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InternatioRneaslearcahndDevelopmenCtorporation SPONSOR: COMPOUND: SUBJECT: 3M Company FluoradS Fluorochemical SurfactanL, FC-95 Ninety-Day Subacute Rhesus Monkey Toxicity Study. Edwin 1. Go,.Iaenthal, Ph.D. Vice Pres i.@knt and Director of 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. Lmehring, Ph.D., Director of Large Animal Toxicology Date: December 18, 1978 137-092 InternatioRneaslearcahndDevelopineCnotrporation TA BLE 0F C0NTENTS I. Synopsis . . . . . . . . . . . . . . . . . . . . II. Compound . . . . . . . . . . . . a . . . . . . . . . . . . . III. Clinical Studies . . . . . . . . . . . . . . . . A. Method . . . . . . . . . . . . . . . . . . . . . . . . . 1. General Procedure . . . . . . . . . . . . . . o . 2o Compound Administration. . . o . o o o . . . . . . 3o Observations . . . o . . . . . . . . . . . 4. Clinical Laboratory Tests. a* Hematology a . o a . 0 b. Biochemistry . . . . . . . . c. Urinalysis . . . . . . . . . . . . . . . . . . . d. StatisticalAnalysis . . . . . . . . . . . . . . B. Results. . . . . . . . . . . . . . . . . . . . . . . . . 1. General Behav ior, Appearance and Survival . . . . . . a. Control. . . . . . . o . . o . o . . . o . o b. 0.5 mg/kg/day. . o . o . o . . . . . o o . . . o c. 1.5 mg/kg/day . . . . . o . . . a .0 0 0 .0 d. 4.5 mg/kg/day. . 0 . 0 0 . 0 . 0 . . . . . 0 0 . 2o Body Weights . . . o o o . . . 0 . . 0 0 .0 .. 3. Laboratory Tests . . o . . o . . . . . . . . . a o o a. One Month of the Study . . . o . 0 0 0 0 .. b. Three Months of the Study. . o o a . . . . . . . IV. Pathological Studies o o . . . o . o o o ....a * 0 . Ao Methods* a o o o . o0 0 e 0 0 0 0 0 4 ...0 0 0 0 1. Gross Pathology, o o . . . . . . . . . o o o a o . o 2. Histopathology o o . . . . . . . . o . . . . . . o . B. Results. o ........o o . o . . o o . 1. Gross Pathology and Organ Weights . . . . . o o o . . 2. Histopathology . o o o ......o oo. Page 1 3 4 4 4 5 5 5 5 6 6 6 6 6 7 7 8 8 8 8 9 10 10 10 10 11 11 11 137-092 InternatioRneaslearcahndDevelopmenCtorporation TABLE 0F C0N TENT S (Continued) Table No. 1. Individual Body Weights . . . o . . . . . . . . . . . . 2. Means and Significance of Remtalogical Values . . . . . 3- 5. Individual Hematological Values . . . . . . . . . . . . 6. Stimmary of Mean Biochemical Values . . . . . . . . . . . 7- 9. IndividuaBliochemicaVlalues. . . 10. Summary of Mean Urinalysis Values 11-13. Individual Urinalysis Values* . . . . 14. Necropsy Observations . . . . . . . . . . o . . . . . . 15. Absolute and Relative Organ Weights . . . o . . . . . . 16. Microscopic Observations . . . . . . . . . . . . . . . . Page 13 14-15 16-18 19-20 21-23 24-25 26-28 29 30 31-35 137-092 InternatioRneaslearcahndDevelopmenCtorporation Page 1 I. SYNOPSIS FluoradS Fluorochemical Surfactant FC-95 was administered by gav- age to rhesus monkeys at dosage levels of 0, (distilled water only) 0.5, 1.5 and 4.5 mg/kg/day for 90 days. 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 and biochemical studies and urinalysis were conducted once in the control period and at the end of the first and third month of the study. The monkeys treated at the 4.5-mg/kg/day dosage level died or were sacrificed in extremis between week 5 and 7 of the study. These.monkeys exhibited signs of toxicity in the gastrointestinal tract (anorexia, emesis, black stool and dehydration) from the first or second day of study. All the high-dose monkeys had decreased activity and before death showed marked to severe rigidity, convulsions, generalized body trembling, prostration and loss of body weight. The mean body weight decreased from 3.44 kg at the beginning of the study to 2.70 kg at week 5 of study. At I month of study all monkeys at the 4.5-mg/kg/day dosage level had decreased serum cholesterol values and serum alkaline phosphatase activity. All monkeys at the 1.5-mg/kg/day dosage level survived to the end of the study. The monkeys exhibited slightly decreased activity from the first week of the study which occasionally became moderate to marked. Monkeys at the 1.5-mg/kg/day dosage level occasionally had black stools, diarrhea, mucous in the stool and bloody stool and exhibited dehydration or general body trembling at the end of study. The monkeys from this group had a slight decrease in mean body weight. 137-092 InternatioRneaslearcahndDevelopmenCtorporation Page 2 In the laboratory tests, there was a decrease in the alkaline phosphatase activity and the concentration of inorganic phosphate in the serum at 3 months of study. All monkeys at the 0.5-mg/kg/day dosage level survived to the end of the study. Monkeys at this dosage level exhibited an occasional soft stool, diarrhea, anorexia and emesis. Slightly decreased activity was noted in three monkeys at this dosage level. At 3 months of study a slight decrease in the serum alkaline phosphatase activity was noted. No gross or microscopic pathological lesions which-were considered compound-related were seen in tissues other than the adrenals, pancreas, and submandibular salivary glands of male and female rhesus monkeys at the 4.5-mg/kg/day dosage level. Microscopically, the adrenals from male and female monkeys at the 4.5-mg/kg/day dosage level had compound-related marked diffuse lipid depletion; the pancreas from male and female monkeys at the 4.5-mg/kg/day dosage level had compoundrelated moderate diffuse atrophy of exocrine cells; the submandibular salivary glands from male and female monkeys had compound-related moderate diffuse atrophy of the serous alveolar cells. No statistically significant variations in sex group mean weights of organs occurred between the control and experimental groups. 