Document JMEBLvd7JmyO1Jv7KYJJeJ8Z

InternatioRneaslearcahndDevelopineCnotrporation SPONSOR: COMPOUND: SUBJECT: 3M Company FluoradS Fluorochemical FC-143 Ninety Day Subacute Rhesus Monkey Toxicity Study. Edwin 1. Goldenchai, Vice Pres.,@"mt and Director oLz/- Research Collaborators: D. C. Jessup, Ph.D., Associate Director of Research R. G. Geil, D.V.M., Vice President and Director of Pathology J. S. Mehring, Ph.D., Director of Large Animal Toxicology 137-090 Date: November 10, 1978 InternatioRneaslearcahndDevelopmenCtorporation TA BL E 0 F C0 N T E N T S (Continued) Table No. 5- 7. Individual Hematological Values . . . . . . . . . . . . . . 8. Means and Significance of Biochemical Values . . . . . . . 9-11. Individual Biochemical Values . . . . . . . . . . . . . . . 12. Means and Significance of Urinalysis Values . . . . . . . . 13-15. Individual Urinalysis Values . . . . . . . . . . . . . . . 16. Summary of Gross Necropsy Observations . . . . . . . . . . 17. Absolute and Relative Organ Weights . . . . . . . . . . . . 18. Microscopic Observations . . . . . . . . . . . . . . . . . Page 18-20 21 22-24 25 26-28 29-30 31-32 33-39 137-090 InternatioRneaslearcahndDevelopineCnotrporation Page 1 SYNOPSIS In a ninety day oral study in rhesus monkeys, FluoradID Fluorochemical FC-143 was administered at dosage levels of 0 (control, treated only with 0.5% Methocels), 3, 10, 30 and 100 mg/kg/day. Two male and two female monkeys were initiated at each dosage level and also in a control group. The monkeys were observed twice daily for general physical appearance and behavior and pharmacotoxic signs. Body weights were recorded weekly. Hematological, biochemical and urinalysis studies were conducted once in the control period, at the end of the first and third months of study. The monkeys treated with the higher dose, (100 mg/kg/day) all died during weeks 2 through 5 of the study. At the 30 mg/kg/day dosage level, three monkeys died--duringweeks 7-12. They all showed signs of toxicity in the gastrointestinal tract (anorexia, emesis, sometimes brown in color, black stools), pale face and gums, swollen face and eyes, slight to severe decreased activity and prostration. The monkeys of the 30 and 100 mg/kg/day dosage level showed body weight losses from the first week of the study. Because of the early deaths of the monkeys at the 100 mg/kg/day dosage level, the clinical laboratory tests were not conducted. The monkeys at the 30 mg/kg/day dosage level showed, in the first month of the study, slight increase in prothrombin time and in activated partial thromboplastin time (A.F.T.T.) values, as well as decreased alkaline phosphatase activity in the serum (statistically significant). Only one monkey from this dosage level in this period showed a low albumin value. At the end of the study, the only remaining monkey from the 30 mg/kg/day dosage level showed apparent anemia, low blood glucose, alkaline phosphatase, total protein and albumin values. There was no mortality at the 10 mg/kg/day dosage level. One monkey had black stool on several days in week 12 and occasionally 137-090 InternatioRneaslearcahndDevelopineCnotrporation Page 2 anorexia and one monkey exhibited pale face and gums. At this dosage level there was a very slight increase in the activated P.T.T. values in the female monkeys during the first month of the study (not statistically significant). There were no changes in the other indices and no changes in the body weight. In single monkeys from the 3 and 10 mg/kg/day dosage levels, there were trends toward decreased alkaline phosphatase in the serum. In the control and the 3 mg/kg/day dosage level there was no