Document 2qnRrYMKBk2Q3dz69r7K4dK06

mi-oisQ International Research and Development Corporation SPONSOR: COMPOUND: SUBJECT: 3M Company FM-3422 Ninety Day Subacute Rhesus Monkey Toxicity Study. Edwin I. Goldenthal, Ph.D. Vice Presiant and Director o f 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 T. M. Saulog, D.V.M., M.S., Staff Pathologist Date: January 16, 1979 137-088 001449 International Research and Development Corporation T A B L E OF C O N T E N T S I. S y n o p s i s ..................................................... II. C o m p o u n d ..................................................... III. Clinical Studies ............................................. A. M e t h o d ................................................... 1. General Procedure .................................. 2. Compound Administration ............................ 3. Observations ................... . . . . . . . . . . 4. Clinical Laboratory Test ........................... a. H e m a t o l o g y ...................................... b. Biochemistry .................................... c. U r i n a l y s e s ...................................... d. Statistical Analysis ........................... B. R e s u l t s ................................. 1. General 3ehavior, Appearance and Survival . . . . . 2. Body W e i g h t s ........................................ 3. Laboratory Tests .................................... IV. Pathology Studies ......................................... . A. M e t h o d s ................................................. 1. Gross Pathology .................................... 2. Histopathology............ B. R e s u l t s ................................................ 1. Gross Pathology and Organ Weights ................. 2. Histopathology...................................... Table No. 1. Individual and Group Mean Body W e i g h t s .................. 2- 4. Individual Hematological Values ........................ 5- 7. Individual Biochemical Values .......................... 8-10. Individual Urinalysis .................................. 11. Necropsy Observation .................................... 12. Absolute and Relative Organ Weights ................... 13. Microscopic Observations ................................ 137-088 001450 Page 1 3 4 4 4 4 5 5 5 5 6 6 6 6 7 8 9 9 9 9 10 10 10 12-13 14-16 17-19 20-22 23 24-25 26-31 International Research and Development Corporation Page 1 I. SYNOPSIS FM-3422 was administered to rhesus monkeys by gavage at dosage levels of 1," 3, 10 or 30 mg/kg/day. A control group received the vehicle, propylene glycol. Two male and two female monkeys were ini tiated at each dosage level and also in the control group. The monkeys were observed twice daily for general physical appearance, behavior and pharmacotoxic signs. Body weights were recorded weekly. Hematological, biochemical and urinalysis studies were conducted once in the control period and at 1 and 3 months of study. One monkey treated with 30 mg/kg/day died during the last week of the study. On and after the second day of study, all the monkeys, including the control group showed anorexia, slight to marked decrease in activity and ataxia. The ataxia disappeared from all the monkeys directly after the amount of propylene glycol used was reduced from 5 to 2 ml/kg on study day 3. Occasional emesis and diarrhea (sometimes severe) were observed. Several weeks after the initiation of the study black stool, mucus and bloody mucus in the stool were observed in most of the monkeys from each group. For two monkeys receiving 30 mg/kg/day the above mentioned signs of toxicity persisted for almost all the treatment period. One monkey at the 30 mg/kg/day dosage level died during the last week of the study. Most of the monkeys, Including those in the control group lost body weight early in the study. At 12 weeks of study all the monkeys were at or near the original body weight except for the groups receiving 10 and 30 mg/kg/day. At the end of the study the differences in the mean body weights of the treated and control groups were not statistically significant. 137-088 001451 International Research and Development Corporation Page 2 Microscopically, the adrenals from one male and two female rhesus monkeys at the 30 mg/kg/day dosage level had compound-related slight to severe lipid depletion. The pancreas from the two female monkeys at the 30 mg/kg/day dosage level had compound-related moderate atrophy of exocrine cells. None of the tissues from the other monkeys had lesions that would be considered compound-related. Statistically significant variations in sex group mean weights of liver and brain occurred between the control and experimental groups. These variations were of unknown biological significance and were not accompanied by morphologic alterations. 137-088 14SZ International Research and Development Corporation Page 3 II. COMPOUND The compound was received from 3M Company, Saint Paul, Minnesota on October 28, 1977 as indicated below: Label Description FM-3422 41-2700-3422-0 Lot 784/Net-35 DR-1 off-white to tan waxy substance 137-088 001453 International Research and Development Corporation Page 4 III. CLINICAL STUDIES A. METHOD: 1. General Procedure: Ten male (weighing from 3.00 to 4.35 kg) and 10 female (weighing from 3.05 to 4.20 kg) rhesus monkeys were initiated into this study. The monkeys were purchased from Primate Imports Corporation, Port Washington, New York on October 25, 1977. The monkeys were housed individually in hanging wire mesh "squeeze-type" cages and maintained in a temperature-, humidity- and light-controlled environment. Purina Monkey Chow was fed twice each day and fresh apples were fed 3 times a week. Water was available ad libitum. During the conditioning period (14 weeks), the monkeys were tattooed on the inner surface of the thigh and intrapalpebral tuberculin tests were conducted. Tuberculin tests also were conducted at bimonthly intervals during the treatment period. Complete physical examinations were conducted by the staff veterinarian prior to initiation of the com pound administration and only monkeys in good health were selected for use. This study was initiated on February 9, 1978. Terminal sacrifi ces were conducted on May 10, 1978. 