137-092 InternatioRneaslearcahndDevelopmenCtorporation Page 3 COMPOUND The compound was received from 3M Company, Saint Paul, Minnesota on October 24, 1977 as shown below: Label Description Fluorade Fluorochemical Surfactant FC-95 3-M Stock No. 98-0207-0103-7 Lot 640 Net wt. 5 lbs. 2,2 kg. white powder 137-092 InternatioRneaslearcahndDevelopmenCtorporation Page 4 CLINICAL STLDIES A. METHOD: 1. General Procedure: Eight male (wei,--hing4-:rom2.55 to 3.55 k-m,)and ei-aht female (weighing from 2.70 to 3.75 kg) rhesus monkeys were initiated i-nthis study. The monkeys were Durchased from Primate Imports, Port Washington, New York. The monkeys were housed individually in hanging wire mesh "squeeze-type" cages and maintained in a temperature-, humid- ity- and light-controlled environment. Purinat)Monkey Chov*Ew@as fed twice each day and fresh apples were fed 3 times a week. Water was available ad libitum. Durinc, t@ieconditioning period, the monkeys were tattooed on the inner surface of the thigh and intrapalpebral tuberculin tests were conducted. Tuberculin tests also were conducted twice during the treat-.nentperiod. Complete physical examinations were conducted by the staff veterirarian prior to initiation of compound administration. Only monkeys in good health were selected. This study was initiated on February 16, 1978. Terminal sacrifices were conducted on '-,la1y7, 1973. 2. ComDound Administration: At the end of the conditioning period the monkeys were divided into four -,roupson a random @asis, so that the initial average body weights were similar: Dosage Level -(mg/kg/day) 0 (Control) 0.5 1.5 4.5 Number )Iale 2 2 2 2 of @!onkevs Female 2 2 2 2 137-092 InternatioRneaslearcahndDevelopmenCtorporation Page 5 The monkeys in the control group were previously employed as the control group in an aborted 90 day study in monkeys on FC-95 (study 137-087). The test compound suspended in distilled water, was administered 7 days a week by gavage. All doses were given in the same volume of water. This volume of distilled water was given to the 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, behavior and pharmacotoxic signs. Individual body weights were recorded weekly. General physical examinations were conducted in the control period and monthly during the study. Food consumption 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: hemoglobini . hematocrit2 erythrocyte count3, tota,3 and differential leucocyte counts, reticulocyte count4, platelet count5, prothrombin time6 and activated partial thromboplastin time7 (APTT). Mean corpuscular hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin concentration were calculated. b. Biochemistry: Biochemical studies included: the determinations of fasting blood glucose8, blood urea nitrogen8, the activities of serum alkaline phosphatase8, serum glutamic oxalacetic 137-092 InternatioRneaslearcahndDevelopmenCtorporation Page 6 transaminase8, and serum glutamic pyruvic transaminase8, and the concentrations of cholesterol9, total protein9, albumin8 I sodiumio, potassiumio . chloride9. inorganic phosphate9 , as well as the activities of Y-glutamyl transpeptidasell and creatinine phosphokinasel2. C. Urinalysis: Urinalysis included: measurement of volume, pHl3 and specific gravity; description of color and appearance; qualitative tests for proteinl3, glucosel3. ketonesl3 , occult bloodl3 and microscopic examination of the sediment. d. Statistical Analysis: All statistical analyses compared the treatment groups with the control group, by sex. Body weights (week 13), percent change in body weights bet- ween control period and 1, 2 and 3 months (sexes combined), hematological, biochemical and urinalysis parameters (months 1 and 3) and absolute and relative organ weights (terminal sacrifice) were compared by analysis of variance (one-way classification),Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torriel4 using Dunnett'sl5 multiple comparison tables to judge significance of differences. B. RESftTS: 1. General Behavior, Appearance and Survival: There was no mortality in the control, 0.5- and 1.5-mg/kg/day dosage levels. Three monkeys at the 4.5-mg/kg/day dosage level died between week 5 and 6 of the study. The fourth monkey from this group was sacrificed in extremis in week 7 of the study. a. Control: The monkeys from this group showed an occasional soft stool or diarrhea (slight to severe). For one day Monkey 7358 had 137-092 InternatioRneaslearcahndDevelopmenCtorporation Page 7 bloody diarrhea, anorexia and