mortality, no changes in the body weights and no signs of toxicity. Soft stool, diarrhea or emesis were observed occasionally. The mortality and the above mentioned signs of toxicity in the 30 and 100 mg/kg/day dosage levels were compound-related. There was a trend toward the same signs of toxicity in single monkeys at the 10 mg/kg/day dosage level. The 3 mg/kg/day dosage level seems to be free of signs of toxicity. There is an evident relationship between the administered doses and the degree of the toxicity. No gross or microscopic lesions which were considered compoundrelated were seen in tissues other than the adrenals, bone marrow, spleen and lymph nodes for male and female monkeys at the 30 and 100 mg/kg/day dosage levels. Microscopically, the adrenals from male and female monkeys at the 30 and 100 mglkg/day dosage levels had compoundrelated marked diffuse lipid depletion; the bone marrow from male and female monkeys at the 30 and 100 mg/kg/day dosage levels had compoundrelated slight to moderate hypocellularity; the spleen and lymph nodes from male and female monkeys at the 30 and 100 mgfkg/day dosage levels had compound related moderate atrophy of lymphoid follicles. Statistically significant variations in sex group mean weights of a few organs occurred between the control and experimental groups. These variations were of unknown biological significance and were not accompanied by morphologic alterations. 137-090 InternatioRneaslearcahndDevelopmenCtorporation Page 3 COMPOUND The compound was received from 3M Company, Saint Paul, Minnesota on October 24, 1977 as shown below: Label Fluorad(D Fluorochemical FC-143 3M Stock No. 98-0211-0008-0 Lot 340 Description white powder 137-090 InternatioRneaslearchandDevelopineCnotrporation Page 4 CLINICAL STUDIES A. METHODS: 1. General Procedure: Ten male rhesus monkeys (weighing from 2.60 to 3.90 kilograms) and 10 females (weighing from 2.95 to 3.80 kilograms) were initiated on this study. The monkeys were purchased from Primate Imports Corporation, Port Washington, N. Y. 11050. The monkeys were housed individually in hanging wire mesh, "squeeze type" cages and maintained in a temperature, humidity and light controlled enviroment. Purinae) 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, the monkeys were tattooed on the inner surface of the thigh and intrapalpebral tuberculin tests were conducted. Tuberculin tests were conducted at bimonthly inter- vals during the treatment period. Also a complete physical examina- tion was conducted by the staff veterinarian prior to initiation of compound administration. Only monkeys in good health were selected for the study. This study was initiated on January 11, 1978. Terminal sacri- fices were conducted on April 12, 1978. 2. Compound Administration: At the end of the conditioning period the monkeys were divided into five groups on a random basis, so that the initial average body weights were similar: Number of Monkeys Male Female Dosage Level 2 2 2 2 2 2 2 2 2 2 Control 3 mg/kg/day 10 mg/kg/day 30 mg/kg/day 100 mg/kg/day 137-090 InternatioRneaslearcahndDevelopmenCtorporation Page 5 The test compound, suspended in 0.5% Methocels, was administered by gavage, 7 days each week. All doses were given in a constant volume. Also the same volume of 0.5% Methocels was given to the vehicle control group. Individual daily doses were based upon the body weights obtained weekly. 3. Observations: The monkeys were observed twice daily for general physical appearance and behavior and pharmacotoxic signs. Individual body weights were recorded weekly. General physical examinations were conducted in the control period and monthly during the study. 