2. Compound Administration: At the end of the conditioning period the monkeys were divided into 5 groups on a random basis, so that the average body weights were similar: Group Number of Monkeys Male Female Dosage Level I 22 Control II 2 2 1 mg/kg/day III 2 2 3 mg/kg/day IV 22 10 mg/kg/day V 2 2 30 mg/kg/day 137-088 001454 International Research and Development Corporation Page 5 The test compound was dissolved in propylene glycol by heating to approximately 30 C. The solution was administered by gavage. For study day 1 and 2 all of the treated monkeys received 5 ml/kg of the solution. On and after study day 3 the amount of propylene glycol was reduced to 2 ml/kg. The control group received 5- and then 2-ml/kg of propylene glycol on the same regimen as the treated groups. 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. Food con sumption was estimated. 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, reticulocyi count^, platelet count, prothrombin time, activated partial throm boplastin time (APTT)^. Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) were calculated. b. Biochemistry: Biochemical studies included: blood glucose, blood urea nitrogen, serum alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), 137-083 001455 International Research and Development Corporation Page 6 cholesterol^, total protein^, albumin, sodium1-^, potassium1-*1, chloride^, inorganic phosphate^, Y-glutamyl transpeptidase1-1-, creatinine phosphokinase 1 . Sorhitoi dehydrogenase was not deter mined because reliable data could not be obtained with the present instrumentation. c. Urinalyses: Urinalyses included: measurement of volume, pH1- and specific gravity; description of color and appearance; qualitative tests for protein1-, glucose1-, ketones1-, occult blood1-; and microscopic examination of the sediment. d . Statistical Analysis: Analysis of terminal body weights and organ weights (absolute and relative) and clinical laboratory tests were performed using analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal and unequal variances) as described by Steel and Torrie using Dunnett's multiple comparison table to judge significance of differences. 3. RESULTS: 1. General Behavior, Appearance and Survival: Monkey 7490 receiving 30 mg/kg/day died during the last week of the study. The death was preceded by a marked loss of body weight (1.25 kg) with a marked decrease in activity and ataxia. Except for one monkey receiving 3 mg/kg/day, ataxia was observed for all the monkeys in the control and treated groups beginning at day 2. For most of the monkeys the ataxia was slight but for a few the ataxia was moderate or marked. With the reduction in the amount of propylene glycol use the ataxia disappeared usually before the end of the first week. In addition to the ataxia the monkeys in the control and treated groups had anorexia, slight to moderate decreased activity appearing on study day 2. Occasional emesis also was observed. 137-088 001456 International Research and Development Corporation Page 7 For the monkeys in the control group, diarrhea was occasionally jjhserved but for Monkey 7470, the diarrhea, was chronic at the end of the study. After the second week of study, bloody mucus in the stool and black stool were noted. Except for the chronic diarrhea, the observations for the monkeys receiving 1 mg/kg/day were the same as that of the controls. At the 3 mg/kg/day dosage level Monkey 7487 was observed to have black stool and mucus in the stool during weeks 11 and 13. Frequently, severe diarrhea was noted for Monkey 7474 during week 12. For the monkeys at the 10 mg/kg/day dosage level, occasional diarrhea was observed. Of the monkeys receiving 30 mg/kg/day, 7499 had bloody mucus in the stool, emesis and severe diarrhea from the third day of the study. Severe diarrhea was observed for Monkeys 7472 and 7490. In addition for Monkey 7490 mucus in the stool, bloody mucus and blood in the stool also was noted. For Monkeys 7499 and 7490 the signs of toxicity persisted for most of the treatment period. Monkey 7490 that died in the last week of the study showed marked decrease in activity and marked ataxia on the day prior to death. 2. Body Weights (Table 1 ) : During the first month of study, all the monkeys lost weight including those in the control group. The percentage change in mean body weight, at monthly intervals were: Study Weeks 0 Group, dose in mg/kg/day 1 3 10 30 0- 4 4- 8 8-12 -3.94 +1.16 +3.76 -0.29 +3.25 +2.87 -0.29 +4.57 +1.09 -7.04 +1.82 +0.60 -7.32 -3.04 -3.98 For the group receiving 30 mg/kg/day the low mean body weight resulted mainly from the 1.25 kg loss in body weight for Monkey 7490, 137-088 601457 International Research and Development Corporation Page 8 which died. However, there were no statistically significant dif ferences between the body weights of the treated and control monkeys. 3. Laboratory Tests (Tables 2-10): After the first month of treatment no unusual changes were observed for the blood and urine analyses. For Monkey 7491, receiving 10 mg/kg/day, there was a slight decrease in hematocrit, hemoglobin concentration and erythrocyte count at 1 month of study as compared to the pretreatment period. This decrease was not found at 3 months of study. For most of the monkeys at 3 months of study, the blood glu cose values were in the lower range of expected values. Also at 3 months of study, low cholesterol values (56 and 67 mg/100 ml) were found for two monkeys receiving 30 mg/kg/day, and for one monkey receiving 10 mg/kg/day (84 mg/100 ml). For Monkey 7477 which had a cholesterol value of 67 mg/100 ml, a low potassium value (3.5 meq/liter) was found also. 137-088 001458 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. The monkey which died during the study was 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 s tornach testes/ovaries thyroid parathyroid thymus trachea tonsil tongue urinary bladder vagina tattoo and any other tissue(s) with lesions. ^Phencyclidine HCl - BioCeutic Laboratories, Inc., St. Joseph, Missouri. 