slight ataxia and for 3 days Monkey 7368 had anorexia. Emesis was noted rarely. b. 0.5 mg/kg/day: Monkeys 7466 and 7504 exhibited occasional diarrhea or soft stools. For Monkeys 7463 and 7483 the soft stools and diarrhea were frequent with occasional appearance of mucus in the stools. On one occasion bloody mucus in the stool and in the refuse pan was observed for Monkey 7483. Occasional anorexia and emesis were noted for Monkeys 7463, 7466 and 7504. Similarly, a slight intermittent decrease in activity was noted for Monkeys 7463, 7483 and 7504. c. 1.5 mg/kg/day: All monkeys at this dosage level exhibited a -slight decrease in activity during the first week of study. For Monkey 7501 the decreased activity frequently was noted throughout the study and by week 13 had become moderate. Although no emesis, soft stools and diarrhea were noted for this monkey, slight general body trembling and mucus in the stool was observed in week 12, as well as slight dehydration in weeks 12 and 13. For Monkey 7501 and 7500 anorexia became persistent during weeks 12 and 13. For Monkey 7500 diarrhea and soft stool appeared along with mucus in the stool at week 2, black stool at week 8 and slight dehydration in week 12. This monkey exhibited '*bruising"around the right eye followed by "bruising" around both eyes at week 12. For Monkey 7486 occasional soft stool and diarrhea were observed along with anorexia which became persistent in week 10. During weeks 10 and 11 slight dehydration was also noted. Monkey 7462 had occasional soft stool, emesis for I day each in weeks 1 and 3 and the decreased activity was observed in week 1 only. 137-092 InternatioRneaslearcahndDevelopmenCtorporation Pa-e 8 d. 4.5 mg/kg!day: At 4.5 ma@i'kc,,/dtahye monkeys showed apparent signs of toxicity in the (,:,astro?-ntestitnraa'cLt from the first to the second day of the study (anorexia and partial anorexia, emesis, black stool and/or dehydration from slight to moderate). All had decreased ac,livity from sliaht to severe. Before death they showed marked to severe riaidity, convulsions, moderate generalized body tremblina and finally prostration. m-on-,ey1'485had petechial hemorrhaaes on the skin of the in,--,,uinaarlea, thorax and face and Nlonkey 7484 had pale aums after week 3 of the study. 2. Body Weights (Tab'Le1): Chanoes in the body weiohts were similar for monkevs in the control and at the 0.5--ma.ilk,,/ddaoysaae level. The male monkeys in the 1.5-ma'ka/dav dosaoe 'Levelhad a decrease in their body wei,-,ht from 3.15 ka,at the beoinnina of the study to 2.93 1-1-a1t the end of the study and from 3.22 ko' to 2.75 ka for the female monkeys. Tne chanae in body -we4-ohtfor this group of monkeys -wasnot statisticallv si.an4--;icanftrom the control aroup. The monkevs a!--the 4.5-r-aa/kg/daydosaae level showed a loss of the b*odywei.cht-a-fter 2 weeks of the study. Their average body wei,.,htdecreased -.rom3.44 k--at the beginninc,of the study to 3.23 kg (week 2) - 3.13 kg (week 3) 2.97 kg (week 4) - 2.70 kg (week 5) --Por both sexes. At week 6 ard 7 of the study they died. There was no statistical evaluation of the body weights for monkeys at the 4.5mc,/kg/dav dosa-e level, ',@ecausethey were not alive at week 13, when the statistics were done. 3. Labora@--orvTests (Tables 2-1^3): a. One Month of the Study: At 1 month o-@'study there were no palholocical chan,-,es4.n values for monkeys -@cro,t.Ln'Lecontrol and 0.5-mg/'&*/day dosa-3e leiel. 1.37-09"-@ InternatioRneaslearcahndDevelopmenCtorporation Page 9 At the 1.5-mg/kg/day dosage level only Monkey 7501 had a slight decrease in the erythrocytes which was recovered in the third month of study. Both the male and female monkeys at the 4.5-mg/kg/day dosage level had low values for serum cholesterol which were statistically significance. Monkey 7484 had a decreased alkaline phosphatase activity (312 unit/1), serum potassium (3.6 meq/liter) and chloride concentration (102 meq/liter) and Monkey 7503 also had low serum chloride concentration (102 meq/liter). Although the S.G.O.T. activity of male Monkeys 7484 and 7485 was in the highest expected normal range (115 units) the differences between these values and that of the control were not statistically significant. The only unusual changes in the urinalysis were the appearance of glucose from Monkey 7500 (1.5 mg/kg/day) and from Monkeys 7485 and 7503 (4.5 mg/kg/day). Rowever, these monkeys had no pathological increase of the blood glucose. b. Three Months of the Study: There was a statistically significant decrease in the serum alkaline phosphatase activity for the male monkeys at the 0.5mg/kg/day dosage level and for two Monkeys, 7500 and 7501, at the 1.5mg/kg/day dosage level. These latter monkeys also had a decreased values of serum potassium concentrations. Monkey 7501 at 1.5mg/kg/day had very low serum cholesterol and Monkey 7500 at 1.5mg/kg/day had a slight decrease in the inorganic phosphate (4.2 mg/100 ml) concentration. 