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Pathology and Toxlcotogy RHcar Laboratories, Inc. Building 270-3S -05, 3M C enter St. Paul, M innesota 5 5 1 44 -1 0 0 0 AR m -0 4 3 1 TWO YEAR ORAL (DIET) TOXICITY / CARCINOGENICITY STUDY OF FLUOROCHEMICAL FC-143 IN RATS (RIKER Experiment No . 0281CR0Q12) Volume 1 of 4 Conducted During April, 1981 - May, 1983 RIKER LABORATORIES, Inc. / 3M Company St . Paul, Minnesota 55149-1000 U.S.A. 0003S3 STUDY REPORT AMENDMENT NO. 1 EFFECTIVE DATE: NOVEMBER 2, 1987 Study Title: Two Year Oral (Diet) Toxicity/Oncogenicity Study of Fluorochemical FC-143 in Rats RIKER Experiment No.: 0281CR0012 The Table of Contents and the titles for individual clinical chemistry values for the males (Table 14; pages 66-70) and females (Table 15; pages 73-77) should read "Individual Plasma Chemistry Values" Reason: This was an inadvertent typographical error only and does not change the interpretation of the clinical data. Approval: L.J. Sibinski Study Director " / -/S '? Date 000354 TOO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FC-143 IN RATS (RIKER Experiment No. 0281CR0012) TABLE OF CONTENTS PAGE(s) REPORT SUMMARY ..................................................... 1 INTRODUCTION ....................................................... 3 MATERIALS AND METHODS ............................................ 4 R E S U L T S ........................................................... 10 D I S C U S S I O N ......................................................... 19 CONCLUSIONS ....................................................... 25 PRINCIPAL PERSONNEL LIST .......................................... 6 SIGNATURE P A G E ..................................................... 27 REFERENCES.................. ' .................................... 28 REPORT TABLES ..................................................... 29-92 TABLE 1 -Analysis of FC-143 in the D i e t .................... 29 TABLE 2 -Summary of Mean Body Weights M a l e s ............................................ 30 TABLE 3 -Summary of Mean Body Weights F e m a l e s .......................................... 32 TABLE 4 - Summary of Mean Feed Consumption Per Kilogram Body Weight - Males .................. 34 TABLE 5 - Summary of Mean Feed Consumption Per Kilogram Body Weight - Females ................ 36 TABLE 6 - Summary of Mean Absolute Feed Consumption M a l e s ............................................ 38 TABLE 7 - Summary of Mean Absolute Feed Consumption F e m a l e s .......................................... 40 TABLE 8 - Estimated Mean FC-143 Consumption In Milligrams Per Kilogram Per Day .................. 42 C003S5 TABLE OF CONTENTS - Continued PAGE(s) TABLE 9 -Mortality D a t a ..................................... 44 TABLE 10 -Summary of Clinical S i g n s ......................... 46 TABLE 11 -Summary of Ophthalmologic Changes ................. 48 TABLE 12 -Mean and Individual Hemogram Values - Males . . . . 50 TABLE 13 -Mean and Individual Hemogram Values - Females . . . 57 TABLE 14 -Mean and Individual Serum Chemistry Values M a l e s ............................................ 64 TABLE 15 - Mean and Individual Serum Chemistry Values F e m a l e s .......................................... 71 TABLE 16 -Urinalysis V a l u e s ................................. 78 TABLE 17 -Individual Organ Weight, And Absolute Mean Organ Weights, Mean Organ Relative Percent To Whole Body Weight, And Organ To Brain Weight Ratios At One Y e a r .......................................... 1 81 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 ........................................ 86 TABLE 19 - Summary of Major Microscopic Findings - NeoplasticLesions .................... 91 TABLE 20 - Summary of Major Microscopic Findings -Non-NeoplasticLesions .................. 92 REPORT FIGURES ..................................................... 93-96 FIGURE 1 - Mean Body Weights - M a l e s ........................ 93 FIGURE 2 - Mean Body Weights - F e m a l e s ...................... 94 FIGURE 3 - Mean Feed Consumption Per Kilogram Mean Body Weight - Males ................ 95 FIGURE 4 - Mean Feed Consumption Per Kilogram Mean Body Weight - Females .............. 96 C003S6 TABLE OF CONTENTS - Continued PAGE(s) APPE ND IX........................................................... 97-1223 ITEM A - Air Monitoring of Arrimal R o o m s ..................... 98 ITEM B - Diet Analytical Data S h e e t s ......................... 103 ITEM C - Acceptable Ranges for Clinical Pathology Parameters ................................ 116 ITEM D - Histopathologic Examination and PathologyReport by Dr. Robert G. Geil, External Consultant Veterinary Pathologist .............................. 119 ITEM E - Biostatistical Analysis Procedures ................. 407 ITEM F - Summary of Mean Body Weights and Individual Animal Body Weight and Feed Jar Weight D a t a .................411 ITEM G - Ophthalmoscopic Evaluation and Data by ^ Dr. Stephen I. Bistner, External Consultant Veterinary Ophthalmologist ......................... 1203 ITEM H - Copy of the Study Protocol with Amendments ......... 1206 ITEM I- Quality Assurance Unit Statement.....................1214 ITEM J - Chemical Analyses of FC-143 and Stability Analyses of FC-143 in D i e t ..........................1215 G003S7 TWO YEAR ORAL (DIET) TOXICITY/ONCOGENICITY STUDY OF FLUOROCARBON FC-143 IN RATS (RIKER Experiment No. 0281CR0012) REPORT SUMMARY The purpose of this study was to assess the potential toxicity and oncogenicity of FC-143 (ammonium perf1uoroalkyl carboxyl ate) mixed in the diet and fed to 50 rats per sex per group for two years. An interim sacrifice and evaluation was performed at one year on 15 additional rats per sex from the control and high-dose groups. A total of 360 Sprague-Dawley male and female rats were assigned to three experimental groups. The FC-143-treated groups were fed diets containing either 300 or 30 ppm of FC-143 for two years, while a control group received only untreated feed. In-life observations performed during the course of the study included: daily observations for abnormal signs; periodic physical examinations; body weight and feed consumption; ophthalmoscopic examinations; and clinical pathology including hematology, clinical chemistry and urinalysis. Macroscopic postmortem examinations were performed on all animals that died or were terminated prior to the end of the scheduled dosing. Selected organ weights were obtained from all of the rats necropsied at 1 year as well as from 15 rats/sex/group, randomly selected from the control and both FC-143-treated groups, at the termination of the study. Selected tissue specimens were harvested from each animal at necropsy, and preserved for future histopathologic examination. Microscopic evaluation was performed on all tissues saved from all of the control and high-dose rats, while a similar evaluation was performed on a modified list of tissues obtained from the low-dose animals. The major in-life findings associated with FC-143 administration consisted of: a dose-related decrease in mean body weight and a treatment-related 1. C003S8 increase in feed consumption per kilogram of mean body weight in males; and a slight treatment-related increase in the incidence of ataxia in the females. There was no increase in mortality in the high-dose treatment group when compared to similar values for the control population. FC-143 related hematologic changes in both treated groups consisted of a decrease in red blood cell counts, hemoglobin concentration and hematocrit values at various times throughout the study. Generally, these hematology parameters remained within the acceptable ranges for the rat. The primary FC-143 associated changes were found in the liver. These alterations were characterized by increased liver weights, hepatomegalocytosis with vacuolation of the cytoplasm, and some evidence of hepatocellular degeneration with occasional signs of necrosis. These liver changes were found early in the study and showed very little evidence of progression at the end of two years. The incidence of almost all neoplasms in this study was relatively low, and the types and incidence of neoplasms were generally not different from those commonly found in geriatric Sprague-Dawley rats. Hepatocellular tumors were very slightly increased in the high-dose male rats. The other neoplasms in this study were associated with endocrine and/or endocrinesensitive organs. The increased incidence of mammary or testicular tumors in the high- and low-dose groups was not statistically significant and/or was similar to the spontaneous incidence reported for Sprague-Dawley rats. Under the conditions of this study and based on tumor incidence, types of tumors, time of tumor appearance, and the survival rate at two years, FC-143 is not considered to be carcinogenic in the rat. 2. 0003S9 TWO YEAR ORAL (DIET) TOXICITY - CARCINOGENICITY STUDY OF FLUOROCHEHICAL FC-143 IN RATS INTRODUCTION This study was designed to evaluate the chronic toxicologic and carcinogenic potential of FC-143, an industrial grade of ammonium perfluoroalkyl carboxyl ate, 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 5, 1983. A copy of the study protocol with amendments is contained in this report as Appendix Item H. L 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 FC-143 treatment while the results relating to the FM-3924 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. 3. 000390 MATERIALS AND METHODS p Test System: Three-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 three groups. The control and high-dose groups each contained 65 males and 65 females, whereas the low-dose group contained 50 male and 50 female rats. The rats were housed in hanging stainless steel cages with wire mesh floors and fronts. The males were housed individually, but the females were housed two per cage. The control animals were housed in separate rooms from those which received FC-143 in order to prevent a possible cross contamination by potential vaporization and/or sublimation of the test article which has a finite vapor pressure at room temperature. Air samples were taken from each of the animal treatment rooms four months after the initiation of the study in order to assay for the presence of airborne contaminants. The samples were analyzed by the Analytical Section of the 3M Central Research Laboratory and were found to be below detectable limits for the suspected fluorochemicals. In addition to the air monitoring, 30 untreated sentinel rats were placed in each of the two animal rooms. From each 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 a<i libitum. Test Substance/Diet Preparation: FC-143 (Lot 37) 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. 308, 348 and 413 in Appendix Item J). 4. 000391 The test substance was a white powder which was added (ie, stratified) directlDy into an appropriate quantity of untreated diet and mixed in a Hobart blender for approximately 20 minutes for each separate batch. Prior to initiating compound administration to any animals, the test substance/diet mixture was assayed. FC-143 was found to be uniformly blended and stable for one to two- weeks in the ground feed (see CCD Analytical Report No. 209 in Appendix Item J). Test article/diet mixtures were prepared fresh weekly during the study 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 FC-143 was generally within a few percent of that desired (Table 1). The rats received either FC-143 treated or control (ie, 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 two treatment groups. The dosage levels and animal distribution are listed hereinafter. Treatment Groups Dosage Levels (ppm) 1 - Control 5 - High 6 - Low 0 300 30 Group Size & Animal Numbers Males Females (An. Nos.) (An. Nos.) 65 (3516-3580) 65 (3581-3645) 50 (3646-3695) 65 (4576-4640) 65 (4641-4705) 50 (4706-4755) 5. 000392 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 Stiff Veterinarian prior to compound administration and at approximately one year. The eyes of the surviving control and high-dose animals were examined 2-3 weeks prior to the termination of the study by a consulting Veterinary Ophthalmologist (see Appendix Item G). Clinical pathology determinations included hematology, clinical (serum) chemistry and urinalysis. Tests were conducted on samples obtained from 15 rats per sex from each group at 3, 6, 12, 18 and 24 months; animals were 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 known as SGOT), alanine aminotransferase (ALT-formerly SGPT), and calcium. Urine tests included pH, specific gravity, albumin, glucose, bilirubin, occult blood and ketones. Blood samples were collected from the retrobulbar venous plexus of anesthetized rats which had been fasted overnight. Blood was generally collected from the right eye. Urine samples were obtained by placing each rat in an individual metabolism cage for 20-22 hours. The specific methods 6. 000393 used for hematology, clinical chemistry and urinalysis are outlined in Appendix C. The mean hematology and clinical chemistry values from the treated groups were compared to both the concurrent control group as well as normal ranges for these parameters obtained from historical control animal data generated in this laboratory (Appendix C). Metabolic Examination: Overnight (ie, about 24 hour) urine and fecal samples were collected at 2, 5, 11 and 23 months from five rats per sex per group for total organic fluoride analysis, and for the presence of FC-143. At the scheduled one and two year necropsies, samples of liver, blood, kidney, spleen, lung and bone marrow (ie, from the femur) were saved from five rats/sex/group. After collection, all specimens were frozen pending subsequent analysis by the RIKER Drug Metabolism Department. Once these specimens are analyzed, a separate report regarding this experimental work will be prepared by the Drug Metabolism department. Postmortem Examinations: i Gross postmortem examinations were performed on all rats which died during the study and those which were terminated at the one year interim and two year necropsies. At necropsy, an examination was made of the external body surface and body orifices. The carcass was then opened and the contents of the abdomen, thorax and 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 both FC-143 treated groups at the two year necropsy. The weights of the adrenal glands, brain, testes, heart, kidneys, liver, spleen and uterus were recorded for 15 randomly selected rats/sex/group. Body weights were obtained just prior to necropsy from the same rats in order to calculate organ weights relative to whole body weights. Representative samples of the following tissues and organs from each rat were fixed in 10% neutral, buffered formalin for subsequent histologic processing: Aorta Adrenals Brain (3 (2) Sections including Liver (2 Sections) Lung (2 Sections) Lymph node (mesenteric) 7. 000394 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) 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-dise (Group 5) populations regardless of the cause of death. Microscopic examination of tissues from the low-dose (Group 6) rats included the tissues listed above except: aorta, brain, eyes, small and large intestines, lymph node(s), and spinal cord/bone marrow. The histopathologic examination and evaluation of these tissues was performed by Dr. Robert G. Geil, consulting Veterinary Pathologist (see Appendix Item D). Biostatistical Methods: The means and standard deviations for body weights, feed consumption, absolute organ weight, relative organ weight to whole body weight, organ weight to brain weight ratios and other laboratory data were determined separately for each sex and dose group. These data were analyzed using Bartlett's test for homogeneity of variance. If this test was not significant at alpha - 0.001, the data were further analyzed by comparing each treated group to the control group using a two-tailed Dunnett's test at the alpha 0.05 significance level. The results of Dunnett's test have been indicated by asterisks on the mean tables. If Bartlett's test was significant at alpha - 0.001, the data were ranked and a two-tailed Dunnett's test was performed on the ranks. These results have been indicated by the pound sign (#) on the mean tables. 8. C0039 In addition, for each organ/lesion classification the sexes were analyzed separately using a two-tailed Fisher's Exact Test comparing each treated group to the controls. An alpha - 0.05 significance level with Bonferroni's adjustment for multiple comparisons was used within each organ/lesion/sex category. If the expected value of each cell was greater than 20, then Yates' corrected 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. i 9. 0039 RESULTS In-Life Findings: Body weight gains were depressed in excess of 10% in the FC-143 high-dose males compared to the control males through 66 weeks of the study. There was an approximate 21% decrease in the high-dose body weights by week 6. This difference was statistically significant from week 2 of the study until week 98 when the high-dose and control male body weights had gradually equalized. Likewise in the low-dose male group, a 5% decrease in body weights was observed at week 6, however, there was little additional decrease thereafter (Table 2, Figure 1 and Appendix F). The occurrence of a mild SDA virus outbreak at different times during the study may have had a slight influence on the body weight data (see p. 12). Mean body weights were only very slightly decreased in the FC-143-treated females compared to the control female values through the first 18 months of the study. At 18 months, there was a gradual decrease in mean body weights of high-dose females that reached a maximum of -11% at 92 weeks. The low-dose females also showed a decreased body weight, but the effect was not statistically significant and the change was of a much lower magnitude (Table 3, Figure 2 and Appendix F). Mean feed consumption, presented as grams of diet consumed per day per kilogram of mean body weight, was increased in all of the FC-143-treated males throughout the study when compared to the male control feed consumption. This change was more pronounced in the high dose group where there was roughly a 13% increase noted with sporadic values going as high as 29% during the two year test period. In the females the pattern was less consistent, but there was a trend toward lowered feed consumption in both FC-143-treated groups compared to the female control values (Tables 4 and 5 and Figures 3 and 4). Overall, these variations were related to the variation of body weight among groups. Actual mean feed consumption (without regard for body weight change) was slightly decreased in the high-dose males relative to control males, for the first year of the study. Feed consumption in low-dose males, while somewhat inconsistent, was slightly increased during this same period. 10. 000397 During the second year, the feed consumption of both FC-143-treated male groups was reasonably stable and consumption was comparable to that of the control group. All of the treated female groups tended to consume less feed than the comparable controls throughout the study. The greatest decreases occurred from 18 months to termination with the high- and low-dose groups being equally affected (Table 6 and 7 and Appendix F). The test article concentration measured as parts per million in the diet was determined at 3 month intervals with a duplicate analysis performed when aberrant values were detected. The mean deviations from the target concentration of the high- and low-dose FC-143 groups were less than 3% (Table 1). Actual test article consumption was determined for each 2 week period for each sex and each experimental group, and expressed as mg/kg/day. The mean test article consumption was estimated to be: males, 14.2 and 1.3 mg/kg/day; females 16.1 and 1.6 mg/kg/day for the high- and low-dose groups, respectively. Mean test article consumption values calculated at 2 week intervals for the entire study are presented in Table 8. Overall survival rates for the FC-143-treated rats were good during the full two years of the test period. There were fewer deaths recorded in the high-dose males and females than in the comparable control populations. At the end of 1 year, 15 rats/sex from the control and high-dose groups were terminated to fulfill the protocol requirement for the interim sacrifice. The final survival rate then based on 50 rats/sex/group at the end of 104 weeks was: males, 70%, 88% and 72%; and females, 50%, 58% and 48% for the control, high- and low-dose groups, respectively. The increased survival rate observed in the high-dose male rats compared to the control male rats, was statistically significant (p < 0.05). Monthly mortality data are presented in Table 9. A summary of the most commonly seen clinical signs is contained in Table 10. The only clinical sign that occurred more frequently in the test article-treated groups was a dose-related increase in ataxia reported for the FC-143- treated females. While the ataxia was most commonly associated 11. with morbid animals and was seen in the control males and females, only the treated females showed an increase in the incidence of this clinical sign; 2, 15 and 9 cases in the control, high- and low-dose groups, respectively. The incidences of all other clinical signs in the FC-143-treated groups were generally less than or equal to the incidence of the same signs in the control group. Rats administered the test article experienced a suspected outbreak of sialodacryoadenitis (SDA) viral infection between the first and second months of the study. Clinical signs included swollen submandibular salivary glands and occasional ocular manifestations. The submandibular swelling was resolved within 10 days, and the incidence of ocular changes was extremely low. Similarly, the control animals had comparable symptoms during the sixteenth month of the study. Thirteen males and 13 females in the control group demonstrated signs of this condition which lasted for about 16 days from the time of onset. One male and 3 females developed ocular opacities during this period. The incidence of palpable tissue masses in FC-143-treated groups was comparable to that of the control group. There were more animals with masses in the male controls than in the male treated groups; that is, 19, 10 and 7 animals in the control, high- and low-dose groups, respectively. Likewise, when the number of palpable masses which regressed or resolved before the termination of the experimental period were evaluated, there were still fewer masses found in the FC-143-treated animals than in the control group (Table 10). The results of the final ophthalmoscopic examinations were negative relative to any FC-143 treatment-related effects. Changes that were observed included a random distribution of cataracts believed to be normal geriatric changes of the lens and some cases of chronic uveitis and superficial keratitis which were also considered to be within normal limits for aging populations of rats (Table 11 and Appendix G). Many of the rats found to have ocular lesions were identified as rats which were used to obtain blood samples via the retrobulbar venous plexus. 12. ooo$99 Red blood cell counts, hemoglobin and hematocrit values were minimally decreased in the high-dose male rats compared to control values, from 3 through 18 months. Statistically significant (p - <0.05) decreases were seen at various times in the following parameters: erythrocytes at 6, 12 and 18 months; hemoglobin, 3 and 18 months; and hematocrit at 3, 12 and 18 months. While some of these parameters were also altered in the low-dose males, the changes were of a lesser magnitude and in some cases, were increased as well as decreased (Table 12). The female high-dose erythrocyte counts and hematocrits were slightly decreased at 3 months, but were slightly increased at 6 months compared to control values. At 12 months there was a statistically significant decrease in erythrocyte count, hemoglobin, and hematocrit (Table 13). Mean leucocyte counts were increased in both male treatment groups compared to control values, through the first year of the study. These changes were due to increases in absolute counts of lymphocytes at 3 and 6 months, ind in neutrophils at 12 months. Statistically significant increases were observed: in lymphocyte counts at 3 months in the high- and low-dose groups, and at 6 and 18 months in the low-dose group; and in neutrophil counts at 12 months in both groups (Table 12). Similar changes were not seen in the FC-143-treated females with the exception of a slight increase in neutrophils and a slight decrease in lymphocytes seen in the low-dose group at 18 months (Table 13). Clinical chemistry findings at 3 months included slight increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP), as well as a moderate decrease in creatine phosphokinase (CPK) in both FC-143- treated male groups. From 6 until 18 months, the high- and low-dose male ALT, AST and AP values were increased above the concurrent control values, whereas these values in the high-dose group were still elevated at 24 months. Albumin values remained very slightly elevated in the high-dose males until the end of the study. Similar changes in clinical chemistry were not observed in the FC-143-treated female groups (Tables 14 and 15). 13. Urinary findings included increases in incidence and severity of albumin and occult blood in all of the male and female control and FC-143-treated groups at 12, 18, and 24 months. These findings were more pronounced in the males than in the females at the termination of the study. Other than an occasional incident of slight ketonuria in both control and FC-143-treated animals, there were no other remarkable urinary findings (Table 16). Postmortem Findings: The Consulting Pathologist's complete report is located in Appendix D. The gross pathology findings seen at the 1 year interim sacrifice were unremarkable with the possible exception of a single high-dose male having small testes and 3/15 high-dose females with mammary masses compared to an incidence of 1/15 in control female rats. Possible FC-143-related gross findings seen in male and female high-dose rats which were either found dead, euthanized in extremis. or euthanizedcat the termination of the study, included liver and testicular observations in the males and only a very slight increase in the incidence of mammary masses in the low-dose females. The liver findings seen in the males consisted of a slight increase in the incidence of liver masses, nodules and raised lesions, mottled livers and yellow or pale liver foci. While small testes were observed grossly in the control males as well as in both treated groups, testicular masses were found in 6/50 high-dose and 1/50 low-dose rats, but not in any of the controls. Mammary masses reported at necropsy in 1 high-dose and 2 low-dose males were found microscopically to be non-mammary lesions. Mammary masses were observed in 27/50, 26/50 and 37/50 of the control, high- and low-dose female rats, respectively. No remarkable FC-143-related liver changes were seen grossly in the female rats. Other gross pathologic findings were typical of findings in aging rats of this strain (Appendix D). Organ weights presented as either absolute or relative (ratio of organ/body weight or organ/brain weight) values are contained in Tables 17 and 18. At the 1 year interim sacrifice where the only groups examined were the high-dose and controls (n * 15/sex/group), there was no change in male body weight (absolute) but a statistically significant (p - <0.05) increase in 14. 000401 relative liver and kidney weights (vs. body weight) for the FC-143-treated males only. At the terminal necropsy, slight increases in relative (organ vs. body weight) liver weights were noted for both the males and females of both dose groups, but the increases were not statistically significant. Slight increases in relative kidney weights were observed in both the male and female rats in the high-dose group; however, only in the females was this finding statistically significant. Complete details of the histopathologic findings are contained in Appendix D and a summary of the major neoplastic and non-neoplastic microscopic changes found after 2 years of continuous oral administration of FC-143 are listed in Tables 19 and 20. Histopathologic evaluation of the tissues from the animals necropsied at 1 year indicated the major FC-143 effects were confined to the liver. Diffuse hepatomegalocytosis (12/15 animals), hepatocellular necrosis (6/15 animals), and portal mononuclear cell infiltration (13/15 animals) were seen in the high-dose males while incidences in the control group were 0/15, 0/15 and 7/15, respectively. Testicular tubular atrophy with marked aspermatogenesis was found in 2/15 high-dose males but was absent in the control males. The only remarkable change seen in the high-dose females was minimal to mild hepatocellular vacuolation; the incidence for this finding was 11/15 at the high dose and 5/15 in the control group. The majority of neoplasms observed after 2 years of dosing with FC-143, involved either the liver or one of several endocrine or endocrine-related organs (Table 19). Hepatocellular carcinomas were found in 6%, 10%, and 2% of the males from the control, high-, and low-dose groups, respectively. For the females, hepatocellular carcinomas were found only in the high-dose group with an incidence of 2%. The organ with the highest incidence of tumors was the pituitary gland where the incidences of adenomas in the males was 35%, 28% and 36%, and in the females at 71%, 71% and 83% for the control, high- and low-dose groups, respectively. Mammary gland adenocarcinomas were present in both control and treated females at an incidence of 15%, 11% and 31% for the control, high- and 15. 000402 low-dose groups, respectively. In a similar comparison, fibroadenomas were seen in 22%, 48% and 42% of the female rats at the end of the study. Mammary gland adenomas (7%) and carcinomas (2%), were seen only in the female controls, while one high-dose female had a lymphangiosarcoma. An increase in testicular Leydig cell adenomas was statistically significant (p * <0.05) in the high-dose males. Jhe incidence for this lesion was 0%, 14% and 4% in the control, high- and low-dose groups, respectively. There were minor variations in the tumor incidence patterns in the adrenals (pheochromocytomas) and thyroids which represent deviations in two commonly occurring spontaneous tumors of this strain of rat. Only the incidence of C-cell adenomas of the thyroid in male rats, appeared to show a slight dose dependent increase; namely, 0%, 9% and 4% for the control, high- and low-dose groups, respectively. However, C-cell carcinomas were seen only in the controls at an incidence of 5%. Non-neoplastic changes were found at the termination of the study in the adrenals, heart, liver, lung, pancreas, ovaries, salivary glands, spleen, testes, thyroids and uterus (Table 20). As noted in the 1 year interim histopathologic evaluation, the liver was the primary organ associated with FC-143 treatment-related effects, and there was a remarkable consistency in the type of findings observed in the males after the second full year of test article administration. Megalocytosis, cystoid degeneration, and portal mononuclear cell infiltration were the major dose-related changes seen in both male and female test article-treated groups. Megalocytosis was found at an incidence of 0%, 80% and 12% in the males, and 0%, 16% and 2% in the females from the control, high- and low-dose groups, respectively. Hepatic cystoid degeneration, a condition characterized by areas of multilocular microcysts in the liver parenchyma, was more commonly seen in male rats with a control incidence of 8%, whereas the high- and low-dose males had incidences of 56% and 14%, respectively. The incidence of this lesion in females was 2% in both of the FC-143-treated groups. Hepatocellular necrosis was equally distributed between the control and FC-143-treated groups. The incidence of hyperplastic nodules, a localized proliferation of hepatic parenchymal cells, was slightly increased in the high dose groups with an incidence of 6% in the males and 2% in the females as compared to 0% and 2% in the control males and females, respectively. 16. 000403 No hyperplastic nodules were found in the low-dose group. The incidences of other hepatic changes such as basophilic hepatocyte alteration and/or chronic inflammatory changes consisting of portal mononuclear cell infiltration were slightly increased in the high-dose males, but only against a high incidence of similar .changes in the control group. Pulmonary changes that may be associated with the administration of FC-143 in the high-dose males, consisted of an increase in the incidence of alveolar macrophages (62%) and hemorrhage (44%) compared to control incidences of 20%. However, the incidence of chronic interstitial pneumonia and perivascular mononuclear infiltration was greatly reduced in the high-dose males when compared to the male controls. Pulmonary vascular mineralization was observed commonly in both control and test article-treated male and female rats; however, the FC-143-treated females displayed an increase that was inversely related to the dose. The incidence of chronic sialadenitis, an inflammatory change of the salivary gland and often associated in rats with an antemortem viral infection, was increased in both the high- and low-dose males. Hemosiderin, an iron rich pigment, was found in greater concentrations in the spleens of both high-dose males and females, but in greatly reduced amounts in the low-dose males and females as compared to controls. Two changes observed in the gonads of both sexes, appeared to be related to the administration of FC-143. Vascular mineralization of the testes occurred in 18% of the high-dose males and 6% of the low-dose males, but was not seen in the controls. The incidence of testicular tubular atrophy was only slightly increased in the high-dose (22%) and low-dose (20%) males compared to the control males (14%). In the test article-treated females, there was a dose-related, statistically significant increase in tubular hyperplasia of the ovarian stroma. Tubular hyperplasia is considered to be a diffuse, non-neoplastic increase in stromal tubular elements which is usually bilateral and associated with decreased or absent follicular development. The incidence OO104O4 of this change was 0%, 32% and 14% in the control, high- and low-dose groups, respectively. Cystic glands of the uterine endometrium were found at a higher incidence in the low-dose females (24%) when compared to the controls (14%) and high-dose females (10%). Other non-neoplastic lesions (Table 30) are commonly associated with either endemic diseases and/or geriatric changes found in this strain of rat. The following changes were considered equivocal test article-related findings or were usually decreased below the concurrent incidence in control rats. Adrenal changes are commonly seen in aging rats of this strain and the incidences were inconsistently either higher or lower than the control values. The incidence of sinusoidal ectasia (dilatation) was increased very slightly only in the high-dose males (32%) compared to the control males (22%), while the control and FC-143-treated females were almost equally affected (82 and 86%). The incidence of chronic myocarditis was reduced in an apparent dose-related fashion in the females while being increased above the control incidence in the high- and low-dose males. The incidence of thyroid C-cell hyperplasia was slightly increased in the high dose females, while only the low-dose males showed a similar change. The incidence of acinar atrophy of the pancreas was very slightly increased in the treated males, while being slightly depressed below control values in the high-dose female. 18. G00405 DISCUSSION The purposes of this study was to define the long term toxicity and oncogenicity profile of FC-143, an anionic fluorochemical surfactant belonging to the chemical class of ammonium perf1uoroalkyl carboxylates. The study was successfully completed with sufficient numbers of animals surviving in all of the experimental groups. The survival rates for the high-dose male and female rats were actually higher than those of the control rats after 24 months of the test. The general health of a rat exposed to the experimental conditions of a 2 year feeding study may be examined at the beginning of the test by evaluating body weight gains and feed consumption compared to the study control animal population. Body weight gains of the FC-143-treated males decreased as early as the second week of the study, stabilized after 6 weeks, but remained slightly depressed in the high-dose males by at least 10% through 66 weeks. The treated females did not demonstrate any real decrease in body weight until the 18th month, so there appeared to be a rather obvious sex difference in this parameter. The body weight changes did not appear to be associated with the palatability of the diet admix since feed consumed on a body weight basis was actually increased. Further, since there was a modest dose-related effect seen in the male FC-143-treated rats, it appears that these body weight changes could be associated with a direct test article effect. The concentration of the test article in the diet was within a 3% range of the proposed levels of 300 and 30 ppm for the full 2 years of the study. The average daily dose of FC-143 for the same time period and for both sexes combined, was estimated to be 15 and 1.5 mg/kg/day. Both in-life and postmortem results confirmed the systemic absorption of the test article and the 300 ppm dosage level appeared to adequately comply with the concept of a maximum tolerated dose for a long term study in this strain of rat. The only clinical sign seen during the study which was associated with a test article effect was ataxia. The incidence of ataxia was increased in a dose related manner in the females, but not in the treated males. A ooifeee background incidence of this finding was seen in the male and female control population. During the early course of the study, a decrease in red blood cell parameters was observed in the high-dose males. While these hematologic values were often decreased below the control male measurements at a statistically significant level (p < 0.05), generally the decreased values were still within the acceptable ranges for these parameters in the rat. The elevation of serum alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase activities only in test article-treated male rats, suggested that FC-143 affected hepatocytes. These changes were seen from 3 to 18 months in both of the male FC-143-treatment groups, but only in the high-dose males at 24 months. These findings were substantiated by organ weight changes and histopathology observed at the 1 and 2 year sacrifices. Changes in the character of the urine specimens were similar in both control and treated rats examined during the course of the study. These findings were considered to be associated with the slowly developing degenerative changes of naturally occurring chronic renal disease commonly found in rats of this strain. The liver was the primary target organ affected as seen by an increase in relative organ weights, gross findings at necropsy, and histopathologic alterations. These changes seen at the 1 year necropsy showed remarkably little progression 1 year later. The FC-143-treated males were more obviously affected than the females. The sex differences seen in this study were consistent with earlier pharmacokinetic studies using carbon-14 labeled ammonium perfluorooctanoate, in which the females during 24 hours had excreted essentially 100% of an intravenous dose in the urine while the males excreted only 20%. Radioactive tissue residues were not detectable after 17 days in the females, while at 36 days, male rats had 2.8% of the carbon-14 in the liver, 1.1% in plasma, and lower but still detectable amounts in other organs.* Similar results were reported by Hanhijarvi, et 20. 000407 Hepatomegalocytosis and hepatocellular vacuolation are characteristic of increased metabolic activity in the rat. Following chronic hepatic stimulation, evidence of cystoid degeneration and, occasionally, hepatocellular necrosis may also be observed. Since the liver in the rat rarely repairs parenchymal cell loss with fibrosis or scar tissue, the most common finding is hepatocellular hyperplasia. In this study, the incidence of hyperplastic nodules was increased very slightly in the high-dose group, but the incidence was not significantly different from controls. It is also important to note that no proliferative hepatic lesions (i.e. neither hyperplasia nor neoplasia) were seen in any of the high-dose rats receiving FC-143 for 1 year. The observed hepatomegalocytosis was similar to that reported by Pastoor et al in which perfluorooctanoic acid was administered p orally to male rats at a higher dosage (50 mg/kg/day). It was proposed that the hepatocytic enlargement was due to proliferation of smooth, endoplasmic reticulum, mitochondria, and peroxisomes. The only hepatic neoplasms found in this study were hepatocellular carcinomas. The incidence of this tumor was 6%, 10% and 2% in the control, high- and low-dose male rats, respectively. Only one high-dose female was found to have this liver tumor. The incidence of hepatocellular carcinomas in high-dose males was not significantly greater than that of the control males and was comparable with the reported spontaneous incidence of this 3 tumor. Based on these findings, FC-143 was not considered to be a hepatic carcinogen in the rat. The other neoplasms observed in this study originated from endocrine and/or endocrine sensitive organs; namely, the adrenal gland, mammary gland, pituitary gland, testes, and thyroid gland. The incidence for each of these tumors are presented in Table 19. The incidence of mammary gland adenocarcinomas was 15%, 11% and 31% for the control, high- and low-dose female groups, respectively. While mammary gland carcinomas and adenomas were found only in the controls, there was an increased incidence of fibroadenomas in the high-dose (48%, statistically significant: p < 0.05), and the low-dose (42%) compared to controls (22%). It should also be noted that 2/13 of the high-dose females necropsied at 1 21. 000408 year were found to have fibroadenomas, while 0/15 of the controls were similarly affected. Although the incidence of fibroadenomas in high-dose females was significantly greater than that for the control females, the incidence was similar to that reported for untreated aging rats.^ In addition, when the incidences for benign mammary gland tumors (adenoma and fibroadenoma) are combined, the tumor incidence in the high-dose group is no longer statistically significant. Leydig cell adenomas (i.e. benign tumors of the testicular interstitial tissue), were found at an incidence of 0%, 14% and 4% in the control, highl and low-dose groups, respectively. The high-dose incidence for this lesion was statistically significant (p < 0.05) because the incidence in the control group was unusually low (0%). In addition, the spontaneous incidence reported for this neoplasm in this strain of rat was 7.4% for rats 24 to 29 months of age and was 14.6% at 30 to 38 months of age3 . Based on another set of Sprague-Dawley two year study data compiled by Hazleton Laboratories, the spontaneous incidence of interstitial cell 5 tumors was 28.7%. The remaining non-neoplastic findings reported from the histopathologic evaluation of all of the animals originally scheduled for the 2 year phase of the study were mostly geriatric lesions common to this strain of rat. The organs in which these lesions were found included: adrenal, heart, kidney, lung, testes, ovary, thyroid, urinary bladder and uterus. Specific deviations from control values seen in FC-143-treated groups were addressed in the results section of this report; however, the following changes may be considered incidental or equivocal test article-related effects. The incidence of nodular hyperplasia of the adrenal cortex was increased (not statistically significant) in the high-dose males (18%) compared to the same finding in the controls (4%), while the high-dose females showed a much lower incidence (2%). Increases in the incidences of adrenal gland sinusoidal extasia (dilatation) were reported in the high- (32%) and low(26%) dose males compared to male controls (22%) while the incidences in 22. 000409 all test article-treated females were equal to control values. It should be noted that adrenal lesions are commonly seen in old rats. Thyroid C-cell hyperplasia was seen in the control males and FC-143-treated groups with an incidence of 10% and 7% for the low-dose males and the high-dose females, respectively. The incidences were not dose-related or statistically significant and were lower than the reported spontaneous 3 incidence of this lesion. Chronic myocarditis (inflammation) was seen at a slightly higher incidence in the low-dose (36%) and the high-dose (34%) males compared to the control (28%) group. The female incidence for this lesion was 32%, 20% and 10% in the control, high- and low-dose groups, respectively. Inflammation of the heart is common in old rats. The lack of a true dose-related effect in either sex suggests that this finding is probably not a treatment related phenomenon. Chronic renal histopathologic changes, commonly observed in aging rats, were not meaningfully altered by FC-143 treatment. None of these changes were apparently severe enough to produce pathologic lesions over a 2 year period. Therefore, none of these findings are considered to be directly related to treatment. Lung changes which were seen more commonly in FC-143-treated rats than in controls included an increase in alveolar macrophages, pulmonary hemorrhage (agonal) and vascular mineralization. The first two lesions were seen predominantly in the high-dose males where the incidences were statistically significant (p < 0.05). Control males on the other hand, had higher incidences of interstitial pneumonia and pulmonary perivascular mononuclear cell infiltration. Pulmonary changes are common in aging 3 rats. Other than the possibility that an increase in the alveolar macrophages may be associated with FC-143 administration, all of the pulmonary changes were not considered related to test article treatment. Chronic sialadenitis or inflammation of the salivary glands was significantly (p < 0.05) increased in the test article-treated males, but 23. C00410 not in the test article-treated females. These changes were attributed to outbreaks of sialodacryoadenitis viral infections which occurred in both the control and FC-143 animal rooms, but at different time periods and apparently with different levels of intensity. The incidence of splenic hemosiderosis, depositions of iron-containing pigment in the sinusoids of the spleen, was increased above control levels by approximately 12% in only the high-dose males. However, the incidence in high-dose males was not significantly greater than the control incidence. The incidence of this lesion in FC-143 treated females was significantly lower than the incidence of splenic hemosiderosis in control females. A statistically significant, dose-related increase in the incidences of ovarian (stromal) tubular hyperplasia was found in low and high-dose groups. The interpretation of these changes in the absence of any observable progressive pathologic lesion after 2 years of treatment, must be considered as equivocally related to FC-143 treatment. 24. 000411 CONCLUSIONS The results obtained under the conditions of this study when FC-143 was administered in the diet of male and female rats at concentrations of 300 and 30 ppm for 2 years may be summarized as follows: 1. FC-143-related changes were found more commonly in males than in females of each of the two treatment groups. This finding supports earlier pharmacokinetic studies that demonstrated a increased FC-143 retention by treated males compared to treated female rats. 2. The major dose-related findings were observed in the liver and consisted of megalocytosis and cystoid degeneration with only a minimal proliferative response and related elevations of serum enzyme activities. 3. Other non-neoplastic findings reported in this study were not considered primary test article-related effects, but rather were related to spontaneous changes occurring in aging rats. 4. Based on the incidence, types of tumors, time of tumor appearance, malignancy patterns of tumors and survival rate after 2 years, FC-143 is not considered to be carcinogenic in the rat. 25. 000412 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.D. R.G. Gei1, 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.D. C.E. Ludemann, B.S., M.T. L.A. Marschke S.E. McCarville, B.S., M.S. W.C. McCormick, III, B.S. J.R. Nelson, H.T. 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 Hi stotechnologi st/Mi croscope Slide Preparation Supervisor, Laboratory Animal Care Laboratory Technician Senior Laboratory Technician/ Assisted With Study Data 26. 000413 SIGNATURE PAGE TWO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHENICAL FC-143 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: Senior Toxicologist Q M ^Report Reviewed By: la Jamiss L. Allen, Ph.D. Diplomate, A.B.T. Research Toxicologist Date Report Approved By: Edward E. Erickson, Ph.D. Laboratory Manager Date 27. 000414 REFERENCES 1. Johnson, J.D. Extent and Route of Excretion and Tissue Distribution of Total Carbon-14 in Male and Female Rats After a Single IV Dose of FC-143- C. Riker Laboratories', Inc., St. Paul, MN 55101, Internal Drug Metabolism Report, 1-20, January 30, 1980. 2. Pastoor, T.P., Lee, K.P. and Gillies, P.J. Morphological and Biochemical Characteristics of Perfluorooctanoate - Induced Liver Enlargement. The Toxicologist, 5(1):155, March 1985. 3. Anver, M.R., Cohen, B.J., Lattuada, C.P. and Foster, S.J. Age-Associated Lesions in Barrier-Reared Male Sprague-Dawley Rats: A Comparison Between Hap: (SD) and Crl: COBS CD (SD) Stocks. Exper. Aging Res., 8(l)Part 1:3-24, Spring, 1982. 4. Prejean, J.D., Peckman, J.C., Casey, A.E., Griswold, D.P., Weisburger, E.K., and Weisbureger, J.H. Spontaneous Tumors in Sprague-Dawley Rats and Swiss Mice. Cancer Research 33:2768-2773, November, 1973. 5. Hazleton Laboratories, Vienna, VA. Historical Control Data, page 16, February 17, 1984. 6. Hanhijarvi, H., Ophaug, R.H. and Singer, L. The Sex-Related Difference in Perfluorooctanoate Excretion in the Rat. Proc. Soc. Expr. Biol. Med, 171:50-55, 1982. 28. 000415 Table 1 Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FC-143 in Rats Analytical Analysis of FC-143--a (% Above/Below Desired Concentration) Approximate CCD Analytical Study Month Report Numbers 0 (Initial) 213 1 229 4 250 7 289 10 319 11 328 13 340 16 366 19 384 22 395 24 404 Dosage Levels (ppm) 300 30 + 0.6% + 0.3% + 5.0% + 1.2% - -34.0% - 6.1% - 2.3% + 2.6% + 2.0% + 3.0% + 9.4% - 1.0% + 1.0% - 2.3% + 0.0% - 6.7% -- + 7.7% + 4.4% + 2.2% + 3.3% +10.0% Mean Deviation for the Study - + 1.6% + 1.9% a -- commercial Chemicals Division (CCD) --b Incorrect values given at this level due to instrument malfunction: this dosage level was reanalyzed after new detector was installed. --c Excluding from mean deviation the percentages over + 20% acceptable limit. 29. 000416 Table 2 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Mean Body Weights (g) % Difference from Control MALES 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 300 ppm Mean Wt. Mean Wt. % Diff. 165.3 270.9 334.0 390.7 429.2 456.2 475.5 493.2 502.9 515.3 526.8 542.3 550.4 561.0 567.5 576.3 580.6 582.9 591.0 599.4 608.4 612.9 619.8 623.5 626.1 639.2 638.6 162.1 234.3 276.7 308.6 353.2 380.1 398.0 412.8 425.4 436.0 447.4 456.1 464.2 475.0 484.9 497.2 505.7 511.8 514.2 524.8 535.2 540.9 550.8 552.0 558.5 566.7 570.1 1 eo - 1.9 -13.5 -17.2 -21.0 -17.7 -16.7 -16.3 -16.3 -15.4 -15.4 -15.1 -15.9 -15.7 -15.3 -14.6 -13.7 -12.9 -12.2 -13.0 -12.4 -12.0 -11.7 -11.1 -11.5 -10.8 -11.3 30 ppm Mean Wt. % Diff. 167.0 271.0 328.5 369.4 410.3 441.5 458.1 475.4 487.9 498.5 512.1 519.4 526.3 538.9 546.2 558.6 566.4 571.3 575.4 584.0 592.5 600.5 610.4 612.1 618.9 627.1 633.6 + 1.0 + 0.0 - 1.6 - 5.4 - 4.4 - 3.2 - 3.7 - 3.6 - 3.0 - 3.3 - 2.8 - 4.2 - 4.4 - 3.9 - 3.8 - 3.1 - 2.4 - 2.0 - 2.6 - 2.6 - 2.6 - 2.0 - 1.5 - 1.8 - 1.1 - 1.9 - 0.8 30. 000417 Table 2 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study o Fluorocarbon FC-143 in Rata Summary of Mean Body Weights (g) _+ % Difference from Control 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 300 ppm Mean Wt. Mean Wt. % Diff. 654.3 661.6 668.0 673.2 674.4 664.5 650.8 656.6 661.9 658.3 660.8 667.7 668.8 670.6 663.1 668.1 675.6 678.9 690.0 686.0 678.3 677.5 675.7 671.1 665.9 642.0 577.6 583.1 587.9 590.8 593.2 596.8 598.2 604.9 608.2 608.5 601.1 605.4 604.6 611.8 610.0 617.5 617.4 614.7 624.6 621.8 627.6 621.0 627.2 625.5 629.4 613.3 -11.7 -11.9 -12.0 -12.2 -12.0 -10.2 - 8.1 - 7.9 - 8.1 - 7.6 - 7.6 - 9.3 - 9.6 - 8.8 - 8.0 - 7.6 - 8.6 - 9.5 - 9.5 - 9.4 - 7.5 - 8.3 - 7.2 - 6.8 - 5.5 - 4.5 30 ppm Mean Wt. % Diff. 641.9 646.4 652.7 656.8 655.7 658.3 662.5 666.5 666.2 664.4 659.2 663.8 661.7 669.2 666.9 662.3 664.5 654.7 662.4 652.9 660.0 653.4 659.7 660.0 664.0 650.8 - 1.9 - 2.3 - 2.3 - 2.4 - 2.8 - 0.9 + 1.8 + 1.5 + 0.6 + 0.9 - 0.2 - 0.6 - 1.1 - 0.2 + 0.6 - 0.9 - 1.6 - 3.6 - 4.0 - 4.8 - 2.7 - 3.6 - 2.4 - 1.7 - 0.3 + 1.4 31. 000418 Table 3 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Mean Body Weights (g) _+ % Difference from Control FEM ALES 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 300 ppm Mean Wt. Mean Wt. % Diff. 138.2 159.2 209.5 238.7 256.9 269.2 279.5 289.7 291.8 306.8 311.6 319.1 324.5 327.3 333.7 338.3 345.5 350.7 355.5 359.3 363.2 371.2 380.1 385.7 392.3 398.6 406.1 138.1 167.3 213.8 237.4 254.6 263.3 274.2 286.4 285.4 299.4 307.6 314.6 322.5 326.0 331 .6 338.6 344.1 352.8 357.1 362.3 366.0 373.2 380.4 385.9 391.6 399.3 406.1 + 0.0 + 5.1 + 2.1 - 0.5 - 0.9 - 2.2 - 1.9 - 1.1 - 2.2 - 2.4 - 1.3 - 1.4 - 0.6 - 0.4 - 0.6 + 0.1 - 0.4 + 0.6 + 0.5 + 0.8 + 0.8 + 0.5 + 0.1 + 0.0 - 0.2 + 0.2 + 0.0 30 ppm Mean Wt. % Diff. 137.2 166.0 214.9 235.7 253.8 261.3 275.5 282.8 285.9 298.0 304.1 309.9 318.6 323.6 330.4 339.0 344.9 353.5 358.0 363.1 367.5 375.9 382.0 389.7 395.8 399.7 406.2 - 0.7 + 4.3 + 2.6 - 1.3 - 1.2 - 2.9 - 1.4 - 2.4 - 2.0 - 2.9 - 2.4 - 2.9 - 1.8 - 1.1 - 1.0 + 0.2 - 0.2 + 0.8 + 0.7 + 1.1 + 1.2 + 1.3 + 0.5 + 1.0 + 0.9 + 0.3 + 0.0 32. 000419 Table 3 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Mean Body Weights (g) _+ % Difference 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 300 ppm Mean Wt. Mean Wt. % Diff. 414.1 419.1 420.9 423.6 426.6 426.1 424.9 427.5 431.4 435.2 446.5 455.2 464.8 474.9 484.0 484.8 492.7 499.1 500.6 512.5 505.7 506.9 500.0 501.2 503.6 502.0 411.5 421.2 426.4 427.0 431.9 434.0 435.5 433.0 429.1 432.8 444.6 447.4 452.7 457.0 461.8 457.6 458.2 456.6 451.8 455.9 451.0 464.5 468.0 464.2 462.8 450.3 - 0.6 + 0.5 + 1.3 + 0.8 + 1.2 + 1.9 + 2.5 + 1.3 - 0.5 - 0.6 - 0.4 - 1.7 - 2.6 - 3.8 - 4.6 - 5.6 - 7.0 - 8.5 - 9.7 -11.0 -10.8 - 8.4 - 6.4 - 7.4 - 8.1 -10.3 30 ppm Mean Wt. * Diff. 412.6 420.7 427.3 430.0 435.7 439.9 446.5 445.3 443.5 448.6 463.3 468.8 471.3 475.8 485.7 476.3 479.7 483.4 485.2 486.3 492.0 504.3 505.5 505.6 503.3 501.8 - 0.4 + 0.4 + 1.5 + 1.5 + 2.1 + 3.2 + 5.1 + 4.2 + 2.8 + 3.1 + 3.8 + 3.0 + 1.4 + 0.2 + 0.4 - 1.8 - 2.6 - 3.1 - 3.1 - 5.1 - 2.7 - 0.5 + 1.1 + 0.9 - 0.1 + 0.0 33. 000420 Table 4 Two Tear Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Mean Food Consunption Per Kilogram Body Weight (g of diet consumed per day) ._+ % Difference from Control MALES Control 300 ppm Mean Wt. Mean Wt. % Diff. 30 ppm Mean Wt. % Diff. 1 102.0 98.6 - 3.3 103.8 + 1.8 2 85.2 96.8 +13.6 85.0 - 0.2 4 76.4 84.0 +1 0.0 77.0 + 0.8 6 69.4 67.7 - 2.5 61.2 - 11.8 8 61 .5 70.6 +14.8 64.1 + 4.2 10 53.7 63.0 +17.3 57.4 + 6.9 12 50.7 58.1 +14.6 51.3 + 1.2 14 51.7 59.5 +15.1 53.5 + 3.5 16 48.0 55.2 +15.0 49.3 + 2.7 18 46.8 52.6 +12.4 47.7 + 1.9 20 46.9 54.5 +16.2 48.9 + 4.3 22 44.9 51.9 +15.6 47.3 + 5.4 24 45.0 52.0 +15.6 46.3 + 2.9 26 43.7 49.2 +1 2 . 6 44.9 + 2.8 28 42.8 48.3 +12.9 44.5 + 4.0 30 43.2 48.7 +12.7 43.7 + 1.2 32 42.9 47.2 +1 0 . 0 44.0 + 2.6 34 41.8 46.5 +1 1 . 