4. Clinical Laboratory Tests: Blood and urine samples were obtained for analysis from all monkeys once during the control period and at 1 and 3 months of study. The monkeys were fasted overnight prior to the collection of blood and urine samples. a. Hematology: Hematological studies included: hemoglobinl, hematocrit2, erythrocyte count3, tota,3 and differential leucocyte counts, reticulocyte count4, platelet count5, prothrombin time6, activated partial thromboplastin time7 (A.P.T.T.). Mean corpuscular hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin concentration were calculated. b. Biochemistry: Biochemical studies included: fasting blood glucose8, blood urea nitrogen8, serum alkaline phosphatase8, serum glutamic oxalacetic and pyruvic transaminase activities8, cholester9o,l9l total protein9 , albumin8, sodiumio, potassiumio, chloride inorganic phosphate9, Y-glutamyl transpeptidasell (y-G.T.P.) and creatinine phosphokinase9. 137-090 InternatioRneaslearchandDevelopineCnotrporation Page 6 c. Urinalysis: Urinalysis included: measurement of volume, pH12 and specific gravity; description of color and appearance; qualitative tests for proteinl2, glucosel2, ketonesl2, occult bloodl2 and microscopic examination of the sediment. d. StatisticalAnalysis: Analysis of body weights and clinical laboratory tests were performed. All statistical analyses compared the treatment groups with the control croup, by sex. The tests were compared by analysis of variance (one-way classification)Bartlett's test for homogeneity and the appropriate t-test (for equal or unequal variances) as described by Steel and Torriel3 using Dunnett'sl4 multiple comparison tables to judge significance of differences. B. RESULTS: 1. General Behavior, Appearance and Survival: There was no mortality in monkeys at 0, 3 and 10 mg/kg/day dosage levels. The monkeys from the control and 3 mg/kg/day dosage levels did not show any unusual behavior or signs of toxicity. Soft stool or moderate to marked diarrhea were noted occasionally. was also noted occasionally. Frothy emesis At the 10 mg/kg/day dosage level the monkeys did not show any unusual signs of toxicity, except Monkey 7363. In week 7 its face appeared swollen and pale. It had been occasionally anorexic in week 4 and black stools appeared for several days in week 12 of the study. At the 30 mg/kg/day dosage level, three monkeys died during weeks 7, 12 and 13 of the study. From week 4, the monkeys were anorexic. Slight to moderate and sometimes severe decreased activity was noted occasionally to frequently for the four monkeys. Emesis and ataxia were very rarely noted, for one monkey. 137-090 InternatioRneaslearchandDevelopineCnotrporation Page 7 Swollen face, eyes and vulva, as well as pallor of the face and gums were noted. From week 6, for two monkeys, black stools were noted. Monkey 7387 showed slight to moderate dehydration and ptosis of the eyelids. All monkeys from the 100 mg/kg/day dosage level died during weeks 2 through 5 of study. They showed the same symptoms of toxicity as the previous group, but they appeared sooner in the study (from week 1) and were more marked: anorexia, frothy emesis (sometimes brown in color) pale face and gums, swollen face and eyes, decreased activity from slight to severe, prostration and body trembling. 2. Body Weights (Tables 1-3): Changes in bodyweight were similar for monkeys from the control and the 3 and 10 mg/kg/day dosage levels. Monkeys at the 30 and 100 mg/kg/day dosage levels lost body weight after the first week of study. There was statistically significant decreases in the body weight for the male monkeys at the 30 mg/kg/day dosage level in week 13 of the study. The female monkeys of the same dosage level and the monkeys from the 100 mg/kg/day dosage level were dead in this period. 