137-092 InternatioRneaslearcahndDevelopmenCtorporation Page 10 IV. PATHOLOGICAL STMIES A. EMODS: 1. Gross Pathology: After completion of the compound administration period all surviving monkeys were anesthetized with Sernylan(D*, exsanguinated and necropsied. At necropsy the heart, liver, adrenals, spleen, pituitary, kidneys, testes/ovaries and brain were weighed and representative 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 animals in the control and treatment groups. The following tissues were examined; adrenals aorta 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 bone/bone marrow (rib junction) 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 137-092 *Phencyclidine HC1 - BioCeutic Laboratories, Inc., St. Joseph, Missouri. InternatioRneaslearcahndDevelopmenCtorporation Page 11 B. RESULTS1. Gross Pathology (Table 14) and Organ Weights (Table 15): No gross lesions considered compound-related were seen in male and female rhesus monkeys which died or were sacrificed in extremis or were sacrificed after 90 days of study. No statistically significent variations in sex group mean weights of organs occurred between the control and experimental groups. 2. Histopathology (Table 16): All male and female monkeys-at the 4.5 mg/kg/day dosage level had marked diffuse lipid depletion in the adrenals. one male and two females at the 4.5 mg/ka/day dosage level had moderate diffuse atrophy of the pancreatic exocrine cells. The lesion consisted of decreased cell size and loss of zymogen granules. Two male and one female monkeys at the 4.5 mg/kg/day dosage level had moderate diffuse atrophy of the serous alveolar cells characterized by decreased cell size and loss of cytoplasmic aranules. These microscopic findings were consid- ered compou-.id-related. No microscopic changes which were considered compound-related were seen in the adrenals, pancreas or submandibular salivary glands in male and female monkeys at the 0.5 and 1.5 mg/kg/day dosage levels. No microscopic lesions in tissues other than the adrenals, pancreas and submandibular salivary glands of male and female monkeys at the 4.5 mg/ ka/day dosage level were considered compound-related. 137-092 InternatioRneaslearcahndDevelopmenCtorporation 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. Gradwholls Clinical Laboratory @lethods 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 Street, 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 Methodology. 10. Atomic Absorption IL Model 353. 11. Sigma Technical Bulletin 545, Sigma Chem. Co., St. Louis, Missouri. 12. Sigma Technical Bulletin 520, Sigma Chem. Co., St. Louis, Missouri. 13. Bililabstix (Ames Reagent Strips). 14. Steel, R. G. D. and Torrie, J. H. (1960), Principles and Procedures of Statistics, McGraw-Hill, New York, N. Y. 15. Dunnett, C. W., New Tables for \iultipleComparisons With a Control, Biometrics, Sept. 1964. 137-092 FC-95: TABI.E I. Group, Monkey Numiter Sex Control: 7355 m 7358 m 7368 r 7372 p Mean 0.5 mg/kg/day: 7463 ti 7483 m 7466 F 7504 p Mean 1.5 mg/kg/day: 7462 m 7486 m 7500 v 7501 F- Mean 4.5 mx/kg/day: 7484 m 7485 7502 p 7503 p mean Wntrut -1. 0 1 3.20 3.65 3.10 3.55 3.38 3.20 3.55 3.10 3.65 3.38 3.25 3.65 3.15 3.60 3.41 2.40 3.50 3.20 3.25 3.09 2.55 3.55 3.40 3.15 3.16 2.55 3.45 3.25 3.10 3.09 2.70 3.40 3.65 2.75 3.18 2.90 3.4o 3.75 2.70 3.19 2.70 3.15 3.75 2.55 3.04 3.45 3.25 3.50 3.80 3.50 3.30 3.15 3.20 - 3.30 3.50 3.55 3.75 3.80 3.44 3.45 Ninety-Day Subacute BliestisMonkey Ti)xLctty Study. Individual Body Weiglits.Kilograms. Study Weeks 2 3 4 5 6 7 a 9 3.15 3.30 3.10 3.35 3.23 3.25 3.30 3.20 3.80 3.39 3.25 3.45 3.20 3.85 3.44 3.15 3.50 3.10 3.80 3.39 3.30 3.70 3.20 3.90 3.53 3.20 3.70 3.15 4.10 3.54 3.30 3.60 3.05 4.10 3.51 3.40 3.90 3.25 4.35 3.73 2.40 3.40 3.35 3.10 3.06 2.50 3.50 3.35 3.20 3.14 2.60 3.60 3.50 3.30 3.25 2.40 3.55 3.50 3.15 3.15 2.50 3.55 3.70 3.20 3.24 2.55 3.65 3.70 3.30 3.30 2.55 3.55 3.60 3.20 3.23 2.70 3.65 3.70 3.40 3.36 2.60 3.30 3.45 2.45 2.95 2.70 3.15 3.45 2.50 2.95 2.75 3.30 3.40 2.55 3.00 2.70 3.10 3.30 2.50 2.90 2.70 3.20 3.35 2.55 2.95 2.80 3.20 3.40 2.55 2.99 2.80 3.30 3.30 2.50 2.98 2.90 3.35 3.45 2.55 3.06 3.25 3.00 3.20 3.45 3.23 2.90 3.00 3.25 3.35 3.13 2.55 2.75 3.25 3.35 2.98 2.20 2.50* 3.10 2.80 2.70 2.15* Died 3.10 2.55* 3.10 Died 2.70 Dted 2.70 2.65* Died Uted to 3.40 3.90 3.30 4.40 3.75 2.65 3.65 3.80 3.40 3.38 3.OS 3.40 3.40 2.50 3.09 11 3.45 4.10 3.45 4.70 3.93 2.55 3.75 3.65 3.35 3.31 3.00 3.30 3.50 2.50 3.08 137-092 *Terminal weigist not Included In mean. FC-95: TABLE 2. Hematology Erytgrocytas, 10 /c= Hemoglobin, 8/100 al Rematocrit. % Pla1 telets, 03/ Raticulocytes, Prothrombin Time, see Activated P.T.T.. sac Leu1c0o3c/y,te-s .4cv .4cH, ,4CHC, &/100 ml Ninety-Day Subacute Rheaus Ilonkey Toxicity Study. MALES: Means and Significance of Rematological Values. Study %Ionth Control 0.5 mg/kg/day 1.5 mg/kg/day Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 4.93 4.67 4.63 12.3 12.4 12.3 35 37 39 129 181 205 0.5 0.3 0.2 11 11 12 29 24 25 7.03 10.59 8.67 71 79 84 25 27 27 36 34 32 5.36 4.81 4.84 12.7 13.8 12.4 38 37 39 140 226 226 0.9 0.3 0.3 11 12 11 28 25 22 10.29 10.41 7.06 70 77 so 24 29 26 34 37 33 5.04 4.66 4.45 12.3 13.2 11.6 37 37 36 114 161 223 0.6 0.2 0.1 11 11 11 29 24 28 8.22 8.39 9.04 73 so 81 25 28 26 34 36 32 Page 14 4.5 mg/kgiday 5..7 4.71 - 13.7 12.8 - 39 -37 - 180 177 - 1.0 0.2 - 11 12 - 26 29 - 6.39 11.37 - 71 78 - Z5 27 - 36 35 - 137-092 lot available FC-95: TABLE 2. Cont. Hematology Eryt#roc3rtes, 101/cm Hemoglobin, s/100 ml Rematocrit, Platelets. 