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PpXrOH'ft International Research and Development Corporation SPONSOR: 3M Company COMPOUND: Fluorad Fluorochemical FC-143 SUBJECT: Ninety Day Subacute Rhesus Monkey Toxicity Study. Vice Preessiicdii:ne and Director or Research Collaborators: D. C. Jessup, Ph.D., Associate Director of Research R. G. Geil, D.V.M., Vice President and Director of Pathology J. S. Mehring, Ph.D., Director of Large Animal Toxicology 137-090 Date :_____November 10, 1978 001723 ________International Research and Development Corporation______ T A B L E OF C O N T E N T S (Continued) Table No. 5- 7. Individual Hematological Values ........................... 8. Means and Significance of Biochemical Values ............ 9-11. Individual Biochemical Values ............................. 12. Means and Significance of Urinalysis Values .............. 13-15. Individual Urinalysis Values ............................ 16. Summary of Gross Necropsy Observations .................. 17. Absolute and Relative Organ Weights ...................... 18. Microscopic Observations ................................. Page 18-20 21 22-24 25 26-28 29-30 31-32 33-39 137-090 001724 International Research and Development Corporation Page 1 I. SYNOPSIS In a ninety day oral study in rhesus monkeys, Fluorad Fluorochemical FC-143 was administered at dosage levels of 0 (control, treated only with 0.5% Methocel), 3, 10, 30 and 100 mg/kg/day. Two male and two female monkeys were initiated at each dosage level and also in a control group. The monkeys were observed twice daily for general physical appearance and behavior and pharmacotoxic signs. Body weights were recorded weekly. Hematological, biochemical and urinalysis studies were conducted once in the control period, at the end of the first and third months of study. The monkeys treated with the higher dose, (100 mg/kg/day) all died during weeks 2 through 5 of the study. At the 30 mg/kg/day dosage level, three monkeys died during weeks 7-12. They all showed signs of toxicity in the gastrointestinal tract (anorexia, emesis, sometimes brown in color, black stools), pale face and gums, swollen face and eyes, slight to severe decreased activity and prostration. The monkeys of the 30 and 100 mg/kg/day dosage level showed body weight losses from the first week of the study. Because of the early deaths of the monkeys at the 100 mg/kg/day dosage level, the clinical laboratory tests were not conducted. The monkeys at the 30 mg/kg/day dosage level showed, in the first month of the study, slight increase in prothrombin time and in acti vated partial thromboplastin time (A.P.T.T.) values, as well as decreased alkaline phosphatase activity in the serum (statistically significant). Only one monkey from this dosage level in this period showed a low albumin value. At the end of the study, the only remaining monkey from the 30 mg/kg/day dosage level showed apparent anemia, low blood glucose, alkaline phosphatase, total protein and albumin values. There was no mortality at the 10 mg/kg/day dosage level. One monkey had black stool on several days in week 12 and occasionally 137-090 001725 International Research and Development Corporation Page 2 anorexia and one monkey exhibited pale face and gums. At this dosage level there was a very slight increase in the activated P.T.T. values in the female monkeys during the first month of the study (not sta tistically significant). There were no changes in the other indices and no changes in the body weight. In single monkeys from the 3 and 10 mg/kg/day dosage levels, there were trends toward decreased alkaline phosphatase in the serum. In the control and the 3 mg/kg/day dosage level there was no mor tality, no changes in the body weights and no signs of toxicity. Soft stool, diarrhea or emesis were observed occasionally. The mortality and the above mentioned signs of toxicity in the 30 and 100 mg/kg/day dosage levels were compound-related. There was a trend toward the same signs of toxicity in single monkeys at the 10 mg/kg/day dosage level. The 3 mg/kg/day dosage level seems to be free of signs of toxicity. There is an evident relationship between the administered doses and the degree of the toxicity. No gross or microscopic lesions which were considered compoundrelated were seen in tissues other than the adrenals, bone marrow, spleen and lymph nodes for male and female monkeys at the 30 and 100 mg/kg/day dosage levels. Microscopically, the adrenals from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compoundrelated marked diffuse lipid depletion; the bone marrow from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compoundrelated slight to moderate hypocellularity; the spleen and lymph nodes from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compound related moderate atrophy of lymphoid follicles. Statistically significant variations in sex group mean weights of a few organs occurred between the control and experimental groups. These variations were of unknown biological significance and were not accompanied by morphologic alterations. 137-090 001726 International Research and Development Corporation Page 3 II. COMPOUND The compound was received from 3M Company, Saint Paul, Minnesota on October 24, 1977 as shown below: ___________ Label______________ Description Fluorad Fluorochemical FC-143 3M Stock No. 98-0211-0008-0 Lot 340 white powder 137-090 001727 International Research and Development Corporation Page 4 111 CLINICAL s t u d i e s A. METHODS : 1. General Procedure: Ten male rhesus monkeys (weighing from 2.60 to 3.90 kilograms) and 10 females (weighing from 2.95 to 3.80 kilograms) were initiated on this study. The monkeys were purchased from Primate Imports Corporation, Port Washington, N. Y. 11050. The monkeys were housed individually in hanging wire mesh, "squeeze type" cages and maintained in a temperature, humidity and light controlled enviroment. Purina Monkey Chow was fed twice each day and fresh apples were fed 3 times a week. Water was available a<i libitum. During the conditioning period, the monkeys were tattooed on the inner surface of the thigh and intrapalpebral tuberculin tests were conducted. Tuberculin tests were conducted at bimonthly inter vals during the treatment period. Also a complete physical examina tion was conducted by the staff veterinarian prior to initiation of compound administration. Only monkeys in good health were selected for the study. This study was initiated on January 11, 1978. Terminal sacri fices were conducted on April 12, 1978. 2. Compound Administration; At the end of the conditioning period the monkeys were divided into five groups on a random basis, so that the initial average body weights were similar: Number of Monkeys Male Female Dosage Level 22 22 22 22 22 Control 3 mg/kg/day 10 mg/kg/day 30 mg/kg/day 100 mg/kg/day 137-090 COI728 International Research and Development Corporation Page 5 The test compound, suspended in 0.5% Methocel, was admin istered by gavage, 7 days each week. All doses were given in a constant volume. Also the same volume of 0.5% Methocel was given to the vehicle control group. Individual daily doses were based upon the body weights obtained weekly. 