3. Laboratory Test (Tables 4-15): a. Hematol-ozv: There were no noteworthy changes in monkeys from the 3 and 10 mg/kg/day dosage levels. In the first month of the study there was a slight increase (not statistically significant) of the A.P.T.T. values in the females at the 10 mg/kg/day dosage level and a statisti- cally significant increase of the A.P.T.T. and prothrombin time values in monkeys at the 30 mg/kg/day dosage level. In the third month of the study there was a high increase in the above mentioned indices for the one surviving monkey from the 30 mg/kg/day dosage level. monkey (#7455) had pronounced anemia as well. The same 137-090 InternatioRneaslearcahndDevelopineCnotrporation Page 8 The statistically significant increase in the hematocrit in monkeys at the 10 mg/kg/day dosage level and in the platelet count in monkeys at the 3 mg/kg/day dosage level at 3 months of study, were within the normal physiological limits. b. Biochemistry: There were no noteworthy changes in monkeys from the control, 3 and 10 mg/kg/day dosage level. Only one monkey from the 3 mg/kg/day dosage level and one monkey from the 10 mg/kg/day dosage level showed trends toward decreases of alkaline phosphatase (432 and 474 units/l, respectively),without statistical significance. In the first month of the study, decrease in serum alkaline phosphatase was noted in monkeys at the 30 mg/kg/day dosage level (statistically significant) and in one monkey in the same dosage level, the albumin in the serum was lower (3.22 g/100ml). The one surviving monkey (7455) from the 30 mg/kg/day dosage level showed decreasing of: blood sugar (66 mg/100ml), total protein (5.52 g/100ml) with albumin (2 g/100ml) and alkaline phosphatase (360 units/1) and slightly elevated cholesterol (240 mg/100ml). c. Urinalysis: No changes considered to be related to compound were seen in the urinalysis studies. 137-090 InternatioRneaslearcahndDevelopmenCtorporation Page 9 IV. PATHOLOGICAL STUDIES A. METHODS: 1. Gross Pathology: After completion of the compound administration period all surviving monkeys were anesthetized with Sernylan5*, 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 monkeys in the control and treatment groups. The following tissues were examined: adrenals aorta bone brain esophagus eyes gallbladder heart (with coronary vessels) duodenum ileum jejunum cecum colon rectum kidneys liver lung skin mesenteric lymph node retropharyngeal lymph node mammary gland nerve (with muscle) spleen pancreas prostate/uterus rib junction (bone marrow) salivary gland lumbar spinal cord pituitary stomach testes/ovaries thyroid parathyroid thymus trachea tonsil tongue urinary bladder vagina tattoo and any other tissue(s)with lesions *Phencyclidine HC1 - Bio-Ceutic Laboratories, Inc., St. Joseph, Missouri. 137-090 InternatioRneaslearcahndDevelopmenCtorporation B. RESULTS: Page 10 1. Gross Pathology (Table 16) and Organ Weights (Table 17): No gross lesions considered compound related were seen in male and female rhesus monkeys which died on study or were sacrificed after 90 days of study. Statistically significant variations in sex group mean weights of few organs occurred between the control and experimental groups. The following statistically significant organ weight variations occurred: Orga:n Dosage s Level e mg/kg/day x Heart 10 F Brain 10 F Pituitary 3 m Weight absolute,relative absolute relative Change decrease,decrease decrease increase P< 0.05,0.01 0.01 0.05 The biological significance of these variations is unknown. These organ weight variations were not accompanied by morphologic changes which were considered compound related. 