1031 taticulocytas, z Prothrombin Time, sec Activated P.T.T., see Lau"cytes, 103/cam ,NICE, uug ,mmc, &1100 mi Ninety-Day Subacute Rhasus Monkey Toxicity Study. Tm4Aus: Means and Signi.licanceof HematologicialValues. Study '4onth 6ontrol 0.5 mg/kg/day 1.5 mg/kg/day Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 5.66 5.02 4.71 13.1 14.1 12.0 39 40 38 176 151 232 0.4 0.2 0.1 11 11 12 27 27 25 7.39 8.77 4.62 68 79 al 23 28 26 34 36 32 5.56 4.56 4.79 12.6 13.4 12.2 38 38 39 164 177 236 o.i 0.1 0.1 10 11 11 27 27 29 10.31 7.82 9.09** 69 82 81 23 30 26 33 36 31 5.11 .3.95 4.37 12.3 12.0 11.7 34 35 37 16/A iss 229 0.3 0.2 0.1 11 11 11 26 25 27 8.81 9.14 6.84* 67 88 as 25 31 27 37 35 32 Page 15 4.5 mglkg/day 5.08 5.00 - 11.8 12.9 - 35 37 - 182 194 - 0.8 0.1 - 11 12 - 27 2S - 12.71 11.28 - 68 75 - 23 26 - 34 35 - 137-092 *Significantlydifferent from Control group mean, p<0.05. **Significantlydifferent from Control group mean. p<0.01. Not available FC-95: TAIII.E3. (.rutip, tk)nkey Number Sex grytliro- llemocltes globtii 10 /em S/100 mi llematocrit 2 Plateeta I 10 /em Nitiety-Day Subacute RiiesionMonkey Toxicity Study. Individual Hematological Values - Control. Reticulocytes Z Pro- titromijiAnctivaLed Leuco- Time see P.-r.T. see c3tes 10 /cm Noutropliils Seg,. Hoei-Seg. z % Lymplio- Eosino- Cytes plills x % NotioCyLeS Control: 7355 m 4.65 11.4 32 110 0.7 10 31 5.39 19 0 so 7358 m 5.20 13.2 38 147 0.2 11 27 8.66 13 0 84 7368 F 5.78 13.4 41 too 0.5 11 25 7.61 24 1 74 7372 F 5.53 12.7 36 172 0.3 it 28 7.17 12 0 87 Men 11 5.29 12.7 37 152 o.4 It 28 7.21 17 0 82 0.5 mil/kg/day; 7463 m 5.38 12.7 37 131 0.5 10 27 9.73 58 0 40 7483 m 5.34 12.7 38 148 1.2 11 28 10.84 47 ol 50 7466 F 5.64 13.2 39 157 1.2 10 29 j.61 20 0 so 7504 F 5.47 11.9 37 170 0.3 10 25 11.00 28 0 72 Mean 5.46 12.6 38 152 0.8 10 27 10.30 38 0 61 1.5 ni/laAaz: 7462 m 5.03 12.2 37 101 0.2 11 28 7.28 t6 0 83 7486 m 5.04 12.4 36 126 0.9 11 29 9.15 22 0 78 7500 F 4.96 12.4 32 142 0.2 11 26 10.07 53 0 43 7501 p 5.25 12.5 36 186 0.3 11 26 7.54 34 0 64 Mean 5.07 12.4 35 139 0.4 11 27 8.51 31 0 67 i_,.5MR/kg/day: 7484 m 5.40 12.9 36 197 0.5 11 27 6.72 20 0 79 7485 m 5.54 14.5 41 162 1.2 11 25 6.05 33 0 64 7502 F 5.27 12.7 35 191 0.5 10 25 13.89 34 0 63 7503 p 4.88 10.9 34 t73 1.0 11 29 11.53 35 0 60 Mean 5.27 12.8 37 181 0.9 11 27 9.55 31 0 65 0 1 3 0 1 0 1 0 1 0 .2 0 3 0 0 0 0 0 1 0 1 0 0 0 3 1 2 0 2 0 0 0 3 0 2 0 5 0 3 0 137-092 FC-95: Ninety-Day Subacute RiassuiaMonkey Toxicity Stud)p. TAIII.E4. Individual liena.tologicalValues - I Month. Grotal), Fit)iikey Number Sex Frytitro- liewo- llemato- cites alt)blii crit 10 /cmm g/100 mi 2 Plateto ii 10 cam Pro- Rettcii- ttirombin Activated Incytes Time P.T.T. z sec sec l.aticoc5tes 0 /em NeutrOI)IIII&I l.yamplio-Eoulno- Seg. Non-Seg. cytes plills z % % I Nano cyte z Control: 7355 m 4.74 12.5 38 166 0.0 12 26 5.22 48 0 52 0 0 7358 4.60 12.3 36 196 0.5 10 21 15.95 61 0 34 5 0 7368 p 5.41 14.7 42 134 0.1 11 25 lt.05 64 0 35 0 1 7372 F 4.60 13.4 37. 166 0.2 11 28 6.48 23 0 72 5 0 mean 4.84 13.2 38 166 0.2 11 25 9.68 49 0 48 3 0 !!:.Img/kl,/dU: 7463 m 4.92 14.0 37 220 0.2 11 26 10.52 65 0 34 1 0 7483 m 4.69 13.5 37 232 0.3 12 24 10.29 53 0 47 0 0 7466 F 4.74 14.0 39 222 0.0 11 24 7.42 37 0 62 1 0 754)4 F 4.38 12.7 36 131 0.1 11 29 8.22 40 0 sa 2 0 Mean 4.68 13.6 37 201 0.2 11 26 9.11 49 0 50 1 0 mg/kg/day: 7462 m 4.67 13.3 37 160 0.2 11 24 8.54 59 0 41 0 0 7486 4.64 13.1 37 161 0.2 11 24 8.23 47 0 51 1 1 7500 F 4.01 12.0 32 -15@ 0.2 11 26 11.06 50 0 50 0 0 7501 F 3.89 12.0 37 160 0.1 11 23 7.21 48 0 50 2 0 Mean 4.30 12.6 36 159 0.2 11 24 8.76 51 0 48 1 0 @.5 mglklt/day: 7484 N 4.66* 12.0 34 204 0.0 12 32 11.83 82 0 17 0 1 7485 m 4.76 13.5 39 149 0.4 11 26 10.90 66 0 32 1 1 7502 p 4.20 12.7 35 202 0.1 li 27 12.90 60 0 40 0 0 7503 F 5.80 13.0 38 186 0.1 12 29 9.66 62 0 37 1 0 Mean 4.86 12.8 37 185 0.2 12 29 11.32 68 0 30 1 1 137-1)92 *IiAnisocytouts Niiiery-Day Subactite Rioesus Moitkay Toxicity Sttitly. TABI-E 5. Indtvidtiallii-niatologicaVlaloes - 3 Months. (.rotall, M)iikey HiititberSex Eryttiro- llemocited gitibin 10 /c@ g/100 ol llematocrit % Pro- lllate- Reticti- thrombin Activated leto 103/c@ locytes t Time sec P;T.;T. Lo--ucocited 0 /con Neutrtiplills Lymplio- Eosino- Seg. Non-Seg. cytes plills 2 1 % % None cyte % Coiitrol: 7355 m 4.59 12.1 37 187 0.3 12 26 6.63 49 0 51 0 0 7358 m 4.67 12.5 40 222 0.0 11 23 10.10 20 0 76 3 1 7368 r 5.05 12.5 40 235 0.2 12 24 4.33 38 0 61 1 0 7372 F 4.36 11.5 36 228 0.0 It 25 4.91 27 0 66 7 (1 ML!all 4.67 12.2 38 218 0.1 12 25 6.64 34 0 63 3 0 R.5 ati@,/kit/day. 7463 N 5.01 12.8 39 230 0.3 10 20 7.15 46 0 53 1 0 7483 m 4.66 12.0 38 222 0.2 11 24 6.96 42 0 54 4 0 7466 F 4.86 12.9 41 229 0.0 11 27 9.30 15 0 83 2 0 7504 F 4.72 11.5 37 242 0.1 11 31 8.82 33 0 66 1 0 mean 4.81 12.3 39 231 0.2 11 26 8.06 34 0 64 2 0 1.5 mg/kg/day: 7462 N 4.30 11.3 35 230 0.1 11 29 7.71 le 0 al 1 0 7486 m 4.60 11.9 37 216 0.1 11 26 10.37 is 0 al 1 0 7500 F 4.12 11.1 35 234 0.1 11 26 7.22 34 0 64 2 0 7501 F 4.61 12.2 39 224 0.0 11 27 6.45 47 0 so 3 0 Mean 4.41 11.6 37 226 0.1 11 27 7.94 29 0 69 2 0 7484 H 7485 m 7502 v 7503 F Mi.