2 42.8 + 2.4 36 38.4 42.5 +10.7 39.7 + 3.4 38 40.7 46.0 +13.0 42.2 + 3.7 40 39.5 43.9 +11.1 41.8 + 5.8 42 39.3 44.0 +1 2 . 0 41.3 + 5.1 44 38.9 43.6 +12.1 40.5 + 4.1 46 39.0 42.6 + 9.2 39.7 + 1.8 48 39.0 43.3 +1 1 . 0 38.9 - 0.3 50 38.5 43.2 +1 2 . 2 39.4 + 2.3 52 36.5 41.1 +1 2 . 6 36.1 - 1.1 34. 000421 Table 4 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Mean Food Consuoption Per Kilogram Body Height (g of diet consumed per day), _+ % Difference from Control MALES Control 300 ppm Mean Wt. Mean wt. % Diff. 30 ppm Mean Wt. % Diff. 54 37.0 42.2 +14.1 36.3 - 1.9 56 36.6 41.2 +12.6 37.9 + 3.6 58 36.1 40.7 +12.7 37.5 + 3.9 60 35.4 40.6 +14.7 37.3 + 5.4 62 35.9 37.1 + 3.3 37.1 + 3.3 64 31.0 40.2 +29.7 34.5 +11.3 66 36.3 40.8 +12.4 36.4 + 0.3 68 32.9 36.5 +10.9 33.5 + 1.8 70 32.6 37.7 +15.6 33.0 + 1.2 72 33.0 37.5 +13.6 34.9 + 5.8 74 34.4 37.9 +10.2 36.7 + 6.7 76 37.1 39.2 + 5.7 36.9 - 0.5 78 36.6 39.7 + 8.5 34.9 - 4.9 80 34.6 39.4 +13.9 36.8 + 6.4 82 36.3 36.7 + 1.1 37.6 + 3.6 84 35.6 38.5 + 8.2 34.3 - 3.7 86 35.1 38.6 +10.0 35.4 + 0.9 88 34.8 33.0 - 5.2 33.0 - 5.2 90 34.9 36.3 + 4.9 34.7 - 0.6 92 35.1 37.3 + 6.3 35.1 + 0.0 94 38.5 40.5 + 5.2 36.8 - 4.4 96 37.1 40.1 + 8.1 37.5 + 1.1 98 37.3 38.9 + 4.3 37.4 + 0.3 100 36.7 38.1 + 3.8 37.3 + 1.6 102 35.0 38.3 + 9.4 37.2 + 6.3 104 33.8 37.8 +11.8 37.5 +11.0 35. 000422 Table 5 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rata Summary of Mean Food Consuiqption Per Kilogram Body Weight (g of diet consumed per day), jf % Difference from Control FEMALES Control 300 ppm Mean Wt. Mean Wt. % Diff. 30 ppm Mean Wt. % Diff. 1 98.8 96.6 - 2.2 96.1 - 2.7 2 107.0 101.6 - 5.1 103.0 - 3.7 4 97.2 81.8 -15.8 83.6 -14.0 6 81.0 81.1 + 0.1 82.8 + 2.2 8 74.1 74.9 + 1.1 73.4 - 0.9 10 72.6 72.5 - 0.1 73.5 + 1.2 12 70.2 70.4 + 0.3 69.7 - 0.7 14 64.2 62.0 - 3.4 64.9 + 1.1 16 57.2 56.3 - 1.6 58.8 + 2.8 18 64.3 62.9 + 2.2 64.6 + 0.5 20 63.4 61.5 - 3.0 65.5 + 3.3 22 58.6 61.2 + 4.4 63.2 + 7.9 24 59.5 58.0 - 2.5 61.2 + 2.9 26 57.0 56.2 - 1.4 57.0 + 0.0 28 61.7 58.1 - 5.8 58.3 - 5.5 30 59.7 57.4 - 3.9 59.0 - 1.2 32 58.4 56.1 - 3.9 55.7 - 4.6 34 52.9 51.4 - 2.8 51.5 - 2.7 36 56.7 54.2 - 4.4 57.0 + 0.5 38 56.8 52.7 - 7.2 54.3 - 4.4 40 58.4 51.6 -11.6 50.3 -13.9 42 54.2 53.6 - 1.1 52.9 - 2.4 44 54.7 51.8 - 5.3 53.9 - 1.5 46 48.5 50.8 + 4.7 52.1 + 7.4 48 49.2 50.3 + 2.2 51.8 + 5.3 50 51.4 45.1 -12.3 50.0 - 2.7 52 48.3 48.3 + 0.0 48.0 - 0.6 36. 000423 Table 5 (concluded) Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Mean Food Consunption Per Kilogram Body Weigh (g of diet consumed per day) ^+ % Difference from Control FEMALES Control 300 ppm Mean Wt. Mean Wt. % Diff. 30 ppm Mean Wt. % Diff. 54 48.1 47.1 - 2.1 47.3 - 1.7 56 51.5 48.4 - 6.0 47.1 - 8.5 58 46.3 47.6 + 2.8 46.3 + 0.0 60 49.6 49.2 - 0.8 47.7 - 3.8 62 47.1 46.5 - 1.3 44.8 - 4.9 64 48.4 46.1 - 4.8 44.1 - 8.9 66 41.0 39.5 - 3.7 39.6 - 3.4 68 44.9 41.3 - 8.0 39.8 -11.4 70 46.1 43.1 - 6.5 41.0 -11.1 72 45.3 44.1 - 2.7 44.4 - 2.0 74 48.4 45.9 - 5.2 44.5 - 8.1 76 48.3 45.8 - 5.2 44.4 - 8.1 78 44.1 44.0 - 0.2 43.7 - 0.9 80 45.7 44.4 - 2.8 38.5 -15.8 82 44.0 42.0 - 4.6 39.1 -11.1 84 43.5 39.8 - 8.5 38.2 -12.2 86 44.3 39.1 -11.7 37.7 -14.9 88 45.3 42.3 - 6.6 37.2 -21.8 90 46.1 45.6 - 1.1 38.5 -16.5 92 45.9 43.9 - 4.4 39.9 -13.1 94 46.9 47.5 + 1.3 42.7 - 9.0 96 42.4 44.4 + 4.7 37.7 -11.1 98 46.8 44.2 - 5.6 41.4 -11.5 100 41.5 44.0 + 6.0 42.5 + 2.4 102 42.5 46.2 + 8.7 46.3 + 8.9 104 41.6 50.9 +22.4 43.2 + 3.9 37. 000424 Table 6 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Mean Food Consumption - Absolute (g/rat/day) _+ % Difference from Control MALES Control Mean Wt. 300 ppm Mean Wt. % Diff. 30 ppm Mean Wt. % Diff 1 22.2 18.7 -15.8 22.9 + 3.2 2 23.1 22.7 - 1.7 23.0 - 0.4 4 25.5 23.2 - 9.0 25.3 - 0.8 6 27.1 20.9 -22.9 22.6 -16.6 8 26.4 24.9 - 5.7 26.3 - 0.4 10 24.5 24.0 - 2.0 25.4 + 3.7 12 24.1 23.1 - 4.2 23.5 - 2.5 14 25.5 24.6 - 3.5 25.4 - 0.4 16 24.1 23.5 - 2.5 24.1 + 0.0 18 24.1 22.9 - 5.0 23.8 - 1.2 20 24.7 24.4 - 1.2 25.1 + 1.6 22 24.3 23.7 - 2.5 24.6 + 1.2 24 24.8 24.1 - 2.8 24.4 - 1.6 26 24.5 23.4 - 4.5 24.2 - 1.2 28 24.3 23.4 - 3.7 24.3 + 0.0 30 24.9 24.2 - 2.8 24.4 - 2.0 32 24.9 23.9 - 4.0 24.9 + 0.0 34 24.3 23.8 - 2.1 24.5 + 0.8 36 22.7 21.9 - 3.5 22.8 + 0.4 38 24.4 24.1 - 1.2 24.7 + 1.2 40 24.0 23.5 - 2.1 24.8 + 3.3 42 24.1 23.8 - 1.2 24.8 + 2.9 44 24.1 24.0 - 0.4 24.7 + 2.5 46 24.3 23.5 - 3.3 24.3 + 0.0 48 24.4 24.2 - 0.8 24.1 - 1.2 50 24.6 24.5 - 0.4 24.7 + 0.4 52 23.3 23.4 + 0.4 22.9 - 1.7 38. 000425 Table 6 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Mean Food Consusption - Absolute (g/rat/day) _+ % Difference from Control MALES Control Mean Wt. 300 ppm Mean Wt. % Diff. 30 ppm Mean Wt. % Diff 54 24.2 24.4 + 0.8 23.3 - 3.7 56 24.2 24.0 - 0.8 24.5 + 1.2 58 24.1 23.9 - 0.8 24.5 + 1.7 60 23.8 24.0 + 0.8 24.5 + 2.9 62 24.2 22.0 - 9.1 24.3 + 0.4 64 20.6 24.0 +16.5 22.7 + 10.2 66 23.6 24.4 + 3.4 24.1 + 2.1 68 21.6 22.1 + 2.3 22.3 + 3.2 70 21.6 22.9 + 6.0 22.0 + 1.9 72 21.7 22.8 + 5.1 23.2 + 6.9 74 22.7 22.8 + 0.4 24.2 + 6.6 76 24.8 23.7 - 4.4 24.5 - 1.2 78 24.5 24.0 - 2.0 23.1 - 5.7 80 23.2 24.1 + 3.9 24.6 + 6.0 82 24.1 22.4 - 7.1 25.1 + 4.2 84 23.8 23.8 + 0.0 22.7 - 4.6 86 23.7 23.8 + 0.4 23.5 - 0.8 88 23.6 20.3 -14.0 21.6 - 8.5 90 24.1 22.7 - 5.8 23.0 - 4.6 92 24.1 23.2 - 3.7 22.9 - 5.0 94 26.1 25.4 - 2.7 24.3 - 6.9 96 25.1 24.9 - 0.8 24.5 - 2.4 98 25.2 24.4 - 3.2 24.7 - 2.0 100 24.6 23.8 - 3.3 24.6 + 0.0 102 23.3 24.1 + 3.4 24.7 + 6.0 21.7 23.2 + 6.9 24.4 + 12.4 39 000426 Table 7 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rata Summary of Mean Food Consunption - Absolute (g/rat/day) _+ % Difference from Control FEMALES Control Mean Ht. 300 ppm Mean Wt. % Diff. 30 ppm Mean Wt. % Diff 1 13.5 13.5 + 0.0 13.3 - 1.5 2 17.0 17.0 + 0.0 17.1 + 0.6 4 20.4 17.5 -14.2 18.0 -11.8 6 19.3 19.2 - 0.5 19.5 + 1.0 8 19.0 19.1 + 0.5 18.6 - 2.1 10 19.5 19.1 - 2.1 19.2 - 1.5 12 19.6 19.3 - 1.5 19.2 - 2.0 14 18.6 17.8 - 4.3 18.4 - 1.1 16 16.7 16.1 - 3.6 16.8 + 0.6 18 19.7 18.8 - 4.6 19.3 - 2.0 20 19.8 18.9 - 4.6 19.9 + 0.5 22 18.7 19.2 + 2.7 19.6 + 4.8 24 19.3 18.7 - 3.1 19.5 + 1.0 26 18.7 18.3 - 2.1 18.4 - 1.6 28 20.6 19.3 - 6.3 19.3 - 6.3 30 20.2 19.4 - 4.0 20.0 - 1.0 32 20.2 19.3 - 4.5 19.2 - 5.0 34 18.5 18.1 - 2.2 18.2 - 1.6 36 20.2 19.4 - 4.0 20.4 + 1.0 38 20.4 19.1 - 6.4 19.7 - 3.4 40 21.2 18.9 -10.9 18.5 -12.7 42 20.1 20.0 - 0.5 19.9 - 1.0 44 20.8 19.7 - 5.3 20.6 - 1.0 46 18.7 19.6 + 4.8 20.3 + 8.6 48 19.3 19.7 + 2.1 20.5 + 6.2 50 20.5 18.0 -12.2 20.0 - 2.4 52 19.6 19.6 + 0.0 19.5 - 0.5 40". 000427 Table 7 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Mean Food Consumption - Absolute (g/rat/day) _+ % Difference from Control FEMALES Control Mean Wt. 300 ppm Mean Wt. % Diff. 30 ppm Mean Wt. % Diff 54 19.9 19.4 - 2.5 19.5 - 2.0 56 21.6 20.4 - 5.6 19.8 - 8.3 58 19.5 20.3 + 4.1 19.8 + 1.5 60 21.0 21.0 + 0.0 20.5 - 2.4 62 20.1 20.1 + 0.0 19.5 - 3.0 64 20.6 20.0 - 2.9 19.4 - 5.8 66 17.4 17.2 - 1.2 17.7 + 1 .7 68 19.2 17.9 - 6.8 17.7 - 7.8 70 19.9 18.5 - 7.0 18.2 - 8.5 72 19.7 19.-1 - 3.1 19.9 + 1.0 74 21 .6 20.4 - 5.6 20.6 - 4.6 76 22.0 20.5 - 6.8 20.8 - 5.5 78 20.5 19.9 - 2.9 20.6 + 0.5 80 21.7 20.3 - 6.5 18.3 -15.7 82 21.3 19.4 - 8.9 19.0 -10.8 84 21.1 18.2 -13.7 18.2 -13.7 86 21.8 17.9 -17.9 18.1 -17.0 88 22.6 19.3 -14.6 18.0 -20.4 90 23.1 20.6 -10.8 18.7 -19.1 92 23.5 20.0 -14.9 19.4 -17.5 94 23.7 21.4 - 9.7 21.0 -11.4 96 21.5 20.6 - 4.2 19.0 -11.6 98 23.4 20.7 -11.5 20.9 -10.7 100 20.8 20.4 - 1.9 21.5 + 3.4 102 21.4 21.4 + 0.0 23.3 + 8.9 104 20.9 22.9 + 9.6 21.7 + 3.8 41. 000428 TABLE 8 Estimated Mean FC-143 (mg/kg Body Weight) Consumption Per Day 300 -Efim Male Female 30_Efi!D Male Female 1 29.6 29.0 3.1 2.9 2 29.0 30.5 2.6 3.1 4 25.2 24.5 2.3 2.5 6 20.3 24.3 1.8 2.5 8 21.2 22.5 1.9 2.2 10 18.9 21.8 1.7 2.2 12 17.5 21.1 1.5 2.1 14 17.9 18.6 1.6 2.0 16 16.6 16.9 1.5 1.8 18 15.8 18.9 1.4 1.9 20 16.4 18.4 1.5 2.0 22 15.6 18.3 1.4 1.9 24 15.6 17.4 1.4 1.8 26 14.8 16.9 1.4 1.7 28 14.5 17.4 1.3 1.8 30 14.6 17.2 1.3 1.8 32 14.2 16.8 1.3 1.7 34 13.9 15.4 1.3 1.6 36 12.8 16.3 1.2 1.7 38 13.8 15.8 1.3 1.6 40 13.2 15.5 1.3 1.5 42 13.2 16.1 1.2 1.6 44 13.1 15.5 1.2 1.6 46 12.8 15.2 1.2 1.6 48 13.0 15.1 1.2 1.5 50 13.0 13.5 1.2 1.5 52 12.3 14.5 1.1 1.4 42 000429 TABLE 8 (Continued) Estimated Mean FC-143 (mg/kg Body Weight) Consumption Per Day 300 -BEE Male Female 30-BEE Male Female 54 12.7 14.1 1.1 1.4 56 12.4 14.5 1.1 1.4 58 12.2 14.3 1.1 1.4 60 12.2 14.8 1.1 1.4 62 11.1 14.0 1.1 1.3 64 12.1 13.8 1.0 1.3 66 12.2 11.9 1.1 1.2 68 11.0 12.4 1.0 1.2 70 11.3 12.9 1.0 1.2 72 11.2 13.2 1.1 1.3 74 11.4 13.8 1.1 1.3 76 11.7 13.8 1.1 1.3 78 11.9 13.2 1.1 1.3 80 11.8 13.3 1.1 1.2 82 11.0 12.6 1.1 1.2 84 11.6 11.9 1.0 1.2 86 11.6 11.7 1.1 1.1 88 9.9 12.7 1.0 1.1 90 10.9 13.7 1.0 1.2 92 11.2 13.2 1.1 1.2 94 12.1 14.2 1.1 1.3 96 12.0 13.3 1.1 1.1 98 11.7 13.3 1.1 1.2 100 11.4 13.2 1.1 1.3 102 11.5 13.9 1.1 1.4 104 11.4 15.3 1.1 1.3 000430 TABLE 9 TwO YEAR O R AL(DIET) TOX I C I T Y - O N C 0 G E N I C I T Y STUOY OF f l u o r o c a r b o n f c -- 1A 3 IN RATS MOHTALITY DATA WEEK OF STUOY POSE GROUP INITIAL 1- 5NO* ___ 4 ___ a *- 13- li- 21- 25- 29- 33- 37- 41- 45- 49- 53_ 1 4 -- _ - 2 4 __fi _ _ 2 2 -- 2 6 0 -- 44 __ 42 __ 52 -- Sfi HALES CONTROL 0 PP* HIGH DOSE 300 PN LOM DOSE 30 PPM 50 0 0 0 0 0 0 0 0 1 0 0 0 0 1 50 0 0 0 0 1 0 1 0 0 0 0 0 0 0 50 0 0 0 0 0 0 0 0 0 1 0 0< 0 0 FECALES CONTROL 0 PPM HIGH OOSE 300 PPM LOW OOSE 30 PPM 50 0 0 0 0 0 0 l 0 0 1 0 0 1 1 50 0 0 0 0 e 0 0 0 0 0 0 0 1 1 50 0 0 0 0 0 0 0 0 0 1 1 1 0 codiai Q Q 5 _!iS Q U " ALES CONTROL 0 P" H I G H >)OSE 300 PPM LON DOSE 30 PPM females CONTROL 0 PPM HIGH OOSE 300 p j m LOW OOSE 30 P P M TABLE 9 T.O YEAR O R A L (DIET) TOX IC 1T Y-ONCOot'wICl TY STuOY OF F L u O R U C A R H O N FC - 1 A 3 IN HATS M O R T A L I T Y O a T WtEK OK STUOY INITIAL 5 7 - 61- >5- 60- 73- 77- 81- 85- 89- 43- 97- 101- 105- 1-104 WEEK *2* _ M __fit -- fen_12 ,, i t __an _ _ * _as -- aa - 2 b -ittJl - M l - 1 M till -1 50 0 10 0 10 1A 12 12 1 16 32 50 000 2 0000 10 10 0 6 12 50 002 20 00 11A 12 0 1A 28 50 0300 1322 135 10 25 50 50 1 10 0 12 13 1A 2 3 0 21 A2 50 000 1105 116 7 10 26 52 000432 CHI-SUUAHt TESTS FOH OUSE GROUP OIFFEHENCES FROM CONTROL G iiS -fi2U ti MALES CHISUUAHt P*UM. FEMALES C-tl- SQUARE PROR. 300 PP" A. T2 0.02H 0.36 0.555 30 PPM ll.OS O . h U 0.00 1.000 cn Significant difference from control at the St level Table 10 Two Year Oral (Diet) Toxicity - Oncogenicity Study o Fluorocarbon FC-143 in Rats Summary of Clinical Observations Initial number of rats Survivors at end of study Mass(es)--b in various areas (Mass{es] resolved prior to term) Alopecia in various areas Swollen throat^ Pale (blanched) eyes and/or appears thin (emaciated) Excessive lacrimation Ataxia Convulsions (clonic) Occasional urinary incontinence and/or hematuria Raiaed ulcerated lesion on hind foot pad(s) Occasional bloody nares Control MF 65 65 100.0 34 25 45.4 19 38 43.8 ( I D ( 7) ( 13.9) 6 14 13 10 15.4 15.4 9 9 13.9 8 12 15.4 42 30 4.6 2.3 54 6.9 70 31 5.4 3.0 300 ppm MF 65 65 100.0 44 29 56.2 10 40 38.5 ( 8) ( 7) ( 11.5) 9 16 29 19.2 8.5 5 8 10.0 9 7 12.3 2 15 20 13.1 1.5 12 2.3 11 06 1.5 4.6 30 -EE" MF 50 50 100.0 36 24 60.0 7 41 48.0 ( 4) 1l 5) ( 9.0) 6 16 4 ,8 22.0 12.0 9 10 19.0 8 5 13.0 59 40 14.0 4.0 34 7.0 50 01 5.0 1.0 000433 ^ -- (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 000434 Occasional bloody feces and/or diarrhea Occasional episode of dyspnea Listing of the head Circular ulcerated area on skin Swollen (distended) abdomen Swelling in inguinal area Swollen leg and/or foot Swollen ears Swollen penis Paresis of hind leg(s)/feet Table 10 Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FC-143 in Rate Summary of Clinical Observations Control NF 20 10 10 43 02 11 30 00 010 300 -EE2. MF 21 10 05 10 20 00 21 01 010 'vi 30 J>E" MF 10 00 12 1, 0 02 00 10 01 1 20 Observations Phthisis Bulbi (Atrophy) Posterior Subcapsular Cataractes) Corneal (ocular) Opacity (Diffused; ulcerated; focal with iris staphyloma; with pannus; partially collapsed). Chronic superficial Keratitis Tabla 11 Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FC-143 in Rata Summary of Clinical Ophthalmologic Findings Bye(s) Right Left Right Left Bilateral Right Left Bilateral Control - 0 ppm MF 01 01 20 21 10 02 02 01 300 ppm MF 33 00 10 10 00 00 00 00 30 ppm NF 13 00 00 00 0P 20 20 00 Right Bilateral 01 10 20 20 00 00 Note: Blood samples were taken via the retro-orbital venus plexus from almost all of the above animals with ophthalmologic abnormalities. 00043 -P 03 000436 (M) Group Malea (1) Control (1) Control (1) Control (1) Control (1) High doae (1) High doae (1) High doae (1) High doae Feaalaa (1) Control (1) Control (1) Low doae P VO Table 11 Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FC-143 In Rata Summary of Clinical Ophthalmologic Findings Eye(a) Description of Abnormality Right Right Bilateral Bilateral Right Bilateral Bilateral Left Left Right Left Chronic uveitia (aecondary to blood aanpling) Diffused lena opacity and chronic iritis with microphthalnos Posterior lena opacity Very pale choroidal circulation Dacryadenitia Chronic uveitia with anterior synechia in right eye Diffused lens opacity Focal, posterior, capaul lens opacity . Chronic uveitia with aecondary exophthalmia Dacryadenitia * Diffused lens opacity with pannua and microphthalmia TABLE 12 THO YEAR ORAL <OIET> T0 X lC 1T Y-UNC06ENICITY STUDY OF FLUOROCARBON FC-1A3 IN RATS MEAN ERYTHROCYTE VALUES MITH STANDARD DEVIATIONS ERYTHROCYTES (CELLS X 10**6) HEMOGLOBIN (G/DL) HEMATOCRIT (* PACKED CELLSI MCV (MICRONS*^! MCH (PICOGRAMS) N MEAN S.DEV MEAN SOEv MEAN S.DEV MEAN S.DEV MEAN S.DEV. MCHC (SI MEAN S.DEV. MALE MONTH 3 0 PPM 300 PPM 30 PP" 15 8.29 0.322 15 T.9I 0.7A3 15 7.87 0.A75 16.4 15.5* 16.1 0.39 0.50 0.67 *5.9 *3.3* **.5 0.96 1.10 1.92 MONTH 6 0 PPM 300 PPM 30 PPM 15 8.42 0.384 15 7.91* 0.350 15 7.58* 0.306 15.1 14.5 14.8 0.94 1.01 0.83 *4.5 43.1 *3.9 2.70 1.64 2.39 MONTH 12 0 PPM 300 PPM 30 PPM 14 8.44 0.554 15 8.01* 0.473 15 8.38 0.354 15.9 15.2 1 15.5 1.17 0.70 0.52 46.7 42.7* *4.5 3.69 1.98 1.88 MONTH 18 0 PPM 300 PPM 30 PPM 15 7.48 2.071 15 7.55* 0.635 15 8.62 1.106 15.1 14.8* 15.8 3.12 1.15 1.52 40.8 40.6 46.1 9.14 3.00 4.41 MONTH 2* 0 PPM 300 PPM 30 PPM cOn 15 7.84 1.083 15 7.92 0.670 1* 7.95 0.869 14.5 14.6 14.7 1.59 1.42 1.23 42.3 43.3 42.5 5.34 5.72 4.22 t P <* .05, THO TAILEO DUNn ETT t ON RAW d a t a . I P < .05. TMO t a i l e d d u n n e t t t b n r a n k e d d a t a 55 1.9 19.8 0.80 35.6 0.47 56 *.3 19.7 1.55 35.8 0.45 57 2.5 20.5 0.83 36.2* 0.55 58 4.3 56 3.0 58* 1.9 17.9 18.4 19.6* 1.41 1.34 0.79 33.9 33.7 33.8 0.77 1.93 1.02 55 2.2 5J* 1.7 53* 1.2 18.8 19*0 18*5 0.84 0.54 0.72 34.0 35.7* 34.8* 0.97 0.76 0.99 56 6.2 21.0 3.09 37.2 1.53 54 2.2 19.6 0.92 36.4 0.69 54 4.6 18.4* 0.93 34.3* 1.40 54 3.4 18.6 1.27 34.4 0.89 55 5.6 18.4 1.10 33.8 1.70 54 2.0 18*6 0.91 34.6 0.78 000437 o o U1 o QO TABLE 12 TWO YEAR OHL (01 T 1 TUXICITY-ONCObNICITY STUDY OF FLUOROCARBON FC-1A3 IN RATS MEAN LEUKOCYTE VALUES WITH STANDARD DEVIATIONS LEUKOCYTES NEUTROPHILS LYMPHOCYTES MONOCYTES EOSINOPHILS (CELLS X 10**3) (CELLS X 10**3) (CELLS X 10**31 (CELLS X 10**3) (CELLS X 10** N MEAN S'DEV. MEAN S'DEV' MEAN S'DEV. MEAN S'DEV. MEAN S.DEV. MALE MONTH 3 0 PPM 300 PPM 30 PPM MONTH 6 0 PPM 300 PPM 30 PPM MONTH 12 0 PPM 300 PPM 30 PPM MONTH 18 0 PPM 300 PPM 30 PPM MONTH 24 0 PPM 300 PPM 30 PPM 15 12 .73 2.07* 15 1* .93 2.R01 15 15 .22* 3.052 1.65 1.5 2.1* 0.656 0.936 0.870 10. 72 1:B03 13. oa* 2 5206 12. 83* 2 5861 0.1 0.10 0.17 0.196 0.102 0.173 0.17 0.16 0.11 0.136 0.176 0.157 15 10.7* 2.*23 15 12.72 2.160 15 1* .*6* 3.223 1 A3 1 .99 1.92 0.727 0.989 1.1*6 8.85 25*16 10.06 25316 11.81* 25978 0.2* 0.38 0.33 0.180 0.15* 0.235 0.17 0.20 0.31 0.121 0.227 0.362 16 7.9* 1.572 15 8.1A 1.789 IS 10.38* 1.7*7 1.10 0.612 2.26* 0.656 2.21* 1.396 6.35 5.36 7.5 15256 15246 25151 0.40 0.3V 0.44 0.216 0.247 0.233 0.10 0.14 0.18 0.107 0.105 0.117 15 11.41 7.325 15 9.91 1 .479 15 11.16 5.157 5.06 2.78 2.55# 6.402 1.657 3.353 5.61 15504 6.30 15070 8.20* 25568 0.5* 0.69 0.30* 0.405 0.294 0.190 0.16 0.20 0.11 0.128 0.156 0.163 15 10.79 7.529 15 9.09 2.351 14 10.44 3.464 3.72 2.41 3.24 5*666 1.488 2.032 6.66 6.34 6.72 25140 15619 25171 0.34 0.26 0.3* 0.398 0.176 0.292 0.08 0.08 o.ov 0.083 0.109 0.106 1 P <* .05' TWO TAILED OUNNETT T ON RAW OATA. A I P <* .05' TWO TAILEO OUNNETT T ON RANKED DATA. 6H)00 DOSE 0 HP" 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM a PPM 0 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PP" 300 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 30 PPM animal A1R3518 A1R3527 A1R3532 A1R3534 A1R3S37 A1R3540 A1R3542 A1RJ548 A1R3552 A1R3559 A1R3S62 A1R3564 A1R3S6S A1R3567 AIR3S69 B1R3585 R1R3587 B1R35R9 R1R359? R1R3593 81R359S R1R3604 81R3605 R1R3610 RIR3611 RIR3617 RIR3623 8193634 81P3640 81R3643 C1R3654 C1R3655 C1R3665 C1R3667 C1R366H C1R3673 C1R3675 C1R3677 C1R3679 C1R3683 C1R3687 CIR3690 C1R3691 C1R3692 C1R1695 FRVTH 8.10 7.77 8.69 8 . IS 7.71 8.04 8.70 8.13 8.20 8.63 8.73 8.37 8.41 8.24 8.46 7.33 7.83 7.67 7.73 6.09 7.81 7.77 7.64 7.99 8.27 7.70 9.02 8 . IS 8.17 9.44 7.10 7.8S 7.77 7.88 8.31 B.?7 7.30 8.58 8.41 7.83 8.37 7.01 7.90 7.91 7.52 HE MO 16.1 15.5 16. S 16.3 16.3 lbT 16.8 16.5 16.6 16.4 IS.6 16.6 16.3 16.8 16.6 15.0 16.0 1S.1 15.0 14.7 15.5 14.8 15.4 15.5 15.9 16.0 16.0 15.8 15.5 16.3 15.6 15.7 15.8 16.5 17.0 16.0 15.0 16.5 16.6 16.5 17.6 15.5 15.8 16.0 15.6 TABLE 12 TWO YtAH OHAL (DIET TOXIC ITY-ONCOGENICITY ST UD Y OT E L U O W O C A H H O N E C - 1 4 3 IN MA LE HA TS In d i v i d u a l h e m u o k a m v a l u e s - MONTHS* HERAT MtV m c h MCHC WHC 45 55.5556 19.8766 35.7778 12.60 44 56.6261 19.9486 36.2273 11 .00 46 52.9344 l.9d73 35.869* 10.00 45 55.2147 20.0000 36.2222 13.30 45 56.3658 21.1414 36.2222 11.30 46 57.2139 20.7711 36.3043 12.60 47 54.0230 19.3103 35.7447 12.60 47 57.8106 20.2952 36.1064 15.50 46 56.0976 20.2439 36.0870 14.00 46 53.3024 19.0035 35.6622 11.60 45 51.5464 17.8694 34.6667 11.90 47 56.1529 19.8 127 35.3191 12.60 46 S4.69b6 19.3817 35.4348 9.58 47 57.0388 20.3883 35.7447 15.50 47 55.5556 19.6217 36.3191 17.00 42 57.2908 20.4638 35.7143 14.20 44 56.1941 20.4342 36.363* 14.30 43 56.0626 19.6871 35.1163 13.40 43 55.6274 19.4049 34.8837 19.60 41 67.3235 24.1379 35.8537 10.70 43 65,0576 19.8464 36.0465 13.90 42 54.0541 19.0476 35.2381 14.00 43 56.2827 20.1571 36.8140 15.20 43 53.8173 19.3992 - 36.0465 21.70 44 53.2044 19.2261 36.1364 17.90 44 57.1429 20.7792 36.36.16 14.40 45 49.8891 17.7384 35.5556 13.60 46 53.9877 19.3665 35.9091 14.70 43 52.6316 18.9718 36.0465 12.20 45 47.b695 17.2669 36.2222 14.30 43 60.5634 21.9718 36.2791 16.40 42 53.5032 20.0000 37.3810 10.40 43 55.3411 20.3346 36.7442 12.70 45 57.1066 20.9391 36.6667 14.70 46 55.3550 20.4573 36.9565 11.50 44 53.2044 19.3470 36.3636 15.10 42 57.5342 20.5479 35.7143 17.00 46 53.6131 19.2 108 36.669* 14.50 4b 54.6968 19.T 184 36.0670 20.80 4b 58.7484 21.0728 35.869* 17.20 4V 58.5424 21.0276 35.9184 15.70 43 61.1664 22.0484 36.0465 14.60 45 56.9620 20.0000 36.1111 21.30 44 66.6258 20.2276 36.363* 13.40 43 67.1809 20.7447 36.2791 12.80 pmnab 1.3860 1.6500 1.0000 1.3300 2.4860 1.8750 1.3860 2.6350 1.9600 1.0350 2.2610 1.3860 0.7664 2.7900 0.8500 1.1360 1.7160 1.0720 2.1560 0.5350 1 .2510 0.4200 2.1280 3.6890 1.9690 3.0240 1.3500 0.5880 0.7320 2.0020 2.2960 0.5200 2.1590 2.3520 2.4150 2.6670 3.4000 2.3200 2.2880 1.7200 0.9420 1.3320 3.4080 3.2160 1.1520 LYMAH MONOAB 10.9620 9.0200 8.9000 11.5710 8.8140 9.8750 10.9620 12.0900 11.4600 10.1200 9.4010 10.8360 8.8136 12.5550 15.4700 13.0640 12.4410' 11.92b0 17.2480 10.0580 12.3710 13.3000 12.9200 17.7940 15.3940 11.0880 11.6100 13.9650 11.3460 11.7260 13.9400 9.8800 10.5410 11.7600 8.7400 12.3820 12.7500 12.0350 18.5120 15.4800 14.6010 13.0240 17.8920 9.6480 11.2640 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 ' 0.000 0.000 0.268 0.000 0.107 0.139 0.000 0.000 0.217 0.000 0.288 0.135 0.147 0.122 0.143 0.164 0.000 0.000 0.441 0.345 0.151 0.510 0.000 0.208 0.000 0.157 0.296 0.000 0.000 0.256 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 0.000 0.143 0.134 0.196 0.000 0.139 0.280 0.152 0.000 0.537 0.000 0.405 0.000 0.000 0.429 0.000 0.000 0.000 0.147 0.000 0.000 0.340 0.145 0.208 0.000 0.000 0.148 0.000 0.536 0.128 TABLE 12 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAL A1R3519 A1R3524 A1R3529 A1R3533 A1R3537 A1R35A1 A1R3SA7 A1R3550 A1R3S53 A1R3SS7 A1R3559 A1R3S62 A 1R3567 A1R35T3 A 1R3575 B1R3583 B1R350A B1R3596 B1R3598 B1R3600 R1R360* RlR3S0ft B1R3A09 R1R3613 BIR3617 R1R3628 BJR3029 R1R3631 B1R3633 R1R3642 C1R3646 CIR3650 C1R3656 C1R3S58 C1R3660 C1R3664 C1R3665 ClR3hh7 CIR3679 C1R3680 C1R3682 C1R3887 C1R3S89 C1R3691 CIR369* ERYTM 8.2* 8 . SI 8.23 8.30 8.13 8. *2 7. *0 8.38 8.30 8.95 9.03 8.58 8.69 8.70 8.*4 8.16 7.93 7.63 7.71 8.27 7.79 A.08 8.00 8.03 7.01 8.32 8.07 8.03 7.42 8.20 7.48 7.79 7.71 7.60 7.58 7.SI 6.95 7.65 7.95 7.31 7.99 7.95 7.OS 7.7? 7.44 MEMO 15.0 14.4 14.6 15.7 15.9 15.9 14.8 15.4 15.6 1 3.0 16.2 14.8 16.2 15.0 13.5 14.8 14.5 11.7 15.1 15.6 13.8 14.ft 15.7 15.0 15.1 14.4 14.2 14.8 13.3 15.2 14.7 14.8 15.7 15.3 14.2 14.8 14.0 15.2 15.8 14.0 14.5 16.7 14.1 15.2 1 3.6 TwO YEAR (JMAL (OItT) TOa IC ITY-ONCOGE NIC ITY STUDY Of FLUOKtCAHhON FC-143 IN MALE WATS INO IVIOUAL HEMOGRAM VALUES M0NTH=6 hemat MCV m c h MCHC WMC 46 55.8252 18.2039 32.6087 7.70 4? 49.3637 16.9213 34.2857 8.98 44 S3.4b29 17.7*00 33.1818 11.70 45 54.2169 16.9157 34.8889 9.96 47 57.8106 19.5572 33.0298 9.14 46 54.6318 18.8836 34.5652 9.83 44 59.4595 20.0000 33.6364 14.00 45 53.6993 18.3771 34.2222 7.71 46 55.4217 18.7952 33.9130 10.90 37 41.3408 14.5251 35.1351 13.40 47 52.04H7 17.9*02 34.4661 8.20 45 62.4476 17.2494 32.0889 10.70 47 54.0862 18.6421 34.4681 11.30 45 51.72*1 17.2*14 33.3333 11.30 41 48.5782 15.99*3 32.9268 16.30 43 52.6961 18.13/3 34.4186 13.40 42 52.9634 18.PH50 34.5238 11.70 43 56.3565 15.33*2 27.2093 12.70 43 55.7717 19.5850 35.1163 9.74 44 53.20*4 18.8634 35.45*5 15.30 41 52.6316 17.7150 33.6585 12.00 43 53.2178 16.3168 3*.4186 10.60 46 57.5000 19.6250 34.1304 12.60 44 54.7946 18.6800 34.0909 13.80 45 64.1940 21.5*07 33.5556 10.50 44 52.88*6 17.3077 32.7273 12.70 43 51.2838 17.5960 33.0233 18.70 43 53.5492 18.4309 34.4186 11.50 39 52.5606 17.9248 3*.1026 12.60 44 53.6585 18.5366 34.5456 12.10 44 58.8235 19.6524 33.4091 14.80 45 57.766* 18.9967 32.8889 15.30 45 56.3658 20.3632 34.8869 16.90 42 55.2632 20.1316 36.*266 9.05 42 55.*090 18.7335 33.8095 14.10 43 57.2570 19.7071 3*.*166 13.40 41 58.992m 20.1*39 3*.1*63 11.20 45 58.8235 19.8693 33.7778 14.00 46 57.8616 19.8742 3*.3*78 20.50 41 56.0876 . 19.1518 34.1*61 14.00 45 56.3204 18.1477 32.2222 19.00 SO 02.6931 ' 21.0063 13.4000 9.11 4? 59.57*5 20.0000 31.5714 13.10 45 58.2902 19.6691 33.7776 17.50 4? 56.% 5 1b 18.2796 32.3610 15.00 PMNAB 1.3090 1.2572 1.0530 1.5936 1.6*52 0.9830 1.2600 1.6962 3.5970 1.7*20 0.5740 1.1770 0.3390 1.5820 1.6300 1.0720 1.1700 1.6510 3.6038 1.9890 1.1520 3.2060 2.0160 4.0020 1.9950 0.8890 2.6180 0.9200 2.0160 1.4520 1.6280 0.4590 4.2250 3.1675 2.9610 2.5460 1.7920 2.2400 1.6400 1.8200 3.2300 0.0911 0.7860 1.0500 1.2000 LYMAB MONOAB 6.0830 7.6330 10.4130 7.9680 7.0378 8.3555 12.0400 5.62b3 6.6490 11.1220 7.0520 H.8810 10.7350 9.0*00 14.1810 10.7200 ' 10.0620 10.5410 5.8440 13.1580 10.7520 6.7840 10.2060 8.4180 8.0850 11.1760 15.3340 10.0050 9.7020 10.1640 12.2840 12.5460 11.9990 5.3395 10.7160 10.3180 8.7360 11.2000 17.0150 11 .6200 15.5800 8.7*56 12.0520 15.7500 13.2000 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 0.1340 0.4680 0.5080 0.2922 0.1530 0.38*0 0.4240 0.1260 0.5520 0.2100 0.3810 0.5610 0.4600 0.5040 0.4840 0.7400 0.6120 0.1690 0.1810 0.4230 0.1340 0.5600 0.5600 0.4100 0.2800 0.1900 0.0000 0.1310 0.5250 0.0000 EOSAB 0.0770 0.0B98 0.0000 0.2988 0.2742 0.2949 0.2H00 0.0000 0.2180 0.2680 0.3280 0.1070 0.2260 0.1130 0.0000 0.1340 0.0000 0.0000 0.0974 0.0000 0.5120 0.1060 0.2520 0.8280 0.2100 0.2540 0.1870 0.1150 0.3780 0.0000 0.1*80 0.1530 0.5070 0.3620 0.0000 0.4020 0.1120 0.0000 1.4350 0.2800 0.0000 0.3644 0.1310 0.1750 0.6000 000440 TABLE 12 OOSE 0 PPH 0 PPM 0 PPM 0 PPM 0 PPM Q PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM I) PPM 0 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 POM 30 PPM 30 PPM ANIMAL A1H3516 A1R35IT A1R3520 A1R3522 AIH352T A1R3535 A1R3S43 A1R354A A1H3550 A1R3551 A1R35S4 A1H356B A1R3570 A1R3575 A1R3S80 81*0584 81*0588 B 1*0589 B1R3592 81*0598 B1R3604 B1R3A13 61*0617 R1R3620 BlR3b22 B1H3626 81*0627 H1R3638 81*43642 81*43643 C 183649 0*43650 C1R3652 0*43663 C1P366B 0*43670 C1R3672 083676 083679 0 83680 OH3681 083683 C 183685 0 83691 083694 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 7.78 8.06 8.15 6.60 7.68 8.04 8.07 8.83 7.89 8.16 8.13 8.01 8.12 8.30 8.38 8.57 8.69 8.29 8.87 8.19 8.05 8.00 9.02 8.59 7.97 7.89 8.10 8.76 8.33 8.41 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 15.0 15.6 14.9 13.4 14.8 14.7 15.5 16.6 14.9 15.6 15.5 15.7 15.3 15.7 15.3 16.2 15.7 14.8 15.6 15.7 15.3 14.9 16.1 16.2 14.6 15.3 16.1 15.3 15.6 15.1 TWO Yt AH OWAL 4011:T ) T O X 1C 1T Y - 0 N C 0 6 E N 1 C I TV STUOY OF FL UO HO CA KH ON F C - U 3 IN HALE RATS INDIVIDUAL HEHOGHAH VALUES ----------------- - MONT Ha 12 -------------- * ---- hemat 48 45 45 47 46 45 48 55 51 47 46 47 38 46 42 44 41 38 41 44 43 47 4? 43 42 4* 43 44 43 46 47 43 47 45 43 42 47 45 42 42 45 46 45 43 MCV 57.6230 55.7621 53.0035 55.4900 52.0362 53.1287 53.5117 5H.0781 55.9211 55.4245 58.3756 56.6948 52.2696 57.2139 53.9846 54.5906 50.3067 57.5758 53.3854 54.7264 53.2838 53.2276 53.2319 52.6961 51.6605 54.9313 52.9557 53.0120 51.3126 53.6756 54.0852 51.8697 52.9876 54.9451 53.4161 52.5000 51.7052 52.3865 52.6976 53.2319 55.5556 52.5114 54.0216 51.1296 MCH mchc 18.7275 19.4548 18.4923 19.3625 17.7602 18.4179 18.2832 19.1130 17.9825 18.6321 20.0508 19.7829 17.1939 19.7761 19.2802 19.3548 18.2822 20.3030 19.2708 18.2836 19.2069 18.7995 18.8847 19.1176 19.0652 19.6005 18.8424 18.9157 18.2578 18.9032 18.0667 17.8528 17.5874 19.1697 19.0062 18.6250 17.7118 18.8591 18.3187 19.3916 19.8765 17.4658 18.7275 17.9548 32.5000 34.8889 34.8889 34.8936 34.1304 34.6667 34.1667 32.9091 32.1569 33.6170 34.3478 34.8936 32.8947 34.5652 35.7143 35.4545 36.3415 35.2632 36.0976 33.4091 36.0465 35.3191 35.4762 36.2791 36.90*8 35.6818 35.5814 35.6818 35.5814 35.2174 33.4043 34.4186 33.1915 34.8889 35.5814 35.4762 34.2553 36.0000 34.7619 36.4286 35.7778 33.2609 34.6667 35.1163 wee 7.9 5.2 6.8 9.2 7.4 9.1 6.9 8.2 5.7 9.2 # 8.0 7.0 9.9 10.7 7.6 5.6 6.8 6.9 8.1 8.5 9.7 4.7 8.2 9.3 9.1 9.3 6.7 10.3 11.3 11.5 7.7 9.0 8.0 8.6 10.2 12.4 13.9 12.2 10.2 11.9 10.5 9.3 10.4 9.9 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 2.660 1.232 1.836 1.932 2.511 2.380 2.522 1.175 2.214 3.069 2.639 3.162 1.206 2.369 2.938 2.185 2.233 2.160 1.120 3.354 4.692 1.364 4.170 1.586 4.590 0.238 0.840 1.488 2.184 0.891 LYMA8 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 4.332 4.088 4.148 4.347 5.184 5.610 6.402 3.431 5.412 5.115 6.097 5.487 5.293 7.622 7.797 8.510 4.466 6.390 6.400 4.730 5.100 10.416 8.896 9.882 5.202 11.067 9.450 7.347 7.176 8.316 MONOAB 0.632 0.156 0.476 0.460 0.51B 0.819 0.276 0.574 0.228 0.184 0.240 0.070 0.594 0.428 , 0.380 0.224 0.612 0.414 0.324 0.510 0.485 0.000 0.492 1.023 0.182 0.279 0.134 0.206 0.565 0.575 0.693 0.360 0.400 0.344 0.102 0.372 0.834 0.488 0.204 0.357 0.210 0.372 0.936 0.297 EOSAB 0.158 0.000 0.068 0.276 0.000 0.182 0.000 0.082 0.000 0.184 0.080 0.070 0.000 0.321 0.228 0.056 0.204 0.207 0.081 0.000 0.291 0.094 0.082 0.093 0.182 0.372 0.134 0.103 0.000 0.230 0.308 0.090 0.080 0.172 0.306 0.248 0.000 0.244 0.204 0.238 0.000 0.093 0.104 0.396 Tul) Yk STUDY DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PM 1) PPM 0 PPM 0 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAL AIM3519 A1R3521 A1R3528 A1H3S31 A1R3538 AIH3539 A1R3542 A1R3552 A1R3S53 A1R3555 A1R3S61 AlR3Sb5 A1R3567 A1R3574 AIH3577 8183583 B1H3593 8183596 8183600 R1R360I R1R360S 8183608 R1R3610 B1H3612 HIR361S 81H362A 81R3632 R1R3641 B1R3644 B1R3645 1*3647 Cl3651 C1R3654 C1R3658 C1R3662 C1R3663 C1R3664 C1R3667 C1R366B C1R3676 CIR3679 C1R3681 CIR36B5 C1H3689 C1R369S ERVTM 8.2 P.48 8.92 8.43 8.23 8.14 8.79 8.17 ".32 7.99 9.06 4.75 8.25 3.59 8.04 6.04 6.88 7.84 7.28 7.05 7.82 7.71 7.11 7.59 8.03 8.16 8.55 7.48 8.31 7.36 6.20 8.70 8. 19 8.98 11.48 9.21 9.26 7.95 8.79 8.90 8.90 7.65 8.74 8.37 8.02 MEMO 15.3 7.2 16.5 16.9 15.9 16.4 16.8 16.8 16.9 15.8 17.6 12.3 16.4 8.9 16.7 11.8 13.8 15.6 13.9 14.6 16.0 14.2 15.5 14.7 15.6 14.9 16.6 14.3 15.5 14.6 11.7 16.3 15.6 15.9 19.1 16.1 16.5 16.5 16.2 16.2 16.5 14.8 15.9 15.2 14.7 HERAT 44 18 44 46 45 43 47 44 45 43 48 31 46 23 45 33 39 43 38 40 44 39 41 40 42 4P 45 39 44 40 35 47 45 47 53 47 48 54 47 46 46 41 46 46 44 000442 TABLE 12 AH UH*L (DIET) TUAIClTY-ONCOliENlCITY OF FLUOHUCAHhON FC- 141 IN MALE HATS INDIVIDUAL rtEHOOHAN VALUtS MONT He 1H MCV 52.2565 72.5006 49.3274 54.5670 54.6780 52.8256 53.4699 53.H556 54.0b65 53.8173 52.9801 65.2632 55.7576 64.0669 52.0833 54.6358 56.6h60 54.8469 52.1976 56.7376 56.2660 50.583T 57.6653 52.7009 52.3039 51.4706 52.6316 52.1390 52.94,83 54.347H 56.4516 54.0230 54.94,51 52.3385 46.1672 51.0315 51.8359 67.9245 53.4699 5 1.6654 51 .6654 53.594H 52.6316 54.9562 54.6626 MCH 18.1710 29.0323 18.4918 20.0474 19.3196 20.1474 19.1126 20.5630 20.3125 19.7747 19.4260 25.6947 19.6788 24.79(1 19.3267 19.5364 20.0561 19.6980 19.0934, 20.7092 20.4604 18.4176 21.6003 19.3676 19.4271 18.2598 19.4152 19.1176 18.6522 19.8370 18.6710 1 8 . /35b 19.0476 17.7060 16.63/6 17.4810 17.8186 20. /S47 16.4300 18.2022 18.5393 19.3464 18.1922 18.1601 18.3292 MCHC 34.7727 40.0000 37.5000 36.7391 35.3333 38.1395 35.7447 38.1618 37.5556 36.7442 36.6667 39.6774 35.6522 38.6957 37.1111 35.7576 35.3846 36.2791 36.5789 36.5000 36.3636 36.4103 17.8049 36.7500 37.1429 35.4762 36.8889 36.6667 35.2273 36.5000 33.4286 34.bH09 14.6667 31.8298 16.0377 34.2553 34.3750 30.5556 34.4681 35.2174 35.8696 16.0976 34.5652 31.0435 13.4091 BHC 10.0 35.4 H.7 9.1 6.1 7.3 7.8 9.9 6.7 8.7 9.7 10.5 12.1 19.4 9.7 9.6 6.7 9.0 9.6 9.8 9.3 11.A 9.5 13.6 9.2 10.5 11.2 9.3 10.0 9.9 21.9 10.5 9.5 6.5 21.5 9.3 8.7 7.6 6.7 16.1 12.5 14.5 8.6 7.1 6.4 PMNAB 4.400 26.196 4.176 1.729 1.769 3.139 2.418 2.574 2.211 1.218 3.977 4.725 3.872 12.028 1.455 1.440 2.680 2.070 1.440 2.352 1.209 5.700 1.805 7.208 2.11b 3.360 3.584 2.046 2.700 1.980 11.826 1.260 0.570 1.560 7.955 1.953 0.609 0.608 0.402 5.474 0.375 1.740 3.010 0.426 0.448 LYHA8 HONOAB 4.600 7.080 4.17b b. 734 3.904 3.577 4.836 6.336 3.953 b.960 4.850 4.725 8.107 6.790 7.469 7.584 ' 4.020 6.300 7.488 6.664 7.533 4.78a 6.935 4.896 5.980 5.985 b. 496 5.859 6.700 7.227 9.198 8.715 8.740 4.680 12.900 6.975 7.830 6.916 5.963 9.660 11.750 12.180 5.332 6.319 5 b24 1.000 1.770 0.261 0.546 0.244 0.438 0.460 0.594 0.402 0.435 0.485 0.945 0.121 0.388 0.679 0.400 0.000 0.450 0.384 0.490 0.465 0.684 0.760 0.952 0.828 1.155 0.784 1.023 0.500 0.495 0.65 7 0.420 0.095 0.130 0.645 0.372 0.261 0.076 0.335 0.322 0.250 0.435 0.258 0.284 0.000 EOSA8 0.000 0.354 0.087 0.091 0.183 0. 146 0.078 0.396 0.134 0.087 0.380 0.105 0.000 0.194 0.097 0.096 0.000 0. 180 0.288 0.294 0.093 0.228 0.000 0.544 0.276 0.000 0.336 0.372 0.100 0.198 0.219 0.105 0.095 0.130 0.000 0.000 0.000 0.000 0.000 0.644 0.125 0.145 0.000 0.071 0.120 TABLE 12 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAL A1R351A A1R352A A1H3528 M3531 AIR3S34 A1B3538 AIR3542 A1R3548 A1B3554 A1R3557 A1R3562 A1R356A A1H3569 A1R3573 AIR3S78 R1H3581 R1R3SH5 B 1R 3501 H1R3594 R1R3597 PIR3801 BIR3605 B1R360B B1R3611 R1R3618 R1R3623 H1R3630 B1R3633 B1R3636 H1R3641 C1R3646 C1R36S0 C1R3654 C1R3858 C1R3663 C1R3667 C1R3670 C1R3672 C1R3676 C1R3670 CIR3682 C1R3684 C1R3689 C1R36R) C1R3694 ERYTH 7.44 8.08 8.70 8.33 7.06 8.54 8.86 8.09 b.08 9.47 7.74 7.68 5.38 8.52 6.70 8.42 7.94 7.9R 8.17 8.03 6.21 8.02 8.21 8.06 8.58 8.00 8.59 6.51 8.15 7.92 8.35 7.90 8.96 8.34 7.34 7.21 8.87 5.93 9.14 8.37 7.73 8.14 6.97 8.0? HE MO 13.1 14.4 15.5 16.0 15.3 15.1 16.0 15.6 11.8 16.7 13.2 14.4 12.0 16.1 12.7 15.5 14.8 16.0 14.4 15.3 12.0 15.8 13.6 15.2 15.3 15.6 16.3 11.6 13.4 13.8 15.0 14.2 16.0 15.2 15.2 13.7 15.4 11.2 15.7 15.1 14.7 15.2 13.4 15.3 T*0 YtAW OWa L <I)11 T ) rUAlCITY-ONCOUENICITY STUUY of FLuOHOCAWhON F C - U 3 IN HLt MATS INOlVlUUAL HEMOUKAM VALUtS 90NTH=2* HERAT MCV MCH MCHC MHC 37 49.7312 17.6075 35.4054 13.2 43 53.2178 17.8216 33.4884 6.6 45 51.7241 17.6161 34.4444 7.2 47 56.4226 19.2077 34.0426 8.4 46 57.7889 19.2211 33.26*9 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 .*.079 34.7059 4.4 50 52.7983 17.6346 33.4000 8.0 37 47.8036 17.0543 35.6757 12.6 4? 54.6875 18.7500 34.2657 12.4 33 61.3383 22.3048 36.363b 9.7 47 55.1643 18.8967 34.2553 7.4 37 55.2239 18.9552 34.3243 12.7 46 54.6318 18.4086 33.6957 6.2 43 54.1562 18.6398 34.4186 10.5 48 60.1504 20.0501 33.3333 8.4 43 52.6316 17.0255 33.4884 5.7 44 54.7945 19.0535 34.7727 8.7 35 56.3607 19.3237 34.2837 9.6 53 66.0848 19.7007 29.8113 6.3 39 47.5030 16.5652 34.8718 9.8 43 53.4826 18.9055 35.3488 11.0 45 52.4476 17.322 34.0000 8.2 52 65.0000 19.5000 30.0000 9.5 48 55.8789 \8.975b 33.9583 7.5 33 50.6912 17.8187 35.1515 14.2 38 46.6258 16.4*17 35.2632 12.6 40 50.5051 17.4242 34.6000 8.2 45 53.8922 17.9641 33.3333 9.3 41 51.8987 17.9747 34.6341 13.1 47 52.4554 17.8571 34.0426 5.0 44 52.7578 18.2254 34.5455 8.7 43 58.5831 20.7084 35.3488 7.4 39 54.0915 19.0014 35.1282 12.8 46 51.8602 17.3619 33.4783 14.7 31 52.2766 18.8870 36.1290 18.0 46 50.3282 17.1772 34.1304 12.5 44 52.5687' 18.0406 34.3182 10.2 4? 54.333 ' 19.0166 35.0000 9.5 45 S5.2M26 18.6732 33.7778 7.4 38 54.5194 19.2253 35.2632 10.4 44 54.8628 19.0773 34.7727 7.2 PMNAB 3.036 1.632 0.432 1.092 22.506 1.564 0.710 1.445 0.264 1.840 5.922 4.712 0,776 1.554 8.255 0.666 2.100 3.526 0.741 2.697 4.606 1.197 1.662 1.540 1.722 1.805 1.050 4.544 5.544 2.378 5.208 3.537 1.400 2.349 1.776 4.096 7.644 6.120 2.37b 4.590 1.900 1.850 1.976 0.57b lymah 9.106 4.760 6.624 6.972 12.342 5.256 6.246 6.865 4.136 6.000 b. 300 6.820 8.924 5.328 4.191 4.960 6.085 4.620 4.645 5.655 4.416 5.040 7.742 8.910 6.232 7.410 6.300 9.514 5.922 5.494 3.613 8.908 3.450 5.829 5.254 7.808 6.468 10.600 9. 75U 5.202 7.410 4.958 7.904 b.552 MONOAB 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 0.372 0.210 0.252 0.114 0.261 0.384 0.000 0.196 0.330 0.246 0.190 0.075 0.142 0.756 0.328 0.279 0.655 0.100 0.435 0.222 0.768 0.568 1.080 0.125 0.306 0.190 0.370 0.208 0.072 E0SAB 0.132 0.068 0.144 0.000 0.000 0.072 0.071 0.000 0.000 0.080 0.000 0.246 0.000 0.222 0.127 0.000 0.105 0.000 0.000 0.08 V 0.192 0.063 0.000 0.220 0.000 0.095 0.075 0.000 0.378 0.000 0.000 0.000 0.050 0.087 0.148 0.128 0.000 0.000 0.250 0.102 0.000 0.222 0.312 0.000 000443 O O en lis tfk TABLE 13 TNO VEAR ORAL (DICTI TOXICI TY-ONCOGENICITY SltfDY OF FLU0H9CARBON FC-1A3 IN RATS ME AN ERYTHROCYTE VALUES NI TH STANOAHO DEVIATIONS ERYTHROCYTES (CELLS X 10**6> HEMOGLOBIN CG/DL) HEMATOCRIT ( PACKED CELLS) MCV (MIORONS**3) MCh 4PICOGRAMSI N MEAN S.OEV MEAN S*DEV. MEAN S.OEV. MEAN S.DEV MEAN S.OEV. MCHC (I MEAN S.OEV. FEMALE MONTH 3 0 PPM 300 PPM 30 PPM MONTH 6 0 PPM 300 PPM 30 PPM MONTH 12 0 PPM 300 PPM 30 PPM MONTM 10 0 PPM 300 PPM 30 PPM MONTH 24 0 PPM 300 PPM 30 PPM 15 6.91 0.319 15 6.67 0.266 15 7.26 0.505 15.0 15.4 16.0 0.40 0.56 0.70 43.7 42.0 43.9 t.ll 1.05 1.75 15 7.32 0.413 15 7.37 0.327 15 6.92* 0.475 15.0 15.4 13.7* 0.55 0.64 0.95 42.3 42.5 SB. 7* 1.04 1.60 3.20 15 7.60 0,>300 15 6.92 1..193 15 7.29 1..212 15.6 14.6 15.1 0.40 1.74 1.70 44.3 40.5 42.5 1.39 9.73 4.76 15 7.37 0.660 15 7.24 0.009 15 7.01 0.763 15.4 14.9 14.8 1.43 1.33 1.32 42.9 41.9 41.5 4.13 9.06 3.05 15 7.06 1.129 15 7.14 0.744 15 7.06 1.097 14.8 14.4 14.6 1.00 1.26 2.03 42.3 40.4 41.7 i.40 3.66 5.97 1 P < .05. TMO TAILED OUNn ETT T ON RAN DATA. P <* .05, THO TAILED DUNNETT T ON RANKED DATA. 69 2.2 69 2.3 61* 3.5 22<9 23.0 22*1* 0.75 0.63 1.37 36.2 36.6 36.3 0.44 0.50 0.49 50 2.2 20.6 0.95 35.4 1.01 50 2.2 21.0 0.93 36.3 0.03 56 4.9 19.9 1.93 35.5 1.65 58 2.1 20.6 0.71 35.3 0.40 60 0.1 21.5 3.19 36.0 1.20 59 6.0 21.0 2.47 35.5 0.64 50 1.7 21.0 0.60 36.0 0.05 50 2.6 20*7 0.96 35.6 0.52 59 3.0 21.2 1.09 35.0 0.65 60 3.5 50* 2.1 50 2.5 21.2 20.3* 20.7 1.45 0.74 0.91 35.1 35.6 35.0 0.07 0.99 0.01 TABLE 13 TMO YEAR ORAL (DIET) T O X I C I T Y - O N C O G E N I C I T Y STUDY OE F L U O R O C A R B O N EC -1 43 IN RATS MEAN LEUKOCYTE VALUES WITH STANDARD DEVIATIONS LEUKOCYTES NEUTROPHILS LYHPHOCVTES MONOCYTES EOSINOPHILS ICELLS X 103> ICELLS X 103> CELLS X I0**3I ICELLS X 103I ICELLS X 10*3I N m e a n S.OEV. m e a n SDEV MEAN S.OEV MEAN S.DEV. MEAN S.OEV. FEMALE MONTH 3 0 PPM 300 PPM 30 PPM MONTH 6 0 PPM 300 PPM 30 PPM MONTH 12 0 PPM 300 PPM 30 PPM MONTH 10 0 PPM 300 PPM 30 PPM MONTH 24 0 PPM 300 PPM 30 PPM 15 18.98 2.698 15 18.51 3.778 15 18.06 3.470 2.57 3.24 3.33 1.406 15.73 1.728 . 14.78 1.347 14.23 27970 27834 31105 0.37 0.28 0.22 0.217 0.312 0.250 0.31 0.22 0.30 0.262 0.258 0.258 15 7.52 2.559 1.44 1.566 15 8.60 1.953 1.55 0.705 15 7.18 1.723 1.76 1.023 5.87 6.73 5.06 27160 17784 17607 0.18 0.20 0.28 0.096 0.122 0.142 0.08 0.11 0.15 0.067 0.102 0.119 15 5.73 2.120 15 5.72 1.818 15 5.83 1.135 1.27 1.45 1.34 1.562 1.281 0.679 4.13 3.95 4.13 17049 17061 0 7792 0.21 0.22 0.25 0.108 0.165 0.098 0.12 0.09 0.10 0.125 0.094 0.091 15 5.75 2.230 1.01 1.631 15 6.30 2.368 2.21 1.950 15 6.83 2.608 2.69* 2.240 4.48 3.62 3.51* 07973 17305 17061 0.29 0.36 0.36 0.249 0.226 0.148 0.03 0.057 0.10* 0.108 0.07 0.074 15 6.73 4.064 2.87 2.959 15 6.39 1.691 2.15 0.962 15 8.57 3.434 3.44 2.915 3.61 4.04 4.81 17329 17190 17641 0.11 0.10 0.24 0.151 0.062 0.241 0.07 0.06 0.08 0.074 0.057 0.094 I P O .OS, TMO TAILED DUNNETT T ON RAM U A T A I P * * .05, TMO TAILED DUNNETT T ON RANKED DATA. 000445 000446 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAL N1R4S76 N1R4578 NIR4582 N1RAS83 N1R4584 N1H4592 N1R4610 N1R4612 N1R4613 N1R4619 N1R462I N1R4626 N1H4627 NIR4633 N1R46A0 01R4645 01R4654 01R4660 01R4664 0184668 0)84669 01H4672 01H4673 01R4674 0184679 01R4680 0184693 01R4698 0184700 0IR4701 P1R4708 P1R4710 P1R4720 PIR472I P1R4730 P1R4731 P1M4734 PIR4735 P1R4736 P1R4737 P1R473B P1R4T44 P1R4749 P1R47S? P1R4753 ERYTH 6.98 7.72 6.79 6.74 6.31 7.03 6.94 6. HR 6.73 7.35 6.60 6.9A 6.A4 6.84 6.99 6.51 6.77 6.34 6.36 7.02 6.99 6.35 6.42 6 . HR 6.72 6.46 6.RR 6.99 6.92 6.42 7.79 6.95 6.83 6.71 7.44 6.80 6.41 7.65 7.8 7.12 7.40 7.14 7.05 8.30 7.39 HE MU 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 16.2 14.6 14.8 15.8 15.5 14.8 14.8 16.1 14.7 15.4 15.2 15.9 16.1 15.1 16.7 15.5 15.7 15.7 16.4 15.9 16.0 15.8 17.1 16.6 15.8 15.8 14.9 17.0 14.6 TABLE 13 TMO YtAH OMAL 1UIE TI TOXIC1TY-ONCOGENICI TV STUDY OF FLUOROCARBON FC-143 IN FEMALE BATS INDIVIDUAL HEMOGHAM VALUES - ----- --- -------- M 0 N T H * 3 --------- -- -- ---- HE**AT MC V MCH mchc UBC 43 61.6046 22.3496 36.2791 17.5 44 56.9948 20.8549 36.5909 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 42 64.5161 23.5023 36.4286 12.4 45 66.4697 23.9291 36.0000 16.7 40 63.0915 23.0284 36.5000 19.2 40 62.8931 23.2704 37.0000 18.3 43 61.2536 22.5071 36.7442 18.6 42 600858 22.1745 36.9048 15.3 40 62.9921 23.3071 37.0000 17.8 40 62.3053 23.0530 37.0000 28.4 44 63.9535 23.4012 36.5909 16.3 39 58.0357 21.8750 37.6923 18.0 42 65.0155 23.8390 36.6667 23.7 4? 61.0465 22.0930 36.1905 18.3 44 62.9471 22.7468 36.1364 21.6 44 63.5838 23.2659 36.5909 16.9 43 66.9782 23.5202 35.1163 16.1 45 57.7664 21.4377 37.1111 15.3 43 61.8705 22.3022 36.0465 20.4 43 62.9575 22.9868 36.5116 15.5 44 65.5738 23.3979 35.6818 22.0 45 60.4839 22.0430 36.4444 16.6 44 64.7059 23.3824 36.1364 18.1 43 67.0827 24.9610 37.2093 13.2 43 56.2092 20.6536 36.7442 26.8 47 59.6447 21.7005 36.3830 19.4 45 63.2022 23.3146 36.8889 20.6 44 59.4593 21.3514 35.9091 16.0 44 61.6246. 22.1289 35.9091 18.0 41 58.1560 21.1348 36.3415 17.3 47 56.6265 20.4819 36.1702 17.9 41 55.4804 19.7564 35.6098 13.8 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 1.860 2.171 1.728 6.771 2.046 1.224 3.204 6.532 2.282 2.340 4.977 3.660 3.456 2.028 4.347 2.448 2.040 2.170 4.400 1.992 3.077 1.320 3.752 3.880 3.708 4.960 5.220 3.287 5.728 1.932 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 10.168 14.028 17.088 11.163 15.624 13.923 13.706 21.016 13.855 15.480 17.301 14.091 18.144 14.703 11.431 12.546 18.156 12.710 16.940 14.110 14.842 11.616 21.976 15.326 16.068 10.720 11.700 14.013 10.919 11.868 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 0.124 0.167 0.384 0.366 0.372 0.153 0.712 0.284 0.163 0.000 1.185 0.000 0.000 0.169 0.161 0.153 0.204 0.155 0.000 0.166 0.181 0.000 0.804 0.000 0.618 0.160 0.360 0.000 0.537 0.000 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 0.248 0.334 0.000 0.000 0.558 0.000 0.178 0.852 0.000 0.180 0.237 0.549 0.000 0.000 0.161 0.459 0.000 0.465 0.660 0.332 0.000 0.264 0.268 0.194 0.206 0.160 0.720 0.000 0.716 0.000 TABLE 13 OOSE 0 PPM 0 99* 0 99* 0 99* 0 PPM 0 99* 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PP 0 PPM 0 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PP" 300 PPM 300 PPM 300 PPM 300 PPM 300 PP" 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 30 PPM 30 PPM 30 PP" 30 PPM 30 PP" 30 PP" 30 PP" 30 PP" 30 PP" 30 PPM 30 PP" 30 PPM 30 PPM 30 PP" 30 PPM ANIMAL N1RA582 N1RA58A N1R45H6 N1R4590 N1R459R N1RA603 N1R4607 NIR4616 N1R4619 N1RA62I N1RA622 N1R4629 NIRA631 NIR4632 N1R4639 01R4650 01R4653 01R46S7 01R4660 01R4663 01R4670 01R4673 0IR46B1 01R4682 01R4692 0IR4693 01R469* 0IR469B 01R4699 01R4700 P1R4710 PIR471I PIR47I7 P1R4719 P1R4729 P1R4731 P1R4732 PIR4733 P1R4737 P1R4740 PIR4743 P1R4745 P1H4746 P1R4749 P1R4750 ERVTN 7.32 7.85 6 . HI 7.19 7.31 A.60 7.80 8.03 7.70 6.80 7.23 7.32 7.36 7.28 7.05 6.91 7.47 7.32 7.49 7.72 7.38 6.71 6.87 7.44 7.75 7.65 7.64 7.07 7.56 7.53 6.66 6.85 6.98 7.03 7.00 6.78 6.35 7.30 5.95 7.02 6.80 7.18 7.12 8.13 6.71 MEMO 15.0 15.8 13.8 15.3 15.1 14.7 15.8 14.6 15.3 14.3 14.4 15.1 14.8 15.1 15.4 15.1 16.6 15.1 15.3 15.0 16.0 14.6 14.8 15.8 15.0 15.0 16.5 14.9 15.5 16.2 13.8 12.2 13.2 14.8 12.4 12.8 15.0 14.7 14.1 12.6 13.0 14.8 14.1 14.1 13.6 TaO Yt AH OHAL 4DItTl TOXICITY-ONCOGENICITY stuoy of f l u o r o c a r b o n f c -iaj in fe ma le rats INDIVIDUAL HEMOGHAH VALUES MONTHafc HEMAT MCV MCH MCHC BBC 43 58.7432 20.4918 34.8837 8.59 46 58.5987 20.1274 34.3478 6.45 39 57.2687 20.2643 35.384* 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 44 54.7945 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 21.844 35.8140 7.28 42 60.7815 21.8524 35.9524 7.98 43 57.5636 22.2222 38.6047 6.80 41 56.0109 20.6284 36.8293 12.70 43 57.4099 20.4272 35.5814 11.30 42 54.4041 19.4301 35.7143 7.86 43 58.2656 21.6802 37.2093 8.77 40 59.6125 21.7586 36.5000 9.73 41 59.6798 21.5429 36.0976 9.50 44 59.1398 21.2366 35.9091 9.18 42 54.1935 19.3548 35.7143 7.29 42 54.9020 19.6078 35.7143 9.41 45 58,9005 21.5969 36.6b67 9.99 41 57.9915 21.0750 36.3415 6.55 43 56.8783 20.5026 36.0465 6.39 46 61.0890 21.5139 35.2174 5.55 39 58.5566 20.7207 35.3846 10.80 35 51.0949 17.8102 34.8571 5.65 37 53.0066 18.9112 35.6757 8.13 43 61.1664 21.0526 34.4186 6.99 35 50.0000 17.7143 35.4286 5.16 36 53.0973 18.8791 35.5556 7.23 41 64.6669 23.6220 36.5854 9.28 42 57.534? 20.1370 35.0000 5.49 35 68.8235 23.6975 40.2857 6.83 35 49.8575 17.9487 36.0000 4.06 36 52.9412 19.1176 36.1111 8.81 43 59.8886 20.6128 34.4186 6.64 40 56.1798 19.8034 35.2500 7.07 41 50.4305 17.6892 34.8780 8.14 42 62.5931 20.2683 32.3810 7.48 PHNAB 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 2.1546 2.3120 2.9210 1.4690 1.8078 1.4032 1.5568 0.8550 0.5508 2.3328 2.1643 1.0989 1.0480 0.8946 0.7215 1.6200 1.8080 3.4146 2.0271 1.3932 1.3014 1.0208 0.6588 1.2977 0.5278 4.3169 2.0584 0.7777 1.7094 2.3936 L YMAB MONOAB 7.5592 0.2577 5.8695 0.0000 4.0560 0.0624 6.5190 6.3155 0.2385 0.0000 7.0748 0.0769 5.7227 6.3940 0.1286 0.1390 5.3222 0.0598 5.2219 0.0661 4.0392 0.0918 9.8340 0.1490 9.2400 0.3300 3.5224 0.0952 1.3832 0.2184 5.7456 '0.0000 4.1480 0.1360 9.2710 0.3810 9.6050 5.8950 0.2260 0.1572 7.1914 0.1754 7.4921 0.3892 8.2650 0.2850 8.3538 0.1836 4.7385 0.2187 6.7752 0.1882 8.3916 0.3996 5.2400 0.0000 5.3037 0.1278 4.5510 0.1665 8.9640 0.2160 3.5030 0.1695 4.2276 0.2439 4.6134 0.2097 3.1476 0.4644 5.3502 0.5061 7.7024 0.0928 4.7214 0.0549 4.9859 0.2732 3.3292 0.0812 4.0526 0.4405 4.3160 0.1992 5.8681 0.2121 6.2678 0.0814 4.7872 0.1496 EOSAB 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 0.0798 0.2040 0.1270 0.0000 0.0000 0.0000 0.2919 0.0950 0.0918 0.0000 0.2823 0.0999 0.2620 0.0639 0.1110 0.0000 0.1695 0.2439 0.1398 0.1548 0.0723 0.4640 0.0549 0.2732 0.1218 0.0000 0.0664 0.2121 0.0814 0.1*96 000447 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PpM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 30 PPM 10 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PPM 30 PP" 30 PPM 30 PPM ANIMAL nirasts N1R45B2 N1R4S8S N1R458B N1R4589 N1R4590 N1RA601 N1R4608 N1R4610 N1R4A20 N1R4629 N1RA630 N1RA631 N1R4632 N1R4O40 01H4042 01R46S2 01R4055 01RA6S6 U1R4064 0lR466b 0 IRA069 01KA071 01H4G74 01R4676 01RAOR7 01R46B9 01RA092 01R4099 OIRA70A P1RA711 P1RA714 P1R4T1S P1R47I6 P1R4717 PIR4721 PIR4725 P1H4727 P1R4729 PI 4 734 P1H4742 P1R4743 PIR4749 P1R47S0 P1R4755 ERVTM 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 7.22 7.31 6.96 7.81 7.11 6.90 7.16 6.95 7.92 6.76 6.54 2.83 7.45 7.18 7.67 8.03 7.69 7.74 7.18 8.56 7.74 3.15 7.45 7.89 7.13 6.97 7.46 7.27 7.52 7.57 MEMO 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 14.2 14.8 15.3 15.4 15.0 13.9 15.3 15.0 16.0 14.8 12.4 9.2 15,3 16.0 15.7 15.5 15.3 15.6 15.2 16.7 16.1 9.3 15.0 15.8 16.0 14.0 15.2 15.0 15.5 16.6 TWO YEAH OHAL T D I t n TOXICITY-ONCOOENIOITY STUDY Of FLUOROCARBON FC-143 IN FEMALE ATS INDIVIDUAL HfMUGRAM VALUES +-- -- ----- -- M O N T H 12 - -- -------- -------- ---- --- -- -- r HEMAT MCV MCH MCHC WBC PMNA8 44 58.2781 20.7947 35.6818 3.5 0.840 44 66.1242 20.7398 35.6818 6.9 0.621 45 57.3980 20.2806 35.3333 4.1 0.451 43 59.4744 21.0235 35.3488 3.9 0.390 43 54.1562 19.0176 35.1163 6.8 3.264 44 59.1398 21.2366 35.9Q91 5.4 0.648 43 59.9721 21.1994 35.3488 4.6 0.598 46 55.6901 19.7337 35.4348 7.1 0.710 42 57.3770 20.6284 35.9524 3.8 0.152 43 55.1262 19.6154 35.5814 5.2 0.156 47 59.9490 20.4082 34.0428 12.1 6.171 44 59.1396 20.9677 35.4545 6.5 1.365 45 56.5938 20.5729 35.1111 5.9 1.239 46 60.9272 21.5894 35.4348 4.9 1.666 45 61.6438 21.3699 34.6667 5.2 0.728 40 55.4017 19.6676 35.5000 7.0 0,560 40 54.7196 20.2462 37.0000 5.1 1.530 41 56.9080 21.9828 37.3171 5.3 1.378 44 56.3360 19.7183 35.0000 8.1 2.187 42 59.0717 21.0970 35.7143 8.1 2.349 39 56.5217 20.1449 35.6410 9.2 5.428 43 60.0559 21.3687 35.5814 4.4 0.660 40 57.5540 21.5827 37.5000 4.9 1.421 44 55.5556 20.2020 36.3636 4.8 0.960 40 59.1716 21.8935 37.0000 2.4 0.024 38 5 H . 1040 18.9602 32.6316 7.1 1.562 25 88.3392 32.5088 36.8000 4.4 0.440 43 57.7181 20.5369 35.5814 4.3 0.688 44 61.2813 22.2841 36.3636 4.9 0.833 44 57.3664 20.4694 35.6818 5.8 1.740 44 54.794b 19.3026 35.2273 4.9 1.666 43 55.9166 19.8960 35.5814 6.0 1.380 45 56.1395 20.1550 34.6667 6.9 2.277 44 61.2813 21.1699 34.5455 5.2 0.416 48 56.0748 19.5093 34.7617 6.7 2.613 46 59.4315 20.8010 35.0000 3.3 0.132 27 82.5397 29.6238 35.7692 4.3 0.258 42 56.3758 20.1342 35.7143 6.0 1.680 45 57.0342 20.0253 35.1111 6.2 1.302 44 61.7111 22.4404 36.3636 6.7 1.541 39 55.9541 20.0861 35.8974 7.2 1.440 43 57.6406 20.3753 35.3488 6.8 1.700 41 56.3961 20.6327 36.5854 4.5 1.170 43 57.1809 20.6117 36065 6.5 1.170 43 56.8032 20.6077 36.2791 6.2 1.364 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 6.230 3.264 3.657 5.508 4.941 3.036 3.608 3.087 3.552 2.352 5.325 3.784 3.569 3.626 3.770 2.744 4.380 4.416 4,524 3.618 2.937 3.913 3.540 4.464 4.623 5.400 4.760 3.060 5.005 4.588 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 0.140 0.153 0.159 0.162 0.486 0.644 0.088 0.294 0.240 0.024 0.213 0.132 0.043 0.294 0.290 0.343 0.120 0.207 0.104 0.335 0.198 0.129 0.420 0.372 0.335 0.288 0.272 0.180 0.260 0.186 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 0.070 0.153 0.106 0.243 0.324 0.092 0.044 0.098 0.048 0.000 0.000 0.044 0.000 0.147 0.000 0.147 0.120 0.000 0.156 0.134 0.033 0.000 0.360 0.062 0.201 0.072 0.068 0.090 0.065 0.062 000448 TABLE 13 TWO STUDY I DUAL lltlETI TOXICITY-ONCO0ENICITY F l UUROCa HBON FC-143 IN FEMALE HATS INDIVIDUAL MF.MOttHAM VALUES DOSE 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM A PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAL N1R4581 N1R45B3 N1H4506 N1R4592 NIH4595 N1R459B N1R4S99 N1H4602 N1R4604 N1R4606 N1R4609 N1M4611 NIR4612 N1R462T NIR463S 0JR4645 0104647 01R464B 01W4661 0104663 01R4667 01R4675 0104679 0104604 0104680 OIR4690 0IO4693 01H4694 01R4696 01R469B P1R4T07 P1R4709 P1H47I4 PIH471B P1H4720 P1H4722 P1R4725 P1R4729 PIH4732 P1H4T33 P1R4737 P1R474B P1R4749 P 1H47S? P1R4754 ERYTH 0.16 7.52 7. Ofl A . 04 7.52 7.44 7.B0 7.72 7.97 5.05 7.07 0.95 H.27 7.36 7.76 7.49 7.57 5.54 7.60 7.B4 5.04 B.H3 7.31 6.57 7.45 7.21 7.97 7.30 6.95 7.20 6.67 6.05 7.46 6.65 6.46 5.47 7.54 7.31 6.42 b .oh 6.91 7.32 7.PA B.17 6*0 l MEMO 12.3 15.6 14.5 16. B 15.3 16.4 16.1 16.6 16.4 12.4 15.5 14.7 16.5 16.2 16.4 15.4 15.2 12.0 15.3 15.7 12.2 16. 14.4 14.3 15.7 15.3 15.4 16.4 14.4 15.4 13.5 14.4 15.3 14.7 14.1 11.0 16.H 15.2 13.7 15.7 15.2 14.7 16.2 16.9 14.5 HFMAT 34 44 41 46 44 45 44 45 47 34 41 41 47 46 45 44 43 34 43 44 34 48 41 40 45 42 43 46 40 42 3 40 43 39 39 33 4H 42 30 44 43 42 45 47 41 MCV 55.1940 50.5106 57.9096 57.2139 50.5106 60.4839 56.4103 5H.2902 50.9711 50.1197 57.9915 5H.9920 56.B319 62.5000 57.9B97 50.7450 56.0032 61.3710 56.5709 5 b . 1224 50.2192 54.3601 56.0076 60.002H 60.4027 50.2524 53.9523 63.0137 57.5540 50.3333 56.9715 661157 57.6400 58*6466 60.3715 60.3291 63.6605 57 *4555 59.1900 54.4554 62.2207 57.3770 57.1066 57.5275 6U.205O MCH 19.9675 20.7447 20.4002 20.8955 20.345/ 22.0430 20.6410 21.5026 20.5772 21.1966 21.9236 21.1511 19.9516 22.0109 21.1340 20.5607 20.0793 21.6606 20.1316 20.0255 20.8904 19.0260 19.6990 21.7656 21.0730 21.2205 19.3225 22.4650 20.7194 21.3009 20.2399 23.8017 20.5094 22.1053 2 1 .H266 21.5722 22.2012 20.7934 21.3396 19.4307 21.9971 20.0020 20.5504 20.6054 21.2922 MCHC 36.1765 35.4545 35.3659 36.5217 34.7727 36.4444 36.5909 36.0809 34.0936 36.4706 37.0049 35.0537 35.1064 35.2174 36.4444 35.0000 35.3408 35.2941 35.5814 35.6818 35.0824 35.0000 35.1220 35.7500 34.HB89 36.4206 35.0140 35.6522 36.0000 36.6667 35.5263 36.0000 35.5014 37.6923 36.1530 35.7576 35.0000 36.1905 36.0526 35.6018 35.3400 35.0000 36.0000 35.9574 35.3659 BBC 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 4.5 4.5 12.6 5.3 3.7 10.1 7.8 6.3 6.3 7.1 4.2 6.1 5.4 5.3 5.3 7.7 3.7 4.9 4.9 10.3 9.2 3.9 5.1 10.8 4.1 5.8 6.6 0.2 5.9 11.4 PMNAB 6.600 0.200 0.517 1.690 1.075 0.200 0.384 0.195 0.441 1.632 0.931 0.371 0.84 0 0.050 0.076 2.475 1.215 8.568 1.378 1.184 3.131 2.652 2.016 3.213 1.917 2.142 0.610 0.864 1.219 0.636 3.080 0.740 0.490 1.176 5.459 5.428 1.014 2.601 4.212 1.312 1.624 3.366 2.870 1.416 0.550 LYMAB 5.544 4.036 3.854 4.600 2.967 4.650 4.120 6.305 4.410 3.060 3.675 4.664 5.950 4.900 3.610 1.405 2.000 3.024 3.498 2.109 6.161 4.680 4.095 2.709 4.615 1.806 4 .9a 1 4.158 3.445 4.664 4.150 2.701 4.116 3.332 4.120 3.312 2.535 2.193 6.156 2.542 3.654 2.970 4.592 4.012 2.200 MONOAB 1.056 0.156 0.100 0.130 0.129 0.150 0.144 0.065 0.049 0.400 0.294 0.265 0.210 0.050 0.114 0.405 0.315 0.002 0.371 0.370 0.000 0.390 0.109 0.315 0.426 0.160 0.183 0.324 0.310 0.000 0.462 0.259 0.245 0.343 0.618 0.460 0.195 0.306 0.216 0.205 0.340 0.190 0.574 0.4| 3 0.570 EOSAB 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 0.135 0.090 0.126 0.053 0.037 0.000 0.078 0.000 0.063 0.142 0.084 0.366 0.054 0.318 0.000 0.000 0.000 0.049 0.049 0.103 0.000 0.156 0.000 0.216 0.04 1 0.174 0.066 0.164 0.059 0.000 000449 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAL N1R4583 N1R4506 N1R*591 N1H4595 N1R4598 N1H4603 N1H4606 N1H461I N1R461* NIRA616 NIH4626 N\R*628 N1HA63A N1R4636 N1HA63R 0]RAO** 01HA6A6 01H*69 01R4657 01R4659 010*061 010*663 01RA67? 0IRA6T9 010*603 010*608 01HA693 01RA695 010*697 O1RA70I P1HA70R P1R*T 11 P1H*71* P1R*716 P1HA720 P1RA723 P1R*7?0 P1H*7?9 P1H4733 P1RA730 P 1H*739 P1R*7*S Pl**7*7 PIRA752 P1R*7S* ERVTH 7.*fl 7.22 7.91 7.97 7.*3 7.07 7.78 A. 21 7.3* 7.2* 7.31 6.21 *.06 7.90 7.99 7.07 6.0* 7.12 6.05 5.00 7.*2 8.75 6.00 7.1* 7.67 7.2* 7.60 6.02 7.00 7.62 7.26 6.09 7.11 7.3* 6.91 6.30 7.6* 7.53 0.81 7.97 * 01 7.*5 7.05 7.82 6.70 MEMO 15.3 1A.3 15.7 15.9 16.* 1* .9 15.9 10.3 16.0 15.2 1* .5 13.* 11.7 16.1 16. H 1*. 0 1A.2 1*.6 14.0 11.0 16.0 16.6 13.9 1*.6 15.1 15.2 16.1 13.0 15.1 15.2 15.1 13.7 15.0 15.0 14.9 12.0 16.3 15.2 1 7.0 16.* 0.9 16.* 13.5 16.* 12. TwO YEAR OHa L IDIETI TOXIC1TY-ONCOOENIClTY STUOr Oh FLUOROCARBON F C - 1*3 IN FEMALE HATS IND1V10UAL MFMObRAM VALUES -------------------------------------------- M O N T H S ? * ------------------------------ --------- HERAT *2 *? *5 *6 *7 ** *6 29 ** *3 *2 30 32 *7 *7 *1 *1 *2 37 30 *2 *5 *0 *0 *2 *2 *2 36 *3 *3 ** 30 *2 *5 *3 37 *6 ** *9 *7 25 *5 39 *6 36 MCV 56.1*97 58.1717 56.8900 57.716* 63.2571 62.23*8 59.1260 68.6636 69.9*55 59.3923 57.4555 61.1916 65.8*36 59.4937 58.8236 67.9915 59.9*15 58.9088 66.*805 59.2086 66.6030 53.8922 56.8236 56.022* 6*.7688 6 6 . 0 1 lu 64,8303 52.7869 65.1202 66.430* 60.6061 55.152* 69.0717 61.3079 62.2207 66.1761 60.209* 68.4329 6 5 .b186 58.9711. 62.3**1 6U.4027 65.3191 67.5*48 62.5000 MCH 20.45*5 19.8061 19.8*83 19.9*98 22.0727 21.0760 20.4370 ?*.*66b 21.798* 20.99*5 19.8358 21.5701 24.07*1 20.3797 21.0263 19.8020 20.7602 20.5056 21.37*0 21.7391 20.215b 19.802 20.4*12 20.4*82 19.6871 20.99*5 19.7120 |9.Ob 16 19.3690 19.9*76 20.7989 19.8839 21.0970 20.4360 21.6630 20.125 21.3351 20.1869 19.2963 20.5772 22.19*5 20.6711 19.1*89 20.9719 22.2222 HCHC 36.4286 34.0*76 34,8889 34.5652 34.093b 33.8636 34.5652 35.5172 36.3636 35.3*88 34.5238 35.2632 36.5625 34.2553 35.74*7 34.1*63 34.63*1 3*.T619 37.8370 36.6667 35.71*3 36.8869 34.7500 36.5000 35.952* 36.1905 35.952* 36.1111 36.1163 35.3*88 34.3182 36.0526 35.71*3 33.3333 34.6612 3*.59*6 35.43*8 34.5*55 34.6939 34.8936 36.6000 34.2222 34.615* 36.**** 36.5656 WBC 18.7 4.1 4.9 4.6 6.2 4.2 4.7 9.2 5.1 4.5 5.4 0.6 12.2 5.0 3.5 4.8 7.9 8.3 6.0 8.6 6.5 3. 6.5 5.9 8.0 5.4 4.6 9.3 5.0 *.* 7.0 13.7 5.8 *.* 8.6 9.9 6.4 7.4 5.2 6.2 12.0 6.2 12.6 6.6 15.7 PMNAB 12.529 1.1*8 0.735 2.71* 2.232 1.092 1OH 1 3.496 1.989 2.115 2.592 3.870 5.2*6 1.650 0.630 1.056 2.607 3.652 1.920 3.956 1.365 1.216 2.600 3.363 2.080 1.13* 1.79* 2.790 1.508 1.232 3.580 7.672 1.91* 1.936 3.698 2.57* 0.6*0 2.1*6 2.3*0 1.7 36 2.760 0.6H2 5.418 2.706 11.775 LYMAH 5.98* 2.952 4.018 1.702 3.8*4 3.06b 3.525 5.428 3.060 2.3*0 2.6*6 4.386 6.222 3.250 2.695 3.600 5.293 .399 3.8*0 4.386 5.070 2.508 2.990 2.419 5.760 4.212 2.622 6.231 4.118 3.12* 3.900 5.3*3 3.828 2.208 4.472 7.128 5.696 4.88* 2.70* 4.3*0 8. *00 5.332 6.426 3.762 3.611 MONOAB 0.187 0.000 0.000 0.092 0.062 0.000 0.09* 0.18* 0.051 0.000 0. 108 0.086 0.610 0.100 '0.140 0.096 0.000 0.083 0.180 0.172 0.065 0.000 0.130 0.11 0.160 0.05* 0.0*6 0.186 0.116 0.0*4 0.078 0.5*0 0.058 0.132 0.258 0.198 0.06* 0.07* 0.156 0.062 0.720 0.12* 0.756 0.066 0.31* E0SA8 0.000 0.000 0.1*7 0.13 0.062 0.0*2 0.000 0.092 0.000 0.0*5 0.05* 0.25 0.122 0.000 0.035 0.0*8 0.000 0.166 0.060 0.086 0.000 0.076 0.130 0.000 0.000 0.000 0.138 0.093 0.058 0.000 0.23* 0.137 0.000 0.0*4 0.172 0.000 0.000 0.296 0.000 0.062 0.120 0.062 0.000 0.066 0.000 000450 TABLE 14 TWO YEAR ORAL (DIET) T O * I C ITY-0NC06ENICI TY STUDY OE FLUOROCARBON FC-143 IN RATS RE AN BLOOD CHEMISTRY VALUES WlTh STANDARD DEVIATIONS GLUCOSE CMG/DL) BLOOD UREA NITROGEN (MGSOL) ALT (IU/L) AST (lU/L) N MEAN .DEV. MEAN S.DEV. MEAN S.DEV. MEAN S.DEV. MALE MONTH 3 0 PPM 300 PPM 30 PPM MONTH 6 0 PPM 300 PPM 30 PPM 15 120.6 13.74 15 129.5* 8.38 15 134.6* 8.83 16.3 19.4* 7,1 1.84 2.06 1.46 21.4 91.9# 94.5# 2.67 21.94 15.33 45.3 58.2 69.7 7.26 27.23 22.47 15 119.0 13.29 15 123.7 11.17 15 134.9* 10.33 17.5 20.7* 15.9* 1.36 1.40 1.44 24.1 54.8 63.3 3.75 29.26 29.34 49.7 14.98 97.8# 34.83 92.1# 45.60 MONTH 12 0 PPM 300 PPM 30 PPM 14 154.3 26.17 15 136.7 B.B5 15 131.1# 8.70 16.4 17.5 16.2 2.50 1.73 1.15 93.5 19.45 196.1 70.00 77.6 56.59 79.1 192.7 124.4 44.61 76.94 94.04 MONTH IB 0 PPM 300 PPM 30 PPM 15 123.4 15 139.3 15 120.6 26.39 16.14 27.62 18.1 17.6 16.5# 3.38 1.88 6.48 94.1 10.68 94.3# 55.95 69.7# 33.41 99.1 123.3 116.4 68.14 62.98 57.99 MONTH 24 0 PPM 15 122.5 23.07 16.5 3.16 93.4 8.10 64.9 25.76 300 PPM 15 147.1* 13.26 17.2 5.03 81.8* 20.13 95.7* 29.76 Ch 30 PPM 14 121.3 13.72 16.6 6.70 42.5 10.00 68.0 17.64 P r P .05, TWO TAILED DUNNETT T ON RAW DATA. # I P .05 TWO TAILED DUNNETT T ON RANKEO DATA 000451 TABLE 14 TWO YEAR ORAL (DIET! TOXICITY-ONCOGENICIfV STUDY OF FL UO RO CA RB ON FC -1A3 IN RATS MEAN BLOOD CHEMISTRY VALUES (TB1L1. ALB, TPROT, ALKPHOS, CPK, OA) WITH STANDARD DEVIATIONS TOTAL BILIRUBIN IMG/DL1 ALBUMIN I6M/DL1 TOTAL PROTEIN ISM/DLI ALKALINE PHOSPHATASE (IU/LI CREATINE PHOSPHOKINASE (IU/LI CALCIUM (M6/0LI N MEAN StDEV MEAN S.DEV MEAN S.OEV MEAN S.8EV MEAN S.DEV MEAN S.DEV MALE MONTH 3 0 PPM 300 PPM 30 PPM MONTH 6 0 PPM 300 PPM 30 PPM MONTH 1? 