Document Qgn5xgRw2Gw1a5k3VgE85jor8

InternatioRneaslearcahndDevelopmenCtorporation SPONSOR: C OL.1P 0 U'-.,M SUBJECT: 3M Company FM-3422 Ninety Day Subacute Rhesus Nfonkey Toxicity Study. Edwin I Go/,laentha Vice Pres ut and 115-A Director of Research Ph.D. Collaborators: D. C. Jessup, Ph.D., Associate Director of Research R. G. Geil, D.V.M., Vice President and Director of Pathology -T. 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 InternatioRneaslearcahndDevelopmenCtorporation TA BL E 0F C0NTE NTS I. Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . II. Comoound . . . . . . . . . . . . . . . . . . . . . . . III. Clinical Studies . . . . . . . . . . . . . . . . . . . . . . A. Method . . . . . . . . . . . . . . . . . . . . . . . . . 1. General Procedure . . . . . . . . . . . . . . . . . 2. Compound Administration . . . . . . . . . . . . . . 3. Observations . . . . . . . . . . . . . . . . . . . . 4. Clinical L;iboratory Test . . . . . . . . . . . . . . a. Hematology b. Biochemistry* c. Urinalyses . . . . . . . . . . . . . . . . . . . d. Statistical Analysis . . . . . . . . . . . . . . B. Results . . . . . . . . . . . . . . . . . . . . . . . . 1. General Behavior, Appearance and Survival 2. Body Wei-hts . . . . . . . . . . . . . . . . . . . . 3. Laboratory Tests . . . . . . . . . . . . . . . . . . IV. Pathology Studies . . . . . . . o . . . . . . . . A. Methods . . . . . . . . . ... . . . . . . . . . . . . . 1. Gross Pathology . . . o . t . . . . . . . . . . . . 2. Histopathology . . . . . . t . . . . . . . B. Results . . . . . . . . . . . . 0 . . . . . . . . . . . 1. Gross Pathology and Organ Weights . . . . . . . . 2. Histopathology . . . . . . . . . . . . . . . . . . . Table tNo. 1. Individual and Group Mean Body Weights . . . . . . . . . 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 . . . . . 0 . . . . . . . . . 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 26-31 137-088 InternatioRneaslearcahnd DevelopmenCtorporation Page 1 SYNOPSIS FX-3422 was administered to rhestis 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 initiated 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 receivina 30 mo/kg/dav the above mentioned signs of toxicity persisted for almost all the treatment period. One mon-key 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 weivht 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 di.1ferences in the mean body weiaohts of the treated and control aa roups were not statistically significant. 137-088 InternatioRneaslearcahnd DevelopmenCtorporation Pac0 e 2 txicroscopically, 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 InternatioRneaslearcahnd DevelopmenCtorporation Page 3 II. COMPOUND The compound was received from 3M Company, Saint Paul, Minnesota on 0--tober '-)8,1977 as indicated below: Label FM-3422 41-2700-3422:-0 Lot 784/Net-35 DR-1 Description off-white to tan waxy substance 137-088 InternatioRneaslearcahnd DevelopmenCtorporation Page 4 CLINICAL STUDIES A. @ETHOD: 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. PurinaOD Monkey ChowS 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 1 11 111 IV v Number of Monkeys Male Female 2 2 2 2 2 2 2 2 2 2 Dosage Level Control 1 mg/k-/day 3 mg/k:/day 10 mg/kg/day 30 mg/kg/day 137-088 InternatioRneaslearcahnd DevelopmenCtorporation Page 5 The test compound was dissolved in propylene OIycol by heating to approximately 300 C. The solution was administered by oaavage. For study day 1 and 2 all of the treated monkeys received 5 ml/'Kgof -he solution. On and after study day 3 the amount of propylene gC2lycol 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 sians. Individual body weiyhts 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 overniaht prior to the collection of blood and urine samples. a. Hematology: Hematological studies included: hemoglobini . hematocrit2 erythrocyte count3, total3 and differential leucocyte counts, reticulocyte count4, platelet count5 prothrombin time6 . activated partial thromboplastin time (APTT)7.' LXean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (@XCHC) were calculated. b. Biochemistry: Biochemical studies included: blood glucose blood urea nitrogen8, serum alkaline phosphatase8, serum alutamic oxaloacetic transaminase (SGOT)8, serum glutamic pyruvic transaminase (SGPT)8, 137-088 InternatioRneaslearcahndDevelopmenCtorporation Page 6 cholesterol9, total protein9, albumin8, sodiumio, potassiumio chloride9, inorganic phosphate9, Y-glutamyl transpeptidasell, creatinine phosphokinasel2. Sorbitol dehydrogenase was not determined because reliable data could not be obtained with the