-kill I)Ied I)Ied I)ted nied 137-092 FC-95: TABLE 6. Biochemistry Glucose, mg/100 ml B.U.N., mg/100 ml Alkaline Phosphac"a. int'lunits/1 S.C.O.T.. ine'l units/1 S.G.P.T.. int'lunits/1 Cholesterol, ms/100 al Total Protein, g/100 ml S/100 ml Sodium, maq/1 Potassium, maq/1 Chloride, meq/1 Inorganic Phosphate, mg/100 al y - Clutamyl Transpopcidase slgw units/ml Creatinine Phosphakinase. Sig= un:Lcs/al Ninety-Day Subacute Rh"us t4onkoy Toxicity Study. MALES: Sums" of Mean Biochemical Values. Study *,4onth Control 0.5 mg/kg/day 1.3 mglkg/day Control 1 3 Control 1 3 Central 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 118 96 77 23.7 23.3 28.2 1070 1113 1095 22 56 56 40 42 35 183 198 162 8.38 8.46 7.85 4.96 4.75 4.70 150 161 153 4.9 4.9 4.2 iiz 117 112 6.8 8.1 7.4 56 42 56 25 62 20 106 .92 80 29.8 33.3 26.5 680 $97 747* 23 49 49 32 27 28 172 200 152 8.74 8.59 8.07 5.22 5.17 4.69 156 160 151 5.6 4.6 4.2 IL4 118 110 6.4 6.4 6.5 36 45 29 44 34 40 102 115 107 31.4 32.8 19.6 1035 iiio $91 18 54 53 29 38 28 185 213 122 8.68 8.74 8.38 5.36 5.22 4.98 156 160 150 5.4 4.7 4.8 116 121 ill 6.0 8.5 6.0 50 55 45 11 67 40 Page 19 4.3 mg/kg/day 116 99 - 19.6 29.1 - 1300 564 - 25 115 - 35 27 - L90 87** - 8.90 8.90 - 5.50 5.31 - 160 153 - 4.6 4.7 - 113 105 - 6.4 4.9* - 46 26 - 13 55 - 137-092 *Significantlydifferent from Control group mean, p<0.05. **Significantlydifferent from Control group mean, p<0.01. Not available FC-95: TABLE 6. Cant. Biochemistry Glucose, mg/100 ml B.U.N., mg/100 ml A.Lkaline Phosphatase, int'l units/1 S.G.O.T., int'l units/I S.C.P.T., int'l units/1 Cholesterol, mg/100 ml Total Protein, g/100 al Albumin, 3/100 ml Sodium, moq/1 Potassi=. maq/1 Chloride, meq/1 InorgazLic Phosphate, mg/100 ml y - Glutazyl Transpeptidase Sigma Units/uLl Creatimine Phosphokinase, Sigma unirs/ml Ninoty-Day Subacute Rhasus Monkey Toxicity Study. FEMALES. Sumary of Mean Biochemical Values. Study '4onth Control 0.5 mg/kg/day 1.5 mg/kg/day Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control 1 3 Control L 3 Control 1 3 Control 1 3 Control 1 3 107 163 as 23.6 25.2 28.7 1173 1092 831 16 46 36 23 23 29 iso 198 165 7.70 7.66 7.49 4.71 4.86 4.77 156 155 152 4.8 4.7 4.6 ill ill 113 6.4 6.5 6.5 38 41 32 10 50 5 139 98 97 22.0 25.5 21.5 1013 942 861 39 55 36 42 37 27 208 221 169 8.77 8.47 8.02 5.27 5.41 4.82 158 162 151 5.3 5.1 5.1 112 116 ill 7.5 8.2 7.3 50 47 40 20 39 10 113 119 108 20.7 26.4 22.6 770 753 618 20 45 27 32 35 34 204 169 100 8.67 8.63 8.47 5.20 5.42 5.21 157 157 149 5.2 3.8 3.7 115 113 109 5.4 5.7 4.7 43 28 30 24 31* 7 Page 20 4.5 mg/kg/day 144 164 - 22.4 31.6 - 875 6L5 - 37 75* - 37 45 - 176 112* - .8.88 8.82* - 5.16 5.39 - 139 156 - 5.3 4.3 - 116 110 - 6.4 5.6 - 34 30 - 27 49 - 137-092 .*Significantly different from Control group mean, p<0.05. **Significantly different from Control group mean, p<0.01. 4ot available FC-95: TABLE 7. Group. Monkey "limber Sex Clucome mg/100 ml Ninety-Day Subacute itikesusMonkey Toxicity Study. Individual BloelteimicalValises- Control. Alkaline S.C.O.T. B.U.N. Piloopliatage Intel mg/100 all Intel u/l u/i S.C.P.T. Intel u/j Cholestc-rot mg/loo ml Total Protein g/100 =1 Albumin g/100 ol Potas- Citio- Iiiorg Sodium sium ride Pitoop maq/1 maq/1 seq/t mg/10 Control: 7355 m 119 7358 m 117 7368 p 117 7372 p 97 Mean 113 20.2 27.2 24.9 22.2 2:1.6 1050 1090 1170 1175 1121 46 24 192 8.65 4.92 153 5.4 115 7. 33 21 174 8.11 5.00 148 4.4 110 6. 23 is 155 8.09 4.93 158 5.4 111 6. 23 14 204 7.30 4.49 153 4.2 ill 6. 31 19 181 8.04 4.84 153 4.9 112 6. 0.5 mglkg/day: 7463 m 123 7483 K 90 7466 v t21 7504 p 156 Mean 123 26.5 33.2 19.1 24.9 25.9 635 725 1250 775 846 33 29 182 7.94 4.96 149 4.4 III 5. 31 17 161 9.53 5.49 164 6.7 117 7. 33 31 208 8.61 5.07 161 5.6 114 a. 51 46 208 8.93 5.46 155 5.0 109 6. 37 31 190 8.75 5.25 157 5.4 113 6. 1..5 tog/kg/day: 7462 m 96 7486 m 109 7500 F 116 750t F 109 29.9 32.9 18.4 22.9 Soo 1270 1080 460 36 17 196 8.26 5.00 150 4.6 III 5. 22 20 174 9.10 5.71 162 6.2 120 6.. 29 19 172 8.82 5.18 162 5.4 lig 5. 34 21 236 8.52 5.22 151 4.9 112 5 Mean 108 26.0 903- 30 19 195 8.68 5.28 156 5.3 115 S. It.5 mg/kg/day: 7484 m 120 19.0 985 4300 i32s 119846 98..5245 55..6390 116536 44..75 111142 66.. 77458052 1F1 i13t7z 2203..26 1691655 36 22 182 8.90 5.17 160 5.0 116 6. 750'1 p 150 21.1 785 36 51 170 8.86 5.14 157 5.6 116 6. Meal% 130 21.0 1088 36 31 183 8.89 5.33 159 5.0 115 6. 137-092 Ninety-Day Subactite Rhasue Monkey Toxicity Study. TABI.E 8. Group, Munkey Number Sex (111cose mg/100 ml D.U.N. ma/100 at Alkaline Phoopliatsee lnt'l u/l IntlividisaBtlocliemical Values - I Mantis. S.C.O.T. int'l u/l S.C.P.T. $1 a U71mil Cliolestorn) mg/100 at Total Protein g/100 at Albumin g/100 at Potas- Clilo- lnorg Sodium alum ride Pliumpi meq/1 meq/1 neq/1 mg/10 Control: 7355 m 103 7358 H 89 7368 F 196 7372 F 129 mean 129 5 mu/kglday: 7463 82 7483 H 101 7466 F 100 7504 F 96 Mean 95 1.5 mg/kg/day-. 