3. Observations: The monkeys were observed twice daily for general physical appearance and behavior and pharmacotoxic signs. Individual body weights were recorded weekly. General physical examinations were con ducted in the control period and monthly during the study. 4. Clinical Laboratory Tests; Blood and urine samples were obtained for analysis from all monkeys once during the control period and at 1 and 3 months of study. The monkeys were fasted overnight prior to the collection of blood and urine samples. a. Hematology: Hematological studies included: hemoglobin*, hematocrit^, erythrocyte count, total-* and differential leucocyte counts, reti culocyte count^, platelet count, prothrombin time, activated partial thromboplastin time^ (A.P.T.T.). Mean corpuscular hemoglo bin, mean corpuscular volume and mean corpuscular hemoglobin con centration were calculated. b. Biochemistry: Biochemical studies included: fasting blood glucose, blood urea nitrogen, serum alkaline phosphatase, serum glutamic oxalacetic and pyruvic transaminase activities, cholesterol^, total protein^, albumin, sodium1**, potassium1**, chloride^, inorganic phosphate?, Y-glutamyl transpeptidase11 (y-G.T.P.) and creatinine phosphokinase^. 137-090 001729 International Research and Development Corporation Page 6 c. Urinalysis: Urinalysis included: measurement of volume, p H ^ and specific gravity; description of color and appearance; qualitative tests for protein^ f glucose^ t ketones^> occult blood^ and microscopic examination of the sediment. d. Statistical Analysis: Analysis of body weights and clinical laboratory tests were performed. All statistical analyses compared the treatment groups with the control group, by sex. The tests were compared by analysis of variance (one-way classification) Bartlett's test for homogeneity and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie^ using Dunnett's^ multiple comparison tables to judge significance of differences. B. RESULTS: 1. General Behavior, Appearance and Survival: There was no mortality in monkeys at 0, 3 and 10 mg/kg/day dosage levels. The monkeys from the control and 3 mg/kg/day dosage levels did not show any unusual behavior or signs of toxicity. Soft stool or moderate to marked diarrhea were noted occasionally. Frothy emesis was also noted occasionally. At the 10 mg/kg/day dosage level the monkeys did not show any unusual signs of toxicity, except Monkey 7363. In week 7 its face appeared swollen and pale. It had been occasionally anorexic in week 4 and black stools appeared for several days in week 12 of the study. At the 30 mg/kg/day dosage level, three monkeys died during weeks 7, 12 and 13 of the study. From week 4, the monkeys were anorexic. Slight to moderate and sometimes severe decreased activity was noted occasionally to frequently for the four monkeys. Emesis and ataxia were very rarely noted, for one monkey. 137-090 001730 International Research and Development Corporation Page 7 Swollen face, eyes and vulva, as well as pallor of the face and gums were noted. From week 6, for two monkeys, black stools were noted. Monkey 7387 showed slight to moderate dehydration and ptosis of the eyelids. All monkeys from the 100 mg/kg/day dosage level died during weeks 2 through 5 of study. They showed the same symptoms of toxicity as the previous group, but they appeared sooner in the study (from week 1) and were more marked: anorexia, frothy emesis (sometimes brown in color) pale face and gums, swollen face and eyes, decreased activity from slight to severe, prostration and body trembling. 2. Body Weights (Tables 1-3): Changes in body weight were similar for monkeys from the control and the 3 and 10 mg/kg/day dosage levels. Monkeys at the 30 and 100 mg/kg/day dosage levels lost body weight after the first week of study. There was statistically significant decreases in the body weight for the male monkeys at the 30 mg/kg/day dosage level in week 13 of the study. The female monkeys of the same dosage level and the monkeys from the 100 mg/kg/day dosage level were dead in this period. 3. Laboratory Test (Tables 4-15): a. Hematology: There were no noteworthy changes in monkeys from the 3 and 10 mg/kg/day dosage levels. In the first month of the study there was a slight increase (not statistically significant) of the A.P.T.T. values in the females at the 10 mg/kg/day dosage level and a statisti cally significant increase of the A.P.T.T. and prothrombin time values in monkeys at the 30 mg/kg/day dosage level. In the third month of the study there was a high increase in the above mentioned indices for the one surviving monkey from the 30 mg/kg/day dosage level. The same monkey (#7455) had pronounced anemia as well. 137-090 C01731 International Research and Development Corporation Page 8 The statistically significant increase in the hematocrit in monkeys at the 10 mg/kg/day dosage level and in the platelet count in monkeys at the 3 mg/kg/day dosage level at 3 months of study, were within the normal physiological limits. b. Biochemistry: There were no noteworthy changes in monkeys from the control, 3 and 10 mg/kg/day dosage level. Only one monkey from the 3 mg/kg/day dosage level and one monkey from the 10 mg/kg/day dosage level showed trends toward decreases of alkaline phosphatase (432 and 474 units/1, respectively), without statistical significance. In the first month of the study, decrease in serum alka line phosphatase was noted in monkeys at the 30 mg/kg/day dosage level (statistically significant) and in one monkey in the same dosage level, the albumin in the serum was lower (3.22 g/lOOml). The one surviving monkey (7455) from the 30 mg/kg/day dosage level showed decreasing of: blood sugar (66 mg/lOOml), total protein (5.52 g/lOOml) with albumin (2 g/lOOml) and alkaline phosphatase (360 units/1) and slightly elevated cholesterol (240 mg/lOOml). c. Urinalysis: No changes considered to be related to compound were seen in the urinalysis studies. 137-090 GO1732 International Research and Development Corporation Page 9 IV. PATHOLOGICAL STUDIES A. METHODS : 1. Gross pathology: After completion of the compound administration period all surviving monkeys were anesthetized with Sernylan*, exsanguinated and necropsied. At necropsy, the heart, liver, adrenals, spleen, pituitary, kidneys, testes/ovaries and brain were weighed and repre sentative tissues were collected in buffered neutral 10% formalin. Eyes were fixed in Russell's fixative. The thyroid/parathyroid was weighed after fixation. Monkeys which died during the study were necropsied as above. 2. Histopathology ; Microscopic examination of formalin fixed hematoxylin and eosin stained paraffin sections was performed for all monkeys in the control and treatment groups. The following tissues were examined: adrenals aorta bone brain esophagus eyes gallbladder heart (with coronary vessels) duodenum ileum jejunum cecum colon rectum kidneys liver lung skin mesenteric lymph node retropharyngeal lymph node mammary gland nerve (with muscle) spleen pancreas prostate/uterus rib junction (bone marrow) salivary gland lumbar spinal cord pituitary stomach testes/ovaries thyroid parathyroid thymus trachea tonsil tongue urinary bladder vagina tattoo and any other tissue(s) with lesions *Phencyclidine HC1 - Bio-Ceutic Laboratories, Inc., St. Joseph, Missouri. 