0 PPM 300 PPM 30 PPM MONTH IB 0 PPM 300 PPM 30 PPM MONTH 24 0 PPM 300 PPM 30 PPM 15 0.6 0.16 A.A 0.3A 6.S 0.3A 91.1 16.2 a 100.7 26.A6 11.1 0.68 IS O.H O.AO 5.1* 0.29 6.5 0.31 153.5* 91.BA 67.0* 24.26 10.8 0.50 IS 0.7 0.09 A . 7* 0.37 6*6 0.3A 138.7* 93.16 60.5* 12.65 11.0 0.78 15 0.8 0.19 A.6 0.20 7.0 0.36 97.1 0.41 89.9 41.32 11.5 0.40 15 0.7 0.22 5.A* 0.31 6.6* 0.28 147.3* 94.86 81.4 26.66 11.1* 0.22 15 0.5* 0.1A 5.0* O.AO 6.7* 0.33 146.9* 97.18 58.3* 31.23 10.9* 0.33 14 0.7 0.20 3.7 0.20 6.8 0.27 105.8 3.94 79.7 47.61 10.5 0.30 15 0.6 0.12 4.4* 0.34 6.8 0.31 166.5* 9.28 68.3 23.65 10.6 0.24 15 0.8 0.22 3.9 0.26 6.9 0.33 128.3 1.75 67.6 19.45 10.6 0.29 15 0.9 0.35 3.2 0.38 7.1 0.61 85.2 93.T8 T9.9 T4.52 11.1 0.93 15 0.7 0.31 3.T* 0.34 6.9 0.42 184.4* 73.37 82.5 45.87 10.8 1.10, IS 0.7 0.25 3.2 0.29 7.2 0.45 112.5 92.61 106.5 69.23 HI. 4 o.eo" 15 0.4 0.25 2.8 0.23 6.9 0.44 70.1 >5.58 111.1 68.04 10.9 0.43 15 0.2# 0.06 3.1* 0.27 6.9 0.50 113.5* 22.86 88.3 37.33 10.8 0.25 14 0.4 0.12 2.8 0.30 6.8 0.39 81.2 26.20 71.1* 20.55 10.5* 0.31 I P .05, TWO TAILED DUNNETT T ON RAW DATA. I P .05. TWO TAILED DUNNETT T ON RANKED DATA. - K BOMBER 18 14 FOR THIS MEAN. 000452 000453 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAL A1R3S18 A 1R3527 A1B3532 A1R3534 A1R3537 A1R3540 AIR3542 A1H3548 A1R3552 AIR3559 A1R3S62 A1R3564 AIR3S6S A1R3567 A1R3569 H1R3505 RIR3S07 H1R35H9 R1R3592 H1R3593 B1R3595 R1R3604 R1R3605 M1R3610 P1R3611 R1R3617 R1R3623 R1R3634 R1R3640 B1R3643 CIR3654 C1R3655 CIR3665 C1R3667 C1R366B C1R3673 C1R3675 C1R3677 C1R3679 C1R3603 C1R36H7 C1R3N90 CIR3N91 C1R3692 C1R369S TABLE 14 TWO YtAK ORAL <011 T ) TO*ICITY-ONCOGENICITY STUUY OF FLUOh U C a KHON F C - U 3 IN ALE RA TS INDIVIDUAL SERUM c h e m i s t r y VALUES ------------------ m o n t w * j --------- --------- -- GLU HUN ALT AST THILI ALB TPROT 112 17 140 21 130 17 112 17 129 IS 102 17 111 14 9H 14 141 lb 100 17 130 lb 125 10 129 17 114 15 120 14 135 22 120 20 139 17 120 17 121 IP. 131 21 141 19 145 19 124 19 120 17 13b 24 115 10 124 22 120 19 127 19 120 lb 152 20 130 16 13b 16 13 16 119 17 139 1H 135 lb 142 15 144 10 132 19 130 19 125 16 130 10 131 17 20 30 22 42 20 3b 22 50 20 59 21 42 22 4 3 21 46 1 30 10 44 21 51 24 SO 20 47 19 36 2b 5H 24 40 26 75 23 37 2ft 4H 24 50 2b 44 23 42 25 46 110 140 34 65 21 49 33 51 23 47 27 49 30 75 21 43 39 62 30 50 2b 5b 74 120 20 51 43 02 2b 45 23 37 21 41) 26 ` 3ft 5b H2 51 7H 30 50 25 53 0.6 0.5 0.9 0.0 0.0 0.5 0.7 0.5 0.5 0.5 0.4 0.0 0.9 0.6 0.7 0.5 0.5 0.5 1.9 0.5 0.7 0.5 0.7 0.6 0.9 0.7 0.9 Q.b 0.5 1.4 O.b 0.7 0.7 0.7 0.6 0.6 0.7 0.7 0.0 0.7 0.0 0.5 0.7 O.P 0.6 4.2 4.4 4 .4 5.1 4.4 4.1 4.4 3.9 4.2 4.4 4.1 5.1 4.6 4.2 3 4.0 4.6 5.1 4.7 4.9 5.0 5.2 5.0 4.9 5.3 5.0 5.3 5.4 5.3 5.7 4.2 4.b 4.9 4.7 4.6 4.4 A .7 5.1 5.3 5.0 5.3 4.9 4.3 4.1 4.7 6.0 6.6 7.1 7.8 6.6 6.5 6.7 6.5 6.0 6.6 6.5 6.6 6.0 6.5 7.0 6.3 6.4 6.3 6.5 6.4 6.2 6.8 6.3 6.6 6.5 6.6 6.0 6.2 6.4 7.4 6.3 6.2 6.0 6.4 6.3 6.3 6.9 7.0 7.2 6.7 7.0 6.5 b.l 6.3 6.5 ALKPHOS 107 106 58 105 100 00 60 125 71 52 73 125 120 69 100 140 124 114 162 103 124 142 143 212 101 160 120 134 130 217 86 140 147 192 156 108 163 180 97 96 160 139 145 109 1 30 CPK CA 115 11.5 104 11.3 69 11.2 140 12.4 144 10.0 120 10.0 00 10.0 00 11.2 7a 11.1 109 11.6 5 9.3 72 12.0 113 11.0 72 11.2 134 11.0 41 ,11.4 80 , 10.3 47 11.0 97 11.2 82 10.9 60 11.2 43 11.4 54 11.1 72 10.0 53 10.0 45 9.8 72 11.3 117 10.3 41 11.1 101 10.1 71 10.2 69 10.0 73 12.0 79 11.0 59 10.4 67 10.9 76 12.1 40 11.1 53 11.9 47 12.2 30 10.0 bb 11.0 59 10.0 52 10.1 5H 11.5 TABLE 14 TWO YtAR ORAL DIET TO*IC ITY-ONCOGENICITY STUDY OF FLuOMOCAHHON FC-143 IN MALE HATS INDIVIDUAL SEHUM CHEMISTRY VALUES DOSE ANIMAL GLU BUN ALT AST TBILI ALU TPROT ALKPHOS CPK CA 0 PPM A 1 R 3 5 1 9 133 19 <1 PPM A1 R 3 S 2 4 139 17 18 39 0.6 4.3 6.4 21 54 0.8 4.4 7.3 0 PPM A 1 R 3 5 2 9 130 16 20 25 0.6 4.7 6.7 0 PPM A1R3533 124 19 0 PPM A1 R 3 5 3 7 109 16 28 41 0.0 4.8 7.5 27 58 1.1 4.9 7.0 0 PPM A1R3S41 124 18 19 35 0.7 4.5 7.2 0 PPM A1R3S47 115 19 29 28 1.1 %o4 7.5 0 PPM A 1 R 3 5 5 0 128 15 25 43 0.6 4.7 7.0 0 PPM A1R3553 99 20 29 53 0.7 4.6 7.1 0 PPM AI R 3 5 5 7 109 17 22 74 1.1 4.7 7.3 0 PPM A 1 R 3 S 5 9 ion 17 21 51 0.9 4. * 6.7 0 PP,M A1R3562 133 18 20 55 0.6 4.7 6*6 0 PPM A1 R 3 S 6 7 129 18 23 49 0.8 4.6 6.8 0 PPM AJR3573 102 17 26 74 1.0 5.0 7.5 0 PPM A I R 3 S 7 5 111 17 25 67 0.7 4.4 6.7 300 PPM B1R35A3 119 21 29 57 0.7 5.7 6.4 300 PPM B1R3584 152 23 84 112 1.2 5.1 6.7 300 PPM B1R3596 119 21 21 47 0.9 5 . 3 6*4 300 PPM 81R3590 121 21 92 122 0.8 6.0 7.2 300 PPM 51R3600 110 22 27 47 1.1 5.1 6.3 300 PPM R1R3604 144 21 60 0b 0.5 5.4 7.0 300 PPM R I R 3 6 0 8 117 19 73 80 0.7 5.3 6.3 300 PPM H1R3609 123 21 37 89 1.0 5.5 6.7 300 PPM 81R3613 112 20 05 174 0.6 5.0 6.5 3011 PPM 01R3617 122 23 35 73 0.6 5.5 7.0 300 PPM 0 1 R 3 6 2 8 120 21 73 95 0.6 5.0 6.9 300 PPM 81R3629 122 20 37 79 0.6 4.9 6.3 300 PPM 81R3631 117 19 34 70 0.5 5.5 6.6 300 PPM R1R3633 129 20 111 130 0.6 5.2 6.5 300 PPM 81R3642 128 10 24 56 0.6 5.7 6*4 30 P P M C 1 R 3 6 4 6 14b 19 35 64 0.6 5.0 6.5 30 PPM C1R3650 151 16 53 83 0.4 4.9 6.5 30 PPM C 1 R 3 6 5 6 149 15 131 212 0.5 4.8 6.5 30 PPM C1R3658 137 15 48 65 0.4 4.7 6.4 30 PPM C1R3660 138 15 2b 49 0.4 4.9 6.7 30 PPM C1R3664 138 16 81 11A 0.4 4.5 6.5 30 PPM C1R3665 133 16 87 140 0.4 4.9 6.8 30 PPM C 1 R 3 6 6 7 133 17 39 72 0.4 5.0 6.7 30 PPM C I R 3 6 T 9 144 16 39 77 0.6 5.8 7.6 30 PPM C1R3680 130 15 49 . ?7 0.4 5.6 7.1 30 PPM C1R3682 122 16 75 139 0.4 4.4 6 . 9 30 PPM C1R3687 112 10 3o ' 74 0.9 5.3 7.1 30 PPM C I R 3 6 8 9 128 13 20 39 0.4 5.2 6*4 30 PPM CIH369I 134 15 53 105 0.3 4.4 6*4 30 PPM C1R3694 129 17 20 59 0.5 5.1 6.7 123 70 10.6 109 82 11.6 72 51 11.3 85 119 11.7 110 204 11 *4 65 58 11.3 114 62 12.2 213 57 11.6 62 57 11.9 120 119 11.6 50 85 11.4 69 79 10.9 69 05 11.4 118 144 11.7 78 77 11.0 162 77 11.0 178 7b ` 11.2 156 80 11.4 183 106 11.5 97 75 10.9 123 46 11.4 160 bl 11.2 127 142 11.1 109 55 11.0 162 58 11.2 172 110 11.3 102 63 10.7 166 65 10.9 211 115 11.0 102 92 11.1 94 50 11.0 163 91 10.6 188 64 10.6 165 42 10.9 79 43 10.6 121 20 10.9 185 40 11.2 172 41 10.0 97 157 11.4 135 38 11.3 209 58 11.0 158 63 11.5 156 51 10.7 1 34 45 10.4 140 63 10.7 000454 TABLE 14 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 300 PPM 100 PPM ano PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 100 PPM 300 PPM 300 PPM 300 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 30 PPM animal A1R3516 A1R3S17 A1R3520 AIR3S22 A1R3S27 A1R3535 A1R3543 A1R3546 A 1R3 55 0 A1R3551 AIR3554 A1R1G68 A1R3570 A1R3575 A1R35B0 B1R3564 RIR35R8 B1R3589 B1R3592 B1R3598 B1H3604 B1R3613 B1R3617 R1R3620 BIR3622 B1R3626 B1R3627 R1R363A R1R3642 H1R3643 C1R3649 C1H3650 C1R3652 C1R3663 C1R3668 C1R3670 C1R1672 C1R3676 C1R3679 C1R36B0 C1R36R1 C1R1683 C1H36R5 C1H3691 C 1H3 69 4 TvO YEAR ORAL 40IbT) TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FC-143 IN RALE HATS INDIVIDUAL SERUM CHEMISTRY VALUES ---------------- - MONTH* 1 2 ------------- ---- GLU BUN ALT AST TBILt ALB TPROT 147 18 22 56 0.9 3.6 6.9 ISO 16 16 40 o.s 3.8 7.1 124 16 15 43 0.4 3.8 6.6 134 15 65 123 0.6 3.7 6.7 1SS 18 37 67 0.6 3.9 6.8 141 17 23 56 0.6 3.8 6.8 183 17 33 85 1.0 3.9 7.0 178 17 37 118 0.9 4.0 6.9 185 18 32 79 1.0 3.9 6.9 165 20 41 86 0.6 3.9 6.7 214 18 87 212 0.6 3.5 6.3 123 14 18 43 0.7 3.3 6.2 125 9 23 54 0.5 3.6 6.5 143 16 23 63 0.4 3.5 6.9 1*8 17 31 59 0.7 3.9 7.1 151 IT 133 166 0.6 3.7 6.3 130 17 35 69 0.7 4.7 6.9 144 18 105 116 0.4 4.7 6.8 127 16 JO 59 0.5 4.1 6.5 1*2 17 162 171 0.5 4.3 6.8 153 16 185 202 0.6 3.9 6.9 145 18 64 137 0.7 3.9 6.4 127 16 208 236 0.7 4.4 7.2 150 19 105 106 0.4 4.5 6.5 131 22 76 126 0.7 4.7 7.3 136 17 50 53 0.8 4.3 7.0 135 17 46 66 0.7 4.2 7.1 138 20 48 75 0.7 4.5 6.6 142 17 84 82 0.7 4.7 7.1 129 17 261 326 0.7 4.7 7.1 139 16 39 76 0.8 4.1 7.0 132 17 46 93 0.6 4.3 7.1 128 16 54 75 0.6 3.7 7.1 147 17 75 103 0.6 3.8 6.9 123 15 241 436 0.6 3.9 7.0 139 17 94 127 0.8 3.8 6.8 120 16 105 158 0.7 3.8 6.7 130 16 37 64 0.9 3.6 7.4 137 16 52 94 0.9 4.6 7.6 132 17 159 . i^s 0.6 4.1 6.9 129 18 62 121 1.4 4.0 7.2 141 16 26 65 1.1 4.0 6.9 122 17 83 73 0.7 4.0 6.5 132 13 83 126 0. 7 3.7 6.4 116 16 39 62 0.7 3.7 6.5 ALKPHOS 139 104 49 108 102 113 115 107 225 95 88 48 72 70 152 205 145 153 118 212 208 103 235 117 190 158 101 105 139 309 89 168 177 82 215 154 84 128 93 145 12* 67 159 111 109 CPK 72 43 42 61 80 103 88 234 89 65 105 50 39 58 66 50 108 84 67 64 67 78 107 39 56 57 40 36 54 96 91 56 78 54 66 41 110 66 73 49 96 67 55 59 51 CA 11.0 10.8 10.5 10.4 10.8 10.6 10.7 10.4 10.5 10.2 10.3 10.4 9.8 10.4 10.9 10.4 10.8 10.7 10.5 10.4 10.5 10.2 10.6 10.3 10.9 10.8 10.7 10.8 10.9 11.0 10.9 10.5 10.6 10.4 10.3 10.6 10.4 11.3 10.6 10.6 10.7 10.7 10.5 10.1 10.3 000455 000456 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAI. A1R3519 A1R3S21 A1R3528 AIR3531 A1R3538 A1R3539 A1R3542 A1R3552 1R3553 AIR3555 A1R3561 A1R3565 A1R3567 A1R3574 A1R3577 R1R3583 H1R3593 B1R3S96 B1R3600 R1R3601 1R3605 81R3608 R1R3610 D I R 3612 81R3615 81R3624 B1R3632 B1R3641 R1R3644 R1R3645 CIR3647 C1R3651 C I R 3654 C1R3658 C1R3662 C1R3663 C1H3664 C1R3467 C1R3668 C1R3676 C1R3679 C1R36R1 C1R36R5 C1R1689 C1R3695 GLU 151 125 148 143 129 132 107 117 127 140 135 126 134 91 46 135 124 137 140 13R 136 124 150 14 117 118 168 145 173 136 116 142 134 156 31 121 125 134 128 ilo 123 136 113 126 114 TABLE 14 TWO YEAR ORAL DIET) TOXICITY-ONCOGENICITY STUOY OF FLUOROCARBON FC-143 IN RALE RATS INDIVIDUAL SERUM CHEMISTRY VALUES MONTH*18 BUN ALT AST TBILt ALB TPROT 1 A1 94 0.7 3.2 6. a 29 59 317 0.2 2.1 5.5 19 2A 55 0.6 3.2 7.0 IB A 2 98 1.0 3.4 7.4 IS 38 93 0.7 3.3 6.8 16 24 54 0.9 3.7 8.1 ia 30 61 1.1 3.4 7.2 21 23 54 1.1 3.3 7.4 17 AA 74 0.9 3.4 7.5 IT 35 84 1.1 3.3 T.3 17 26 61 0.9 3.4 7.6 IS 23 62 0.9 3.3 6.6 17 34 133 0.9 3.2 7.7 17 24 79 0.2 2.6 6.7 17 45 168 1.6 3.4 7.3 19 31 42 0.4 3.a 5.8 17 as 109 0.9 3.8 7.5 19 39 68 1 . 0 3.4 7.4 19 92 139 0.4 4.0 6.9 1 * 96 132 0.6 3.8 7.0 20 51 68 0.6 3.9 7.0 1A 124 163 0.4 3.2 6.5 19 75 117 0.7 3.9 7.0 19 11 205 0.8 3.4 6.6 17 63 101 o.a 4.1 7.4 ia 42 95 0.4 2.9 T.O 19 91 142 1.1 4.0 7.3 16 47 78 0.9 3.6 6.9 18 25 295 1.5 3.7 7.0 16 53 95 0.7 4.0 6.8 12 40 117 0.3 2.4 7.8 13 37 60 0.6 3.4 7.0 16 43 100 0.8 3.2 7.1 16 71 108 0.6 3.3 6.7 39 53 161 0 . 1 2.9 8.3 IB 5 120 0.7 3.1 7.1 16 97 153 o.a 3.4 6.9 IS 82 156 0.8 3.4 7.2 15 160 289 0.7 3.5 7.1 17 34 60 1.1 3.0 7.6 13 41 89 1 . 0 3.5 7.5 12 45 87 0.7 3.2 7.2 16 34 64 0.8 3.2 6.9 15 62 95 0.7 3.4 6.7 1 A 39 67 0.5 3.4 6.7 ALKPHOS 128 164 57 56 113 82 41 55 65 124 90 87 66 82 68 148 214 113 142 213 172 177 202 168 129 106 233 156 413 180 105 138 92 134 100 69 133 124 186 105 68 82 95 156 101 CPK CA 37 10.6 79 10.5 39 11.9 34 12.0 96 10.9 35 11.8 49 11.5 41 12.0 83 11.9 108 11.1 59 10.2 41 9.0 77 10.9 87 10.1 334 12.4 59 `11.3 45 10.9 67 11.5 54 11.3 83 11.5 57 10.3 64 7.8 55 11.7 212 11.7 104 11.4 152 9.9 53 12.0 52 9.9 109 9.8 71 11.1 73 10.4 46 9.3 86 10.7 71 9.8 327 12.5 186 10.8 71 9.8 79 10.6 115 11.0 80 9.B 110 10.5 89 9.8 108 56 10.5 100 9.6 000457 00SE 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM MI MAL. A1R3518 A1R3524 A1R3526 A1R3531 A1R3S34 A1R3538 A1R3542 A1R3548 A1R3554 A1R3557 A1R3562 A1R3564 A1R3569 A1R3573 A1R3578 B1R3581 B1R3585 H1R3591 B1R3594 B1R3547 B1R3601 B1R3605 B1R3608 B1R3611 818361 B1R3623 H1R3630 BIR3633 B1R3636 R1R3641 C1R3646 C1R3650 C1H3654 C1H3658 C1H3663 C1R3667 C1R3670 C1R3672 CIR3676 C1R3679 C1R3682 C1R3684 CIR 3689 CIM3641 C1R3694 GLU 130 138 141 104 67 147 46 122 168 117 134 116 143 105 115 120 155 147 154 143 146 157 136 128 169 142 137 163 153 152 144 147 133 123 115 107 Ilo 107 125 122 1 16 132 126 49 113 TABLE 14 TWO YEAH OHAL <01fcTI TOa ICITY"O N C O 0 E N 1CITY STUDY OF FLUOHOCAHHON FC-143 IN MALE HATS INDIVIDUAL SF.HUM CHEMISTRY VALUES MONTM*24 RUN ALT AST TH1L1 ALH TPROT 1A 2 52 0.2 2.6 6.6 23 2V 42 O.b 2.7 7.1 IS 28 47 0.2 3.0 6 . 8 14 36 60 0.3 3.1 7.1 20 21 142 0.3 2.7 5.9 12 38 6V 0.2 2.8 6.4 15 35 50 O.b 3.0 7.0 15 32 48 0.4 2.9 7.0 17 43 74 0.2 3.0 6.6 16 42 66 0.6 3.0 7.3 17 33 53 0.1 2.4 6.8 IV 27 60 0.5 2.5 6 . 9 22 2V 74 ` 1.0 2.7 7.4 14 2V 5 0.7 3.1 7.7 15 53 V7 0.4 2.6 7.3 15 41 57 0.2 3.4 6.6 17 111 133 0.2 3.2 6 . 8 17 88 130 0.3 2.9 7.9 16 75 10V 0.3 3.4 7.1 15 64 117 0.2 2.9 6.4 16 47 68 0.2 3.0 6.2 14 43 5V 0.1 3.3 7.4 14 41 76 0.2 2.8 6.5 IV 4 1 5b 0.3 3.5 6.8 17 82 162 0.2 3.1 6.9 14 60 96 0.3 3.6 7.3 17 61 101 0.3 3.4 7.8 34 62 110 0.2 2.7 6.7 13 52 91 0.2 3.0 6.4 20 sv 83 0.3 3.0 6.9 17 47 70 0.4 3.1 6.6 14 35 51 0.3 2.8 7.1 13 b4 89 0.3 2.8 6.7 15 43 66 0.3 3.2 6. 8 14 27 43 0.6 2.6 6.8 15 45 72 0.4 3.0 6.8 1 46 105 0.3 2.3 6.4 10 2V 44 0.2 2.6 7.7 3V 33 62 O.b 2.2 6.6 16 41 69 0.4 2.9 7.1 1H 3V 64 0.3 3.0 7.0 12 bO ' 92 0.4 3.1 6.5 15 43 64 0.2 2.9 6.3 15 1 74 0.3 3.0 6 . 3 15 *5 75 0.4 3.1 7.3 ALKPHOS 118 74 39 55 61 66 37 97 29 109 68 77 58 86 77 97 122 132 162 74 127 99 108 133 105 107 111 121 75 129 62 100 102 102 47 103 75 20 91 64 104 77 118 65 88 CPK CA h7 51 63 72 190 69 64 108 73 90 76 187 299 101 146 82 57 79 176 95 85 83 86 57 54 162 114 51 86 57 64 71 74 47 51 76 44 47 77 57 105 86 11* 73 80 10.5 11.5 10.8 11.0 11.1 10.5 11.6 10.9 11.0 11.2 10.1 10.5 10.3 11.3 10.9 ' 10.8 10.5 10.5 10.8 10.6 10.7 10.5 10.7 11.2 10.8 10.9 11.3 11.0 10.6 11.0 11.4 10.4 10.2 10.8 10.5 10.5 10.6 10.1 10.7 10.5 10.7 10.4 10.2 10.4 10.6 TABLE 15 TWO YEAR ORAL (OIETI TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FC-143 in r a t s MEAN BLOOD CHEMISTRY VALUES WITH STANDARD DEVIATIONS GLUCOSE <MG/OLI BLOOD UHtA NITROGEN (MG/OLI ALT IIU/LI AST (lU/LI N MEAN S.DEV MEAN S.DEV MEAN S.DEV. MEAN S.DEV. FEMALE MONTH 3 0 PPM 300 PPM 30 PPM MONTH b 0 PPM ' 300 PPM 30 PPM MONTH 12 0 PPM 300 PPM 30 PPM MONTH lft 0 PPM 300 PPM 30 PPM MONTH 2A 0 PPM 300 PPM 30 PPM IS 138.9 15 132.9 15 132.1 9.79 10.9b 12.0b 19.7 2*.5 18.5 1.62 3.91 2.07 22.6 36.2 19.* 4.87 6.72 3.18 46.0 51.6 *4.9 9.20 13.42 5.79 15 15*.8 1*.9S 15 133.6 9.61 15 128.6* 13. *1 21.6 20.7 19.1 3.22 2.9b 2.00 23.5 *.3 25.7 17.20 20.46 14.55 69.7 59.2 69.9 38.56 29.11 28.60 15 13*.9 15 135.3 15 135.A 10.51 B.1B 10.35 19.8 21.2 19.9 2.1* 5.21 2.83 *.l 28.6 27.1 15.17 21.59 12.9* 68.1 66.2 72.6 38.77 30.37 36.65 15 123.5 15 120.0 15 122.2 15.51 9.39 15.39 18..1 18.,7 20,.1 2.*9 3.37 4.02 68.7 *6.4 89.4 11.60 6.36 14.31 70.1 63.5 63.5 24.40 16.97 25.21 15 122.2 15 115.3 15 119.* 13.75 18.72 15.23 17.9 16.2 15.3 4.10 3.7b 3.35 *0.0 *3.1 88.6 10.11 25.27 9.61 67.8 67.0 63.5 30.03 35.26 12.95 P < .05. TWO TAILED OUNNETT T ON HA* DATA. I P <= .05. TWO TAILED DUNNETT T ON RANKED DATA TABLE 15 TMO YEAR ORAL (DIET) TUX ICITY-DNCOGENICI TY STUDY OF FLUOROCARBON FC-1A3 IN RATS MEAN BLOOD CHEMISTRY VALUES ITBILI ALB T P R O T ALKPHOS CPK, CA) MITH STANDARD DEVIATIONS TOTAL BILIRUBIN (MG/DL) ALBUMIN (GM/DL) TOTAL PROTEIN (G M / D L ALKALINE PHOSPHATASE (IU/LI CREATINE PHOSPHOKINASE (IU/ L ) CALCIUM (MG/OLI N MEAN S.DEV MEAN S.DEV MEAN S.OEV MEAN S.BEV MEAN S.DEV MEAN S.DEV FEMALE MONTH 3 0 PPM 300 PPM 30 PPM MONTH 6 0 PPM 300 PPM 30 PPM MONTH 1? 0 PPM 300 PPM 30 PPM MONTH IA 0 PPM 300 PPM 30 PPM MONTH ?4 0 PPM 300 PPM ro 30 PPM IS 0.6 0 1B 5.3 0.A5 7.2 0.41 83.7 32.2* 93.9 51.44 11.0 0.55 15 0.5 0.11 5.0 0.52 6.9* 0.41 89.1 25.36 87.7 37.12 11.1 0.S2 15 0.6 0.09 5.0 0.41 7.0 0.32 69.9 25.98 86.7 21.06 10.5* 0.69 15 0.6 0.14 5.9 0.65 7.4 0.64 77.8 30.50 56.5 14.79 11.7 0.53 15 0.5 0.09 5.6 0.46 7.4 0.34 82.1 22.06 66.7 21.17 11.7 0.43 15 0.6 0.10 5.5 0.66 7.3 0*57 80.9 >5.76 89.2 45.03 11.B 0.45 15 0.8 0.38 4.3 0.26 7.3 0.52 76.5 30.01 54.6 20.02 11.2 0.60 15 0.6 0.21 4.2 0.32 7.1 0.46 91.1 42.86 41.3 11.52 11.1 0.33 15 0.8 0.21 4.4 0.26 7.5 0.46 89.4 >9.87 78.7 78.42 11.0 0.43 15 0.6 0.26 3.9 0.23 7.9 0.57 65.5 32.10 37.3 9.81 11.4 0.53 15 0.6 0.23 3.9 0.28 7.8 0.47 76.1 28.36 35.1 9.64 11.1 0.43 15 0.6 0.24 . 3.8 0.26 8.3 0.73 39.7* 13.47 27.6 19.18 10.6* 1.01 15 0.6 0.31 3.4 0.21 7.6 0.69 68.7 33.39 68.4 32.23 11.5 0.64 15 0.4 0.17 3.4 0.28 7.4 0.56 63.1 19.6* 67.7 27.06 11.2 0.46 15 0.5 0.21 3.3 0.38 7.2 0.75 56.7 19.90 71.3 35.73 11.3 0.45 1 P <* .05 T*0 TAILED Do n n e t t T ON RAM DATA. P <* .05 Tm O TAILED DUNNETT T ON r a n k e d OATA. 000459 TABLE 15 T*0 YEAH OMAL (UIETl TOXIC 1TY-ONCOOENICITY STUDY F FLUUHOCa HUN FC-143 1N FEMALE RATS INDIVIDUAL SERUM CHEMISTRY VALUES OOSE animal 6LU RUN ALT AST t m i l i AL8 TPROT ALKPHOS CPK CA 0 PPM NIR456 143 22 20 47 0.5 4.8 6*8 0 PPM N1R4578 ISO 22 Id 49 0 PPM N1R4582 129 20 17 55 0 PPM N1R4583 147 18 19 4 1 0.8 5.1 7.0 0.8 6.9 7.8 0.5 4.9 7.1 0 PPM N1R4584 129 19 29 66 0.5 4*8 7.1 0 PPM N1R4592 J34 17 25 62 0 PPM NIR4610 143 21 32 57 0 PPM N1R4612 147 20 19 39 0.6 5.2 7.0 0.7 6.9 7.8 0.5 4*8 6 6 0 PPM N1N4613 129 19 19 41 0 PPM N1R4619 139 18 22 51 0.5 4.9 7.0 1.0 5.3 6.9 0 PPM N1R4621 131 19 23 49 0.5 4.9 7.1 0 PPM N1R4626 163 20 28 48 0.4 5.3 7.1 0 PPM N1R4627 133 1 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 7.6 300 PPM 01R4645 126 28 29 37 0.4 4.7 6.2 300 PPM 01R4654 129 19 35 47 0.5 5.3 7.2 300 PPM 01R4660 119 29 32 45 300 PPM 01R4664 122 26 25 59 300 PPM 01R4668 130 20 32 70 0.6 3.6 6.2 0.4 5.1 7.1 0.6 5.5 7.3 300 PPM 01R4669 138 27 20 39 0.5 5.1 7.0 300 PPM 01R4672 136 19 21 40 0.5 5.3 7.1 300 PPM 01R4673 129 26 38 77 0.3 6.0 8*8 300 PPM 01R4674 124 25 31 72 0.4 5.0 7.1 300 PPM 01R4679 154 23 26 49 0.3 5.0 7.0 300 PPM OIR46RO 139 25 15 33 O.* 4.8 6.8 300 PPM 01R4693 145 28 19 49 0.6 5. 1 6.8 300 PPM 01R4698 130 31 20 56 0*5 5.0 6.7 300 PPM 01R4700 162 20 21 43 0.7 6.1 7.4 300 PPM 01R4701 120 21 29 5 0.6 4.7 6.1 30 PPM P1R4708 148 20 19 44 0.6 5.3 6*6 30 PPM P1R47I0 121 19 19 32 0.5 4.9 7.0 30 PPM P1R4720 135 18 2b 60 30 PPM P1R472I 142 18 22 47 0.7 5.7 7.5 0.6 4.9 7.0 30 PPM P1R4730 140 16 18 39 0.6 5.1 7.3 30 PPM PIR4731 145 21 22 40 0.7 4*4 6.7 30 PPM P1R4734 137 1 21 50 0.7 5.5 7.4 30 PPM P1R4735 117 21 14 4? 0.6 5.2 7.0 30 PPM P1R4736 106 22 20 53 0*6 5.3 7.1 30 PPM P1R4737 125 16 15 50 0.6 4.6 6.9 30 PPM P1R4738 141 16 17 45 0.6 4.6 6.7 30 PPM P1R4744 11 1 23 4* 30 PPM P1H4749 133 21 16 38 0.6 5.4 7.3 0.6 4.9 6.9 30 PPM P1R4752 140 18 20 46 0.8 5.2 7.4 30 PPM P1R4T53 133 16 19 51 0.4 4.3 6.4 120 71 10.1 61 95 10.7 152 150 11.7 61 58 10.6 95 234 11.2 12 168 11.3 68 60 12.2 89 58 10.8 61 50 10.6 65 94 11.2 67 80 10.7 120 58 10.6 40 66 10.9 70 90 11.4 58 76 11.7 51 72 ,10.1 65 63 10.8 73 57 10.5 125 90 10.9 54 136 11.2 86 84 10.6 118 46 11.3 106 123 11.1 111 186 11.9 2 90 11.5 55 56 11.6 95 100 10.8 124 60 11.8 93 57 11.6 99 88 11.4 75 74 11.8 104 65 9.8 45 99 9.6 97 89 10.7 53 63 10.9 99 84 10.8 61 114 11.5 47 109 11.1 33 111 11.0 33 69 9.8 55 83 9.9 99 98 10.6 58 58 9.8 91 121 10.7 9tt 63 9.9 000460 TABLE 15 DOSE 0 PPM 0 PPM 0 PPN Q PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPN 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM animal N1R4582 N1R45B4 NIRAS06 NIRAS90 N1R4598 N1R4603 N1R4607 N1R4616 N1R4619 N1RA621 N1RA622 N1R4629 N1R4631 N1R4632 N1R4639 01R4650 01R4653 01R4657 01R4660 01R4663 OIR4670 01R4673 01R4681 01R4682 01R4A92 01R4693 01R4694 01R4698 01R4699 01R4700 P1R4710 P1R4711 P1R47I7 P1R4719 PIR4729 P1R4731 P1R4732 P1R4733 P1R4737 P1R4740 P1R4743 P1R474S P1R4746 P1R4749 P1R47S0 TWO YtAN 0AL DIET TOXICITY-0NC06ENICITY STUDY OF FLUOROCARh ON FC-143 IN FtMALE MATS INDIVIDUAL SERUM CHEMlSTHY VALUES -------------- - ------M O N T H s # > ---------------------- 6LU HUN ALT AST THILI ALH TPHOT 178 21 21 3 7 0.9 7.2 7.7 172 22 55 11 0.6 5.8 8.9 159 23 88 183 0.5 6. 7.9 183 22 26 48 0.6 5.6 7.2 141 20 20 48 0.6 5.8 7.2 161 22 32 71 0.4 6.1 7.5 147 23 35 96 0.5 5.5 7.0 ISO 18 26 56 0.4 5.2 6.9 140 18 26 57 0.6 6.0 7.2 154 20 26 47 0.7 6.9 8.1 160 18 34 79 0.6 5.6 7.2 130 20 33 58 .0.4 4.9 6.3 137 22 26 55 0.4 5.2 6.7 154 24 27 30 0.7 6.4 8.0 156 31 30 62 0.6 6 . 4 7.6 133 18 76 122 0.6 6.2 7.4 128 19 30 50 0.6 6.2 7.6 123 19 76 115 0.5 5.2 7.5 136 25 22 61 0.6 5.1 7.3 125 17 16 43 0.4 4.9 7.0 151 19 14 30 0.6 6.0 7.9 125 24 66 100 0.4 5.7 7.5 125 21 34 40 0.5 5.4 7.5 118 22 26 44 0.5 5.8 7.7 142 22 23 42 0.4 5.1 7.4 137 24 23 41 0.6 5.1 7.0 144 17 23 3 0.6 5.2 6.8 135 26 29 53 0.6 6.6 7.3 147 18 27 45 0.5 5.5 7.0 135 20 31 64 0.7 6.3 8.0 109 19 25 54 0.5 4.6 6.7 152 22 41 70 0.6 6.0 8.1 144 17 32 33 0.7 6.1 7.8 116 20 40 63 0.7 6.0 7.7 144 18 59 61 0.7 6.3 8.0 140 19 27 42 0.5 4.4 6.3 122 20 26 3H 0.6 5.7 7.3 127 18 22 40 0.7 5.0 6.6 140 18 25 40 0.5 5.3 7.4 133 21 28 53 0.6 5.4 7.0 112 19 27 ` 41 0.5 4.6 7.1 133 14 23 ' 75 0.5 4.8 6.7 117 21 SH 102 0.5 6.1 7.9 125 21 35 47 0.8 6.2 7.7 115 20 67 140 0.7 5. 7.6 alkphos 137 125 85 101 51 39 61 55 67 51 108 98 90 50 59 59 111 76 78 88 41 97 81 56 57 97 73 100 116 101 110 140 95 78 93 100 68 57 74 99 42 50 81 61 65 CPK CA 71 55 41 69 33 85 49 52 66 73 50 55 32 59 57 52 63 ` 60 126 84 80 54 51 51 53 40 83 69 58 77 134 52 49 117 103 38 74 78 45 51 133 205 107 80 72 12.9 11.2 12.2 11.8 11.6 11.6 11.4 11.0 11.8 12.2 11.0 11.4 11.3 12.3 11.8 12.3 11.7 11.5 11.4 11.0 12.3 11.9 11.9 12.1 11.6 11.5 11.3 11.4 11.5 12.5 11.6 12.1 11.8 12.1 12.3 11.1 12.3 11.3 11.9 12.0 11.6 10.8 12.3 12.0 11.8 000461 TABLE 15 T<|0 Yt AH ORAL (DIET! TUX ICI TY-ONLUUENIC IT Y STUDY UF FLUOROCARBON F C - 143 IN FtMALfc HATS INDIVIDUAL SERUM CHEMISTRY VALUES DOSE animal g l u HUN ALT AST T8ILI ALB TPROT ALKPHOS CPK CA 0 PPM N1R457B 146 24 0 PPM N1R45B2 124 18 0 PPM N1R45B5 132 24 0 PPM N1R4580 137 20 0 PPM N1R4S89 132 19 0 PPM N1R4590 136 19 0 PPM NIR4601 143 20 0 PPM N1R460B 131 1 0 PPM N1R4610 127 21 0 PPM N1R4620 146 19 0 PPM N1R4629 136 18 0 PPM N1R4630 157 22 0 PPM NIR4631 128 20 0 PPM N1R4632 113 18 0 PPM N1R4640 135 17 300 PPM 01R4642 137 18 300 PPM 01R4652 12 20 300 PPM 014455 132 24 300 PPM 01R4656 136 22 300 PPM 014444 127 25 300 PPM 014466 125 15 300 PPM 0IR4664 129 23 300 PPM 01R4671 139 18 300 PPM 01H4474 125 22 300 PPM 01R4676 134 17 300 PPM 01B4407 132 37 300 PPM 01R4689 148 22 300 PPM 01R4692 146 18 300 PPM 01R4499 149 19 300 PPM 01R4704 143 18 30 PPM PIR4711 141 17 30 PPM P1B4714 121 17 30 PPM P1R4715 142 19 30 PPM PIH4716 12 19 30 PPM P1H4717 134 22 30 PPM P1R4721 124 19 30 PPM PIR4725 159 19 30 PPM PIH472T 149 19 30 PPM P 14729 131 1H 30 PPM PIR4734 135 19 30 PPM P1R4742 135 25 30 PPM P1H4743 125 21 30 PPM P1R4749 146 27 30 PPM P1R4750 130 18 30 PPM P1H4755 131 19 27 48 22 42 33 60 23 47 67 183 24 46 40 59 24 51 25 62 31 51 67 119 42 79 41 94 19 33 26 47 28 51 112 163 28 51 32 56 29 54 26 57 23 48 3 59 40 79 41 65 26 52 35 52 32 50 38 53 51 103 38 62 29 57 49 86 36 56 31 51 39 72 76 94 33 4H 37 58 36 68 30 65 26 194 42 83 Jft 74 18 43 1.2 1.5 0.8 0.5 0.T 0.6 0.6 1.1 1.0 0.6 0.4 fl.b 0.5 1.4 0.2 0.5 0.6 0.7 0.6 0.6 0.4 0.6 1.0 0.4 0.6 0*3 0.4 0.6 0.9 0.4 1.2 0.6 0.8 0.6 0.8 1.0 0.4 0.5 0.7 0.7 0.8 1.0 0.9 0.8 0.9 4.1 4.T 4.5 4.4 4.6 4.5 4.1 4.2 4.1 4.1 3.9 3.8 4.4 4.3 4.4 4.5 4.6 4.6 4.6 4.3 3.T 4.3 4.3 *0 4.3 3.5 4.2 4.2 4.5 4.1 4.7 4.7 4.1 4.0 4.2 4.7 4.1 4.T 4.4 4.3 4.0 4.5 4.6 4.4 4.4 7.3 8.6 7.6 7.0 7.T 7.3 7.3 7.2 7.1 7.0 6.7 6.6 7.4 8.2 7.2 7.7 7.8 7.5 7.4 7.0 6.6 7.0 7.1 6.7 7.0 6.6 6.9 7.2 7.8 6.3 8.1 8.3 7.2 6.9 7.7 7.9 6.9 7.T 7.4 7.3 6.9 8.2 7.5 7.5 7.6 71 62 11.7 134 82 12.5 84 42 11.5 44 56 10.a 104 50 11.7 84 38 11.3 127 41 10.8 39 60 11.1 72 104 10.7 71 55 10.9 HO 40 10.9 54 37 10.5 99 29 10.8 43 76 12.A 42 47 11.1 39 31 11.1 115 42 < 11.7 137 36 11.5 46 41 11.4 99 40 11.2 44 51 10.7 101 37 10.9 56 67 11.5 155 58 10.7 132 40 10.9 124 41 10.5 96 16 11.1 39 44 11.2 142 38 11.2 41 38 11.0 121 52 12.1 94 38 11.3 86 271 10.9 102 35 10.5 131 42 10.5 122 248 11.1 102 42 10.4 108 26 11.0 5 48 11.2 76 39 10.9 87 59 10.8 22 46 11.5 53 45 11.1 48 145 11.2 104 44 11.2 000462 ovr/ W O^ 'f*PS* 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAL N1R45B1 N1R4583 N1R4586 N1R4S92 N1R4595 N1R4598 N1R4599 N1R4602 N1R4604 N1R4606 N1P4609 N1R46I1 N1R461? N1R4627 N1R4638 01R4645 01R4647 01R4648 01R4651 Q1R4A63 01R4667 01R4675 01R46T9 01R4684 01R4688 01R4690 01R4693 01R4694 01R4696 O1R4690 P1R4T07 PIR4709 P1R4T14 P1R4718 P1R4720 P1R4722 P1R4725 P1R4729 P1R4732 P1R4733 P1R4737 P1R4748 P1R4749 P1R4752 P1R4754 Tm O Yt AH ORAL 1UIET) TOXICITV-ONCOGENIOITY STUDY OK FLUOROCARBON EC-143 IN FEMALf HATS INDIVIDUAL SERUM CHEMISTRY VALUES MONTH*! fiLU BUN ALT AST TH1LI ALB TPROT 128 22 37 50 0.3 3.3 6.4 120 17 40 64 O.d 3.9 8.4 98 19 59 93 0.3 3.7 7.8 107 23 35 53 0.6 4.2 8.4 118 18 71 132 0.* 4.0 8.6 123 17 55 79 0.5 4.0 7.8 133 16 69 106 0.5 4.0 7.7 103 21 43 58 0.8 4.0 8.2 ISO 14 38 44 0.5 3.8 7.4 126 1 58 79 0.7 3.8 7.8 110 15 48 65 1.0 4.2 8.6 143 19 40 49 0.6 4.0 7.5 138 18 42 49 1.2 3.8 7.9 116 16 42 65 0.6 3.7 7.8 141 18 54 65 0.9 4.0 8.3 119 21 50 65 0.5 3.7 7.2 117 19 5b 49 1.2 4.1 8.5 121 21 51 61 0.3 3.4 6.6 130 20 33 48 0.5 4.0 7.4 134 13 49 57 0.7 4.3 8.2 121 19 54 112 0.3 3.4 7.6 116 24 52 HI 0.8 3.6 8.2 118 lb 42 52 0.6 3.8 8.1 109 15 49 47 0.5 4.0 8.1 128 18 45 65 0.5 4.0 7.9 124 13 49 66 0.5 4.2 7.9 118 20 44 95 0.5 4.2 7.8 134 15 44 47 0.6 4.0 8.0 112 21 37 51 0.3 3.8 7.7 99 23 41 57 0.5 3.9 7.9 102 20 18 62 0.4 3.9 7.7 118 22 51 60 0.7 3.6 8.7 123 20 3b 42 0.7 3.9 9.4 122 24 45 51 0.9 3.9 8.9 98 20 28 56 0.6 3.6 8.0 126 16 24 65 0.3 3.3 6.7 148 14 21 51 0.3 3.6 7.6 127 27 57 48 0.8 3.8 8.8 120 19 39 59 0.6 3.8 8.0 143 21 60 76 0.7 4.2 8.6 136 23 48 60 0.8 3.6 8.0 94 13 24 48 0.5 3.6 8.0 116 16 42 148 0.6 4.3 9.0 127 22 61 52 1.2 3.9 9.3 133 25 37 74 0.5 4.0 8.0 ALKPHOS 88 51 152 91 63 40 53 55 62 88 56 17 60 27 79 36 68 59 105 74 149 78 65 63 90 79 91 65 30 89 53 S3 53 30 49 31 47 42 40 41 57 21 13 44 22 CPU CA 33 11.8 39 11.7 27 11.3 42 11.7 37 11.5 32 11.7 47 11.3 37 12.1 27 11.0 27 11.6 33 11.3 36 11.2 66 10.0 41 12.2 35 11.0 31 ` 11.0 35 9.9 18 10.6 37 11.3 26 11.3 43 10.9 54 10.9 26 11.3 32 11.2 26 11.5 29 11.4 38 11.6 40 11.0 49 11.5 42 11.3 30 12.1 lb 8.8 24 11.1 18 9.5 41 10.2 37 11.5 25 11.0 11 9.5 16 10.5 22 9.8 18 11.1 17 11.3 89 11.6 35 9.3 15 11.6 TABLE 15 TUO YEAR OHAL (DIET) TOXICITY-ONCOGENICITY STUDY OE f l u o r o c a h h o n EC-143 IN FEMALE HATS INDIVIDUAL SERUM CHEMISTRY v a l u e s DOSE ANIMAL GLU HUN ALT AST THILI ALU TPRUT ALKPHOS CPK CA 0 PPM N1H4583 135 17 0 PPM N1R4586 121 18 0 PPM N1R459] 118 20 0 PPM N1R4595 123 17 0 PPM N1R4598 IAO 16 0 PPM N1R4603 13R 26 0 PPM N1R4606 120 17 0 PPM MIRAMI 148 21 0 PPM N1R4614 115 17 0 PPM N1R4616 118 16 0 PPM N1R4626 112 10 0 PPM N1R4628 107 15 0 PPM N1R4634 97 26 0 PPM NIR4636 130 15 0 PPM N1R4638 111 17 300 PPM 01R4644 154 19 300 PPM 01R4646 113 15 300 PPM IR4649 loo 17 300 PPM 01R4657 117 15 300 PPM 01R4659 108 13 300 PPM 01R4661 148 26 300 PPM 01R4663 121 12 300 PPM 01R4672 loo 11 300 PPM 0IR4679 114 19 300 PPM 01R4683 105 14 300 PPM 01R46R8 109 13 300 PPM 01R4693 129 19 300 PPM 01R4695 Hl 18 300 PPM 01R4697 104 17 300 PPM 01R4701 127 15 30 PPM PIR470R 108 17 30 PPM PIRATI 1 106 16 30 PPM PIR4714 114 12 30 PPM PIRATI 6 117 17 30 PPM P1RA720 115 14 30 PPM PIRA723 141 17 30 PPM P1R4726 103 19 30 PPM P1R4729 119 14 30 PPM ' P 1RAT33 127 15 30 PPM PIRA736 137 12 30 PPM P1R4739 ini 15 30 PPM P1R4745 121 10 30 PPM P1RA7A7 116 13 30 PPM P1R4752 110 15 30 PPM PIRA 754 156 24 36 52 52 HH 32 58 66 158 37 52 34 56 36 52 42 81 37 42 42 73 27 52 36 48 42 98 29 42 52 65 30 41 41 51 2H 50 33 52 32 58 37 54 36 4* 29 52 37 59 4& 100 131 183 36 61 33 53 45 83 53 59 33 50 37 56 27 41 34 63 40 53 36 80 58 86 38 54 61 78 38 , 82 32 71 30 ' 55 31 67 39 58 45 79 1.0 3.3 0.3 3.4 1.2 3.5 0 *b 3.6 0.** 3.4 0.4 3.4 0.7 3.3 0.5 3.2 0.6 3.7 0.4 3.3 0.2 3.7 0.4 3.2 0.2 2.9 0.6 3.4 1.1 3.5 o.<* 3.4 0.5 3.5 0.2 2.8 0.4 3.4 0.3 3.0 0.4 3.4 0.8 3.8 0.4 3.5 0.6 3.2 O.b 3.2 0.2 3.4 0.7 3.7 0.3 3.8 0.3 3.6 0.5 3.6 0.5 3.3 1.0 3.4 0.4 3.5 0.2 3.3 0.4 3.2 0.3 3.3 0.6 3.3 0.6 3.2 0.6 3.8 0.4 3.6 0.2 2.2 0 3 3.1 0.3 3.0 0.6 3.7 O.A 3.6 8.1 7.3 7.8 8.5 7.2 7.2 7.9 6.5 7.6 7.5 8.6 7.5 6.1 7.5 8.4 7.0 7.0 6 S 7.2 7.9 7.2 7.5 7.2 7.8 8.8 7.4 7.9 6*8 7.5 7.0 6.4 7.8 7.7 6.8 8.1 7.2 7.5 6.9 7.9 7.4 5.5 6.6 6.2 8.0 7.3 49 7b 12.4 149 45 11.2 127 109 12.4 53 57 12.0 38 34 11.5 35 59 11.0 78 119 11.4 70 50 11.3 76 36 11.3 46 80 11.0 39 52 11.1 39 75 11.0 87 35 10.5 61 58 11.6 84 141 12.8 77 48 11.1 93 78 < 11.2 47 39 10.3 51 59 10.9 60 110 10.8 91 62 10.9 73 86 11.5 67 38 11.5 46 117 11.9 27 111 11.1 64 57 10.9 75 71 11.7 30 42 12.0 72 53 11.0 74 45 11.6 56 35 11.2 76 83 11.3 33 37 11.5 70 37 10.4 65 70 11.1 35 42 11.3 72 58 11.4 63 63 11.5 57 107 11.7 29 75 11.4 104 59 11.5 46 93 10.4 36 171 10.7 60 93 12.0 49 46 11.6 0004 TABLE 16 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats 0281CR0012 Ranges of Urinalysis Values at 3 and 6 Months Dose Group 3 Mo. Male Control 300 PPM 30 PPM 3 Mo. Female Control 300 PPM 30 PPM 6 Mo. Male Control 300 PPM 30 PPM 6 Mo. Female Control 300 PPM 30 PPM Specific Gravity 1.025-1.062 1.030-1.046 1.018-1.090 1.011-1.052 1.015-1.052 1.016-1.056 1.021-1.066 1.022-1.054 1.018-1.070 1.028-1.072 1.018-1.046 1.024-1.050 C1D PH 7-9 7-9 7-8 7-9 7-8 6-8 7-8 6-8 6-7 6-8 6-8 Albumin N-Tr N-1 + N-Tr N-1 + N-N N-N N-3+ N-Tr N-Tr N-3+ N-3+ N-Tr Bilirubin N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N Glucose N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N Occult Blood N-4+ N-N N-3+ N-N N-N N-N N-3+ N-1 + N-1 + N-1 + N-2+ N-Tr Ketones N-N N-N N-N N-N N-N N-N N-N N-1 + N-N N-1 + N-1 + N-1 + s^ooo Code: N - negative Tr - trace --I oo in 1+ - slight 2+ - slight to moderate 3+ - moderate marked 4+ - marked TABLE 16 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats 0281CR0012 Ranges of Urinalysis Values at 12 and 18 Months Dose Group Specific Gravity 12 Mo. Male Control 300 PPM 30 PPM 1.040-1.093 1.015-1.054 1.029-1.063 12 Mo. Female Control 300 PPM 30 PPM 1.023-1.070 1.012-1.059 1.008-1.048 18 Mo. Male Control 300 PPM 30 PPM 1.016-1.064 1.024-1.050 1.022-1.066 18 Mo. Female Control 300 PPM 30 PPM 1.016-1.058 1.011-1.034 1.016-1.050 pH 7.0-8.5 7.0-8.5 7.5-8.5 6.5-7.5 6.5-9.0 6.5-7.5 6.5-8.0 7.0-8.5 6.5-8.0 7.0-7.5 6.5-8.0 6.0-7.5 Kz+1> Albumin Bilirubin N-4+ N-3+ N-4+ N-N N-N N-N N-3+ N-3+ N-N 'N-N N-N N-3+ N-4+ N-4+ N-N N-N N-N N-3+ N-2+ N-3+ N-N N-N N-N Glucose N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-N N-Tr Occult Blood N-3+ N-Tr N-3+ N-N N-2 + N-2+ N-2+ N-N N-3+ N-Tr N-Tr N-4+ Ketones N-Tr N-Tr N-N 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 000466 -vl VO TABLE 16 Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats 0281CR0012 Ranges of Urinalysis Values at 24 Months Dose Group 24 Mo. Male Control 300 PPM 30 PPM 24 Mo. Female Control 300 PPM 30 PPM Specific Gravity 1.018-1.054 1.023-1.043 1.018-1.056 1.012-1.034 1.009-1.037 1.014-1.030 wz+1 in oG1O r-e PH 6.5-8.5 6.5-8.5 6.0-8.0 5.0-8.0 7.0-8.0 Albumin N-4+ N-4+ N-2+ N-- 2+ N-1 + Bilirubin N-N N-N N-N N-N N-N N-N Glucose N-N N-N N-N N-N N-N N-N Occult Blood Ketones N-4+ N-N N-4+ N-N N-N N-N N-N N-N N-4+ N-N N-N -N-N Code: N - negative Tr - trace 1+ - slight 2+ - slight to moderate 3+ - moderate to marked 4-1- - marked TABLE 17 TWO YEAR ORAL (DIET) TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FC-143 IN RATS ABSOLUTE ANO RELATIVE MEAN ORGAN WEIGHTS ONE YEAR INTERIM ABSOLUTE ORGAN WEIGHTS (GRAMS) 0 PPM 300 PPM MALE N = 15 N = 15 ORGAN WT SO WT SD BODY LIVER HEART SPLEEN KIDNEYS ADRENALS TESTES BRAIN PITUITARY 62S.5+-65.905 19.IS- 3.212 1.629- 0.157 0.694- 0.144 3.854- 0.507 .0679- 0.013 3.553- 0.419 2.113- 0.111 .0205- 0.006 580.8-51.153 21.33+- 2.497 1.452- 0.053 0.800- 0.109 4.047- 0.419 .0553- 0.008 3.459- 0.325 2.064- 0.067 .0115- 0.004 FEMALE ORGAN BODY LIVER HEART SPLEEN KIDNEYS ADRENALS UTERUS BRAIN PITUITARY N = 15 WT SO 401.1-77.172 12.28- 1.904 1.117- 0.134 0.663- 0.123 2.533- 0.383 .0761- 0.012 0.775- 0.247 1.963- 0.128 .0227- 0.006 N = 15 WT SO 403.1-66.702 12.90- 1.781 1.086- 0.121 0.613- 0.120 2.599- 0.283 A 0..0770926-- 00..202119 1.970- 0.119 .0195- 0.007 : P <* .OS. TWO TAILEO DUNNETT T ON RAW DATA. I : P <= .05, TWO TAILED DUNNETT T ON RANKED DATA. A ; N = 14. 000468 oo TABLE 17 TWO YEAR ORAL (OIET) TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FC-143 IN RATS ABSOLUTE AND RELATIVE MEAN ORGAN WEIGHTS ONE YEAR INTERIM ORGAN WEIGHT/BODY WEIGHT (X) 0 PPM 300 PPM MALE N * 15 N = 15 ORGAN % SO % SO LIVER HEART SPLEEN KIDNEYS ADRENALS TESTES BRAIN PITUITARY 3.0534-0.318 0.262^-Q.021 0.144+-0.025 0.6174-0.057 0.0114-0.002 0.5704-0.057 0.3404-0.026 0.0034-0.001 3.6964-0.504 0.2524-0.024 0.1384-0.018 0.7014-0.090 0.0104-0.001 0.5984-0.064 0.3584-0.029 0.0024-0.001 FEMALE ORGAN LIVER HEART SPLEEN KIDNEYS ADRENALS UTERUS BRAIN PITUITARY N 15 * SO 3.0904-0.293 0.2644-0.038 0.1684-0.031 0.6424-0.091 0.0204-0.005 0.2014-0.077 0.5074-0.105 0.0064-0.002 N = 15 % SO 3.2394-0.423 0.2744-0.040 0.1584-0.048 0.6494-0.111 A 0.0204-0.006 0.1814-0.074 0.4994-0.077 0.0054-0.002 : P <= .05. TWO TAILED DUNNETT T ON RAW DATA. 1 : P <= .05, TWO TAILED DUNNETT T ON RANKED DATA A : N = 14. oroo 000469 TABLE 17 TWO YEAR ORAL (DIET) TOXICITY-ONCOGENICITY STUDY OF FLUOROCARBON FC-143 IN RATS ABSOLUTE AND RELATIVE MEAN ORGAN WEIGHTS ONE YEAR INTERIM ORGAN WEIGHT/BRAIN WEIGHT (GRAMS) 0 PPM 300 PPM MALE N = 15 N * 15 ORGAN RATIO SO RATIO SO LIVER HEART SPLEEN KIDNEYS ADRENALS TESTES PITUITARY 9.0494-1.321 0.7724-0.071 0.4244-0.070 1.021+-0.192 0.032*-- 0.006 1.678*-- 0.150 0.010-*-- 0.003 10.3394-1.187 0.7054-0.036 0.3894-0.058 1.9644-0.227 0.0274-0.004 1.6754-0.129 0.005+-0.002 FEMALE ORGAN LIVER HEART SPLEEN KIONEYS ADRENALS UTERUS PITUITARY N = 15 RATIO SD 6.273-*-- 1.001 0.571-*-- 0.073 0.3374-0.056 1.2944-0.197 0.0394-0.006 0.3974-0.130 0.0124-0.004 N = 15 RATIO SD 6.5504-0.826 0.5524-0.065 0.3124-0.064 1.3234-0.123A 0.0414-0.010 0.3564-0.111 0.0104-0.003 : P <= .OS, TWO TAILEO DUNNETT T ON RAW DATA. : P <= .05, TWO TAILEO DUNNETT T ON RANKED DATA A : N = 14. oo CO 000470 TABLE 17 TWO YEAR ORAL DIET TOk ICITY-ONCOGENICITY STUDY OF FLUOROCARHON FC-143 IN HALF HATS ONE YEAR INTERIM INDIVIDUAL ORGAN WEIGHTS DOSE ANIMAL BODY LIVER HEART SPLEFN KIDNEYS ADRENALS^ 0 PPM o 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM AIR-3416 AIR-3617 AIR-3620 AIR-3622 AIR-3527 AIR-3535 AIR-3543 AIR-3546 AIR-3550 AIR-3651 AIR-3559 AIR-3500 AIR-3570 AIR-3575 AIR-3500 B1R-3504 B1R-3500 R1R-35M9 'B I R - 3 5 9 2 B1R-3590 R1R-3604 B1R-3613 B1R-3617 R1R-3620 B1R-3622 B1R-3626 B1R-3A27 BIR-3630 B1R-3642 RIB-3643 720 651 655 627 634 594 747 656 566 494 627 600 575 551 590 547 564 562 657 565 554 606 552 641 407 603 595 559 543 607 23.00 21.74 20.07 16.10 16.71 10.12 24.96 17.61 15.19 13.96 19.53 22.31 16.55 19.08 19.77 10.56 25.31 24.34 10.67 22.90 21.43 10.07 20.60 22.91 17.00 25.32 20.94 20.30 20.35 22.38 1.706 1.565 1.719 1.675 1.517 1.654 1.703 2.018 1.476 1.361 1.536 1.629 1.526 1.636 1.556 1.407 1.516 1.506 1.402 1.440 1.503 1.360 1.405 1.499 1.357 1.395 1.481 1.412 1.439 1.409 1.079 0.H74 0.772 0.776 0.650 0.095 0.904 0.905 0.704 0.751 0.072 1.091 0.991 1.113 1.020 0.603 0.593 0.794 0.020 0.742 0.054 0.963 0.H75 0.059 0.700 0.013 0.715 0.746 0.007 0.950 3.970 4.043 4.352 4.201 3.356 3.4T4 4.365 3.950 3.656 2.657 3.640 6.679 3.525 3.701 4.170 3.046 4.504 3.06? 3.669 4.396 4.0?6 3.693 3.916 4.096 3.44? 4.69? 3.703 3.793 3.006 4.446 94 66 62 67 57 07 59 77 41 59 70 64 64 67 76 53 63 55 66 61 62 70 40 59 61 47 47 47 49 43 NOTES: Body weights and organ weights in grams, a. - indicates organ weights in mg. TESTES 3.727 4.147 3.967 3.794 3.316 3.230 3.704 3.460 3.911 2.501 3.331 3.070 3.603 2.944 3.006 3.226 3.995 3.700 3.039 3.264 3.220 3.376 3.604 3.404 2.700 3.205 3.381 3.022 3.649 3.410 H h a In 2.330 2.111 2.204 2.227 2.088 1.963 2.194 2.079 2.160 1.920 2.074 2.207 2.114 1.971 2.071 1.981 2.1*7 2.076 2.166 2.069 1.9h 7 2.0*6 2.033 2.109 1.999 2.066 2.12* 2.12* 2.101 1.936 RITUTARY- 9 10 19 2(1 33 27 16 26 IS 28 23 18 26 IS 16 6 16 11 20 in 10 9 in 11 16 12 11 6 14 11 00 000471 TABLE 17 T W O Y t A H O H A L DITTI 1 U X 1C I T Y - O N C O u F N I C I T y STUDY UK ELUUHOCAHHON KC-14J IN ft H*Lt HATS ONf ytAH INTIHlH INDIVIDUAL OHGAN WEIGHTS OOSE ANIMAL BOOT LIVEH HfAHT SPLEEN SIDNEYS a o n e n a l s - UTEMUS HHAIN PI TUTANY 1 PPN P*N 0 PPN PPM 0 PPN 0 PPN 0 PPN 0 PPN PPN 0 PPN 0 PPN 0 PPN PPN PPN 0 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN 300 PPN NIP-4570 NIP-4582 NIP-ASPS NIP-ASPS N|P--ASPS NIP-4590 NIP-4601 NIP-4608 NIP-4610 NIP-4620 NIP-4629 NIP-4630 NIP-4631 NIP-4632 NIP-4640 OIP-4642 OIP-465? 01R-465S OFP-4656 01P-4664 01P-4666 010-4669 01P-4671 01P -- 4674 01P-4676 OIR-46P7 010-4689 01R-4692 01 P-4699 OIP-4704 540 305 353 306 375 373 470 429 345 320 401 466 240 531 395 323 303 372 447 399 339 305 497 355 519 329 363 531 395 409 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 10.05 13.12 12.16 13.49 14.26 12.28 12.10 17.67 13.59 14.36 12.56 11.72 13.64 11.59 1 0 . IP 1.390 1.IH5 1.035 1.117 1.095 1.037 1.164 1.021 0.9H2 1.176 1.0H4 1.260 0.830 1.128 1.230 0.920 1.119 1.045 1.160 1.166 1.066 0.952 1.181 0.927 1.206 1.108 1.312 1.210 0.9H? 0.943 0.761 0.410 0.626 0.679 0.661 0.571 0.860 0.640 0.601 0.7R9 0.643 0.725 0.4|4 0.723 0.731 0.73? 0.609 0.603 0.40S 0.606 0 . 6 10 0.470 0.663 0.594 0.630 0.837 0.790 0.460 0.561 0.527 3.279 2.405 2.223 2.535 3.106 2.300 3.116 2.356 2.435 . 2.470 2.176 2.616 1.044 2.620 2.512 2.679 2.972 2.527 3.020 2.384 2.708 2.396 2.862 2.290 2.800 , D -- 2.647 2.400 2.304 2.067 00 HI 66 87 76 78 62 85 87 89 65 80 6? 59 92 76 64 71 78 76 106 59 114 64 90 08 116 60 70 64 0.696 0.870 0.674 0.654 1 .03? 0.033 0.407 0.943 1 .171 0.046 0.623 0.520 0.620 0.890 0.813 l .150 0.766 0.543 0.888 0.557 0.86 3 0.766 0.816 0.440 0.704 0.924 0.660 0.356 O.TOH 0.350 2.044 1.67m 1.912 2.073 1 .963 1.875 1.928 2.124 1.969 2.1.15 1.947 2.164 1.883 . 1.893 1 .9*6 2.265 1.790 2.011 1 .940 1.966 1.856 2.008 2.009 2.098 2.0-47 1.437 1.99| 1.6 30 1.54,4 2? ?7 18 18 26 17 26 19 30 18 19 17 20 40 ?6 26 26 6 6 21 22 16 17 26 30 17 21 22 20 1" NOTES: Body weights and organ weig'hts in grams. a Kil Indicates organ weights in m g . Kidney wei ghts not recorded due to marked hydronephrosi S . 0c0n 000472 TABLE 18 TWO YEAR ORAL (DIET) T O X I C I T Y - O N C OG E N I C I T Y STUDY OF F L U O R O C A R B O N FC-143 IN RATS ARSOLUTF AND RFLa TTv F MEAN ORGAN WEIGHTS ABSOLUTE ORGAN WFIGHT TORAHS) 0 PPM 300 PPM 30 PPM z it ji MALE N = IS N = 15 ORGAN WT SO WT SO WT sn BODY LIVER HEART SPLEEN KIDNEYS ADRENALS TESTES RRAIN 6^6 99*761 18.15*- 3.07* l*720*- 0*226 1.217*- 0*339 4.464*- 0*746 Oflf1 - 0*018 3478*- 0*702 2.105*- 0*133 632i6*-9l.947 19.1?.- 3.037 1.665*- 0.295 1.15*- 0.310 4.590*- 0.525 .0866*- 0.018 3.626*- 0.643 2.185*- 0.072 648.2*-l06.96 18.81*- 3.427 1.806*- 0.313 1.105*- 0.206 5.185*- 1.782 .0900*- 0.027 3.696*- 0.727 2.203*- 0.130 FEMALE ORGAN BODY LIVEP heart SPLEEN KIDNEYS ADRENALS UTERUS brain N 15 WT SD Sl2<5*-82*585 15.11*- 3*752 1.366*- 0*199 0.797*- 0*140 3.129*- 0*287 .1030*- 0* 046A 0.814*- 0*290 2.034*- 0*102 N = 15 WT SD 4512*-,68.116 14.05*- 2.735A 1.310*- 0. ITO 0*698*- 0.195 3.155*- 0.465 .1126*- 0.039 0.819*- 0.391 2.049*- 0.111 N = 15 WT SD 533.3*-82.486 17.06*- 3.847 1.489*- 0.192 1.153*- 0.681W 3.475*- 0.446* .1365*- 0.044 0.858*- 0.487 2.030*- 0.131 : P <= .65 TWO t a i l e d DUNNETT T ON RAW DATA* oo 9 : P <= .05 TWO t a i l e d DUNNETT T ON r a n k e d d a t a . CT> A : N = 14 a n i m a l s 000473 o o o 00 n I TABLE 18 TWO YEAR ORAL (DIET) T 0 X I C I T Y - O N C OO E N I f I T Y STUDY OF F L U O R O C A R B O N FC-1 4 3 IN RATS a b s o l u t e and r e l a t i v e m e a n ORGAN WEIGHTS ORGAN w e i g h t /r o o y w e i g h t <*> 0 PPM 300 PPM 30 PPM hale N = IS N = ]5 N * IS ORGAN % SO * SO * SD LIVEP HEART SPLEEN KIDNEYS ADRENALS TESTES brain 2.733+-0.939 0.?1*0.37 0.187+-0.059 0.f.66*-0.l01 O.O12*-O.0O3 0*536*-0.l44 O.322+-O.049 3O43*-O.4O0 0.267*-0.054 0 * ISA'.-O 047 0 736*-0109 0.0*4*-0.003 O.57B*-O.1O0 0393^-0054 2.934*-0.531 0.2B3*-0.055 0 1 7 4 * - 0 042 0.B21-0*350 0.014*-0.005 0.574*-0.093 0.347*-0.05G FEMALE ORGAN liver heart SPLEEN KIDNEYS adrenals UTERUS BRAIN N e IS * SD 2.941+-0.46S 0.?9*-0.036 0*158+-0.I33 0.621*-0;B0 O.030+-0.A0BA 0*llt-0.8S5 0.4tB-0.77 N = 15 * SD 3125*-0.41VA 0 296*-0056 0.197*-0.046 0<709*-0*120* 0 0g5*-0 010 0*183*-0*076 046S*-007 N = 15 * SD 3.19f>*-0.550 0283*-0046 0.210*-0.078* 0.662*-0.102 0.02ft-0.007 0.163*-0.092 0.388*-0.056 1 P <= .05 TWO t a i l e d DUNNETT T ON RAW DATAS t P <= .05. TWO t a i l e d DUNNETT T ON RANKED DATA. A : N = 14 ANIMALS TABLE 18 TWO YEAR ORAL (DIET) T O * I C T T Y - Q N C O G E N I C I T y STUDY OF F L U O R O C A R B O N FC - 1 4 3 IN RATS ABSOLUTE AND RFLATIv F MEAN ORGAN WEIGHTS ORGAN WEIGHT/BRAIN WEIGHT (GRAMS) 0 PPM 380 PPM 30 PPM MALE N = IS N = 15 N = 15 ORGAN RATIO SD RATIO SD PATIO SD LIVER HEART SPLEEN KIDNEYS adrenals TESTES 8*648*-1.587 0.R9+-0.103 0.578T-0.155 2.099+-0.977 0.038*-0.010 1.65R*-0.936 8*796*-1.424 0 * 7 6 0 * - 0 . 119 0.531*-0.149 2*101" 0*232 0.040+-0.008 1*699*-o.287 8.544*-l.485 0 . 8 2 1 - 0 . 141 0.501-0.086 2.360*-0.827 0.041*-0.013 1.675*-0.?97 IT II Z 00047 fem ale ORGAN LIV E R HEART SPLEEN K ID N EYS a d r en a ls UTERUS N a 15 R A T IO SD 7 * 4 5 6 + l .918 0 . 6 7 3 + - 0 . 100 0. 394+ - 0 . 87B 1. 543+ - 0.166 0 . 0 5 0 + - 0 . 0? 2 A 0. 404^ ^ 0.156 N = 15 R A T IO SD 6 . 883* - l * 50B A 0 * 642* - 0.097 0 * 3 4 3 * - 0 . 100 l * 545* - 0.?59 0 . 055* - 0*019 0. 4004- 0.173 R A T IO SO 8 . 4 6 0 * - 2 . 162 0 . 738* - 0.117 0 . 568+ - 0 3250 1. 716* - 0.231 0 . 068* - 0 023 0. 419* - 0.226 P <= .05* TWO t a i l e d p u n n e t t T ON RAW DATA. oo 00 : P < ~ .05* TWO t a i l e d DUNNETT T ON R a n k e d d a t a . A I N = 14 ANIMALS i TABLE 18 nose A PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM 0 PPM PPM PPM 0 PPM S PPM 0 PPM 0 PPM 0 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300. PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM ANIMAL A1R3SI8 A1R3S2* *103520 A1R3531 *101533 A1R3S38 *1035*2 1035*8 10355 *103557 A 103562 *10356 *103564 AIH3ST3 A1R3578 8103501 misos 103591 omaso* H103597 0103601 omisos omasott 0103611 Hmaom 8mao23 BlR3b30 B103633 010303* omaoAi cmaoAb C1R30SO CJH30S* cmaoSM C 101003 cmaooT cmaoTo C 103672 C1R3676 C1H3679 003682 CIR300* cmaooo C1R3091 cmaoo* TWO V t AR ORAL 1il11 T I 4 IC ITY-0NC06ENIC IY STUDY OF FLuORuCARHON F 0 1 * 3 IN HALL HATS THU YtAH INDIVIDUAL OHOAN wF.IbMlS BOOV 556 63B 012 733 765 760 33 706 517 612 5BB 676 696 759 621 73* 656 **0 77* 63* 6*3 626 606 6*1 BOI 622 507 632 56* 609 600 5R6 70* 620 713 503 653 616 539 921 5*5 772 *91 595 697 LIVtR 15.12 23.*5 19.67 17.52 IB.07 21.72 17.60 IR.** 1*. 19 17.71 15.1* 16.20 21.** 22.*1 13.62 18.*2 21.*2 l*.o* 23.03 1*.99 21.09 20.0* 1H.66 18.03 10.91 20.26 15.62 2*.01 16.** 19.45 10.71 10.17 21.0* 10.07 26.06 17.03 19.03 16.77 24.00 23. HO 10.02 10.90 13.9* 10.09 16.68 HEART 1.023 1.511 1. 70* 1.071 1.675 2.261 1.666 1.667 1.6*7 1.700 1.016 1.679 2.172 1.625 1.630 1.786 1.*65 1.*27 1.*86 1.602 2.530 1.623 1.305 1.602 1 .57* 1.803 l.**3 1.066 1.605 2.032 1.* 09 1.805 2.020 1.293 2.172 1.072 2.010 1.026 2.326 2.120 l .*6* 2.022 1.*10 1.707 1 .031 SPLEtN 1.318 1.*16 1.111 0.070 0.991 1.093 0.728 1.1*8 1.135 1.106 1.75* 1.396 1.586 0.907 0.900 1.227 1.**7 0.062 1.237 0.992 1.023 0.995 1.6*0 1.320 0.790 1.217 0.02* I.HOII 1.067 1.129 1.0*2 1.* 17 1.108 0.037 1.170 0.979 1* 17 1.002 1.*1* 0.962 0.406 1.161 0.773 1.277 1.033 MONEYS 3.913 4.0*6 *.92* 3.8*2 *.128 *.635 4.233 *.670 3.461 *.718 3.980 3.7*5 6.10 5.011 3.6*1 *.*72 4.6*1 3.031 5.013 *.032 S.bOO 4.160 *.787 *.271 *.3*2 S.057 4.U01 5.125 *.222 5.133 3.7*0 *.3*7 5.309 *.197 6.023 *.6*2 7.178 *.*68 10.00* 6.66* *.1*7 6.650 *.170 3.900 *.626 ADRENALS? 60 57 87 75 loo 9* 5* 73 00 70 61 93 ion 113 77 92 8* 62 76 97 09 92 0* 107 77 91 78 136 60 67 66 9* 03 60 99 70 12* 73 1*3 90 6 91 62 01 1*2 NOTES: Body weights and organ weights in grais. Indicates adrenal weight in mg. TESTES *.523 3.914 4.0H2 3.57* 2.996 3.770 1.*30 3.62o 3.620 *.123 3.*76 3.320 3.203 3.561 3.015 *.177 3.9*0 2.631 3.967 *.066 3.903 2.067 3.25* 3.777 3.0*9 3.943 3.806 3.*36 2. lio A.*** 3.144 *.003 5.371 *.001 3.740 3.306 3.206 2.*52 3.204 *.5** 3.000 *.1(|4 3 .llf)H 3.0 12 *.174 H HAlN 2.160 2.006 2.076 2.127 2.000 2.193 2.200 2.329 1.990 2.262 2.061 2.223 2.006 1.061 1.060 2.200 2.07* 2.041 2.210 2.1 i* 2`.2 72 2.191 2.046 2.202 2.123 2.212 2.210 2.130 2.2*7 2.231 2.210 2.*73 2.317 2.160 2.220 2.111 2.206 2.060 2.160 2. JO* 1.43 2. 1*R 2. 112 2.2*M 2.040 mstcopyAmu 89 000476 TABL E 18 TWO YtAR OHM. 30IETI TO* 1C ITY-ONCUUtNIC 1TY STUDY OF FLUOHOCAHdON FC-13 IN FEMALE HATS TWO YtAH INDIVIDUAL HOAN wtlbHlS 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 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 PPM 300 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 30 PPM NOTES: ANIMAL BODY LIVtH HAHT SPLEEN KIDNEYS adrenals N1R4583 N1R45B6 N1R4591 N1H4S95 N1R4598 N1R4603 N1R4606 N1R4611 N1R4A14 N1R4A16 N1RA626 NIR462B NIR4634 N1R4634 MH4638 01P4644 0IR4646 01H4649 01R4667 Q1R46S9 01R4461 01R4663 01R4672 01H4679 01R4683 0lH46ttd 0184693 01R4695 0184697 01R4701 P1R470 P1R4711 P1R4714 P1H4716 P1R4720 P 184723 PIR4726 P184729 P 184733 P1H4736 P184739 P18474S P 184747 P1847S2 P1R47S4 494 480 516 455 471 401 692 604 618 307 363 535 567 560 675 460 539 378 410 519 459 400 380 551 376 375 480 449 354 642 526 659 545 404 539 542 606 502 452 533 756 420 545 575 407 15.99 11.86 14.21 11.98 13.46 14.37 14.99 24.00 14.40 11.77 10.20 13.34 19.23 19.57 16.28 14.35 17.04 11.32 14.60 15.84 12.22 14.01 10.92 21.39 13.96 13.32 12.13 _c 11.60 13.98 17.63 22.66 23.62 10.49 19.79 16.73 16.9b 19.16 12.22 13.87 22.13 14.03 16.67 15.09 14.88 1.174 1.215 1.32? 1.416 1.630 1.465 1.601 1.567 1.490 1.254 0.949 1.182 1.523 1.100 1.612 1.208 1.258 1.066 1.179 1308 1.163 1.452 1.403 1 .521 1.675 1.334 1.187 1.610 1.122 1 .280 1 .376 1 .456 1 .693 1 .594 1.411 1 .432 1.864 1.693 1.217 1.399 1.708 1.464 1.274 1.538 1.210 1.032 0.983 0.749 0.740 0.983 0.657 0.76 7 0.721 0.697 0.717 0.581 0.938 0.665 0.933 0.798 0.608 0.946 0.495 0.677 1.134 0.630 0.688 0.944 0.717 0.84 1 0.454 0.66/ 0.471 0.722 0.589 0.857 1.016 1.027 0.989 1.296 1.089 1.057 0.94/ 0.707 0.920 3.561 0.824 0.993 0.864 1.16/ 3.3b8 2.024 3.161 2.768 3.466 3.210 3.374 3.310 3.356 3.012 2.464 3.082 2.870 3.261 3.390 2.81? 3.680 2.806 2.844 3.293 2.390 3.276 2.930 4.125 3.490 3.183 2.692 3.737 2.937 3.194 3.809 3.085 3.904 2.722 3 . 7h 8 4.066 3.878 3.608 2.997 3.216 3.113 3.670 3.407 4.012 2.866 98 63 04 108 .--0 84 114 263 91 12? TO 79 108 05 75 76 09 38 131 102 64 138 100 120 183 137 129 175 87 112 173 123 202 106 106 118 103 169 94 73 210 111 126 168 89 Body weights and organ weights in grams. - Indicates adrenal weights in mg . - Indicates adren al weight not re corded; left adren al - Indicates liver weight not re corded due to mass. greatly UTEHU5 0.84 1 1.066 0.884 0.729 1.166 0.725 1.691 0.566 0.6/0 0.803 0.354 0.812 0.7 3 0.746 0.63 0.466 0 . 7h7 0.688 0.696 1.465 0.424 1.076 0 66 0.926 0.4 18 1.0) 0.42 1.53? 0.003 0.529 0.949 0.517 0.EI2 0.4U8 0.610 2.460 1.064 1.035 0.811 0.540 0.622 0.4/4 0.4b 0.864 0.614 HHA IN 2.0 )6 2.069 1.460 ? .089 1.428 2. 174 1.427 2.115 2.066 2.140 2.0 32 1.971 1.414 1.874 2.216 1.468 2.2 3 2.196 2.043 2.016 2.085 2.024 1.934 1.47 ? .066 2.264 2.086 2.031 1.433 1.468 1 .4/6 1.927 1.864 1.840 2.010 2.127 2.117 1 .841 2.103 2.001 2.086 2.047 2.3| 2. 10 1.48/ enlarged. BEST COPlf AVAI1ABLE 000477 TABLE 19 Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Major Microscopic Findings - Percent Incidence at 2 Years Oraan/Lesion n=1 Adrenal Pheochromocytoma, benign Pheochromocytoma, malig . Liver Hepatocellular Carcinoma Mammary Gland Adenocarcinoma Adenoma Carcinoma Fibroadenoma Lymphangiosarcoma Pituitary Adenoma Testes/Epididymis Leydig Cell Adenoma Thyroid C-cell Adenoma C-cell Carcinoma NEOPLASTIC LESIONS Controls Male Female 50 50 High Male Female 50 50 Low Male Female 50 50 448080 000 2 20 60 - 15 -7 -2 - 22 -0 10 2 - 11 -0 -0 48* -2 20 - 31 -0 -0 - 42 -0 35 72 28 72 36 83 0 - 14* 4- 0 2 90 5 0 00 40 00 1 * 50 rats/sex/group were at risk, % values derived from actual tissues examined * = Significantly different ( - 0.05) from controls 91. 000478 TABLE 20 Two Year Oral (Diet) Toxicity - Oncogenicity Study of Fluorocarbon FC-143 in Rats Summary of Major Microscopic Findings - Percent Incidence at 2 Years NON-NEOPLASTIC LESIONS Oraan/Lesion n=1 Controls Male Female 50 50 High Male Female 50 50 Adrenal Nodular Hyperplasia 4 0 18 2 Sinusoidal Ectasis 22 84 32 82 Heart Myocarditis, Chronic 28 32 34 20 Liver Cystoid Degeneration 8 0 56* 2 Hepatocellular Alt. Basophil . 4 16 12 4 Hyperplastic Nodule 0264 Megalocytosis 0 0 80* 16* Portal Mononuclear 74 38 96* 38 Cell Infil. Necrosis 6 10 10 4 Lung Alveolar Macrophages 20 28 62* 38 Hemorrhage 20 28 44* 38 Perivas. Mono. Infil. 42 26 14* 28 Vascular Mineralization 86 44 94 52 Pneumonia, Interstitial 32 14 14 18 Testis/Epididymis Tubular Atrophy 14 - 22 - Vascular Mineralization 0 - 18* - Ovary Cyst - 13 - 11 Tubular Hyperplasia - 0 - 32* Thyroid C-Cell Hyperplasia 20 2 7 Uterus Cystic Glands - 14 - 10 Pancreas Acinar Atrophy 13 12 22 9 Salivary Gland Sialadenitis, Chronic 2 2 30* 5 Spleen Hemosiderosis 32 50 44 24* Low Mal e Female 50 50 26 26 86 36 10* 14 2 2 16 00 12 2 64 22 10 12 32 20 28 26 6* 4* 86 76* 10* 6 20 6- - 18 - 14* 13 2 - 24 20 12 27* 2 8* 6* 1 - 50 rats/sex/group were at risk, % values derived from actual tissues examined * - Significantly different ( = 0.05) from controls 92. 000479 FIGURE 1 TWO YEAR ORAL (DEI) TOXKfTY-ONCOGENCfTY STUDY OF FLUOROCARBON FC-143 W RATS MEAN BODY WEIGHTS (G) OF MALES O A Control O X 300 ppm 30 ppm FIGURE 2 TWO YEAR ORAL (bEl) TOWOTY-ONCOGEMCITY STUDY OF FLUOROCARBON FC-143 N RAIS MEAN BODY WEIGHTS (G) OF FEMALES A Control O O X 300 ppm O t 30 ppm 00 TWO YEAR ORAL MEAN FIGURE 3 TY-ONCOGEMCmr STUDY OF FLUOROCARBON FC-143 IN RATS JMPTK3N (QrtCG OF MEAN BODY WEIGHT) OF MALES o o VtOn 00 A Control X 300 ppm 30 ppm FIGURE 4 TWO YEAR ORAL (DEI) T ICUY-ONCOGEMCITY STUDY OF FLUOROCARBON FC-143 N RATS MEAN FOOD CCONSUMPTION (Q/KG OF MEAN BODY WEIGHT) OF FEMALES A Control X 300 ppm 30 ppm TWO YEAR ORAL (DIET) TOXICITY / CARCINOGENICITY STUDY OF FLUOROCHEMICAL FC-143 IN RATS APPENDIX ITEMS 0004S4 BESTCOPYAVAilM E Internal Correspondence cc: ?. D W. C Appendix Item A Griffith - 220-2E-02 McCormick - 220-2E-02 rc : J . K Sugg - 220-2E-02 F. A Ubel, M.D. - 22C-2E-02 t0 --M. T. CASE - RIKER LABORATORIES - 218-3S P'or* S. D. SORENSON - MEDICAL, IND. HYG. SERV. - 220-2E-02 Sucec: Air Monitoring, Project 89003107 Ds*e August 27, 1981 3M Summary Air monitoring has been conducted In three animal treatment room used in fluorochemical studies. The purpose of the monitoring was to evaluate possible airborne 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-3924 and FC-HI3* The study has been in progress since April 21, 1981. Area samples were collected In each of the several treatment rooms by meansi of either irapingers 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. 0004S5 98 Appendix Item A M. T. C a s e 2- August 27, 1981 The sample results Indicate that airborne concentrations of the test fluorochemicals, 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 G004S6 APPENDIX ITEM A M. T. C a n -3- Sample Data Building 218-3 Project #89003107 August 7, 1981 Sample Number CCL81-20 CCLB1-23 CCL81-21 CCL81-2S 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 roam air exhaust about 16 inches above floor. D-338. FC-143, dose Roam. Sampler on top of high dose rack. Same as OCXS1-22, duplicate sample using silica gel tube. Time 922-122S 922-1225 926-1236 1055-1236 925-1228 931-1228 August 27, 1961 Compound FM-3924 FC-143 FM-3924 Concentration < 0.003 <0.001 <0.003 FM-3924 <0.025 FC-143 FC-143 <0.001 < 0.002 SAMPLING METHOD: FM-3924 SRC silica gel sampling tubes. PC-143 Dapinger - methanol. ANALYTICAL METHOD: PM-3924 - gas chromatography, electron capture detector. PC-143 - derivatiration; gas chromatography, electron capture detector. ANALYTICAL REQUEST: A80248. 1U Internal Correspondence I APPENDIX ITEM A To: From: Subject: Date: L. J. Sibinskl J. D. Johnson Analysis of Plasma Samples from Sentinal Rats Housed in Room with Two Year Tox Study-Rats (Riker Study No. 0281CR0012) October 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. On 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 sang>lea were leas than one part per million. From this, it can be concluded that there vas no airborne fluorine present that vas interfering with this study. These data are in SJG Notebook 56531, p 53. James D. J^iuuon Research specialist Riker Laboratories, Znc. 000488 Io Internal Correspondence Appendix Item A c c : M.T. Case L'.D . Griffith R.E. Ober w.u. Pear Ison R.A. Prokop U S' - 3 lb: v . Po thapragada From: j .d . Jo hn so n Subiect Analysis of Plasma Sa mp le s from Sentinal Rats Ho u s e d in Room with Two Year Tox Study Rats (Riker Study No. 0281 CR 0012). Date: 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 ZR 3865) and 5 female (ZR 4921, ZR 4922, ZR 4923, ZR 4924, and ZR 4925) which were sacrificed before dosing was initiated. The other thirty plasma samples w e r e 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 rats are receiving FM-3924. The numbers for these rats are as follows: 5 male Control Room (ZR 3866, ZR 3867, ZR 3868, ZR 3869, ZR 3870) 5 female Control Room (ZR 4926, ZR 4927, ZR 4928, ZR 4929, ZR 4930) 5 male FC-143 Room (ZR 3876, ZR 3877, ZR 3878, ZR 3879, IR 3880) 5 female FC-143 Room (ZR 4936, ZR 4937, ZR 3838, ZR 3839, ZR 3840) 5 male FM-3924 Room (ZR 3886, ZR 3687, ZR 3888, ZR 3889, IK 3890) S female FM-3924 Room (IR 4946, IR 4947, IR 4948, IH 4949, ZR 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. 0.0. Jqlfason/mho G004S9 102 Appendix Item B CCD ANALYTICAL REPORT #213 From Subject Daie P. J. Colbert - 236-2B GLC Analysis of FW-3924 (T-2999CoC) FC-143 (T-2998CoC) Blended into Ground Lab Chow. (Riker Study #0281CR0012) April 29, 1981 3 000490 103 APPENDIX ITEM B L. J. Sibinski CCD Analytical Report April 29, 1981 Page 2 #213 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: Compound Theoretical ppm Actual ppm (uq/g)FC-143 FC-143 Top Sample 300 326 Mid Sample Bottom Sample Blank for 300 ppm level FC-143 Top Sample Mid Sample 300 300 0 30 30 282 1 * 297 0 24 \/ 23 / ' Bottom Sample 30 28' ^ Blank for 30 ppm level 0 ' f0 Because two of the three 30 ppm level samples were low, another ') set of samples were received from L. J. Sibinski on 4/27/81 for analysis. The results are: i, 000491 104 APPENDIX ITEM B L. J. Si binski CCD Analytical Report #213 April 29, 1981 Page 3 Compound FC-143 Top Sample Mid Sample Bottom Sample Blank for Theoretical ppm 30 30 30 LJS/mao cc: M. T. Case - 218-2 E. G. Lamprecht - 218-3 W. C. McCormick - 220-2E-02 J. D. LaZerte - 236-1L R. A. Prokop - 236-2B V. Pothapragada - 236-3A Actual ppm (ug/q) FC-143 28 0 0C0492 105 APPENDIX ITEM B Internal Correspondence M. T. Case E. 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 236-2B 236-2B Commercial Chemicals Analytical Report /.229 Subject. Dale L. J. Sibinski 218-3-3 P. J. Colbert 236-2B GLC Analysis of FM-3924 (T-2999 CoC) FC-143 (T-2998 CoC) Blended Into Ground Lab Chow (Riker Study #0281CR0012) June 15, 1981 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 5-18-81 for analysis. All samples were run in triplicate. The results are: Sample Theoretical ppm Actual ppm JL3ZS_ FC-143 Blank for 300 ppm 0 0 FC-143 Top Mid Bottom 300 300 300 / 303 305 n t c'' 295 Blank for 30 ppm 0 0 FC-143 Top Mid Bottom 30 30 30 31 */ ( 31 , 29 The next set of Ground Lab Chow Samples will be submitted for analysis on August 17, 1981. PJC:da J) 000493 106 Inib luti CoriuspondcM ict* APPENDIX ITEM B Comnercidl Chemicals Analytical Report #250 To. L. J. Slblnskl - 21-3-3 From P. J. Colbert - 236-2B Sub|OCI GLC Analysis of FC-143 (T-299GCoC) Blended into Ground Lab Chow (R1ker Study #0281CR0012) Dale August 20, 1981 Reference: Commercial Chemicals Analytical Laboratory r Request #17449, and CCD Method G31-0481 Six samples of FC- 143 blended Into Ground Lab Chow, along with two Blank Ground Lab Chow samples, were received from L. J. Sibinskl on August 17, 1981, for analysis. All samples were run 1n triplicate. The results are: Actual ppm Sample Theoretical ppm ug/g FC-143 Blank for 300 ppm FC-143 Top Mid Bottom 0 300 300 300 0 308 310 328 Blank for 30 ppm FC-143 Top Mid Bottom 0 30 30 30 0 28 % . 