7462 m 131 7486 m 98 7500 F 125 7501 p 112 Mean 117 4.5 !!!&/kit/day: 7484 m 97 7485 H 100 7502 F 172 7503 p 155 Mean 131 23.3 23.2 30.0 20.3 24.2 30.8 35.8 24.1 26.9 29.4 29.8 35.8 23.9 28.9 29.6 35.0 23.2 26.2 37.0 30.4 1146 1080 it5a 1026 1103 924 870 1164 720 920 870 1350 816 690 93i 312 816 564 666 590 40 39 72 45 5t 25 41 20 51 32 58 31 40 22 48 38 61 36 52 32 50 37 58 38 40 39 50 31 50 36 115 21 115 32 60 54 69 36 95 36 212 8.36 184 8.55 188 8.13 208 7.19 198 8.06 208 8.06 192 9.12 230 8.45 211 8.48 210 8.53 222 8.60 204 8.87 154 8.55 184 8.70 191 8.68 76 8.11 97 9.69 128 8.90 96 8.74 99 8.86 5.19 164 5.0 119 a. 4.30 157 4.7 114 7. 5.16 157 5.0 109 6. 4.55 152 4.3 113 6. 4.80 158 4.8 114 7. 5.36 159 4.5 121 5. 4.97 161 4.6 115 7. 5.30 165 5.7 118 8. 5.51 158 4.5 113 7. 5.29 161 4.8 117 7. 5.30 161 4.1 123 B. 5.14 159 5.3 119 B. 5.15 t59 3.9 113 6. 5.69 155 3.7 112 5. 5.32 159 4.3 117 7. 5.02 154 3.6 102 4. 5.59 152 5.7 107 5. 5.69 163 4.2 118 6. 5.08 149 4.3 102 4. 5.35 155 4.5 107 5. 137-092 FC-95. TABI,E 9 croul), tkinkey Number Sex Glucose mg/100 ol R.U.N. mg/100 at Ninety-Disy Subacute ltl)esuatloj)keyToxicity SLIlijy. Individual Biochemical Values - 3 Months. Alkaline S.C.O.T. Pliospliataoe fnt'i lnt'l u/l u/l S.C.P.T. Sigma u/mt Cliolesterof mg/100 ml Total Protein g/100 ml Albumin &/100 mi Sodium meq/1 Potasmium meq/1 ('lil4)-litur r ftle pikuh meq/1 mg/i CA)Iitrt)l 7355 N 83 7358 m 70 7368 v 112 7372 F 63 mean 82 2.5 mg/ka/day% 7463 m 83 7483 m 76 7466 F 106 7504 p 87 Meal% Be 1.5 mg/kg/day: 7462 N 92 7486 121 7500 p 106 7501 F Ito mean 107 L.5 mK/k_/day: 7484 N 7485 m 7502 F 7503 p mean DIL-D [)led Died Died 34.1 22.3 26.9 30.4 28.4 22.8 30.1 18.1 24.8 24.0 15.2 23.9 17.7 27.5 21.1 iiio 1080 876 786 963 690 804 978 744 804 816 966 690 546 755 59 40 52 29 33 29 39 29 46 32 179 7.69 144 8.00 144 7.68 185 7.30 163 7.67 4.78 4.61 5.01 4.53 4.73 154 4.0 115 8 152 4.3 109 6 152 4.4 110 5 151 4.8 its 7 152 4.4 112 6 42 26 160 7.62 4.97 152 4.2 111 3 56 29 143 8.52 4.41 150 4.1 108 7 32 27 178 8.11 4.80 153 5.5 110 8 40 27 160 7.92 4.83 148 4.7 111 6 43 27 160 8.04 4.75 151 4.6 Ito 6 82 35 132 8.51 4.85 149 5.0 112 6 23 20 112 8.24 5.11 151 4.5 109 5 22 33 113 8.81 4.98 150 3.4 109 4 32 34 87 8.12 5.44 148 3.9 109 5 40 31 111 8.42 5.10 150 4.2 Ito 5 137-092 FC-95: TABLE 10. Urinalysis Vol=e, mi PH Specific Gravity Ninat7-Day Subacute Rhesus Monkey Toxicity Study. MAU$: Sumary of Mean Urinalysis Values. Study Month Control 0.5 mg/kg/day 1.5 mg/kg/day Control 1 3 Control 1 3 Control 1 3 22 30 10 7.2 6.4 7.0 1.032 1.028 1.034a 22 25 33 8.3 5.5 7.2a 1.027 1.027 1.033a 28 40 75 8.5 5.9 8.Oa 1.030 1.021 1.024 Page 24 4.5 mg/kg/day 58 38 8.4 6.4 1.034 1.033 - 137-092 a'Significancenot determined due to only one value in the Control group. Not available FC-95: Ninety-Day Subacute Rhesus Monkey Toxicity Study. TABLE 10. Cont. FEMALES: Simmiaryof Mean Urinalysis Values. Urinalysis Study Month Control 0.5 mg/kg/day 1.5 mg/kg/day Vol=e, mi PH Specific Gravity Control 1 3 Control 1 3 Control 1 3 32 25 80 8.1 5.8 8.0 1.031 1.032 1.021 53 13 30 7.9 5.5 9.0 1.027 1.032 1.021 20 28 40 8.3 6.4 8.0 1.031 1.028 1.025 Page 25 4.5 mg/kg/day 30 23 8.8 6.5 1.027 1.036 - 137-092 Not available FC-95: TABI.E 11. Groul), Nuiakey Nuiul)er Ninety-Day Subacute Riiesus Monkey Toxicity Study. individual UriiialysioValues - CA)ntro.t CA)Ior Vo Iume and Spec. Occul t Ke- Leuco- Eryt[iro- Epi. Triple Cat. Sex nt Appear. pit Grav. Protein Glucose Blood tones cytes cytes Cells Urates Plius. Ox. CUIILCOI: 7355 7358 7360 7372 H 25 LS-el 7.7 1.029 N m 20 I.S-cl 6.7 1.035 N F a DS-cl 9.0 1.034 2+ v 55 LS-cl 7.2 1.028 N 0. 5 MR 7463 7483 7466 7504 m 30 LS-el 9.0 1.020 N N 15 DS-el 7.6 1.034 N F 8() I.S-cl 6.8 1.023 N F 25 S-C 9.0 1.031 N 1.5 mg/kg/day: 7462 7486 7500 7501 25 I.S-cl 8.0 1.033 N m 30 S-C 9.0 1.027 N F 30 S-C 7.7 t.024 N F 10 S-C 8.8 1.037 N 7484 7485 7502 7503 H 105 LS-el 7.7 1.034 N m 12 S-C 9.0 1.633 N v 30 LS-C 8.8 1.028 m p 30 LS-C 8.8 1.025 N N - occ p F N m N - - oce occ oce p N 3+ m - 30+ 1-3 p oce - N N N - 1-3 occ F oce - N tr N - - F occ oce N N N - F occ p N N N - occ occ F occ occ N N N - oce occ occ F N N m - F occ p N m N - oce F F occ N tv 1+ - oce occ F occ - N N N - occ F p oce N N - occ Dec p oce - N - occ p occ - tr 1+ - - occ F F - N tr N - - occ F occ F tr - Trace S - Straw N - Negative oce 1+ - Trace to slight LS - Light Straw v - Few QNS 137-092 2+ - Slight to moderate DS - Dark Straw L - tonded 3+ - Moderate LAs - I.IglitAmber H - Molly 4+ - Marked DAm - Dark Amber R - Rare el - Cloudy C - Clear FC-95: TABLE 12. Group, Monkey Number Ninety-Day Subacute Riiesue Monkey Toxicity Study. individual Urinalysto Values - I Month. Volume Sex ml Color and Appear. Spec. pH Grav. Occult Protein Glucose Blood Ketones Leuco- Erytliro- Elp. Triple Cal. cytes cytes Cella Urates Plioa. Ox. Control: 7355 7358 7368 7372 N 25 1,S-C 6.6 1.030 N m 35 LS-cl 6.0 1.025 F 15 r 35 S-cl 6.0 1.032 N S-el 5.5 1.032 N !1.5 mg/kg/day: 7463 7483 7466 7504 m 25 LS-cl 5.5 1.024 m 25 LS-cl 