2. Histopathology (Table 18): One male and two female rhesus monkeys at the 30 mg/kg/day dosage level and all male and female rhesus monkeys at the 100 mg/kg/day dosage level had marked diffuse lipid depletion in the adrenals. All male and female rhesus monkeys at the 30 and 100 mg/kg/day dosage levels had slight to moderate hypocellularity of the bone marrow. All male and female rhesus monkeys at the 30 and 100 mg/kg/day dosage levels had moderate atrophy of lymphoi-dfollicles in the spleen. one female at the 30 mg/kg/day dosage level and all male and female rhesus monkeys at the 100 mg/kg/day dosage level had moderate atrophy of the lymphoid follicles in the lymph nodes. No microscopic changes considered compound related were seen in the adrenals, bone marrow, spleen and lymph nodes of male and female rhesus monkeys at the 3 and 10 mg/kg/day dosage levels. No microscopic 137-090 InternatioRneaslearcahnd DevelopmenCtorporation Page 11 lesions in tissues other than the adrenals, bone marrow, spleen and lymph nodes at the 30 and 100 mg/kg/day dosage levels were considered compound-related. 137-090 InternatioRneaslearcahnd DevelopmenCtorporation Page 12 Reference 1. Coulter Hemoglobinometer. Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 2. Microhematocrit, John B. Miale, 3rd Ed., 1967, The C. V. '.4osby Company, p. 1154. 3. Coulter Particle Size Counter, Model ZBI Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 4. Gradwhol's Clinical Laboratory Methods and Diagnosis, Frankel and Reitman, Editors 6th Ed., 1963, The C. V. Mosby Company, p. 1132. 5. Coulter Particle Size Counter, Model A, Coulter Electronics, 590 W. 20th Steet, Hialeah, Florida. 6. General Diagnostics - Warner Chilcott Laboratories Revised April 1965. 7. General Diagnostics - Warner Chilcott Laboratories Revised Janurary 1967. 8. Technicon Auto Analyzer 6/60 Micro Methodology. 9. Micro Auto Analyzer 11, 6/60 Micro Methodology. 10. Atomic Absorption IL, Model 353 11. Sigma GGTP Procedure Bulletin #545. Sigma Chem. Co., St. Louis, Mo. 12. Bililabstix (Ames Reagent Strips). 13. Steel, R. G. D. and Torrie, J. H. (1960), Principles and Procedures of Statistics, McGraw-Hill, New York, N. Y. 14. Dunnett, C. W., New Tables for Multiple Comparisons With a Control, Biometrics, 'L4cGraw-Hill,New York, N. Y. 137-090 FC-143: TABLE 1. Sex m F Group I (Control) 3.78 3.55 Ninety Day Subacute RtiesusMonkey Toxicity Study. Mean Body Weiglits of Monkeys Week 13 of Study. Group 11 (3 mg/kg/day) 3.50 3.68 Group III (10 mg/kg/day) 3.68 3.78 Group IV (30 mg/kg/day) 2.30* dead 137-090 *Statistical significance. FC-143: TABLE 2. Group, Monkey Number Sex Control: 7362 m 7365 m 7336 F 7386 F Mean 3 mg/kg/day; 7364 m 7366 m 7384 F 7385 F Mean 10 mg/kg/day: 7363 m 7458 m 7328 F 7383 F Mean Control I 3.15 3.50 3.05 3.90 3.40 3.30 3.50 3.20 3.70 3.43 3.70 2.60 3.55 3.50 3.34 3.90 2.60 3.60 3.55 3.41 3.55 3.10 3.30 3.60 3.39 3.70 3.10 3.30 3.60 3.43 Ninety Day Subacute Rliesus Monkey Toxicity Study. Individual Body Weights, Kilograms. Week of Study 1 2 3 4 5 6 7 8 9 10 3.15 3.50 3.25 3.70 3.40 3.30 3.50 3.25 3.65 3.43 3.35 3.50 3.35 3.55 3.44 3.10 3.40 3.15 3.45 3.28 3.20 3.55 3.00 3.40 3.29 3.20 3.60 3.15 3.55 3.38 3.00 3.60 3.20 3.40 3.30 3.15 3.80 3.30 3.40 3.41 3.20 3.75 3.45 3.55 3.49 3.05 3.75 3.30 3.40 3.38 3.85 2.70 3.70 3.45 3.43 3.95 2.60 3.80 3.45 3.45 3.85 2.65 3.80 3.45 3.44 3.85 2.65 3.80 3.45 3.44 3.80 2.70 3.70 3.40 3.40 3.80 2.70 3.70 3.40 3.40 3.85 2.50 3.60 3.50 3.36 4.10 2.70 3.55 3.55 3.48 4.10 2.70 3.80 3.60 3.55 4.05 