present instrumentation. c. Urinalyses: Uriualyses included: measurement of volume, pR13 and specific gravity; description of color and appearance; qualitative tests for proteinl3, glucosel3, ketonesl3, occult bloodl3; and microscopic examination of the sediment. d. StatisticalAnalysis: Analysis of terminal body weights and organ weights (absolute and relative) and clinical laboratory tests were performed using a-,ialysiosf 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 judae si-nificance of differences. B. PESULTS: 1. General Behavior, Appearance and Survival: Monkey 7490 receiving 30 mglkg/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 appearin- on study day 2. Occasional emesis also was observed. 137-088 InternatioRneaslearcahnd DevelopmenCtorporation Page 7 For the monkeys in the control group, diarrhea was occasionally observed but for Xonkey 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 Xonkey 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 InternatioRneaslearcahnd DevelopmenCtorporation Page 8 which died. However, there were no statistically significant differences bet-ween 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 glucose 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 InternatioRneaslearcahndDevelopmenCtorporation Page 9 IV. PATHOLOGICAL STUDIES A. METHODS: 1. Gross Pathology: After completion of the compound administration period all surviving monkeys were anesthetized with Sernylane*, 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'fixiieive."The thyroid/parathyroidwas weighed after fixation. The monkey which died during the study was necropsied as above. 2. Histopatholog z 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 thym=s trachea tonsil tongue urinary bladder vagina tattoo and any other tissue(s) with lesions. *Phencyclidine HCI - BioCeutic Laboratories, Inc., St. Joseph, Missouri. 137-088 InternatioRneaslearcahnd DevelopmenCtorporation Page 10 B. RESULTS: 1. Gross Pathology (Table 11) and organ Weights (Table 12): 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 x 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 morphologi-c changes which were considered compound-related. 2. Histopathology (Table 13): 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 compound- related. 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 ma./kg/day levels were considered compound-related. 137-088 InternatioRneaslearcahndDevelopmenCtorporation Page 11 References 1. Coulter Remoglobinometer, Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 2. Microhematocrit, John B. LMiale, 3rd Ed., 1967, The C. V. Mosby Company p. 1154. 3. Coulter Particle Size Counter, Model ZBI Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 4. Gradwholls 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 11, 6/60 Micro kxethodology; 10. Atomic Absorption IL Model 353. 11. Glutamyl transpeptidase, Siama GGPT, Bulletin 545. 12. Creatinine phosphokinase Sigma Procedure Bulletin 520. 137-088 7479 m 7493 F 7495 F Mean 1 pL/k clay: 7467 m 7473 ti 7489 F 7492 F Mean 3 mg/kg/day: 7469 H 7474 m 7487 F 7497 r Mean 3.10 3.75 3.00 3.56 3.85 3.25 3.05 4.15 3.58 4.10 3.45 3.60 3.05 3.55 3.00 3.80 3.05 3.55 4.00 3.20 3.05 4.00 3.56 4.00 3.20 3.75 3.10 3.51 3.25 3.70 3.00 3.59 3.75 3.30 2.95 3.85 3.46 4.05 3.45 3.45 3.20 3.54 3.15 3.70 3.00 3.55 3.95 3.25 3.00 3.75 3.49 4.00 3.55 3.45 3.30 3.58 3.15 3.60 2.85 3.48 3.75 3.10 2.90 3.60 3.34 3.95 3.55 3.30 3.30 3.53 3.05 3.55 2.85 3.41 3.85 3.10 3.00 3.55 3.38 4.00 3.55 3.30 3.15 3.50 3.15 3.60 2.90 3.41 3.85 3.10 3.05 3.55 3.39 4.05 3.60 3.40 3.20 3.56 3.20 3.60 3.00 3.43 3.95 3.25 3.10 3.55 3.46 4.00 3.75 3.50 3.20 3.61 3.25 3.70 3.05 3.45 3.95 3.20 3.20 3.65 3.50 4.10 3.75 3.55 3.30 3.68 3.30 3.70 3.00 3.45 4.00 3.15 3.15 3.65 3.49 4.10 3.75 3.50 3.30 3.66 3.20 3.60 2.90 3.38 3.95 3.10 3.15 3.60 3.45 4.00 3.70 3.45 3.10 3.56 3.20 3.80 2.95 3.43 4.00 3.10 3.25 3.50 3.46 4.15 3.80 3.55 3.20 3.68 137-088 *Terminal weight. FM-3422: TABLE 1. Cont. Group, Monkey Number Sex Control 0 Ninety Day Subacute Rheaus Monkey Toxicity Study. Individual and CrotipMean Body IJelglits,Kilograms, Week of Study 1 2 3 4 5 6 7 8 9 10 10 ing/kl,,!day: 7475 7480 m 3.80 m 3.45 7491 7498 Mean F 4.20 F 3.10 3.64 30 mg/kg/day: 7472 m 7477 m 3.45 3.50 7490 7499 Mean F 4.00 F 3.00 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 2195 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 3.39 137-088 *Terminal weight. **Terminal weight not included in mean. Fti-'142 2: itinlty ilily;soliticuHtiotesiotnuiiskeyToxicity $tufty. TARI.E 2. 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