30 c 30 3M / PJC/mao de: M. T. Case - 218-2 E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1L W. C. McCormick - 220-2E-02 V. Pothapragada - 236-3A R. A. Prokop - 236-2B L. D. Winter- 236-2B R. M. Payfer - 236-2B G. W. Kirsch - 236-3A G00494 107 Internal Correspondence APPENDIX ITEM B COMMERCIAL CHEMICALS ANALYTICAL REPORT #289 To: L. J. S I B I N S K I - 2 1 8 - 3 - 3 From: R . M. PAYFER - 236-2B Subject LAB Date: GLC ANALYSIS OF FC-1U3 (T-2998 CHOW (RIKER STUDY #2081cR0012) November 30, 1981 CoOBLENDED INTO GROUND 3M References: Commercial Chemicals Analytical Laboratory Request #17779 Six samples of FC-143 blended into ground lab chow, along with t w o b l a n k g r o u n d l a b c h o w s a m p l e s , w e r e 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 a n a l y s i s . All s a m p l e s w e r e run in triplicate with the following results: Sample Theoretical PPM Actual PPM ug/g F C - U 3 Blank for 300 PPM FC-1U3 Top Middle Bottom 0 300 300 300 0 278 310 323 Blank for 30 PPM FC-143 Top Middle Bottom 0 30 30 30 0 29 28 33 RMP/hc de: M. T. Case - 21-2 G. W. Kirsch - 236-3A E. G. lamprecht - 218-3 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E-02 V. Pothapragada- 236-3A R. A. Prokop - 236-28 L. D. Winter - 236-2B (2 cooies) 000495 108 APPENDIX ITEM B Internal Correspondence dc: M.T. Case - 2 U 2 G.W. Kirsch - :36E.G. Lamprech; - Z'.,\-3 J.D. LaZerte - 236-' W.C. McCormick - 22C-2E-02 V. Pothapragada - 236-3A L.D. Winter - 236-23 To: L. J. SIBINSKI - 218-3-3 COMMERCIAL CHEMICALS ANALYTICAL REPORT #319 From: R. M. PAYFER - 236-2B Subject: GLC ANALYSIS OF FC-143 (T-2998 CoC) BLENDED INTO GROUND LAB CHOW (RIKER STUDY #2081 CR 0012) Date: MARCH 5, 1982 Reference: Commercial Chemicals Analytical Laboratory Request #18069 Six samples of FC-143 blended into ground lab chow, along with two blank ground lab chow samples, were received from L. J. Sibinski on February 15, 1982. These samples were analyzed in triplicate for FC-143 with the following results: Sample Theoretical PPM Blank for 300 PPM 300 PPM Top 300 PPM Middle 300 PPM Bottom Blank for 30 PPM 30 PPM Top 30 PPM Middle 30 PPM Bottom 0 300 300 300 0 30 30 30 000496 109 Internal Correspondence APPENDIX ITEM B COMMERCIAL CHEMICALS ANALYTICAL REPORT #328 To: 1. J. SIBINSKI - 218-3-3 * From: R. M. PAYFER - 236-2B Subject: GLC RE-ANALYSIS OF FC-143 (T-2998 COC) BLENDED INTO GROUND LAB CHOW (RIKER STUDY #2081 CR0012) Date: ________ March 31, 1982________________ 3M Reference: Commercial CHemlcals Analytical Laboratory Request #18100 Three samples of FC-143 blended Into ground lab chow, along with one blank ground lab chow sample, were received from L. J. Sibinski on March 8, 1982. These samples were analyzed 1n triplicate for FC-143 with the following results: Sample Theoretical PPM Actual PPM ug/g FC-143 Blank for 300 PPM 300 PPM Top 300 PPM Middle 300 PPM Bottom 0 300 300 300 0 278 V 283 284 iifl- RMP/hc ac: 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 - 236-3A L. D. Winter - 236-2B C00497 ] j o Internal Correspondence 1ST COPY AVAUABIj APPENDIX ITEM B COMMERCIAL CHEMICALS ANALTYICAL REPORT #340 iu tL. J. SIBlNSKi - 218-3-3 From R. M. PAYFER - 236-2B r-hr-i GLC ANALYSIS OF FC-143 (T-2998 Coc) BLENDED INTO GROUND LAB CHOW (RIKER STUDY #0281 CR0012) May 28, 1982 Reference: Commercial Chemicals Analytical Laboratory Reguest #18320 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 May 17, 1982. These samples were analyzed in triplicate for FC-143 with the following results: Sample Theoretical PPM Actual PPM ug/g FC- Blank for 300 PPM 300 PPM Top 300 PPM Middle 300 PPM Bottom Blank for 30 PPM 30 PPM Top 30 PPM Middle 30 PPM Bottom 00 300 310 300 280 300 289 00 30 31 30 33 30 33 de: M. T. Case - 218-2 G. W. Kirsch - 236-GB E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E-02 V. Pothapragada - 236-GB L. D. Winter - 236-2B 000498 APPENDIX ITEM B To From Subject Date COMMERCIAL CHEMICALS ANALTYICAL REPORT 366 L. J. SIBINSKI - 218-3-3 R. M. PAYFER - 236-2B GLC ANALYSIS OF FC-143 (T-2998 Coc) BLENDED INTO GROUND LAB CHOW (RIKER STUDY #0281 CR0012) Sept. 13. 1982 3M Reference: Commercial Chemicals Analytical Laboratory Request #18609 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 Aug. 16, 1982. These samples were analyzed in triplicate for FC-143 with the following results: Sample Theoretical PPM Actual PPM ug/g FC-143 Blank for 300 PPM 300 PPM Top 300 PPM Middle 300 PPM Bottom Blank for 30 PPM 30 PPM Top 30 PPM Middle _ 30 PPM Bottan 00 300 300 300 319 300 304 00 30 29.5 30 35 30 29.5 dc: M. T. Case - 218-2 G. W. Klrsch - 236-GB E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E-D2 V. Pothapragada - 236-GB L. D. Winter - 236-2B 000499 112 Internal Correspondence APPENDIX ITEM B EST COPYA V A iW To Ci. 1. Slblnskl - 218-3 From. G. W. Kirsch - 236-2B Commercial Chemicals Analytical Report #384 Subject: GLC Analysis of FC-143 (T-2998 CoC) Blended into Ground Lab Chow (Riker Study #0281 CR0012) Date: December 8, 1982 3M Reference: Commercial Chemicals Analytical Laboratory Request #18855. 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 December 5, 1982. These samples were analyzed In triplicate for FC-143 with the following results: Sample Blank for 300 ppm 300 ppm Top 300 ppm Middle 300 ppm Bottom Blank for 30 ppm 30 ppm Top 30 ppm Middle 30 ppm Bottom Theoretical ppm 0 300 300 300 0 30 30 30 Actual ppm P 9 / 9 FC-143 o 323 - \ 292 303 / 0 , t'4- +r 32 - V 32 - *Y G^vtV>\ GWK:ch cc: M. T. Case - 218-2 E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1L W. C. McCormick - 220-2E R. M. Payfer - 236-28 V. Prothapragada - 236-G8 L. D. Winter - 236-28 000500 1 13 Internal Correspondence APPENDIX ITEM B Comercial Chemicals Analytical Report #395 To: 4*- IT. STBTNSKI -*218-3 From G. W. KIRSCH - 236-2B Subject Date: GLC ANALYSIS OF FC-143 (T-2998 CoC) BLENDED INTO GROUND RODENT CHOW (RIKER STUDY #0281-CR0012) MARCH 7, 1983 3M Reference: Commercial Chemicals Analytical Laboratory Request #19121 Six samples of FC-143 blended into ground lab chow, along with two blank ground lab chow samples, were received from L. J. Sibinski on February 16, 1983. These samples were analyzed in triplicate for FC-143 with the following results: Sample Theoreti cal ppm Actual ppm ug/g FC-143 Blank for 300 ppm 300 ppm Top 300 ppm Middle 300 ppm Bottom Blank for 30 ppm 30 ppm Top 30 ppm Middle 30 ppm Bottom 0 300 300 300 0 30 30 30 0 ^ 317 - 286 323 0 32 30 31 '. , 5 ** -v- GWK/hc cA\\ncV\ dc: M. T. Case - 218-2 E. G. Lamprechts - 218-3 0. D. LaZerte - 236-1 W. c . McCormi ck - 220-2E R. M. Payfer - 236-2B W. H. Pearl son - 223-6SE L. 0. Winter - 236-2B 000501 1 14 BEST COPY M M ABU Internal Correspondence APPENDIX ITEM B Commercial Chemicals Analytical Report #404 To * L. J. SIBINSKI - 218-3 Fron G. W. KIRSCH - 236-2B Subiect. Date GLC ANALYSIS OF FC-143 (T-2998 CoC) BLENDED INTO GROUND RODENT CHOW (RIKER STUDY #0281-CR0012) MAY 2, 1983 Reference: Commercial Chemicals Analytical Laboratory Request #19333 Six samples of FC-143 blended into ground rat chow, along with two blank ground rat chow samples, were received from L. J. Sibinski on April 13, 1983. All samples were analyzed in triplicate for FC-143 with the following results: Sample Theoreti ca ppm Actual ppm ug/g FC-143 Blank for 300 ppm 300 ppm Top 300 ppm Middle 300 ppm Bottom Blank for 30 ppm 30 ppm Top 30 ppm Middle 30 ppm Bottom 0 300 300 300 0 30 30 30 0 326 ^ e? u 331 X - 328 0 33 34 --- - ' 32 GWK/hc dc: M. T. Case - 2181-2 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 000502 I 15 Appendix Item C Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats Normal Ranges for Hematologic .and Blood Chemistry Values of Rats at Riker 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 Alanine 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 microns3 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 000503 ! 16 Appendix Item C Methods Used for Hematology On Bleedings at 3 and 6 Months Parameters Units Me thods 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 000504 117 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 Di fferenti al Chemi strv Total Bilirubin, Glucose Blood Urea Nitrogen Albumin, Total Protein Alkaline Phosphatase AST, ALT, CPK Urinalysis Specific Gravity pH, Albumin, Bilirubin, Glucose, Occult Blood and Ketones Units______ cel 1s(10^/mm^) cells(10ymnr ) 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 IIA Travenol Laborataories,Inc. TS Meter, AO Instrument Co. Bi 1iLabst ix Ames Company 000505 118 APPENDIX ITEM D PATHOLOGY REPORT OF RATS RECEIVING FLUOROCHEMICAL FC-143 IN DIET FOR TWO YEARS 000506 119 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 300 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 ppm group included all the above listed tissues except aorta, brain, eyes, small and large intestine, lymph node and spinal cord/bone marrow. 02S1CR0012 (FC-143) 000507 1 RESULTS Gross Pathology There were no gross findings suggestive of a compound effect in any rats from the 30 ppm group which were sacrificed at the 1 year interim. At the 2 year terminal sacrifice and in rats which-died or were sacrificed in extremis during the course of study (TS/DOS), possible compound related lesions included an increased incidence of masses, nodules or raised lesions in the liver, an increased incidence of yellow or pale liver foci or lesions and an increased incidence of mottled livers and testicular masses in male rats from the 300 ppm group. There were no findings suggestive of a compound effect in TS/DOS female rats from the 300 or 30 ppm groups or in male rats from the 30 ppm group. Other gross pathologic findings were typical of findings in ageing rats of this strain. These included mammary masses, pituitary foci and masses, ulcers on the bind footpads, pale livers and pale, pitted and enlarged kidneys. Organ Weights There were statistically significant (p 0.05) variations in absolute and relative weights (organtbody or organ:brain weight ratios) of a number of organs in 3C0 ppm group male rats sacrificed at the 1 year interim. Except for an increase in the liver:body weight ratio, these variations were not considered toxicologically significant. The increase in liverrbody weight ratio correlated with compound related morphologic liver changes. The mean absolute liver weight and the liver:brain weight ratio in these rats also were increased but not to a statistically significant degree. There were no statistically significant variations in organ weights in 300 ppm females sacrificed at the 1 year interim. None of the several statistically significant organ weight variations in rats sacrificed at the 2 year termination occurred in target organs or showed a dose response; none was considered toxicologically significant. Histopathology Compound related microscopic changes were observed in the liver of male rats from the 300 ppm group at the 1 year interim sacrifice and in liver of male and female TS/DOS rats at both the 300 and 30 ppm levels. The principal compound related liver change was megalocytosis. which was characterized by an increase in size of liver parenchymal cells due to increased cytoplasmic volume. The increased cytoplasm was of a finely granular "ground glass" appearance. The coarser cytoplasmic organelles were relatively decreased and were displaced 0231CR0C12 (FC-143) -2- COOKOfl 121 to the cell membrane. The nucleus:cytoplasm ratio was decreased by the increase in cytoplasm in affected cells. In affected livers, most or all lobules were involved and the centrilobular cells were more severely affected. At the 1 year interim, megalocytosis occurred to a minimal to moderate degree in 12/15 males from the 300 ppm group. No females were affected at the 1 year interim. In TS/DOS rats, megalocytosis.to a minimal to moderate degree occurred in 40/50 males at the 300 ppm level and to a minimal to mild degree in 8/50 females at the same level. At the 30 ppm level in TS/DOS rats, megalocytosis to a mimimal degree occurred in 6/50 males and in 1/50 females. In more markedly involved livers, the megalocytic hepatocytes were frequently vacuolated with multide small spherical cytoplasmic vacuoles which in life probably contained lipid. Livers which had appreciable involvement with megalocytosis and cytoplasmic vacuolation also commonly had focal areas of necrosis. This association of hepatocyte vacuolation and necrosis with megalocytosis suggests that the pro gression of lesions is megalocytosis to fatty degeneration to necrosis. Incidence of hyperplastic nodules was also increased at 300 ppm, indicating regeneration also occurred. The association of hepatocyte vacuolation and focal necrosis with megalocytosis was more clear-cut at the 1 year interim than in TS/DOS rats because of the normally higher background incidence of the former in older rats. Cystoid degeneration, characterized by areas of multilocular microcysts in the liver parenchyma, also was increased in male TS/DOS rats from the 300 ppm group. Incidence of this lesion was 4/50, 2S/50 and 7/50. in the 0, 300 and 30 ppm males, respectively. The increased incidence of cystoid degeneration, megalocytosis and portal mononuclear cell infiltration in the 300 ppm dosage group was statistically significant at the 5% level in male rats. In females from the 300 ppm level, only the increased incidence of megalocytosis was statistically significant. Occurrence of these histomorphologic changes in the liver correlates with elevation of alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase levels observed in male rats. The markedly reduced incidence and severity of histomorphologic liver changes in females parallels the absence of alterations in liver specific serum biochemical values in females. There was no direct or indirect compound effect in tissues other than liver at the 1 year interim sacrifice. In TS/DOS rats, changes which were considered secondarily compound related, probably through to FC-143 altered liver metabolism of endogenous steroids, were observed in the adrenals, ovaries and 02S1CR0012 (FC-143) -3- 000509 122 testes. In the adrenals, an increased incidence of nodular hyperplasia of the cortex occurred in males at the 300 ppm level. Incidence of this finding in males was 2/49, 9/50 and 1/50 in 0, 300 and 30 ppm males, respectively. The increased incidence of nodular hyperplasia in males at the 300 ppm level was not statistically significant, however. In females, tubular hyperplasia of the ovarian stroma occurred in 0/48, 15/47 and 7/50 rats from the 0, 300 and 30 ppm groups, respectively. This incidence was statistically significant at both the 300 and 30 ppm levels. Tubular hyperplasia of the stroma was a non-neoplastic diffuse increase in tubular elements of the ovarian stroma which was usually bilateral and associated with absent or markedly reduced follicular development. In male rats, there was a statistically significant, compound related occurrence of benign Leydig cell tumors of the testes at the 300 ppm level. Incidence of Leydig cell tumors was 0/49, 7/50 and 2/50 at the 0, 300 and 30 ppm levels, respectively. Although occurence of 2 Leydig cell tumors at 30 ppm is also suggestive of a compound effect, these neoplasms are not uncommon in untreated rats, although none were found in control rats from this study. The occurence of Leydig cell tumors correlated with the observations of testicular masses at necropsy. Testes which contained Leydig cell tumors were usually totally aspermic. Mineralization of vessels within the testes occurred in 0/49, 9/50 and 3/50 rats from the 0, 300 and 30 ppm groups respectively. The increased incidence of testicular vascular mineralization at 300 ppm was statis tically significant. In female rats, there was a statistically significant increased incidence in mammary fibroadenomas at the 300 ppm level. Incidence of this tumor was 10/46, 21/44 and 19/45 at the 0, 300 and 30 ppm levels, respectively. An increased incidence of focal accumulations of foamy alveolar macrophages occurred in the lungs of males from the 300 and 30 ppm groups. The incidence of this finding was 10/50, 31/50 and 16/50 at the 0, 300 and 30 ppm levels respecitively. The increased incidence of alveolar macrophages at 300 ppm was statistically significant. In females, the incidence of 14/50, 19/50 and 10/50 at the 0, 300 and 30 ppm levels did not have a statistically significant increase in treated animals. Other microscopic lesions in tissues from FC-143 treated rats were typical of naturally occurring inflammatory, degenerative and neoplastic lesions in an ageing population of Charles River CD rats. Commonly occurring inflammatory lesions included chronic nonsuppurative myocarditis, with associated myocardial fibrosis, mononuclear inflammatory cell infiltrate into the portal 0281CR0012 (FC-143) -4- 000510 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. A high incidence of chronic sialadenitis occurred in male rats from the 300" and 30 ppm groups sacrificed at termination. The appearance of the salivary glands in these animals was typical of glands in the recovery stages of dacryosialadenitis, a common, highly contagious disease of laboratory rats. Its peculiar incidence in this study was attributed to the housing arrangement. Both affected groups were housed in the same room and the unaffected groups were housed in other rooms. Although the incidence of sialadenitis in male rats from the 300 and 30 ppm groups was statistically significant, this increase was not considered compound related since it was explainable by the housing arrangement. Other statistically significant variations in incidence of non-neoplastic lesions which were not considered of toxicological significance included decreased chronic myocarditis in females from the 30 ppm group, increased lung hemorrhage in males from the 300 ppm group, decreased perivascular mononuclear cell infiltrate in the lung in males from the 300 ppm group and in males and females from the 30 ppm group and decreased splenic hemosiderosis in females from the 300 ppm group and in males and females from the 30 ppm group. 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. 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 (FC-143) -5- 000511 124 BEST COPT MUtfH TABLE OF CONTENTS Table Number Page 1 Macroscopic Incidence for Males - 1 Year Interim............... 1 2 Macroscopic Incidence for Females - 1 Year Interim.............2 3 Macroscopic Incidence for Males'................................ 3-5 4 Macroscopic Incidence for Females.............................. 6-7 5 Non-neoplastic Incidence for Males - 1 Year Interim.............. 11 6 Non-neoplastic Incidence for Females - 1 Year Interim.......... 12-15 7 Non-neoplastic Incidence for Males............................. 16-24 8 Non-neoplastic Incidence for Females........................... 25-33 9 Neoplastic Incidence for Males - 1 Year Interim................ 34 10 Neoplastic Incidence for Females - 1 Year Interim................ 35- 11 Neoplastic Incidence for Males................................. 36-37 12 Neoplastic Incidence for Females............................... 38-39 Appendix Table Number Page 1 Single Tabulated Animal Report -1 Year Interim................ 1-27 2 Single Tabulated Animal Report................................. 28-214 3 Tissue Inventory - 1 Year Interim..............................215-218 4 Tissue Inventory...............................................21-242 0261CR0012 (FC-143) 000512 125 BIST COP^ Macroscopic Incidence for iiales Ri.;er Laboratories, lac. cM rC-i-ic: Two Yoar Oral Toxicity-Oncogenici ty Study in Rats - On a Year Interim Tabic: I Pr: act UuniDsf i-lCRStii Species: Rot Si te/ Description Group 1 Group 3 No visible lesions Eye opacity Pituitary ClaSS Liver pal e/ta > col or Mesentery fat necrosis Kidney nydrcnepni-osi s cystic lesion depressed area Testis sna 11 S -i n edjlo Soft Tissue (lag) sac!1an feet 1 1 1 1 1 1 1 1 Titles: Group 1 CONTROL ppm Srojp j FC-l-ib S3G ppm Macroscopic Incidence Pago: 1 000513 126 BEST COW M M IR B li Macroscopic Incidence for Femalif"" " w Rixer Laboratories, Inc. 3M Tabic-: 2 FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Project Number: 0231CR0U12 Species: Rat Si te/ Description Group 1 Group 5 No visible lesions Eye atrophy Pituitary enlarged Adrenal enlarged Liver pale/tan* Lymph Node (mesenteric) hemorrhagic Mesentery mass Kidney hydronephrosi s calculi Ureter dilatation, calcul i Urinary Bladder distended, calculi Uterus cystic lesion enlarged dilated, fluid filled Mammary Gland mass SLin hair loss 59 12 3 1 11 1 1 11 1 1 1 1 1 1 13 2 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 20C ppm * includes "possibly" Macroscopic Incidence Page: 2 127 000514 BEST COPY km mMacroscopie Incidence for Males Riker Laboratories, Inc. 3M Table: 3 FC-143: Two Year Oral Toxicity-' icity Study in Rats Project Number: D231CRD012 Species: Rat Si te/ Description Group 1 Group 5 Group i No visible lesions Brain dari; area Eye opacity/cloudy hypopyon Pituitary mass/enlarged/raised lesion dark/hemorrhagic/red foci Thyroi d enlarged* Adrenal enlarged/raass Throax (internal) fluid filled Thymus enlarged* hemorrhagic/henorrhagic lesion mass Lung mottled frothy tracheal exudate consol idation* mass/raised lesion multiple white lesions Heart flaccid/flabby enlarged* pale Abdomen (internal) gas, gastrointestinal tract stomach empty of food mass, omentum fatty tumor Stomach edema/thickened wall erosi ons/ulcerati ons* Small Intestine enlarged, reddened Peyer's patches Large Intestine enlarged, reddened Peyer's patches impaction 11 12 18 1 14 1 7 3 11 422 111 223 1 1 1 11 1 1 1 11 12 1 1 1 Titles: Group 1 Group 5 Group 5 CONTROL FC-143 FC-143 0 ppm 300 ppm 30 ppm * includes "possibly" Macroscopic Incidence Page: 3 128 000515 $E$T U <ifM-:< Macroscopic Incidence for Male Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats ;ii?i : ? Table 3 Project Humber: 0231CR3012 Species: Rat Si te/ Description Pancreas mass/nodule Liver p3le/pale lobes* mass/oodule/raised lesion mottled* yello.v/pale foci/lesion enlarged possible congestion Spl eon enlarged raised lesion pal: foci pole, depressed area small* Group 1 LO. Group 5 Group 10 3 7 371 65 10 11 1 323 1 n l 1 Lymph node (nesenteric/abdomi.nal) enlarged greenish color Mesentery nodular/enlarged/thickened vessels mass !<idney enlarged, pale, pitted enlarged, pitted pale, pitted pale, enlarged* pale pale area hydronephrosis, pelvic dilatation cystic/polycysti: Urinary Bladder di stended hematuria/filled with reddish/dark fluid hemorrhagic wall Testis/Epididymis small mass Penis swollen Mannary Gland mass 222 1 12 11 OJ 1 ? 1 211 i3 1 23 32 12 1 1 *A 5 6 01 1 12 Titles: Group 1 Group 2 Group 5 COUTROL FC-143 FC-143 0 ppm 3b3 ppm 30 ppm * includes "possibly" Macroscopic Incidence Page: 4 000513 129 BEST COPY AYAHABU Macroscopic Incidence for Males Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 3 Project Number: 0231CROJL2 Species: Rat Si te/ Description Skin ulcers/inflaned/circular/raised lesions, hind footpads dernati ti s/ulcer/1esi on/ inflamed area* moist area hair loss mass/thickoning abscess inflamed fat Soft Tissue (neck) mass Soft Tissue (thorax) mass Soft Tissue (leg) swollen paws/feet Bone swollen joints Group 1 Group 5 Group 6 714 12 1 11 111 11 1 11 I 12 11 Titles: Group 1 Group 5 Group 5 CONTROL FC-143 FC-143 0 ppm 300 ppm 3C ppn * includes "possibly" Macroscopic Incidence Page: 5 0G017 130 Macroscopic Incidence for Females Riker Laboratories, Inc. 3M bestcopy h- I r FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: CJ2-1CR0C12 Species: Rat Site/ Description Group 1 Group 5 Group 6 No visible lesions Eye opacity/cloudy infl animation atrophy Pi tuita ry nass/enlarged/raised lesion hemorrhagie/dark lesion Adrenal enlarged mass/raised lesion pale small Lung mottled consol idation nodule pale Lymph Node (bronchial) enlarged Heart enlarged* Abdomen (internal) gas, gastrointestinal tract bloody fluid filled nodular tissue, omentum, mesentery Stomach ulcerations/erosions red mucosal areas/reddenod Small Intestine inflamed ulceration/ulcerated outpouching Large Intestine impaction Pancreas mass/nodule Liver pale* rtass/nodule/raised lesion mottled circular lesion/pale foci/ pale lesion/yellowish lesion enlarged* 43 3 j 1 1 25 25 25 23 n37 1 1 1 1 n11 11 1 1 11 1 2 1 1 2 1 11 12 3 6 22 4 11 12 2 I2 Titles: Group 1 Group 5 Group 5 CONTROL FC-K3 FC-143 0 ppm 3QC ppm 30 ppm * includes "possibly" Macroscopic Incidence Page: 6 00518 131 BEST COPY AVAU A B UMacroscopic Incidence for Females Riker Laboratories, Inc. 3M Table: ! FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project lumber: 321CR0312 Species: Rat Site/ Description Liver (continued) dark red area/lobe rough/irregular surface Spleen enlarged* Lymph node- (mesenteric/abdominal) enlarged reddened cystic Kidney enlarged, pale, pitted enlarged* pale, pitted pitted pale* cyst Urinary Bladder enlarged calculi thickened walls Ovary mass uterus enlarged filled with dark/bloody fluid mass dark area/lesion hemorrhagic lesion Mammary Gla.iu mass/nodule milk cyst Skin raised/inflamed/ulcerated lesion, footpad mass raised lesion hair loss/thilining circular lesion Soft Tissues (neci) mass reddened, gland like structures Soft Tissues (leg) swollen foot Group 1 Group 5 Group 1 1 5 21 1 1 L. 1 12 2 T 2 l 14. 1 1 1 1 1t 1 1 u0 27 ? ri 3 1 1 1 1 1 37 3 1 11 1 2 Jn 1 1 1 1 Titles: Group 1 Group S Group 6 CONTROL FC-143 FC-143 0 ppm 303 ppm 30 ppn * includes "possibly" Macroscopic Incidence Page: 7 132 000519 Non-Neoplastic Incidence for Males Rilcer Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Stu<ty in Rats - One Year Interim Table: 5 Project Number: 0281CR0012 Species: Rat Tissue/ Diagnosis/ Modifier Adrenal Within normal limits Cortical vacuolation mild Nodular hyperplasia, cortex moderate Sinusoidal ectasia, cortex moderate Aorta Within normal limits Bone Marrow Within normal limits Brain Within normal limits Esophagus Within normal limits Eye Within normal limits Cataract Retinal atrophy minimal Heart Within normal limits Myocardial fibrosis minimal mild Myocarditis, chronic nonsuppurative minimal mild Kidney Within normal limits Calculus Chronic progressive nephropathy minimal mild Cyst Hydronephrosis moderate Mineralization Nephritis, interstitial, chronic mild Group 1 Group ' ( 15) 12 1 1 1 1 1 1 ( 15) 15 ( 14) 14 ( 15) 15 ( 15) 15 ( 15) 15 0 0 0 ( 15) 14 0 0 0 1 0 1 ( 15) 5 1 8 5 3 1 1 1 0 1 1 ( 15) 15 0 0 0 0 0 0 ( ID 11 ( 15) 15 { 15) 15 ( 15) 15 ( 15) 13 1 1 1 ( 15) 12 2 1 1 2 2 0 ( 15) 4 0 10 6 4 0 0 0 1 0 0 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm {) * Total Examined Microscopic Incidence Page: 8 000520 133 Non--TJeoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Inie Project lumber: Q2J1CR3312 Species: Rat Tissue/ Diagnosis/ Modifier Kidney (continued) Pyelitis, acute ni nimal mild Large Intestine Within noma! limits Nematodiasi s Liver Within normal limits Hepatccyte alteration, vacuolated minimal mil d Hepatocyte vacuo! ation mi nimal ni 1d legal ocytosi s minimal mild moderate Necrosis minimal mil d Pigment, Kupfer cell minimul mild Portal bile duct proliferation minimal mild Portal mononuclear cell infiltrate minimal mild Lung Within normal limits Alveolar macrophages mild Atelectasis mild Hemorrhage mild moderate Hyperplasia, septal cell mild Group 1 Group 5 ---------- ---------- 1 I 3 ( 15) 15 g ( 13) 7 2 1 1 0 0 0 0 0 0 'J 0 0 0 c n 5 1 4 7 1 5 ( 15) 1 3 J X 1 D G j 1 1 1 r> W 1 ! 15 14 1 ( 15 j 0 0 3 0 1 1 12 7 3 2 3 Z 4 2 1 1 1 X O l 13 < 3 ( 15 2 0 5 0 3 3 2 1 0 rv Titles: Group 1 CONTROL 3 ppm Group 5 FC-142 303 ppm () * Total Examined Microscopic Incidence Pag 000521 Non-Heoplastic Incidence for Hales (cont . . ^ Riker Laboratories, Inc. 3M ^ FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 5 Project Humber: 0231CR0Q12 Species: Rat Tissue/ Diagnosis/ Modifier Lung (continued) Perivascular mononuclear infiltrate mild Pneumonia, interstitial, chronic minimal mil d Vascular mineralization mi nimal mild Lymph Node (mesenteric) Within normal limits Hemorrnage minimal mild Mammary 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 Prostatitis, chronic minimal Salivary Gland Within normal limits Small Intestine Within normal limits Group 1 Group 5 ---------- ---------- 2 2 3 1 Z 7 4 3 ( 13) 13 0 0 0 ( 3) 3 ( 1) 1 1 1 1 ( 15) 11 3 0 1 3 3 ( 7) 7 ( 14) 13 1 ( 15) 15 0 c ( 15) 15 ( 15) 15 1 1 -> 3 2 S 1 7 ( 13) 11 2 1 1 ( 0) 0 ( 0) 0 0 0 0 ( 15) 13 0 G G Ci 0 ( 3) 3 ( 12) 12 G ( 13) 12 1 1 ( 14) 14 ( 15) 15 Titles: Group 1 CONTROL 0 ppm Group 5 FC-142 30J ppm {) * Total Examined Microscopic Incidence Page: 13 000522 135 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interin Table: 5 Project Number: 0281CR0012 Species: Rat Tissue/ Diagnosis/ Modifier Spinal Cord Within normal limits Spleen Within normal limits Hemosiderosis mild Stomach Within normal limits Testis/Epididymis Within normal limits Tubule atrophy, aspermatogenesis marked Thyroi d Within normal limits Trachea Within normal limits Urinary Bladder Within normal limits Group 1 Group f 14) 14 ( 15) 15 0 0 ( 14) 14 ( 15) 15 0 0 ( 11) 11 ( 15) 15 ( 15) 15 ( 15) 15 ( 15) 14 1 1 ( 15) 15 ( 15) 13 2 2 ( 13) 13 ( 15) 15 ( 13) 13 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm () * Total Examined Microscopic Incidence Page: 11 000523 136 Non-Neoplast1c Incidence for Females Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 6 Project Number: 0Z81CR0012 Species: Rat Ti ssue/ Diagnosis/ Modifier 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 mild Kidney Within normal limits Calculus mild moderate Chronic progressive nephropathy mild Cyst mild Hydronephrosis moderate marked Hyperplasia, pelvic epithelium mild Mi neral ization mild Group 1 Group 5 '( 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 0 ( 15) 6 4 1 1 1 1 1 1 1 1 0 1 1 0 0 ( 15) 11 1 1 3 3 0 ( 13) 13 ( 15) 15 ( 15) 15 ( 13) 13 ( 15) 13 2 2 2 2 ( 15) 14 1 0 1 ( 15) 9 2 1 0 3 3 0 0 1 0 1 0 0 1 1 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm () * Total Examined Microscopic Incidence Page: 12 00524 13 7 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 6 Project Number: 0281CR0012 Species: Rat Tissue/ Diagnosis/ Modifier Kidney (continued) Pelvic mineralization minimal mild Pyelitis, chronic moderate Large Intestine Within normal limits Nematodiasis Liver Within normal limits Hepatocyte alteration, vacuolated mild Hepatocyte vacuolation minimal mild Portal bile duct proliferation mild Portal mononuclear cell infiltrate minimal mild Lung Within normal limits Alveolar macrophages mild Hemorrhage mild moderate Perivascular mononuclear infiltrate mild Pneumonia, interstitial, chronic mild Vascular mineralization mild Lymph Node (mesenteric) Within normal limits Hemorrhage marked Mammary Gland Within normal limits Galactocele Group 1 Group 5 4 4 0 0 0 ( 14) 12 2 ( 15) 6 1 1 5 3 2 2 2 2 1 1 ( 15) 3 1 1 11 9 2 1 1 1 1 1 1 ( 12) 12 0 0 ( 15) 13 2 1 0 1 1 1 ( 14) 12 2 ( 15) 3 0 0 11 1 10 1 1 2 0 2 ( 15) 5 1 1 S 7 2 0 0 0 0 1 1 ( 13) 12 1 1 ( 13) 10 1 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm () Total Examined Microscopic Incidence Page: 13 000525 I38 Non-Ncoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-1 Two Year Oral Toxicity-Oncogenicity Study in Rat; - One Year Interim Table: 5 Project Number: Q231CP.G312 Species: Rat Tissue/ Diagnosi s/ Modifier 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 Shin Within normal limits Small Intestine Within normal limits Spinal Cord Within normal limits Spleen Within normal limits Hemosiderosis mild Stomach Within normal limits Thyroid Within normal limits Trachea Within normal limits Ureter Calculus Dilatation marked Inflammation, chronic moderate Group 1 Group i 1) ( 3) best co py available AV 1 i'h V IO 1 rL..' ( 15) IT ( 15) 15 10 ( 15) 14 ( 15) 15 13 10 ( 6) 5 ( 9) 9 ( 15) 14 ( 14) 14 ( 15) ( 15) 15 15 ( 2) 2 { 0) r- ( 15) ( 15) 15 15 ( 14) ( 15) 14 15 ( 15) 14 { 15) 15 1C 1 ( 15) ( 15) 15 15 , ( 14) ( 13) 14 13 ( 15) ( 15) 15 15 ( G) ( 1) 1 1 01 31 31 Titles: Group 1 CONTROL 0 ppn Group 5 FC-142 300 ppm () = Total Examined Microscopic Incidence Page: IT GC0526 139 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Ora) Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 6 Project Number: 0281CR0012 Species: Rat Tissue/ Diagnosis/ Modi fier Urinary Bladder Within normal limits Cystitis, chronic moderate Epithelial hyperplasia, simple mild Uterus Within normal limits Cystic glands marked Endometritis, chronic mild Hydrometra moderate Hyperplasia, glandular epithelium mild Metaplasia, squamous mild Group 1 Group ( 12) 12 0 0 0 0 ( 15) 12 1 1 0 0 0 0 2 2 2 2 ( 15) 14 1 1 1 1 ( 15) 13 0 0 1 1 2 1 0 0 0 0 Ti ties: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm () * Total Examined Microscopic Incidence Page: 15 000527 140 Mon-Neoplastic Incidence for Males Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR3012 Species: Rat Table: 7 Ti ssue/ Diagnosis/ Modifier Adrenal Within normal limits Cortical degeneration moderate Cortical vacuolation minimal mild modarate marked Medullary cell hyperplasia mi nimal mild moderate Nodular hyperplasia, cortex minimal mild moderate Sinusoidal ectasia, cortex minimal mild moderate marked Aorta Within normal limits Mineralization mild Necrosi s moderate Bone Arthritis, synovitis; joints moderate marked Bone Marrow Within normal limits Brain Within normal limits Abscess mild Hemorrhage moderate Group 1 Group 5 Group 6 . DOS SAC DOS SAC DOS SAC ( 15) ( 34) 6 13 00 00 7 17 02 4 13 32 00 26 0a 14 12 02 00 01 01 47 02 23 22 00 ( 15) { 34) 13 34 10 10 10 10 ( 0) ( 2) 02 00 02 ( 15) ( 32) 15 32 ( 15) ( 34) 14 33 10 10 10 10 ( 6) ( 44) 2 12 00 00 2 11 12 15 04 00 16 02 14 00 1 r* 10 07 01 0 16 02 0 13 03 01 { 6) ( 43) 6 43 00 00 00 00 ( 0) ( 1) 01 01 00 ( 6) { 42) 5 42 ( 6) ( 44) 5 44 00 00 00 00 ( 14) { 35) 0 IS 32 02 45 30 35 00 10 03 30 3A \J 0 A U 01 03 00 01 58 01 45 12 00 ( 0) ( 0) 00 00 30 00 30 ! 0) ( 1) 01 01 00 ( 3) ( 0) 00 ( 0) ( 1) 30 00 00 00 00 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 5 FC-143 30 ppm 0 * Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrifice Microscopic Incidence Page: 1G 05ZS Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: 7 Ti ssue/ Diagnosis/ Modifier Esophagus Within normal limits Eye Within normal limits Cataract Keratitis, acute marked Keratitis, chronic mild moderate Phthsis bulbi marked Retinal atrophy mild marked Heart Within normal limits Endocarditis, chronic marked Myocardial fibrosis mild Myocarditis, chronic nonsuppurative minimal mild moderate Kidney Within normal limits Calculus minimal mild Chronic progressive nephropathy minimal mild moderate marked Cyst moderate marked Hydronephrosis mild moderate Group 1 Group 5 Group 5 - DOS SAC DOS SAC DOS SAC ( 15) ( 33) 15 33 ( 12) ( 33) 12 32 00 00 00 00 00 00 00 00 01 01 00 ( 16) ( 34) 8 23 00 00 32 32 4 10 02 47 01 ( 16) ( 34) 40 01 01 00 10 34 14 5 16 2 11 23 13 01 12 12 10 02 ( 6) { 41) 5 41 ( 6) ( 44) 4 41 00 10 10 01 00 01 01 01 01 00 01 ( 6) ( 44) 6 27 00 00 01 01 0 17 05 0 12 00 ( 6) { 44) 12 10 00 10 3 40 19 0 23 16 12 01 01 00 01 01 00 ( 13) ( 32) 13 32 ( 2) ( 3) 10 12 00 00 01 01 00 00 00 01 0 00 ( 14) ( 36) 9 19 01 01 16 16 5 13 01 4 12 10 ( 14) ( 35) 32 01 00 00 9 34 22 3 22 27 23 11 10 00 00 00 00 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm 0 ' Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrificai! Microscopic Incidence Page: 17 000529 Non-Neoplastic Incidence for Hales (continued) Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modifier Kidney (continued) Hyperplasia, pelvic epithelium mild moderate Mineralization mild Nephrosis moderate Papillary necrosis moderate Pelvic mineralization minimal mild moderate marked Protein resorption droplets mild Pyelitis, acute mild Pyelonephritis, acute mild moderate Vacuo!ation, conv. tub. epitheium minimal Large Intestine Within normal limits Nematodiasis Liver Within normal limits Cystoid degeneration minimal mild moderate Hematopoiesis, extramedullary mild Hepatocyte alteration, basophilic minimal mild moderate Hepatocyte alteration, vacuolated mild moderate Group 1 .DOS SAC Group 5 DOS SAC Group 6 DOS SAC 00 00 00 00 00 10 10 1u 10 13 01 12 00 00 00 00 00 00 10 10 00 00 00 ( 14) ( 34) 14 23 06 ( 16) ( 34) 20 04 01 02 01 -0 0 00 02 00 01 01 19 03 02 01 01 01 00 00 00 00 03 01 02 00 00 00 00 00 00 03 02 01 00 00 ( 6) ( 44) 6 44 00 ( 6) ( 44) 00 1 27 02 1 22 03 00 00 06 01 02 03 0 10 00 00 00 o0 00 00 00 00 00 46 01 33 02 10 10 10 12 12 00 00 00 10 10 ( 1) ( 0) 10 00 ( 14) ( 36) 16 25 01 24 00 10 10 01 00 01 00 1 10 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm () * Total Examined DOS- Unscheduled Oeath(s) SAC* Protocol Scheduled Sacrifice(s) 143 Microsgoie Incidence Page: 18 Non-Meoplastic Incidence for Hales (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: G281CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modifier Liver (continued) Hepatocyte vacuo!ation minimal mild moderate marked Hyperplasia, Kupffer cell moderate Hyperplastic nodule Megalocytosi s minimal mild moderate Mononuclear cell infiltration mild Necrosis minimal mild moderate Portal bile duct proliferation minimal mild moderate Portal mononuclear cell infiltrate minimal mild Lung Within normal limits Alveolar macrophages minimal mild moderate marked Atelectasis moderate Edema mild moderate marked Fibrosis mild moderate Group 1 - DOS SAC Group 5 DOS SAC Group 5 DOS SAC 3 14 2 10 G2 01 11 01 4 13 0e 31 20 1l 30 20 00 00 00 00 01 00 00 01 0C 03 00 00 2 33 05 00 2 24 05 00 0 10 00 00 04 00 00 00 01 00 21 00 23 01 23 00 01 01 10 11 12 11 11 10 5 21 1 14 5 13 00 31 00 5 21 1 13 5 13 10 00 00 7 3C 5 43 7 25 02 02 03 7 23 5 41 7 25 ( 15) ( 34) ( 5) ( 44) ( 14) ( 35) 01 55 03 f 27 12 6 1C 12 00 00 42 01 3 25 02 68 02 00 10 0c 00 00 13 00 30 00 3 r\ 1U 00 10 00 00 10 00 00 10 00 00 10 01 00 10 ow 0 00 01 00 00 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm {) = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) ]4 4 Microscopic Incidence Page: 1 000531 Non-Neoplastic Incidence for Males Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 02C1CR0012 Species: P.at P.^f ^ Tab! : Ti ssje/ Diagnosis/ Modi fier Lung {continued) Granj Iona Honcrrhsge ni 1d moderate njr<ed Medial hypertrophy, arteries noderate Necresi s marked Peribronchial lymphoid hyperplasia mild Derivascular mononuclear infiltrate mi ninal mi 1d moderate Pneumonia, interstitial, acute moderate Pneumonia, interstitial, chronic mild moderate Thrombus Vascular mineralization minimal mild moderate Lymph Node (mesenteric) Within normal limits Granuloma moderate Hemorrhage minimal mild Sinusoidal ectasia mild Mainary Gland Within normal limits Mesentery Polyarteritis marked Group 1 -DOS SAC Group 5 DOS SAC Group 2 DOS SAC .* 4 21 1w 31 0s ) 1J X1 *- g1 01 o 10 ;) 2 4*.> 14 03 J0 00 2 1* 1 11 13 10 10 33 22 10 31 0> ( 12) ( 33) 10 29 00 o0 24 12 11 '0 0 00 ( 0) { 0) 00 ( 0) ( 2) 02 02 1 r 1 13 1c 1 1 r> 0 ') oj 0 *j 07 0 fi 0 m 01 0n 00 1 <) 1G 00 13 .1 '3 00 4 41 C2 ( G) ( 44) 5 33 01 01 04 01 n3 0i 0i ( 0) ( 0) 00 ( 0) { 0) r, 0 00 3; 1f 2 jo J- ss 0s nJ J. ns n t J r\ 2 U r1w 1u 05 JJ 00 00 11 -> 00 11 22 00 ( 0) ( 1) 01 00 00 c0 00 00 00 00 ( 1) ( 0) 10 ( 1) ( 1) 1i 11 Titles: Group 1 CONTROL 0 ppm Group 5 FC-142 300 ppm Group C FC-143 30 ppm {) = Total Examined D0S= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 145 Microscopic Incidence Pago: 000532 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modi fier Pancreas Within normal limits Acinar atrophy minimal mild moderate marked Hyperplasia, acinar cell mild moderate Hyperplasia, islet cell mild moderate Polyarteritis minimal moderate marked Parathyroid Within normal limits Pi tui tary Within normal limits Cyst Hyperplasia mild Prostate Within normal limits Edema moderate Prostatitis, acute minimal mild moderate marked Salivary Gland Within normal limits Sialadenitis, acute moderate marked Sialadenitis, chronic minimal mild moderate Group 1 Group 5 Group 6 -DOS SAC DOS SAC DOS SAC ( 13) ( 33) 10 24 24 00 12 11 01 00 00 00 02 00 02 04 00 02 02 ( S) ( 15) 5 16 { 15) ( 33) 7 15 22 02 02 ( 13) ( 33) 10 27 10 10 36 00 12 13 11 (12) ( 32) 12 31 00 00 00 01 01 00 00 ( 6) { 43) 4 27 0 11 01 06 04 00 11 01 10 13 00 13 02 00 02 00 ( 5) ( 31) 5 29 { 5) ( 41) 3 25 02 00 00 ( 6) ( 43) 5 40 00 00 13 01 00 01 11 ( 5) ( 41) 4 25 01 01 00 0 14 00 00 07 ( 12) ( 34) 10 21 1 On 11 05 02 00 02 01 01 11 11 00 03 01 02 00 ( 7) ( 25) 7 26 ( 13) ( 34) 3 20 14 02 01 ( 13) ( 35) 11 35 00 00 21 00 11 0 0 10 ( 10) ( 34) 10 21 01 00 01 0 12 00 01 06 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm () * Total Examined DOS* Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 146 Microscopic Incidence Page: 21 000533 Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modifier Group 1 DOS SAC Group 5 DOS SAC Group 6 DOS SAC Salivary Gland (continued) Sialadenitis, chronic marked Skin Abscess Pododermatitis, ulcerative marked U1 cer marked Small Intestine Within normal limits Polyarteritis moderate marked Spinal Cord Within normal limits Spleen Within normal limits Atrophy moderate Fibrosi s moderate Hematopoiesis, extramedullary, increased mild moderate marked Hemosiderosis mild Necrosi s moderate Polyarteritis moderate Stomach Within normal limits Edema moderate marked Gastritis, acute mild Ulcer marked 00 ( 0) ( 7) 00 35 35 10 10 ( 14) ( 34) 13 32 02 01 01 ( 15) ( 32) 15 32 ( 16) ( 34) 5 20 00 00 01 01 40 i9m 0 10 10 5 11 5 11 01 01 00 00 ( 16) ( 33) 11 33 30 20 10 00 00 10 10 07 ( 0) ( 2) 00 01 01 00 00 ( 6) ( 44) 5 44 00 00 00 ( 6) ( 42) 5 42 ( 6) ( 44) 1 25 10 10 00 00 11 01 10 00 3 19 3 19 00 00 00 00 5) { 44) 5 43 00 00 00 10 10 00 00 05 ( 5) ( 4) 10 22 22 01 01 ( 1) ( 0) 10 00 00 00 ( 0) ( 0) 00 ( 14) ( 35) 8 35 00 00 00 90 10 00 00 10 40 40 00 00 01 01 ( 14) ( 35) 11 36 00 00 00 00 00 30 30 Titles: Group I CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm () * Total Examined DOS* Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 147 Microscopic Incidence Pago: 22 000534 Non-Neoplastic Incidence for Hales (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: C281CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modifier Testis/Epididymis Within normal limits Granuloma, spermatic Leydig cell hyperplasia mild moderate Mineralization mild Polyarteritis mild moderate marked Tubule atrophy, aspermatogenesis mild moderate marked Vascular mineralization mild moderate Thymus Hemorrhage marked Thyroid Within normal limits Cyst, colloid mild Follicular hyperplasia, cystic moderate marked Hyperplasia, C cell mild moderate Ultimobranchial cyst Trachea Within normal limits Urinary Bladder Within normal limits Calculus Cystitis, acute moderate Cystitis, chronic minimal Group 1 Group 5 Group 6 - DOS SAC DOS SAC DOS SAC ( 16) ( 33) 13 26 00 00 30 00 01 01 15 11 01 03 34 11 11 12 30 03 00 ( 1) ( 0) 00 00 ( 12) ( 31) 11 25 01 01 01 01 00 01 01 00 11 ( 15) ( 34) 15 34 ( 13) ( 33) 13 32 03 10 10 00 00 ( 6) ( 44) 5 23 00 01 31 00 02 02 32 00 02 03 1 13 01 03 16 09 07 02 ( 1) { i) 0i 0i ( 5) ( 42) 4 33 11 13 01 01 00 01 01 00 03 ( 6) ( 42) 6 42 ( 6) ( 44) 5 41 00 00 00 00 00 ( 14) ( 35) 7 25 10 11 01 10 00 00 15 0 12 01 55 30 11 14 33 33 00 ( 1) ( 0) 00 00 ( 12) ( 35) 10 25 01 00 11 00 11 15 13 32 12 ( 13) ( 35) 13 35 ( 14) ( 35) 11 35 10 00 00 10 10 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 330 ppm Group 6 FC-143 30 ppm 0 * Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrifice(s) 148 Microscopic Incidence Page: 23 000535 Non-Meoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M *FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: 7 Tissue/ Diagnosis/ Modifier Urinary Bladder (continued) Epithelial hyperplasia, papillary mild Epithelial hyperplasia, simple minimal mild Hemorrhage minimal marked Group 1 - DOS SAC Group 5 DOS SAC Group 5 DOS SAC 00 0 wO 21 00 21 10 00 10 0c 00 13 01 12 01 01 00 I0 10 30 00 30 00 00 00 Titles: Group Group Group ICONTROL 0 ppm 5 FC-I43 300 ppm S FC-143 30 ppm () = Total Examined D0S= Unscheduled Death(s) SAC' Protocol Scheduled Sacrifice(s) 149 Microscopic Incidence Page: 24 600536 Non-Neoplastic Incidence for Females Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CRUJ12 Species: Rat Table: 3 Tissue/ Diagnosis/ Modifier Adrenal Within normal limits Cortical atrophy moderate Cortical degeneration mild moderate marked Cortical vacuolation mild moderate Hematopoiesis, extramedullary mild moderate marked Hemosiderosis mild Medullary cell hyperplasia mild moderate Necrosis moderate marked Nodular hyperplasia, cortex moderate Sinusoidal ectasia, cortex minimal mild moderate marked Aorta Within normal limits Mineralization mild Bone Marrow Within normal limits Brain Within normal limits Esophagus Within normal limits Group 1 Group 5 Group 5 DOS SAC DOS SAC OOS SAC i 25) ( 25) -2 0 00 00 25 10 13 02 3O 21 11 40 30 10 00 00 00 12 12 rJ 0 30 10 20 03 00 19 23 01 34 53 59 ( 21) ( 23) 17 23 20 23 { 25) ( 23) 23 25 ( 25) ( 25) 25 24 ( 15 ) ( 21) 14 21 ( 20) ( 29) 42 12 12 1 03 00 10 13 12 01 00 03 00 00 0c 00 20 10 10 00 00 00 01 01 15 25 01 96 37 4 11 ( 19) ( 27) 19 27 00 00 ( 21) ( 2 9 ) 21 29 ( 21) ( 29 ) 21 29 ( 9 ) ( 15) 9 15 ( 25) { 24) 31 03 00 44 12 32 00 41 11 30 11 0a 0i 10 10 10 02 02 30 00 00 00 12 12 21 22 10 73 7 13 50 ( 0) ( 0) 30 00 00 ( 0) { 0) 00 ( 0) { 3) 00 ( 23) ( 22) 23 22 Titles : Group 1 CONTROL 3 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm 0 * Total Examined DOS" Unscheduled Death(s) SAC* Protocol Scheduled Sacrifice! Microscopic Incidence Page: 25 000537 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Ora) Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: S Tissue/ Diagnosis/ Modi fier Eye Within normal limits Cataract Keratitis, acute marked Panophthalmitis marked Phthsis bulbi moderate Heart Within normal limits Myocardial fibrosis minimal mild Myocarditis, chronic nonsuppurative mi nimal nil d moderate Kidney Within normal limits Chronic progressive nephropathy minimal mild moderate marked Cyst moderate Hydronephrosis moderate Hyperplasia, pelvic epithelium mild Mineralization mild moderate Nephrosi s mild moderate marked Pelvic mineralization minimal mild moderate Group 1 Group 5 Group 6 DOS SAC DOS SAC DOS SAC ( 20) ( 23) 17 21 10 10 10 01 01 01 01 ( 25) { 25) 19 14 0 t0m 00 02 6 10 00 4 10 20 ( 25) ( 25) 33 12 1C 34 5 10 23 21 01 20 10 10 41 41 2n 20 00 70 10 -> 0 20 14 16 46 38 12 ( 16) ( 23) 15 28 00 00 00 00 00 00 00 ( 21) ( 29) 15 24 11 01 10 55 11 44 00 ( 21) ( 29) 74 7 19 54 1 12 02 11 00 00 01 0 r\ 00 00 00 00 00 00 00 00 00 10 14 46 47 10 ( 2) ( 1) 11 00 1 10 0 00 00 00 ( 26) ( 24) 25 20 o0 00 00 14 00 14 00 ( 26) ( 24) 55 12 9 45 8. 4 00 00 00 00 00 00 00 00 10 00 10 12 01 01 10 12 15 46 66 02 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 5 FC-143 30 ppm 0 * Total Examined DOS- Unscheduled Death(s) SAC* Protocol Scheduled Sacrifice! Microscopic Incidence Pag C00538 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 3231CR'1312 Species: Rat Table: 3 Tissue/ Diagnosis/ Modifier Kidney (continued) Pelvic mineralization narked Pigment, conv. tub. epithelium minimal moderate Polyarteritis minimal Protein resorption droplets mild narked Pyelitis, acute mild moderate Pyelonephritis, acute moderate Vacuolation, conv. tub. epitheium moderate Large Intestine Within normal limits Nematodiasis Liver Within normal limits Atrophy moderate Cystoid degeneration minimal mild Hematopoiesis, extramedullary minimal mild moderate Hepatocyte alteration, basophilic minimal mild moderate Hepatocyte alteration, eosinophilic mild moderate Hepatocyte alteration, vacuolated minimal mild Group 1 DOS SAC Group 5 DOS SAC Group 6 DOS SAC 10 00 00 00 00 00 00 00 00 30 30 30 10 10 10 10 ( 24) ( 23) 22 22 11 ( 25) ( 25) 10 30 00 00 00 00 30 00 30 00 17 00 15 02 12 3 2 10 2 11 00 2 11 11 31 01 00 00 00 10 30 13 20 13 10 00 03 00 00 ( 17) ( 29) 17 27 02 ( 21) ( 23) 44 3 00 01 31 00 10 00 C0 10 02 01 01 00 00 00 33 24 13 14 21 02 3n 02 31 01 11 01 10 30 30 30 00 03 03 0 P\ji ( 0) ( 3 ) 00 00 ( 25) { 24) 77 10 13 13 30 10 52 31 21 30 53 03 53 00 30 00 03 15 01 04 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 30C ppm Group 5 FC-143 30 ppm () * Total Examined DOS* Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 152 Microscopic Incidence Page: 27 000539 BEST COPY AVAIiABLE Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 02S1CR0312 Species: Rat Table: 3 Tissue/ Diagnosis/ Modi fier Liver (continued) Hepatocyte alteration, vacuolated marked Hepatocyte vacuolation minimal mild moderate marked Hyperplastic nodule Megalocytosis minimal mild Mitotic activity, increased modera te Mononuclear cell infiltration mild Necrosi s minimal mild moderate marked Pigment, Kupfer cell mild Portal bile duct proliferation mi 1d moderate marked Portal mononuclear cell infiltrate minimal mild moderate Telangiectasis mild Lung Within normal limits Abscess Alveolar macrophages minimal mild moderate Atelectasis mi 1d Group 1 DOS SAC Group 5 OOS SAC Group 5 DOS SAC 00 15 15 11 3 13 31 20 01 00 00 00 10 10 0 00 41 30 11 10 20 00 00 4 13 3 12 01 10 10 s 10 39 10 10 10 < 25) ( 25) 23 i0 59 1C 49 00 00 00 30 8 13 03 5n A0 1J 02 17 16 01 0 0 00 10 10 20 c0 13 00 10 13 10 55 53 0i 0 4 15 0 y 4 12 01 00 00 ( 21) ( 29) 13 0Q 5 13 20 4 12 01 00 00 13 79 2 A. *> 7 20 1 rw> ni 0 3l 0i 0V 00 00 00 00 60 10 3 -) 0n o r> 0 w0 14 14 30 0 nj 55 32 54 00 00 00 ( 25) ( 24) 22 03 37 01 36 0 AU 13 10 Titles: Group 1 CONTROL 3 ppm Group 5 FC-143 333 ppm Group 5 FC-143 33 ppm 0 Total Examined DOS* Unscheduled Death(s) SAC= Protocol Scheduled Sacri ficis) 153 Microscopic Incidence Page: 2 000540 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 3 Tissue/ Diagnosis/ Modifier Lung (continued) Edema mild Granuloma mild marked Hemorrhage mi nimal mild moderate marked Hyperplasia, septal cell mild Perivascular mononuclear infiltrate minimal mild moderate Pigment moderate Pneumonia, acute exudative mild moderate Pneumonia, foreign body marked Pneumonia, interstitial, chronic minimal mild marked Vascular mineralization minimal mild moderate Lymph Node Hyperplasia, reactive moderate Lymph Node (mesenteric) Within normal limits Granuloma Hemorrhage mild moderate marked Group 1 DOS SAC Group 5 DOS SAC Group 6 DOS SAC 00 00 00 00 0 95 00 33 11 01 00 00 49 01 47 01 01 01 10 n0 i0 00 00 AT 3 00 43 00 12 10 00 12 10 00 ( 0) ( 0) 00 00 ( 19) ( 23) 14 22 00 21 11 10 00 00 00 04 02 01 9 10 00 65 24 10 00 00 59 34 25 00 00 00 00 00 00 00 00 36 11 15 10 15 11 00 15 10 01 ( 0) ( 0) 00 00 ( 14) ( 29) 14 21 01 02 00 01 01 10 10 01 01 00 94 01 80 02 11 01 01 02 00 02 00 00 00 10 10 00 10 10 03 00 03 00 13 20 73 11 12 00 ( 1) ( 1) 11 11 ( 0) ( 0) 00 00 00 00 00 00 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 303 ppm Group S FC-143 30 ppm () * Total Examined DOS* Unscheduled Oeath(s) SAC= Protocol Scheduled Sacrifice(s) 154 Microscopic Incidence Page: 29 000541 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 8 Ti ssue/ Diagnosis/ Modi fier Lymph Node (mesenteric) (continued) Pigment, brown minimal mild moderate Sinusoidal ectasia moderate marked Mammary Gland Within normal limits Fibrosis mild Galactocele Lobular hyperplasia Ovary moderate Within normal limits Cyst Tubular hyperplasia mild moderate marked Pancreas Within normal limits Acinar atrophy minimal mild moderate marked Cyst Edema moderate Hyperplasia, islet cell mild Pancreatitis, chronic moderate Polyarteritis minimal Parathyroid Within normal limits Group 1 DOS SAC Group 5 DOS SAC Group 6 DOS SAC 00 00 00 00 10 10 00 ( 23) ( 23) 49 00 00 54 43 10 ( 25) ( 23) 19 17 33 00 00 00 00 ( 24) ( 25) 22 16 06 01 02 03 00 01 00 00 00 00 00 00 00 00 ( 5) ( 0) 50 05 01 02 02 02 01 01 ( 17) ( 27) 79 01 01 21 21 20 ( 18) ( 29) 11 15 05 78 02 66 10 ( 19) ( 23) 15 24 22 01 21 00 00 00 10 10 01 01 10 10 00 00 ( 9) ( 14) 9 14 00 00 00 30 00 03 00 ( 23) ( 22) 47 00 00 72 21 03 ( 26) ( 24) 23 11 27 07 01 06 00 ( 22) ( 21) 18 17 32 11 10 01 10 00 00 00 01 01 00 00 01 01 ( 15) ( 15) 15 15 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm () * Total Examined DOS* Unscheduled Oeath(s) SAC= Protocol Scheduled Sacrifice(s) Microscopic Incidence Page: 30 000542 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 02G1CR0012 Species: Rat Table: 3 Tissue/ Diagnosis/ Modifier Group 1 ---------- DOS SAC Group 5 ---------DOS SAC Group 6 ---------DOS SAC Pituitary Within normal limits Cyst Hemorrhage marked Necrosis moderate Salivary Gland Within normal limits Sialadenitis, chronic mild moderate Skin Within normal limits Acanthosis mild Pododermatitis, ulcerative marked Ulcer moderate marked Small Intestine Within normal limits Edema mild Granuloma Ulcer marked Spinal Cord Within normal limits Malacia moderate Spleen Within normal limits Hematopoiesis, extramedullary, increased mild moderate marked Hemosiderosis minimal mild moderate ( 22) ( 24) 57 00 10 10 10 10 ( 19) ( 24) 13 24 10 00 10 ( 3) ( 3) 00 01 01 00 00 20 10 10 ( 24) ( 25) 24 25 00 00 00 00 00 ( 25) ( 23) 23 23 10 10 ( 25) { 25) 4 11 72 11 41 20 12 13 00 8 13 40 ( 21) ( 29) 77 C0 00 00 00 00 ( 15) ( 25) 15 23 02 00 02 ( 2) ( 0) 00 00 00 10 1 0 00 00 00 ( IS) ( 29) 17 28 10 10 01 00 00 ( 21) ( 29) 21 29 00 00 ( 21) ( 29) 12 23 21 10 10 01 75 01 63 11 ( 23) ( 24) 34 01 00 00 09 00 ( 22) ( 24) 22 23 01 01 r\\J n ( 6) ( 4) 22 00 00 00 00 00 30 00 ( 1) ( 1) 00 00 00 00 10 10 ( 0) ( 0) 00 00 00 ( 24) ( 23) 10 17 11 5 52 42 21 21 00 01 10 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm 0 - Total Examined DOS' Unscheduled Death(s) SAC Protocol Scheduled Sacrifice(s) 156 Microscopic Incidence Page: 31 G00543 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: S Tissue/ Diagnosis/ Modi fi er Spleen (continued) Hemosiderosis marked Stomach Within normal limits Edema moderate Hemorrhage mild moderate Mineralization mild Necrosis mild moderate Ulcer mild Thyroid Within normal limits Follicular hyperplasia, cystic mild Hyperplasia, C cell mild U1timobranchial cyst Trachea Within normal limits Urinary Bladder Within normal limits Calculus Epithelial hyperplasia, papillary marked Epithelial hyperplasia, simple mild moderate Hypertrophy mild Uterus Within normal limits Cystic glands minimal mild moderate Group 1 DOS SAC Group 5 DOS SAC Group 6 DOS SAC 00 ( 25) ( 25) 20 25 00 00 10 00 10 10 10 20 10 10 10 00 ( 25) ( 25) 20 23 10 10 00 00 21 ( 25) ( 25) 25 25 ( 25) ( 25) 17 25 10 10 10 70 60 10 00 00 ( 25) ( 25) 21 17 25 00 01 21 00 ( 20) ( 29) 13 29 20 20 00 00 00 00 00 00 00 00 00 00 ( 15) ( 26) 14 22 00 00 12 12 02 ( 20) ( 25) 20 25 ( IS) ( 26) 15 25 00 00 00 01 01 00 01 01 ( 19) ( 29) 17 24 14 01 12 01 10 ( 25) ( 24) 20 24 00 00 10 10 00 00 00 10 10 00 40 20 ( 23) ( 22) 22 21 00 00 10 10 01 ( 24) ( 23) 24 23 ( 25) ( 22) 22 22 00 00 00 20 20 00 00 00 ( 26) ( 23) 17 17 75 00 11 21 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm 0 * Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacri fice (: 157 Microscopic Incidence Page: 32 000544 Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR0012 Species: Rat Table: 8 Tissue/ Diagnosis/ Modi fier Uterus (continued) Cystic glands marked Hydrometra marked Hyperplasia, endometrial moderate Group 1 DOS SAC - Group 5 DOS SAC Group 6 DOS SAC 03 01 01 00 00 00 10 10 00 00 43 00 00 01 01 Titles: Group Group Group 1 CONTROL 0 ppm S FC-143 300 ppm 6 FC-143 30 ppm () Total Examined DOS* Unscheduled Oeath(s) SAC= Protocol Scheduled Sacrifice(s) |5 8 Microscopic Incidence Page: 33 000545 Neoplastic Incidence for Hales Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 9 Project Number: 0281CRQ012 Species: Rat Tissue/ Diagnosis/ Modifier Sk in Keratoacanthoma Group 1 Group 5 '( 0) 0 ( 1) 1 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm () * Total Examined 159 Microscopic Incidence Page: 34 000546 Neoplastic Incidence for Females Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Project Number: 0281CR0012 Species: Rat Table: 10 Tissue/ Diagnosis/ Modifier Mamary Gland Fibroadenoma Pituitary Adenoma Group 1 Group 5 ( 15) 0 { 15) 1 { 13) 2 ( 14) 0 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm () * Total Examined 160 Microscopic Incidence Page: 35 000547 lisnspv WiMLtF, It Neoplastic Incidence for Males Riker Laboratories, Inc. 3M Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 3281CRG312 Species: Rat Table: 11 Tissue/ Diagnosis/ Modifier Adrenal Carcinoma, cortical Ganglioneuroma Pheochronocytoma, benign Pheochronocytoma, malignant Hemolymphoreticular neoplasm present Bone Marrow Hemolymphoreticular neoplasm present Brain Astrocytoma, benign Oligodendroglioma, benign Hemolymphoreticular neoplasm present Eye Hemolymphoreticular neoplasm present Heart Hemolymphoreticular neoplasm present Kidney Hemolymphoreticular neoplasm present Liver Hepatocellular carcinoma Hemolymphoreticular neoplasm present Lung Hemolymphoreticular neoplasm present Lymph Node (abdominal) Hemolymphoreticular neoplasm present Lymph Node (mesenteric) Hemangiosarcoma Hemolymphoreticular neoplasm present Pancreas Adenocarcinoma Islet cell adenoma Hemolymphoreticular neoplasm present Parathyroid Adenoma Pituitary Adenoma Salivary Gland Carcinoma Skin Fibroma Fibrosarcoma Group 1 Group 5 Group 6 DOS SAC DOS SAC DOS SAC ( 15) i( 34) 'U 1 00 11 00 00 ( 15) 1[ 32) 00 ( 16) i[ 34) 01 10 00 ( 12) 1[ 33) 0C ( 16) (: 31) 1C ( 16) 1[ 34) 10 ( 15) !! 