5.5 1.029 N F 6 LS-cl 5.5 1.028 N r 20 I.S-cl 5.5 1.035 N 1.5 mg/kg/day: 7462 7486 7500 7501 H 30 LS-C 6.2 1.025 N N so I.S-c1 5.5 1.017 N F 40 LS-cl 6.8 1.020 m F 15 LS-el 6.0 1.036 N 5 __n/@k 7484 7485 7502 7503 m 40 LS-cl 6.5 1.030 N m 35 I.S-el 6.2 1.035 tr p 5 LS-cl 7.0 1.037 N F 40 LS-cl 6.0 1.035 N N N 3+ 1-3 oce 1-3 F v - 3+ - oce 1-3 F occ - N m 3+ 3-5 - oce F F N N N N - occ m F occ N N 3+ - N N 3+ - - occ F F F - acc F occ F N N 3+ - occ 1-3 p F N N u 3+ - - occ F oce N m m N m 1+ N N N 3+ - 3+ - N occ 3+ occ 1-3 - - occ - oce 1-3 oce F v - r occ - r occ occ p Dee occ N N - 1+ tr N - N N 2+ - 1+ 3+ 2+ - oce occ F F occ - m p - 1-3 F F - occ F occ tr Trace S - Straw N - Negative oce 1+ Trace to slight LS - Light Straw P - Few qms 137-092 2+ Slight to moderate DS - Dark Straw L - loaded 3+ Moderate LAn - Light Amber M - Many 4+ Harked DAn Dark Amber R - Rare cl Cloudy C Clear FC-95. I'AIII.E13. nioikey Htiiiil)er Ninety-I)ay Subacute RiiesueMonkey Toxicity Stutly. Color Vultime and Sex st Appear. Spec. pil Grov. Individual Uri"alysis Values - 3 Mositliti. Occult Protein Glucose Blood Ketones Letteo- Erytioro- Epi. cytes cytes Cells Urates Urates Triple Cal. Triple Cal. Plias. Ox. 7355 7358 7368 7372 N 20 S-cl 7.0 1.034 N N N 4+ - oce 8-10 F occ H (I r 30 S-et 7.5 1.026 N N N 4+ - - 1-3 m occ F v 130 S-el 8.5 1.016 2+ N 4+ 1+ 1-3 oce 5-8 m m - R.I_m /k ld&iy: 7463 7483 7466 7504 m 35 S-cl 7.3 1.028 N 30 S-cl 7.0 1.038 N F 25 S-el 9.0 1.021 N F 35 S-cl 9.0 1.020 N N N 1+ ()CC occ m occ m m N 4+ occ m m ace N N N 5-8 m N v N 1+ occ - 1-3 F F v _L-_l 7462 7486 7500 7501 m 50 11 100 F 55 F 25 S-cl 8.0 1.025 N S-el 8.0 1.023 S-cl 8.0 1.016 N S-cl 8.0 1.033 N N N N N N N N 4+ 3+ N 4+ 3+ - 1-3 m F F - F F F occ F acc ace oce p F occ 4.5 mg/kg/day: 7484. 7485 7502 750) m Died m D I %!d F Died p Died tr - Trace S - Straw N - Negative 1+ - 1'raceto sliglit LS - Ligiot Straw V - Few QNS t37-092 2+ - Sliglitto moderate DS - Dark Straw L - Loaded 3+ - tk)derate 4+ '- Marked lAs - I.IglitAmber DAm - Dark Amber M - many R - Rare el - Cloudy C - Clear tn 9L-3 r vr 0 0 a 4a n C7 0na -0 a.-g :3 cr 0 a 0* :3 n I.r,1.4 n 04 0 0a 0 1.-" 1 0 ?A IN n 0.0 1 n A- a 1.- 04 n a onI n Is 0 aq o 0 r. n PV PV t- 0, n n ts : I-L o 9 t"i 4 Ir -0 no n0 004 n ILI- n Mtno n S3 0 C3 0 .4 0. 0 n i i@ :r n 0 t3 t 9 rt 0 n 'a. QQ n OP. a. "a-M a 0" 0 0n 0 44 0 a0 tes rm o. @ p :3r-ftn 0 0 00 a 00 1 nr0 0 ta3 10 0 I- n 0 ri 0 11 rr 0* 2s 0.0 71- & C- "0 Ir n I..c 1 0 ft lm r 0n I n l@ 0 r 00 C, 0 0 r 14 PC m xx 0 n n0 a. 04 rt x x x TABLE 15. Group, Monkey Ntind3er Sex Body Wt. kg CUF%trOl: 7355 m 7358 N Mean 3.55 3.75 3.65 7368 7372 p 3.15 p 4.20 Mean 3.68 0.5 mg/kg/day: 7463 m 7483 m Mean 2.65 3.55 3.10 7466 7504 r 3.55 p 3.35 Mean 3.45 1.5 mg/kg/day: 7462 m 7486 m Mean 2.80 3.05 2.93 7500 F 7501 p Mean 3.20 2.30 2.75 Died on 4.5 nig/kg/day: 7484 7485 7502 7503 m 2.15 t4 2.50 p 2.65 F 2.55 137-092 Spleeti 9 % Ninety Day Subacute RitestisMonkey Toxicity Study. Absolute (Grants)and Relative (% Body Weight) organ Weights, Terminal Sacrifice. Liver 9 % Adrennin 9 IYXIO Kidneys - 9 % Testes 9 % ovaries 9 %Xlo, lfeart 9 % Thyroid/ Paratityroid 9 %Xlo 3.70 4.01 3.86 2.81 4.03 3.42 O.tO 0.11 0.11 0.09 0.10 0.09 87.49 68.48 77.99 59.58 95.60 77.59 2.46 1.83 2.15 t.89 2.28 2.08 0.77 0.79 0.78 0.85 0.80 0.83 0.22 0.21 0.2t 0.27 O.t9 0.23 15.47 16.60 16.04 15.06 16.25 15.66 0.44 0.44 0.44 0.48 0.39 0.43 1.04 1.40 1.22 0.35 0.30 0.33 0.03 0.04 0.03 l.tl 0.71 0.91 14.69 14.83 14.76 13.39 16.94 15.17 0.41 0.40 0.40 0.43 0.40 0.41 0.557 0.885 0.721 0.485 0.857 0.671 0.16 8 0.24 9 0.20 8 0.15 7 0.20 8 0.18 7 2.68 2.19 0.10 0.06 St.09 86.79 3.06 2.44 0.61 0.58 0.23 0.16 11.64 15.32 0.44 0.43 0.45 0.95 0.02 0.01 9.35 IS.OT 0.35 0.42 0.444 0.580 0.17 0 0.16 8 2.44 0.08 83.94 2.75 0.60 0.20 13.48 0.44 0.70 0.02 12.18 0.39 0.512 0.17 a 4.07 4.85 0.11 0.14 92.19 87.28 2.60 2.61 O.St 0.59 0.23 0.18 16.14 12.75 0.45 0.38 0.67 0.11 1.89 0.33 14.11 13.00 0.40 0.39 0.693 0.747 0.20 a 0.22 7 4.46 0.13 89.74 2.60 0.70 0.20 14.45 0.42 0.39 1.11 t3.56 0.39 0.720 0.21 8 3.39 2.44 2.92 3.51 t.55 2.53 0.12 0.08 0.10 0.11 0.07 0.09 80.63 85.38 83.01 84.15 16.03 50.09 2.88 2.80 2.84 2.63 0.70 1.66 0.65 0.80 0.73 0.91 0.79 0.85 0.23 0.26 0.25 0.28 0.34 0.31 11.82 13.79 12.St 16.76 10.77 13.77 0.42 0.45 0.44 0.52 0.47 0.50 0.59 1.77 1.18 0.32 0.11 0.22 0.02 0.06 0.04 1.00 0.48 0.74 11.70 14.85 13.28 15.48 9.66 12.57 0.42 0.49 0.45 0.48 0.42 0.45 0.627 0.902 0.765 0.772 0.814 0.793 0.22 a 0.30 8 0.26 8 0.24 7 0.35 7 0.30 7 1.22 2.06 2.21 1.25 0.06 0.08 0.08 0.05 80.55 79.73 86.20 78.44 3.75 3.19 3.25 3.08 1.45 1.82 1.14 1.70 0.67 0.73 0.43 0.67 15.73 tS.17 15.08 14.97 0.73 0.73 0.57 0.59 0.54 0.62 0.15 0.06 0.03 0.03 0.57 0.31 11.13 12.33 15.20 11.45 0.52 0.49 0.57 0.45 0.805 0.37 a 0.8248 0.338 7 0.709 0.668 0.27 7 0.26 8 Group man relative organ weights shown in this table were calculated by averaging the individually calculated relative organ weights. a - Weight of thyrolds only. 4 0 ti x ts 00 110 I "0" oo n ti cr n ry kA 49@ W n M Ir,. 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