinary Bladder, Aorta, Uterus, Trachea, Thyroid, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-481B Sex: Feaale 6roup`. ( 2) FH-3924 100 ppa Fate: (Neek= 104) Sacrificed in extreais Nacroscopic Observations: P itu ita ry Adrenal Kidney Hicroscopic Observations: Adrenal Kidney Liver Lung Ovary Parathyroid P itu ita ry Spleen Stoaach Thyroid Uterus -Raised aass, 0.8 ca dia. -Right adrenal appears enlarged. -Pale, pitted and enlarged. -C o rtica l vacuolation, operate Sinusoidal ectasia, cortex, aoderate Cortical atrophy, u n ila te ra l, aoderate -Chronic progressive nephropathy, narked Pelvic aineralization, ainiaal -Hepatocyte vacuolation, d iffu se, ain iaal -Vascular ain eralization , a ild Alveolar aacrophages, focal, a in iaal Perivascular aononuclear in f ilt r a t e , ain iaal -Tubular hyperplasia, b ila te ra l, a ild -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, a ild -G a s tritis , acute, aoderate -Hyperplasia, C c e ll, local areas, aoderate C c e ll carcinoaa -Cystic glands, aoderate The following tissues ere found to be within noraal lia it s : Brain, Spinal Cord, Bone Narro, Heart, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Haaaary Gland, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4819 Sex: Feaale 6roup: ( 2) FH-3924 100 ppa Fate: (Heek= 105) Terainal S a crifice Nacroscopic Observations: P itu ita ry Naaaary 61and Liver -Dark lesion, 0.3 ca dia. -Lobular aass, 3 x 1.5 x 1 ca, le f t inguinal area. -Pale circ u la r lesion, 1.4 ca d ia ., aedian lobe. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page*. ISO 351 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FH-3924: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4819 Sex: Feeale Group: ( 2) FH-3924 100 ppa Fate: (Week= 105) T e riin al S a crifice Microscopic Observations (continued): Adrenal Heart Kidney Liver Lung Haaaary Gland Ovary Parathyroid P itu ita ry Thyroid Uterus -C ortical vacuolation, local areas, e ild Sinusoidal ectasia, cortex, aiId -Myocardial fib ro s is , local areas, eoderate -Pelvic aineralization, ainiaal -Portal aononudear c e ll in filt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Megalocytosis, aoderate Hyperplastic nodule -Perivascular aononudear in filt r a t e , a ild -Adenocarcinoaa -Tubular adenoaa, b ila te ra l -Not exaained, not in plane of section -Adenoaa -C c e ll carcinoaa -Cystic glands The folloNing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4820 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Heek- B0) Found Dead Macroscopic Observations: Skin Liver Stoaach Microscopic Observations: Adrenal Aorta Eye Heart Kidney Large Intestine Liver -Large ulcerated aass, 8 x 4.5 x 5 ca, surrounding le f t hind leg. -Mottled, enlarged -Fu ll of blackish, yellowish flu id . -Malignant lyaphoaa, h is tio c y tic -Not exaained, aissing -Not exaained, aissing -Malignant lyaphoaa, h is tio c y tic -Pelvic aineralization, aild Malignant lyaphoaa, h is tio c y tic Protein resorption droplets, aoderate -Not exaained, aissing -Malignant lyaphoaa, h is tio c y tic Extensive nodular and d iffu se p ro life ra tio n with vascular involveaent. Species: Rat Project Nuaber: 0281CR0012 001S3G Suaaarized STAR Page: 161 352 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FH-3924: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4B20 Sex: Feaale Group: ( 2) FH-3924 100 ppa Fate: (Neek= BO) Found Dead Hicroscopic Observations (continued): Lung Lyaph Node (aesenteric) Hasaary Gland Pancreas Saall Intestine Soft Tissues (leg) Spleen Stoaach Urinary Bladder -Vascular ain eralization , a ild Halignant lyaphoaa, h is tio c y tic -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Halignant lyaphoaa, h is tio c y tic Hass involving hindleg aas aalignant lyaphoaa, necrotic and ulcerated. -Heaosiderosis, aoderate -Necrosis, aucosal, local areas, aoderate -Not exaained, aissing The folloN ing tissues uere found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Uterus, Ovary, P itu ita ry , Trachea, Thyroid, Parathyroid, Esophagus, Salivary 61and. 001337 Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 162 353