137-090 001733 International Research and Development Corporation Page 10 B. RESULTS: 1. Gross Pathology (Table 16) and Organ Weights (Table 17) : No gross lesions considered compound related were seen in male and female rhesus monkeys which died on study or were sacrificed after 90 days of study. Statistically significant variations in sex group mean weights of few organs occurred between the control and experimental groups. The following statistically significant organ weight variations occurred; Organ Dosage S Level e mg/kg/day x Heart 10 F Brain 10 F Pituitary 3 M Weight absolute,relative absolute relative Change decrease,decrease decrease increase P< 0.05,0.01 0.01 0.05 The biological significance of these variations is unknown. These organ weight variations were not accompanied by morphologic changes which were considered compound related. 2. Histopathology (Table 18): One male and two female rhesus monkeys at the 30 mg/kg/day dosage level and all male and female rhesus monkeys at the 100 mg/kg/day dosage level had marked diffuse lipid depletion in the adrenals. All male and female rhesus monkeys at the 30 and 100 mg/kg/day dosage levels had slight to moderate hypocellularity of the bone marrow. All male and female rhesus monkeys at the 30 and 100 mg/kg/day dosage levels had moderate atrophy of lymphoid follicles in the spleen. One female at the 30 mg/kg/day dosage level and all male and female rhesus monkeys at the 100 mg/kg/day dosage level had moderate atrophy of the lymphoid follicles in the lymph nodes. No microscopic changes considered compound related were seen in the adrenals, bone marrow, spleen and lymph nodes of male and female rhesus monkeys at the 3 and 10 mg/kg/day dosage levels. No microscopic 137-090 COI734 International Research and Development Corporation Page 11 lesions in tissues other than the adrenals, bone marrow, spleen and lymph nodes at the 30 and 100 mg/kg/day dosage levels were considered compound-related. 137-090 C01735 International Research and Development Corporation Page 12 Reference 1. Coulter Hemoglobinometer. Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 2. Microhematocrit, John B. Miale, 3rd Ed., 1967, The C. V. Mosby Company, p. 1154. 3. Coulter Particle Size Counter, Model Zg, Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 4. Gradwhol's Clinical Laboratory Methods and Diagnosis, Frankel and Reitman, Editors 6th Ed., 1963, The C. V. Mosby Company, p. 1132. 5. Coulter Particle Size Counter, Model A, Coulter Electronics, 590 W. 20th Steet, Hialeah, Florida. 6. General Diagnostics - Warner Chilcott Laboratories Revised April 1965. 7. General Diagnostics - Warner Chilcott Laboratories Revised Janurary 1967. 8. Technicon Auto Analyzer, 6/60 Micro Methodology. 9. Micro Auto Analyzer II, 6/60 Micro Methodology. 10. Atomic Absorption IL, Model 353 11. Sigma GGTP Procedure Bulletin //545. Sigma Chem. Co., St. Louis, Mo. 12. Bililabstix (Ames Reagent Strips). 13. Steel, R. G. D. and Torrie, J. H. (1960), Principles and Procedures of Statistics, McGraw-Hill, New York, N. Y. 14. Dunnett, C. W., New Tables for Multiple Comparisons With a Control, Biometrics, McGraw-Hill, New York, N. Y. 137-090 C01736 FC-143: TABLE 1. Sex M F Group I (Control) 3.78 3.55 Ninety Day Subacute Rhesus Monkey Toxicity Study. Mean Body Weights of Monkeys Week 13 of Study. Group II (3 mg/kg/day) 3.50 3.68 Group III (10 mg/kg/day) 3.68 3.78 Group IV (30 mg/kg/day) 2.30* dead Group V (100 mg/kg/day) dead dead Page 13 001737 137-090 *Statistical significance. FC-143: Ninety Day Subacute Rhesus Monkey Toxicity Study. TABLE 2 Individual Body Weights, Kilograms Group, Monkey Control _______________________________________Week of Study Number Sex 1 2 1 2 3 4 5 6 7 8 9 10 11 12 13 Control: 7362 7365 M M 7336 7386 F F Mean 3 mg/kg/day: 7364 7366 M M 7384 7385 F F Mean 10 mg/kg/day: 7363 7458 M M 7328 7383 F F Mean 3.15 3.50 3.05 3.90 3.40 3.30 3.50 3.20 3.70 3.43 3.15 3.50 3.25 3.70 3.40 3.30 3.50 3.25 3.65 3.43 3.70 2.60 3.55 3.50 3.34 3.90 2.60 3.60 3.55 3.41 3.85 2.70 3.70 3.45 3.43 3.95 2.60 3.80 3.45 3.45 3.55 3.10 3.30 3.60 3.39 3.70 3.10 3.30 3.60 3.43 3.70 3.25 3.45 3.50 3.48 3.65 3.20 3.40 3.80 3.51 3.35 3.50 3.35 3.55 3.44 3.10 3.40 3.15 3.45 3.28 3.85 2.65 3.80 3.45 3.44 3.85 2.65 3.80 3.45 3.44 3.65 3.10 3.40 3.60 3.44 3.65 3.05 3.30 3.55 3.39 3.20 3.55 3.00 3.40 3.29 3.20 3.60 3.15 3.55 3.38 3.00 3.60 3.20 3.40 3.30 3.80 2.70 3.70 3.40 3.40 3.80 2.70 3.70 3.40 3.40 3.85 2.50 3.60 3.50 3.36 3.65 2.95 3.20 3.50 3.33 3.60 3.20 3.30 3.60 3.43 3.60 3.00 3.25 3.60 3.36 3.15 3.80 3.30 3.40 3.41 3.20 3.75 3.45 3.55 3.49 4.10 2.70 3.55 3.55 3.48 4.10 2.70 3.80 3.60 3.55 3.70 3.15 3.45 3.65 3.49 3.65 3.10 3.60 3.80 3.54 3.05 3.75 3. 30 3.40 3.38 4.05 2.45 3.55 3.40 3.36 3.75 3.10 3.50 3.65 3.50 3.20 3.80 3.35 3.50 3.46 4.05 2.55 3.70 3.30 3.40 3.85 3.25 3.40 3.75 3.56 3.40 4.00 3.35 3.50 3.56 4.20 2.50 3.90 3.40 3.50 3.90 3.25 3.60 3.75 3.63 3.50 4.05 3.60 3.50 3.66 4.30 2.70 3.75 3.60 3.59 3.90 3.45 3.75 3.80 3.73 Page 14 Oo F*---<1 ^7-090 FC-- 143 : TABLE 2. Cont Group, Monkey Control Number Sex 1 2 Ninety Day Subacute Rhesus Monkey Toxicity Study Individual Body Weights, Kilograms. ____________________________________Week of Study 12 34 56 78 9 10 11 12 13 30 mg/kg/day: 7367 7455 M 3.40 M 3.50 7382 7387 F 3.25 F 3.70 Mean 3.46 100 mg/kg/day: 7361 7456 7335 7381 M 3.50 M 3.10 F 2.80 F 3.85 Mean 3.31 3.40 3. 30 3.30 3.75 3.44 3.85 3.10 2.95 3.80 3.43 3.25 3.20 3.20 3.50 3.29 3.50 2.60 2.70 3.55 3.09 3.25 3.05 3.20 3.55 3.26 3.10 2.85 3.05 3.50 3.13 2.95 2.65 3.00 3.45 3.01 2.65 2.45 2.85 3.10 2.76 2.30 2.50 2.80 2.95 2.64 3.30 2.70* 2.45 3.20 3.00 Died 2.05* 2.80 2.55 Died 2.60* 2.40* Died Died 2.98 2.90 2.55 2.10* Died 2.55 2.60 2.80 2.80 2.85 2.85 2.73 2.75 2.70 2.80 2.70 2.73 2.70 2.80 2.65 2.72 2.65 2.80 2.50 2.65 2.50 2.30 2.60 2.25* Die, 2.25* Died 2.55 2.30 00173 (0L37-O9O *Terminal weight not included in mean. t) Pi 0n0> FC-143: TABLE 3. Study Week Sex 13 M F Ninety Day Subacute Rhesus Monkey Toxicity Study. T-Test Comparison of Body Weights. Page 16 Control 3.78 3.55 3 mg/kg/day 3.50 3.68 10 mg/kg/day 3.68 3.78 30 mg/kg/day 2.30a - 100 mg/kg/day - 137-090 *p<0.05 **p<0.01 aNot included in statistical analysis due to only one surviving animal. - Line indicates animals had died prior to week 13. 001.740 FC-143: TABLE 4. Hematology Ninety Day Subacute Rhesus Monkey Toxicity Study. Means and Significance of Hematological Values. Month of Study Control 3 mg/kg/day 10 mg/kg/day Erythrocytes, 10^/cmm Hemoglobin, g/100 ml Hematocrit, /e Platelets, lO^/cmm Reticulocytes, % Prothrombin Time, sec Activated P.T.T., sec Leucocytes, 10 /cmm Neutrophils, % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % MCV, MCH, uug MCHC, g/100 ml 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 4.46 4.90 11.7 12.9 38 37 253 210 0.2 0.3 12 11 28 26 9.49 9.40 . 24 16 75 80 1 3 0 1 0 0 86 75 27 26 31 36 4.26 4.74 11.4 12.7 37 37 233 285* 0.5 0.2 12 11 28 26 9.78 9.83 19 19 76 76 5* 3 0 2 0 0 86 78 27 27 31 35 4.71 5.47 12.1 13.3 39 40** 210 216 0.5 0.2 13 11 31 24 9.93 11.96 26 25 72 67 2 6 0 2 0 0 82 73 26 24 32 34 Page 17 30 mg/kg/day 4.53 3. 84a 11. 7 9 . 