2.45 3.55 3.40 3.36 3.70 3.25 3.45 3.50 3.48 3.65 3.20 3.40 3.80 3.51 3.65 3.10 3.40 3.60 3.44 3.65 3.05 3.30 3.55 3.39 3.65 2.95 3.20 3.50 3.33 3.60 3.20 3.30 3.60 3.43 3.60 3.00 3.25 3.60 3.36 3.70 3.15 3.45 3.65 3.49 3.65 3.10 3.60 3.80 3.54 3.75 3.10 3.50 3.65 3.50 137-090 FC- 14 3: TABLE 2. Cont. Ninety Day Subacute Rtiesus Monkey Toxicity Study. Individual Body Weiglits, Kilograms. Group, Monkey Control Week of Study Number Sex 1 2 1 2 3 4 5 6 7 8 9 10 30 mg/kg/day: 7367 m 7455 m 7382 F 7387 F Mean 100 mg/kg/day: 7361 m 7456 m 7335 F 7381 F Mean 3.40 3.50 3.25 3.70 3.46 3.50 3.10 2.80 3.85 3.31 3.40 3.30 3.30 3.75 3.44 3.85 3.10 2.95 3.80 3.43 3.25 3.20 3.20 3.50 3.29 3.50 2.60 2.70 3.55 3.09 3.25 3.05 3.20 3.55 3.26 3.10 2.85 3.05 3.50 3.13 2.95 2.65 3.00 3.45 3.01 2.65 2.45 2.85 3.10 2.76 2.30 2.50 2.80 2.95 2.64 3.30 2.70* 2.45 3.20 2.98 3.00 Died 2.05* 2.80 2.90 2.55 Died 2.60* 2.55 2.40* Died Died 2.10* 2.55 2.80 2.85 2.73 Died 2.60 2.80 2.85 2.75 2.70 2.80 2.70 2.73 2.70 2.80 2.65 2.72 137-090 *Terminal weiglit not included in mean. FC-143: TABLE 3. Study Week Sex 13 m F Ninety Day Subacute Rhesus 14onkey Toxicity Study. T-Test Comparison of Body Weights. Page 16 Control 3.78 3.55 3 mg/kg/day 3.50 3.68 10 mg/kg/day 3.68 3.78 30 mg/kg/day 2.30a 100 mg/kg/day 137-090 *P<0.05 **P<0.01 anot included in statistical analysis due to only one surviv-ing arximal. - Line indicates animals had died prior to week 13. FC-143: TABLE 4. Hematology Ninety Day Subacute Rhesus !Ionkev Toxicitv Study. Means and Significance of Hematological Values. Month of Study Control 3 mg/kg/day 10 mg/kg/day Erythrocytes, 1 106,/cmm 3 Hemoglobin, 1 g/100 ml 3 Hematocrit, 1 T, 1. 3 Platelets, 1 103/cmm 3 Reticulocytes, 1 % 3 Prothrombin 1 Time, sec 3 Activated 1 P.T.T., sec 3 LeucScytest 1 10 /cmm 3 Neutrophils, 1 % 3 Lympriocytes, 1 % 3 Eosinophils, 1 % 3 Monocytes, 1 % 3 Basophils, 1 % 3 mcv, 1 .13 3 MCH, 1 lilig 3 MCHC, 1 g/100 ml 3 4.46 4.90 11.7 12.9 38 37 253 210 0.2 o.3 12 11 28 26 9.49 9.40 24 16 75 80 1 3 0 1 0 0 86 75 27 26 31 36 4.26 4.74 1'L.4 12.7 37 37 233 285* 0.5 0.2 12 11 28 26 9.78 9.83 19 19 76 76 5* 3 0 2 0 0 86 78 27 27 31 35 4.71 5.47 12.1 13.3 39 40** 210 216 0.5 0.2 13 11 31 24 9.93 11.96 26 25 72 67 2 6 0 2 0 0 82 73 26 24 32 34 Page 17 30 mg/kg/day 4.53 3.84a 11.7 9.7a 36 30' 219 26,a 0.2 0.2a 15** 30 a 35** 65a 8.44 10.14 a 15 36a 85 54 a 0 3a 0 7a 0 oa 80 78a 26 25a 32* 32a 137-090 *Significantly different from control group, p<0.05. **Significantly different from control group, p<0.01. avalue not used in statistical analysis due to only one animal surviving. (:r4)III,, t%liikt@@v Nitmij.,r Si,x I-ryIllro- 11,-Ill. 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I I'l 7'116 r 5.77 12.8 I,) 226 (1.6 14 7196 1. 4.21) 11.1 If, 227 ().5 14 Plt-.iil 4.82 12.2 III 245 0.4 14 7'164 ti 4 . 11.5 11 7 l(ifi @l 4 .toK 12.0 17 7384 v 4.55 11.7 'IR 7185 1.- to. 11) 11.4 3 r) Heiiii 4./#3 11.7 37 .10.-nig@kUl.t!i!y 7363 m 5.24 13.7 42 745)1 m 5.29 I'l@2 732R p 5.32 12,5 738) p 5.04 1').5 42 Plegin 5.22 1 4f) 1!! !@,Hl@._V/..(aIy -. 7367 ti 4.98 12.4 38 7to5S 5.16 11.6 40 7382 F 4.8/1 12.14 38 73117 v 4.61 12.2 11It Pleiiii 11.91 12.8 ]a 1-1.)0 a.l&l@k6/.(-Liy: 7161 Pi 4.75 12.4 36 74')6 m 5. )(I 13.4 I,@) 7331 I,- S. /#(I 12.R 411 7381 F 4.82 11.5 '1(% 155 0.4 1 '1 297 0.1 It, 160 4).2 11 145 (1.6 13 232 0.4 1] 26/1 0.4 13 261 0.2 11 11)2 1).R 13 12(l 0.4 1 '1 21() ().5 11 143 0.2 12 I)) ().S 12 157 0.6 11 113 (1.6 1/4 1'17 ().5 11 282 12 196 11.2 11 185 14 11 r) 14 A.-I lviiif,,l .'I'.11'. St.(, fii-fil 1101@lif 1!1 ;-I I 1-!t @".-1'.. - !;.-1, 7. l.yolli,lito 1*v I 1-', 1 III,JillI I !I@l y -t; 29 1(1.