34) 21 21 ( 16) 1: 34) 31 ( 0) 1: o) 00 ( 12) 1: 33) 00 10 ( 13) (: 33) 0r\ J 01 10 ( 6) (: 16) 00 ( 15) (: 33) 6h ( 12) (: 32) 00 ( 8) (: 7) 10 10 { 6) ( 44) 00 01 04 00 10 ( 6) t 42) 10 ( 6) ( 44) 00 00 10 ( 6) ( 44) 10 ( 6) f < 41) 00 ( 5) ( 44) 10 ( 6) ( 44) 14 11 ( 6) ( 44) 10 ( 1) ( 0) 10 ( G) ( 44) 01 10 ( 6) ( 43) 01 01 00 ( 5) ( 31) 02 ( 5) ( 41) 2 11 ( 5) ( 41) 10 ( 0) ( 2) 0D 00 ( 14) ( 36) 00 00 04 01 u0 ( 0) ( 0) 00 ( 0) ( 1) 01 J 00 ( 2) ( 3) 00 ( 14) ( 36) 00 ( 14) ( 36) 10 ( 14) ( 36) 13 10 ( 14) ( 36) 10 ( 1) ( 3) 13 ( 0) ( 1) 00 00 ( 12) ( 34) 01 00 00 / \ 7) ( 26) 00 ( 13) ( 34) 93 ( 10) ( 34) 00 ( 5) ( 4) 00 21 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm () * Total Examined DOS* Unscheduled Oeath(s) SAC* Protocol Scheduled Sacrifice!s) 161 Microscopic Incidence Page: 36 000548 Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 02S1CR012 Species: Rat Table: 11 Tissue/ Diagnosis/ Modifier Skin (continued) Keratoacanthoms Liposarcoma Papilloma Hemolymphoreti cul ar neoplasm present Small Intestine Hemolymphoreticul ar neoplasm present Soft Tissues (abdomen) Fibroma Soft Tissues (thorax) Histiocytoma, malignant Spleen Hemangi osarcoma Hemolymphoreti cul ar neoplasm present Stomach Adenocarcinoma Henolymphoreticular neoplasm present Testis/Epididyrais Leydig cell adenoma Thymus Hemolymphoreticul ar neoplasm present Thyroid C cell adenoma C cell carcinoma Follicular adenoma Urinary Bladder Hemolymphoreti cul ar neoplasm present Hemolymphoreticular System [# affected] Malignant lymphoma, lymphocytic Malignant lymphoma, histiocytic Leukemia, myeloid Group 1 DOS SAC Group 5 DOS SAC Group 6 DOS SAC 12 10 01 10 ( 11) ( 31) 10 ( 0) ( 0) n0 ( 0) ( 0) 00 ( 16) ( 34) 01 11 ( 16) ( 33) 00 10 ( 16) ( 33) 00 ( 1) ( 0) 10 { 12) ( 31) 00 02 00 ( 13) ( 33) 10 [ 3] r 1] n0 31 00 01 o0 00 00 ( 5) ( 44) 10 ( 0) ( 0) 0a ( 0) ( 1) 01 ( 6) ( 44) 00 10 ( 6) ( 44) 01 00 ( 6) ( 44) 07 ( 1) ( 1) 10 ( 5) ( 42) 04 o0 0n ( 6) ( 44) 10 [ 1] r 1] 11 10 00 00 00 00 00 ( 1) ( 0) 00 ( 0) ( 1) 01 { 0) ( 0) 00 ( 14) ( 36) 00 10 ( 14) ( 36) 00 00 ( 14) ( 36) 02 ( 1) ( 0) 10 ( 12) ( 35) 02 00 01 ( 14) ( 35) n0 [ h [ 0] 00 00 1 0 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm () * Total Examined DOS* Unscheduled Oeath(s) SAC* Protocol Scheduled Sacrifice(s) 162 Microscopic Incidence Page: 37 000549 Neoplastic Incidence for Females Riker Laboratories, Inc- 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CRQ012 Species: Rat Table: 12 Tissue/ Diagnosis/ Modifier Adrenal Adenoma, cortical Carcinoma, cortical Pheochromocytoma, beni gn Pheochronocytoma, mali gnant Hemolymphoreticular neoplasm present Aorta Hemolymphoreticular neoplasm present Bone Marrow Hemolymphoreticular neoplasm present Brain Oligodendroglioma, benign Esophagus Hemolymphoreticular neoplasm present Eye Hemolymphoreticular neoplasm present Hardarian Gland Adenocarcinoma Heart Hemolymphoreticular neoplasm present Kidney Hemolymphoreticular neoplasm present Large Intestine Hemolymphoreticular neoplasm present Liver 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 Lymphangiosarcoma Hemolymphoreticular neoplasm present Group 1 Group 5 Group 6 DOS SAC DOS SAC DOS SAC ( *5) ( 25) 00 00 02 00 20 ( 21) t 23) 20 ( 25) ( 25) 20 ( 25) ( 25) 01 ( 15) ( 21) 10 ( 20) ( 23) 10 ( 0) ( 0) 00 ( 25) ( 25) 10 ( 25) ( 25) 30 ( 24) ( 23) 10 ( 25) < 25) 00 50 ( 25) ( 25) 50 ( 19) t 23) 30 ( 0) t 0) 00 t 23) ( 23) 3 O1 o1 64 00 20 ( 20) ( 29) 01 00 00 10 00 ( 19) / 27) 00 ( 21) ( 29) 00 ( 21) ( 29) 00 ( 9) ( 15) 0 ( 15) ( 28) 00 ( 0) ( 0) 00 ( 21) ( 29) 00 ( 21) ( 29) 00 ( 17) ( 29) 00 ( 21) ( 29) 01 10 ( 21) ( 29) 10 ( 14) ( 29) 00 ( 0) ( 0) nw 0 ( 17) ( 27) 23 00 00 5 16 10 00 ( 25) ( 24) 01 10 00 00 00 ( 0) ( 0) 00 ( 0) ( 0) 00 ( n) ( 0) 00 ( 23) ( 22) 00 ( 2) ( 1) 00 ( 1) ( 9) 10 ( 25) ( 24) 00 ( 25) ( 24) i) 0 ( 0 ) ( 0) 00 ( 25) ( 24) 00 10 ( 26) ( 24) 10 ( 0) ( 0) 0 0\ ( 1) ( 0) 10 ( 23) ( 22) 0r 00 00 p 11 00 00 Titles: Group 1 CONTROL 0 ppn Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm () * Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrifice(s) 163 Microscopic Incidence Page: 3C coosso Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0231CR3012 Species: Rat Table: 13 Tissue/ Diagnosi s/ Modifier Mesentery Mesothelioma, malignant Hemolymphoreticul ar neoplasm present Ovary Granulosa cell tumor, benign Leiomyoma Tubular adenoma Hemclymphoreticular neoplasm present Pancreas Islet cell adenoma Islet cell carcinoma Hemolymphoreticular neoplasm present Pituitary Adenoma Skin Fibroma Fibrosarcoma Small Intestine Leiomyosarcoma Spinal Cord Hemolymphoreticul ar neoplasm present Spleen Hemolymphoreticular neoplasm present Stomach Hemolymphoreticular neoplasm present Thyroid C cell adenoma Hemolymphoreticular neoplasm present Unidentified Tissue Lipoma Urinary Bladder Hemolymphoreticular neoplasm present Uterus Adenoma Hemangioma Leiomyoma Polyp Hemolymphoreticular neoplasm present Hemolymphoreticular System [# affected] Malignant lymphoma, histiocytic Malignant lymphoma, lymphocytic Group 1 Group 5 Group 6 DOS SAC DOS SAC DOS SAC ( 0) ( 0) 00 nw ( 25) ( 23) 00 13 04 23 ( 24) ( 25) 01 0I 2 |V-> ( 22) ( 24) IG 17 ( 3) ( 3) 12 00 ( 24) ( 25) 00 ( 25) ( 23) 1 ( 25) ( 25) 30 ( 25) { 25) 10 ( 25) ( 25) 0 *X 20 ( 0) ( 0) 00 ( 25) ( 25) 10 ( 25) ( 25) 01 C0 r* J 01 20 [ 5] rL 0] 20 30 ( 0) ( 0) 00 03 ( 1C) 3 0 ( 29) 0 3 1 30 ( 19) ( 23) 01 01 03 ( 21) ( 29) 14 22 ( 2) ( 0) 1V 0n ( 13) ( 29) 03 { 21) { 23) n0 ( 21) { 23) 00 ( 20) ( 29) Q0 ( 15) ( 23) 00 00 { 1) ( 0) 10 ( 15) ( 26) 1 ( 13) ( 29) 0 r\ 00 00 0l 0 [ 1] [ 0] 10 00 ( 2) ( 0) 1 `J 10 ( 23) ( 24) 01 30 33 10 ( 22) ( 21) 10 00 13 ( 23) ( 24) 20 13 ( 5) ( 4) 41 11 ( 1) ( 1) 01 ( 3) ( 0) C0 ( 24) ( 23) 10 ( 25) { 24) C0 ( 23) ( 22) 00 00 ( 0) ( 0) 00 ( 25) ( 22) 13 ( 25) r~23) 0 10 01 21 03 [ 13 [ 0] 10 c0 Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 333 ppm Group 6 FC-143 3Q ppm () = Total Examined DOS* Unscheduled Death(s) SAC* Protocol Scheduled Sacrificet Microscopic Incidence Page: 3 000551 S u m m e d Single Tabulated Aniaal Report Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-3516 Sex: Hale 6roup: t 1) CONTROL 0 ppa Fate: (Meek* 53) 1 Year Interia S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Lung Lyaph Node (aesenteric) Pancreas Parathyroid Snail Intestine Thyroid -No v is ib le lesions. -Chronic progressive nephropathy, a ild -Vascular aineralization, ainiaal -Not exaained, aissing -Acinar atrophy, a ild -Not exaained, aissing -Mithin noraal lia it s Fewer than protocol nuaber -Not exaained, aissing The follow ing tissues were found to be w ithin noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, L iv er, Heart, Stoaach, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, Naaaary Gland, P itu ita ry , Adrenal, Trachea, Esophagus, Salivary 61and, Eye. Aniaal Nuaber: 1R-3517 Sex: Male Group: I 1) CONTROL 0 ppa Fate: (Meek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Lung Parathyroid Thyroid -No v is ib le lesions. -Chronic progressive nephropathy, a in ia a l -Vascular aineralization, a ild -Not exaained, aissing -Not exaained, aissing The follow ing tissues were found to be w ithin noraal l ia it s : Brain, Spinal Cord, Bone Narrow, Spleen, L iver, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, Maaaary Gland, P itu ita ry , Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3520 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Meek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Adrenal Kidney -No v is ib le lesions. -Sinusoidal ectasia, cortex, b ila te ra l, aoderate -Chronic progressive nephropathy, a in ia a l Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 1 G00S52 165 Suaairized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-3520 Sex! Male Group: ( 1) CONTROL 0 ppa Fate: IMeek= 53) 1 Year In te ria S a c rific e Microscopic Observations (continued): Liver Lung Lyaph Node (aesenteric) Parathyroid P itu ita ry -Hepatocyte a lte ra tio n , vacuolated, focal ainiaal -Vascular aineralization, ainiaal -Not exaained, aissing -Not exaained, not in plane of section -Not exaained, aissing The fo llo a in g tissu es ere found to be w ithin noraal U n its : Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Epididyais, Prostate, Thyroid, Trachea, Esophagus, Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3522 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Week= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Li ver Microscopic Observations: Kidney Liver Lung Parathyroid Thyroid -Lig ht (pale) tan in color. -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in filtr a t e , ainiaal -Vascular a in e ra liz a tio n , ai Id Heaorrhage, a u ltifo c a l, ai Id Perivascular aononudear in filtr a t e , a ild -Not exaained, aissing -Not exaained, aissing The follow ing tissues were found to be within noraal l ia i t s ! Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, Maaaary Gland, P itu ita ry , Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3527 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Week= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Liver Lung -No v is ib le lesions. -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild -Heaorrhage, a u ltifo c a l, a ild The follow ing tissu es were found to be w ithin noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Species: Rat Project Nuaber: 0281CR0012 Suaairized STAR Page: 2 1 000553 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-3527 Sex: Hale 6roup: ( 1) CONTROL 0 ppa Fate: (Ueek= 53) 1 Year Interia S a c rific e Microscopic Observations (continued): The fo llo a in g tissues ere found to be Mi thin noraal l i a i t s (continued): Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3535 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Hesentary Microscopic Observations: Lung Hesentary Parathyroid Thyroid -Area of fa t necrosis, 2 x 3 x 0.5 ca. -Alveolar aacrophages, a u ltifo c a l, a ild w '-itte lle cta sis, focal, aild -Necrosis, fa t, aarked S t e a titis , chronic, aoderate -Not exaained, aissing -Not exaained, aissing The folloH ing tissues ere found to be a ith in noraal l ia it s : Brain, Spinal Cord, Bone Narroa, L iv er, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Spleen. Aniaal Nuaber: 1R-3543 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: !Neek= 53) 1 Year Interia S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Liver Lung -No v is ib le lesions. -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , focal, a in ia a l -Vascular aineralization, ainiaal The fo llo a in g tissu es aere found to be a ith in noraal l ia it s : Brain, Spinal Cord, Bone Narroa, Spleen, Heart, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, S a liva ry Bland, Eye. Species: Rat Project Nuaber: 0261CR0012 Suaaarized STAR Page: 3 167 C00554 Suaaarized Single Tabulated Anieal Report (continued) Individual Racroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te rie Table: 1 Anieal Nuaber: 1R-3546 Set: Hale Group: I 1) CONTROL 0 ppa Fate: (Meek3 53) 1 Year In te rie S a c rific e Macroscopic Observations: Microscopic Observations: Adrenal Liver Lung Stoaach -No v is ib le lesions. -Nodular hyperplasia, cortex, u n ila te ra l, aoderate -Portal aononuclear 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 a lte ra tio n , vacuolated, a u ltifo c a l, a ild -Perivascular aononuclear in f ilt r a t e , a ild -Not etaained, aissing The fo llo a in g tissues Mere found to be within noraal l ia i t s : Brain, Spinal Cord, Bone Marroa, Spleen, Kidney, Heart, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Anieal Nuaber: 1R-3550 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Meek3 53) 1 Year In te rie S a c rific e Macroscopic Observations: Kidney Microscopic Observations: Heart Kidney Liver Lung Pancreas -B ila te ra l hydronephrosis -M yocarditis, chronic nonsuppurative, focal, a ild -Hydronephrosis, b ila te r a l, aoderate Calculus, pelvic -Portal aononuclear c e ll in f ilt r a t e , a ild -Vascular aineralization, a ild -Acinar atrophy, fo c a l, aoderate Pancreatitis, chronic, focal, a ild The follow ing tissu es aere found to be within noraal l ia it s : Brain, Spinal Cord, Bone Marroa, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary 61and, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 4 G00555 168 Suaaarizcd Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-3SS1 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Macroscopic Observations: Liver Microscopic Observations: Liver Lung -Rale tan -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild -Pneuaonia, in t e r s t it ia l, chronic, fo c a l, Heaorrhage, a u ltifo c a l, a ild Hyperplasia, septal c e ll, focal, a ild a ild The fo llo K in g tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marroa, Spleen, Kidney, Heart, Stoaach, Seal 1 Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate; P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3559 Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Liver Lung -No v is ib le lesio ns. -P y e litis , acute, d ila te ra i, ainiaal Nephritis, in t e r s t it ia l, chronic, focal, unilaterali aild -Portai aononudear c e li in filtr a t e , a ild Portai b ile duct p r o l if e r a t i c i a ild -Heaorrhage, a u ltifo c a l, a ild The follow ing tissues were found to be w ithin noraal l ia it s : Brain, Spinal Cord, Bone Marroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-35&B Sex: Male Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Pancreas Parathyroid -No v is ib le lesions. -Chronic progressive nephropathy, a ild -Pan creatitis, chronic, focal, a ild Acinar atrophy, focal, a ild -Not exaained, not in plane of section Species: Rat Project Nuaber: 02B1CR0012 Suaaarizcd STAR Page: 5 169 000556 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-356B Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Week- 53) 1 Year in te ria S a c rific e Microscopic Observations (continued): The fo llo a in g tissu es aere found to be a ith in noraal lia it s : Brain, Spinal Cord, Bone Marroa, Spleen, L iv er, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , 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 S a c rific e Macroscopic Observations: Microscopic Observations: Adrenal Lung Parathyroid -No v is ib le lesions. -C o rtic a l vacuolation, a u ltifo c a l, ai Id -Pneuaonia, in t e r s t it ia l, chronic, fo ca l, ainiaal Heaorrhage, a u ltifo c a l, a ild -Not exaained, not in plane of section The fo llo a in g tissu es aere found to be a ith in noraal l ia it s : Brain, Spinal Cord, Bone Marroa, Spleen, L iv er, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3575 Sex: Male 6roup: ( 1) CONTROL 0 ppa Fate.' (Heek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Soft Tissues (leg) Microscopic Observations: Kidney Lung P itu ita ry -S u o lien le f t hind foot at the hock jo in t. -Chronic progressive nephropathy, a in ia a l -Vascular aineralization, ainiaal Alveolar aacrophages, a u ltifo c a l, a ild Heaorrhage, fo ca l, a ild -Cyst, pars d is ta lis The fo llo a in g tissu es aere found to be a ith in noraal l ia it s : Brain, Spinal Cord, Bone Marroa, Spleen, L iver, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: A 170 000557 Suaearized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Too Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-3580 Sex: Male Broup: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Macroscopic Observations: Kidney Microscopic Observations: Bone Narrow Kidney Lung Pancreas Parathyroid Spinal Cord -Bark c y stic lesio n , 0.4 ca d ia ., le f t . -Not exaained, aissing -Chronic progressive nephropathy, a ild Cyst, c o rtica l, unilateral -Alveolar aacrophages, a u ltifo c a l, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild -Pan creatitis, chronic, focal, a ild -Not exaained, not in plane of section -Not exaained, aissing The following tissues were Found to be Mi thin no rial lia it s : Brain, Spleen, L iv er, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Bland, Eye. Aniaal Nuaber: 1R-4578 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: tHeek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Lyaph Node (aesenteric) Parathyroid -No v is ib le lesions. -Pelvic aineralization, ainiaal -Not exaained, aissing -Not exaained, not in plane of section The follow ing tissues ere found to be within noraal l ia i t s : Brain, Spinal Cord, Bone Harrow, Spleen, L iv er, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Bland, P itu ita ry , Adrenal Thyroid, Trachea, Esophagus, Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-4582 Sex: Feaale Broup: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Macroscopic Observations: Nesentary Microscopic Observations: Heart Kidney -Yellow nodular aass, 1 x 0.5 ca. -Myocarditis, chronic nonsuppurative, focal, ainiaal -Calculus, pelvic, unilateral Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 7 171 G00558 Suaaarized Single Tabulated Aniaal Report (continued) Individual Racroscopic and flicroscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-4S82 Sex: Feaale Group: < 1) CONTROL 0 ppa Fate: <Neek= 53) 1 Year In te ria S a c rific e Microscopic Observations (continued): Large Intestine Lung Hesentary Parathyroid Urinary Bladder Uterus -Not exaained, aissing -Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild Heaorrhage, local areas, a ild Perivascular aononudear in filtr a t e , a ild -Necrosis, fa t, nodular, aoderate S te a titis , chronic, aoderate -Not exaained, not in plane of section -Not exaained, aissing -Hyperplasia, glandular epitheliua, a ild Metaplasia, squaaous, glandular, a ild The follow ing tissues aere found to be w ithin noraal l ia it s : Brain, Spinal Cord, Bone Narrow, Spleen, L iv e r, Stoaach, Saall Intestine, Aorta, Ovary, Naaaary Gland, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4585 Sex! Feaale Group: I 1) CONTROL 0 ppa Fate: (Heek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid -No v is ib le lesions. -Sinusoidal ectasia, cortex, focal, unilateral, a ild -Pelvic aineralization, ainiaal -Portal aononudear ce ll in filtr a te , ainiaal - Vascular a inera li iation, a ild Heaorrhage, a u ltifo c a l, a ild -Not exaained, not in plane of section The follow ing tissu es were found to be w ithin noraal l ia it s : Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Naaaary Gland, P itu ita ry , Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 8 17 0 1 /2 000559 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-4588 Sex! Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= S3) 1 Year In te ria S a c rific e Macroscopic Observations: Skin Adrenal Microscopic Observations: Adrenal Kidney Liver Lung Spinal Cord Spleen -Hair loss, neck. -Left enlarged -Sinusoidal ectasia, cortex, u n ilateral, aarked C o rtica l degeneration, u n ila te ra l, ai 1d -Hyperplasia, pelvic epitheliua, a ild Calculus, pelvic, u nilateral Cyst, aedullary, a ild -Hepatocyte vacuolation, a u ltifo c a l, a ild -Heaorrhage, d iffu se , aoderate -Not exaained, aissing -Heaosiderosis, a ild The fo llo a in g tissues ere found to be ith in noraal l ia it s : Brain, Bone Marroa, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Gland, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Skin. Aniaal Nuaber: 1R-45B9 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Macroscopic Observations: P itu ita ry Microscopic Observations: Liver Maaaary 61and Parathyroid -S lig h tly enlarged -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild -Galactocele -Not exaained, not in plane of section The follotting tissues ere found to be a ith in noraal l ia it s : Brain, Spinal Cord, Bone Marroa, Spleen, Kidney, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 9 173 000560 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations R ile r Laboratories, Inc. 3H FC-143: Teo Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-4590 Sex: Feaale Sroup: ( 1) CONTROL 0 ppa Fate: (Neek= S3) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations! Lung -No v is ib le lesions. -Heaorrhage, local areas, aoderate The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, L iv e r, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Gland, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 81and, Eye. Aniaal Nuaber: 1R-460I Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Macroscopic Observations: Kidney Microscopic Observations: Kidney Liver Lung -Hydronephrosis, u n ila te ra l -Hydronephrosis, u n ila te ra l, aoderate Calculus, u n ilateral, a ild -Hepatocyte vacuolation, a u ltifo c a l, a in ia a l -Heaorrhage, a u ltifo c a l, a ild The f o l 1owing 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, Ovary, Maaaary Gland, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4608 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= S3) 1 Year In te ria S a c rific e Macroscopic Observations: Uterus Microscopic Observations: Liver Lung Lyaph Node (aesenteric) Uterus -L e ft horn c y stic looking lesio n , 1 x 0.6 ca. -Hepatocyte vacuolation, a u ltifo c a l, ainiaal -Heaorrhage, a u ltifo c a l, a ild -Not exaained, aissing -C ystic glands, fo ca l, aarked The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Narrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Maaaary Gland, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 10 000561 S u m m e d Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-4610 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Weeks S3) 1 Year In te ria S a c rific e Hacroscopic Observations: P itu ita ry Uterus Hicroscopic Observations: Adrenal Large Intestine Lung Pancreas Parathyroid Uterus -S lig h tly enlarged -S lig h tly enlarged -Sinusoidal ectasia, cortex, a ild -Neaatodiasis -Alveolar aacrophages, a u ltifo c a l, a ild -Pan creatitis, chronic, fo cal, a ild -Not exaained, not in plane of section -Hyperplasia, glandular ep itheliu a, a ild Hetaplasia, squaaous, glandular, a ild The follow ing tissues uere found to be w ithin noraal lia i t s : Brain, Spinal Cord, Bone Harrou, Spleen, L iv er, Kidney, Heart, Stoaach, Snail Intestine, Urinary Bladder, Aorta, Ovary, Haaaary Bland, P itu ita ry , Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Bland, Eye. Aniaal Nuaber: 1R-4620 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Week* 53) 1 Year In te ria S a c rific e Hacroscopic Observations: Eye Hicroscopic Observations: Eye Kidney Lung Urinary Bladder -Atrophy, rig h t eye. -Panophthalaitis, u n ila te ra l, aarked Atrophy, u n ila te ra l, narked -Pelvic aineralization, ainiaal -Heaorrhage, a u ltifo c a l, a ild -Not exaained, aissing The follow ing tissues uere found to be w ithin noraal l ia i t s ! Brain, Spinal Cord, Bone Harrow, Spleen, L iv e r, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Uterus, Ovary, Haaaary Bland, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland. Aniaal Nuaber: 1R-4629 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek- 53) 1 Year In te ria S a c rific e Hacroscopic Observations: Skin Hicroscopic Observations: Adrenal -Hair loss, head, neck, face. -C o rtic a l degeneration, fo c a l, u n ila te ra l, a ild Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 21 175 000562 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4429 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year In te ria S a c rific e Microscopic Observations (continued): Aorta Large Intestine Liver Parathyroid -Not exaained, aissing -Neaatodiasis -Portal b ile duct p ro life ra tio n , a ild -Not exaained, not in plane ofsection The follow ing tissues were found to be w ithin noraal l ia i t s : Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Lung, Stoaach, Saall Intestine, Urinary Bladder, Uterus, Ovary, Haasary Gland, P itu ita ry , Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye, Skin. Aniaal Nuaber: 1R-4630 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Heek= S3) 1 Year In te ria S a c rific e Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Parathyroid Thyroid -Possibly s lig h tly pale in color. -Calculus, p e lvic, u n ila te ra l, soderete -Hepatocyte a lte ra tio n , vacuolated, a u ltifo c a l, a ild -Heaorrhage, a u ltifo c a l, a ild -Not exaained, aissing -Not exaained, aissing The follow ing tissu es were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Gland, P itu ita ry , Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4631 Se?: Feaale Group: ( 1) CONTROL 0 ppa Fate.' (Neek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Lung Lyaph Node (aesenteric) Parathyroid Urinary Bladder -No v is ib le lesions. -Pelvic aineralization, ainiaal -Heaorrhage, local areas, a ild -Not exaained, aissing -Not exaained, not in plane of section -Not exaained, aissing The follow ing tissu es were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Narrow, Spleen, L iver, Heart, Stoaach, Saall Intestine, Species: Rat Project Nuaber: 02B1CR0012 Suaaari zed STAR Page: 12 176 000563 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3R FC-J43: Tmo Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nueber: 1R-4631 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Microscopic Observations (continued): The follow ing tissues were found to be w ithin noraal' l i a i t s (continued): Large Intestine, Aorta, Uterus, Ovary, Naaaary Gland, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4632 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Heek- 53) 1 Year In te ria S a c rific e Macroscopic Observations: P itu ita ry Naaaary Gland Microscopic Observations: Adrenal Kidney Liver Lung Naaaary Gland Ovary P itu ita ry -S lig h tly enlarged with a dark red focus on surface. -S a a ll spherical aass, 1.2 ca d ia ., containing dark red f lu id , le f t inguinal. -Sinusoidal ectasia, cortex, focal, un ilateral, a ild -Chronic progressive nephropathy, a ild -Hepatocyte vacuolation, a u ltifo c a l, a ild -Heaorrhage, a u ltifo c a l, a ild -Galactocele Chronic in flaaaatio n and heaorrhage in cysts. -Cyst, unilateral -Adenoaa The follow ing tissu es were found to be within noraal lia i t s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4&40 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Liver Lung Parathyroid -No v is ib le lesions. -Hepatocyte vacuolation, a u ltifo c a l, a in ia a l -Heaorrhage, a ild -Not exaained, not in plane of section The follow ing tissu es were found to be w ithin noraal lia i t s : Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Naaaary Gland, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 13 ] 000564 Suiaarized Single Tabulated Anieal Report Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Tno Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 ftnital Nuaber: 1R-3584 Sex'. Hale Broup: ( 5) FC-143 300 pps Fate: (Neek= 53) 1 Year I n te ri! S a crific e Macroscopic Observations: Liver Microscopic Observations: Aorta Kidney Liver Lung Parathyroid -Pale -Not exaiined, aissing -Chronic progressive nephropathy, a ild -Portal aononudear ce ll in filtr a te , aild Portal b ile duct p ro life ra tio n , a ild Negaiocytosis, aoderate Necrosis, focal, ainiaal -Vascular ain eralization , a ild Alveolar aacrophages, a u ltifo c a l, a ild -Not exaained, not in plane of section The fallow ing tissues ere found to be within no rial l ia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, T e stis/Epididyais, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-35B8 Sex: Male Broup: ( 5) FC-143 300 ppa Fate: (Neek= 531 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Spleen -No v is ib le lesions. -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in filtr a t e , a ild Negaiocytosis, a ild Necrosis, a u ltifo ca l, a ild -Vascular aineralization, a ild -Heaosidero5is, a ild The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Narrow, Heart, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 14 178 000565 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-35B9 Sex: Hale Group: ( 5) FC-143 300 ppa Fate: (Ueek= 53) 1 Year Interia S a c rific e Hacroscopic Observations: Hicroscopic Observations: Aorta Liver Lung Parathyroid Thyroid -No v is ib le lesions. -Not exaained, aissing -Portal aononudear c e ll in filtr a t e , a ild Hegalocytosis, a ild -Vascular aineralization, a ild -Not exaained, aissing -Not exaained, aissing The follow ing tissues were Found to be a ith in noraal l ia it s : Brain, Spinal Cord, Bone Harroa, Spleen, Kidney, Heart, Stoaach, Saall Intestine, . Large Intestine, Urinary Bladder, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3592 Sex: Hale 6roup: ( 5) FC-143 300 ppa Fate: (Week= 53) 1 Year In te ria S a c rific e Hacroscopic Observations: P itu ita ry Hicroscopic Observations: Kidney Liver Lung Parathyroid Urinary Bladder -S a a ll dark red aass, 0.3 ca dia. -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in f iltr a t e , ainiaal Hepatocyte vacuolation, a u ltifo c a l, a ild Pigaent, Kupfer c e ll, a u ltifo c a l, brown, a ild -Vascular aineralization, a ild Alveolar aacrophages, a u ltifo c a l, a ild -Not exaained, not in plane of section -Not exaained, aissing The follow ing tissues ere found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3598 Sex: Hale 6roup: ( 5) FC-143 300 ppa Fate: (Week= 53) 1 Year In te ria S a c rific e Hacroscopic Observations: Hicroscopic Observations: Heart -No v is ib le lesions. -Hyocarditis, chronic nonsuppurative, a u ltifo ca l, ainiaal Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 15 1/9 000566 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te rie Table: 1 Aniaal Nueber: 1R-3598 Sex: Male Group: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Microscopic Observations (continued): Kidney Liver Lung Parathyroid P itu ita ry -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in filtr a t e , a ild Negalocytosis, ainiaal Necrosis, a u ltifo ca l, ainiaal -Alveolar aacrophages, a u ltifo c a l, a ild -Not exaained, not in plane of section -Not exaained, aissing The follow ing tissues were found to be w ithin noraal 1ia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3604 Sex: Male Broup: ( 5) FC-143 300 ppa Fate: (Heek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Aorta Heart Kidney Liver Lung Parathyroid Salivary Gland -No v is ib le lesions. -Not exaained, aissing -Myocardial fib ro s is , focal, a ild -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a t e , a ild Negalocytosis, ainiaal Necrosis, a u ltifo ca l, a ild -Vascular aineralization, a ild Alveolar aacrophages, a u ltifo c a l, a ild Heaorrhage, loca l areas, a ild -Not exaained, not in plane of section -Not exaained, aissing The follow ing tissues were found to be w ithin noraal l ia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, T e stis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 16 180 000567 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te rie Table: 1 Aniaal Nuaber: 1R-3613 Sex: Male Broup: ( 5) FC-143 300 ppa Fate: INeek= 53) 1 Year ln te ria S a c rific e Macroscopic Observations: Liver Kidney Microscopic Observations: Eye Liver Lung Parathyroid T e s tis /E p id id y a is -Pale tan color. -Saall depressed area, 0.2 ca d ia ., rig h t kidney. -Retinal atrophy, fo cal, ainiaal -Portal aononudear c e ll in filtr a te , a ild Hegalocytosis, ainiaal -Vascular aineralization, a ild -Not exaained, not in plane of section -Tubule atrophy, asperaatogenesis, u n ila te ra l, aarked The follow ing tissues ere found to be within noraal lia i t s : Brain, Spinal Cord, Bone Narrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nuaber: 1R-3617 Sex: Hale 6roup: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year ln te ria S a c rific e Macroscopic Observations: Skin Microscopic Observations: Kidney Liver Lung Lyaph Node (aesenteric) Skin -Ulcerated nodule in the dorsal area, 1.5 ca dia. -M ineralization, a u ltifo ca l, cortical P y e litis , acute, u n ila te ra l, a ild -Hegalocytosis, ainiaal -Alveolar aacrophages, a u ltifo c a l, a ild -Heaorrhage, a in ia a l -Keratoacanthoaa The follow ing tissu es were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 17 181 000568 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-3620 Sex: Male 6roup: ( S) FC-143 300 ppa Fate*. (Reek- 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Aorta kidney Liver Parathyroid -No v is ib le lesions. -Not exaained, aissing -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in filtr a t e , aild Hepatocyte vacuolation, a u lt if o c a l, a in ia a l Megalocytosis, ainiaal -Not exaained, not in plane of section The follow ing tissues ere found to be w ithin noraal lia i t s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Lung, Stoaach, Snail Intestine, Large Intestine, Urinary Bladder, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyeph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3&22 Sex: Male Group: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Eye Testis Microscopic Observations: Eye kidney Liver Lung Lyaph Node (aesenteric) Parathyroid Prostate T e s tis /E p id id y a is -Ocular opacity, b ila te ra l. -Left testis saall. -Cataract, bilateral -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a t e , ainiaal Megalocytosis, ainiaal Pigaent, Kupfer c e ll, brown, a in ia a l -Vascular aineralization, ainiaal Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild -Heaorrhage, a ild -Not exu ined, not in plane of section -Not exaained, aissing -Tubule atrophy, asperaatogenesis, u n ila te ra l, narked The follow ing tissu es were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Pancreas, Salivary Bland. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: IB 182 000569 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-3626 Sex: Hale Broup: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Parathyroid P itu ita ry Prostate -No v is ib le lesions. -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in filtr a t e , a ild Megalocytosis, ainiaal -Alveolar aacrophages, a u ltifo c a l, a ild -Not exaained, not in plane of section -Not exaained, aissing -P ro s ta titis , chronic, focal, in t e r s it it ia l, a in ia a l The follow ing tissues were found to be w ithin noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesentenc), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3&27 Sex: Hale 6roup: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Macroscopic Observations: Liver Microscopic Observations: Liver Lung Parathyroid -S lig h tly pale tan in color. -Portal aononudear c e ll in f ilt r a t e , ainiaal -Heaorrhage, local areas, a ild -Not exaained, not in plane of section The follow ing tissues were found to be w ithin noraal lia i t s : Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3638 Sex: Male Group: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Liver Lung Lyaph Node (aesenteric) -No v is ib le lesions. -Portal aononudear c e ll in filtr a te , ainiaal Necrosis, a u ltifo ca l, a ild -Heaorrhage, local areas, aoderate -Not exaained, aissing Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 19 183 000570 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interie Table: 1 Aniaal Nuaber: 1R-3638 Sex: Male Broup: ( 5) FC-143 300 ppa Fate: (Neek= S3) 1 Year Interie S a c rific e Microscopic Observations (continued): P itu ita ry Prostate Urinary Bladder -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing The Following tissues were found to be a ith in noraal l ie it s : Brain, Spinal Cord, Bone Narroa, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, Testis/Ep id id yais, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3642 Sex: Hale 6roup: ( 5) FC-143 300 ppa Fate: (Week- 53) 1 Year In te rie S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Large Intestine Liver Lyaph Node (aesenteric) Parathyroid Thyroid -No v is ib le lesions. -Chronic progressive nephropathy, a in ia a l -Neaatodiasis -Hegalocytosis, a ild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing The follow ing tissu es ere found to be within noraal l ia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart,, Lung, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3643 Sex: Hale 6roup: ( 5) FC-143 300 ppa Fate: (Heek= 53) 1 Year In te rie S a c rific e Macroscopic Observations: Microscopic Observations: Heart Kidney Liver Lung -No v is ib le lesio ns. -Myocardial fib ro s is , fo cal, ain iaal Myocarditis, chronic nonsuppurative, focal, ainiaal -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a te , a ild Hegalocytosis, aoderate Necrosis, a u ltifo c a l, a ild -Vascular aineralization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild Perivascular aononudear in filt r a t e , a ild Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 20 184 000571 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3N FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-3643 Sex: Hale Broup: ( S) FC-143 300 ppa Fate: (Heek= 53) 1 Year Interia S a c rific e Microscopic Observations (continued): Parathyroid -Not exaained, not in plane of section The follow ing tissues ere found to be within noraal l ia i t s : Brain, Spinal Cord, Bone Harro, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-4642 Sex: Feaale Broup: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Hacroscopic Observations: Eye Uterus Microscopic Observations: Eye Kidney Large Intestine Li ver Parathyroid Uterus -Atrophy, rig h t eye. -Both horns enlarged, f ille d with clear flu id . -Panophthalaitis, u n ila te ra l, narked Atrophy, u n ila te ra l, aarked -Chronic progressive nephropathy, a ild -Neaatodiasis -Hepatocyte vacuolation, a u ltifo c a l, a ild -Not exaained, not in plane of section -Hydroaetra, aoderate Endoaetritis, chronic, a ild The follow ing tissues were found to be within noraal l ia i t s : Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Lung, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Ovary, Haasary 61and, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and. Aniaal Nuaber: IR-4652 Sex: Feaale Broup: ( 5) FC-143 300 ppa Fate: INeek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Liver Parathyroid -No v is ib le lesions. -Chronic progressive nephropathy, a ild -Hepatocyte vacuolation, a u ltifo c a l, a ild -Not exaained, not in plane of section The follow ing tissues were found to be w ithin noraal lia i t s : Brain, Spinal Cord, Bone Narrow, Spleen, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Bland, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 21 j 000572 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year I n te rn Table: 1 Aniaal Nuaber: 1R-4655 Sex: Feaale Group: ( 5) FC-143 300 ppa Fate: (Week 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Aorta Liver Lung P itu ita ry -No v is ib le lsions. -Not exaained, aissing -Hpatocyte vacuolation, a u ltifo c a l, a ild -Heaorrhage, local areas, a ild -Not exaained, aissing The follow ing tissues ere found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Uterus, Ovary, Haaaary Gland, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-445& Sex: Feaale 6roup: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Lyaph Node (aesenteric) -No v is ib le lesions. -Chronic progressive nephropathy, a ild Mineralization, a u ltifo ca l, c o rtic a l, a ild -Hepatocyte vacuolation, a u ltifo c a l, a ild -Heaorrhage, a u ltifo c a l, a ild -Not exaained, aissing The follow ing tissues were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Gland, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4&64 Sex: Feaale 6roup: ( 5) FC-143 300 ppa Fate: (tdeek= 53) 1 Year Interia S a c rific e Macroscopic Observations: Haaaary 61 and Microscopic Observations: Liver Haaaary 61and -Subcutaneous aass, 3.5 ca d ia ., le f t inguinal area. -Hepatocyte vacuolation, a u ltifo c a l, a ild -Fibroadenoaa The follow ing tissu es were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Narrow, Spleen, Kidney, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, P itu ita ry , Adrenal, Thyroid, Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 22 186 000573 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-4664 Sex: Feaale Group: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year In te ria S a c rific e Microscopic Observations (continued): The follow ing tissues ere found to be within noraal 1 ia it s (continued): Parathyroid, Trachea, Esophagus, Lyaph Node (aesen tericl, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-466& Sex: Feaale Group: ( 5) FC-143 300 ppa Fate: (Week- 53) 1 Year Interia S a c rific e Macroscopic Observations: Microscopic Observations: Liver -No v is ib le lesions. -Portal aononudear c e ll in filtr a te , a ild Portal b ile duct p ro life ra tio n , a ild The follow ing tissues ere found to be w ithin noraal 1ia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary 61and, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4669 Sex: Feaale 6roup: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Hacroscopic Observations: Microscopic Observations: Liver Lung Haaaary Gland -No v is ib le lesions. -Hepatocyte vacuolation, a u ltifo c a l, a ild -Heaorrhage, a u ltifo c a l, a ild -Not exaained, aissing The follow ing tissu es were found to be within noraal lia it s : Brain, Spinal Cord, Bone Narrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4671 Sex: Feaale Group: ( 5) FC-143 300 ppa Fate: (Meek- 53) 1 Year In te ria S a c rific e Hacroscopic Observations! Haaaary Gland Microscopic Observations: Kidney -Subcutaneous aass, 5 ca d ia ., behind le f t shoulder. -Pelvic aineralization, aild Calculus, pelvic, a ild Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 23 ! 87 G00S74 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te rie Table: 1 Aniaal Nueber: 1R-4671 Sex: Feaale Broup: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Microscopic Observations (continued): Liver Lung Maaiary Gland Parathyroid -Hepatocyte vacuolation, a u ltifo c a l, a in ia a l -Heaorrhage, a u ltiF o c a l, at Id -Fibroadenoaa -Not exaained, not in plane of section The -following tissues were found to be w ithin noraal l ia it s : Brain, Spinal Cord, Bone Marrou, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4674 Sex: Feaale Group: ( 5) FC-143 300 ppa Fate: (Heek= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Microscopic Observations: Aorta Esophagus Large Intestine Lung Parathyroid -No v is ib le lesions. -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Heaorrhage, a u ltifo c a l, a ild -Not exaained, not in plane of section The follow ing tissues ere found to be within noraal l ia it s : Brain, Spinal Cord, Bone Harro, Spleen, L iv e r, Kidney, Heart, Stoaach, Saall Intestine, Urinary Bladder, Uterus, Ovary, Naasary Gland, P itu ita ry , Adrenal, Thyroid, Trachea, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4676 Sex: Feaale 6roup: ( 5) FC-143 300 ppa Fate: (Week= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Haaaary 61 and Microscopic Observations! Adrenal Heart Kidney Liver -To subcutaneous aasses in both inguinal areas, 1.5 and 2 cs dia. Left side s ilk cyst, rig h t side cyst f i ll e d with rust colored flu id . -Sinusoidal ectasia, cortex, a ild -Myocarditis, chronic nonsuppurative, focal, a ild -Calculus, pelvic -Hepatocyte vacuolation, a u ltifo c a l, a ild Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 24 188 000575 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and flicroscopic Observations Riker Laboratories, Inc. 3H FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te ria Table: 1 Aniaal Nuaber: 1R-4676 Sex: Feaale 6roup: ( S) FC-143 300 ppa Fate: (Neek= 53) 1 Year Interia S a c rific e Microscopic Observations (continued): Lung Haaaary Gland -Alveolar aacrophages, a u ltiF o c a l, a ild -Bal'actocele Galactocele One cyst involved a ith chronic inFlaaaatory process a ith extensive heaorrhage into cyst. The follow ing tissues aere Found to be a ith in noraal l ia it s : Brain, Spinal Cord, Bone Harroa, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: IK-4687 Sex: Feaale Group: ( 5) FC-143 300 ppa Fate: (Neek= 53) 1 Year In te ria SacriFice Macroscopic Observations: Urinary Bladder Ureter Kidney Microscopic Observations: Esophagus Kidney Maaaary Gland Parathyroid Ureter Urinary Bladder Uterus -Distended a ith urine and containing greenish spherical c a lc u li, 0.6 ca dia. -B ila te ra l d ila ta tio n oF ureters; F ille d aith c a lc u li near the end oF the bladder. -B ila te ra l aarked hydronephrosis a ith nuaerous c a lc u li in the p e lvic area. -No diagnosis, inadequate section -Hydronephrosis, b ila te r a l, aarked P y e lit is , chronic, aoderate -Not exaained, aissing -Not exaained, not in plane of section -Calculus InFlaaaation, chronic, diFFuse, aoderate D ila ta tio n , aarked -E p ith e lia l hyperplasia, siaple, diFFuse, a ild C y s t it is , chronic, diFFuse, aoderate -Hydroaetra The follow ing tissu es aere Found to be a ith in noraal lia it s : Brain, Spinal Cord, Bone Harroa, Spleen, L iver, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Aorta, Ovary, P itu ita ry , Adrenal, Thyroid, Trachea, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 25 000576 189 Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year In te rie Table: 1 Aniaal Nuaber: 1R-46B9 Sex: Feaale Broup: ( 5) FC-143 300 ppa Fate: (Week= 53) 1 Year In te ria S a c rific e Macroscopic Observations: Eye Liver Lyaph Node (aesenteric) Microscopic Observations: Adrenal Eye Liver Lung Lyaph Node (aesenteric) Parathyroid Thyroid -Right eye atrophied. -PaTe tan in color. -Heaorrhagic -Sinusoidal ectasia, cortex, a ild -Atrophy, u n ila te ra l, aarked Panophthalaitis, chronic, u n ila te ra l, aarked -Hepatocyte vacuolation, a u ltifo c a l, a ild -Heaorrhage, local areas, a ild -Heaorrhage, aarked -Not exaeined, not in plane of section -No diagnosis, inadequate section The follow ing tissues were found to be w ithin noraal 1ia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Haaaary Bland, P itu ita ry , Trachea, Esophagus, Pancreas, Salivary 61and. Aniaal Nuaber: 1R-4692 Sex: Feaale Group: ( 5) FC-143 300 ppa Fate: (Week- 53) 1 Year Interia S a c rific e Macroscopic Observations: Microscopic Observations: Lung Lyaph Node (aesenteric) -No v is ib le lesions. -Heaorrhage, local areas, aoderate -Not exaeined, aissing The follow ing tissues were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Harrow, Spleen, L iver, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus , Ovary, Haaaary Gland, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4699 Sex: Feaale 6roup: ( 5) FC-143 300 ppa Fate: (Weeks 53) 1 Year Interia S a c rific e Macroscopic Observations: Microscopic Observations: Adrenal Large Intestine Liver -No v is ib le lesio ns. -Sinusoidal ectasia, cortex, a ild -Neaatodiasis -Hepatocyte vacuolation, a u ltifo c a l, a ild Species: Rat Project Nuaber: 0281CR0012 Suuarized STAR Page: 26 190 000577 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interia Table: 1 Aniaal Nuaber: 1R-4699 Sex: Feaale Croup: ( S) FC-143 300 ppa Fate: (Week: 53) 1 Year Interia S a c rific e Microscopic Observations (continued): Lung -Heaorrhage, local areas, aoderate The follow ing tissu es ere found to be a ith in noraal lia it s : Brain, Spinal Cord, Bone Narroa, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Gland, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4704 Sex: Feaale 6roup: ( 5) FC-143 300 ppa Fate: (Week: 53) 1 Year In te ria S a c rific e Hacroscopic Observations: Microscopic Observations: Adrenal Liver Lung Thyroid -No v is ib le lesions. -C o rtic a l degeneration, fo c a l, u n ila te ra l, a ild -Portal aononuclear c e ll in f ilt r a t e , a ild Hepatocyte vacuolation, a u ltifo c a l, a ild -Vascular ain eralization , a ild Heaorrhage, a u ltifo c a l, a ild -Not exaained, not in plane of section The follow ing tissu es were found to be a ith in noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Bland, P itu ita ry , Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 27 Sueaarized Single Tabulated A nital Report Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-351B Sex: Male Fate: (Ueek= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Macroscopic Observations: Skin Microscopic Observations: Adrenal Heart Kidney Liver Lung Parathyroid P itu ita ry Skir Thyroid -Raised inflaeaed lesion on rig h t rear Footpad. -C ortical vacuolation, a u ltifo ca l, a ild Medullary c e ll hyperplasia, a u ltiF o c a l, a ild -M yocarditis, chronic nonsuppurative, local areas, aoderate -Chronic progressive nephropathy, a in ia a i Pelvic aineralizaticn, ainiaai -Portal aononudear c e ll in filtr a t e , ainiaai Portal b ile duct p ro life ra tio n , a ild -Vascular in eralization, ainiaai Pneuaor.ia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild Perivascular aononudear in f ilt r a t e , aoderate -Not exaained, aissing -Acenoaa -Pododeraatitis, u lcera tive, hindleg, aarked -Not exaained, aissing The follow ing tissues ere Found to be within noraal lia it s : Brain, Spiral Cord, Bone Marrow, Spleen, Stoaach, Saall Intestine, Large Intestine Urinary Bladde', Aorta, T e stis/Epididyais, Prostate, Trachea, Esophagus, Lyeph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaa! Nuaber: 1R-3519 Sex: Male Fate: (Keek5 106) Teraina! S a c rific e Group: ( l i CONTROL 0 ppi Macroscopic Observations: Microscopic Observations: Adrenal Esophagus Heart Kidney Liver -No v is ib le lesions. -Sinusoidal ectasia, cortex, a u ltifo ca l, aild Cortical vacuolation, a u ltifo ca l, a ild -Not exaained, aissing -Myocarditis, chronic nonsuppurative, a u ltifo cal, aild -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild Hepatocyte a lte ra tio n , vacuolated, a u ltifo c a l, a ild Species: Rat Project Nuaber: 02B1CR0012 BESTCOPY AVAILABLE Suaaarized STAR Page: 28 192 000S79 Suaearized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FC-143: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3519 Sex! Hale Fate: (Ueek= 10b) Terainal S a c rific e Group: ( 1) CONTROL 0 ppi Microscopic Observations (continued): Lung -Vascular aineralization, a ild Perivascular aononudear in f ilt r a t e , aoderate Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, aoderate / The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Eiadder, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3S21 Sex: Male 6roup: ( 1) CONTROL 0 ppa Fate: (Week* 92) Sacrificed in extreais Macroscopic Observations: Skin Liver 5pleen Microscopic Observations: Adrenal Heart kidney Liver Lung Parathyroid Skin Spi een Stoaach -Both hind footpads ulcerated. -Pale -Enlarged -C ortical vacuolation, local areas, a ild Medullary c e ll hyperplasia, a u ltifo c a l, a ild -Myocardial fib r o s is , a u ltifo c a l, a ild -Chronic progressive nephropathy, aoderate -Hepatocyte vacuolation, c e n trilo b u la r, aoderate -Vascular ain eralization , a ild Pneuaonia, in t e r s t it ia l, chronic, local areas, a ild Edeaa, local areas, a ild Fibrosis, pleural, aild Throabus -Not exaained, aissing -Pododeraatitis, ulcera tive, hindleg, narked -Heaatopoiesis, extraaedullary, increased, aoderate -Edeaa, subaucosal, narked The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/E p id id y a i5, Prostate, P itu ita ry , Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 29 93 CCG580 Suaaarized Single Tabulated A n iia l Report (continued) Individual Hacroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FC-143: Tio Year Oral Tonicity-Oncogenicity Study in Rats Table: 2 A n iia l Nucber: 1R-3523 Sex: Rale 6roup: ( 1) CONTROL 0 ppi Fate: (Neek= 95) S acrificed in e x tr e iis Racroscopic Observations: Soft Tissues (thorax) Stoiach Ricrosccpic Observations: Adrenal Heart Kidney Liver Lung Prostate Skin Stoiach -Rass, 10 x 9 x 4 c i in le f t a x illa involving ausde and rib , extending into le f t thoracic ca vity, collapsing le f t lung. Hass soft and fa tty , -N all edeiatous with possible ulceration in cardia. -C o rtic a l vacuolation, a u ltifo c a l, s i Id Sinusoidal ectasia, cortex, diffuse, l ild -Hyocardial fib ro s is , a u ltifo c a l, l i l d -Chronic progressive nephropathy, ai 1d -Portal lononudear c e ll in filtr a t e , l i l d Portal b ile duct p ro life ra tio n , iiI d Hepatocyte a lte ra tio n , vacuolated, l i l d -Vascular ineralization, a ild Hemorrhage, fo c a l, l i l d Alveolar aacrophages, l i l d - P r o s ta titis , acutE, suppurative, aarked -Fibrosarcoaa, thorax Neil d iffe re n tia te d , highly c e llu la r with oberate collagen formation. -U lcer, aarked The fo llo a in g tissues were found to be within norial l i i i t s : Brain, Spinal Cord, Bone Rar rou, Spleen, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e s tis /E p id id y iis, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyeph Node (aesenteric), Pancreas, Salivary Bland, Eye. A n iia l Nueber: 1R-3524 Sex: Hale Fate: (Neek= 106) T e riin a l S a c rific e Broup: ( 1) CONTROL 0 ppi Hacroscopic Observations: P itu ita ry Hicroscopic Observations: Adrenal Kidney Large Intestine Liver - S ia li red lesion. -Hedullary c e ll hyperplasia, a u ltifo c a l, iiI d -Chronic progressive nephropathy, aoderate Pelvic aineralization, lild -Neaatodiasis, colon -Hepatocyte a lte ra tio n , vacuolated, aoderate Portal lononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild Species: Rat Project Nuaber: 0281CR0012 Sunarized STAR Page: 39 194 000581 Suuarized Single Tabulated A n iia l Report (continued) Individual Hacroscopic and Ricroscopic Observations Riker Laboratories, Inc. 311 FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuaber: 1F.-I524 Sex: Rale Broup: ( 1) CONTROL 0 ppi Fate: (Week= 106) T e n in a l S a c rific e Ricroscopic Observations (continued): Lung Lyiph Node iiesen teric) Parathyroid P itu ita ry Thyroid -Vascular aineralizatior., l il d -Not examined, aissing -Not exanined, not in plane of section -Adenoia -F o llic u la r hyperplasia, cystic, u n ilateral, oderate Large c y stic lesion occupying auch of one thyroid lobe. The fo llo a in g tissues aere found to be a ith in nornal lia it s : Brain, Spinal Cord, Bone Harroa, Spleen, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaai Nuaer: 1R-3525 Sex: Rale Fate: (Week- 106! Terainal S a c rific e 6roup: ( 1) CONTROL 0 ppi Racroscopic Observations: Bone Liver Ricroscopic Observations: Adrenal Bone Heart Kidney Liver Lung Parathyroid Spleen T e s tis /E p id id y a is -Jo in ts of rig h t fo re lia b and rig h t hindliab saollen. -Raised pale c irc u la r lesio n , 2 ca d ia ., in aedial lobe. -C o rtic a l vacuolation, loca l areas, aoderate -A rth ritis , synovitis! jo in ts, foreleg, hindleg, larked -Hyocarditi5, chronic nonsuppurative, loca l areas, ai Id -Chronic progressive nephropathy, aoderate -Portal aononuclear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Hepatocellular carcinoaa Large, poorly d iffe re n tia te d , anaplastic, in f ilt r a t iv e . Adenoid areas. M ultiple tuaor . eaboli in lung. -Vascular aineralization, a ild Retastatic neoplas# -Not exaained, not in plane of section -Heaosiderosis, a ild -Tubule atrophy, aspernatogenesis, a ild The fo llo a in g tissues aere found to be a ith in noraal lia it s : Brain, Spinal Cord, Bone Harroa, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 31 95 G005S2 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3525 Sex: Rale Fate: (Neek= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Microscopic Observations (continued): The follow ing tissues were found to be within ncraal l i a i t s (continued): Aorta, Prostate, P itu ita ry , Thyroid, Trachea, Esophagus, Lyiph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nueber: 1R-3526 Sex: Kale Fate: (Neek= 106! Terainal S a c rific e Group: l 1) CONTROL 0 ppi Macroscopic Observations: Microscopic Observations: Kidney Liver Lung -No v is ib le lesions. -Chronic progressive nephropathy, a ild -Portal aononuclear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Cystoid degeneration, fo ca l, a ild Hepatocvte a lte ra tio n , vacuolated, a ild -Vascular aineralization, a ild The follow ing tissu es were found to be within noraal l ia i t s ! Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis /E p id id y iis, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyiph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: R-3E2E Sex: Rale Fate: (tieek= 106) Terainal S a c rific e Group: I 1) CONTROL 0 ppa Macroscopic Observations: Kidney Microscopic Observations: Adrenal Kidney Liver Lung P itu ita ry -Hydronephrosis -C ortical vacuolation, focal, a ild -Chronic progressive nephropathy, aoderate Hydronephrosis, u n ila te ra l, aoderate -Portai aononuclear 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, s u it i fo c a l, t il d -Vascular aineralization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild -Hyperplasia, focal, pars d is ta lis , a ild The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 32 196 G00583 Sunarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-3528 Sex; Male Fate: (Week* 106) T e riin a l S a c rific e Group: ( 1) CONTROL 0 ppi Microscopic Observations (continued): The follow ing tissues ere found to be within no rial l i i i t s (continued): Lyiph Node fie s e n te ric ), Pancreas, Salivary Gland, Eye. A n iia l Nuiber: 1R-3529 Sex: Male Group: ( 1) CONTROL 0 ppi Fate: (Week= 96) S acrificed in e x tr e iis Macroscopic Observations: Skin Liver Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid Prostate Salivary Gland Skin Urinary Bladder -Areas of d e ra a titis with hair loss, soie scabbed; back, side, abdoisen. -Raised pale la ss, 1.2 c i dia. in le f t la te ra l lobe. -C ortical vacuolation, m ltifo c a l, t ild -Chronic progressive nephropathy, t ild -Portal iononudear c e ll in filt r a t e , l il d Hepatocellular carcinoia Trabecular pattern, f a ir ly well d iffe r e n tia te d . -Vascular lin e ra liza tio n , t ild Edeia, subpleural, toderate -Not exaiined, not in plane of section -Not exaiined, tis s in g -Not exaiined, lis s in g -U lcer, back, abdoien, larked -E p ith e lia l hyperplasia, s iip le , diffuse, l i l d The follow ing tissues were found to be within no nal l i i i t s : Grain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoiach, S ia ll Intestine, Large Intestine, Aorta, T e s tis /E p id id y iis, P itu ita ry , Thyroid, Trachea, Esophagus, Lyiph Node fie se n te ric), Pancreas, Eye. A n iia l Nuiber: 1R-3530 Sex: Male Fate: (Heek= 106! T e riin a l S a c rific e Group: ( 1) CONTROL 0 ppi Macroscopic Observations: Microscopic Observations: Heart Kidney Liver -No v is ib le lesions. -M yocarditis, chronic nonsuppurative, focal, iniial -Chronic progressive nephropathy, ai Id -Portal iononudear c e ll in filt r a t e , l i l d Portal b ile duct p ro life ra tio n , l i l d Cystoid degeneration, fo c a l, derate Hepatocyte a lte ra tio n , vacuolated, l i l d Species: Rat Project Nuiber: 0281CR0012 Suuarized STAR Page: 33 197 000534 Suaearized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3530 Sex'. Hale Fate: (Heek= 106! Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Microscopic Observations (continued): Lung Spleen -Vascular a in e ra liza tio n , s i Id Peribronchial lyaphcid hyperplasia, a ild -Heaosiderosis, a ild The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Eone Marrow, Stoeach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id vais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyiph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3531 Sex.' Male Fate: (Neek= 106) Terainal S a c rific e Sroup: I 1) CONTROL 0 ppa Macroscopic Observations: Microscopic Observations! Kidney Liver Lung -No v is ib le lesions. -Chronic progressive nephropathy, a ild -Hepatocyte vacuolation, a u itifo c a l, a ild Portal aononudear ce ll in filtr a t e , ainiaal -Vascular aineralization, a ild Pneuaonia, in t e r s t it ia l, chronic, local areas, aoderate The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoeach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lvaph Node (aesenteric), Pancreas, S a liva r y Sland, Eye. Aniaal Nuaber: 1R-3532 Sex: Male Fate: (Heek= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Macroscopic Observations: P itu ita ry Kidney Microscopic Observations: Eye Heart Kidney Liver Lung -Raised red aass, 0.4 ca dia. -F lu id f i ll e d cyst, 1 ca d ia ., in rig h t kidney -Retinal atrophy, focal, a ild -Myocardial fib ro s is , focal, a ild -Chronic progressive nephropathy, aoderate Cyst, c o rtic a l, aarked -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild -Vascular aineralization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u itifo c a l, a ild Heaorrhage, local areas, a ild Perivascular aononudear in filtr a t e , a ild Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 34 198 0005S5 S u m m e d Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3d FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Ar.iaal Nuaber: IR-3532 Sex! Rale Fate: (Week- 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Microscopic Observations (continued): Lyaph Node (aesentenc) P itu ita ry Spleen -Heaorrhage, aiId -Adenoaa -Heaosiderosis, a ild The fo lio a in g tissues aere found to be within noraal lia it s : Brain, Spinal Cord, Bone Harroa, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Epididyais, Prostate, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland. Aniaal Nuaber: 1R-3533 Sex: Hale Fate: (Neek= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Hacroscopic Observations: Spleen Hicroscopic Observations: Eye Heart Kidney Liver Lung Prostate Spleen -Pale c irc u la r depressed area, 0.4 ca dia. -No diagnosis, inadequate section -H yocarditi5, chronic nonsuppurative, au ltifocal, aild -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a t e , a ild Hepatocyte vacuolation, a u ltifo c a l, a ild -Vascular aineralization, a ild Pneueonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild Perivascular aononudear in f ilt r a t e , a ild -P ro s ta titis , acute, suppurative, a ild -Heaosiderosis, a ild F ib ro sis, local areas, aoderate The fo lio a in g tissues aere found to be within noraal lia it s : Brain, Spinal Cord, Bone Harroa, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61and. Aniaal Nuaber: 1R-3534 Sex: Hale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Sacrificed in extreais Hacroscopic Observations: Thyaus Pancreas -Enlarged -Hassive beige colored aass, 7.5 x 3 ca in area of pancreas coapletely surrounding spleen and adhering to posterior areas of rig h t and le f t la te ra l Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 35 199 GG05S6 Suaiarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: JR-3534 Sex.' Rale 6roup: ( 1) CONTROL 0 ppa Fate: Week1 105) S acrificed in extreeis Macroscopic Observations (continued): Pancreas (continued) Kidney T e s tis /E p id id y a is Liver Microscopic Observations: Adrenal Kidney Liver Lung Lyaph Node (aesenteric) Pancreas Parathyroid P itu ita ry Saall Intestine Spleen Stoiach T e s tis /E p id id y a is Thyius Thyroid Urinary Bladder -liv e r lobes. -Pale and pitted . -Right te stis saall. -Pale with yellow ish c irc u la r lesion 0.3 c i diaaeter in rig ht anterior lobe -C o rtic a l vacuolation, diffu se, aoderate Medullary c e ll hyperplasia, local areas, aoderate -Chronic progressive nephropathy, aoderate Malignant lyiphoaa, h is tio c y tic -Hepatocyte vacuolation, d iffu se , earked -Heaorrhage, d iffu se , aarked Malignant lyaphoaa, h is tio c y tic -Heaorrhage, ai Id Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic -Not exaained, aissing -Adenoaa -Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic -Tubule atrophy, asperaatogenesis, u n ila te ra l, aarked -Malignant lyaphoaa, h is tio c y tic M u ltip le sections of tuaor fro* thyaic and aediastinal areas. -Not exaained, aissing -Malignant lyiphoaa, h is tio c y tic The follow ing tissues were found to be within noraal U n its : Brain, Spinal Cord, Bone Marrow, Heart, Trachea, Esophagus, Salivary Bland, Eye, Large Intestine, Aorta, Prostate. Species: Rat Project Nuaber*. 0281CR0012 Suaaarized STAR Page: 36 200 000557 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3536 Sex: Male Fate: (Neek= 106! Terainal S a c rific e Group! ( 1) CONTROL 0 ppa Macroscopic Observations: Skin Microscopic Observations: Adrenal Kidney Large Intestine Liver Lung Skin -Raised lesion, 1.5 ca d ia ., appears to be abscess. -Cortical vacuolation, focal, a ild Sinusoidal ectasia, cortex, focal, acderate -Chronic progressive nephropathy, a in ia a l -Neaatodiasis, colon -Portal b ile duct p ro life ra tio n , u lt ifo c a l, a ild Portal aononudear ce ll in filtr a t e , a ild Hepatocyte vacuolation, a u ltifo c a l, ainiaal -Vascular aineralization, aild Perivascular aononudear in filtr a t e , a ild -Keratoacanthoaa Raised lesion froa back. The follotting tissues Mere found to be within noraal b a it s : Brain, Spinal Cord, Bone Marroa, Spleen, Heart, Stoaach, Saall Intestine, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node ia esen teric), Pancreas, Salivary Gland, Eye, Urinary Bladder. Aniaal Nuaber! IR-3537 Sex: Male Fate: (Heek= 73) Found Dead Group: ( 1) CONTROL 0 ppa Macroscopic Observations: Liver Lyaph Node (abdoainal) Abdoaen (internal) P itu ita ry Microscopic Observations: Eye Heart Liver Lung Lyaph Node (aesenteric) Pancreas Parathyroid -Very pale -Renal lyaph nodes enlarged. -M u ltilo b u la r, fleshy aass, 4 x 3.5 x 3.5 attached to oaentua, le f t inguinal area. -Heaorrhagic aass, 0.7 ca dia. -Not exaained, aissing -Malignant lyaphoaa, h is tio c y tic -Hepatocyte vacuolation, d iffu se , aarked Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic Heaorrhage, local areas, aoderate -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 37 201 000558 Suuarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tmo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuaber: 1R-3537 Sex: Male Fate: (Ueek= 73) Found Dead Group: ( 1) CONTROL 0 ppi Microscopic Observations (continued): P itu ita ry Skin Spleen Thyroid -Adenona -Malignant lyiphoia, h istio c y tic Hass froe inguinal area uas aalignant lyip h o ia . There Mas extensive necrosis in tuner. -Heiosiderosis, lild -Not exaiined, lis s in g The FolloNing tissu es ere Found to be within noreal H a lts : Brain, Spinal Cord, Bone Marrou, Kidney, Stonach,, S ia li Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Epididynis, Prostate, Adrenal, Trachea, Esophagus, Salivary Gland. flniia! Nuaber: IR-353B Sex! Male Fate: (Neek= 106) Ternnai S a c rific e Group: ( 1! CONTROL 0 ppe Macroscopic Observations: P itu ita ry Liver Spleen Microscopic Observations: Aorenal Kidney Liver Lung Lysph Node (eesenteric) Parathyroid Prostate Spleen Urinary Bladder -S ta ll heiorrhagic area, 0.2 ct dia. -M ultiple pale fo ci, a ll lobes. -Enlarged -C ortical vacuolation, focal, iiI d -Chronic progressive nephropathy, l i l d -Malignant lyiphoia, h istio c y tic -Vascular lin e ra liza tio n , l il d Alveolar lacrophages, iiI d Malignant lyip h o ia , h is tio c y tic Perivascular eononuclear in f ilt r a t e , l i l d -Heiorrhage, t in iia l -Not exaiined, not in plane of section -P ro s ta titis , acute, suppurative, larked -Malignant lyiphoia, h istio cy tic -E p ith e lia l hyperplasia, s iip le , diffuse, l i l d The fo llo u in g tissues were found to be Mithin n o ria l l i i i t s : Brain, Spinal Cord, Bone Marrou, Heart,, Stoiach, S ta ll Intestine, Large Intestine, Aorta, T e stis/E p id id y iis , P itu ita ry , Thyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nutber: 0281CR0012 Suiaarized STAR Page: 38 2 02 000589 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacrcscopic and Hicroscopic Observations Riker Laboratories, Inc. 3H FC-143: Tec Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3539 Sex: Hale Fate: (Week= 106) Tereinal S a c rific e Group: ( 1) CONTROL 0 ppa Hacroscopi: Observations: - .. Hicroscopic Observations: Kidney Large Intestine Liver Lung Parathyroid P itu ita ry Spleen Thyroid -Nc v is ib le lesions. -Chronic progressive nephropathy, a ild -Neaatodiasis, colon -Portal aononudear c e ll in F iltra te , a ild Hepatocyte vacuolation, a u ltifo c a !, a ild -Vascular aineralization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltiF o c a l, a ild Perivascular aononudear in F iltra te , a ild -Not exaained, not in plane oF section -Cyst, pars d is ta lis -Heaosiderosis, a ild -Ultieobranchial cyst The Following tissues Mere Found to be within nornal l ia it s : Brain, Spinal Cord, Bone Rarrou, Heart, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas Salivary Gland, Eye. Aniaal Nuaber: 1R-3540 Sex: Hale Fate: (Neek= 64) Found Dead Group: ( 1) CONTROL 0 ppa flacroscopic Observations: Hicroscopic Observations: Bone Harrow Liver Lung Prostate Spinal Cord Thyroid Urinary Bladder -No v is ib le lesions. -Not exaained, aissing -Portal aononudear ce ll in F iltra te , add Portal b ile duct p rc liF e ra tio n , a ild -Vascular a in eralizatio n , a ild Alveolar aacrophages, a ild -Not exaained, aissing -Not exaained, aissing -Ultiaobranchial cyst -Not exaained, aissing The Fol 1awing tissues were Found to be within noraal U n its : Brain, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, T e stis/Ep id id yais, P itu ita ry , Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaari2ed STAR Page: 39 203 000590 Suaaarized Single Tabulated Am a il Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3541 Sex: Male Fate: (Neek= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Macroscopic Observations: Skin Microscopic Observations: Adrenal kidney Liver Lung Prostate Skin T e s tis /E p id id y a is Urinary Bladder -Raised lesion on le f t rear footpad. -C ortical vacuolation, focal, Gild Sinusoidal ectasia, cortex, ainiaal -Chronic progressive nephropatny, Giniaal -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild -Vascular G ineralization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifc c a l, a ild Heaorrhage, diffu se, aarked Perivascular aononudear in f ilt r a t e , a ild -Not exaained, aissing -Pododeraatitis, u lce ra tive , hindleg, aarked -Not exaained, aissing -Not exaained, aissing The follow ing tissues ere found to be within noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary eland, Eye. Aniaal Nu*ber: 1R-3542 Sex; Male Fate: (Neek= 106) Terainal S a c rific e 6roup: ( 1) CONTROL 0 ppc Macroscopic Observations: T e s tis /E p id id y a is Microscopic Observations: Kidney Liver Lung Lyaph Node (aesenteric) Pancreas T e s tis /E p id id y a is Thyroid -Both testes s a a ll. -Chronic progressive nephropathy, aoderate -Hepatocyte vacuolation, a u ltifo c a l, a ild -Vascular Bineraiization, ainiaal -Heaorrhage, a in ia a l -Hyperplasia, is le t c e ll, aoderate -Tubule atrophy, asperaatogenesis, b ila te r a l, aarked Polyarteritis, aild -Not exaained, aissing The follow ing tissu es were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Adrenal, Parathyroid, Trachea, Salivary Gland, Eye, Esophagus. Species: Rat Project Nuaber: C281CR0012 Suaaarized STAR Page: 40 204 000591 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tea Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: IK-3544 Sex: Male Fate: (Neek= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppi Macroscopic Observations: P itu ita ry Kidney Testis/Epididyais Microscopic Observations: Adrenal Kidney Liver Lung Pancreas Parathyroid P itu ita ry Spleen T e s tis /E p id id y a is -Heaorrhagic lesion, 0.7 ca dia. -Both enlarged, pale and pitted . -Left testis saall. -C o rtica l vacuolation, a u ltifo c a l, aoderate Sinusoidal ectasia, cortex, aoderate -Chronic progressive nephropathy, Barked -Hepatocyte vacuolation, a u ltifo c a l, ai Id -Vascular aineralization, eiId Alveolar aacrcphages, a ild -Acinar atrophy, a ild P o ly a r te ritis , aoderate -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, a ild -Tubule atrophy, asperaatogenesis, u n ila te ra l, aarked P o ly a rte ritis , aarked The follotting tissues aere found to be within noraal l ia it s : Brain, Spinal Cord, Bone Marroa, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye, Heart. Aniaal Nuaber: 1R-3545 Sex: Hale Fate: (Meek* 104) Found Dead Group: ( 1) CONTROL 0 ppa Macroscopic Observations: Skin Liver Microscopic Observations: Adrenal Eye Heart Kidney Lung Pancreas P itu ita ry -C irc u la r lesio ns, 2.5 ca dia. on both hind footpads. -S lig h tly pale -Sinusoidal ectasia, cortex, aoderate C o rtica l vacuolation, a u ltifo c a l, aoderate -Not exaained, aissing -Myocardial fib ro s is , local areas, a ild -Chronic progressive nephropathy, a ild -Vascular aineralization, a ild Alveolar aacrophages, a ild -Acinar atrophy, aoderate -Adenoaa Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 41 205 000592 Suaiarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Vear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3545 Sex: Hale Fate: <Week= 104) Found Dead Group: ( 1) CONTROL 0 ppa Microscopic Observations (continued): Skin Spleen -Pododeraati t i s, ulcerative, hindleg, b ila te r a l, aarked -Heaatopciesis, extrasec.Ils-y, increased. EllC The follow ing tissues were found to be within norcal l is it s : Brain, Spinal Cord, Bone Marrow, Liver, Stoaach, E sall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyscs, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Lysph Node (aeser.teric), S a liv a ', Eland. - r i s i i Nuaber: IE-3547 Ses: Male Group: ( 1) CONTROL 0 ppa -a te : ilis* 351 Sacrificed in extresis Macroscopic Observations: P itu ita ry Liver Microscopic Observations: Adrenal Erain Kidney Live' Lure P itu ita ry Stoaach -Mass, 0.4 ca dia. -Pale -Sinusoidal ectasia, cortex, foderate -Oligodendrogliona, benign Large necplasa coaposed of large, f a ir ly uni for polyhedral c e lls in cerebral cortex. -Chronic progressive nephropathy, l in e a l Pyelonephritis, acute, ni 1d -Portal lonsnuclear ce ll in filtr a t e , c ild Hepatocyte vacuolation, p e rip o rta l, loderate -Vascular lin e ra liz a tio n , ni 1d -Adenoia -Edena, subiucosal, oderate The follow ing tissues were found to be w ithin n o n a l l i i i t s : Spinal Cord, Bone Marrow, Spleen, Heart, S ia ll Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/E p id id ysis, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Lyi,ph Node (le se n te ric ), Pancreas, Salivary Bland, Eye. A rila ! Nueber: 1R-J548 Sex: Male Fate: (Neek= 106) T e riin a l S a c rific e Group: ( 1) CONTROL 0 pp# Macroscopic Observations: Microscopic Observations: Adrenal -No v is ib le lesions. -C ortical vacuolation, u ltifocal, l i l d Species: Rat Project Nuiber: 02E1CR0012 Suiaarized STAR Page: 42 206 G00593 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: To Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3548 Sex: Hale Fate: (Heek= 106) Teraina! S a c rific e Group: ( 1) CONTROL 0 ppa Microscopic Observations (continued): kidney Liver Lung Lysph Node (aesenteric) Parathyroid P itu ita ry Thyroid -Chronic progressive nephropathy, a ild -Portal acnonudear c e ll in filtr a t e , aild Hepatocyte vacudation, p e rip o rta l, a ild Hepatocyte vacudation l i a i ted to one area of liv e r. -Vascular aineralization, a ild Alveolar aacrophages, aim aal Perivascular aononudear in f ilt r a t e , a ild -Heaorrhage, a ild -Not exaained, not in plane of section -Cyst, pars d istal is -C c e ll carcinoaa The follow ing tissues ere found to be ith in noraal l ia it s : Brain, Spinal Cord, Bone Marro, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Epididyais, Prostate, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3549 Sex: Male Group: ! 1) CONTROL 0 ppa Fate: (Neeki 86) Sacrificed in extreais Macroscopic Observations: P itu ita ry Liver Microscopic Observations: Heart Liver Lung Parathyroid P itu ita ry Spleen Thyroid -Heaorrhagic aass, 1.4 x 0.8 ca. -S lig h tly pale -Myocarditis, chronic nonsuppurative, aultifocal, aild -Hepatocyte vacuolation, a u ltifo c a l, a ild -Vascular aineralization, a ild Alveolar aacrophages, a in ia a l -Not exaained, aissing -Adenoaa -Heaosiderosis, a ild -Not exaained, aissing The fo llo in g tissues ere found to be ith in noraal lia it s : Brain, Spinal Cord, Bone Harro, Kidney, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, Adrenal, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland , Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 43 U i 000594 Suiaarized Single Tabulated A n iia l Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 31! FC-143: To Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A riaal Nuaber: 1R-3S52 Sex: Hale Fate: !Week= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppc Macroscopic Observations: Spleen Microscopic Observations: Adrenal Kidney Live- Lung Pancreas Parathyroid P itu ita ry Prostate Spleen -C irc u la r raised lesion, 1.2 ca dia. -C ortical vacuolation, a u ltifo ca l, a ild Medullary c e il hyperplasia, loca l areas, aoderate -Chronic progressive nephropathy, aoderate -Portal aononudear ce ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild -Vascular aineralization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild -Acinar atrophy, a ild -Not exaained, not in plane of section -Adenoaa -P ro s ta titis , acute, suppurative, B ile -HeaangiosarcoBa The follow ing tissues ere found tc be ith in noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Head, Stoaach, Saal! Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric) Salivary Eland, Eye. Anisal Nueter; 1R-35C3 Sex: Male Fate: (Keek- 8E) Found Dead Group: ( 1) CONTROL 0 pps Macroscopic Observations: Adrenal Microscopic Observations: Adrenal Eye Heart Kidney Large Intestine Liver Lung Lyaph Node (aesenteric) -L e ft enlarged by a 1 ca dia. aass. -Sinusoidal ectasia, cortex, a ild PheochroaocytDaa, benign, u n ila te ra l -Not exaained, aissing -M yocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, a ild -Not exaained, aissing -Portal aononudear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , aoderate Hepatocyte vacuolation, a u ltifo c a l, a ild Necrosis, a u ltifo c a l, a ild -Vascular aineralization, a ild -Not exaained, aissing Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page! 44 20 000595 Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3553 Sex: Hale Fate: <Heek= 68) Found Dead Group.' ( 1) CONTROL 0 ppa Microscopic Observations (continued): Pancreas P itu ita ry Salivary 61and Saall Intestine -Not exaained, aissing -Cyst, pars d is ta lis -Not exaained, aissing -Not exaained, aissing The follow ing tissues were Pound to be within noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Stoaach, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, Thyroid, Parathyroid, Trachea, Esophagus. Aniaal Nuaber: 1R-3554 Sex: Hale Fate: (Week= 106) Terainal S a crifice 6roup: ! II CONTROL 0 ppa Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Parathyroid Prostate -No v is ib le lesions. -Chronic progressive nephropathy, soderate -Portal aononudear c e ll in f ilt r a t e , ai Id Portal b ile duct p ro life ra tio n , a ild Hepatocyte a lte ra tio n , vacuolated, a ild -Alveolar aacrophages, a u lti fo ca l, aoderate Perivascular aononudear in f ilt r a t e , aoderate Vascular B ineraiization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, aoderate -Not exaained, not in plane of section - P r o s ta titis , acute, suppurative, aoderate The follow ing tissues were found to be within nortal l ia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Acrta, T e stis/Epididyais, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node iaesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: R-3555 Sex: Male 6roup: ( 1) CONTROL 0 ppa Fate: (Heek= 102) Sacrificed in extreais Macroscopic Observations: Kidney Urinary Bladder Microscopic Observations: Adrenal -Pale, enlarged; a ild hydronephrosis. -Enlarged, f lu id f ille d , wall appears heaorrhagic. -C o rtic a l vacuolation, loca l areas, aoderate Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 45 209 000596 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3555 Sex: Hale Group: ( 1) CONTROL 0 ppi Fate: (Week- 102) S acrificed in extreais Microscopic Observations (continued): Aorta Heart kidney Liver Lung Parathyroid Prostate Saall Intestine Spleen Stcaach Urinary Bladder -M in era liza tio n , ai Id -M yocarditis, chronic nonsuppurative, a u ltifo c a l, c i 1d -Nephrosis, tubular, aoderate P a p illa ry necrosis, aoderate Hydronephrosis, ai Id Tubules dilated with low, basophilic epitheliua, scattered aineralized tubules. -Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolation, a u ltifo c a l, a ild -Vascular aineralization, a ild Alveolar aacrophages, a ild Heaorrhage, fo c a l, a ild -Not exaained, not in plane of section -P ro s ta titis , acute, suppurative, a ild Edeaa, in t e r s it it ia l , aoderate -N ithin noraal lia it s Fetter than protocol nuaber -Heaosiderosis, a ild -Edeaa, subaucosal, aoderate -Heaorrhage, aarked E p ith e lia l hyperplasia, siaple, diffuse, aild C y s titis , acute, aoderate The follow ing tissu es were found to be within noraal l ia i t s : Brain, Spinal Cord, Bone Marrow, Large Intestine, T e stis/Ep id id yais, P itu ita ry , Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3556 Sex: Male Fate: <Heek= 106) Terainal S a c 'ific e Group: ( 1) CONTROL 0 ppa Macroscopic Observations: Adrenal Microscopic Observations: Adrenal Kidney Liver -Right enlarged by aass, 2 x 1 ca. -Carcinoaa, c o rtic a l, u n ilateral Large neoplasa, aostly n ecrotic. C e lls foaay, polyhedral arranged in cords and sheets. High a it o t ic a c tiv it y . M u ltiple lung aetasta5es. -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a te , a ild Portal b ile duct p ro life ra tio n , a ild Species: Rat Project Nuaber: 0281CR0012 _ Suaaarized STAR Page: 46 C 000597 Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-3556 Sex: Male Fate: (Week= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppi Microscopic Observations (continued): Lung - Parathyroid -Pneuionia, in t e r s t it ia l, chronic, a u ltifo c a l, ild Metastatic neoplasi Perivascular aononuclear in f ilt r a t e , aiId Vascular a in eralizatio n , a ild -Not exaiined, not in plane of section The follow ing tissues were found to be within ncrca! l i n t s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoiach, S ia ll Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis /E p id id y iis, Prostate, P itu ita ry , Thyroid, Trachea, Esophagus, Lyiph Node (esenteric!, Pancreas, Salivary Stand, Eye. A n iia l Nuiber: 1R-3557 Sex! Male Fate: (Keek= 106) T e n in a l S a c rific e 6roup: ( 1) CONTROL 0 ppi Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Thyroid -No v is ib le lesions. -Chronic progressive nephropathy, l i l d -Portal aononuclear c e ll in f ilt r a t e , l i l d Hepatocyte a lte ra tio n , vacuolated, aiId -Vascular m ineralization, a ild Pneuionia, in t e r s t it ia l, chronic, a u ltifo c a l, ild -Hyperplasia, C c e ll, a ild The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Farathyroid, Trachea, Esophagus, Lyaph Node laesen teric), Pancreas, Salivary Gland, Eye. A n iia l Nuaber: 1R-35SB Sex: Male Fate: (Neek= 106) Terainal S a c rific e Group! ( 11 CONTROL C ppi Macroscopic Observations: P itu ita ry Microscopic Observations: Adrenal Kidney Liver -Raised aass, 0.9 ca dia. -Sinusoidal ectasia, cortex, a ild -Chronic progressive nephropathy, a ild Calculus, pelvic, ainiaal -Cystoid degeneration, fo ca l, a in ia a l Species: Rat Project Nuaber: 02B1CR012 Suaaarized STAR Page: 47 211 G00S98 Sueaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riicer Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-355B Sex! Male Fate: (Week= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Microscopic Observations (continued!: Parathyroid P itu ita ry Spleen -Not exaained, not in plane of section -Adenora -Heaosiderosis, a ild The follow ing tissues were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Harrow, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Epididyais, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3560 Sex; Male Group: i 1) CONTROL 0 ppa Fate: (Heek= 35) S acrificed in extreais Macroscopic Observations: Brain Lung Spleen Lyaph Node (abdoainal) Liver Microscopic Observations: Brain Liver Lung Lyaph Node (aesenteric) Saall Intestine Spleen -Focal circuascribed dark area, dorsal surface, le ft cerebral heaisphere (0.2 ca dia.) and la te ra l surface of rig h t cerebral heaisphere (0.2 ca dia.) -Oark red diffuse a o ttlin g , a ll lobes; red frcthy exudate at trachea. -Enlarged -Hepatic and renal nodes enlarged. -Pale, appears enlarged. -Abscess, a ild Heaorrhage, a u ltifo c a l, aoderate -Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic Heaorrhage, d iffu se, narked Necrosis, local areas, narked -Heaorrhage, ainiaal -Within noraal lia it s Fewer than protocol nuaber -Heaatopciesis, extraaedullary, increased, ' aarked The follow ing tissues were found to be within noraal lia it s : Spinal Cord, Bone Harrow, Kidney, Heart, Stoaach, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 48 212 000599 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143; Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3561 Sex: Male Fate: (heel- 106) Terainal S a c rific e Broup: ( 1) CONTROL 0 ppa Macroscopic Observations: . .. Soft Tissues (leg! kidney Microscopic Observations: Adrenal Bone Bone Marrow Kidney Large Intestine Liver Lung Parathyroid P itu ita ry Spinal Cord Spleen Testi s/Epi didyais Thyroid .. -Right and le f t hindpaw and rig h t forepaa swollen. -Right kidney po lycystic. -C ortical vacuolation, a u ltifo c a l, a ild Medullary c e ll hyperplasia, a u ltifo c a l, a ild -A rth ritis , synovitis; jo in ts, hindleg, foreleg, aarked -Not exanined, aissing -Chronic progressive nephropathy, a ild Pelvic aineralization, a ild Cyst, c o rtic a l, u n ila te ra l, aarked -Necatodiasis, colon -Portal eononudear c e ll in filtr a t e , ai id Portal b ile duct p ro life ra tio n , a ild -Perivascular aoncnuclear in f ilt r a t e , a ild Vascular a in e ra liza tio n , a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild Heaorrhage, local areas, aoderate -Not exaained, aissing -Adenoaa -Not exaained, aissing -Heacsiderosis, a ild -Tubule atrophy, asperaatogenesis, aoderate P o ly a r te ritis , aarked -Not exaained, aissing The falloH ing tissues aere Found to be ai thin noraal lia it s : Brain, Heart, Stoaach, Saal 1 Intestine, Urinary Bladder, Aorta, Prostate, Trachea, Esophagus, Lvaph Node (aesenteric), Pancreas, Salivary Bland , Eye. Aniaal Nuaber: IR-3562 Sex: Hale Fate: (Week= 106) Terainal S a c rific e Broup: ( 1) CONTROL 0 ppa Macroscopic Observations: Skin Spleen Microscopic Observations: Adrenal -Raised ulcerated inflaaaed lesion, right rear footpad. -Several pale foci. -Nodular hyperplasia, cortex, u n ila te ra l, aoderate Species: Rat Project Nueber: 0281CR0012 Sunarized STAR Page: 49 2 000600 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuiber: 1R-3562 Sex: Hale Fate: (Heex= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppi Microscopic Observations (continued): Heart Kidney Large Intestine Liver Lung Parathyroid P itu ita ry Salivary Gland Skin -Myocarditis, chronic nonsuppurative, ultifo c a l, ai 1d -Chronic progressive nephropathy, ai 1d -Neaatodiasis, colon -Portal acnonudear c e ll in filtr a te , a ild -Vascular aineralization, aild Pneuaonia, in t e r s t it ia l, chronic, a ild Perivascular aononudear in filtr a t e , add -Not exaained, not in plane of section -Adenona -Not exaained, aissing -Pododeraatitis, ulcera tive, hindleg, Barked The follow ing tissues were found to be within noraal l i n t s : Brain, Spinal Cord, Bone Marrou, Spleen, Stoaach, Snail Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-3563 Sex: Male Fate: !Neek= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Macroscopic Observations: Thyroid Skin Microscopic Observations: Adrenal Brain Heart Kidney Liver Lung Pancreas P itu ita ry Prostate -One side enlarged, 1 x 0.B ca. -Mass, 1.7 x 1.4 ca, dorsal area. -C ortical vacuolation, a u ltifo c a l, a ild Sinusoidal ectasia, cortex, ainiaal -Astrocytoaa, benign Poorly defined lesion in basal area of cerebrua. Tuaor c e lls spindelate. -M yocarditis, chronic nonsuppurative, ultifocal, aild -Chronic progressive nephropathy, aoderate -Hepatocyte a lte ra tio n , ba sophilic, aoderate -Portal aononudear c e ll in f ilt r a t e , a ild Hepatocyte a lte ra tio n , vacuolated, aoderate Necrosis, local areas, aoderate -Vascular aineralization, a ild Perivascular aononudear in f ilt r a t e , a ild -Acinar atrophy, narked -Adenoaa - P r o s t a titis , acute, suppurative, aoderate Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 50 2 14 000601 SuMarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tmo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-3563 Sex: Male Fate: (Neek= 106) T e riin a l S a c rific e Broup: ( 1) CONTROL 0 ppi Microscopic Observations (continued): Skin Thyroid ' -Keratoacanthoia, back -C c e ll carcinota The fo l 1owing tissues were found to be Mithin nomai 1i l i ts: Spinal Cord, Bone MarroM, Spleen, Stotach, S ia li Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis /E p id id y iis, Parathyroid, Trachea, Esophagus, Lyiph Node (esenteric), Salivary Gland, Eye. A n iia l Nuiber: 1R-3564 Sex: Male Fate: (Neek= 106) T e riin a l S a c rific e Broup: ( 1) CONTROL 0 ppi Macroscopic Observations: Kidney Microscopic Observations: Adrenal Bone HarroM Heart Kidney Liver Lung Pancreas Parathyroid P itu ita ry Salivary Bland Spinal Cord T e s tis /E p id id y iis -Pale area in cortex of one kidney. -C ortical vacuolation, r u ltifo c a l, iiI d Medullary c e ll hyperplasia, lu lt if o c a l, oderate -Not exaiined, lis s in g -Myocarditis, chronic nonsuppurative, ultifocal, lild Myocardial fib r o s is , u ltifo c a l, ild -Chronic progressive nephropathy, derate Cyst, un ilateral, loderate Area of e u ltilo c u la r cysts in cortex with lip id change in surrounding parenchyia. -Portal b ile duct p ro life ra tio n , iiI d Hepatocyte vacuolation, u ltifo c a l, l i l d Portal aoncnudear c e ll in filtr a te , lild -Vascular lin e ra liz a tio n , ild -Not exaiined, lis s in g -Not exaiined, not in plane of section -Adenoia -Not exaiined, lis s in g -Not exaiined, lis s in g -M ineralization, focal, i i id The follow ing tissues were found to be Mithin nomai l i i i t s : Brain, Spleen, Stoiach, S ta ll Intestine , Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lyiph Node ( esenteric!, Eye. 9 Species: Rat Project Nuiber: 0281CR0012 Suaiarized STAR Page: SI . Z 15 000602 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: To Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3565 Sex: Rale Fate: (Meek: 84) Found Dead Macroscopic Observations: Skin Liver Microscopic Observations: Adrenal Aorta Esophagus Eye Kidney Large Intestine Liver Lung Lymph Node (aesenteric) Pancreas Parathyroid P itu ita ry Prostate Salivary SI and Skin Saall Intestine Spleen Thyroid Trachea Urinary Bladder 6roup: ( 1) CONTROL 0 ppa - -Large aass, 7 x 7 ca, scro tal area. -Pale -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -No diagnosis, inadequate section -Chronic progressive nephropathy, a ild -No diagnosis, inadequate section -Hepatocyte vacuolation, a u ltifo c a l, a ild Necrosis, a u lt if o c a l, aoderate -Vascular m ineralization, aild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Liposarcoaa The scrotal aass as coaposed of large, vacuolated aononudear c e lls . The degree of auto iysis aade diagnosis soaehat uncertain. -Not exaained, aissing -Heaatopoiesis, extraaedullary, increased, a ild -Net exaained, aissing -Not exaained, aissing -Not exaained, aissing The follow ing tissues ere Found to be ith in noraal lia it s : Brain, Spinal Cord, Bone Marro, Heart,, Stoaach, T estis/Epididyais. Aniaal Nuaber: 1R-3566 Sex: Male Fate: (Heek= 106) Terainal S a c rific e Broup: ( 1) CONTROL 0 ppa Macroscopic Observations: P itu ita ry Microscopic Observations: Adrenal Kidney -Sa a ll dark lesion. -Within noraal lia it s One of pa ir present -Chronic progressive nephropathy, a ild Species: Rat Project Nuaber: 0261CR0012 Suaaarized STAR Page: 52 2 16 000603 Summarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-U3: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuaber; IR-3566 Sex: Male Fate: (Week: 106) Terainal S a c rific e Sroup: ( 1) CONTROL 0 ppi Microscopic Observations (continued): Liver Lung Pancreas Parathyroid Spleen -Portal lononuclear c e ll in filt r a t e , l i l d Portal b ile duct p ro life ra tio n , n l d -Vascular m ineralization, s i 1d Perivascular aononudear in f ilt r a t e , l il d -P o ly a rte ritis , loderate -Not exaiined, not in plane of section -Hemosiderosis, a ild The follow ing tissues were found to be within normal lia it s : Brain, Spinal Cord, Eone Marrow, Large Intestine, Urinary Bladder, Aorta, T e stis /E p id id y iis, Prostate, P itu ita ry , Thyroid, Trachea, Lyeph Node laesenteric), Salivary Gland, Stomach, S ra ll Intestine, Heart, Eye, Esophagus. i l Nuaber: 1R-3567 Sex: Male (Neek.= 106) Terainal S a c rific e 6roup: ( 1) CONTROL 0 ppa Macroscopic Observations: Skin Spleen Microscopic Observations: Adrenal Kidney Liver Lung Skin Spleen -Raised papilloaa type aass on back; raised inflaaaed lesion, rig h t rear footpad. -Two pale fo c i. -C ortical vacuolation, a u ltifo ca l, a ild Nodular hyperplasia, cortex, fo ca l, a ild -Chronic progressive nephropathy, moderate -Portal mononuclear c e ll in f ilt r a t e , a ild -Vascular ain eralization , a ild Alveolar aacrophages, minimal Perivascular aononudear in filtr a t e , ainiaal -Pap illo aa, back Pododeraatitis, ulcera tive, hindleg, aarked -Necrosis, local areas, acderate The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node la esen teric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 9 Summarized STAR Page: 53 000604 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3569 Sex: Male Fate: (Week: 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Macroscopic Observations: Kidney Microscopic Observations: Adrenal Heart Kidney Liver Lung P itu ita ry T e s tis /E p id id y a is -B ila te ra lly enlarged; pale, pitted. -C ortical vacuolation, focal, ainiaal Sinusoidal ectasia, cortex, a ild Medullary c e ll hyperplasia, a u ltifo c a l, a: -M yocarditis, chronic nonsuppurative, au ltifocal, aild -Chronic progressive nephropathy, aarked -Portal aononudear c e ll in filtr a t e , a ild Hepatocyte vacuolation, a u ltifo c a l, a ild -Vascular aineralization, a ild Perivascular aononudear in filtr a t e , a ild -Hyperplasia, focal, pars d is ta lis , a ild - P o ly a r te ritis , aoderate The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, 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 Fate: (Week: 106) Terainal S a c rific e 6roup: ( 1) CONTROL 0 ppa Macroscopic Observations: Liver Kidney Mesentery Microscopic Observations: Adrenal Heart Kidney Liver Lung Mesentery Pancreas Parathyroid P itu ita ry -Pale -Pale, pitted, enlarged. -Mesenteric vessels thickened -Cortical vacuolation, focal, ainiaal -Myocarditis, chronic nonsuppurative, a u ltifo ca l, ainiaal -Chronic progressive nephropathy, narked -Portal aononudear c e ll in filtr a t e , a ild f o r t a l b ile duct p ro life ra tio n , a ild Hepatccyte vacuolation, a u ltifo c a l, a ild -Vascular mineralization, a ild Perivascular aononudear in filtr a t e , ainiaal - P o ly a r te ritis , aarked - P o ly a r te ritis , aarked -Not exaained, not in plane of section -Not exaained, aissing Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page! 54 218 000605 Sunaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tmo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-357I Sex: Male Fate: (Week- 106! Terainal S a c rific e Croup: ( 1) CONTROL 0 ppa Microscopic Observations (continued): S ta ll Intestine Spleen T e s tis /E p id id y a is -P o ly a r te ritis , aesentery, aarked -Heaosiderosi s, ai Id - P o ly a r te ritis , aarked The follow ing tissues were found to be a ith in noraal U n its : Brain, Spinal Cord, Bone Marrow, Stoaach, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3572 Sex: Male Fate: (Neek= 106) Terainal S a c rific e Group: ( I) CONTROL 0 ppa Macroscopic Observations: Microscopic Observations: Kidney Liver Lung Pancreas Parathyroid Stoaach -No v is ib le lesions. -Chronic progressive nephropathy, a in ia a l -Portal acnonudear c e ll in f ilt r a t e , ai Id Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuclation, a u ltifo c a l, a ild -Vascular aineralization, a ild -Hyperplasia, is le t c e ll, aoderate -Not exaained, not in plane of section -Not exaained, aissing The follow ing tissues were found to be Mithin noraal l ia i t s : . Brain, Spinal Cord, Bone Marrou, Spleen, Heart, Saall Intestine, Large Intestine, Urinary Eladder, Aorta, T e stis/Epididyais, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3573 Sex: Male Fate: (Neek= 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Macroscopic Observations: Pancreas Microscopic Observations: Adrenal Kidney Large Intestine Liver -S a a ll c irc u la r pale aass, 0.5 ca dia. -C ortical vacuolation, a u ltifo ca l, a ild Pheochroaocytoaa, benign, u n ila te ra l -Chronic progressive nephropathy, a ild -Neaatodiasis, colon -Hepatocyte a lte ra tio n , vacuolated, a ild Hepatocyte a lte ra tio n , baso philic, a ild Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolation, a u ltifo c a l, a ild Portal aononuclear c e ll in f ilt r a t e , a ild Species: Rat Project Nuaber: 02BICR0012 Suaaarized STAR Page: 55 219 000606 Suaearized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-H3: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A nnal Nueber: 1R-3S73 Sex: Hale Fate: (Heek= 10b) Terainal S a c rific e Sroup: ( 1) CONTROL 0 ppe Microscopic Observations (continued): Lung Pancreas Parathyroid -Vascular ein eralization , c ild Perivascular eononudear in filt r a t e , eiId -Acinar atrophy, eoderate Isle t c e ll adenoaa -Not exaained, not in plane of section The foIloM irg tissues vere found to be within noreal lia it s : Brain, Spinal Cord, Bone Narrow, Spleen, Heart,, Stoaach, Saall Intestine, Urinary Bladder, Aorta, Testis/Ep id id yeis, Prostate, P itu ita ry , Thyroid, Trachea, Esophagus, Lyeph Node (eesenterici, Salivary 61and, Eye. A n iia l Nueber: 1F-3574 Sex: Male Group: ! 1) CONTROL 0 ppe Fate: (HEek= 99) Sacrificed in extreeis Macroscopic Observations: Skin Thorax (internal) Heart Liver Kidney T e s tis /E p id id y e is Microscopic Observations: Adrenal Aorta Heart Kidney Liver Lung Lyeph Node (aesenteric) Pancreas Parathyroid -Ulcerated rig h t and le f t hind footpads; c irc u la r white subcutaneous aass, l.S ce d ia ., in rig h t inguinal area. - F ille d with flu id . -S lig h tly pale and fla c c id . -S lig h tly pale -Pale and pitted; 1.5 ce cyst in rig h t kidney. -Testes saall -C ortical vacuolation, e u ltifo c a l, a:Id -Necrosis, local areas, eoderate Unifore in tie a l necrosis with reactive cellu lar in filtra te . -Myocarditis, chronic nonsuppurative, a u ltifo cal, aild -Chronic progressive nephropathy, aarked Cyst, u n ila te ra l, aarked -Portal eononudear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild -Pneuaonia, in t e r s t it ia l, chronic, diffuse, eoderate Perivascular aononudear in f ilt r a t e , a ild Edena, loca l areas, aarked -Not exaained, aissing -Acinar atrophy, a ild -Not exaained, not in plane of section Species: Rat Project Nuiber: Q2B1CR0012 Sunarlzed STAR Page: 5i 220 000607 Summarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuiber: 1R-3574 Sex! Male Group: ( 1) CONTROL 0 ppi Fate: (Neek= 99) S acrificed in extreeis Microscopic Observations (continued): P itu ita ry Prostate Salivary Eland Skin T e s tis /E p id id y iis -Cyst, pars intermedia -P ro s ta titis , acute, suppurative, derate -Not examined, missing -Fibroma, subcutaneous, inguinal Pododermatitis, ulcera tive, hindleg, marked -Tubule atrophy, aspermatogenesis, b ila te r a l, moderate The follow ing tissues mere found to be within normal lim its : Brain, Spinal Cord, Bone Harrow, Spleen, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Thyroid, Trachea, Esophagus, Eye. Aniaal Number: 1R-3576 Sex: Male 6roup: I 1) CONTROL 0 ppm Fate: !Neek= 55) Sacrificed in extremis Macroscopic Observations: Skin Abdomen (internal) Microscopic Observations: Kidney Lung Parathyroid Spleen Urinary Bladder -Moist area around genital p a p illa . -Large amount of gas in gastro in testinal tra ct; no food in stomach. -P e lv ic m ineralization, mild -Hemorrhage, diffuse, marked -Not examined, not in plane of section -Hemosiderosis, mild -Not examined, missing The tallowing tissues mere found to be within normal lim its : Brain, Spinal Cord, Bone Harrow, Liver, Heart, Stomach, Small Intestine, Large Intestine, Aorta, Testis/Epididym is, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. Aniaal Number: 1R-3577 Sex'. Male Fate: (tieek= 106) Terminal S a c rific e 6roup: < 1) CONTROL 0 ppi Macroscopic Observations: Microscopic Observations: Kidney Li ver -No v is ib le lesions. -Chronic progressive nephropathy, moderate -Portal mononuclear c e ll in f ilt r a t e , mild Portal b ile duct p ro life ra tio n , mild Hepatocyte vacuolation, m u ltifo ca l, mild Cystoid degeneration, m u ltifo ca l, mild Hepatocyte a lte ra tio n , vacuolated, mild Species: Rat Project Number: 02B1CR0012 Summarized STAR Page: 57 221 000608 Suaaarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 5M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuaber: 1R-3577 Sex: Hale Fate: (Meek1 106) Terainal S a c rific e Group: ( 1) CONTROL 0 ppa Microscopic Observations (continued): Lung Mesentery Pancreas Seal! Intestine Spleen Thyroid -Vascular aineralization, a ild - P o ly a r te ritis , aarlted - P o ly a r te ritis , aarked - P o ly a r te ritis , aesentery, aoderate -Heacsidercsis, a ild -Cyst, co llo id , aild The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuaber: 1R-357B Sex: Hale Fate: (Neek= 106) Terainal S a crific e Broup: ( 1) CONTROL 0 ppa Macroscopic Observations: P itu ita ry Skin Microscopic Observations: Kidney Liver Lung P itu ita ry Prostate Salivary Gland Skin -Heaorrhagic tass, 0.7 ca dia. -Raised ulcerated inflaaaed lesion, 1.5 ca d ia ., le f t hind footpad. -Chronic progressive nephropathy, a ild Hydronephrosis, u n ila te ra l, aoderate C a lcu li present in ureter of hydronephrotic kidney. -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 -Vascular aineralization, a ild Heaorrhage, loca l areas, aoderate -Adenoaa - P r o s t a titis , acute, suppurative, aoderate -S ia la d e n itis, chronic, ainiaal Very a in ia a l lesio n , only one duct affected. -Pododeraatitis, u lcera tive, hindleg, aarked The follow ing tissu es were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: SB 222 000609 Suuarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Rileer Laboratories, Inc. 3M FC-143: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-3579 Sex: Male Group: ( 1) CONTROL 0 ppi Fate! (Heek= B6) Sacrificed in e x tre iis Macroscopic Observations: P itu ita ry Liver Skin Microscopic Observations: Kidney Liver Lung Farathyroid P itu ita ry Skin S ia ll Intestine Spleen Testis/Epi d id yii s -Raised la ss, O.B c i dia. -Raised pale 2 c i dia. la ss in right lateral lobe. -Mass seen c lin ic a lly on rig h t side appears to be healed lesion. -Chronic progressive nephropathy, arked -Portal b ile duct p ro life ra tio n , l i l d Hepatocellular carcinoia Portal sononudear c e ll in filt r a t e , BiId -Perivascular lononudear in filtr a t e , liI d -Not exauineb, not in plane of section -Adenoia -Keratoacanthoia Skin lesion f r o i rig h t side. -Nithin norial lia it s Fewer than protocol nuiber -Heosidero5i5, iiI d -Tubule atrophy, aspenatogenesis, u n ila te ra l, ild Polyarteritis, lild The following tissues were found to be within noria! l i i i t s : Brain, Spinal Cord, Bone Marrow, Heart, Stoiach, Large Intestine, Urinary Bladder, Aorta, Prostate, Adrenal, Thyroid, Trachea, Esophagus, Lyiph Node (le se n te ric ), Pancreas, Salivary Eland, Eye. A n iia l Nuiber: 1R-4576 Sex: Fetale Group: ( 1) CONTROL 0 ppi Fate: (HeeK= 25! Sacrificed in e x tr e iis Macroscopic Observations: Liver Lyiph Node (bronchia!) Lung Spleen Stciach Lyiph Node (lesenteric) Microscopic Observations: Adrenal Bone Marrow Kidney -Enlarged; lo ttle d yellow color. -Enlarged -Pale -Enlarged -Red patchy areas on aucosa. -Enlarged and reddened. -Sinusoidal ectasia, cortex, l i l d -Malignant lyiphoia, lyaphocytic -Malignant lyiphoia, lyaphocytic M ineralization, co rtica l, iiI d Species: Rat Project Nuiber: 02B1CR0012 Suuarized STAR Page: 59 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4576 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 25) S acrificed 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, a u ltifo c a l, a ild -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Not exaained, aissing -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Ulcer -E p ith e lia l hyperplasia, siapie, diffuse, a ild The FgI lowing tissues aere found tc be within noraal lia it s : Brain, Heart, Snail Intestine, Large Intestine, Aorta, Uterus, Ovary, Maaaary Gland, P itu ita ry , Trachea, Thyroid, Parathyroid, Esophagus, Eye. Aniaal Nuaber: 1R-4577 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: !Heek= 99! Found Dead Macroscopic Observations: P itu ita ry Maaaary Eland Microscopic Observations: Adrenal Kidney Liver Lyaph Node (aesenteric) Maaaary Gland P itu ita ry Spleen Uterus -Heaorrhagic aass, O.B ca dia. -M u ltilo b u la r aass, 4.5 x 3.5 x 2 ca, in rig ht axilla . -Sinusoidal ectasia, cortex, Moderate -Pelvic M ineralization, a ild Nephrosis, tubular, aarked -Portal aononudear c e ll in filtr 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 -Not exaained, aissing -Lobular hyperplasia -Heaorrhage, aarked Necrosis, Moderate -Hecosiderosis, a ild -C ystic glands, Moderate The follow ing tissues were found to be Mithin noraal l ia it s : Brain, Spinal Cord, Bone Marroa, Heart, Lung, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Thyroid, Parathyroid, Esophagus, Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: &0 224 000611 Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Ani al Nunber: 1R-4579 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Keek 84) Sacrificed in extreais Macroscopic Observations: P itu ita ry Skin Liver Stoaach Kidney Microscopic Observations: Adrenal Ao'ta Heart Kidney Liver Lung Lvaph Node (aesenteric) Parathyroid F itu ita ry Skin Spleen Stoaach -Raised aass, 0.5 ca dia. -Raised thickened lesion with scab on rig ht side. -S lig h tly pale -Soiewhat reddened -F lu id f ille d cyst in le f t kidney. -Sinusoidal ectasia, cortex, a ild -M ineralization, a u ltifo ca l, aild -Myocarditis, chronic nonsuppurative, a u ltifo c a l, aoderate -Nephrosis, tubular P elvic a in e ra liza tio n , aarked Cyst, c o rtic a l, aoderate Hyperplasia, pelvic epitheliua, diffuse, a ild -Hepatocyte vacuolation, a u ltifo c a l, a ild -Vascular aineralization, aild -Not exaained, aissing -Not exaained, not in plane of section -Adenona -U lcer, aarked Skin lesion froa side. -Heaosiderosis, a ild -M ineralization, aucosal, a ild The follow ing tissues were found to be within noraal liaits*. Grain, Spinal Cord, Bone Marrow, Saal! Intestine, Large Intestine, Urinary Bladder, Uterus, Ovary, Maaeary Gland, Trachea, Thyroid, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-45B0 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week 52) Sacrificed in extreais Macroscopic Observations: P itu ita ry Microscopic Observations: Adrenal Aorta Esophagus Lyaph Node (aesenteric) Maaaary 61and Parathyroid -Enlarged; dark red aass, C.5 ca dia. -Sinusoidal ectasia, cortex, e ild -Not exaained, aissing -Not exaained, aissing -Not exaained, aissing -Galactocele -Not exaained, not in plane of section Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 61 225 000612 Sueaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tea Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A m a i Nuaber: 1R-4580 Sex! Fetale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 52) S acrificed in extreais Microscopic Observations (continued): P itu ita ry Spleen -Adenoaa -Heaosiderosis, aoderate The follow ing tissues were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Liver, Kidney, Heart, Lung, Stoaach, S ta ll Intestine, Large Intestine, Urinary Bladder, Uterus, Dvar y, Trachea, Thyroid, Pancreas, Salivary Blar.d, Eye. Anita! Nuaber: 1R-45B1 Sex: Fetale Group: ( 1) CONTROL 0 ppa Fate: (Neek= E5: Sacrificed in extreais Macroscopic Observations: Hateary Gland Liver Spleen Microscopic Observations: Adrenal Liver Lung Maaaary Gland Parathyroid Spleen -Ulcerated aass, 6 x 6 x 3 ca behind rig h t shoulder. -Po ssibly s lig h t ly pale and swollen. -Enlarged -Sinusoidal ectasia, cortex -Portal aononudear c e ll in filtr a te , aild Hepatocyte v a lid a t io n , a u ltifo c a l, a ild Hepatocyte a lte ra tio n , basophilic, a ild Heiatopoiesis, extraaedullary, a ild -Vascular nineralization, aild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild -Adenocarcinoaa -Not exaained, not in plane of section -Heaatopoiesis, extraaedullary, increased, aarked The follow ing tissues were found to be within noraal lia it s : Brain, Spina! Cord, Bone Marrow, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, P itu ita ry , Trachea, Thyroid, Esophagus, Lytph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4583 Sex: Feaaie Group: ( 1) CONTROL 0 ppa Fate: (Neel 105) Terainal S a c rific e Macroscopic Observations: Eye Maaaary Gland -Extensive post bleeding in flaaaatio n of rig h t eye. -F ira nodular aass, 6 x 5 x 3 ca, le f t inguinal. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 62 0 000613 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FC-143: Tho Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-45B3 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Tereinal S a c rific e Microscopic Observations (continued): Adrenal Eye Kidney Liver Lung Maaaary Gland Ovary Parathyroid Spleen Uterus -Sinusoidal ectasia, cortex, aarked -Panophthalaitis, u n ila te ra l, aarked -Pelvic aineralization, aild Chronic progressive nephropathy, a in ia a l -Hepatocyte vacuolation, a u ltifo c a l, a ild Necrosis, focal, aild -Alveolar aacrcphages, a ild Perivascular aononudear in f ilt r a t e , a ild -Fibroadenoaa -Tubular adenoaa, u n ila te ra l -Not exaained, not in plane of section -Heaatopoiesis, extraaedullary, increased, aoderate -C ystic glands, aarked The fo llo x in g tissu es were Found to be within n o n a l l i n t s ! Brain, Spina! Cord, Bone Marro*, Heart, Stcaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, P itu ita ry , Trachea, Thyroid, Esophagus, Lyaph Node (eesenteric), Pancreas, Salivary Gland. Aniaal Nuiber: 1R-4584 Sex! Feiale Group: ! 1) CONTROL 0 ppa Fate: (Neek= 105) Tereinal S a c rific e Macroscopic Observations! Eye P itu ita ry Adrenal Microscopic Observations: Adrenal Eye Heart Kidney Liver Lung Parathyroid -S lig h t atrophy with corneal opacity, rig ht eye. -Enlarged -Left adrenal enlarged. -Sinusoidal ectasia, cortex -Phthsis bulbi, aoderate -Myocarditis, chronic nonsuppurative, a u ltifo cal, aild -Chronic progressive nephropathy, a ild -Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolation, a u ltifo c a l, a ild -Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild Perivascular aononudear in filtr a t e , a ild Heaorrhage, loca l areas, a ild -Not exaained, not in plane of section Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 63 007 227 000614 Suiaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-45B4 Sex: Feiale Group: ( 11 CONTROL 0 ppi Fate: (Neek= 105) Tereinal S a c rific e Microscopic Observations (continued): P itu ita ry Spleen -Adenoia -Heiosiderosis, iiI d The follow ing tissues were found to be within n o ria l l ia it s : Brain, Spinal Cord, Bone Harrow, Stoaach, Seal 1 Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Mairary Gland, Trachea, Thyroid, Esophagus, Lyeph Node (eesenteric), Fancreas, Salivary Gland. Anita! Number: 1R-45B6 Sex: Fetale Group: ! 