7a 36 30 a 219 261a 0.2 0.2a 15** 30a 35** 65a 8.44 10.14a 15 36 a 85 54a 0 3a 0 7a 0 0a 80 78a 26 25 a 32* 32a *Significantly different from control group, p<0.05. **Significantly different from control group, p<0.01- aValue not used in statistical analysis due to only one animal surviving. C01741 I'T-Wfl: N i n e t y Day Si i l meul e Kl i csus Monkey T o x l e l t y S t u d y . TARI.K '> 1ud1vtduat Hemal n|n)*|r,il Va 1uns ('mi 1rn) 1 . Ornup, Fry thro- Memo- Monkey e yl i'ii f; Inti III Number Sex I0%nmi k/IOO ml Hetnnloeilt 7. I'l.iteletH 1(d/ciiim Relleu1uey 1 its t rroilirumliiu T 1me see A e l I v n l d I' . T. T sec l.eiicn- Neul ntpli 1 1a eytefi Noll-Sn)* . 1(* / 1'IBIH * 7. l.yni|din eyd*s % CuntHil: 7162 7165 M 5.08 H 6.72 7116 F 5.27 7186 F 6.20 Menu 6.82 I J/ku/d.|y: 716/, 7166 M 6.50 M 6.6 7186 F 6.55 U S ') F 6 .1 0 Mean 6.61 10 iHg/kB/clay 7161 7618 M 5.26 M 5.29 7128 F 5.32 7181 F 5.06 Mean 5.22 1. nili/ku/Ojiy 7167 76 51 M 6.98 M 5.16 7182 7187 F 6.86 F 6.67 Mean 6.91 iOO j^ /J cg /c liiy : 7161 7656 M 6.75 M 5.16 7115 7381 F 5.66 F 6.82 Menu 5.10 11.0 11.9 12.8 11 .1 12.2 11.5 12.0 11.7 11.6 11.7 11.7 12.2 12.5 11.5 11.0 12.6 11.6 12.8 12.2 12.8 12.6 11.6 12.8 11.5 12.5 60 18 19 16 3 17 17 18 35 17 62 16 19 62 40 18 60 18 15 18 16 62 60 16 19 207 0.1 119 0 .1 226 0 .6 227 0 .5 265 0.6 155 0 . 6 297 0 .1 160 0 . 2 165 0 . 6 232 0.6 266 0 .6 261 0 .2 192 0 . 8 120 0 .6 210 0.5 163 0 .2 133 0 . 5 157 0 . 6 111 0 . 6 117 0 . 5 282 0 .1 196 0 . 2 185 0 . 2 115 0 . 5 195 0 . 1 n n 16 16 16 11 16 11 13 13 11 n ii n ii 12 12 n 16 11 12 11 16 16 11 29 10.96 16 1 10 16.79 27 0 29 7.86 18 u 21 12.09 59 0 27 11 .63 60 0 25 8 .9 8 62 0 29 7 .19 61 0 30 16.72 11 0 26 8 . 1 6 18 0 27 9.81 18 0 11 12.97 46 0 29 17.36 16* 0 11 7 .8 9 15 0 28 8 .2 2 67 0 36 11.61 10 0 28 10.86 61 0 26 8 . 6 5 21 (1 26 5.8.1 26 0 27 5.10 29 0 26 7.61 29 0 27 10.77 1(1 0 28 5.86 18 n 28 12.8 18 0 26 10.16 56 n 27 9.58 60 0 62 72 59 19 58 57 59 66 59 60 69 78 65 68 60 57 76 71 68 68 67 60 57 66 57 Iuim inn|>lil In'' 7. Mono- Hasne V1e s ' pi,it'* MOV MOM hoik: 7. 7. | d imp. p / i n i l ml 1 0 0 79 26 ii 1 0 0 HI 25 it 1 0 0 76 26 13 1 1 0 81 26 i i 2 0 0 79 25 it 0 1 0 82 20 il 0 0 0 81 27 12 5 0 0 86 26 11 3 (1 0 86 27 11 2 0 0 81 27 12 5 0 0 8(1 26 11 6 0 0 68 21 I'l 0 0 0 71 21 12 6 1 0 81 27 2 6 0 0 76 25 11 2 0 0 76 25 11 3 0 0 78 26 16 | (1 0 79 20 16 1 2 0 75 20 15 2 1 (1 77 26 16 3 0 n 76 26 16 0 1 1 78 ? s 11* 5 0 0 7 1 21 12 1 0 1 75 26 P 2 0 1 76 2'i 11 BEST COPY AVAfl ABLE 001742 delei'wlnnl Inn ' H k - (111 t I ' r r n l i n I I n i r n c y 1** men u s h a v e li nen .id j u s t r d l u r*(u,i| 100* . F U - 141: N i n e t y liny S u b a c u t e Khesus Monkey T o x i c i t y S t u d y . TAIM.1% ft. 1iuilvirlu.il Ileumto Ini i ca I Valili* - I Monti. Cri>ii|>, Kiytlirn- Memo- Monkey c v Lew g l o b in N u m b e r S e x M 1V f m m g / 1 0 0 ml Mentaloet it 7 IMatelots 10 / c m m KetIon- loeytoH X 1'niMirnnililn T 1ute sec A e 1 1v a 1eil P.T.T. see l.eiieo- Nell t rojili 11 h oy t o s Soy,. Nou-Keg. 10 Votum % % l.yiupho- cytos' X Fits I int Moio~ Has- u 11** r y t e s a |tll I 1s ' '1 MOV non 7. 1 z mo: none r / I oo Con im l: 7362 H 6.80 7365 H 6.71 11.9 11.9 7 336 7386 I- 6 . 2 0 I- 6 . 1 7 11.2 11.9 Mean 4 . 4 ft 11.7 3 nig/ky/<*>': 7366 M 6.35 7366 M 3.96 11.6 10.7 7386 7385 F 6.66 F 6.25 11.9 11.2 Mean 6.26 11.6 10 mg/kg/day ; 7363 77.58- M M 6.62 6.81 12.1 11.3 7328 F 6.70 73B3 F 6.92 12.0 12.8 Mean 6.71 12.1 30 mg/k/il.iy 7367 M 6.59 7655 H 6.66 11.2 11.8 7382 7387 F 6.51 F 6.56 11.9 12.0 Mean 6.53 jOOJ5B/kj5Al.iji: 11.7 7361 M Died, week 5 7656 M Died, week 2 7775 7381 F Died, week 3 F Died, week 6 78 79 37 78 38 37 75 39 35 77 38 77 39 60 79 36 37 75 37 36 226 369 266 191 257 266 188 236 267 233 168 281 18) 209 210 175 237 268 237 219 0.2 0.2 0.2 0.3 0.2 0.5 0.6 0.2 0.9 0.5 1.0 0.3 0.5 0.1 0t5 0. 1 0.2 0.3 0.2 0.2 12 12 17 12 12 11 12 13 12 12 13 13 13 12 11 13 16 15 16 15 70 6.91 28 0 69 3 0 o 79 25 71 2R 1 6 . 5R 15 0 86 1 0 0 8 7 25 71 28 7.66 11 0 89 0 n 0 88 27 70 27 8.99 62 0 58 0 0 0 92 29 II 28 9 . 6 9 26 0 75 1 0 0 86 27 11 27 6.81 17 0 80 3 0 0 85 77 71 28 5 .8 3 16 0 78 6 0 0 88 27 II 28 17.07 22 1 73 3 1 0 87 27 71 29 9.61 18 0 73 9 II 0 82 26 12 28 9 . 7 8 19 0 76 5 0 0 86 27 II 27 8,08 62 0 31 17.98 11 0 57 87 1 0 0 86 28 72 1 0 1 77 21 11 31 7.01 35 0 63 2 1) 0 81 26 31 33 6.66 18 0 79 7 0 0 81 26 12 31 9.97 26 0 72 2 0 0 82 26 32 36 7.92 12 0 88 O 1) 0 78 26 71 37 ll.lt 27 0 73 0 (I 0 8 1 27 72 35 6.19 9 0 90 1 0 0 78 26 76 38 8.56 17 0 87 0 0 0 81 26 12 35 8.66 15 0 85 0 0 0 80 26 72 MST COPYAVAIlABLE 001743 117-090 Tli! il i Cf f l i n t l a l l e u c o c y t e m e a n s h a v e I n e n a d j u s t e d I o e q u a l IIMIfc. U) OQ fD FC-143: Ninety Day Su bacute Kliemis Monkey T o x i c i t y S t u d y . TAIII.K 7. liu llv id u a ) Denialinlof lent V alues - ) Months, C.nmi, Frylliro- Homo- Monkey tyli'H ftlob 1u Number Sex 10 /cmiii r/ 100 ml Heina t o C1 11 z llel 1. u- 1' 1;i Lt*1e l s l o e v t l*s 10 /cmin z Prothrombin Act 1voted Time r.T.T. sec sec heuco- Neul ro|dt11s cyl es Se,(. Nnn~S*j*. 10 Velum z % Lvmphocy t es z linn 1lie- |>tll Is' z Mono- cyl es % Huso- |dil 1s* 7. MTV neu IMD\ MCIH' )/ IOO iloiii rot : 7362 7 165 M 4.89 M 4.74 12.9 1 1. 1 71. r 4.72 7 186 1 4 .6 9 12.4 12.8 Nimm 4.9(1 12.9 3 mg/kg/tl.iy: 7 364 7366 M 4.86 H 4.46 12.9 12.0 7384 F 4.92 7)8 3 F 4.71 13.0 13.0 Me.in 4.74 12.7 10 mg/kg/ilnv 736) 74 58 M 5.04 M 5.70 13.6 12.6 732 7381 F 5.47 F 5.65 13.4 13.5 Mivin 5.47 0 mu/kg/ilny 13.3 7367 7455 M 01eil. week 7 M 3.84^ h 9.7 7382 7387 F IMeil, weck 11 I- Died, week 12 Heim 3.84 9.7 UM) mg/kti/d.-iy: 7361 7456 M Died, week 5 M O lid , week 2 7335 7381 F Died, week 3 F Dt cd. week A 37 37 16 w> 37 37 14 19 37 37 Alt 40 40 19 40 30 30 217 0 . 2 218 0 .3 170 0 .4 234 0 .3 210 0 .3 299 0.1 278 0 .2 313 0 .2 248 0 .2 285 0 .2 214 (1.2 218 0 .3 219 0 .3 212 0.1 216 0 .2 261 0 . 2 261 0 . 2 11 10 II 11 11 11 11 11 11 11 II 11 II II 11 30 30 32 7.82 20 0 25 12.84 10 II 25 8.41 16 0 2(1 8.51 18 i 26 9 . 4 0 16 0 24 7 .3 3 24 0 26 5.44 25 D 28 18.21 16 0 24 8 . 3 5 10 0 26 9 . 8 3 19 0 24 8.41 34 0 2J 20.18 4 0 23 10. 72 3) 0 27 8 .5 2 30 0 24 11.96 25 (1 65 10.14 36 0 65 10.14 36 0 74 85 79 80 80 71 74 76 82 76 60 94 51 64 67 54 54 4 2 i\ 76 LM v> 4 1 0 70 ;v 14 4 1 0 76 ) i 16 0 1 0 77 7.7 lb \ 1 1) 74 26 w. 4 1 0 76 27 15 0 0 1 /(. 71 15 5 3 (1 79 26 33 5 3 0 79 28 15 3 2 0 78 27 15 4 2 0 79 7 7 14 2 (1 0 70 22 32 11 s 0 73 24 34 4 1 0 fd> 24 r 6 2 0 73 24 34 3 7 0 78 24 12 3 7 0 78 25 32 BEST COPY A V A Il ABLE n7-o<m |*2+ P o l k l o c y t n s l s r 2 Nuclea ted et y llirm yl es/IDO l e u c o c y t e s The d l f f e r c n l l u t l e u c o c y t e m e a n s h a v e b e e n nd}MKtc() t o e i j ua l 1002. 