()(D '1(1 1 i(i It.s74) 27 (1 29 7.86 Ift (1 21 12.(19 )(1 27 11.43 40 0 25 8.98 42 0 -19 7 .'),) III 3t) 14.72 '11 It @'4 8.16 jo 27 9.81 38 31 17.q7 46 (1 29 17 .311 16* 0 31 7.89 31) 1) 28 8.22 47 36 11.61 3(V 28 lfi.84 41 4) 24 8.65 21 (1 26 5.83 26 (1 27 r).10 29 26 7.61 29 27 l(i.77 iti 11 78 r),fit, 19 -PII 12 .fi ;s @oIt 141.rl(, 54 41 62 72 519 19 58 57 59 64 59 60 49 78 65 48 ()0 57 76 71 f)g 6n 67 64) r.I 44 1 1 It 1 (1 1 1 2 0 1 1) 1) 5 4) 1 (1 2 0 1) 4 1 4 11 2 1 1 (1 1 2 2 1 .1 0 1) 1 r) 11 1 11 it. --- - ------------- i.al li,iv,- filiiety1);Iy RIII-sttiiq.@ilksl-,yoxit-ity',tol.ly. th)iiki-y t1-.4 gl4IIIIit 8/1(10 in[ (.11 t ('otitrip 7362 it 14.80 11 .9 18 736') n 4.71 11 .4 11) 7'116 1, 4 .2f) 11 .2 17 7386 1" 4 . I '1 11.9 38 tie;ill 4.46 11 . 7 38 jf,/j ti 4 .I 11 .6 17 7)60 @l '1.96 11).7 '15 73811 1? 4 lo6 11.9 311 7385 1. 11.25 11.2 3r) Fleall 4.26 11.4 17 _!O _Mg tk IS@,@ay : 7363 ft 4.42 12.3 38 7458, it 4.81 11.3 '17 7328 p 4.70 12.1) 39 7183 1. /1.92 12.8 4(1 4.71 12.1 .19 7167 Ff 4.59 11.2 jfi 7455 it 4.44 11.8 '17 7362 1., 4.51 11.9 '15 7,t87 F 4 . 5(@ 12.0 17 Hc;tn 4.53 11.7 3(i -LOq -!!Is k-s 7361 @l 7456 @l : Died, week 5 Died, week 2 71'15 71BI F Illeti, week 3 1. lite(l, week to Ia it!Iet.-; 10 /emm Rt,tit,itIocy t..H 224 ().2 12 349 0.2 12 246 0.2 11 11)1 1).1 12 25 ().2 12 2(14 0.,) 11 188 0.4 12 214 0.2 13 247 0.9 12 233 ().5 12 168 1.0 13 281 (1.3 13 181 13 209 0.1 12 21() Ots 13 ['15 1 13 237 0.2 It, 268 ().1 15 237 0.2 16 219 0.2 15 A,-t Ivi It-tt (-Ntt.q N,4'11_rtillill-1I4 Z z I.Villl)lkoc y I (..q;, z Ill(,1,1111.4 z tl,.Il 1-yr 10 6.91 2R (1 69 28 114.58 1 1 0 84 28 7.46 11 41 89 27 8.99 42 58 2R 1).49 24 15 27 6.81 17 8() 28 r,.83 16 78 20 17.()7 22 1 71 29 9.41 18 73 28 9.78 19 76 27 8.08 42 57 31 17.98 11 87 11 7.(Il .1 1) 63 I'l 6.64 to (1 79 11 li.91 2(1 (1 72 34 7.92 12 88 .1.1 11.11 -17 73 31) 6.19 9 90 38 8.910 11 87 31) 8.1110 15 as 1 1 1 6 1 1 il (I 5 1 1 2 3 2 0 1 1) (I I'll(! till M(!;Ills liovi- 1(1117. tjI IIIt v 1);V) t,111)11141,e )(I11.!;11.9tis.tieky '1'x4I)t-Ity ii(vI ti,itik--v Niotitl,,,jSt-x 1:r y I Iti-(i- 114-iisocy t(--4 1,lk)lIlit 10 '/i-niiigi/111(li"l I)t-r t zI tsitlivl,i%l;il V;11%li.H ltt-1I1-11- 1'r4-flirt,iiAiti-I,iIvi;iit i-ii in(, 0 /t-mfn z 0 lit'llill@. Nt!tit 11 .4 Z 7 I:t,iIo r@)I 7 lf)2 ti 7 1(,5 N 9() 12 .t) '17 ")() 1 1. 1 17 7 110 1.- 72 12.10 7 IM(t 4.61) 12.8 10 fl4@;lli 11.411) 12.ti 17 217 0.2 11 218 11) 170 0.4 11 234 (1.3 11 21(1 1 11 12 7.87 20 (1 2% 1 @..file l(i 11 25 8. toI 1(1 20 8.51 18 1 2(t 9./,() If) (1 I.Villillitt- 1,111 1q" z -------- z -- olit-, I-y @-!4 74 8 r) 1 7(1 4 1 B(i I 81) 1 7164 ti .86 12.9 17 2119 1 11 7*Ififj ti .46 12.11 218 0.2 11 738to F /4.()2 13.41 19 313 0.2 11 1 la @) I.- to.71 1.1(.) 31 248 0.2 11 fli@iiii Is.7/I 12.7 11 285 0.2 11 @O mg/kG,@1.)v: 7363 ti 5.()4 IJ.6 /if) 214 4).2 11 74')R ti 5.711 12.6 40 ZIR (I.I t1 7128 v 5.47 1 1.4 /1(1 219 (1.1 11 1181 1.@ 5.65 13.5 19 212 (), I 11 5.47 13.') 40 216 0.2 11 Iq _!@S@k,&/,Iay: 7367 ti I)Ictl, week I 745r, ft 3.84,1-h 9.7 1($ 261 0.2 111 7382 F 1)[(-41, week 11 138/ F week 12 tl(.ilil 3.84 9.7 3() 261 0.2 30 24 7 . J 1 24 0 11 20 5.4/1 25 (1 74 28 18.21 16 76 24 8.15 10 0 82 2 fi 9.83 19 76 24 04.41 '14 60 2.1 2(1.18 4 (1 q4 2'1 l(lI.'! II (1 51 27 8.52 30 (1 64 24 11.1)6 25 67 6.1) 10.14 @6 0 51, 65 lo.14 16 0 54 1 41 5 1 r) I 12 2 2 11 1t r, 5 1 3 7 1 7 7361 ti 7ti5fi m 7135 F 1181 p I)it!twle.ek 5 1)1t-ii,wf!