137-088 001459 International Research and Development Corporation Page 10 B . RESULTS : 1. Gross Pathology (Table 11) and Organ Weights (Table 1 2 ) : No gross lesions considered compound-related were seen in monkeys sacrificed after 90 days of study. Statistically significant variations in sex group mean weights of liver and brain occurred at the 10 and 30 mg/kg/day dosage levels as follows: Dosage Level Organ (mg/kg/day) Sex Weight Change P< Liver 10 30 M relative increase 0.05 M absolute,relative increase,increase 0.05,0.01 Brain 10 30 M absolute M absolute decrease decrease 0.01 0.05 The biological significance of these organ weight variations is not known. These organ weight variations were not accompanied by morphologic changes which were considered compound-related. 2. Histopathology (Table 1 3 ) : One male and two female monkeys at the 30 mg/kg/day dosage level, sacrificed after 90 days of study, had slight to severe lipid depletion in the adrenal glands. The two female monkeys at the 30 mg/kg/day dosage level had moderate atrophy of pancreatic exocrine cells. The lesion was characterized by decreased cell size with loss of zymogen granules. One of the two pancreas also had several eosinophilic intranuclear inclusions in exocrine cells. These microscopic findings were considered compoundrelated. No microscopic changes which were considered compound-related were seen in the adrenal glands of male or female monkeys at the 1, 3 or 10 mg/kg/day levels. No microscopic changes which were considered compoundrelated were seen in the pancreas of male monkeys at the 30 mg/kg/day level or in male or female monkeys at the 1, 3 or 10 mg/kg/day levels. No microscopic lesions in tissues other than the adrenal glands and pancreas of monkeys at the 30 mg/kg/day levels were considered compound-related. 137-088 001460 International Research and Development Corporation Page 11 References 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 ZB , 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 St., Hialeah, Florida. 6. General Diagnostics - Warner Chilcott Laboratories, Revised April 1965. 7. General Diagnostics - Warner Chilcott Laboratories, Revised January 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. Glutamyl transpeptidase, Sigma GGPT, Bulletin 545. 12. Creatinine phosphokinase - Sigma Procedure Bulletin 520. 137-088 001461 BEST COPY AVAILABLE 3^T00 7479 M 7493 7495 F F Mean 1 mg/kg/day: 7467 7473 M M 7489 7492 F F Mean 3 mg/kg/day: 7469 7474 M M 7487 7497 F F Mean 3.10 3.75 3.00 3.56 3.00 3.80 3.05 3.55 3.25 3.70 3.00 3.59 3.15 3.70 3.00 3.55 3.15 3.60 2.85 3.48 3.05 3.55 2.85 3.41 3.85 3.25 3.05 4.15 3.58 4.00 3.20 3.05 4.00 3.56 3.75 3.30 2.95 3.85 3.46 3.95 3.25 3.00 3.75 3.49 3.75 3.10 2.90 3.60 3.34 3.85 3.10 3.00 3.55 3.38 4.10 3.45 3.60 3.05 3.55 4.00 3.20 3.75 3.10 3.51 4.05 3.45 3.45 3.20 3.54 4.00 3.55 3.45 3.30 3.58 3.95 3.55 3.30 3.30 3.53 4.00 3.55 3.30 3.15 3.50 137-088 *Terminal weight 3.15 3.60 2.90 3.Al 3.20 3.60 3.00 3.A3 3.25 3.70 3.05 3.A5 3.30 3.70 3.00 3.A5 3.20 3.60 2.90 3.38 3.20 3.80 2.95 3.A3 _>.u \.j 3.25 3.60 3.00 3.Al 1 .yj .* 3.35 3.85 3.05 3.58 J .J J* 3.10* 3.55* 2.75* 3.2A 3.85 3.10 3.05 3.55 3.39 3.95 3.25 3.10 3.55 3.A6 3.95 3.20 3.20 3.65 3.50 A.00 3.15 3.15 3.65 3.A9 3.95 3.10 3.15 3.60 3.A5 A.00 3.10 3.25 3.50 3 .A6 A.05 3.25 3.20 3.60 3.53 A. 10 3.60 3.15 3.50 3.59 3.85* 2.90* 3.10* 3.A 5* 3.33 A.05 3.60 3.AO 3.20 3.56 A.00 3.75 3.50 3.20 3.61 A. 10 3.75 3.55 3.30 3.68 A. 10 3.75 3.50 3.30 3.66 A.00 3.70 3.A5 3.10 3.56 A.15 3.80 3.55 3.20 3.68 A.15 A.00 3.55 3.10 3.70 A.20 3.70 3.60 3.30 3.70 A. 10* 3.55* 3.10* 3.05* 3.A5 Page 12 FM-3422: TABLE 1. Cont. Group, Monkey Number Sex Control -1 0 Ninety Day Subacute Rhesus Monkey Toxicity Study. Individual and Group Mean Body Weights, Kilograms. Week of Study 1 2 3 4 5 6 7 8 9 10 11 12 13 10 mg/kg/day: 7475 7480 M 3.80 M 3.45 7491 7498 F 4.20 F 3.10 Mean 3.64 30 mg/kg/day: 7472 7477 M 3.45 M 3.50 7490 7499 F 4.00 F 3.00 Mean 3.49 3.60 3.30 4.15 3.15 3.55 3.40 3.55 4.20 3.05 3.55 3.60 3.40 3.60 2.90 3.38 3.10 3.25 3.65 2.75 3.19 3.50 3.55 3.60 3.05 3.43 3.20 3.50 3.65 2.95 3.33 3.30 3.40 3.50 2.95 3.29 3.15 3.50 3.55 2.80 3.25 3.50 3.25 3.50 2.95 3.30 3.15 3.60 3.50 2.90 3.29 3.45 3.35 3.50 3.00 3.33 3.25 3.65 3.65 2.95 3.38 3.45 3.40 3.45 2.95 3.31 3.25 3.65 3.55 2.85 3.33 3.60 3.45 3.40 3.10 3.39 3.30 3.75 3.65 3.00 3.43 3.55 3.45 3.45 3.00 3.36 3.30 3.75 3.60 2.90 3.39 3.40 3.40 3.35 2.90 3.26 3.25 3.75 3.50 2.85 3.34 3.50 3.50 3.45 3.05 3.38 3.30 3.90 3.45 2.90 3.39 3.50 3.60 3.35 3.00 3.36 3.20 3.95 3.15 2.80 3.28 3.55 3.75 3.20 3.00 3.38 3.25 4.00 2.95 2.85 3.26 3.45* 3.55* 3.05* 2.95* 3.25 3.05* 3.75* 2.85** 2.65* 3.15 Page 13 001463 137-088 *Terminal weight. **Terniinal weight not included in mean. KM-'1422: N i n e t y Day S u lm c u le Kliesuu Monkey T o x i c i t y S t u d y . TAIll.F. 2. iid I v M u a ! Hemal o l o g h a 1 V a lu e - C o n t r o l . Croup, Rrytliro- lltnuo- lleoiatu l.euco- l'ialuii.-t Kelliriilo- lro- Niaitrojihlls l.ym|>lio- KouIno Moim- II.iso Monkey O^toM Ulolila er! t cvtua Conni cylet lliromhJn l'.T.T. Si>g. Non-Seg. cytes lili11a eylea lili11II mc\j MOI HClIC Number Sex 10 /i:m p,/100 ni Z 10 /mu 10 /mu Z Time, Set: See Z Z Z Z Z Z II l'HK g/100 ml Coilitrnl_ 7470 7479 M 9.07 M 9.71 749) 7499 K 4.91 F 9.48 Moan 9.10 l_!^/kg/i)ay: 7467 7473 M 9.54 M 5.05 74H9 7492 F 4.67 F 5.24 Mean 5.13 7 Hj/kg/il.iy: 7469 7474 M 5.14 M 4.98 74H7 7497 F 5.21 F 4.24 Mean 4.90 10 ui|;/lt|;/iliiy 7479 7480 M 5.25 M 4.78 7491 7498 F 5.08 F 4.78 Moan 4.97 30 wg/kg/iluy 7472 7477 M 5.10 M 4.98 7490 7499 F 5.69 F 5.64 Moan 5.40 11.8 37 14.51 142 11.2 37 9.06 119 12.0 36 12.20 109 11.6 16 8.20 103 12.2 17 10.99 118 14.0 12.1 39 37 8.55 9.13 185 116 11.0 35 11.69 236 11.7 36 7.26 102 12.3 37 9.16 160 12.7 38 13.51 110 12.2 16 9.32 182 12.6 10.2 39 30 7.00 5.82 169 246 11.9 16 8.91 182 12.1 37 13.03 234 10.5 31 8.93 168 12.0 36 14.81 174 10.7 33 8.97 107 11.3 35 11.44 171 11.8 32 8.49 248 12.2 39 12.21 252 11.2 41 10.61 144 13.0 33 9.12 241 12.6 36 10.11 221 1.3 0.2 0.9 0.6 0.8 0.2 1.3 0.6 0.4 0.6 0.4 1.2 0.7 0.5 0.7 1.5 0.3 0.5 0.9 0.8 l.l 0.7 0.6 0.7 0.8 12 28 56 0 11 24 15 0 11 21 18 0 12 24 38 0 12 25 12 0 12 26 35 0 II 24 12 0 12 2) 27 0 11 30 12 0 12 26 22 0 II 23 15 0 12 22 31 0 12 24 44 0 12 29 31 0 12 25 30 0 11 24 35 0 12 25 33 1 II 29 57 0 il 25 40 0 11 26 41 0 12 25 32 0 12 21 22 0 13 29 34 0 12 26 27 0 12 26 29 0 43 1 0 0 71 21 12 83 1 1 0 65 2) 36 80 0 2 0 71 24 11 59 3 0 0 66 21 32 66 1 1 0 69 23 33 62 3 0 0 70 25 36 86 0 2 0 73 24 31 71 2 0 0 75 24 II 87 0 1 0 69 22 31 76 1 1 0 72 