0) OQ (t> F C - 143:. TABLE 8. Biochemistry Ninety Day Subacute Rhesus Monkey Toxicity Study. Means and Significance of Biochemical Values. Month of Study Control 3 mg/kg/day 10 mg/kg/day Page 21 30 mg/kg/day Glucose, mg/100 ml B.U.N., mg/100 ml Aik. Phos., int' 1 units/1 S.G.O.T., int'l units/1 S.G.P.T. i n t 'l units/1 Cholesterol, mg/100 ml Total Protein, g/100 ml Albumin, g/100 ml Sodium, meq/liter Potassium, meq/liter Chloride, meq/liter y-G.T.P. , Sigma units/ml C.P.K., Sigma units/ml Inorganic Phosphate, mg/100 ml 1 3 1 3 1 3 1 3 lb 3C 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 89 81 23.0 27.6 597 851 29 45 15 31 165 165 7.94 8.21 4.78 4.82 153 151 5.1 5.5 112 113 61 44 9 7 7.9 6.9 117* 96 21.2 20.2 847 783 35 41 21 31 154 141 8.23 8.24 5.05 5.12 152 154 5.1 5.6 110 112 49 38 14 6 7.2 6.3 104 88 22.5 22.0 601 743 34 35 34* 34 158 154 8.66 8.43 4.66 5.17 155 159** 5.2 6.0 113 114 47 51 16 9 7.0 7.3 122 66a 26.1 22.6a 365* 360a 59** 88a 44 46a 174 240a 8.36 5.52a 4.28 2.00a 152 150a 5.7 5.9a 112 113a 33 49 a 19* 10a 6.7 5.0a *Significantly different from control group, p<0.05. **Significantly different from control group, p<0.01. aValue not used in statistical analysis due to only one animal surviving. b I.U./l cSigma units/ml 001745 F C-143 : Ninety Day Subacute Rhesus Monkey Toxicity Study. TAHI.B 9 . In d ivid u al Biochemical Values - Control 1. Group, Alk. l'h o s . Monkey 01 ucose R.U.N. in t'l Number Sex mg/lUO ml mg/100 ml u n i t s / 1 S.C.O.T. In t'l u n its/1 S.G.F.T. in t' l u n its/1 Choies- Total terni Protein m g/100 ml g / 100 ml Albumin g / 100 ml Fotas- r.blo- Inorganic Sodium sium r id e Phosphate moc|/l meq/1 me|/ l mg/100 ml y-C.T.I*. Sl|>mn u/ntl Creai In hie l'hosphuk Lnnse KIgm.i m/ imI Con t ro 1: 7362 7365 H H 7336 7386 F F Mean 3 mg/kg/day: 7366 7366 M M 7386 7385 F F Mean 10 mg/kg/day: 7363 7658 M M 7328 7383 F F Mean 30 mg/kg/day: 7367 74 55 M M 7382 7387 F F Mean 100 mg/kg/day 7361 7456 H M 7335 7381 F F He an 94 82 79 85 85 m 71 96 107 96 89 180 98 98 116 108 110 132 117 117 93 100 75 119 97 41.0 16.7 24.0 21.0 25.7 19.0 28.7 22.0 22.0 22.9 27.2 26.2 20.0 27.3 26.7 26.9 26.0 27.9 23.8 25.7 29.0 23.0 28.0 22.1 25.5 780 659 915 960 829 880 580 5 70 1320 838 1167 806 776 581 833 970 687 641 978 819 598 799 570 1233 800 40 99 61 88 30 80 39 86 43 88 42 94 60 89 38 106 60 76 50 91 46 118 63 136 26 75 31 91 42 105 47 114 37 86 40 79 45 138 42 104 43 80 40 104 40 96 40 103 41 96 219 8 .6 8 123 9.50 185 9 . 5 2 190 8.52 179 9 .0 6 197 9 . 0 8 172 9 . 1 2 133 10.12 154 8 .72 164 9 .2 6 237 9.84 107 10.08 189 8 .4 8 168 8.32 175 9 . 1 8 150 9 .3 8 205 9.50 176 11.10 194 9 .4 4 181 9 .8 6 155 8 . 6 0 202 9 .0 0 151 8 . 9 8 124 9 . 6 0 158 9 .0 5 5.40 4.30 5.30 5.12 5.03 5.28 5.80 5.19 4.80 5.27 5.10 3.99 5.14 5.25 4.87 5.60 5.31 5.72 5.60 5.56 5.00 5.69 5.19 4.89 5.19 160 5.0 m 155 5 . 3 110 156 4 . 3 110 162 5 .0 111 158 4 . 9 111 155 4 . 3 108 157 4 .9 108 162 6 . 0 158 5 .2 113 116 158 5.1 111 167 6.2 150 4 .9 157 4.4 159 5 . 1 158 5.2 117 107 109 112 111 170 6 .2 163 5 .3 165 5.5 155 3.9 163 5.2 116 Ul 112 113 113 159 5 .9 157 4 .5 157 5 .2 159 5 .2 158 5 .2 116 109 111 112 112 6.5 6. 7 6.5 6.5 6.6 5.0 7-1 6.1 5.4 5.9 6.7 7.7 6.3 6.0 6.7 6.9 6.6 6.8 5.4 6.4 6.9 5. 7 5.6 6. 7 6.2 67 44 41 17 47 50 30 32 41 38 78 55 51 59 61 65 59 43 39 52 64 44 58 47 53 15 18 85 16 34 12 26 16 29 21 16 14 34 6A 32 15 9 18 16 15 17 22 20 10 17 Page 22 001746 137-090 ro-1Vi: Ninety Day Subacute RIIPsua Monkey Toxicity Study. TABLF. to I n d i v i d u a l U iociiem lcal V alu e s - I Month. Group, Alk. Flios. Monkey Clucose B.11.N. Int ' 1 Number Sex m g/100 ml mg/100 ml uni t s / l S.G.O.T. I n t11 lflllls/1 S.G.P.T. ln t'l Choies- Total t e r n i P r o te in Albumin mg/100 ml g / 100 ml g /1 0 0 ml P o t a s Ch l o Sodium sium r id e mej/ 1 roeq/1 meq/l Inorganic Phosphate y- c .t . p . mg/100 ml Sigma u/ml CreaiIn Ine Phosphokinase Sigma u/mi Control : 736Z M 87 33.9 611 27 18 191 7.30 6.82 153 5.6 117 6.6 81 7 365 M 86 16.2 626 33 17 121 8 . 6 0 6.11 153 5.6 111 8.6 50 7336 F 87 23.9 672 25 15 162 7 .90 6.89 168 6 .2 109 8.6 68 7386 F 96 16.9 680 31 10 206 8.15 5.30 158 5 .6 112 8.1 66 Mi>an 89 23.0 597 29 15 165 7.96 6.78 153 5.1 112 7.9 61 3 mg/kg/day : 7366 M 112 18.0 9 70 30 36 173 8.15 5.20 150 6 .3 106 6.9 77 731.6 M 131 23. 3 693 39 19 168 8.05 5.62 156 6 . 9 110 6.6 26 7386 F 105 26.2 539 30 15 161 8 .7 0 6.85 152 5 . 8 111 7.5 67 7385 F 120 19.1 1185 60 13 153 8.0 0 6.72 152 5 . 2 116 7.8 67 Henn 117 10 mg/kg/day: 21.2 867 35 21 156 8 . 2 3 5.05 152 5 . 1 1 10 7.2 69 7363 M 98 26.9 552 60 35 219 9 .6 0 6.62 16) 6 . 3 118 6.9 65 7658 H 97 22.5 732 60 63 136 9 . 0 5 6.32 151 6 . 9 109 8.6 66 7328 F 98 22.7 660 23 19 165 8 .2 0 6.50 152 6 . 3 111 5.6 37 7383 F 126 20.0 680 31 37 132 8 . 0 0 5.19 156 5 .2 113 7.2 63 Meati 106 22.5 601 36 36 158 8.66 6.66 155 5 . 2 113 7.0 67 30 mg/kft/day: 7367 M 112 35.2 376 68 30 180 8 .2 0 6.70 157 6 . 0 110 6.6 60 76 55 M 86 21.0 322 61 80 177 8.55 3.22 168 5.2 112 6.9 60 7382 F 106 25.2 600 83 63 161 8 .1 5 6.21 169 5 . 9 1 11 6.0 28 7387 F 185 22.8 360 65 23 179 8 .5 5 5.00 153 5.6 116 7.2 26 Mean 122 26.1 365 59 66 176 B. 36 6.28 152 5. 7 112 6.7 33 100 mg/kR/day 7361 7656 M Died, week 5 M Died, week 2 7335 7381 F Died, week 3 F Died, week 6 8 11 7 11 9 6 7 39 7 16 7 20 26 16 16 25 16 17 18 19 Page 23 001747 37-090 hi:-IV: Ninety Day Subacute Klicsus Monkey Toxicity Study. TABLE I I . In d iv id u a l Biochem ical Value - 3 Montila. Croup, Monkey Glucose Number Sex in g / 100 ml Aik. Plios. H.U.N. in t'l m g/100 ml u n i t a / 1 S.G.O.T. lot *1 unita/1 S.fi.P.T. S 1f.nia uii I t s /m l Cimi e s T o t a l terni Protein mg/100 ml g / 1 0 0 ml Albumin g / 1 0 0 ml Potas Ohio- Sod 1urn sium r i d e I1KM|/ l m eq/1 moq/1 Inorganic Plionphate y- g . t . i*. m g/100 mL Sigm.i u/mi CroatInlne Pbos|iboklnase Sigma u/ml Control : 7362 7365 M M 95 77 61.9 17.6 7336 7386 F F 67 86 33.1 18.1 Mean 81 2 7 . 6 3 mg/kg/day: 7366 7366 M M 106 ill 17.1 18.1 7386 7385 F F 96 76 23.6 22.0 He an 96 20.2 10 mg/kg/day: 7363 7658 M M 87 88 26.9 21.1 7328 7383 F F 75 100 21.8 20.0 Mean 88 2 2 .0 30 mg/kg/day: 7367 7655 M M Died, week 7 66 2 2.6 7382 7387 F F Died, week 13 D ie d , week 12 Mean 66 22.6 100 mg/kg/day: 7361 7656 M M Died, week 5 Died, week 2 7335 7381 F F Died, week 3 Died, week 6 806 766 786 1068 851 1092 596 632 1016 783 936 936 626 676 763 360 360 55 66 67 30 39 26 39 2 7 65 31 61 28 39 33 39 33 63 29 61 31 62 62 38 31 30 25 30 37 35 36 88 46 88 46 197 7.59 135 9 . 1 8 150 8.31 177 7 .7 6 165 8.21 166 7. 72 126 8.09 132 8 . 9 3 162 8 .2 1 161 8 .26 196 8 .6 6 139 9 .7 1 155 7.93 128 7.62 156 8 .6 3 6.99 6.60 6.98 6.90 6.82 5.09 5.52 6.91 6.97 5.12 5.61 6.69 5.27 5.11 5.17 150 5.5 116 151 6.1 113 151 5 .1 153 5.1 116 109 151 5 . 5 113 153 5 .8 153 5.5 153 5.2 155 6 . 0 156 5 .6 112 109 112 116 112 166 7.0 159 6 .2 156 6 .8 158 5 .8 159 6 . 0 119 112 110 113 116 5.6 8.0 7. 3 6.7 6.9 7.0 5.3 6.5 6.6 6. 3 8.0 9.0 5.6 6.5 7. 3 260 5.52 2.00 150 5 .9 113 5.0 260 5.52 2.00 150 5.9 113 5.0 37 53 62 65 66 65 51 27 29 38 63 52 60 68 51 69 69 7 8 7 6 7 7 6 6 6 f> 7 12 7 9 9 10 10 Page 24 001748 137-090 FC-143: TABLE 12. Urinalysis Volume, ml PH Specific Gravity Ninety Day Subacute Rhesus Monkey Toxicity Study. Page 25 Month of Study Means and Significance of Urinalysis Values. Control 3 mg/kg/day 10 mg/kg/day 30 mg/kg/day 1 35 33 51 3 71 94 51 1 8.5 8.5 8.1 3 8.3 7.6 8.2 1 1.028 1.026 1.026 3 1.018 1.015 1.024 41 40a 8.1 6.6a 1.026 1.031 137-090 aValue not used in statistical analysis due to only one animal surviving. 001749 FC-141: TABLE 13. Group, Color Monkey Vo 1unte miti Nunilie r Sex ml Appetir. N in e ty Day Subacute Rhesus Monkey T o x i c i t y Study. Individual Urinalysis Values - Control i. Uric Spec. Oeetill l.etieo- Erytliro-- Kpl. T r i p l e Cal . Ac Iti pii Grav. P r o t e in (Mucose Blood Ketones c y t c s cytes C e l l U r ates Fltos. Oxnl . C r y s t a l s Control : 7362 7365 M 100 M 28 7336 F 27 7386 F 70 Mean 56 3 mg/kg/dny : 7364 7366 M 25 M 25 7384 7385 Mean F F 215 35 75 10 mg/kg/day: 7363 7458 M 20 M 50 7378 7181 Mt*in F F 35 35 35 30 mg/kg/day: 7367 7455 7382 7387 Mean M M F F 20 35 20 48 31 100 mg/kg/day: 7361 7456 M 21 M 25 7335 7381 F 25 F 40 Moan 28 l.S-cl LS-cl 1.S-C l.S-cl 7.6 1.010 7.2 1.037 7.0 1.036 8.4 1.023 7.6 1.027 N N N N l.S-cl LS-cl I.S-C LS-cl 7.8 1.032 7.2 1.035 8.3 1.026 8.3 1.020 7.9 1.028 N N N N LS-cl LS-cl LS-cl LS-cl 7.7 1.020 7.5 1.036 7.8 1.036 8.2 1.020 7.8 1.028 LS-cl LS-cl LS-cl LS-cl 7. 