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal S a c rific e Macroscopic Observations: P itu ita ry Uterus Microscopic Observations: Adrenal Kidney Liver Lung Ovary Pancreas Parathyroid P itu ita ry Uterus -Raised dark aass, 0.5 c i dia. -Dark area, 0.5 x 0.5 ca, in le f t horn near cervix. -Sinusoidal ectasia, cortex, wild -Chronic progressive nephropathy, a ild Pelvic aineralization, a ild -Porta! aononudear c e ll in filtr a t e , aild Portal b ile duct p ro life ra tio n , a ild Hepatocyte a lte ra tio n , vacuolated, a ild -Perivascular aononudear in filtr a t e , ainiaal -Not exaained, aissing -Acinar atrophy, aoderate -Not exaained, not in plane of section -Adenoaa -C ystic glands, aarked The follow ing tissues were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Naaaary Gland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Salivary Gland, Eye. Aniaal Nuiber: 1R-45B7 Sex: Feiale 6roup: ( 1) CONTROL 0 ppi Fate: (Heek= 105) T e riin a l S a c rific e Macroscopic Observations: Hauary Gland - S ia ll nodular la ss, 3 x 2 c i, a x illa r y ; large ass, 8 x 6 x 3 c i, throat area. Species: Rat Project Nuiber: 0281CR0012 Suuarized STAR Page: 64 000615 Suetarized Single Tabulated A nital Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anital Nutber: 1R-45B7 Sex! Fetale Group: ( 1) CONTROL 0 ppt Fate: (Week= 105) Tertinal S a crific e Microscopic Observations (continued): Adrenal Heart Kidney Liver Haatary Bland Parathyroid Salivary Eland Skin Spleen Uterus - -Sinusoidal ectasia, cortex, larked -Myocarditis, chronic nonsuppurative, tu ltifo ca l, tild -Chronic progressive nephropathy, t il d Pelvic tin e ralizatio n , im ita i -Hepatocyte vacuolation, t u lt if o c a l, t in it a l -Lobular hyperplasia -Not exatined, not in plane of section -Not exatined, tis s in g -FibroEa, subcutaneous -Hetosiderosis, t ild -Within nortal l i t i t s Fewer than protocol nutber The follow ing tissues were found to be within nortal l ia it s : Brain, Spinal Cord, Bone Harrow, Lung, Stonach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, P itu ita ry , Trachea, Thyroid, Esophagus, Lytph Node (tesenteric), Pancreas, Eye. Anital Nunber: 1R-4591 Sex: Fetale Group: ( 1) CONTROL 0 ppt Fate: (Heek= 105) Tertinal S a c rific e Macroscopic Observations: Microscopic Observations: Adrenal Kidney Liver Lung Lytph Node (tesenteric) Pancreas Parathyroid P itu ita ry -No v is ib le lesions. -C ortical vacuolation, local areas, toderate Sinusoidal ectasia, cortex, t in it a l -Chronic progressive nephropathy, t in it a l -Portal tononudear c e ll in filtra te , t ild Hepatocyte a lte ra tio n , vacuolated, t il d -Vascular tin e ra liza tio n , t ild -Not exatined, tis s in g -Acinar atrophy, focal, t in it a l -Not exatined, not in plane of section -Adenona The follow ing tissu es were found to be within nortal l i t i t s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoiach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Nattary Gland, Trachea, Thyroid, Esophagus, Salivary Gland, Eye. Species: Rat Project Nutber: 02B1CR0012 Suttarized STAR Page: 65 229 G00616 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations R ite r Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4592 Sex: Feaale Broup: ( 1) CONTROL 0 ppa Fate: (Week= 8B) Found Dead Macroscopic Observations: P itu ita ry Microscopic Observations: Adrenal Kidney Liver Lung Lyaph Node (aesenteric) Maaaary Bland Parathyroid P itu ita ry Spleen -Enlarged, 0.9 x 1 ca. -Sinusoidal ectasia, cortex, soder ate -Chronic progressive nephropathy, ain ie a l -Hepatocyte vacuolation, a u lti-fo ca l, a ild -Vascular aineralization, a ild Perivascular aononudear in filtr a t e , a ild -Not exaained, aissing -Lobular hyperplasia, aoderate -Not exaained, not in plane of section -Adenoaa -Heaosidero5is, a ild The f o il awing tissues were found to be within noraal 1i a its: Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thy-oid, Esophagus, Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-4593 Sex: Feaale Broup: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal S a c rific e Macroscopic Observations: Microscopic Observations'. Adrenal Liver Lung Parathyroid -No v is ib le lesions. -Sinusoidal ectasia, cortex, larked -Hepatocyte a lte ra tio n , vacuolated, a ild Hepatocyte a lte ra tio n , basophilic, a ild -Vascular a in e ra liza tio n , a ild Not exaained, not in plane of section The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maaaary Bland, P itu ita ry , Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaanzed STAR Page: 6b 230 000617 S u m m e d Single Tabulated A n ita l Report (continued) Individual Hacroscopic and Ricroscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4594 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 79) Found Dead Hacroscopic Observations: Kidney Urinary Bladder P itu ita ry Ricroscopic Observations: Adrenal Aorta Kidney Liver Lung Lyaph Node (aesenteric) Ovary Pancreas Parathyroid P itu ita ry Saall Intestine Spleen Urinary Bladder - -Right kidney appears s lig h t ly enlarged; f ille d with yellow a ilk y flu id . -Enlarged, 4.5 x 2 ca, f i ll e d with large, hard c a lc u li. -Heaorrhagic aass, 0.9 x 0.6 ca -Sinusoidal ectasia, cortex, aoderate One of pair present -Not exaamed, aissing -Pyelonephritis, acute, b ila te r a l, aoderate Hydronephrosis, b ila te r a l, aoderate Nephrosis, tubular, b ila te r a l, aoderate -Hepatocyte a lte ra tio n , vacuolated, a ild -Vascular aineralization, a ild -Not exaained, aissing -Within noraal l ia i t s One of pair present -Not exaained, aissing -Not exaained, not in plane of section -Adenona -Not exaained, aissing -Heacsiderosis, aoderate -E p ith e lia l hyperplasia, p a p illary, diffuse, aarked Calculus The following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Heart, Stoaach, Large Intestine, Uterus, Haaaary Bland, Trachea, Thyroid, Esophagus, Salivary Gland, Eye. Aniaal Nuaber: 1R-4595 Sex: Feaale Group: ( 11 CONTROL 0 ppa Fate: (Neek= 105) Terainal S a c rific e Hacroscopic Observations: P itu ita ry Haaaary Gland Pancreas Ricroscopic Observations: Adrenal -Heaorrhagic aass, 0.8 ca dia. -Sa a ll lobular aass, 2.7 x 1.5 x 1.8 c i, le f t axilla . -Sa a ll lobular aass, 1 x 0.7 ca, in area of pancreas. -Sinusoidal ectasia, cortex, aoderate Species: Rat Project Nuaber: 0281CR0012 Sueaarized STAR Page: 67 231 C00618 Sunnarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Tec Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-4595 Sex: Fetale Group: ( 1) CONTROL 0 ppi Fate: (Heek= 105) T e n in a l S a c rific e BEST COPY AVAILABLE Microscopic Observations (continued): Kidney Liver Lon; Masf.ary Gland Pancreas Parathyroid P itu ita ry Ute-us -Chronic progressive nephropathy, l i n i i a l -Portal nononuclea- c e ll in f ilt r a t e , :ld Portal t i l e duct p ro life -a tic * , d i d Hepatccyta a lte ra tio n , vacuolated, l i l d -Alveolar eacroph.ages, ni Id -Lobular hyperplasia -Is le t c e ll carcinoaa P a r tia lly encapsulated with invasion of capsule. Nell differentiated. -Not exasired, not in plane of section -Adenosa -Adsnoia Snail circuiscribed pap illary lesion. The follow ing tissu es we-e Pound to be within nornal U n its : Brain, Spinal Cord, Eone Marrow, Spleen, Heart, Stoeach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Trachea, Thyroid, Esophagus, Lymph' Node (mesenteric), Saliva-y Gland, Eye, Ovary. finical Sunken: 1R-4596 Sex: Fetale Group: ( ) CONTROL 0 ppn Fate: !Nee)= 78) Sacrificed in extrenis Mac- oscopic Observations: pr ii Iw mu i w o 1 ) Massary Eland LiveKidney Adrenal Microscopic Observations: Adrenal Aorta Kidney Liver -Mass, 0.B s O.o ct. -Mass, 2.5 x 2 x 1.5 ce, in le f t a x illa . -Very pale - B ila te r a lly pale and pitted; s lig h t ly enlarged! 0.4 cs dia. cyst ir, rig h t. -Pale, b ila te ra lly -C o rtica l vacuolation, fo ca l, noderate Sinusoidal ectasia, cortex, noderate Medullary c e ll hyperplasia, n u ltifo o a l, mild C o rtica l degeneration, local areas, noderate -M ineralization, c ild M ineralization also in nedia of an e la s tic artery in section of nesentery subnitted for nesenteric lymph node. -Chronic progressive nephropathy, narked Cyst, c o rtic a l, noderate -Hepatocyte vacuolation, d iffu s e , narked Species: Rat Project Nunber: 02B1CR0012 Sunnarized STAR Page: 6B C.DL. 000619 Suasarized Single Tabulated Anna! Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study tn Rats Table: 2 Aniaal Nuabe-: 1R-4596 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 78) S acrificed in extreais Microscopic Observations (continued): Lung Lyaph Node (aesenteric) Maaaary Bland Pa-athyroid P itu ita ry Salivary Bland Spleen Urinary Bladder -Vascular ain e ra liza tio n , wild Alveolar aacrophages, aim aal -Not exaained, eissm g -Fibroadenoaa -Not exaained, not in plane of section -Adenoaa -Not exaained, aissing -Heeosiderosis, aoderate -E p ith e lia l hyperplasia, staple, diffuse, aild The follow ing tissues were found to be within noraal lim its : 6-ain, Spinal Cord, Bone Marrow, Heart, Stomach, Saall Intestine, Large Intestine, Uterus, Ovary, Trachea, Thyroid, Esophagus, Pancreas, Eye. Aniaal Nuaber: IP-4597 Sex: Feaale 6roup: I 1! CONTROL 0 ppa Fate: ilseek= 105) Terainal S a c rific e Macroscopic Observations: Adrenal Microscopic Observations: Adrenal kidney Liver Lung Lyaph Node (aesenteric) Ovar y Pancreas Parathyroid Spleen Uterus -Right adrenal enlarged. -Sinusoidal ectasia, cortex, aarked Medullary c e ll hyperplasia, fo c a l, a ild -Chronic progressive nephropathy, a in ia a l Pelvic mineralization, a ild -Portal aononuclear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild -Alveolar aacrophages, a ild Perivascular aononuclear in f ilt r a t e , a ild -No diagnosis, inadequate section -Tubular adenoaa, u n ila te ra l -Cyst -Not exaained, not in plane of section -Heaosiderosis, a ild -Nithin noraal lia it s Fewer than protocol nuaber The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Haaaary Gland, P itu ita ry , Trachea, Thyrcid, Esophagus, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR012 Suaaarized STAR Page: 69 Su m arized Single Tabulated Anital Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: T*o Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A nnal Nutber: 1R-459B Sex: Fetale Group: ( 1) CONTROL 0 ppt Fate: (Heek= 105) Tertinal S a crific e Macroscopic Observations: P itu ita ry Adrenal Microscopic Observations: Adrenal Brain Heart Kidney Liver Lung Ovary Pancreas Parathyroid PituitaryUterus -Mass, 0.7 c i dia. -Lett adrenal greatly enlarged. -Sinusoidal ectasia, cortex, larked -Oligodendrogliota, benign -Myocarditis, chronic nonsuppurative, ultifocal, tild -Chronic progressive nephropathy, de-ate Pelvic tin e ralization , t ild Hyperplasia, pelvic e p ith e liu i, local areas, ild -Hepatocyte vacuolation, u ltifo c a l, t ild Hepatocyte a lte ra tio n , basophilic, t ild -Vascular eineralization, t ild Perivascular tononudear in filtr a t e , t ild -Tubular adenota -Acinar atrophy, derate -Not exatined, not in plane of section -Adenota -Cystic glands, derate The follow ing tissues were found to be within no rial l i i i t s : Spinal Cord, Bone Marrot, Spleen, Stooach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Nattary Bland, Trachea, Thyroid, Esophagus, Lytph Node (te se n te ric!, Salivary Gland. Eye. Anita! Nuaber: 1R-4599 Sex: Fetale Group: ! 1) CONTROL 0 ppt Fate: (Neek= 102! Found Dead Macroscopic Observations: Mattary Eland Liver Stoaach Urinary Bladder Eye Microscopic Observations: Adrenal Aorta Esophagus Eye -Subcutaneous tass, 2.5 x 2 x 1 c t, in perinea! area. -Appears settled -Areas of enlongated ulceration. -Thickened a lls! tass 1.5 x 1 c t, with adhesions to abdotinal t a ll . -No tissue taken due to p o s tio rte i changes -Sinusoidal ectasia, cortex, tarked -Malignant lytphota, h is tio c y tic -Malignant lyaphcaa, h is tio c y tic -Not exatined, tis s in g Species: Rat Project Nutber: 02B1CR0C12 Suetan zed STAR Page: 70 234 000621 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Rite'" Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-4599 Sex: Feeale 6roup: ( 1) CONTROL 0 ppa Fate: (Neek= 102) Found Dead Microscooic Observations (continued): Heart Kidney Large Intestine Liver Lung Lyaph Node (aeser.teric) Maaiary Gland Ovary Pancreas Parathyroid P itu ita ry Spleen Stcaach Thyroid Urinary Bladder Uterus -Myocarditis, chronic nonsuppurative, au ltifo ca l, aild -Malignant lyaphoaa, h is tio c y tic Pelvic aineralization, aild Hyperplasia, pelvic epitheliua, local areas, a ild Nephrosis, tubular, a ild -Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic Necrosis, local areas, aarked -Malignant lyaphoaa, h is tio c y tic Heaorrhage, a u ltifo c a l, a ild -Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic -Net exaaineb, not in plane of section -Adenoaa -Heaosiderosis, a ild -Necrosis, aucosal, aoderate -Malignant lyaphoaa, h is tio c y tic -Malignant lyaphoaa, h is tio c y tic E p ith e lia l hyperplasia, siaple, diffuse, t ild -Malignant lyaphoaa, h is tio c y tic The fo llo * in g tissues were found to be a ith in norial lia it s : Brain, Spinal Cord, Bone Marroa, Saall Intestine, Trachea, Salivary Gland, Aniaal Nuaber: 1R-4600 Sex: Feiale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 99' Found Dead Macroscopic Observations: Maaaary Gland Liver Microscopic Observations: Adrenal Eye Heart -Subcutaneous c y stic Bass, 4 x 3.5 x 2 ca, in region of throat; subcutaneous au ltilob u lar aass, 5 x 4 x 2 ca, in right a x illa . -Appears Bottled -Necrosis, u n ila te ra l, aarked -Not exaained, aissing -Myocarditis, chronic nonsuppurative, au ltifocal, aild Species: Rat Project Nuiber: 02B1CR012 Suaaarized STAR Page: 71 COD 000622 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral To*icity-Oncngenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4OO Sex: Feaale Broup: ( 1) CONTROL 0 ppa Fate: (Neek= 99) Found Dead Microscopic Observations (continued): Kidney Liver Lung Maaaary Bland Ovary Parathyroid P itu ita ry Spleen -Chronic progressive nephropathy, a ild Pelvic aineralization, aild Nephrosis, tubular, aoderate -Portal aononudear c e ll in -filtra te , aoderate Portal b ile duct p ro life ra tio n , a ild Mepatocyte vacuo!ation, a u lt if o c a l, a ild Hepatocyte a lte ra tio n , e o sin o p h ilic, aoderate Telangiectasis, aild -Vascular aineralization, a ild -Adenoaa, p a p illa ry Lobular hyperplasia -Cyst, unilateral -Not exaained, not in plane of section -Adenoaa -Heaosiderosis, a ild The follow ing tissues Here found tc be within norsal l ia it s : Brain, Spinal Cord, Bone Marrow, Stoaach, Sea'! 1 Intestine, Large Intestine, Urinary Bladder, Ao-ta, Uterus, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland. Anisal Nuiber: 1R-4602 Sex: Feaale 6roup ( 1) CONTROL 0 ppa Fate: (Week= 105! T e riin a l S a c rific e Macroscopic Observations: Eye P itu ita ry Adrenal Kidney Microscopic Observations: Adrenal Eye Heart Kidney Liver Lung Parathyroid P itu ita ry -Cornea appears cloudy. -Raised aass, ! ca dia. -Right adrenal enlarged. -Pale and pitted . -Sinusoidal ectasia, cortex, aarked C o rtica l degeneration, d iffu se , aarked -No diagnosis, inadequate section -Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, aarked Pelvic aineralization, a ild Cyst, cortical -Hepatocyte a lte ra tio n , baso philic, a ild -Heaorrhage, local areas, aoderate -Not exaained, not in plane of section -Adenoaa Species: Rat Project Nuaber: 0281CR0012 Suaaarized SIM I.,a: 72 2 3 S uiiarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: T*o Year Oral Tosicity-Oncoger.icity Study in Rats Table: 2 A n iia l Nuiber: R-46C2 Sex: Feiale Group: ( 1) CONTROL 0 ppi Fate: !Neek= 105) Terminal S a c rific e Microscopic Observations (continued): Spleen Uterus -Heiosiderosi5, nild -Nithin norial l i i i t s Fever than protocol nuiber The fo llo v in g tissues vere found to be within noma! l i i i t s : Brain, Spinal Cord, Bone Marrov, Stoiach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Maiiary Eland, Trachea, Thyroid, Esophagus, Lyiph Node tie s e n te ric ), Pancreas, Salivary Sland. A n iia l Nuiber: 1R-4603 Sex: Feiale Group: ( 1) CONTROL 0 ppi Fate: (Neek= 105) T e riin a l S a c rific e Macroscopic Observations: Liver Skin Microscopic Observations: Adrenal Heart Kidney Liver Lung Hauary Sland Parathyroid P itu ita ry Skin Spleen -C ircu lar raised lesion, 0.6 c i d ia ., le ft la te ra l lobe. -Hair loss on fo r e liib s . -Sinusoidal ectasia, cortex, aoderate C o rtica l degeneration, d iffu se , derate -Myocarditis, chronic nonsuppurative, ultifocal, e ild -Pelvic lin e ra liza tio n , lild -Portal lononuclear c e ll in f ilt r a t e , i: ld Portal b ile duct p ro life ra tio n , l i l d Kepatocyte a lte ra tio n , vacuolated, l i l d -Perivascular lononuclear in f ilt r a t e , liI d -Salactocele -Not exaiined, not in plane of section -Adenoia -Acanthosis, l il d -Heiosidem sis, lild The f o il awing tissues Here found to be withi n n o ria l l i i i t s : Brain, Spinal Cord, Bone Marroi, Stoiach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Esophagus, Lynph Node (eesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuiber: 02B1CR0012 0 0 203672 4Suaiarized STAR Page: 73 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-460A Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal S a crific e Macroscopic Observations: Adrenal Microscopic Observations: Adrenal Aorta Esophagus Kidney Large Intestine Liver Ovary Parathyroid Uterus -L e ft adrenal enlarged. -Sinusoidal ectasia, cortex, narked -Not exanined, aissing -Not exaained, aissing -Chronic progressive nephropathy, a ild Pelvic aineralization, a ild -Not exaained, aissing -Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolation, a u ltifo c a l, a ild Hyperplastic nodule -Cyst, unilateral -Not exaained, not in plane of section -Within noraal lia it s Fewer than protocol nuaber The -following tissues ere Found to be within unreal 1in it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Lung, Stoaach, Saall Intestine, Urinary Bladder Maaaary Bland, P itu ita ry , Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-4605 Sex: Feaale Group: ( 11 CONTROL 0 ppa Fate: (Week= 77) S acrificed in extreais Macroscopic Observations: Kidney Lung Microscopic Observations: Adrenal Heart Kidney Liver Lung -S lig h tly pitted -Right apical lobe consolidated and soaewhat enlarged; possibly tuaor, ease, chronic pneuaonia. -Necrosis, loca l areas, aoderate Heaatopoiesis, extraaedullary, a u ltifo ca l, a ild -Myocarditis, chronic nonsuppurative, a u ltifo c a l, aoderate Malignant lyaphoaa, lyaphocytic -Chronic progressive nephropathy, aode-ate Pelvic aineralization, ainiaal -Hepatocyte vacuolation, aidzonal, aoderate Malignant lyaphoaa, lyaphocytic -Vascular aineralization, a ild Malignant lyaphoaa, lyaphocytic Large circuascribed aass with extensive necrosis. Species: Rat Project Nuaber: 02B1CR0012 S u m riz e d STAR P .,.: >4 ^ 2 5 Suaaarized Single Tabulated Aniaal Report (continued) Individual Hacroscocic and Microscopic Observations Riker Laboratories, Inc. 5H FC-143: Tao Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4605 Sex: Feaale Group: ( 1) CONTROL 0 ppi Fate: (Neek= 77) S acrificed in extreais Microscopic Observations (continued): Ovary Parathyroid P itu ita ry Spinal Cord Spleen Urinary Bladder -Cyst, unilateral -Not exaained, not in plane of section -Adenoaa -H alacia, local areas, aoderate -Heiosiderosis, a ild -E p ith e lia l hyperplasia, siaple, diffuse, aoderate The follow ing tissues were found to be within noraal l i n t s : Brain, Bone Marrow, Stoaach, Saall Intestine, Large Intestine, Aorta, Uterus, Haaaary Eland, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4606 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate! (Neek= 105) Terainal S a c rific e Macroscopic Observations: Maaaary Gland P itu ita ry Uterus Microscopic Observations: Adrenal Heart Kidney Liver Lung Lyaph Node (aesenteric) Maeeary Gland Ovary Parathyroid P itu ita ry Uterus -Sa a ll aass, 1.4 ca d ia ., le f t la te ra l area. -Enlarged; c irc u la r dark lesio n , 0.4 c i dia. -Dark flu id f ille d lesion, 0.5 x 0.4 c i, rig h t horn. -Sinusoidal ectasia, cortex, a ild C o rtica l degeneration, b ila te r a l, aoderate Pheochroaocytona, benign, u n ila te ra l -M yocarditis, chronic nonsuppurative, eu ltifocal, aild -Chronic progressive nephropathy, a ild Pelvic aineralization, aild -Hepatocyte vacuolaticn, a u ltifo c a l, a ild Hepatocyte a lte ra tio n , vacuolated, a ild -Pigaent, aoderate Scattered sa a ll fo c i of dark brown pigaent-laden aacrophages within a lv e o li. -Heaorrhage, a ild -Adenocarcinoaa -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa -Hydroaetra, aarked The follow ing tissu es were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 75 239 ft Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: IR-4606 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal S a crific e Nicroscopic Observations (continued): The follow ing tissues were found to be within noraal l i a i t s (continued): Urinary Bladder, Aorta, Trachea, Thyroid, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4607 Sex: Feaale Group: 1I 1) CONTROL 0 ppa Fate: !Neek= 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! Maaaary 61and Ovary Parathyroid Salivary Gland Spleen Stoaach Thyroid Uterus -Reddened gland lik e structures, possibly enlarged lyaph nodes or sa liva ry glands. -Enlarged a x illa r y , hepatic, aesenteric and internal i li a c lyaph nodes. -Possibly s lig h tly 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, aiId Abscess -Heaorrhage, aoderate Malignant lyaphoaa, lyaphocytic Massive enlargaent of node by aature appearing lyaphocytes. A ll other nodes exaained were s i a i la r il y 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 follow ing tissues were found to be w ithin noraal l ia it s : Brain, Spinal Cord, Heart, Saall Intestine, Large Intestine, Urinary Bladder, P itu ita ry , Species: Rat Project Nuaber: 02B1CR0012 1>Suaaarized STAR Page: 7 0 Suuarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4607 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Week= 40) Sacrificed in extreais Microscopic Observations (continued): The -following tissues were found to be within noraal l i a i t s (continued): Trachea, Pancreas. Aniaal Nuiber: 1R-46C? Sex: Feaale Sroup: ( 1) CONTROL 0 ppi Fate: (Neek= 105) Terainal S a c rific e Macroscopic Observations: P itu ita ry Maasary Eland Microscopic Observations: Adrenal Heart Kidney Large Intestine Liver Lung Maaeary Eland Pancreas Parathyroid P itu ita ry Spleen Thyroid Uterus -Raised lass, 1 c i dia. -Mass, 5 x 4 c i, throat area! 3 c i d ia ., le f t a x illa . -Sinusoidal ectasia, cortex, loderate -Myocarditis, chronic nonsuppurative, ultifocal, lild -Chronic progressive nephropathy, e ild Pelvic eineralization, derate -Not exasined, lis s in g -Portal lononudear ce ll in filtr a t e , l il d Portal b ile duct p ro life ra tio n , iiI d Hepatocyte vacuolation, e u ltifo c a l, l i l d -Pneuionia, in t e r s t it ia l, chronic, e u ltifo c a l, lild -Carcinoia Highly c e llu la r very undifferentiated tu io r. -Acinar atrophy, loderate -Not exaiined, not in plane of section -Adenoia -Heiosiderosis, lild -C c e ll adenoia -Kithin nomai l i i i t s Fewer than protocol nuiber The follow ing tissues were found to be within nomai lia it s : Brain, Spinal Cord, Bone Marrow, Stoaach, S ia li Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Esophagus, Lyiph Node (le se n te n c), Sal ivary Eland, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suuarized STAR Page: 77 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4611 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: [Heek= 105! Terainal S a crific e Macroscopic Observations: Maaaary Gland Microscopic Observations: Adrenal Liver Lung Maaaary Gland Parathyroid P itu ita ry -Large lobular aass, 10 x 7.5 x 5 ca. -Sinusoidal ectasia, cortex, aarked C o rtica l degeneration, local areas, aoderate -Hepatocyte vacuolation, a u ltifo c a l, a ild Hepatocyte a lte ra tio n , e o sin o p h ilic, a ild -Heaorrhage, a u ltifo c a l, a ild Alveolar aacrophages, a u ltifo c a l, a ild -Fibroadenoaa -Not exaained, not in plane of section -Adenoaa The foilotting tissues were found to be a ith in noraal 1ia it s : Brain, Spinal Cord, Bene Harrou, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Esophagus, Lytph Node (cesenteric!, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-4B12 Sex: Feaale Group: ! 1) CONTROL 0 ppa Fate: (Keek= 105) Terainal S a c rific e Macroscopic Observations: P itu ita ry Maanary 61and Microscopic Observations: Adrenal Eye Liver Lung Maaaary Gland Parathyroid P itu ita ry Uterus -Raised Bass, 0.7 ca dia. -Mass, 3 ca d ia ., le f t a x illa ; 4 ca d ia ., right a x illa ; 7 x 6 x 2 ca, rig h t side. -Sinusoidal ectasia, cortex, aederate -No diagnosis, inadequate section -Hepatocyte vacuolation, a u ltifo c a l, a ild -Heaorrhage, diffuse, Barked Alveolar aacrophages, a ild -Galactocele Fibroadenoaa Fibroadenoaa Two tuaors present. -Not exaained, not in plane of section -Adenoaa -N ithin noraal lia it s Fewer than protocol nuaber The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stoaach, Saall Intestine, Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 7B 242 000629 Suaiariied Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-14I: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nutber: 1R-4612 Sex: Feiale Group: ( 1) CONTROL 0 ppi Fate: (Neek= 105) T e riin a l S a c rific e Microscopic Observations (continued): The follow ing tissues aere fo uni to be within n o ria l f ia it s (continued): Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Aniaal Nutter: 1R-4613 Sex: Fetale Group: ( 1) CONTROL 0 ppe Fate: (kteex= B9) S acrificed in extreais Macroscopic Obse-vations! P itu ita ry Masaary Gland Liver Microscopic Observations: Adrenal Esophagus Kidney Large Intestine Liver Lung Matnary Gland Parathyroid P itu ita ry Spleen Urinary Bladder Uterus -Soaeahat enlarged -Mass, 10 x 8 x 5 ca, inguinal area; surface ulcerated. -Appears pale -Heaatopoiesis, extraaedullary, a ild Sinusoidal ectasia, cortex, a iid Cortical vacuolation, focal, a iid -Not examined, aissing -Pelvic aineralization, aiid Hyperplasia, pelvic epitheliua, local areas, a iid -Not exaained, aissing -Hepatocyte vacuolation, p e rip o rta l, a iid Necrosis, a u ltifo ca l, a iid Heaatopoiesis, extraaedullary, a iid -Heacrrhage, a u ltifo c a l, a iid Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a iid -Lobular hyperplasia -Not exaained, not in plane of section -Adenoaa -Heaatopoiesis, extraaedullary, increased, aoderate -E p ith e lia l hyperplasia, siaple, diffuse, a iid -Within noraal lia it s Fetter than protocol nuaber The follow ing tissues aere found to be within noraal lia it s : Brain, Spinal Cord, Bone Marroa, Heart, Stoaach, Saall Intestine, Aorta, Ovary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 79 243 000630 Sueaarized Single Tabulated A n im i Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3(1 FC-143: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A nnal Nuaber: 1R-4614 Sex: Fecale 6roup: ( 1) CONTROL 0 ppa Fate: (Neefc* 105) Terainal S a c rific e Macroscopic Observations: Maaaary 61and Uterus Microscopic Observations: Adrenal Kidney Liver Maaaary Blanc Pancreas Parathyroid P itu ita ry Spinal Cord Spleen Thyroid Uterus -Hass in perineal area; possible t i l k cyst. -Large gelatinous ce rvica l aass, 2 ca dia. -Sinusoidal ectasia, cortex, aoderate -Pelvic aineralization, ainiaal Chronic progressive nephropathy, a ild -Hpatocyte vacuolation, nult if e c a l, a ild -Adenocarcinoaa -Acinar atrophy, a ild -Not exaained, not in plane of section -Adenoaa -No diagnosis, inadequate section -Heaosiderosis, a ild -Ultiaobranchial cyst -Polyp This aas the aass at cervix noted at necropsy. The follow ing tissues Mere found to be within noraal lia it s : Brain, Bone Marrow, Heart, Lung, Stoaach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Esophagus, Lyaph Node (aesentenc), Salivary Sland, Eye. Aniaai Nuocer: 1R-4615 Sex: Fetale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal S a c rific e Macroscopic Observations: Microscopic Observations: Adrenal Aorta Kidney Liver Lung Maaaary 61and Parathyroid Spleen Uterus -No v is ib le lesions. -Sinusoidal ectasia, cortex, aarked -Not exaained, aissing -Pelvic aineralization, ainiaal -Portal b ile duct p ro life ra tio n , a ild Hepatocyte a lte ra tio n , vacuolated, a ild Hepatocyte a lte ra tio n , baso philic, a ild -Pneuaonia, in t e r s t it ia l, chronic, a ild Alveolar aacrophages, a ild -6alactocele -Not exaained, not in plane of section -Heaosiderosis, a ild -N ithin noraal lia it s Fewer than protocol nuaber Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 80 244 000631 Suaaarized Single Tabulated Aniaal Report (continued! Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. JM FC-143: Tvo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4M5 Sex: Feaale Group: ( 1) CONTROL 0 ppi Fate: (Week= 105) Terainal S a c rific e Microscopic Observations (continued): The fo llo uing tissues aere found to be u ith in noraal lia it s : Brain, Spinal Cord, Bone Marroa, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Ovary, P itu ita ry , Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric!, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-461B Sex: Feeale Group: ( 1) CONTROL 0 ppi Fate: (Keek= 105! Terainal S a c rific e Macroscopic Observations: Microscopic Observations: Adrenal Heart Kidney Liver Lung Maaaary Gland Ovary Parathyroid Spleen -No v is ib le lesions. -C o rtica l degeneration, u n ila te ra l, aarked -Myocardial fib ro s is , fo cal, a ild Myocarditis, chronic nonsuppurative, aultifocal, aild -Chronic progressive nephropathy, a ild Pelvic aineraiization, ainiaal -Portal aononudear c e ll in filtr 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 a lte ra tio n , vacuolated, a ild -Perivascular aononudear in f ilt r a t e , aoderate Vascular ain e ra liza tio n , a ild Alveolar aacrophages, a ild -Not exaained, aissing -Cyst, unilateral -Not exaained, not in plane of section -Heaosiderosis, a ild The follow ing tissues aere found to be within noraal lia it s : Brain, Spinal Cord, Bone Marroa, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, P itu ita ry , Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: SI 0 5uaiarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4617 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Reek1 73) S acrificed in extreais Macroscopic Observations: Ovary Liver Microscopic Observations: Adrenal Liver Lung Haixary Gland Ovary Parathyroid P itu ita ry -Heaorrhagic aass, 5 ca d ia ., le f t ovary. -Pale; le f t la te ra l lobe dark red. -Sinusoidal ectasia, cortex, aild One of pair present -Portal aononuclear c e ll in f ilt r a t e , a ild Necrosis, diffu se, aarked Massive necrosis of one lobe with coapensatory increase in cito ses in another lobe. -Vascular eineralization, a ild -Not exaained, Kissing -Leioayoaa Large well diffe re n tia te d neoplasa, la s tly necrotic, probably arises froa an oviduct. -Not exaained, not in plane of section -Not exaained, aissing The follow ing tissues were found to be within noraal l i n t s : B rainf Spinal Cord, Gone Harrow, Spleen, Kidney, Heart, Stoaach, S ia li Intestine, Large Intestine, Urinary Gladder, Aorta, Uterus, Trachea, Thyroid, Esophagus, Lyaph Node (eesenteric), Pancreas, Salivary Gland, Eye. A n iia l timber: 1R-461B Sex'. Feeale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 93) Sacrificed in extreeis Macroscopic Observations: P itu ita ry Haeiary Gland Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Haeiary Gland Parathyroid P itu ita ry -Raised aass, 1.1 ca dia. -Large ulcerated aass, 10 x 7 x 9 ca, rig ht a x illa r y area. -Sinusoidal ectasia, cortex, a ild -Not exaained, aissing -Pelvic aineralization, ainiaal -Portal aononuclear c e ll in f ilt r a t e , a ild -Vascular aineralization, a ild Alveolar aacrophages, a ild Perivascular aononuclear in f ilt r a t e , a ild -Not exaained, aissing -Not exaained, not in plane of section -Adenoaa Species: Rat Project Mueber: 0281CR0012 Suaaarized STAR Page: B2 246 000633 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Vear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nueber: 1R-4618 Sex: Feaale Group: ( 1) CONTROL 0 ppi Fate: !Heek= 93) S acrificed in extreeis Microscopic Observations (continued): Skin Thyroid Urinary Bladder -Fibror,a, subcutaneous Large neoplase with extensive collagen foreation, large portion necrotic. Described as lasaary lesion but no eaeeary tissue present in section. -Ultiiobranchial cyst -E p ith e lia l hyperplasia, s iip le , diffuse, e ild The follow ing tissues were found to be within noraal l i i i t s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, S ia ll Intestine, Large Intestine, Aorta, Ovary, Trachea, Lyiph Node (eesenteric), Pancreas, Salivary Gland, Eye, Uterus. Aniaal Nuaber: 1R-4619 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 64) Found Dead Macroscopic Observations: Spleen Liver P itu ita ry Microscopic Observations: Adrenal Esophagus Eye Kidney Li ver Lung Lyaph Node (eesenteric) Maaaary Gland Parathyroid P itu ita ry Salivary 61and Spleen Stoaach Urinary Bladder -S lig h tly enlarged -Pale with an irreg u la r surface on a ll lobes. -Enlarged with heaorrhagic fo c i. -Necrosis, diffu se, aarked Malignant lyaphoaa, h is tio c y tic -Not exaained, aissing -Not exaained, aissing -Nephrosis, tubular, aarked -Po rta l b ile duct p ro life ra tio n , aarked Necrosis, local areas, aoderate Malignant lyaphoaa, h is tio c y tic -Vascular ain eralizaticn , aild Malignant lyaphoaa, h is tio c y tic -Heaorrhage, a ild -Galactocele -Not exaained, not in plane of section -Adenoaa -S ia la d e n itis , chronic, aoderate -Malignant lyaphoaa, h is tio c y tic Heaatopoiesis, extraaedullary, increased, aoderate -Necrosis, aucosal, a ild -E p ith e lia l hyperplasia, siaple, diffuse, a ild The follow ing tissu es were found to be within noraal l ia i t s : Brain, Spinal Cord, Bone Harrow, Heart, Saal 1 Intestine, Large Intestine, Aorta, Uterus, Ovary, Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 83 q Suaaarized Single Tabulated A nital Report (continued) Individual Macroscopic and Microscopic Observations Ritter Laboratories, Inc. 3H FC-143: Tno Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-4619 Sex'. Feaale Group: ( 1) CONTROL 0 ppi Fate: (Week: 64) Found Dead Microscopic Observations (continued): The fo llo ning tissu es Mere Found to be within noraal U n it s (continued): Trachea, Thyroid, Pancreas. Aniaal Nuiberl 1R-4621 Sex: Feaale 6rcup: ( 1) CONTROL 0 ppi Fate: !Keek= 99) Sacri -fi ced in extreais Macroscopic Observations: P itu ita ry Maacary 61and Liver Adrenal Microscopic Observations: Adrenal Esophagus Heart kidney Liver Lung Maneary Gland Parathyroid P itu ita ry Spleen -S lig h tly enlarged -Subcutaneous ulcerated aass, 5 x 4 x 1.5 ca, in right a x illa . -Appears nettled. -S lig h tly enlarged. -C o rtical vacuolation, focal, a ild Sinusoidal ectasia, cortex, aarked -Not exasined, aissing -Myocarditis, chronic nonsuppurative, au ltifocal, aild -Chronic progressive nephropathy, a ild Pelvic aineralization, a ild Nephrosis, tubular, aoderate -Portal aononudear c e ll in filtr a t e , ainiaal Hepatocyte vacuolation, p e rip o rta l, a ild -Alveolar aacrophages, a ild Perivascular aononudear in filtr a t e , a ild Heaorrhage, local areas, a ild -Fibroadenoaa Galactocele -Not exaained, not in plane of section -Adenoaa -Hetatopoiesis, extraaedullary, increased, a ild The follow ing tissues Mere found to be w ithin noraal U n its : Brain, Spinal Cord, Bone Marroa, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ute-us, Ovary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Species: Rat Project Nunber: 02B1CR0012 Suaaarized STAR Page: 84 248 000635 Susiarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4622 Sex: Feaale Group: I! 1) CONTROL 0 ppa Fate: (Week= 62' Found Dead Macroscopic Observations: Skin Maiaary Gland Kidney P itu ita ry Lung Microscopic Observations: Adrenal Aorta Kidney Liver Lung Maaaary Gland Parathyroid P itu ita ry Skin ' -S a a ll c irc u la r lesion on back; s lig h t hair loss on le f t la te ra l side. -Mass, 2 ca d ie ., rig h t a x illa r y area; 1.5 ca d ia ., le f t inguinal area. -Raised area, 0.3 c d ia ., on surface of rig ht kidney; appea's flu id f ille d . -Dark red gelatinous aass. -S lig h tly aottled -Sinusoidal ectasia, cortex, aarked -Not exaained, aissing -Chronic progressive nephropathy, aoderate P elvic n in e ra iiza tio n , aoderate Hyperplasia, pelvic epitheliua, local areas, aild -Hepatocyte vacuolation, p e rip o rta l, aoderate -Alveolar aacrophages, a ild -Galactocele -Not exaained, not in plane of section -Not exaained, aissing -U lcer, fo ca l, aoderate The fo llo tiin g tissues were Found to be within ncraal lia it s : Brain, Spinal Cord, Bone Manroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Uterus, Ovary, Trachea, Thyroid , Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Aninal Nuaber: 1R-4623 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (8eek= 96) S acrificed in extreais Macroscopic Observations: Eye Maaaary 61and Adrenal Microscopic Observations: Adrenal Esophagus Eye Kidney Liver -Opacity, rig h t eye. -M u ltilo b u la r aass, 11 x 12 x 3 ca, rig h t axilla . -Appear enlarged -Sinusoidal ectasia, cortex, aarked -Not exaained, aissing -Cataract, unilateral -Pelvic aineralizaticn, ainiaal -Portal aononudear c e ll in f iltr a t e , a ild Hepatocyte a lte ra tio n , vacuolated, a ild Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 85 C.H7 000636 Suiaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-4623 Sex: Feiale Sroup: ( 1) CONTROL 0 ppi Fate: (Meek= 96) S acrificed in extreeis Microscopic Observations (continued): I i,n * Lyph Node (lesenteric! Mastary Eland P itu ita ry Thyroid Uterus -Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, aild Alveola" aacrophages, a ild Perivascular aononuclear in f ilt r a t e , a ild -Sinusoidal ectasia, aoderate -Fibroadenoaa -Adenoaa -F o llic u la r hyperplasia, cy stic, u n ila te ra l, a ild -Nithin noraal lia it s Feier than protocol nuaber The f o il owing tissues were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Parathyroid, Pancreas, Salivary Gland. Aniaal Nuaber: 1R-4624 Sex: Feiale Group: ( 1) CONTROL 0 ppi Fate: (Heek= 100) Sacrificed in e x tre iis Macroscopic Observations: P itu ita ry Maiaary Gland Lung Microscopic Observations: Adrenal Kidney Liver Lung H aiiary Gland Ovary -Heaorrhagic lass, 0.6 c i dia. -Ulcerated, cy stic aass, 4 x 4 x 3.3 ca, in le ft a xilla -th ro a t areal au ltilo b u lar aass, 8.5 x 5.5 x 3 c i, in right inguinal area. -Raised c irc u la r nodule, 0.6 ca d ia ., in le f t lobe. -Sinusoidal ectasia, cortex, aoderate -Chronic progressive nephropathy, ainiaal Pelvic lin e ra liza tio n , aild -Po rtal aononuclear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , iiI d Hepatocyte vacuolation, a u ltifo c a l, a ild -Pneuionia, in t e r s t it ia l, chronic, a u ltifo ca l, lild Metastatic neoplasa Large eetastasis of aanary ader.ocarcinoaa. -Fibroadenoaa Adenocarcinoaa -Cyst, unilateral 5pecie$: Rat Project Nuaber: 0281CR0012 Suiaarized STAR Page: 86 Suaaarised Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaberl 1R-4624 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 100) Sacrificed in extreais Microscopic Observations (continued): Parathyroid P itu ita ry Spleen -Not exaained, not in plane of section -Adenoaa -Heaatopoiesis, extraaedullary, increased, aoderate The follow ing tissues Mere found to be within norna! l is it s : Brain, Spinal Cord, Bone HarroM, Heart, Storach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Trachea, Thyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Eland, Eye. Aniaal Nuaber: 1R-4625 Sex! Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 100) Sacrificed in extreais Macroscopic Observations: P itu ita ry Maasary Gland Adrenal Kidney Microscopic Observations: Adrenal Esophagus Eye Heart Kidney Liver Lung Maaaary Gland Parathyroid P itu ita ry Spleen -Enlarged due to raised aass, 1.2 ca dia. -C ystic aass, 2 ca d ia ., le f t a x illa . -Both appear enlarged. -Soaeahat pitted -Sinusoidal ectasia, cortex, aarked C o rtica l degeneration, lo ca l areas, a ild -Not exaained, aissing -No diagnosis, inadequate section -M yocarditis, chronic nonsuppurative, au ltifo cal, aild -Chronic progressive nephropathy, aarked -Portal aononuclear c e ll in f ilt r a t e , a ild Hepatocyte vacuolation, a u ltifo c a l, ainiaal -Heaorrhage, local areas, aoderate -Fibroadenoaa -Not exaained, not in plane of section -Adenoaa -Heaoside-osis, a ild The follow ing tissues Mere found to be within noraa: lia it s : Brain, Spinal Cord, Bone HarroM, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Gland. Species: Rat Project Nuaber: 0281CR0012 Suaaamed STAR Page: B7 251 000638 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-462A Sex: Feiale Broup: ( 1) CONTROL 0 ppi Fate: Week* 105) T e riin a l S a c rific e Macroscopic Observations: P itu ita ry Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid P itu ita ry Spinal Cord Spleen -Raised aass, 0.9 ce dia. -Pheochroiocytoia, benign, u n ila te ra l -Chronic progressive nephropathy, oderate Pelvic aineralization, loderate -Hpatocyte vacuolation, a u ltifo c a l, ai Id -Vascular Binerai n a tio n , t il s -Not exaained, not in plane of section -Adenoaa -Not exaained, aissing -Heaosiderosis, t ild The follow ing tissues were found to be within noraal lia it s : Brain, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Maasary Gland, Trachea, Thyroid, Esophagus, Lyeph Node (aesenteric), Pancreas, Salivary Bland, Eye. Ar.iaal Nusber: 1R-4A27 Sex! Feaale Group: ( 1) CONTROL 0 ppa Fate: (#eek= 105! Terainal S a c rific e Macroscopic Observations: P itu ita ry Maeaary 61and Microscopic Observations: Adrenal Heart Kidney Liver Lung Haaaary 61and Ovary -Mass, 1 x 0.6 ca. -F ira aass, 5.5 x 4 x 3.5 ca, rig h t la te ra l area; lobular aass, 7 x 6 x 5 ca, le ft axilla . -Sinusoidal ectasia, cortex, aoderate Medullary c e ll hyperplasia, a u ltifo c a l, a ild -Myocarditis, chronic nonsuppu'ative, aultifocal, aild -Chronic progressive nephropathy, aoderate -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , aoderate Hepatocyte a lte ra tio n , basophilic, aoderate -Vascular eineralization, a ild Alveolar aacrophages, a ild Perivascular aononudear in f ilt r a t e , a ild -Adenocarcinoaa Neoplasa arises in several places in a fibroadenoaa. -Tubular adenoaa, u n ila tera l Cyst, bila te ra l Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: BS 252 000639 S u m m e d Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuiber: 1R-4627 Sex! Feeale Group: ( 1) CONTROL 0 ppi Fate: (Neek= 105) Tereinal S a c rific e Microscopic Observations (continued): Pancreas Parathyroid P itu ita ry Skin Uterus - I s le t c e ll adenoia -Not exanned, r.ot in plane of section -Adenoaa -Fibroea, subcutaneous -C ystic glands, aiId The following tissues we^e found to be within noreal l ie it s : Brain, Spinal Cord, Bone Marrow, Spleen, Stoeach, S ia ll Intestine, Large Intestine, Urinary Bladder, Aorta, Trachea, Thyroid, Esophagus, Lyaph Node (eesenteric), Salivary Gland, Eye. Ami aal Nuaber: IR-4628 Sex: Feeale Group: ( 1) CONTROL 0 ppi Fate: (Neek= 105) Tereinal S a c rific e Macroscopic Observations: P itu ita ry Maniary Gland Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Maaeary Gland Parathyroid P itu ita ry -Mass, 1.2 c i dia. - S ia ll nodule, 1.5 c i d ia ., rig h t a x illa ; possible e ilk cyst. -Sinusoidal ectasia, cortex, aoderate -Not exanined, lis s in g -Pelvic aineralization, a in iia l -Portal b ile duct p ro life ra tio n , i i l d Hepatocyte a lte ra tio n , vacuolated, a ild Hepatocyte vacuolation, a u ltifo c a l, a ild -Vascular eineralization, a ild -Salactocele Adenoaa, p a p illa ry Snail highly c e llu la r neoplasa lying adjacent to several large galactocoels. -Not exaained, not in plane of section -Adenoaa The follow ing tissues were found to be within n o r a a l- lia its : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, S ia ll Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuiber: 0281CR0C12 Suaaarized STAR Page: 89 c. C0640 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. IM FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4633 Sex: Feaale Eroup: ( 1) CONTROL 0 ppa Fate: (Week= 3) S acrificed in extreais Macroscopic Observations: Liver Spleen Maiary 61and Microscopic Observations: Adrenal Aorta Esophagus Kidney Liver Lung Maasary Gland Parathyroid Salivary Bland Spleen -Very pale -S lig h tly enlarged -Large subcutaneous aass, 6 x 10 x 2.5 ca, with necrotic areas, containing dark brown flu id , ventral abdoaen. -Heaatopoiesis, extraaedullary, co rtica l, a ild Sinusoidal ectasia, cortex, a ild -Not exaained, aissing -Not exaained, aissing -Chronic progressive nephropathy, ainieal Vacuolation, conv. tub. epitheiua, aoderate -Kepatocyte vacuolation, c e n trilo b u la r, aarked -Vascular aineralization, a ild Heaorrhage, a u ltif o c a l, a ild -Adenocarcinoaa Hell d ifferentiated, ductular pattern, areas of aoderate a it c t ic a c tiv ity , large areas of necrosis. -Not exaained, not in plane of section -Not exaained, aissing -Heaatopoiesis, extraaedullary, increased, aoderate The follow ing tissues were found to be within noraal U n its : Brain, Spinal Cord, Bone Marrow, Heart, Stoiach, Snail Intestine, Large Intestine, Urinary Bladder, Uterus, Cvary, P itu ita ry , Trachea, Thyroid, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-4E34 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal S a c rific e Macroscopic Observations: P itu ita ry Haaaary Gland Microscopic Observations: Adrenal Esophagus Heart -Mass, 0.7 ca dia. -Lobular aass, 8 x 6 x 4 ca, rig h t a x illa ; lobular aass, 9 x 7 x 3.5 ca, le ft inguinal. -Sinusoidal ectasia, cortex, aoderate -Not exaained, aissing -Myocarditis, chronic nonsuppurative, au ltifocal, aild Species: Rat Project Nuaber: 02B1CRC012 Suaaarized STAR Page: 90 254 000641 Suicarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber: 1R-4434 Sex: Feiale Group: ( 1) CONTROL 0 ppi Fate: !Keek= 1C5) Terminal S a c rific e Microscopic Observations (continued): Kidney Liver Lung Maiiarv Gland Parathyroid P itu ita ry Spleen ' -Pelvic lin e ralicatio n , a in iia l -Portal aononuclear c e ll in f ilt r a t e , l i l d Portal b ile duct p ro life ra tio n , ai Id Hepatocyte a lte ra tio n , vacuolated, wild Hepatocyte a lte ra tio n , basophilic, icderate Hepatocyte a lte ra tio n , e o sin o p h ilic, ai 1d -Vascular lin e ra ln a tio n , a ild Perivascular lononudear in f ilt r a t e , Id Heiorrhage, a u ltifo c a l, l i l d -Fibroadenoia Fibroadenoia Both tasses were fibroadenoaas. Areas of necrosis and cy stic areas in tutors. -Not exaiined, not in plane of section -Adenoca -Heiatopoiesis, extraiedullary, increased, ild Heiosiderosis, lild The following tissues were found to be within noria! l i i i t s : Brain, Spinal Cord, Bone Harrow, Stciach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Lyiph Node (le se n te ric!, Pancreas, Salivary Bland, Eye. A n iia l Nuiber: 1R-4635 Sex: Feiale Group: ( 1) CONTROL 0 ppi Fate: (wteek= 94! Found Dead Macroscopic Observations: Saall Intestine Haiiary Gland Microscopic Observations: Adrenal Esophagus Eye Kidney -Jejunua appears in fla ia e d with reddish fluid* ile u i appears inflam ed near cecua. -Mass, 7 x 7.5 x 2 c i, m i t i lobular and ulcerated, right inguinal; lass, lig h t beige in color, sp herical, 2 et d ia ., in le ft a x illa . -Sinusoidal ectasia, cortex, l il d Heiatopoiesis, extraiedullary, co rtica l, oderate -Not exaiined, lis s in g -Not exaiined, lis s in g -Chronic progressive nephropathy, iiI d Pelvic lin e ra liza tio n , e in iia l Species: Rat Project Nueber: 0281CR0012 Suuarized STAR Page: 91 255 000642 S u m m e d Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-H3: Tno Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4635 Sex: Feaale Sroup: ( 1) CONTROL 0 ppa Fate: (Week= 94) Found Dead Microscopic Observations (continued): Liver Lung Maaaary Eland Parathyroid P itu ita ry Salivary Bland Spleen Thyroid -Hepatocyte vacuolation, d iffu se , ai Id Heaatopoiesis, extraieduilary, a ild M ito tic a c tiv ity , increased, aoderate -Vascular aineralization, aild Metastatic neoplasa -Adencaa Adenocarcinoia Extensive necrosis. -Not exaained, not in plane of section -Not exaained, aissing -Not exaained, aissing -Heaatopoiesis, extraaedullary, increased, narked -Ultiaobranchial cyst The -following tissues Mere found to be within n o n al lia it s : Brain, Spinal Cord, Bone Harrou, Heart, Stoiach, Seal 1 Intestine, Large Intestine Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Lyaph Node (aesenteric), Pancreas. Aniaal Nuaber: 1R-4636 Sex: Feaale 6roup: ( 1) CONTROL 0 ppa Fate: (Heek= 105) Teraina! S a c rific e Macroscopic Observations: Hasaary Gland Liver Microscopic Observations: Adrenal Heart Kidney Large Intestine Liver Lung Maaaary Bland Pancreas Parathyroid P itu ita ry -Mass in rig h t a x illa appears to be ai 1k cyst. -S lig h tly raised dark aass, 0.6 ca d ia ., le f t lateral lobe. -Cortical vacuolation, fo cal, a ild Sinusoidal ectasia, cortex, a ild -Myocardial fib ro s is , a u ltifo c a l, a ild -Chronic progressive nephropathy, a ild -N etatodiasis, colon -Hepatocyte vacuolation, a u ltifc c a l, a ild Hepatocyte a lte ra tio n , vacuolated, a ild Hepatocyte a lte ra tio n , baso philic, a ild -Vascular aineralization, a ild Alveolar aacrophages, a ild -Lobular hyperplasia -Acinar atrophy, aild -Not exaained, not in plane of section -Adenoaa Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR PRage: 92 256 000643 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4636 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 105) Teraina! S a c rific e Microscopic Observations (continued): Spleen -Heaosiderosis, a ild The fo llo a in g tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marroa, Stoaach, Snail Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Trachea, Thyroid, Esophagus, Lvaph Node (aesenteric), Salivary Bland, Eye. Aniaal Nuaber: 1R-4637 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: !Neek= B2) Sacrificed in extreais Macroscopic Observations: P itu ita ry Lung Liver Microscopic Observations: Eye Kidney Liver Lung Haaaary 61and P itu ita ry Spleen Uterus -Reddened aass, ! ca dia. -Focal areas of consolidation in anterior part of rig h t and le f t lung. -Possibly pale - K e r a titis , acute, aarked -Pelvic M ineralization, a ild M ineralization, co rtica l, aild Chronic progressive nephropathy, a ild -Hepatocyte vacuolation, p e rip o rta l, aoderate -Pneuacnia, acute exudative, loca l areas, aoderate Hescrrhage, a u ltifo c a l, a ild -Salactocele -Adenosa -Heaosiderosis, aoderate -C ystic glands, aoderate The fc l lowing tissues Mere found to be within noraal lia it s : Brain, Spina; Cord, Bone Marroa, Heart, Stoaach, 5aall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Adrenal, Thyroid, Parathyroid, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland. Aniaal Nuaber*. 1R-4638 Sex: Feaale Group*. ( 1) CONTROL 0 ppa Fate: (Neek= 105) Terainal S a c rific e Macroscopic Observations: P itu ita ry Microscopic Observations: Adrenal Esophagus -Hass, 0.5 ca dia. -Sinusoidal ectasia, cortex, a ild -Not exaained, aissing Species: Rat Project Nuaber*. 02B1CR0012 Suaaarized STAR Page*. 93 257 G00644 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-4638 Sex: Feaale Sroup: ( 1) CONTROL 0 ppa Fate: (lieek= 105! Terainal S a c rific e Microscopic Observations (continued): Kidney Liver Lung Maaaary Gland Parathyroid P itu ita ry Spleen Uterus - -Chronic progressive nephropathy, ai Id -Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolation, a u ltifo c a l, aoderate -Vascular aineralization, a ild -Not exaained, aissing -Not exaained, not in plane of section -No diagnosis, inadequate section -Heaosiderosis, a ild -C ystic glands, aarked The follow ing tissues aere found to be Mithin noraal h a lt s : Brain, Spinal Cord, Bone Marroa, Heart, Stoaach, Saal 1 Intestine, Large Intestine, Urinary Bladder, Aorta, Trachea, Thyroid, Lyoph Node (aesenteric), Pancreas, Salivary Gland, Eye, Ovary. Aniaal Nuaber: 1R-4639 Sex: Feaale Group: ( 1) CONTROL 0 ppa Fate: (Week= 58) Sacrificed in extrecis Macroscopic Observations: Skin Liver Microscopic Observations: Kidney Large Intestine Liver Lung Maaoary Gland Salivary Gland Spleen Uterus -Midsternal subcutaneous nass, 8 x B x 3 ca. -S lig h tly pale -Pelvic aineralization, aild Chronic progressive nephropathy, a ild -NeaatDdiasis, colon -Portal aononudear c e ll in f ilt r a t e , a ild -Heaorrhage, a u ltifo c a l, a ild -Fibroadenoaa -Not exaained, aissing -Heaosiderosis, a ild -Mithin noraal lia it s Feuer than protocol nuaber The fo llo a in g tissues aere found to be w ithin noraal lia it s : Brain, Spinal Cord, Bone Marroa, Heart, Stoaach, Seal 1 Intestine, Ur in a -y E l i d e ', Ac-ta, Ova'?, P itu ita ry , Trachea, Adrenal, Thyroid, Parathyroi i, Esophagus, Lysph Kccs (s e s e rte rid , Pancreas, Eye. Species: Rat Project Kuaber: 02S1CR0012 Suiaarized STAR Fags: 94 25 8 000645 Suaaarired Single Tabulated flniaal Repart Individual Hacroscopic and Microscopie Observations Riker Laboratories, Inc. 3H FC-143: T*o tear Oral Toxicity-Oncogenicity Study in Rats -at.e: * 1 Nutber! 1R-353! Sex: Hale lHeek= 06! T e riin a l S a crifice Group: ( 5) FC-143 300 ppt ObservawOnS. Pituita*'y Hicroscopic Observations: Adrenal Kidney Liver . .. .U r g C ' * 11 "i r j iiv u iu o T ; E p le e T . i r f . i 4 . ; w i - -Raised eass, 0.5 cs dia. -Pheochroeocytoaa, benign -Chronic progressive neprxapathy, e ild -Po rtal aor.onuclear c e ll in f ilt r a t e , e ild Hepatocyte vacuclation, tiltife c a l, * iid Hepatocyte a lte ra tio n , vacuolated, a ild Hegalocytcsis, aim aal -Vascular tin e ra liza tio n , a ild Heao'rhage, a u ltifo c a l, aoderate -Adenoisa -Heaosidercsis, a ild -C c e ll adencta Its r o llo n :-; tissues r e found to be within noral H a lts : Erair., Spinal Cord, Bene Harrow, Heart, Stoeach, Saall Intestine, Large Intestine, Urir.a-y Eladder, Aorta, T e stis /E p id id y iis, Prostate, Parathyroid, Trachea, Esophagus, Lysph Node (nesenteric), Pancreas, Salivary Bland, Eye. Ar.isal Nunber: 1R-J582 Sex: Hale Fate: Keek- 106! T e riin a l S a c rific e Group: ( 51 FC-143 300 ppii Hacrosccpic Observations: Skin P itu ita ry Kidney Adrenal T e s tis /E p id id y iis Hicroscopic Observations! Adrenal Eye Heart Kidney Liver Lung Parathyroid P itu ita ry Salivary Gland Skin -Ulcerated eass, 2.8 c* d ia ., dorsal. -Heecrrhagic lesion, 0.2 ca dia. -Pale -L e ft adrenal enlarged, 0.7 ca dia. eass. -Testes s t a ll, b ila te ra l. -Pheochronocyteea, benign, u n ila te ra l -Retinal atrophy, diffuse, larked -Hyocarditis, chronic nonsuppurative, ultifccal, n ld -Chronic progressive nephropathy, eoderate -Portal eononudear c e ll in filtr a t e , e ild Cystaid degeneration, fo c a l, e ild -Vascular tin e ra liza tio n , eild -Not exasined, eissing -Adenora -Net exaained, eissing -Keratoacanthoea, back Species: Rat Project Nuaber'. 02B1CR0012 Sueaarized STAR Page: 95 259 000646 S u m m e d Single Tabulated Ani al Report (continued) Individual Hacroscopic and Hicrosccpic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Tot:icity-Oncogenicity Study in Rats Table: 2 Anna! Nuaber: 1R-35S2 Set: Hale Fate! (Keek* 106) Terminal S a crifice Broup: ( 5) FC-143 300 ppi Hicrosccpic Observations (continued): Spleen T e s tis /E p id iriy ils Thyroid -Heeosiderosis, iId -Tubule atrophy, asperaatogenesis, KilC -Not exaained, cissm g b ila te ra l, The F o il owing tissues were round to be within n o ria l lie it s : Brain, Spinal Co-d, Bone Harrow, Stoiach, Saall Intestine, Large Intestine, Urinary Bladdsr, Aorta, Prostate, Trachea, Esophagus, Lyeph Node (eesenteric), Pancreas. Arisa! Nurber: 1R-35S3 Sex! Hale Fate: (ieet= 106! Tersinal S a crific e Group: ( 5! FC-143 300 ppe Hacroscopic Observations: Liver HicrGsccpic Observations: Adrenal Kidney Liver Lung T e s tis /E p id id y a is -Pale raised lasses, 1.3 ce d ia ., rig h t la te ra l lobei 0.6 c> d ia ., le f t lateral lobe. -Sinusoidal ectasia, cortex, derate -Chronic progressive nephropathy, >iId -Hepatocellular carcinona Hegalocytosis, a ild Portal aononudear c e ll in filtr a t e , aild Cysioid degeneration, fo ca l, a ild Hepatocyte a lte ra tio n , vacuolated, a ild -Vascular aineralization, a ild Alveolar aacrophages, a ild -Leydig c e ll adenona, u n ila te ra l Vascular a in e ra liza tio n , a ild The following tissues were found to be within norral lia it s : Brain, Spina! Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine Urinary Bladder, Aorta, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (eesenteric), Pancreas, Saliva-y Bland, Eye. Aniaal Nuaber: 1R-35B5 Sex: Hale Fate: (Neek= 106) Terainal S a c rific e Group: ! 