24 82 3 0 0 74 25 31 66 1 2 0 72 24 14 56 0 0 0 75 24 12 67 l 1 0 71 24 14 68 1 1 0 73 24 II 60 5 0 0 70 23 11 61 3 0 0 69 22 32 41 2 0 0 71 24 13 60 0 0 0 69 22 32 56 1 0 0 70 21 11 64 4 0 0 60 22 37 76 2 0 0 78 24 II 66 0 0 0 72 23 12 71 2 0 0 59 23 39 69 2 0 0 67 23 15 Page 001464 IJ7-0HH KM- *1422: TA1U.K 1. Croup, KrytlirO- Monkey CylllH Number Six 10 'll-M* N i n e t y Day Sub.te ti l e Kliesus Monkey T o x i c l i y S t u d y . tml Ivldiial llenuitologJcnl Value*i * 1 Month. llemo- glob III ml llem.ito ll-It Z Leuco Platelet cytes Count 10 /crow l V w M Met M ulo- Pro- cyleu X tliriinlilii r.T.r. TIm., See SH* Neiitrnplil1u Spg. Non-Scg. ZZ Lympho Eos iiiu- Mono cytes phlls cytes Z ZZ lluSu plid H nc:tj HUI 18310 z I' HMg g/100 dl Com rut 7A70 M 7A79 M A.82 A.AH 7A93 7A95 F A.88 F A.27 Mtsin A.H lii;/k|;/(lay: 7A67 771 M A.82 M A.OA 7A89 7A92 F A,66 F A.10 Minim A .96 2 (/``li/'l'.y: 7AM 7A7A M A.89 M A.AA 7A87 7A97 F A.AA F A. IA Minin A.07 10 g/Jyj/`iy. 7A75 7AH0 M A.89 H A.AS 7A'l1 7A`l8 F A.A8 F A.78 Mean A.81 70 Mg/kg/<l.;iy /A77 7A77 M A.9A M A.8/ 7A90 7A99 F 5.76 F A.9A Minim A.03 11.8 17.0 12.A 17.6 12.7 12.6 12./ 12.0 13.A 12.7 12.8 12.A 13.8 13.9 13.2 12.6 II .1 10.9 12.7 11.7 17.7 17. 1 13.2 11.9 12.7 3A 39 18 A1 38 39 3A 76 78 37 37 35 AO 39 38 38 33 70 37 75 15 78 AO 35 37 IA.AA 10.61 IA .59 8.60 12.06 158 157 137 129 IA5 8.10 7.86 IA.53 12.53 10.76 113 117 127 132 122 12. 19 8.79 8.AA 8.2A 9.37 IA0 127 128 120 129 IA.AA 7.22 18.53 8.50 12.A2 129 139 I3A 155 139 9.29 9.A6 II.OA 11.61 10.35 121 128 127 I3A 128 0.7 O.A 0.6 O.A 0.5 0.2 0.3 0.3 O.A 0.3 0.3 O.A 0.2 0.2 0.3 0.5 0.2 O.A 0.3 O.A 0.2 0.2 0.2 O.A 0.3 10 to A5 0 12 28 25 0 12 29 53 0 11 26 26 0 II 28 37 0 II 71 A5 0 12 70 6 0 12 70 73 0 12 31 A9 0 12 31 33 0 12 31 23 0 13 32 39 0 12 26 AA 0 12 29 58 0 12 30 A1 0 12 29 A5 0 12 29 A3 0 13 32 68 0 II 26 57 0 12 29 53 0 13 28 27 0 12 29 2A 0 12 30 29 0 12 32 51 0 12 10 73 0 A9 A 2 0 73 2A IA 75 0 0 0 71 2A 13 A6 1 0 0 78 26 33 73 1 0 0 78 26 33 60 2 1 0 75 25 13 5A 1 0 0 81 26 12 9A 0 0 0 69 25 16 67 0 0 0 77 26 13 AO 1 0 0 72 25 35 66 1 0 0 75 26 IA 77 0 0 0 76 26 15 61 0 0 0 77 27 15 55 0 0 0 72 25 15 A2 0 0 0 76 27 36 59 0 0 0 75 26 35 55 0 0 0 7H 26 31 57 0 0 0 7A 25 IA 32 0 0 0 67 2A 16 A3 0 0 0 69 2 1 11 A7 0 0 0 72 25 IA 71 2 0 0 71 25 15 76 0 0 0 78 27 15 71 0 0 0 75 25 13 A9 0 0 0 a 2A 3A 66 1 0 0 7A 25 IA .Page 15 001465 117-088 FM-1 4 2 2 : N i n e t y Day S ti l n ic n lu IUichiik Monkey T o x i c I Ly S l m l y . TAIII.K A. lm llv lilu . il Oculato lo g le n i V a lu e s - 3 M o n llis, (rniiji, Kry1hru- Mt'IUO- llownto- l.euco- Fintolot ltd lenlo- Pn- Nout ni|ililla l.ytuplio- I'.iKIno Mono- Hiiso- oy ton t*lotIn orlt NlllutllT Sox 10/ciui. k/too ml Z cvteu Cijunl 10 /cum 10 /ohuh yion Z tItI'oiul)lu I'.T.T. Seg. Non-Seg. cyluH Timo, !<h: Soc X X X liliIIk cyloH itiilis Mcy MCII MUIC Z X X M MMI*. b/100 ml ('outrn 1: 74/II 747V H H 74'n 74Vi F F Ho.in 3.16 5.61 5.04 4.70 5.11 ."B/Kfi/iL'y: 7467 747 1 M 5.42 H 5. 10 748!) 7402 F 5.01 F 5.12 Houli 5.21 1 mg/kg/ilny: 746') 7474 II 5.48 M 5.94 7487 74`77 F 6.09 F 5.70 Noun 5.80 .111bZKb /Iy : 7475 7480 M 5.16 M 5.91 74<)l 7498 F 4.57 F 4.91 Heim 5.14 lOing/kg/il'y : 7472 747/ H 4.76 M 5. II. 7490 7449 1 Illoil 5.40 Homi 5.11 11.1 17 12.61 156 I3.fi 38 7.24 144 13.6 16 11.04 174 14.1 19 6.41 194 13.7 38 9.13 170 14.2 12.8 41 15 6.50 5.55 195 164 12.3 36 14.31 118 12.7 35 8.47 111 13.0 37 8.71 153 13.2 40 12.45 158 11.3 36 7.38 133 14.8 14.0 42 18 6.05 9.91 137 157 13.8 19 8.97 146 13.9 40 20.16 127 12.4 37 8.63 129 13.6 19 12.33 114 12.1 16 8.64 109 11.0 18 12.49 120 11.4 1 1.0 11 Il .43 119 19 9.01 145 12.2 12.2 17 36 7.82 9.42 117 140 0.1 0.4 0.4 0.2 0.3 0.0 0.0 0.2 0.1 0.1 0.0 0.5 0.4 0.3 0.3 0.4 0.3 0.1 0.6 0.4 0.5 0. 1 0.1 0.3 11 29 27 0 II 25 10 0 II 26 18 0 II 24 54 0 II 26 37 0 II 24 49 0 11 25 41 0 II 24 46 2 10 24 44 0 11 24 48 1 10 25 52 1 12 24 51 0 11 27 54 0 11 23 70 1 II 25 57 1 11 22 57 0 il 24 52 0 12 24 70 0 II 22 51 0 II 23 58 0 II 22 /! 0 II 21 18 0 II 21 51 0 II 22 51 0 69 1 1 0 72 26 16 69 1 0 0 68 25 36 59 1 0 0 71 27 38 44 1 0 1 83 10 36 61 2 0 0 74 27 37 49 2 0 0 76 27 15 56 2 0 1 66 24 17 49 T 1 (1 72 24 34 45 1 0 0 (.8 24 16 49 2 0 0 71 26 36 41 3 3 (1 73 25 13 47 1 1 0 61 22 37 43 1 2 0 70 24 35 29 0 0 0 67 25 17 39 1 2 0 68 24 36 39 3 1 0 78 27 35 47 0 1 0 61 21 14 29 1 0 0 85 10 15 47 1 1 0 73 25 14 40 1 1 0 75 26 15 28 1 0 0 70 24 14 49 2 1 0 76 24 11 47 1 1 0 69 2 1 II 45 1 1 0 72 24 14 Page 16 001466 I I/-mm |*`M - 141*2: N l n e t y Day S u b a c u t e Hlteuit Hottkuy " TAIll.K 5 Imi Iviiliiiit lllocliowlonl Vaine - CI- Al k. Cliniea- (aui|>. cune ll.U.N. rito. S.G.O.T. 8.C.I*.T. torni Tn!ul Ibittain Mnukny ui*/IOO !!/100 ini '1 Ine *t Int'l is/100 Proto In 11/Ilio Niinher Sox mi ni un ila/1 unita un ita mi mg/100 n| mi ConLtoi ; 7470 7478 M 107 20.5 510 M 12*7 26.0 546 7491 /495 F 123 27.9 1050 F 146 28.1 4*78 Homi 126 25.6 651 69 79 71 47 66 75 159 8.67 4 .3 9 27 160 8.54 4 . 7 0 71 163 9.23 5.80 75 192 8.81 5.67 32 169 8.81 5.14 7467 7473 H M 74B`7 74*72 K F Homi 3 (n/kii/Jay: 746*7 7474 H M 74H7 74*77 F K Meati 9*7 J07 197 125 171 142 114 174 118 127 io. 74/5 /4H0 74*71 74*78 Metili : M 142 M UH F 157 F 12 1 174 10 *"l5/)*.is./*l.iiy: 7472 7477 H M Idi 122 74*70 74*79 Meati F K 150 124 124 20.1 22.7 28.1 18.2 22.2 801 87/ 564 969 797 26.7 1*7.5 21.9 26.0 27.4 1276 471 765 570 761 71.7 14.7 22.1 19.1 21.8 792 648 7611 451 665 25.1 70.0 21.9 25.1 25.5 291 1065 487 627 617 55 88 48 88 40 102 49 64 88 76 58 71 100 48 59 48 71 50 59 57 37 241 8.59 5.24 42 174 8.10 5.23 7 168 8.75 5.12 70 166 8.77 4.70 28 187 8.55 5.07 26 158 8.47 5.38 30 188 8.16 5.39 32 196 8.10 5.20 54 196 8.55 5.16 36 184 8.32 5.28 22 210 8.55 4.99 32 130 8.45 5.07 23 148 8.67 4.80 21 208 8.57 5.30 25 174 8.56 5.04 23 168 8.49 5.51 77 196 8.75 5.50 23 171 9.18 4.92 46 160 9.54 4.52 32 174 8.99 5.11 001467 M /-U H H l'ox l e ILy SLmly. - (alili r o t . Sod Iun ei|/ IlliT rotati- h Ium *<M|/ lllur Clilur lilu *LM|/ IIter Inorganic l'lioH|>ltate r/JOO ml Cltilauyl Trniia|>i'|it lilaae Creai InIn Slguui I,Iioi|iI>Hii.ihu unlla/ial Slf.uia iiitlla/wl 154 5.1 112 159 5.9 118 170 6.7 121 165 5.4 117 162 5.8 117 157 6.5 118 158 5.8 118 160 5.2 114 166 6.1 127 160 5.9 119 162 5.9 119 156 4.7 112 159 5.1 111 152 4.8 111 157 5.1 