1 1.050 6.8 1.030 7.0 1.055 8.2 1.030 7.3 1.041 N N N N N N N N LS-cl LS-cl LS-cl LS-cl 7.6 1.035 7.1 1.042 7.2 1.041 8.1 1.042 7.5 1.040 N N N N N tr N NNH - occ occ F occ " 1-3 OCC F occ N N 1+ - N A+ N - - - occ occ ore - occ occ occ H N tr N N tr N NNN NNN - - - occ F FF - occ F o c c ore - occ ore occ - occ F occ N tr N N tr N N tr N N 31 N - - - occ F F - occ F occ F - 1-3 F occ M - occ occ occ N tr N - 1-3 1-3 occ occ oce N tr N - 1-3 1-3 occ F NNN NNN - - 1-3 F occ - oec K occ oce N tr N - occ - F occ N t r 3 - - occ F occ F N t r 1+ N 1+ 1+ - 1-3 - occ occ F - 1-3 occ occ M M M F H H H H M M M F M Page 26 001750 tr - Trace 1+ - Trace to s l i g h t 2F - S l i g h t t o moderate 3F - Moderate 4F - Marked S - Straw LS - Light Straw l)S - Dark Straw I.Am - Light Andier OAm - Dark Amher cl - Cloudy (' - Gl e u r N - Ncgat i ve F - Few L - Loaded M - Many R - Bare o r e - Orcas 1o n a 1 <}NS - Q u an tity not s u f f i c i e n t norm - Normal - None seen FC-141: TABI.li 14 Uroup, Monkey Number Sex Volume ml Color and Appear. Ninety Day Subacute Rhesus Monkey Toxicity Study. I n d i v i d u a l U r i n a l y s i s Values - I Month. Uric Spec. Ocelli t Leuco Erythro lipl. Triple Cal. Ac 1il pll Cruv. l'r u te In Glucose Ulood Ketones c y t e s cytes (*e 11 s U rates VUo h . Oxa 1. C r y s t a l s Hud er Coin yol : 7162 7365 M M 7136 7386 F F Moan 3 nig/kj'/duy: 7364 7366 It M 7384 7385 F F Mean 10 mg/kg/duy : 736 3 7458 M M 7328 7383 P F Meun JO wg/kfi/diiy : 73b 7 7455 M M 7182 7387 F F Mean HW) mg/kg/duy: 7J61 7456 M M 7335 7381 F F 55 1.S-C 35 1.S-C 20 LS-C 30 LS-C 35 20 LS-C 20 LS-C 40 OS-cl 50 L S - c l 33 65 l.S -cl 35 LS-C 55 L S-el 50 LS-cl 51 30 LS-C 30 LS-r.l 60 LS-cl 45 LS-cl 41 Died, week 5 Oled, week 2 Oled, week 3 Oled, week 4 8.5 1.021 8.5 1.028 8.5 1.033 8.5 1.030 8.5 1.028 8.8 1.019 8.5 1.036 8.0 1.021 8.5 1.027 8.5 1.026 7.5 1.023 8.0 1.028 8.5 1.026 8.5 1.028 8. 1 1.026 7.5 1.024 8.0 1.026 8. 3 1.022 8.5 1.032 8.1 1.026 N N N N N N 1+ H N N N N N N N N NN NN N It N lr NN NN N 41 NN NN NH NN N tr HN NN NN NN N NNN- NN2+ N- NNNN- NN NN- occ occ occ M - - occ F occ - 1-3 F FF - occ M FM occ F - occ F H-12 - F - occ F M occ F occ occ M OCC - o cc - - 1-3 occ F OCC o cc F occ occ occ occ M M M M - occ occ occ OCC occ M F - occ -F F- - occ F occ occ - - - - - - - - - M M M M M M H M M M M M L M M M Casts Page 27 001751 tr - Trace 1+ - Trace t o s l i g h t 2+ - S l i g h t t o moderaLe 3t - Moderate 4i - Marked s - Straw I.S - Li Kill Straw OS - Oavk Straw I.Aiu - Light Ainhe r OAm - Oavk Amlier c l - Cloudy C - Clear N - Negative F - Few L - Loaded M - Many R - Rare uec - Occasional QMS - Q u an tity not s u f f i c i e n t norm - Normal - Hone se e n FC-- 143: TABLE 15. Group, Monkey Number Sex Volume ml Color and Appear. Ninety Day Subacute Rhesus Monkey Toxicity Study. Individual U r in a ly sis Values - 3 Months. Urie Spec. Occult Leuco E rythro K|l. Triple Cal. Arid pll Grav. P r o t e in G lu cose Blood Ketones c y t e s cytes C ells Urates Phos. Oxal. Crystals Bactc Control: 7362 7365 M M 7336 7386 F K Mean 3 mg/kg/day: 7m 7366 M M 7 386 7 385 K F Mean 10 mg/kg/day: 7363 7458 H M 7328 7383 F F Mean 30 mg/kR/dny: 7367 7455 M M 7382 7387 F F Moan 100 mg/kg/day: 7361 7456 M M 7335 7381 F F 110 I.S-C 40 LS-cl 85 I.S-C 50 l.S-C 71 50 LS-C 150 I.S-C 125 LS-C 50 1.S-C 94 40 LS-C 35 LS-cl 50 LS-C 80 LS-cl 51 Died, week 7 40 S-C Died, week 13 Died, week 12 40 Died, week 5 Died, week 2 Died, week 3 Died, week 4 8.2 1.012 8. 1 1.029 8.2 1.015 8.8 1.016 8.3 1.018 6.0 1.020 7.9 1.007 8. 1 1.010 8.5 1.021 7.6 1.015 8.0 1.027 8.7 1.022 9.0 1.029 7.0 1.019 8.2 1.024 6.6 1.031 6.6 1.031 N N N N N N N N N N N N N NN NN NIF - - occ F OCC 1-3 F occ F- NN tr - - OCC F occ F N 3F N o c c - o c c F FF - - - NN NN NN N tr tr N- NN- - - F occ - - occ F occ - - occ F occ 1-3 M F FM - NN NN NN NN NN- NN- - occ F - -F occ occ F occ occ F occ OCC occ - occ -- - - - - N It N 1-3 occ - F M occ - M M M M M M M M M M M M M Casts Page 28 001752 tr - Trace 1F - T r a ie t o s l i g h t 2F - S l i g h t to moderate 3F - Moderate 4 F - Marked S - St raw I.S - Light St raw DS - Dark Straw I.Aiii - Light Amlier DAm - Dark Anther el - Cloudy /t N - Negative F - Few 1. - le a d e d M - Many R - Rare oec - Occasional QNS - Quant i l y not s u f f i c i e n t norm - Normal - Nunc seen FC-li3: TABLE 16. BEST COPY AVAI1ABLE Page 29 Ninety Day subacute Rhesus Monkey Toxicicy Study. Sunnary of Gross Necropsy Observations, Terminal Sacrifice. 0 mg/kt. dav Site Lesion N'o Gross lesions >NU, V tl .c! "" S"}i Z Z! CM J"V C <-- * 30 r*. I1** r*s. :terr.ai swelling, eye ares alopecia dehydrated emaciated red vaginal discharge scab, racial area Lung mite lesion adhes ions dark red foci/reddish purple area yellow, white foci nodules XX X X Heart nemorrkage, subendocardial gelatinized fat, endocardial atrophy Lymph Nodes enlarged reddish black in color X Thymus atropr.y Abdominal Cavity depletion or fat itjmacn dark rad foci erosion, mucosa, pyloric portion mucosal hyperemia yellcvisn gelatinous material, fur.dic portion hemorrhage, fundic mucosa ulcers Small Intestine greenisn-grav mucoid material dark red/brovn mucoid material liquid, blood tinged fluid reddish brown in color congestion, mucosa hemorrhage, mucosa large Intestine congestion, mucosa h e m e r m a g e t mucosa dark reedish black foci semi solid, blood stained contents 3 ag/kg/dav 10 mg/kg/dav 30 mg/kg/dav 100 ns;kg/dav V X X V X X X XXXX XX X XX XX x XX X VX X XX X X X x X X x xx X XX XX X *Died on Study 001753 FC -i3: TA BLE 16. Cont BESTCOPYAV4IMBLFage 30 N'inety Day Subacute Rhesus Monkey Toxicity Study. Su.nmary of Gross Mecropsy Observations. Pancreas accessory spleen Liver cvsc brownish color accentuated lobulations granular surface yellowish mottling reddish yellow color = w >1*s "1 SHi'1i J Z Z 0 m g/kg/dav zz ?N C r** fs. O 0r*-00 3 m g/kg/day Z= .y a X vT> X p* 10 n g /k z /d a v zz is. -- i"* r.XT3*.i XNe f*. X<r*-*i 30 m g/kg/dav nC z Si sc r in SJ rr**s 100 n g /k g /d av SI Z sc sc is. SlCb r-r-Xw> PV X X XX X X X Kidneys brownish discoloration x subcutaneous edema, abdomen subcutaneous hemorrhage, abdomen L 3 '-0 : ''Died on Study 001754 FC-143: N i n e t y Day S u b a c u t e K hesus Monkey T o x i c i t y S t u d y . TAIII.K 17. Absolute ((rants) nttd Relative (X Body Weight) Organ Weights, Terminili Sacrifice and Deal Its. Croup, Moiitcy Terminal Sacr 1flee Conirol: 7162 7365 dean 73 Jb 7386 Menu 3 mg/kg/day: 7364 7166 Mean 7384 7385 Menu 10 mg/kg/daj: 7361 7458 Mean 7128 7383 Mean -'ll 7455 Deaths: 30 mg/kg/day: 7367 7382 7387 100 mg/kg/day: 7361 7456 7335 7381 Sex M M F F M M F k' M M F F M M A* F M II F F Hotly Wt. kg Spleen 8' % 1.1ver gX Adrenals g XxlO K Icliu-ys 8X VsLos/ B Ov.irlcs fi" " xlO 1.25 3.85 3.55 3.40 3.50 3.45 4.10 2.65 3.38 3.70 1.45 1.58 3.80 3.25 3.53 1.55 3.70 1.63 2.40 2.10 -5 2.25 2.40 2.70 2.05 2.60 2.15 7.87 5.11 5.03 3.87 4.45 0.07 0.20 0.14 0.15 0.11 0.13 4.67 1.87 3.2 ? 