3) FC-143 300 ppa Hacroscopic Observations: Lung Hicrosccpic Observations: Kidney -Raised pale lesio n , 0.5 ca d ia ., le f t lobe. -Chronic progressive nephropathy, a ild Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 96 260 000647 S u m m e d Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3ft FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3535 Sex: Male Fate: (Heek= 106' Terainal S a c rific e Group: ( 5) FC-143 300 ppa Microscopic Observations (continued): Liver Lung Pancreas -Portal aononuclear c e ll in f ilt r a t e , a ild Cysioid degeneration, a u ltifo c a l, a ild Malignant lyaphcaa, lyaphccytic Hepatocyte a lte ra tio n , ba sophilic, aoderate Megalocytosis, ainiaal -Vascular m ineralization, a ild Fib ro sis, pleural, aoderate -Acinar atrophy, a ild Hyperplasia, acinar c e ll, a ild The follow ing tissues were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididyais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Mode (aesenteric), Salivary Gland, Eye. Aniaal timber: 1R-3586 Bex: Male Fate: (Week = 106) Terainal S a c rific e Group: ( 5) FC-143 300 ppa Macroscopic Observations: Liver T e s tis /E p id id y a is Microscopic Observations: Adrenal Heart Kidney Liver Lung Pancreas Salivary Gland T e s tis /E p id id y s is -Possible pale fo c i on one lobe. -Pale aass, 1 cc dia. -C ortical vacuolation, focal, a ild Sinusoidal ectasia, cortex, ciId -Myocarditis, chronic nonsuppurative, a ild -Chronic progressive nephropathy, aoderate -Portal aononuclear c e ll in f ilt r a t e , a ild Cystoid degeneration, a u ltifo c a l, aoderate Megalocytosis, a ild -Vascular m ineralization, a ild -Acinar atrophy, aoderate -S ia la d e n itis, chronic, aoderate -Tubule atrophy, asperaatogenesis, aoderate M ineralization, tubular, aild Leydig c e ll adenoaa, b ila te ra l The follow ing tissues were found to be within noraal U n its : Spleen, Stoaach, Saali Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Brain, Spinal Cord, Bone Marrow, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 97 261 000648 Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A nnal Nueber: 1R-3587 Sex: Male Fate: (WeeN 106) Terbi rial S a c rific e Group: ( 5) FC-143 300 ppe Macroscopic Observations: Eye Microscopic Observations: Adrenal Eye Kidney Liver Lung Pancreas Parathyroid P itu ita ry Salivary Gland Spleen -Hypopyon, rig h t eye. -Sinusoidal ectasia, cortex, cin iaal -Phthsis bu lb i, u n ila te ra l, sacked Lesion characterized bv re tin a l atrophy, cataract, and corneal vascularization with collapse of the glebe. -Chronic progressive nephropathy, ai Id -Portal anonuclear c e ll in f ilt r a t e , ai Id Cystoid degeneration, t u lt if c c a l, e ild Hepatocyte a lte ra tio n , bascpr.ilic, a in ic a l Megalocytcsis, nininal -Vascula' aineralization, e ild Alveolar eacrophages, e ild Perivascular aononuclear in f ilt r a t e , ainiaa! -Hyperplasia, is le t c e ll, aoderate -Not exaained, not in plane of section -Cyst, pars d ista l is -S ia la d e n itis , chronic, aoderate Moderate reactive hyperplasia of included lyaph node. -Heaosiderosis, a ild The follow ing tissues were found to be within noraal lia it s : Brain, Spina! Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric). Anisal Nuiber: 1R-3590 Sex: Male Group: ( 5) FC-143 300 ppa Fate: Week 19) S acrificed in extreais Macroscopic Observations: Thyaus Liver Spleen Lyaph Node (aesenteric) Lyaph Node (abdoainal) Saall Intestine Large Intestine Kidney Urinary Bladder Penis -Enlarged, 1.5 x 1.5 x 0.3 ca, dark red. -Enlarged, brown/yellow Bottling. -Markedly enlarged, B x 2 x 1 ca. -Enlarged -Hepatic lyaph nodes enlarged. -Peyer' s patches enlarged and reddened. -Peyer' s patches enlarged and reddened. -S lig h t d ila ta tio n of renal p e lv is , b ila te r a l. -Distended with urine. -Swollen Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 98 262 000649 Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anieal Nuiber! 1R-359C Sex: Male Group: ( 5) FC-143 300 ppi Fate: (Week* 19) S acrificed in e x tre iis Microscopic Observations (continued): Adrenal B o h e Macro* Brain Eye Kidney Liver Lung Lysph Node (abdoiinsl) Lyiph Node (iesenteric) Parathyroid P itu ita ry S ia ll Intestine Spleen Thyius Thyroid Urinary Bladder -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic Parenchyaa alaost coaoletely replaced by diffuse noeplastic c e ll in filtr a te . -Malignant lyaphoaa, lyaphocytic Heaorrhage, local areas, aoderate -Malignant lyaphoaa, h is tio c y tic Extensive neoplastic involveaent of hepatic node. -Malignant lyaphoaa, lyaphocytic -Not exaained, aissing -No diagnosis, inadequate section -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, lyaphocytic -Malignant lyaphoaa, h is tio c y tic -Not exaained, aissing -Malignant lyaphoaa, lyaphocytic E p ith e lia l hyperplasia, siaple, diffuse, a ild The follow ing tissues ere found to be Mithin noraa lia it s : Heart, Stoaach, Large Intestine, Aorta, T e stis/Ep id id yais, Prostate, Trachea, Esophagus, Farcr eas, Salivary Gland, Spinal Cord. Aniaal Nuaber: 1R-3591 Sex: Male Fate: (Neek= 106) Terainal S a c rific e Brsup: ( 5) FC-143 300 ppr Macroscopic Observations: Microscopic Observations: Adrenal Esophagus Kidney Liver Lung -No v is ib le lesions. -Sinusoidal ectasia, cortex, a ild -No diagnosis, inadequate section -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in f iltr a t e , a ild Cystoid degeneration, aoderate Hepatocyte a lte ra tio n , baso philic, aoderate Megalocytosis, ainiaal -Vascular aineralization, a ild Alveolar aacrophages, a ild Heaorrhage, local areas, aoderate Species: Rat Project Nmber: 02S1CR0012 Suaaarized STAR Page: 99 263 000650 Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Ar.iial Nuiber: IK-3591 Sex: Male Fate: Ueek= 106) Terainal S a c rific e Group: ( 5) FC-143 300 ppi Microscopic Observations (continued): P itu ita ry - -Adenoaa The -Fellowing tissues were found to be within ncraal l is it s : Brain, Spinal Lori, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Biadder, Aorta, T e stis/Epididyais, Prostate, Thyroid, Parathyroid, Trachea, Lynch Node ia esen teric), Pancreas, Salivary Gland, Eye. Ar.iaal Nuaber: 1R-3393 Sex: Male Fate! iieer= 106! Terminal S a crific e Group: ( 5) FC-143 300 ppa Macroscopic Observations: Liver Microscopic Observations! Kidney Liver Lung Parathyroid Thyroid -Raised pale lesion, 0.6 c i d ia ., in te rio r caudate lobe. -Chronic progressive nephropathy, a ild -Megalocytosis, aininal Portal aononudear ce ll in filtr a t e , a ild Cystoid degeneration, a u ltifo c a l, a ild Hepatocellular carcinoaa Kell differentiated, trabecular pattern, aoderate a ito tic a c tiv ity , vascular invasion. -Vascular aineralization, a ild Alveolar aacrophages, a ild -Hot exanined, not in plane of section -C c e ll adenoaa The follow ing tissu es acre found to be within noraal l ia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urirar Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Trachea, Esophagus, Lyiph Node iaesenteric), Pancreas, Salivary 61and, Eye. Aniaal Nuaber: 1R-3594 Sex: Hale Fate: (Week: 106) Terainal S a c rific e broup: ( 5) FC-143 300 ppa Macroscopic Observations: Liver Microscopic Observations: Adrenal Heart Kidney -Pale fo ci throughout. -Sinusoidal ectasia, cortex, aoderate -M yocarditis, chronic nonsuopurative, a u ltifo ca l, ainiaal -Chronic progressive nephropathy, a ild Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 100 264 000651 Suaearized Single Tabulated Aniaal Report (continued) Individual Hacroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: To Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3594 Sex: Rale Fate: IHeek= 106) Terair.al S a c rific e 6roup: ( 5) FC-143 300 ppr Hicroscopic Observations (continue:!): Liver Lung Parathyroid P itu ita -y T e s tis 'E p id id y a is Thyroid -Hepatocyte vacuolation, d iffu se , aoderate Cystcid degeneration, ai 1d Hepatocyte a lte ra tio n , vacuolated, aoderate Regalocytosis, aoderate Centrilobular c e lls enlarged with fin e ly granular, eo sin o p h ilic, ` ground glass* appearing cytoplasa. -Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, i id Alveolar aacrophages, aoderate -Not exaained, not in plane of section -Adencaa -Vascular a in e ra liza tio n , aoderate -Hyperplasia, C c e ll, ai 1d The follow ing tissues ere found to be ithin noraal lin it s : Brain, Spinal Cord, Bone Harrc*, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Eiadder, Aorta, Prostate, Trache a, Esophagus, Lyaph Node (aesenteric>, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: IR-3393 Sex: Hale Pate: (Keek* 106) Terair.al S a c rific e Eroup: ( 5) FC-143 300 ppa Hacroscopic Observations: Haiia-y Gland P itu ita ry Hicroscopic Observations: Adrenal Bone Harro Ki dr.ey Liver Lung P itu ita ry Salivary Gland -F ire aass, 3 x 2 x 1.5 ca, rig h t a x illa . -Heaorrhagic aass, 0.5 x 0.7 ca. -Sinusoidal ectasia, cortex, a ild -Not exaained, aissing -Pelvic aine-alizatior,, aild Pyelonephritis, acute, a ild Hyperplasia, pelvic epitheliua, diffuse, a ild -Portal ononudear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Cystoid degeneration, a u ltifo c a l, a ild -Vascular aineralization, a ild Alveolar aacrophages, a ild -Adenoaa -S ia la d e n itis , acute, aoderate Hass described at necropsy as aaaaary gland as apparently the enlarged, inflaaaed sa liv a ry gland. No aaaaary tissu e as present on any s lid e . Species: Rat Project Nuaber: 0281CROO12 Sueaarized STAR Page: 101 265 000652 Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Animal Number: 1R-3595 Sex: Male Fate: (Ueetr= 106) Terainal S a c rific e Eroup: ( 5) FC-143 300 ppi Microscopic Observations (continued): Spinal Cord - Spleen -Not examined, eissing -Hemosiderosis, wild The follow ing tissues ere found to be within noma! l i i i t s : Brain, Heart, Stomach, Snail Intestine, Large Intestine, Urinary Bladde-, Aorta, Testis/Ep id id ynis, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Eye. Animal Number: 1R-3596 Sex: Male Fate: (Neek- 106! Terainal S a c rific e Group: ( 5) FC-143 30 pp Macroscopic Observations: Kidney Microscopic Observations: Adrenal Heart Kidney Liver Lung P itu ita ry Testis/Epididyai s -Pale, enlarged and pitted , b ila te r a l. -C ortical vacuolation, m u ltifocal, ainiaal Medullary c e ll hyperplasia, fo ca l, a ild -M yocarditis, chronic nonsuppurative, m ultifocal, aild -Chronic progressive nephropathy, marked Cyst, c o rtic a l, moderate -Portal mononuclear c e ll in f ilt r a t e , a ild Hepatocyte vacuolation, m u ltifo cal, a ild Hepatocyte a lte ra tio n , vacuolated, a ild Negaiocytosis, a ild -Vascular aineralization, a ild Hemorrhage, local areas, Barked -Adenoma -P o ly a r te ritis , moderate The follow ing tissues ere found to be within norma! H a lts'. Brain, Spinal Cord, Bone Narrow, Spleen, Stomach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Eland, Eye. Animal Number: 1R-3597 Sex: Male Fate: (Week= 106) Terminal S a c rific e Group: ( 5) FC-143 300 ppm Nacroscopic Observations: Microscopic Obse-vations: Heart -No v is ib le lesions. -Myocarditis, chronic nonsuppurative, m u ltifo ca l, mild Species: Rat Project Number: 0281CR0012 Summarized STAR Page: 102 2 6 6 000653 Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3M FC-143; Two tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuiber: 1R-3597 Sex: Male Fate: (Keek* 106) T e n in a l S a c rific e Broup: ( 5) FC-143 300 ppi Microscopic Observations (continued): Kidney Liver Lung Pancreas Prostate -Chronic progressive nephropathy, ai Id -Portal ononuciear c e ll in f ilt r a t e , ai 1d Portal b ile duct p ro life ra tio n , ai 1d Hepatocvte a lte ra tio n , vacuolated, ai 1d Megaiocytosis, lin ia a l -Vascular in e ra liz a tio n , ai 1d -Acinar atrophy, ai Id - P r o s t a titis , acute, suppurative, nini aal The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Ep id id yais, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Mode (aesenteric!, Salivary Eland, Eye. Aniaal Nuaber: 1R-3599 Sex: Male Fate: (HeeK= 106) Terainal S a c rific e Broun! ! 5) FC-143 300 ppa Macroscopic Observations: Kidney Microscopic Observations: Kidney Liver Lung Salivary Gland Spleen -Hydronephrosis, rig h t kidney. -Chronic progressive nephropathy , ai Id Pelvic aineralization, aild Hyperplasia, pelvic epitheliua, a u ltifc c a l, aoderate -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild Cystoid degeneration, a u lt if o c a l, a ild Megaiocytosis, a ild -Vascular aineralization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild Alveolar aacrophages, a ild Heaorrhage, local areas, aoderate -S ia la d e n itis , chronic, aoderate -Heaosiderosis, a ild The follow ing tissu es were found to be within noraal l ia it s : Brain, Spinal Cord, Bone Narrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 103 Z o f C00S54 Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. JM FC-143: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3600 Sex: Male Fate: (Heek= 106) Terainal S a c rific e Group: < 5) FC-143 300 ppa Macroscopic Observations: Liver Microscopic Observations: Adrenal Bone Marrow Heart - .. Kidney Liver Lung Lyaph Node (aeserteric) P itu ita ry Spinal Cord Spleen T e s tis /E p id id y a is - -Mottled -C ortical vacuolation, oild -Not exanined, aissing -Myocarditis, chronic nonsuppurative. c a ltifo c a l, aild -Chronic progressive nephropathy, a ild -Portal aononuclea- c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Cystoid degeneration, fo ca l, a ild Megalocytosis, aoderate -Vascular aineralization, a ild Alveolar aacrophages, a ild Heaorrhage, local areas, aoderate -Keaorrhage, ainiaal -Not exanined, aissing -Not exanined, aissing -Heaosiderosis, a ild -Vascular aineralization, a ild The follow ing tissues aere found to be within noraal lia it s : Brain, Stoaach, Saal 1 Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. Aniaal Nuaber: 1R-3601 Sex: Male Fate: (Neel- 106) Terainal S a c rific e Group: ( 5) FC-143 300 ppa Macroscopic Observations: Liver Lyaph Node (aesenteric) Stoaach Microscopic Observations: Adrenal Heart Kidney Liver -Mottled! yellow raised lesions, 0.7 and 0.9 ca d ia ., posterior caudate lobes. -Enlarged -Enlarged ga stric rugae -C o rtica l vacuolation, a u lti -focal, aoderate -Myocarditis, chronic nonsuppurative, au ltifo ca l, ainiaal -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a t e , a ild Cystoid degeneration, a u ltifo c a l, aoderate Hepatocyte a lte ra tio n , vacuolated, a ild Megalocytosis, aoderate Hepatocyte a lte ra tio n , basophilic, aoderate Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 104 268 000855 Suaaarized Single Tabulated A nital Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A nnal Nueber: 1R-3601 Sex: Male Fate: (Week* 106) Terainal S a crific e Group: ( 5) FC-143 300 ppa Microscopic Observations (continued): Lung Lyaph Node (aesenteric) Pancreas P itu ita ry Stosach -Vascular lin e r a liz a t ic n , s i Id Heaorrhage, local areas, larked -Heiorrhage, *iId Heiangiosarcoia -Acinar atrophy, loderate -Cyst, pars d ista l is -Adenocarcinoaa Extensive in f ilt r a t io n into subaucosa and uscularis. Nell d iffe re n tia te d , high itotic index. Probably pa rieta l c e ll o rig in . Tuior c e lls in ly ip h a tic s . The follow ing tissues were found to be within norial lim its : Brain, Spinal Cord, Bone Marrow, Spleen, S ia ll Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yeis, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Salivary Gland, Eye. Ani sal Nuater: 1R-36C2 Sex: Male Fate: (Neek- 106) T e riin a l S a crific e Group : ( 5) FC-143 300 ppi Macroscopic Observations: Microscopic Observations: Adrenal Heart Kidney Liver Lung Lyaph Node (aesenteric) Pancreas Spleen T e s tis /E p id id y a is Thyroid -No v is ib le lesions. -Nodular hyperplasia, cortex, fo cal, l i l d Medullary c e ll hyperplasia, fo ca l, ai 1d -Myocarditis, chronic nonsuppurative, ultifocal, aild -Chronic progressive nephropathy, ai Id -Portal ononudear c e ll in f ilt r a t e , a ild Megalocytosis, a in iia l -Vascular sineralication, t ild Alveolar aacrophages, a ild -HeaarrhagE, a ild - I s le t c e ll adenoaa -Heaosiderosis, a ild -Vascular lin e ra liz a tic n , a ild -C c e ll adenoaa The follow ing tissu es were found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrow, Stoaach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Parathyroid, Trachea, Esophagus, Salivary Gland, Eye. Species: Rat Project Nutber: 0281CR0012 Suaaarized STAR Page: 105 269 C00S56 Suaaarized Single Tabulated Aniaal Report (continued) estcopyawile Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M Fl- 143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-36C3 Sex: Male Fate: (Week= 106) Terainal S a c rific e Group: i 5) FC-H3 300 ppa Macroscopic Observations: Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid -No v is ib le lesions. -Sinusoidal ectasia, cortex, ainiaal -Chronic progressive nephropathy, t il d -Portal aononudear c e ll in filtr a t e , a ild Cystoid degeneration, fo ca l, a ild Megalocytosis, ainiaal Hepatocyte a lte ra tio n , basophilic, a ild -Vascular aineralization, a ild -Not exaained, not in plane of section ThE folloaing tissues aere found to be aithin noraal liaits: Brain, Spinal Cord, Bone Marroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine. Urinary Bladder, Aorta, T e stis/Epididyais, Prostate, P itu ita ry , Thyroid, Trachea, Esophagus, Lysph Node (aesenteric), Pancreas, Salivary Bland, Eye. Aniaal Nuaber: 1R-3605 Sex: Hale Fate: (iieek= 106) Terainal S a c rific e Group! i 5) FC-143 300 ppa Macroscopic Observations: Liver Microscopic Observations: Heart Ki dney Liver Lung Salivary 61 and Spleen T e s tis /E p id id y a is -Pale, Bottled -Myocarditis, chronic nonsuppurative, au ltifo cal, ainiaal -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr 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 Cystoid degeneration, a u ltifo c a l, a ild Negaiocytosis, ainiaal -Vascular nineralication, t ild Pneueonia, in t e r s t it ia l, chronic, a u ltifo c a l, aild Alveolar aacrophages, aoderate Perivascular aononudear in f ilt r a t e , aoderate -S ia la d e n itis , chronic, aoderate -Heaatopoiesis, extraaedullary, increased, a ild Heaosiderosis, a ild -Tubule atrophy, asperaatogenesis, u n ila te ra l, aarfced Vascular a in e ra liza tio n , a ild Species: Rat Project Nuaber: 02G1CR0012 Suaaarized STAR Page: 106 2 7 0 000657 Sueearized Single Tabulated Aniia! Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anna! Nueber; 1P-3605 Sex: dale Fate: (Ueek= 106! Tereinal S a c rific e Group: ( 5) FC-143 300 ppi Microscopic Observations (continued): - The follow ing tissues werE found to be within nornal lie it s : Brain, Spinal Cord, Bone Marrow, Stoeach, Seall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyeph Node ieese n te ric), Pancreas, Eye. Anieal Nueber: 1R-3606 Sex: Male Fate: (Meek- 106) Tereinal S a c rific e Group: ( 51 FC-143 300 ppe Macroscopic Observations: Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid Spleen -No v is ib le lesions. -Nodular hyperplasia, cortex, focal, e ild -Chronic progressive nephropathy, e in iia l Pyelonephritis, acute, e ild -Portal ecnonuclear c e ll in f ilt r a t e , e ild Hegalocytosis, einieal -Vascular ein e ra liza tio n , eild -Not exaeined, not in plane of section -Heecsiderosis, e ild The follow ing tissu es were found to be within nornal lie it s : Erain, Spinal Cord, Bone Marrow, Heart, Stcaac h, Seall Intestine, Large Intestine, Urinary Bladder, Aorta, Test:s/Epididyeis, Prestate, P itu ita ry , Thyroid, Trachea, Esophagus, Lyeph Node ie e se n te ric!, Pancreas, Salivary Gland, Eye. Anieal Nueber: 1R-3607 Sex: Male rate: ikeek= 106) Tereinal S a c rific e Group: ( 5) FC-143 300 ppe Macroscopic Observations: P itu ita ry Microscopic Observations: Adrenal Kidney Liver Lung Pancreas -Heeorrhagic eass, 1 x 0.7 ce. -C o rtica l vacuolation, e u ltifo c a l, eoderate Pheochroaocytcia, benign, u n ila te ra l -Chronic progressive nephropathy, e ild Pyelonephritis, acute, eoderate Hyperplasia, pelvic epitheliue, diffuse, e ild -Po rtal eononuclear c e ll in f ilt r a t e , e ild -Vascular nineralization, e ild Alveolar eacrophages, e ild -Acinar atrophy, e ild Hyperplasia, is le t c e ll, eoderate Species: Rat Project Nueber: 02B1CR0012 Suuarized STAR Page: 107 000658 BEST COPY AVAUABLE Sutaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-1I3: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Ariaal Nuaber: 1R-3607 Sex: Kale Fate: (Week= 106) Terainal S a c rific e 6roup! ( 5) FC-143 30 ppa Microscopic Observations (continued): Parathyroid P itu ita ry Prostate Salivary Bland Spleen Thyroid Urinary Bladder -Adenora -Adenoaa - P r o s t a titis , acute, suppurative, aarked -S ia la d e n itis , chronic, aoderate -Heaosiderosis, a ild -Ultiaobranchial cyst - E p ith e lia l hyperplasia, staple, local areas, a ild The follow ing tissues were found to be within norcal lia it s : Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, T e stis/Epididyais, Trachea, Esophagus, Lyaph Node (aesenteric), Eye. Aniaal Nuater: 1R-3608 Sex: Male Fate: (Neek= 106) Terainal S a c rific e Broup: ( 5! FC-143 300 ppa Macroscopic Observations: Skin Microscopic Observations: Adrenal Kidney Liver Lung Skin Testi s/Epidi dyais Thyroid -Raised inflaaaed lesion, le f t hind footpad. -Sinusoidal ectasia, cortex, a ild Nodular hyperplasia, cortex, a u ltifo c a l, a ild -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in filtr a t e , aild Portal b ile duct p ro life ra tio n , a ild Cystoid degeneration, fo c a l, a ild Hepatocyte a lte ra tio n , vacuolated, a ild Megalocytosis, a ild -Vascular Bineraiization, a ild Alveolar aacrophages, a ild Perivascular aononudear in filtr a t e , a ild -Pododeraatitis, u lcera tive, hindleg, aar ked -Tubule atrophy, asperaatogenesis, acoerate -Ultiaobranchial cyst The follow ing tissues were found to be Mi thin noraal lia it s : Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Eland, Eye. Species: Rat Project Nuaber: 02B1CR0012 Suaaarized STAR Page: 106 272 000659 Suuarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tea Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaa! Nueber: 1R-3609 Sex: Male Fate: (Meek* 106) Tereinal S a crific e Eroup: ( 5) FC-143 300 ppe Macroscopic Observations: Microscopic Observations! Aerenal kidney Liver Lung Lyaph Node (eesenteric! Pancreas Parathyroid T e s tis /E p id id y e is - -No v is ib le lesions. -Nodular hyperplasia, cortex, focal, eiId -Chronic progressive nephropathy, eim eal -Portal eononudear c e ll in f ilt r a t e , a ild Portal b ile duct p ro life ra tio n , a ild Hegalocytosis, aild -Vascular ain eralization , a ild Heaorrhage, local areas, coderate -Sinusoidal ectasia, e ild -Acinar atrophy, eoderate P o ly a r te ritis , eoderate -Net exaiined, not in plane of section -Leydig c e ll hyperplasia, focal, a ild The follow ing tissues mere found to be mithin noreal lie it s ! Brain, Spinai Cord. Bone Marrou, Spleen, Heart, Stoaach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Thyroid, Trachea, Esophagus, Salivary Gland, Eye. Anieal Nur-ber: 1R-3610 Sex: Male Fate: 1Keek- 106) Tereinal S a c rific e Group: ( 5) FC-143 300 ppe Macroscopic Observations: Liver T e s tis /E p id id y e is Microscopic Observations: Adrenal kidney Liver Lung Pancreas T e s tis /E p id id y e is -Fee pale fo c i. -Testes appear sceemhat s a a ll. -Pheochroaocytoaa, benign, u n ila te ra l -Chronic progressive nephropathy, e ild -Portal eononudear c e ll in filtr a t e , e ild Hepatccyte vacuolation, e u ltifo c a i, e ild Cystcid degeneration, e u ltifo c a i, e ild Megalocytosis, id e a l -Vascular aineralization, a ild Pneueonia, in t e r s t it ia l, chronic, e u ltifo c a i, eild Perivascular eononudear in filtr a t e , ainiaal Heaorrhage, local areas, eoderate -Acinar atrophy, e ild -M ineralization, tubular, a ild Tubule atrophy, aspereatogenesis, b ila te r a l, earked Species: Rat Project Nueber: 02B1CR0012 Suuarized STAR Page! 109 2 7 5 000660 Suaearized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Rifcer Laboratories, Inc. 3H FC-143: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nuiber; 1R-3610 Sex: Male Fate: (Week= 106) Terunal S a c rific e Group: ( 5) FC-143 300 ppi Microscopic Observations (continued): Thyroid - -C cel 1 adenoia F o llic u la r hyperplasia, cy stic, u n ilateral, oderate The follow ing tissues were found to be within n o ria l U n its : Erain, spinal Cord, Bone Marrow, Spleen, Heart, Stoiach, Seal 1 Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Parathyroid, Trachea, Esophagus, Lyiph Mode iie s e n te r ic ', Salivary Gland, Eye. Anna! Number: 1R-3611 Sex: Male Fate: (Week= 106) T e riin a l S a c rific e Group: ( 5) FC-143 300 ppi Macroscopic Observations: Liver Microscopic Observations: Adrenal Esophagus Heart Kidney Liver Lung Pancreas Parathyroid Salivary Gland Thyroid -Few pale fo c i; raised pale lesion, 0.7 c i d ia ., in aedian lobe. -5inuscidal ectasia, cortex, ai Id Cortical vacuolation, focal, l in i ia l -Not exaiined, lis s in g -Myocarditis, chronic nonsuppurative, ultifocal, al Id -Chronic progressive nephropathy, l i l d Pelvic am eralization, n in n ai -Portal loncnudear ce ll in filtr a te , aild Hepatocyte vacuolation, a u ltifo c a l, a ild Cystoid degeneration, a u ltifo c a l, a ild Hepatocyte a lte ra tio n , vacuolated, a ild Megalocytosis, ainiaal Hyperplastic nodule C e lls in cords of sing le c e ll thickness. Many c e lls vacuolated. Large central blood f ille d space. -Vascular Bineraiization, a ild Heaorrhage, local areas, aoderate -Acinar atrophy, a ild -Not exaiined, lis s in g -S ia la d e n itis , chronic, aarked Extensive squaaous aetaplasia of duct e p ith eliu a with soae ducts occluded by hyperplastic, aetaplastic epitheliua. -Not exaiined, aissing Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 11C 274 000661 Summarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-361! Sex: Male Fate: (Heek= 106) Terminal S a c rific e Group: ! 5! FC-143 300 ppa Microscopic Observations (continued): Trachea -Not exaained, aissing The f o il owing tissues were found to be within noraal l i n t s : Brain, Spinal Cord, Bone Marro*, Spleen, Stoiach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Epididyais, Prostate, P itu ita ry , Lyaph Node (aesenteric), Eye. Aniaal Nuaber: 1R-362 Sex: Male Fate: INeek= 99) Found Dead Group: ( 5! FC-143 300 ppa Macroscopic Observations: Liver Microscopic Observations: Adrenal Kidney Liver Lung Pancreas Thyroid -M u ltilo b u la r aass, 4.5 x 4 x 3 ca in area of rig h t la te ra l lobe, attached to caudate lobe. -C o rtica l vacuolation, fo ca l, minimal -Chronic progressive nephropathy, marked -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild Hepatocellular carcinoma Nell differentiated, trabecular pattern, large areas of necrosis within tuaor. -Vascular m ineralization, a ild Alveolar macrophages, marked Medial hypertrophy, a rte rie s, moderate -Hyperplasia, is le t c e ll, moderate -Cyst, co llo id , a ild The folioming tissues ere found to be within noraal lim its : Brain, Spinal Cord, Bone Marro, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Parathyroid, Trachea, Esophagus, Salivary Gland, Eye, Lymph Node (mesenteric). Aniaal Number: 1R-3614 Sex! Hale Fate: (Heek= 106) Terminal S a c rific e Group: ( 5) FC-143 300 ppm Macroscopic Observations: T e s tis /E p id id y a is Microscopic Observations: Kidney Liver -Pale masses of various sizes in both testes. -Chronic progressive nephropathy, a ild -Portal mononuclear c e il in f ilt r a t e , a ild Cystoid degeneration, fo c a l, minimal Species: Rat Project Nuaber: 0281CR0012 Summarized STAR Page: 111 275 000662 Suaaarized Single Tabulated Aniaal Report (continued' Individual Macroscopic and Microscopic Observations pflPY IV lii M i DECTDtOI Owl I HI fillHvLk Riker L ib o rito rie 5 ' Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Number: 1R-3614 Sex: Male Fate: (Week* 106) Terainal S a c rific e Eroup: ( 51i FC-143 300 ppa Microscopic Observations (continued): Lung Prostate Spleen T e s tis /E p id id y a is - -Vascular mineralization, a ild Alveolar aacrophages, a ild -Not exaained, aissing -Heaosiderosis, aild -Tubule atrophy, aspermatogenesis, u n ila te ra l, aoderate Leydig c e ll adenoaa, u n ila te ra l The -following tissues were found to be within noraal U n its : Erain, Spinal Cord, Bone Harrow, Heart, Stomach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary 61 and, Eye. Aniaal Nuaber: 1R-3615 Sex: Male Fate: (Heek= 106) Terainal S a c rific e Group: ( 5) FC-143 300 ppa Macroscopic Observations: P itu ita ry Testis/Epididyais Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid P itu ita ry Salivary Eland Spleen T e s tis /E p id id y a is -Mass, 0.B ca dia. -Right te s tis sa a ll. -Sinusoidal ectasia, cortex, a ild -Chronic progressive nephropathy, aoderate -Porta! aor.onudear c e ll in f ilt r a t e , a ild Cystoid degeneration, a u ltifc c a l, a ild Megalccytosis, ainiaal -Vascular aineralization, a ild Alveolar aaccphages, a ild Hesorrhage, local areas, a ild -Not exaained, not in plane of section -Adenoaa -S ia la d e n itis , chronic, aarked Extensive hyperplasia and aetaplasia of duct e p ith e liu a . -Heaosiderosis, a ild -Tubule atrophy, asperaatogenesis, u n ila te ra l, aarked The -following tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Species: Rat Project Nueber: 02B1CR0012 Suaaarized STAR Page: 1G12 0 27 66 6 3 BESTC Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3616 Sex! Male Fate: (Week- 72) Found Dead Group: l 5) FC-143 30 ppa Macroscopic Observations: F itu ita ry Microscopic Observations: Kidney Liver Lung Pancreas P itu ita ry Salivary Gland Spleen -Enlarged, 0.9 ca dia. -Chronic progressive nephropathy, a in ia a l -Portal aononudear c e ll in filtr a t e , add Hepatocyte vacuclation, a u ltifo c a l, a in ia a l Cystoid degener ation, a u ltifo c a l, a iid Necrosis, a u ltifo c a l, aoderate -Vascular nineralization, a ild Alveolar aacrophages, a ild Heaorrhage, d iffu se , Barked -Hyperplasia, acinar c e ll, aoderate -Adenoaa -Not exaained, aissing -Heaosiderosis, a ild The follow ing tissues ere found to be within nornal b a it s : Brain, Spinal Cord, Bone Marrow, Heart, Stoeach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/E p id id y n s, Prostate, Adrenal, Thyroid, Parathyroid, Trachea. Esophagus, Lyaph Node (aesente-ic), Eye. Aniaal Nursed 1R-361B Sex: Hale Fate.' (Week= l t! T e riin a l S a c rific e Group! ( 51 FC-143 300 ppa Macroscopic Observations: Liver Microscopic Observations: Adrenal Kidney Liver Lung -Appears palei pale raised aass, 1 ca d ia ., caudate lobe. -Cortical vacuolation, a u ltifo c a l, a ild Sinusoidal ectasia, cortex, a ild -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a t e , aild Hepatocyte vacuolation, a u ltifo c a l, ainiaal Necrosis, focal, ainiaal Hegalocytosis, ainiaal Hepatocellular carcinoca Trabecular pattern, aany tuaor c e lls vacuolated, aoderate a ito tic a c tiv ity . -Vascular aineralization, Bild Alveolar BacrophagEs, a ild The follow ing tissues we-e found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Species: Rat Project Nuaber: C2B1CR0012 Suaaarized STAR Page: 113 277 000664 Sutiarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Anns! timber: 1R-3618 Sex: Male Fate: (Neek= 106) Tereinal S a c rific e 6roup: ( 5) FC-143 300 ppa Microscopic Observations (continued): The follow ing tissues were found to be within noreal J i a i t s (continued): Urinary El adder, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyeph tiode (nesenteric), Pancreas, Salivary Gland, Eye. Aniaal Nuater: 1R-3619 Sex: Male Fate: (Keek* 106) Terainal S a c rific e Group! ( 5) FC-143 300 ppa Macroscopic Observations: Liver Kidney Urinary Bladder Microscopic Observations: Adrenal Kidney Liver Lung Salivary Gland Urinary Bladder -Raised lesions, 2 x 1.5 ca, aedi an lobes. -Hydronephrosis, le f t kidney. -Distended into abdaaen, f ille d with dark colored flu id . -Sinusoidal ectasia, cortex, ai ! d Nodular hyperplasia, cortex, fo c a l, aoderate -Chronic progressive nephropathy, aim aal Hydronephrosis, b ila te r a l, a ild -Po rta l aononuclear c e ll in f ilt r a t e , a ild Cystoid degeneration, a u ltifo c a l, a ild Megaiocytosis, a ild Hepatocellular carcinoaa Poorly d iffe re n tia te d , adenoid and trabecular patterns, aoderate a ito tic a c tiv ity . -Vascular aineralization, a ild Heaorrhage, local areas, aodepate -Not exaained, aissing -E p ith e lia l hyperplasia, s itp le , diffuse, a ild Heaorrhage, focal, ainin al The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Aorta, T e stis/Ep id id yais, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyiph Mode (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-362I Sex: Male Fate: (Neek= 106) Terainal S a c rific e Group: ( 5) FC-143 300 ppa Macroscopic Observations: Microscopic Observations: Kidney -No v is ib le lesions. -Chronic progressive nephropathy, a in ia a l Species: Rat Project Nuaber: 0281CR0012 Suaaariced STAR Page: 114 2 7 8 000665 Sutnarized Single Tabulated A nital Report (continued) Individual Macroscopic and Microscopic Observations Piker Laboratories, Ire. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n i Nunber: 1R-3621 Sex: Male Fate: (Heek* 106) Terninal S a c rific e 6roup: ( 5) FC-143 300 ppn Microscopic Observations (continued): Liver Lung Farathyroid Salivary Gland Spleen -Portal lononudear c e ll in filtr a t e , ai id Cystoib degeneration, lu lt if o c a l, l i l d Megalocytosis, n ld -Vascular n in e ra liza tio n , ni Id -Not exanined, not in plane of section -S ia la d e n itis , chronic, noderate -Henosiderosis, n ils The follow ing tissues were found to be within nornal U n its : Brain, Spinal Cord, Bone Marrow, Heart, Stonach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, T estis/Epididynis, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lynph Node inesenteric), Pancreas, Eye. Aninal Nunber: 1R-3623 Sex: Male Fate: (Week= 106) Terninal S a c rific e 6roup: ( 5) FC-143 300 ppn Macroscopic Observations! Microscopic Observations: Adrenal Kidney Liver Lung Lynph Node (nesenteric) P itu ita ry Prostate Salivary 61and Testi 5/Epidi dysis -No v is ib le lesions. -C ortical vacuolaticn, focal, n ild Sinusoidal ectasia, cortex, aoderate -Chronic progressive nephropathy, n ild -Portal nor,enuclear c e ll in f ilt r a t e , n ild Hepatocyte vacuo!ation, n ild Necrosis, n u ltifo c a l, n ild Megalocytosis, ninina! -Vascular nineralization, nild Pneunonia, in t e r s t it ia l, chronic, n u ltifo c a l, n ild Alveolar nacrophages, n ild -Henorrhage, n ild -Not exanined, nissing - P r o s t a titis , acute, suppurative, noderate -S ia la d e n itis , chronic, narked -Vascular nineralization, n ild The follow ing tissu es were found to be w ithin noma! U n its : Brain, Spina! Cord, Bone Harrow, Spleen, Heart, Stonach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Thyroid, Parathyroid, Trachea, Esophagus, Eye, Pancreas. Species: Rat Project Nunber: 02B1CR0012 279Sunnarized STAR Page: 115 000066 Suaaarised Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. JM FC-143: To Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nulter: 1R-3624 Sex: Male Group: ( 5! FC-143 300 ppi Fate: (Meek- 90) S acrificed in e x tre iis Macroscopic Observations: P itu ita ry Liver Kidney T e s tis /E p id id y iis Microscopic Observations: Adrenal Kidney Liver Lung P itu ita ry Prostate Spleen T e s tis /E p id id y iis -Heiorrhagic lass, 1 x 0.5 c i. -Possibly pale -S lig h tly enlarged and pitted . -Both testes appear soient,at s t a ll. -C ortical vacuolation, a u ltifo ca l, *:ld Medullary c e ll hyperplasia, lu lt lf c c a l, l i l d -Chronic progressive nephropathy, oderate -Portal ononuclear c e ll in f ilt r a t e , a ild Hepatocyte vacuclation, p e rip o rta l, ode'-ate -Vascular lin e ra lic a tio n , lil d Pneuionia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild Alveolar aacrophages, a u ltifo c a l, a ild -Adenona - P r o s t a titis , acute, suppurative, aarked -Heaosiderosis, a ild -Tubule atrophy, asperaatogenesis, b ila te r a l, aarked The follow ing tissues aere found to be within noraal lia it s : Brain, Spinal Cord, Bone Harrou, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladde-, Aorta, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Bland, Eye. Ani aal Nuaber: 1R-3625 Sex: Male 6roup: ( 5) FC-143 300 ppi Fate: IWeek= 27) Sacrificed in extreais Macroscopic Observations: Soft Tissues (neck) Spleen Microscopic Observations: Liver Lung -Large aultinodular aass, 9 x 8 x 6 c i, in le f t neck and throat region. Possibly of a a iia ry gland or sa liva ry gland o rig in . Mass contained several c y stic areas that aere f i ll e d with dark flu id . -Possibly s lig h tly enlarged. -Portal aononuclear c e ll in f ilt r a t e , a ild Necrosis, focal, a ild Megalocytosis, ainiaa! -M etastatic neoplasa Throabus Large throabus containing tuaor c e lls froa sa liva ry gland tuaor. M u ltip le saall aetastases of sa liv a ry tuaor throughout lung. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 116 non 280 000667 Suttarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nutter1. 1R-3625 Sex: Male Sroup: ( S) FC-143 300 ppr. Fate: (Week= 27) Sacrificed in extreais Microscopic Observations (continued): Salivary Gland Spleen -Carcinosa Highly c e llu la r , anaplastic tuaor. Apoears to have arisen in parotid gland duct. Saall r i t of sa liva ry gland tissue around aass. -Heeatopoiesis, extraiedullary, increased, O d e r ate The follow ing tissues were found to be within normal lia i'c s : Brain, Spinal Cord, Bone Marrow, Kidney, Hear t, Stotach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, Test!s/Epididyis, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lyiph Node (esenteric), Pancreas, Eye. Aniaal Nutter: 1R-3S28 Sex: Male Fate: (Meet- 106) Terminal S a c rific e Group: ( 5) FC-143 300 ppc Macroscopic Observations: Microscopic Observations: Adrenal Kidney Liver Lung Parathyroid Spleen -No v is ib le lesions. -Cortical vacuolation, focal, toderate -Chronic progressive nephropathy, toderate -Portal tononudear c e ll in filtr a te , t ild Portal b ile duct p ro life ra tio n , t ild Cystoid degeneration, t u lt if c c a l, t il d Megalocytosis, ainiaal -Vascular tin e ra liza tio n , toderate Alveolar tacrophages, t ild Hescrrhage, local areas, toderate -Not exaained, not in plane of section -Hetosiderosis, t ild The following tissu es were found to be within nortal l i n t s : Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/E p id id y tis, Prostate, P itu ita ry , Thyroid, Trachea, Esophagus, Lytph Node (tesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nutter: 02B1CR0C12 Suttarized STAR Page: 117 2 8 000668 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. SM FC-143: Two Tear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3629 Sex: Male Fate: (Neek= 106) Ternnal S a crific e Group: 1 5) FC-143 300 pps Macroscopic Observations: Microscopic Observations: Heart Kidney Liver Lung Salivary Gland Thyroid -Ne v is ib le lesions. -Myocarditis, chronic nonsuppurative, au ltifocal, aild -Chronic progressive nephropathy, a ild -Portal aonoruclear c e ll in f ilt r a t e , a ild Megalocytosis, a ild -Vascular aineralization, a ild Alveolar aacrophages, a ild Heaorrhage, local areas, coderate -S ia la d e n itis , chronic, aarked -Ultiaobranchial cyst The follow ing tissues cere found to be within noraal U n its : Brain, Spinal Cord, Bone Marrow, Spleen, Staeach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Epididyais, Prostate, P itu ita ry , Adrenal, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-3630 Sex: Male Fate: (Week= 106) Teraina! S a c rific e Group! ( 5) FC-143 300 ppc Macroscopic Observations: Microscopic Observations: Adrenal Heart Liver Lung P itu ita ry T e s tis /E p id id y a is -No v is ib le lesions. -Sinusoidal ectasia, cortex, a ild -Myocardial fib ro s is , local areas, a ild Myocarditis, chronic nonsuppurative, local areas, a ild -Portal aononudear c e ll in filtr a t e , aild Cystoid degeneration, a u ltifo c a l, a ild Megalocytosis, ainiaal -Vascular aineralization, a ild -Not exaained, aissing -Vascular aineralization, a ild The follow ing tissues were found to be w ithin noraal U a it s ! Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 118 2 8 2 000S69 Suaiarized Single Tabulated Anieal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Annal Number: 1R-3631 Sex: Male Fate: Week* 106) Terminal S a c rific e Group: 1 5) FC-143 300 pp* Macroscopic Observations: Microscopic Observations: Adrenal Kidney Liver Lung Salivary Gland Spleen -No v is ib le lesions. -Nodular hyperplasia, cortex, fo ca l, a ild Medullary c e ll hyperplasia, fo ca l, ainiaal -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild Hepatocyte vacuolation, local areas, a ild Megalocytosis, ainiaal -Vascular m ineralization, aoderate Alveolar aacrophages, a ild Hemorrhage, local areas, aoderate -S ia la d e n itis , chronic, aarked There were two sections of gland on the s lid e , only one was involved. -Heaosiderosis, a ild The follow ing tissues were found to be within noreal lie it s : Brain, Spinal Cord, Bone Harrow, Heart, Stonach, Seal 1 Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea Esophagus, Lyeph NcdE (eesenteric), Pancreas, Eye. Aniaal Nusber: 1R-3632 Sex: Hale Fate! (Meek* 106) Tereir.a! S a crific e Group: ( 5) FC-143 300 ppa Macroscopic Observations: Liver Testis/Epididycis Microscopic Observations: Kidney Liver Lung Pancreas -Few pale fo c i. -Pale aass, 1.5 ca dia. -Chronic progressive nephropathy, aoderate -Portal aononudear c e ll in filtr a t e , a ild Hepatocyte vacuolation, a u ltifo c a l, a ild Megalocytosis, a ild Hepatocyte a lte ra tio n , basophilic, a ild Single subcapsular area of basophilic a lte ra tio n . About one half of the c e lls have a u ltip le cytoplasaic vacuoles. -Vascular mineralization, a ild Alveolar aacrophages, a ild HeaorrhagE, fo ca l, a ild -Hyperplasia, is le t c e ll, aoderate Species: Rat Project Number; 0281CRQ012 Summarized STAR Page: 119 2 3 000670 Susaarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 flniaal Number: 1R-3632 Sex: Male Fate: (Neek= 10&) Terainal S a c rific e Broup: ( 5) FC-143 3C0 ppa Microscopic Observations (continued): Testi s/Epi didy*is -Tabule atrophy, aspermatogenesis, u n ila te ra l, marked Leydig c e ll adenoma, u n ila te ra l The follow ing tissues were found to be within normal lia it s : Brain, Spinal C c d , Bone Marrow, Spleen, Heart, Stoaach, Seal 1 Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus Lviph Node (aesenteric), Salivary Bland, Eye. flniaal Number: 1R-3E33 Sex: Male Fate: INeet= 10i) Terminal S a c rific e Broup: ! 5) FC-143 300 ppm Macroscopic Observations: Eye Kibney Microscopic Observations: Adrenal Eye Heart Kidney Liver Lung Thyroid -Opacity, rig h t eye. - B ila te r a lly pale and pitted . -Sinusoidal ectasia, cortex, mild Banglioneurosa Large, well diffe re n tia te d tumor a risin g in medulla of one gland. Composed of nerve fib e rs and large ganglion c e lls . - K e ra titis , chronic, moderate -Myocarditis, chronic nonsuppurative, local areas, mild -Chronic progressive nephropathy, marked One of pair present -Portal mononuclear c e ll in f ilt r a t e , mild Portal b ile duct p ro life ra tio n , mild Cystoid degeneration, m u ltifo ca l, mild Hepatocyte a lte ra tio n , vacuolated, mild Megalocytosis, moderate -Vascular m ineralization, mild Alveolar macrophages, mild Perivascular mononuclear in f ilt r a t e , minima! Hemorrhage, local areas, mild -Cyst, colloid The follow ing tissues were found to be within normal lim its : Brain, Spinal Cord, Eone Marrow, Spleen, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Testis'Epididym is, Prostate, P itu ita ry , Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary 61and. Species: Rat Project Number: 0281CR0012 Summarized STAR Page: 120 2 8 4 000671 BEST COPY AVA!! Suaaarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations r Riker Laboratories, Inc. 3M fc -1 4 3 : Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuiber: 1R-3634 Sex: Male Fate: (Week= 106 T e riin a l S a c rific e Group: < 5) FC-143 300 ppa Macroscopic Observations: Testi s/Ep i'di dysis Mesentery Microscopic Observations: Liver Lung Pancreas Parathyroid Spleen Testi s/Epidi dyii s -Pale aasses, 1 ca d ie ., in each t e s t is . -Mass, 3 x l.S ca in area of pancreas. -Portal aononudear c e ll in filtr a t e , aiId Cystoid degeneration, a u ltifo c a l, aiId Hepatocyte a lte ra tio n , vacuolated, aoderate Hegalocytosis, ainiaal -Vascular a in e ra liza tio n , a i1d Alveolar aacrcphages, a ild -Adenocarcincaa Large, highly c e llu la r , well d ifferen tia ted neoplasa aith high a ito tic index. Lyaphatic invasion. -Not exaained, not in plane of section -Heaosiderosis, a ild -Tubule atrophy, aspematogenesis, b ila te r a l, aarkeb Leydig c e ll adenoaa, b ila te ra l The follow ing tissues were found to be within noraal lia it s : Brain, Spinal Co'd, Bone Harrow, Kidney, Heart, Stoaach, Seal! Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Adrenal, Thyroid, Trachea, Esophagus, Lyaph Node (aesentenc), Salivary Bland, Eye. Aniaal Nuaber: IP,-3635 Sex: Male Fate: (Neek= 106) Terainal S a c rific e Group: ( 5) FC-143 300 ppa Macroscopic Observations: P itu ita ry Microscopic Observations: Adrenal Kidney Liver Lung P itu ita ry Salivary Stand -Heaorrhagic area, 0.5 x 0.2 ca. -Medullary c e ll hyperplasia, focal, ainiaal -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in f ilt r a t e , a il; Megalocytosis, ainiaal -Vascular aineralization, si : c Alveolar iscrophsges, a ild Perivascular aononudear in filtr a t e , l i m a i -hder.zr.a -S ia la d e n itis , chronic, aarfced The follow ing tissues were found i : be within noraal l i n t s : Brain, Spinal Cord, Bcr.s Marrow, Spleen, Heart, Stoaach. Saall Intestine, Large Intestine, Species: Rat Project Nuiber: 02eiCR0C!2 Suiaa'ized STAR Page: 121 285 000S72 BEST COPY AVAII ABLE SuriaarizEd Single Tabulated A riaal Report (continued) Individual Macroscopic and Microscopic Observations fille r Laboratories, Inc. JM FC-143: Two Vear Oral Toxicity-Oncogenicity Study ir. Rats Table: 2 Anisa! (iuter: IR-3633 Sex: Male Fata: (ieek= 106! Teraina! S a c rific e Group : i 5) FC-143 300 ppt Microscopic Observations (continued): The follow ing tissues we-e found 'to be within norial U n it s (continued): Urinary Gladder, Ac-ta, Testis E p id id y iis , Prostate, Thyroid, Parathy-oid, Trachea, Esophagus, Lysph Rods (eeser.teri: !, Pancreas, Eye. Anial Nufter: 1R-3636 Sex: Male Pate! ieei:= 106) Tersine! S a c rific e Group : I 5) FC-143 300 ppe Macroscopic Observations: fiere Testisr'Epididysis Microscopic Observations: Bene Heart Kidney Liver Lung Lyaph Node Mesenterio) Pancreas T e s tis /E p id id y a is -Swoller aetatarsal jo in ts , b ila te ra l hind lia b s . -Both testes appear s t a ll. -A rth ritis , synovitis; join ts, hindleg, oberate -Myocarditis, chronic nonsuppurative, focal, iniaal -Chronic progressive nephropathy, ainiaa! -Portal aononudear c e ll in filtr a t e , a ild Portal b ile duct p ro life ra tio n , a ild Cystoid degeneration, fo c a l, ainiaal Hegalocytosis, ainiaal -Vascular aineralization, a ild Alveolar aacrophages, a ild -6ranuloaa, M u ltifo c a l, aoderate - P o ly a r te ritis , aoderate -Tubule atrophy, asperaatogenesis, b ila te r a l, arked P o ly a rte ritis , aoderate Vascular B ineraiiza tio n , a ild The follow ing tissues were found to be within noraal lin it s : Erain, Spinal Cord, Bone Marrow, Spleen, Stoaach, Seal! Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Salivary Gland, Eye. Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 122 2 3 6 G00673 Suaiarized Single Tabulated A n iia l Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 A n iia l Nusber: 1R-3637 Sex: Male Fate: <Neek= 106! T e riin a l S a crific e Macroscopic Observations: Thyroid P itu ita ry Thyius Microscopic Observations: Heart Kidney Liver Lung Pancreas P itu ita ry Salivary Eland Thyius 6roup: ( 5) FC-143 300 ppi - -Possibly s lig h tly enlarged. -Mass, 0.5 cs dia. -S lig h tly enlarged and heiorrhagic. -Myocarditis, chronic nonsuppurative, ultifocal, lin is a l -Chronic progressive nephropathy, a in iia l -Portal lononuclear c e ll in filt r a t e , i i l d Portal b ile duct p ro life ra tio n , ci Id Necrosis, a u ltifo c a l, aoderate -Vascular lin e ra liz a tio n , ai 1d Hesorrhage, local areas, aoderate -Acinar atrophy, a in iia l -Adenoia -Not exasined, aissing -Heaorrhage, aarked The follow ing tissues were found to be within no rial lin it s : Brain, Spinal Cord, Bone Marrow, Spleen, Stoiach, S ta ll Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/E p id id ysis, Prostate, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lycph Node (te se n te ric), Eye. A n ta l Nusber: IR-3639 Sex: Male Fate: (Neek= 106) Tertinal S a c rific e Group: ( 5) FC-143 300 ppi Macroscopic Observations: P itu ita ry Adrenal Microscopic Observations: Adrenal Kidney Liver Lung -Raised dark sass, 0.7 c i dia. -Enlarged, rig h t adrenal -C o rtica l vacuolation, local areas, aoderate Sinusoidal ectasia, cortex, larked Medullary c e ll hyperplasia, fo ca l, a ild -M ineralization, co rtica l, a ild -Portal aononudear c e ll in f ilt r a t e , a in iia l -Vascular aineralization, i il d Alveolar aacrophages, a ild Perivascular aononudear in filtr a t e , iil d Heaorrhage, local areas, aoderate Sranuloaa Fragaent of unidentified foreign aa te ria l in granuloaa. Species: Ret Project Nimber: 02B1CR0012 Suaaarized STAR Peg Suaaarized Single Tabulated Aniaal Report (continued! Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. JM FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3639 Sex! Male Fate: (Week= 10i) Terainal S a c rific e Group: 1 51 FC-143 30C ppa Microscopic Observations (continued): Pancreas Parathyroid P itu ita ry Spleen - -Not exaafned, aissing -Not exaained, not in plane of section -Adenoaa -Heaosiderosi s, ai Id The follow ing tissues were found tc be within nomai l ia it s : Brain, Spinal Cord, Bone Marrow, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, T e stis/Epididyais, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node ia esen teric), Salivary Gland, Eye. Aniaal Nuaber: 1R-3640 Sex: Male Group: ( 5! FC-143 300 ppa Fate: (Week= 72) Sacrificed in extreais Macroscopic Observations: Spleen Abdcaen (internal) Eye Microscopic Observations: Adrenal Eye Kidney Liver Lung Spleen Stoaach -Possibly sa a lle r than noraal. -G astrointestin al tra ct froa stoaach to cecua distended with gas. -xRight eye s lig h t ly atrophied -Nodular hyperplasia, cortex, focal, ainiaal -K e r a titis , acute, aarked Lesion in rig h t eye. Extensive corneal ulceration. -Calculus, pelvic, aild -Portal aononuclear c e ll in f ilt r a t e , a ild Hegalocytosis, ainiaal -Vascular aineralizatior,, a ild Alveolar aacrophages, a ild -Heaosiderosis, a ild Atrophy, aoderate -G a s tritis , acute, diffuse, a ild The follow ing tissu es were found to be within noraal lia it s : Brain, Spinal Cord, Bone Marrow, Heart, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Ep id id yais, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node Iaesenteric), Pancreas, Salivary Gland Species; Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 124 2 8 8 000675 Sunnarized Single Tabulated Aninal Report (continued) Individual Racroscopic and Ricroscopic Observations Riker Laboratories, Inc. 3R FC-143: Two Year Oral Toxicity-D ncogenicity Study in Rats Table: 2 A n iia ! Nueber: 1R-3441 Sex: Rale Fate: (kieek= 106) T e riin a l S a c rific e Group1. ( 5) FC-143 300 ppi Racroscopic Observations: Liver Ricroscopic Observations: Adrenal Heart Kidney Liver Lung Pancreas Spleen T e stis'E p id id yiis -Yellow ish fo c i, 0.3 ce d ia ., nedian lobe. -Hedullary c e ll hyperplasia, local areas, iiI d -M yocarditis, chronic nonsuppurative, ultifocal, n ld -Chronic progressive nephropathy, noderate -Portal eononuclear c e ll in f ilt r a t e , e ild Cystoid degeneration, n u ltifo c a l, e ild Regalocytosis, n in n a i H yperplastic nodule Circunscribed, expansive iesion with preservation of noreal architecture. Portal areas present. C e lls in nodule nore basophilic, vacuolated. -Vascular n in e ra liza ticn , n ild Henorrhage, fo c a l, n ild -Acinar atrophy, noderate -Henosiderosis, n ild -Leydig c e ll adenona, u n ila te ra l The follow ing tissu e s were found to be w ithin n o ria l l i i i t s ! Brain, Sp ira l Cord, Bone Harrow, Stonach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyeph Node (sesenteric S a liv a ry Gland, Eye. Aninal Nuiber: 1R-3644 Sex: Hale Fate: <Neek= 106) Terninal S a c rific e Group: ( 5) FC-143 300 pps Racroscopic Observations: Liver Ricroscopic Observations: Adrenal Heart Kidney Liver -Appears nettled; sn a il pale ar ea in neciar lobe. -C ortical vacuclation, focal, n ild Nodular hyperplasia, cortex, fo c a l, n ild -H yocarditis, chronic nonsuppurative, n u ltifo cal, nild -Chronic progressive nephropathy, ein m a l -Portal eononuclear c e ll in f ilt r a t e , n ild Portal b ile duct p r o life r a tio n , n ild Regalocytosis, nininai H yperplastic nodule C e lls of nodule have s lig h t ly nore basophilic cytoplasn; nany are vacuolated. Species: Rat Froject Nueber: 02B1CR0012 Sunnarired STAR Page: 1 2 5 ^ - 2 3 9 000676 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Tuo Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3644 Sex! Male Fate: (Meek= 106) Terainal S a c rific e Sroup: ( 5) FC-143 300 ppa Microscopic Observations (continued): Lung - Salivary Gland T e s tis /E p id id y iis -Vascular aineralization, a ild Alveolar aacrophages, a ild -S ia la d e n itis , chronic, aarked -Vascular c in e ra liz a tio n , aoderate The T oll owing tissues ere found to be within noraal l iu it s : Grain, Spinal Cord, Bone Marro, Spleen, Stoaach, Seal! Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, P itu ita ry , Thyroid, Parathyroid, Trachea, Esophagus, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-3645 Sex: Male Fate: (Week= 106) Terainal S a c rific e Group! ( 5) FC-143 300 ppa Macroscopic Observations: T e s tis /E p id id y iis Microscopic Observations: Adrenal Aorta Esophagus Kidney Liver Lung Pancreas Parathyroid Salivary Gland Soft Tissues (thorax) Spleen T e s tis /E p id id y iis Trachea Urinary Bladder -Pale aass, 1.3 ca d ia ., in le f t t e s tis . -Nodular hyperplasia, cortex, a u lt if o c a l, a ild -M etastatic neoplasa -M etastatic neoplasa -Chronic progressive nephropathy, a ild -Portal aononudear c e ll in filtr a te , ainiaal Portal b ile duct p ro life ra tio n , a in ia a l Megalocytosis, ainiaal -Vascular aineralization, a ild Pneuaonia, in t e r s t it ia l, chronic, a u ltifo c a l, a ild Alveolar aacrophages, a ild Heaorrhage, focal, a ild -Acinar atrophy, a ild -Adenoaa -S ia la d e n itis , chronic, aoderate -Histiocytoaa, aalignant Diffuse in f ilt r a t e of h is t io c y tic c e lls in aediastinal tissues. Moderate nuaber of aultinudeate giant c e lls . In filtra te extends into ausde around bone. -HEaosiderosis, a ild -Leydig c e il adenoaa, u n ila te ra l -M etastatic neoplasa -E p ith e lia l hyperplasia, sieple, diffuse, ainiaal Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 126 2 9 0 000677 Suaaarized Single Tabulated Aniaal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3H FC-143: Tao Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Aniaal Nuaber: 1R-3645 Sex: Male Fate: (Heek= 106) Terainal S a c rific e Group: < 5) FC-143 300 ppa Microscopic Observations (continued): The fo llo a in g tissues were found to be u ith in noraal h a lt s : Brain, Spinal Cord, Bone Marroa, Heart, Stoaach, Saall Intestine, Large Intestine, Prostate, P itu ita ry , Thyroid, Lyaph Node (aesenteric), Eye. Aniaal Nuaber: 1R-4641 Sex: Feaale Group: ( 5) FC-143 300 ppa Fate: (Week* 73) Sacrificed in extreais Macroscopic Observations: Maasary Gland Microscopic Observations: Adrenal Esophagus Kidney Liver Lung Mannary Gland Ovary Salivary Gland -Large a u ltilo b u la r subcutaneous aass, le f t inguinal and perineal area, 10 x 7 x 3.5 cs. Mass ulcerated on the dorsal sur face; inside cy stic aith a ilk y flu id present. -Sinusoidal ectasia, cortex. Barked -Not exaained, aissing -Chronic progressive nephropathy, air.ieai -Portal b ile duct p ro life ra tio n , a ild Hepatocyte a lte ra tio n , vacuolated, focal a iria a l -Heaorrhage, local areas, a ild Alveolar aacrophages, a u ltifo c a l, a ild -Fibroadenoaa -Not exaained, aissing -Not exaained, aissing 'he fo ilo u in g tissues were found to be within noraal 1ia it s : Brain, Spinal Cord, Bone Marroa, Spleen, Heart, Stoaach, Saall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, P itu ita ry , Trachea, Thyroid, Parathyroid, Lyaph Node (aesenteric), Pancreas, Eye. Aniaal Nuaber: 1R-4643 Sex: Feaale Group! ( 5) FC-14u 300 ppa Fate: (Week- 7B) Sacrificed in extreais Macroscopic Observations: P itu ita ry Microscopic Observations: Esophagus Kidney Liver -Heaorrhagic aass, 0.G ca dia. -Not exaained, aissing -P e lv ic a in e ra liz a tio n , a i Id -Hepatocyte vacuolation, d iffu se , a ild Species: Rat Project Nuaber: 0281CR0012 Suaaarized STAR Page: 127 2 9 1 000678