113 166 4.8 118 158 6.5 117 157 5.1 116 157 6.9 117 158 5.9 117 153 3.9 109 168 5.8 121 162 5.3 119 160 6.2 111 161 5.3 115 4.7 6.4 5.2 3.7 5.0 5.7 6.0 6.1 6.2 6.0 7.0 4.2 4.1 5.0 5.1 5.5 6.6 5.1 4.2 5.4 5.0 5.4 6.7 5.7 5.7 41 28 46 10 36 37 32 35 36 35 5/ 16 35 11 35 51 48 31 22 18 35 76 28 17 19 29 57 52 44 46 5 28 50 80 41 16 15 43 20 34 100 23 104 26 69 22 49 114 24 52 Page 17 KH-Vi22: NhtcLy Day Subacute HIiubiik Moitkcy Toxle Iry Sludy. i'Aiii.K r>. Individual Uimiientlcal Vil1lien - 1 MoiiLh. liruii|), Honkcy Nuwher Clu- Alk. Cholee- Fuma- Cittatuyl cne II.II.N. l'Ima. S.C.I'.T. S.0.0.T. terul lutili AltunaIni Sud litui aluai eliluride Inoriattie Truna|ie|il ld.me Creili inIne mu/100 mg/100 lui *l lnt`1 lul'l mg/IO Frute lu mg/100 UtM|/ e|/ muil/ l'Ima|iluite SIgnu l'ltoH|hiikInane Sex ml wl un IIa/1 imita uni (s tul mg/100 *1 tul 1Iter 111er 1Iter mg/100 mi uuJ I h/mI Sigma unlta/ml Coni ru1: 7470 H H(> 19.0 H82 19 48 174 8.79 4.39 153 5.5 113 7.6 74 79 H 105 24.0 864 20 30 156 8.53 4.81 153 4.6 107 8.4 749 1 K 106 20.0 906 22 29 154 9.29 5.20 154 5.2 108 9.1 7495 K 105 21.2 540 25 33 178 9.18 5.72 159 5.9 111 7.3 Menu 101 21.1 798 22 35 166 8.95 5.03 155 5.3 110 8.1 J. ."H/M/.''J!; l'ibi H 119 17.0 750 20 33 226 8.17 4.92 152 4.9 105 7.2 ni i M 107 29.0 852 18 33 182 7.99 5.23 151 411 111 7.6 7489 K 121 21.R 516 44 29 154 8.74 5.05 156 4.5 109 7.4 7492 1* 100 19.1 85H 17 21 150 9.45 4.52 157 4.7 113 7.9 Memi 112 21.7 744 25 29 178 8.59 4.93 154 4.6 110 7.5 1 "/kli/iluy: 7469 Hm 27.2 1290 21 42 154 8.60 5.58 158 5.1 112 7.3 7474 H 96 1 7 . H 540 17 31 148 7.91 5.17 152 5.0 110 5.6 l'ibi K 126 20.9 612 27 35 172 7.64 5.10 152 4.2 107 6.2 74*17 K 120 26.0 672 15 35 186 8.90 5.49 151 4.8 113 6.8 Mean Il 1 21.0 779 20 36 165 8.26 5.34 153 4.8 HI 6.5 L. : 7475 M 151 22.4 690 22 46 181 9.09 5.00 157 5.0 114 6.4 74H0 M 131 21.2 528 15 29 110 8.84 5.01 152 5.1 113 7.8 7491 F 119 11.0 744 10 30 110 8.22 4.82 150 4.5 111 5.1 7498 K 122 20.1 486 14 31 168 8.25 5.43 150 4.8 III 5.7 Memi n i 19.2 612 15 34 142 8.60 5.07 152 4.9 113 6.3 J*>__>/Ktv/*iri y : 7472 H 90 24.9 276 12 28 132 8.83 5.74 151 3.7 106 6.3 7477 M 9H 22.5 996 19 40 137 8.60 5.39 115 5.6 118 7.4 7490 K H9 15.4 384 15 28 lio 9.21 5.60 154 4.3 110 5.5 7499 F 114 21.0 6 10 14 38 106 9.01 4.90 154 4.4 111 6.3 Mean 98 21.0 572 15 34 121 8.91 5.41 154 4.5 111 6.4 52 36 39 48 44 34 29 37 27 31 51 14 25 31 IO 34 42 29 39 36 40 68 30 38 44 48 16 8 5 19 4 4 2 6 4 6 2 16 4 7 IO 5 5 2 6 3 7 2 3 4 Page 13 001468 117(11111 KH-.1422: N in e ty liny S u b a c u te Hlicaiis Monkey T e x l r l l y S tu d y . I'AIII.K 7. 1milvidimi lllocliemlcnl Values - 3 Montlis. (inti}), Monkey NiiwImm' Sex Clli euse ll.ll.N. }/mo mg/100 ml ml Aik. IMioh. S 1J*IIU| mi lie s.c.i'.r. S.C.O.T. Sigma S Igma unllH unite Clioles tero! Total mg/100 I'roteln ml mg/100 ml AUltimili Sodium k/uio mei|/ ml 1Iter Potila- h Iiim mei|/ liter Clitoride me<|/ liter luorgan It: Pliou|iliate mg/100 ml Cllitamyl TimiB|>e|d Idaue Sigma un lla/ml Croni Inliie i'lm.splHtkinatte Sif.ma uiiliu/ml Control : 7470 747*7 H 1ft M 126 7491 74*14 K `16 K 117 Mean 101 tm^/kg/day : 7447 M 98 7473 M 71 7411*1 K <16 74*12 K 70 Mean 84 i mg/kg/day: 74(i*> M 107 7474 M 82 74H7 K *11 74*17 K HI Mean *11 10 _mg/kg_/day: /47ri M 105 74HO M 125 74*11 K 88 74*JH K H5 Moan 101 30 .g/kg/diiy: 7477 M 92 7477 M 77 749*1 74*10 K 10*1 K Hied Mean *11 2.08 22.2 1*1.0 24.2 21.6 21.0 15.4 22.4 19.8 24.7 25.0 24.9 29.0 27.8 26.7 22.2 15.3 30.2 21.2 22.2 18.4 27.6 15.8 20.6 *172 930 750 504 78*1 840 H52 420 756 717 1110 480 570 780 735 720 708 1032 528 747 1014 3/8 612 668 15 19 19 25 20 17 17 14 12 15 19 15 17 22 18 22 19 15 20 19 23 14 23 20 38 9.00 4.42 163 150 4.5 122 5.8 29 8.40 4.72 162 151 4.4 111 6.7 34 8.95 4.92 160 151 5.5 114 6.9 31 8.68 5.49 179 156 4.7 113 6.3 33 8-76 4.89 166 152 4.8 113 6.4 30 225 8.20 5.10 151 4.2 108 6.0 38 175 7.92 5.20 152 4.5 115 7.1 20 160 8.90 4.70 153 4.2 111 6.1 28 125 8.90 4.21 154 4.7 117 6.1 29 171 8.48 4.80 153 4.4 113 6.3 41 111 8.90 5.34 160 4.8 113 6.4 38 161 8.28 5.12 154 5.0 115 4.9 27 155 7.70 4.96 150 4.3 113 5.0 31 165 8.95 5.12 155 4.8 117 6.3 34 153 8.46 5.19 155 4.7 115 5.7 32 172 9.80 5.09 158 4.3 111 5.8 33 104 8.70 5.12 150 5.0 114 6.3 42 84 9.38 5.14 151 4.5 115 5.5 38 184 8.60 5.48 115 4.5 113 5.0 36 134 9.12 5.21 154 4.6 113 5.7 43 KIH 8.60 5.12 153 4.2 113 5.6 32 67 9.55 6.09 155 3.5 110 6.7 47 56 9.42 4.92 155 5.0 109 5.7 41 77 9.19 5.38 154 4.2 111 6.0 53 46 43 51 48 49 32 23 27 11 47 16 24 32 30 38 41 27 12 14 26 49 10 18 11 9 7 6 8 5 7 9 5 7 6 6 7 5 6 6 a 6 7 7 9 6 5 7 Page 19 001469 I *I KM- IA22: TAIII.F. H. Crou|>, Monkey Volume Numlicr Sex ml Color and Appear. pli Conimi : 7A70 72*79 M M 7491 7495 F K 1 ti/kjt/day: 7467 7471 M M 7AH9 7A92 K F 1 Jt,/Jl/i|ay: 7469 7A7A M H 7A87 7A97 F K .LPj!Bhfi/L*y! 7A75 7A80 M M 7A91 7A98 F K 11 " is/.biilAvy.'- 7A72 7A77 H M 7A9II 7A9`7 F F A5 18 10 23 15 65 25 IA 25 20 A5 25 25 10 20 15 9 10 155 21 S-d S-d S-d US-cl 7.8 7.A 6.2 7.6 S-cl !.S-cl S-cl S-cl 7.8 7.8 6.3 8.0 S-d S-d S-d S-cl 7.8 8.2 9.0 7.1 S-cl S-d S-cl I.S cl 8.0 6.8 7.A 8.0 l)S-cl S-c 1 l-S-cl S-d 7.8 7.7 8.5 7.6 N luci y Oay Suliacule ItluaoH Monkey Toxicity Study. Individual llrinalyaia Values - Cimi m l . Spec. Crav. l'roleln Clucoae Occult Blood Ko tones l.cucocylOH Kryllirocytea Epl. Cells llrntea Triple Calc. Bac FIiuh. Ox. teria 1.024 1.042 1.037 1.040 1.042 1.010 1.033 1.040 1.024 1.032 1.012 1.035 1.040 1.019 1.038 1.0.10 1.033 1.043 1.013 1.041 N N N N N N N N N N N N N N N N N N N N NNN NNN- NNN- N 2+ N - NNN- NNNN tr N NNN NNNNNN- NNN- NNN- NNN- N tr N " NNNN tr N - NNN- NNN NNNN 2+ N - - occ F occ - M - occ F F-F - occ occ occ - F - occ F P-M OCC occ F occ - F - -F occ - F Focc - FF- M F F F 1-3 - occ F - F - - occ F-F - occ F ore - F occ occ p F-M - occ F - -F - -F occ occ F occ H- occ - F- H F F F - -F F- F - -F occ - F occ _ occ occ 1-3 F FF- F H Page 20 001470 117-008 Code: ir - Trace Il - Trace lo al l|thr 71 - Sll|{lit l moderale II- - Moderate 4I - Marked S - Straw I.S - l.l|tlil tilraw OS - Dark atraw cl - Cloudy C - Clear H - Nettai Ive K - Few H - Many I. - laiailcd K - Hare I.Aw - l.li'liL Amlior IIAm - Mark Aiulior occ - Occnalonal None seen KN- M 2 2 : Ni.H`i y Hay Sula*iit is IMtomiH Mmikoy T o x l r l t y S i m l y 3 tm u.