6.82 2.94 4.88 0.11 0.07 0.09 0.18 0.09 0.13 2.39 4.91 3.65 4.06 3.99 4.0) 0.06 0.15 0.11 0.11 0.11 0.11 1.50 0.15 70.73 79.15 74.94 84,79 77.77 81.28 2.18 2.06 2.12 2.49 2.22 2.36 91.40 63.17 77.29 102.64 67.25 84.95 2.23 2.38 2.31 2.77 1.95 2.16 87.25 82.30 84.78 81.00 85.35 84.18 2.30 2.53 2.41 2.34 2.31 2.12 70.76 2.95 1.45 3.01 1.97 0.07 0.13 0.09 1.65 1.76 2.49 3.05 0.07 0.07 0.12 0.12 75.33 112.87 85.17 3.59 5.02 3.79 /9.02 85.08 74.28 82.58 3.29 3.15 3.62 3.18 0.65 0.7 I 0.68 - 0.62 0.62a 0.20 0.18 0.19 - 0.18 0. IBa 0.77 0.82 0.80 0.7R 0.55 0.67 0.19 0.31 0.25 0.21 0.16 0.19 0.74 0.67 0.71 0.66 0.86 0.76 0.19 0.2! 0.20 0. 19 0.23 0.21 0.84 0.15 1.63 1.74 1.20 0.78 0.77 0.53 1.59 1.45 1.01 1.16 0.66 0.54 0.50 0.45 11.82 17.06 14.44 13.80 19.58 16.69 0 . 3b 0.44 0.40 0.41 0.56 0.48 19.76 12.40 16.08 17.60 14.44 16.02 0.48 0.47 0.47 0.48 0.42 0.45 16.84 16.54 16.69 15.32 13.56 14.44 0.44 0.51 0.48 0.43 0.37 0.40 16.85 0.70 16.34 19.03 15.96 21.88 14.77 15.40 18.28 0.78 0.85 0.71 0.91 0.55 0.75 0.70 0.85 1.21 2.04 0.28 0.77 0.28 0.01 0.08 0.06 0.82 0. 77 0. 0 1.66 0.85 2.26 0.18 0.16 0.17 0.09 0.03 0.06 0.49 0.46 0.48 1.75 1.99 1.87 0.29 0.19 0.14 0.05 0.06 0.05 0.82 1 .05 0.94 1.16 0.05 1.94 0.21 0.12 0.09 0.93 1.42 1.37 0.71 0. Ill 0.13 0.06 0.03 0.51 0.50 Page 31 001755 117-090 -- Croup mean relative organ v.-lights simun In this table were cn 1ni 1.( organ weight:-. *SI | ;nl f l e a n t 1v d i f f e r e n t f r o m C o n t r o l g r o u p mean, p-.-0.D5. **S Ijpil f l e a n t ly ill I Cerent from C o n t r o l gr oup mean, p - 0 . 0 1 . ly averaging the !nd ivi timi 11 y cn leu 1aled re 1at 1ve NoI Included In analysis. - *< l i n t a v a l I a b I e Ml-1VI s TAlll.K 17. Coni. 0roii|i, Monkey Number Terminal S a c r i f i c e : Control: 7 162 7165 Mein 7116 7111b Menu 1 mg/kg/day: 7164 7166 Mean 7184 7185 fk'au 10 mg/kg/day: 7161 7458 Mean 7128 7181 Mean 10 mg/kg/day 3 : 7455 Heaths: 30 mg/kg/day: 7367 7382 7387 100 mft/kR/iJny: 7361 7456 7335 7381 N i n e t y Day S u b a c u t e R h e su s Monkey T o x i c i t y S tm ly . Ab s o l ut e (Crams) aiul R e l a t i v e (Z Body Melglit) Organ Wei ght s, Terminal S a c r i f i c e nml De a t hs . Body Wt. Sex kg _ J l e ^ r t ____ g ............. 'X Thyroid/ Pajralhjrrold g"" ' 2x10 _____ B r a i n g" Z M 3.75 11.69 0.36 M 3.85 18.17 0.47 3.55 14.93 0.42 F 1.40 15.30 0.45 K 3.50 14.75 0.42 3.45 15.03 0.44 1.050 0.296 0.673 - 0.819 0.8193 0.32 0.08 0.20 _ 0.24 0.24 M 4.10 18.90 0.46 M 2.65 12.70 0.48 3.38 15.80 0.47 V 3.70 16.87 0.46 F 3.45 15.19 0.44 3.58 16.03 0.45 0.893 0.178 0.616 (J.694 0.543 0.619 0.22 0.14 0.18 0.19 0.16 0.17 M 3.80 15.10 0.40 M 3.25 14.14 0.44 1.211 0.488 0.32 0.15 3.53 14.62 0.42 0.850 0.23 F 3.55 11.85 0.31 F 3.70 U .69 0.12 0.461 0.537 o .n 0.15 3.63 11.77* 0.12** 0.499 0.14 M 2.40 10.50 0.44 0.292 0.12 M 2.10 10.39 0.49 F 2.25 11.93 0.53 F 2.25 10.21 0.45 M 7.40 14.54 0.61 M 2.70 15.55 0.58 F 2.05 11.44 0.56 F 2.60 12.95 0.50 0.532 0.543 0.845 0.791 0.718 0.479 0.417 U . 25 0.24 0.38 0.33 0.27 0.23 0.16 87.04 90.39 88.72 82.64 81.55 82.10 2.68 2.35 2.51 2.41 2.31 2.18 96.01 81.50 89.76 78.66 80.21 79.44 2.34 3.15 2.75 2.13 2.32 2.2 3 77.73 83.38 80.56 77.19 75.88 76.54** 75.01 2.05 2.57 2.31 2.17 2.05 2.11 3.13 82.27 83.22 91.45 92.43 95.42 74.28 86.20 3.92 3.70 4.06 3.85 3.53 3.62 3.32 I'l l ill I a r y g Zxlir 0.053 0.063 0.058 n.oso 0.073 0.06:! 0 . U. 0.16 0.16 0 . 15 0.71 0 . 18 Cl ,0HM 0.051 0.066 0.086 0.051 0.070 0.20 0.19 0.19* 0.2 1 0.15 0.19 0.063 0.047 0.055 _ 0.071 0.07I3 0.17 0 . 14 0.16 0.19 O.IR3 0.049 0.20 (1.068 0.070 0.057 0.072 0.046 0.056 0.082 0.32 0.31 0.25 0.30 0.17 0.27 0.32 Page 32 001756 Croup mean r e l a t i v e organ w e i g h t s shown In l l i l s t a b l e were c a l c u l a t e d by a v e r a g i ng t he i n d i v i d u a l l y c a l c u l a t e d r e l ative organ weights. *SI go ITI cant l y d i f f e r e n t from Cont rol p.roup mean, p 0 , 0 5 . **S I gnl t l eant ly d i f f e r e n t from Cont rol group mean, p l l . t l l . nNot Incl uded In a n a l y s i s . - - Not a v a i l a b l e Page 33 FC-143: TABLE 18. Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations. firoup. Monkey Number 7362 7365 7336 7386 7366 7385 7363 7328 7383 7367* 7382* 7387* 7361* 7381* Tissue Lesion Control U I Xl X X !* ! 3 ag/Wdav X X U- U. r 50 c-i r-u r- 10 mg/kg/dav X X b. h. oU"oV -rav* 30 mg/kg/day X X tu Cu U*5 vrs n* 100 mg/kg/dav x X u. u. ** 50 u*. tri ri cn r** r<- Brain focal perivascular lymphoid infiltrates 11 11 i1i1 1 3 11 i 1_ 1 1 i 1i1 Spinal cord Peripheral nerve Sarcocystis sp. in ocular muscle focal lymphoid Infiltrates in sclera focal lymphoid infiltrates in lacrimal gland focal lymphoid infiltrate in palpebral conjunctiva cystic tarsal gland 11 11 i1i1 111 1 i1 11 i1 i1 11 11 i1 i1 111 1 i1 11 i1i1 1 1111 x x 3 1 11111 3 33 3 3 1 X Pituitary diffuse congestion small parenchymal cyst 111111111 111 x 1 3 33 1 33 Thyroid foci of interstitial lymphoid infiltrates focal interstitial fibrosis diffuse congestion 111 1 11111111 32 3 11 2 2 3 3 Parathyroid diffuse congestion 1111 11 11 3 Tongue foci of inflammatory cell infil trates in lamina propria and mucosal epithelium foci of inflammatory cell infil trates in muscle Sarcocystis sp. 1 3 2 3 11 23 23 3 x 33 32 x 2 11 11 22 2 137-090 Code: x - condition presenc a - autolyzed 1 - not remarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 - extreme - not available *Died or sacrificed in extremis 01757 FC-143: TABLE IS. Cont. Ninety Dy Subacute Rhesus Monkey Toxicity Study. Microscopic Observations. Page 34 Tissue Lesion to 0) XI c-.o>.<uu 3 JJ 1-0 3 OIZ Control z Z be in s0 10 S0 <n en ps en rs er*ns b. -0 30 en is. foci of inflammatory cell infil trates in mucosal epithelium and tonsillar crypt Sarcocystis sp. in muscle Gongylonema sp. in mucosal epithelium atrophy of lymphoid follicles 3 42 X 3 X 3 ng/kg/dav Z Z Ok Ok 10 .ng.'kg/dav Z Z b. Ch >0 <T in vO 39 CO en rs en rs en rs en rs en 00 00 en <0 en r- m rs CM <rns eono rs* i 4333344 30 ag/kg/day Z Z be b. in * fs 4 esj rs 1/3 10 00 30 rs erns en P'S en rs _1 23 4 100 mg/kg/dav Z Z b. be * * * 4 >0 in *0 en OO rs en rs en rs en rs .._ Adrenal foci of dystrophic mineraliza tion diffuse congestion diffuse lipid depletion foci of lymphoid infiltrates in sinusoids acidophilic degeneration of individual to small groups of cells 3322 3 1 32 2 23 32 2 33 2 343 555 2 3 55 43 55 23 Trachea foci of inflammatory cell infil trates in lamina propria 3 Salivary gland focal interstitial lymphoid infiltrates diffuse congestion decreased cell size, loss of cytoplasmic granules 1 23 2 1 34 3 1 223 3 23 33 11 33 Lung acarlan pigment ''peribronchial, peribronchiolar, perivas- cular) 3 222 focal perivascular lymphoid infiltrates focal peribronchial/peribron chiolar lymphoid aggregates 4434 lung mite in bronchiolar lumen X X interstitial pneumonia 34 4 diffuse congestion foreign body pneumonia 5 focal hemorrhage 3 acute focal bronchopneumonia 4 numerous aggregates of pigment laden alveolar macrophages 3222 3 334 3 3 34 5 3 ?23 2 33 344 3 33 4 3 224 3 22 44 333 2 22 33 3 4 3 137-090 Code: x - condition present a - autolyzed 1 not remarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 - extreme - not available Died or sacrificed in extremis 0017S8 Page 35 FC-143: TABLE 18. Cont. Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations Tissue Lesion V3 rtl XU a. a a s -g -i 5sz = CN \0 p* Control x b. m vO sO rs. p-. be 'a oo r** Heart l focal interstitial lymphoid Infiltrates 3 33 focus of lymphoid infiltrate in endocardium focal subendocardial hemorrhage atrophy of epicardial fat 3 ae/ke/d av X z b. b. sO >3* sO 00 eo rv p* fN. re l 233 10 mg/kg/d av X X b. be m eo SO m pr** * SJ iSk ft eo r*% i1 1 3 30 ne /kg/d av X z be be IT1 r- C*N r- <pr* r-. p*i po* p*. 1 3 4 100 m g/kg/dav X X be be ** sO P-T pi * m * r"> p- S P* 1 22 3 44 Aorta 1l11 l111 111l 1111 11 1 1 S p leen 1l11 atrophy of lymphoid follicles diffuse congestion focal amyloidosis in lymphoid follicles increased amount of hemosiderin pigment l 111 l1 33 4 -* 4 4 334 3 3 44 44 44 34 3 Lymoh node 1 1 1 '1 1 1 1 atrophy of lymphoid follicles increased amount of hemosiderin pigment 3 neutrophil infiltrate in sinuses diffuse congestion lymphoid hyperplasia 3 1111 11 4 3 3 4444 3 35 3 Esophagus 11 foci of inflammatory cell infil trates in lamina propria 32 foci of interstitial lymphoid infiltrates in muscularis 2 Gongylonema sp. in mucosal epithelium 1 2 32 2 322 22 2 X 1 32 2 1 11 2 Stomach foci of inflammatory cell infil- trace in lamina propria 3u 33 diffuse congestion foci of inflammatory cell infil- traces in subaucosa foci of inflammatory cell infil trates in muscularis foci of inflammatory cell infil- crates in serosa parasitic granuloma in omentum focal mucosal hemorrhage focal coagulation necrosis in aiucosa 3344 4 3 4 34 3 2 4 43 3 3 X 2 33 33 2 137-090 Code : x - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 - extreme - " not available *Died or sacrificed 3 24 3 3 3 G01759 FC -143: TABLE 18. Cont. Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations. Page 36 Tissue Lesion Control CO <u XI Z Z h* U* a* >1 ks 4 Z o e I g2Z <VrOn- tSnOn ^ ?nn PS. s0o0 ^ 3 ag/kg/day z z ft* a. so >y m psOn sm cn0 <X*> rs. rs rs p^, 10 tng/kg/day ZZ fiu Small intestine 1111 diffuse villous atrophy focal hemorrhage diffuse congestion focal aggregate of brown pigment- laden foamy macrophages in mesentery inflammatory cell infiltrates in serosa atrophy of lymph nodule 1 1 1111 30 ag/kg/dy 2ZSbfih uin-i if0*Nn0 * fs CrrOs> 100 ag/kg/day ZZCfaEb sm*O r<*s v--*O rtns pcr**nnsi * pXpns 1 3 333 55 33 33 X 4 44 Cecum transmural inflammatory cell infiltrates diffuse congestion focal mucosai hemorrhage inflammatory cell infiltrates in serosa parasitic granuloma in muscularis atrophy of lymph nodule 1 1 11111 111 333 2 4 33 24 1 4 Colon 1111 diffuse congestion parasitic granuloma in submucosa transmural inflammatory cell infiltrates focal mucosal hemorrhage atrophy of lymph nodule 111 1111 1 33 3 3 1 33 X 4 Rectum diffuse congestion Inflammatory cell infiltrates in muscularis atrophy of lymphoid nodule Pancreas focal periductal lymphoid infiltrates focal interstitial lymphoid infiltrates diffuse congestion Thymus 1111 1111 1111 1 32 1 33 32 111 3 1111 1111 1111 1 333 4 3 3 alia *> 33 3 137-090 Code; x - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 - extreme - - not available *Died or sacrifie 001760 Page 37 F C - 143 TABLE 18. Cont. Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations. Tissue Lesion Control 10 V XI z X Ch Eft* in v> 33 en r-* Liver portal inf lannatory cell infil trates 333 3 parenchymal inflammatory cell infiltrates 2 2 23 diffuse congestion acidophilic degeneration of individual to small groups of hepatocytes diffuse hepatocellular hyper trophy with cytoplasmic vacuolation neutrophil infiltrates in sinusoids Group, Monkey Number 7362 7336 7364 7366 7385 7363 7328 7383 7367* 7382* 7361* 7335* 7381* 3 msc/kg/dav X X Sfte (he T 00 <n r* 32 33 33 3 10 */kss/day X X Eft. Eft. -3* 30 mx/kg/day X X Eh El* m Pk, m c r** ps* 100 m g/kg/dav X X Eft. Efts * sO IT PN. 332 2 2 1 2 332 4 33 3 32 33 3 33 3 Gallbladder foci of inflammatory cell infil trates in lamina propria 3343 3223 2333 laaa aala Kidney focal interstitial lymphoid infiltrates 22 2 multinucleated lining epithelium in papillary ducts XX cyst in medulla X chronic interstitial nephritis 3 diffuse congestion microlith in renal tubules small foci of dystrophic miner- alizar ion 2 334 2 X 23 23 X 2 22 433 22 22 3333 X 22 Urinary bladder foci of inflammatory cell infil trates in lamina propria 3 2 32 diffuse congestion 2323 11 33 i1 1 3 A 3 33 Testes prepuberal development chronic focal vasculitis focal perivascular lymphoid infiltrate XX 4 XX :< X 2 XX XX Ovaries small foci of dystrophic mineral ization diffuse congestion 1 2 11 11 1 2 3 11 137-090 Code : x - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight 4 - moderate 5 marked 6 - extreme - not available *Died or sacrifie 001761 Page 38 FC-143: TABLE 18. Cont. Ninety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations. Tissue Lesion Prostate focal interstitial lymphoid infiltrates focal lymphoid infiltrate in corpus cavemosum Croup, s Monkey e Number X 7362 M I 7365 7336 7386 7366 7363 7383 7367* 7382* 7387* 7381* Control fa fa 3 ng/ktt/dav X fa fa 5*fCsf0-f.) 0f0f 0U-01 n*. pv 10 m /k * /d * v Z z fa fa ieno ff C0rr>N0-. 30 m g/kg/dav X fa fa tmn ri. 100 mg /k g /d a v fa fa * n r- * re*n ruee*nnr. 11 33 23 23 2 3 22 3 Uterus diffuse congestion blood in uterine glands small foci of hemorrhage in endometrium brown pigment-laden macrophages in endometrium inflannatory cell infiltrates in endometrium proteinaceous fluid and inflam matory cells in uterine lumen 22 22 32 2 3 3 42 11 1 3 2 33 2 3 Vagina foci of lymphoid infiltrates in lamina propria and mucosal epithelium foci of lymphoid infiltrates in auscularis Sarcocyscis sp. focal lymphoid infiltrate in tunica adventitia diffuse congestion focal neutrophil infiltrate in aucosa Skeletal muscle 1 Sarcocystis sp. focal interstitial inflammatory cell infiltrates interstitial fibrosis focal/aultifocal atrophy of muscle increased sareolemma1 nuclei 34 2 11 33 2 x 44 3 3 23 25 3 1 x 3 Skin brovu/black pigment in dermis x xxx dermal inflammatory cell infil trates 2 diffuse acanthosis 33 diffuse congestion hyperkeratos is few large areas of hemorrhage in subcutis XXXX 33 33 3 3 XXXX 33 XXXX 333 XXXX 3 33 5 137-090 Code: x - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 - extreme - m not available *Died or sacrificed in extremis 001762 Page 39 7382* V 7387* F 1 7361* M 7381* F 1 FC-U3: TABLE 18. Cont. Sinety Day Subacute Rhesus Monkey Toxicity Study. Microscopic Observations. Tissue Lesion Control z z Ct* fcu M lA PA iS seOn PS m en fS eo resn 3 mfc/ks/day z X fib Ct. <vr en PS seOn Ps m PS lA eo rns 10 rag/kg/dav z z a . Ct. pa CO eo PA <Pns lA -rTs CM PPAs eo PPAs 3 0 mg/kg/dav zX UA P*s VA < Vrs PPAs Mammary gland brown pigment in dermis XX hyperkeratosis 33 dermal inflaamatory cell lnfll- crates 3 inflammatory exudate in acinar lumen/ducts 2 inflammatory cell infiltrates in intralobular connective tissue 3 diffuse congestion intraepidermal microabscess X 3 3 2 1 X 3 33 23 XXX 33 3 33 2 XX 3 33 2 X 2 X 100 mg/kg/dav z Ct. #* VA eAn PS resn XXXX 3 Femur Bone marrow (Rib junction) hypocellular marrow congestion Miscellaneous acute focal cheilitis, lip 1 1 11i 1 1111 1111 11 1 1 344 3 3 34 4444 334 3 4 137-090 Code: X - condition present a - autolyzed 1 - not remarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 - extreme - not available Died or sacrificed in extremis 0176-3