^ x : x x x x -- x x x -- * x ( I ii ii ii 3:3 3s3 33V(a. i. v3 y3 3u 3 33 !b . X 3 3 X X o X U> U. !b ' 3 tZ b &. L '4 . 9u !h ib U> X Cl, U. Urn . ih*A Ekib 3 3I 3 330 --<AI JK >t I- 3 U i co * I' ii 3 - 3 $X zz zz z z a: z zz zz zz zz z z wz zz zz z zz zz Z zz zz zz zz zz zz aOb U H3 5I r* N crt .--1 Oo cAs fM e> ri co cc ofoS o--n CChN s--o oc o o *o 00 N n n <n CO O O q<ns ri"A --r>fmsi OC OC tA O' r* pb. p** n CO in A* 00 p r* ec 3 33 V*, Vi Vi .yc v: _ 33 a i/*lc*> 00O r>* r. >o a* c3ri. l3vi v3ii i0vt c N -- A 00 sO f* f*. 33 II V v: C ac oc oc 0II3 (C Or '/ K 9 ~9 \A ciA vA q A m clA v - . u !f i 1 3 3 9; j U I ! O' X *4n aU >, x X 3 0b Si x * t C*.fM >?<S*' Si *Jb Sj X X * ' 5i od #j A C r- --O' 3O0' S3 9; N ci q " - Si 5 9 001471 (!mlo: I'17-088 tr - Truci? It- - Tram lo al Iglil 21 - Sllp.hr lo modulate *M - Moderate UI - Market) S - Straw I.S -l.iplil; hi raw l>S -Hark alirtw rl - Cloudy 0. - ('Ioar N - Nt^ul ivc F - Kcu M - Many I, - leaded H - Man* I.Aw -l.lp.hl Amltur MAiu -Hark Awltri occ - OecaMinnnl Noms aee Page 21 KM-V*22: TABI.K |0. Croup, Monkey Volume Number Sex ml Control 7470 747') H M 45 5(1 7493 F 45 74*7S F 15 i "u/Hc/'loyj 746/ 7471 M H 74H`) 7492 3 F F 7469 7474 M M 7487 7497 F F 45 250 15 15 60 Mil 35 125 I*L"B/Jcfi/iLn-X: 7475 7480 U M 7491 7498 F F 50 60 45 25 30 8/kB/`[ay: 7472 747/ H H 7499 7490 F F 5 45 15 Mletl Color and Appear. I'll l-S-el I.S-cl S-cl S~c 1 6.5 7.0 8.5 H.O S-cl I.S-C1 S-cl S-cl 9.0 6.5 9.0 8.5 I.S-cl I.S-cl S-el l-S-cl 7.5 8.0 7.5 7.5 I.S-cl l-S-cl I.S-f1 I.S-c1 8.0 6.5 B.O 8.5 S-rl l-S-cl I.S-cl 6.8 8.5 7.0 N i n e t y Day Subacute? Rhemiw Monkey T o x i c i t y S t u d y . Individual Urinalysis Values - 3 HonlIt8. Spec. Clu- Occult t.'rnv. Prole In COHi? fi1OOtl Ketoilftl l.eucucytes Erythro cytes F.pl. Culls Urate Triple Calc. Bac I'lmH. Ox. teria 1.020 1.026 1.031 1.035 1.034 QNS 1.012 1.032 1.027 1.017 1.035 1.012 1.026 1.024 1.025 1.031 1.043 1.012 1.031 N N N N N N N N N N N N N N N N N N N H tr H NNN- N tr N NN N- OCC K occ H - - F F-F occ occ F - occ K F-U F- F NNN NNN- occ F F F F - occ K OCC - U N 2+ N - 18-20 occ M occ - H N 3+ N - - - K occ - H NNNNNN NNNNNH - occ F F OCC H - occ F occ - F - occ F F- M F occ F N tr N NNN N 2+ N - N 2> N NNN_ NNN" HNN- - OCC _ - - ,, occ F F F F or.c F - -F occ - F F_ F F-F F_ M F~F F_ F F-F F-M Page 22 001472 II7-0HB Cod*?: tr 11 21 31 At - Trace T r a c e Co s i i|>lit S l i g h t t o m odern It; M o de rn to M a rke d S - Straw I.S - 1.1|;li 1 s t r a w US - H ark stra w c l - Cloudy C - C lear N - Nep.a l 1v c F - k'ew H - Many 1. - la n d e d It - H a re !.Ain - l.lp jil AwIm t OAm - Mark Amber ucc - Ocrmiloiiul QNS - Quantity not nufflelonl N*me aeon Page 23 rM-3AZ2: TABLS U. Ninety Day Subacuta Rhesus Monkay Toxicity Study. Necropsy Observations. Sica Las ion Control CO *1 z z X X 1 c fN. S' r* C' \r\ O' e* 1 xP?x -pxs* -s No gross lesions xx Lymph nodes (bronchial, mediastinal) black discoloration Lung yeilow-rad-gray foci (mica lesions) pleural adhesions yellow focus black discoloration x x Heart subendocardial hsmorrhagss, I-V sapturn Abdominal cavity csophagostomum nodules, mesentery Liver gray foci adhered Co diaphragm abscess with necrosts/gray-yellow area of necrosis red-yellow mottling xx x Scomacn mucosal congestion, mucoid contents mucosal thickening, fundie region area of hemorrhage/red focus, fundie region x Small intestine mucoid contents Large intestine mucosal congestion, ileocolic orifice red foci/erosions, mucosa esophagostomum nodules x soft co firm fecal concents x l mg/ka/dav Z X au X rs je. S ' CM xO fSe a S ' xPje px. px. /s, 3 mg/ka/dav ZZX X S ' r. fx* SO p* a s> r - xPS* r* <r xx x x x xx xx x x 10 ag/kg/dav z ZX X sr - a a S ' 5*- Ps* s p- <p* 30 na/kg^dav * =X X * Mpx* P*x p* S' S' S' <Pxre xpxT* T px* PxxS, XX X X X XX X X X 137-083 died 001473 FM-'1422: YAIII.K I - * Croup, Monkey Umiliti' i N i n e t y Day S u b a c u t e KliestiH Monkoy T o x i c i t y S t u d y . A b s o l u t e (C ra n ia ) and IUkla l lvt< ( Z B od y W e ig h t ) Or|^ii W e ig h t s , T e r m in a l S a c r i f i c e am i D e a t h s , Hotly H i. kfi S p le e n R Z l.lv e r 8Z At) r e n a i s K ZxlO K ld tiu y s R Z Testes/ R O varie s ZxlO Page 24 001474 Teimlual Sacri lire: CoiU rnl : //*/ nv) Ik-mi 7/i*n 7495 Hi-.ni 1.0 w^/kg/iliiy: 77,1)7 741 1 U**.-in 7489 7**72 Ik'.in 1.0 '"u/l-lj/'l.iy: 1 Itili, (Inali 77.R7 77,*77 tk-.lll (0.0 M|i/k(;/iliiy: H H F F H H H F M M F F 1.55 3.10 3.33 3.35 2.75 1.15 1.85 2.`JO 1. 38 1.10 3.45 1.28 4.10 1.55 1.83 1.10 1.05 1.08 5.14 3.51 4.41 4.16 2.22 3.19 0.15 0. ti 0. Il 0.12 0.08 0. IO 2.86 3.27 3.07 2.83 3.81 1.32 0.07 0.11 0.09 0.09 0.11 0.10 4.24 3.35 3.80 1.81 3.43 2.62 0. IO 0.09 0.10 0.06 0.11 0.09 70.00 61.88 65.94 74.61 54.72 64.68 74.19 59.39 66.79 74.11 65.96 70.04 90.74 84.32 87.53 77.79 62.79 70.29 1.97 2.00 1.98 2.10 1.99 2.05 1.91 2.05 1.99 2.39 1.91 2.15 2.21 2.38 2.29 2.51 2.06 2.28 0.68 0.89 0.79 0.76 0.77 0.77 0.19 0.29 0.24 0.21 0.28 0.25 0.91 0.71 0.81 0.75 0.55 0.65 0.24 0.24 0.24 0.24 0.16 0.20 0.7,0 0.80 0.70 0.75 0.64 0.70 0.15 0.21 0.19 0.24 0.21 0.23 17.47 12.88 15.18 16.50 14.07 15.29 0.49 0.42 0.45 0,46 0.51 0.49 15.71* 12.37 14.04 13.8^ 15.86 14.84 0.41 0.43 0.42 0.45 0.46 0.45 17.31 17.7(1 17.51 15.08 12.45 13.71* 0.42 0.50 0.46 0.49 0.41 0.45 1.15 0.83 (1.99 0.45 0. lb 0. Il 0.03 (Ml 1 IMI! 1.27 0.58 0.92 1.72 1.21 1.47 0.29 0.28 0.29 0.04 0.04 0.04 0.94 O.RI 0.87 0.88 1.22 1.05 0.22 0.26 0.24 0.02 0.01 0.03 0.71 0.85 (1.78 77,7' 77,HO Hi-,hi It,') 1 77,`JH Ik'im 10.0 mg/kg/day: M M F F 1.45 1.55 3.50 3.05 2.95 1.00 4.28 2.39 3.34 4.90 3.60 4.25 0.12 0.07 0.10 0.16 0.12 0.14 84.65 92.28 88.47 86.57 83.14 84.86 2.45 2.7,0 2.53* 2.84 2.82 2.83 0.6(1 0.82 0.71 0.98 0.90 0.94 0.17 0.23 0.20 0.32 0.31 0.11 16.40 18.48 17.44 15.19 11.82 I4.5| 0.48 (1.52 0.50 (1.50 0.47 0.48 1.40 2.53 1.97 0.24 0.27 0.26 0.04 0.07 0.06 0. 79 0.92 0.85 77,72 11,11 Hi-nii 7**10n [,,utlis; H 3.05 3.79 0.12 97.06 3.18 M 1.75 3.24 0.09 108.04 2.88 0.76 0.84 0.25 0.22 14.27, 16.26 0.47 0.4 3 1.01 11.79 0.03 0.31 1.40 3.52 0.11 102.55* 3.01** 0.80 0.24 15.26 0.45 6.40 0.17 F 2.7,5 3.13 0.12 94.62 3.57 0.70 0.26 15.07 0.57 0.22 0.83 30.0 ii'i'./kfi/dny: I t ,)0'1 F 2.H5 3.21 0.11 111.72 4.7,2 1.42 0.50 15.77 0.55 0.34 1.19 Croup menu re lati ve organ weights simun lu Mil lidilo were calculai:ed hy .uvcraglng the Individually calculated relative organ we igitis. 'Sigilli Iran! ly different from Control group mean, p* 0,.05. "Nili 1IIClllllll.l (li HiHi 1Ht ll'lll1 m m ly Ih . I------ FM-1422: TAIII.K 12. Cimi. 'ruup, Mmtkcy Nuwhcr IVimiiui 1 Sac 11ftee : Coitiro! : 7470 7474 Menti 7491 7494 Momi 1.0 MK/kg/tlay: 7467 7471 Menu 74H9 7442 Homi 1.0 mg/lig/iliiy: 7469 7474 Meni >487 749 7 Homi lo.o wii/loi/iiny' 7474 7480 Meati 7491 7498 Homi 10.0 w</k(*/tlny: 7472 747/ Umili /Vi-." bettihs : li) mi;/kn/iluy; 7440 Ninety Day Subacute Rhesus Monkey Toxicity Hluily. Absolute (Crama) am! Ho tailve (Z Bmly UoigliL) Organ Weight, TernInal Sacrifice ami heaths. Hoily Iliyrolli/ Ut. Heurt I'ar.illiyroWl Brulli Sex k8 KZ K ZxlO KZ ril'ilt.*ty 8 Zxl M M F. F M H F K M H F F M M F F H M K F 3.45 3.10 3.33 3.55 2.75 3.15 3.85 2.90 1.18 3.10 3.45 3.28 4.10 1.55 1.83 3.10 3.05 3.08 1.44 3.55 3.50 3.05 2.95 3.00 3.05 1.75 3.40 2.65 14.60 14.15 14.88 16.53 11.56 14.04 0.41 0.49 0.45 0.47 0.42 0.44 14.34 12.18 11.26 16.12 16.25 16.19 0.37 0.42 0.40 0.52 0.47 0.50 18.06 16.21 17.14 11.88 13.29 11.49 0.44 0.46 0.45 0.45 0.44 0.44 14. 18 16.04 15.21 13.69 11.24 13.47 0.42 0.45 0.43 0.45 0.45 0.45 12.87 15.30 14.09 11.64 0.42 0.41 0.41 0.52 0.693 0.771 0.712 0.950 0.624 0.787 0.20 0.25 0.22 0.27 0.21 0.25 1.062 0.455 0. 759 0.913 0.820 0.867 0.28 0.16 0.22 0.29 0.24 0.27 0.856 1.545 1.201 0.710 0.531 0.622 0.21 0.44 0.32 0.2 1 0.17 0.20 0.818 0.6 79 0.749 0.903 0.411 0.667 0.24 0.19 0.21 0.30 0.15 0.22 0.620 0.670 0.645 0.491 0.70 0.18 0.19 0.14 96.18 92.88 94.63 80.59 84.39 82.49 2.71 1.00 2.86 2.27 1.07 2.67 96.23 93.87 45.05 77.08 81.03 79.06 2.50 1.24 2.87 2.49 2.15 2.42 91.86 90.12 90.99 82.44 82.78 P.2.61 2.24 2.54 2.19 2.66 2.71 2.69 79.36 82.96 81.16** 77.70 79.11 78.51 2. Ill 2.34 2.32 2.55 2.69 2.62 84.67 85.61 85.15* 76.87 2.78 2.28 2.51 7.40 0.0/2 0.028 0.050 0.052 0.068 0.060 O.70 0.09 0.15 0.15 0.25 0.20 0.0/2 0.044 0.058 0.058 0.072 0.065 0.19 0.15 0.17 0.19 0.21 0.20 0.044 0.058 0.076 0.064 0.054 0.062 0.23 0. 16 0.20 0.22 0.18 0.20 0.050 0.062 0.066 0.066 0.051 0.054 O.I4 0.17 0.16 0. 18 0.17 0.18 0.062 0.062 0.062 0.057 0. 20 0.17 0. 18 .? 2.85 16.01 0.56 0.445 0.16 81t29 ____ 2.92 0.1 10 Il1.14 Croup mean irla! Iva nigill welghlih shown in thin table were cal cul atoil by averaging the Imi 1vIiln.i11y riiIni 1:ilml Page 25 001475 yM-34'2: TA3L2 13. Minety Oay Subacute Rhesus Ltonkey Toxicity Study. Hicroscoptc Observations. Page 26 i Tissue Lesion . W Concrol 1 ag/kg/day S 2 . . 3 ag/kg/dav IQ ag/kg/day oS' W*' <r Pk 30 ag/kg/dav Z X i. 3ra in stall focus of neutrophil Infiltrate in leptomeniages Spinal Carl focus of perivascular Lymphoid Infllcraces in arachnoid l l l1 1 l11 lll1 1 l1 3 liiL !iil i L 1 1V illL ll l 3 l11t Peripheral :ierve 111 focus of perivascular lymphoid infiltrate in perineural tissue 2 tll1 1iil i1:l l1ll Eye l 1 acute conjunctivitis focus of lymphoid Infiltrate In ciliary muscle 2 follicular conjunctivitis 4 foci of interstitial lyaphold Infiltrates In lacrimal gland Sarcocystls so. In ocular tsele foci of Lymphoid infiltraces in palpebral/ocular conjunctiva Pituitary small parenchymal cyst - X 11 Thyroid ii1l Parathyroid l- 11 Adrenal i1 small focus/fpcl of dystrophic mineralization XX small foci of lymphoid infiltrates in cortical sinusoids diffuse congestion diffuse lipid depletion acidophilic degeneration of individual to small groups of cells ll l 2 l1 i1 11il 1- i- L1 XX li 3 2 Lili li[i 1- 1i 1 xX X 2 32 l 2 1 1' l l 11l1 1 1- 1 11 1 X 1 2 X 32 ll1i l1li - l- i l X 3 3 5 53 3 Trachea foci of inflammatory cell infiltrates in lamina propria foci of inflammatory call infiltrates in lamina propria and mucosa focal cystic dilatation of tracheal glands ll ii t 2 22 332 3 32 3 2 2 2J 323 3 137-033 ii I Code : , X - condition present l - not remarkable 2 - very slight 3 - slight 4 - moderate 5 - marked 6 - extreme - not available *d le d 001476 Page 27 FM-3422: TA3L 13. Cone. Ninety Day Subacuta Rhesus Monkey Toxicity Scudv. Mistoscopic Observations 715L.e3*s4ion Conerol Xz It '3-3S* -233* * z! iOs 7 p3m P7M fh 7S' 71 S' 7pm Lung acarian p-igneat (peribronchial. peribronchiolar, perivascular) 222i focus/foci of perivascular lymphoid infiltraces 33 foci of peribroncniai/peribronchlolar lymphoid aggregates 22 33 lung nica in bronchlolar lumina X acuta focal bronchopneumonia chronic focal pleuritis intersticial pneumonia 3 acarian pigment in bronchial lymph node focal hemorrhage Heart focus/foci of interstitial lymphoid infiltrates focal subepicardial henorrhag* 1 22 2 Aorta Spleen diffuse congestion 1111 1111 Lymph Nodes parasitic granuloma focal aggregates of hemosiderinladen macrophages Thyzus cyst 1- 3 111 Tonsil keratin-filled cyst foci of interstitial lymphoid infiltrates in muscle foci of inflammatory cell infiltrates in mucosal epithelium and lamina propria Sarcocystis sp. in muscle x Gongyloneaa sp. in mucosal epithelium foci of inflammatory call infiltrates In surface epicheliua arid consular crypts - 1 X Tongue ircocyscis 3?. x foci of iaflaaaaccry call infiitracas in lamina propria and mucosal epithelium 3 32 T foci of inflammatory cell infiltrates in muscle 2 foci of ballooning degeneration of mucosal eoithelium foci of hyaline degeneration of muscle 33 foreign body granuloma 1 ma/ kc/dav z Z "jm ju PsMC P.-1 Ss' 7 pm rM7 <p.7 PM3* 2 3 y 2 3233 X 3 3 3 11 22 2111 1 111 1 111 1 111 X 2 33 3 s 3 3 33 3 3 3 ar/'/dav Z Z j. Ife P-Som7' p7m P* PM P370 P*. pS*T'. 10 ;SV k.2 /dav ZZ <P/M> >P7M as7M 7Pm-Mh a 7PM 30 ma/V.a/dav x 2 It II P-M7 PM PPMM PM7 S7M' S3'> P7M >2 33 3 2. ? .. *333 3322 34 11 22 1i11 1i1 3 i1 23 1 1. X i- 2 223 2222 1111 1111 111 X 1211 1- _ 1 3U2 3 XX i 3 3 4 3 1 233 3 1111 1111 - 3T 3 1 2-1 1 X 2 223 2 - 2 2 333 X > 2 ; 1 2 3 3333 32 3 * 137-083 Coda: x - condition present 1 - not remartable 2 - very slight 3 - slight * soderaca 5 - narked - extreme * noe available Miad i 0 0 1477 r>l-j4 T;: Z A 3 L 1 13. Cone. Xiaety Day Subacuta Rhesus Monkey Toxicity Study. Microscopic Observations Page 28 Tissue lesion i j 25 -Xz Cone rol s X is* is. s Ps 4* s4r** "1 -X Salivary land 3 d o s iacarsciziai Lyapho id 3333 Eiopha^us foci of inflammatory cell infiltrate* in lamina propria foci of interstitial lymphoid infiltrates in auscularis Gongylonema sp. in epithelium foci of black pigment aggregates in periesophageal lymph node 1 322 32 Scomach foci of inflammatory cell 3 infiltraces in lamina propria foci of inflammatory cell Infiltraces in lamina propria and submucosa 3 4 foci of inflammatory cell Infiltrates in lamina propria, submucosa and muscularls foci of inflammatory cell infiltrates in lamina propria, suseucosa, muscularis and serosa 4 foci of inflammatory cell infiltrate* in muscularls and serosa cystic gastric gland diffuse congestion Small Intestine encapsulated abscess in nesentery parasitic granuloma in lamina p r o p ria - 1i1 Cecum parasitic granuloma in sucmucosa parasitic granuloma in muscularls anc aesancery parasitic granuloma in serosa parasitic granuloma in mesentery focal aggregates of hemosiderin pigmenc in muscularis/mesencery focal inflammatory cell infiltrates in nesentery and muscularls parasitic granuloma in muscularls 1i1 X 1 ke/dav X X is. Ifc T- N rX* r*. soX P. i 32 ii 22 24 33 111 X 111 X 3 3 na/ki/dav X X *> is. so* P4s* 4" pPXps -s, sP*osx Ps p3Xs\ 1 2 22 IQ ai/ki/dav X X is. is. P.sp X o -PsoXs *X "pXs 3222 30 ne/ka/dav X2 is. * ps ps ** PXs P, *s 2 22 1 2 22 2 22 2 2 * 2 2 X 2 22 2 3 2 333 3 33 3 33 4 1111 2 X 1 1i 3 1i11 11 XX 3 X i X X 3 X 12 X X 137-033 Code: x - condition present 1 - not remarkable 2 - very slight 3 - slight 4 - zodarace 3 - marked 6 - extreme - not avail; *died 001478 Paga -29 cl-3422: TABL 13. Conc. Ninety Day Subacuta Rhesus Honkey Toxicity Study. Hie:oscopic Observt ions. T33ue Las ion . bai ;il 2J 5 -O i x! Concrol Zs1 x pO>* !S% a-s* T eT Colon parasitic granuloma in jubnucosa parasitic granuloma in muscolari* parasitic granuloma in serosa parasitic granuloma in aesencery foci of inflammatory call iniilcracas in nuscularis, serosa aac nesencary faci of inflammatory call infilcracas in mesentery foci of inflammatory call infiltraras in miscelarla focal aggregates of hamosldarin oignant in nuscularis foci of inflammatory celi inrilrraces la aerosa small focus of mucosal hemorrhage X X XX 33 22 *7 Rectum 11 foci of inflammatory call infilcracas in nuscularis 32 foci of inf1aminatory tall infiltrates in lamina propria 33 focal hyaline degeneration of muscle 3 3 focal aggregates of hemosiderin pigment in subnucosa Pancreas decreased cell size, loss of zynogsn granules focal periductal lymphoid infiltrates focal interstitial lymphoid infiltrates 111 1 Liver portal inflammatory call infilcracas 2 3 4 3 focal/mulcifocal bile duct proliferation 32 acidophilic degeneration of individual co small groups of herac-jcvees 323 diffuse congestion amali focus/foci of inflammatory cell Infiltrates in parenchyma 2 2 32 several large areas of coagulation necrosis focal capsular fibrosis focal cholangiohepacitls A focal parenchymal fibrosis 3 focal oystopiasaic vacuoiacion of heoacccyces ? 1 s;a/'<s/dav XzX X rv. Pe er S'M ii X X 3 ag/kg/dav zzX X S' > p*. * S' >.hT r* sT r ,N* 10 ag/ka/dav zz X X s P>*Te S-3'* S' 11i 1 ]_ 30 ag/kg/dav zz--X * pe s\ fs ,* 11 X XX XX 33 3 2 3 3 3 2 3 2 i 11 1 1 1 i 1 1 l 1 i 11 2 3 i1 3 3 233 3 3 222 2 3 *7 3 1? 17 23 4 33 2 -> 2 3 l1 23 3 24 3 32 7 32 ii 44 3 3 22 2 22 2 - 3 > 4 12T-C83 Code : x - condition present 1 - not remarkable 2 - vary slight 3 - slight i - moderate 3 - marked 6 - extreme not available died 001479 Page 30 ="4-3122: I.idL 13. Cone. Minecy Day Subacuta Rhesus Monkey Toxicity Study. Microscopic Observations. Control 1 mz/ka/dav 3 mz/kz/dav 10 mz/kz/dav 30 mz/kz/dav Gallbladder foci, or inflammatory cell. infiltrates is lamina propria foci of Inflammatory cell infiltracas in lamina propria and auscularis foci of inflammatory cell infiltracas in lamina propria, auscularis and serosa foci of hemorrhage in lamina propria and auscularis 33 3 3 3 Kidney focus/foci of interstitial lymphoid infiltrates small foci of dystrophic ainaralizaclon diffuse congestion mult enucleated lining epithelium in papillary ducts brovn pigment in tubular epithelium ectopic adrenal la cortex 2322 2 Urinary 31adder foci of inflammatory cell infilcraces in lamina propria foci of inflammatory cell infiltrates in lamina propria and muscularls foci of inflammatory cell infilcraces in lamina propria, muscularls and serosa 3 3 3 lestes pracchetai development xx foci c: inflammatory ceil infiltrates in capsule small focus of dystrophic mineralization Ovaries small foci of dystrophic mineralization corpus luteum 11 Prostate foci of Incerstitlal lymphoid infiltrates focus of lymphoid infiltrates in ganglion lymphoid nodule/s)/infiltrates in corpus cavernosum 33 xs 2 2 33 2332 22 x 1 2 3 XX X 1 x 23 x ? 33 3323 2 :c 3 3 2 XX 3 1 x 3 2x 3 2 33 1 2 22 322 2 XX 3 11 33 xx 11a 3 2222 22 3 x 2222 1 X 1 x 3 3 x Code: x - condition present 1 - not remarkable 2 - very slight 3 - slight i - moderate 5 - marked 6 - extreme - noe avail; a * autolyzed died Page'31 r-!-3-:: : TA3L: 13. Cone. Ninety Day Subacute Rhesus Monday roxicity Stuav. .Hieroscop iw Observation, -tis.usauseion >s Wi wss3.*s2a --an35.| Cone rol z 2 2 Zb a * yv U5"%! PTe *Pr. P- r-iarus foci or lymphoid infiltrates in bread iigaaenc and nyociacriua loss of endometrial surface epithelium, blood is lamina propria and uterine 'lands li Vag ir.a foci of lymphoid infiltrates in mucosal epithelium ar.d lamina propria foci of lymphoid infiltrates in nuscularis skeletal Muscle sarcocystis sp. foci of interstitial lymphoid infiliracas 34 23 7 i1 X Mammary 01ar.d dermal inflammatory cell infiltrates iev inflammatory cells in alveolar iuaina hyperkeratosis focal hemorrhage small focus of epidermal hydropic degeneration brows pigment in demi3 Skin dermal inflammatory cell infiltrates diffusa snehosis h*/?*rka?ac3sis fecal hesorrhage brows/black pigment in dermis casur 22 32 X XX 3 3 XXXX ii7 1 Rib i i1 1 1 252/kl/dav Z f|1 'J. p Pi ^y 32 **T 33 34 3 X 2 y *7 3 32 X 33 3 X XX X J32 3 4 XXX X 1 11i 1 11i \ ne/ke/dav 2 2 tb *2. <r p* r* *T p-t X-J* p*k 21 10 :me/'/dav 2 2*. 2b C a p * ^y "*** a p i 30 :s*/ka/dav z 2b 2b P4 p** s T p*s** -T li 3 33 22 1i1i 2 7 3 XX 33 33 22 1i p 2 2 233 X XX 33 34 24 2 li X 2 2 X 3 XXXX 3 XX XX 1112 11 12 X X XX X 3 XXXX 1111 1111 XX XX 2 3 XXXX 111i 1 -1 i i 137-033 k - condition present 1 - not remarkable 2 - very slight 3 - slight 1 - moderate 5 - marked 6 - extreme - not available "died GGi'xbi