*,k2 I)Ied. week 3 1)1 e4l. week to 137-0(10 c 2 Noit-l(-.Iieil FC-143: TABLE Biochemistry Page 21 Ninety Day Subacute Rhesus Monkey Toxicity Study. Means and Significance of Biochemical Values. L%Ionth uf Study Control 3 mg/kg/day 10 mg/kg/day 30 mg/kg/day Glucose, 1 mg/100 ml 3 B.U.N., 1 mg/100 mi 3 Alk. Phos., 1 int'l 3 units,ll S.G.O.T., 1 int'l 3 units/1 b S.G.P.T. 1 c int'l 3 units/1 Cholesterol, 1 mq,lloo ml 3 Total Protein, 1 g/100 ml 3 Albumin, 1 g/l,)O ml 3 Sodium, 1 meq/liter 3 Potassium, 1 meq/liter 3 Chloride, 1 meq/liter 3 y-G.T.P., 1 Sigma 3 units/ml C.P.K., 1 Sigma 3 units/ml Inorganic 1 Phosphate, 3 mg/100 ml 89 81 23.0 27.6 597 851 29 45 15 31 165 165 7.94 8.214.78 4.82 153 151 5.1 5.5 112 113 61 44 9 7 7.9 6.9 117* 96 21.2 20.2 847 783 35 41 21 31 154 141 8.23 8.24 5.05 5.12 152 154 5.1 5.6 110 112 49 38 14 6 7.2 6.3 104 88 22.5 22.0 601 743 34 35 34* 34 158 154 8.66 8.43 4.66 5.17 155 159** 5.2 6.0 113 114 47 51 16 9 7.0 7.3 122 66a 26.1 22.6a 365* 360a 59** 8ga 44 46a 174 240a 8.36 5.52a 4.28 2.ooa 152 150a 5.7 5.ga 112 113a 33 49a jg* loa 6.7 5.oa 137-090 *Significantly different from control group, p<0.05. **Significantly different from control group, p<0.01. avalue not used in statistical analysis due to only one animal surviving. bj.U./I c Sigma units/ml Ft.'1-4 3: Nlncty 1).,iSytil);it-titleiliestisMi)iikey 't'isKiciLy Stal,ly. TABI.E 9. liiilivi(ltBei;tiilt-lienitVcailtites- Control 1. t',roiip, Flt)iikey Niiiii)erSex Citicone ing/IUOmi Alk. Plit)s.S.C..O.T. S.C.P.T. H.U.N. iiit'l jiltI' till,I mg/100 oil tinittiI/ tililts/ I tilltia/ I 'Cotill PoLas- terfil Prt)teIit AttiuiitfiiS(iditiisntuiii r ltle Rig/100 mi g/100 oil g/100 oil MLCI/ I UK-(I/ I MC(I/ I Pliosi)ltite ilig/li)lio)ll %I (;titiro I 7362 m 94 7365 H 82 7336 F 79 7386 F 95 Mean 85 3 mg/kg/day: 7364 7366 m itt 71 7384 F 96 1385 F 107 tteall 96 10 mg/ R/dil: 7363 89 7458 100 7328 F 98 7383 F 98 Mean 116 30 mgl@Ilday: 7367 m 108 7455 110 7382 F t32 7387 F 117 Mean 117 100 mjL/t&/day-. 7361 m 7456 m 93 1()() 7335 F 75 738t F 119 Mean 97 41.0 16.7 24.0 21.1) 25.7 19.0 28.7 22.0 22.0 22.9 27.2 24.2 20.0 27.3 24.7 26.9 24.0 27.9 23.8 25.7 29.0 23.0 28.0 22.1 25.5 70U 659 915 961) B29 880 580 570 1320 838 1167 806 776 581 833 970 687 641 978 819 590 799 570 1233 801) 40 61 3() 39 43 42 60 38 60 50 46 63 26 31 /o2 47 37 40 45 42 43 40 40 40 41 99 OiN fill 86 88 94 89 106 76 91 liB 136 75 91 1()5 114 86 79 138 104 81) 104 96 103 96 219 8.68 123 9.50 185 9.52 190 8.52 179 9.06 5.40 4.30 5.30 5.12 5.03 t97 9.08 172 9.t2 133 10.12 154 8.72 164 9.26 5.28 5.80 5.19 4.80 5.27 237 9.64 107 10.08 189 8.48 168 8.32 175 9.18 5.1(1 3.99 5.14 5.25 4.87 150 21)5 176 194 lot 9.38 9.50 11.10 9.44 9.8() 5.60 5.3t 5.72 5.60 5.56 t55 8.6f) 5. Oil 202 9.0() 5.69 151 8.98 124 9.60 5.19 4.89 158 9.1)5 5.11) 16U 5.0 III 6.5 t55 5.3 110 6.7 156 4.3 110 6.5 162 S.0 III 6.5 158 4.9 III 6.6 155 4.3 ]()8 5.0 157 4.9 IU8 7.1 162 6.0 113 6.1 158 5.2 116 5.4 159 5.t ill 5.q 167 6.2 117 6.7 15() 4.9 107 7.7 1,57 4.4 109 6.3 159 5.1 112 6.0 158 5.2 III 6.7 170 6.2 116 6.9 163 5.3 III 6.6 165 5.5 112 6.8 155 3.9 113 5.4 163 5.2 113 6.14 )59 5.9 116 6.9 157 4.5 109 5.7 157 5.2 III 5.6 159 5.2 112 6.7 llfl 5.2 112 6.2 t37-1190 F('-14 3: NitietyI)iiySiiiiijrititlelivfittlioqiikey'I't)xlt:iStyudy. TABI,G 10. litilividuiBjloclieintcaVlalues - I tiontit. Group, Monkey Niipt)erSex C Iuc4ii;e nig/100mt Alk. Pitoo. S.G.O.T. B. li.H. liltI' lntlt mg/il)ooil tonits/i tuilts/i S. C.P.'r. Clioles- Tot a I Ptitas- Iii4)rgaiilt! II)tI, terol Prclteitt Atbtiiniti Siidiiiityiittimrl-l(- Plit)SllillYte iiii[ts/i mg/1(10 in[ g/100 iiii g/100 nit nK-ii/I me(i/ I nie(lI/ ing/lf)iOiiiS Control: 7162 m 87 33.9 611 27 7j65 m 8/1 14.2 626 33 7336 p 87 23.9 672 25 7380 F 96 14.9 4 IV) 31 Mi-ali 89 23.0 597 29 3-in&LkILLd_,y,:_ 18 19 t 7.30 4.82 153 5.4 117 6.6 17 121 8.4t) 14.11 153 5.4 111 8.4 15 1/02 7.9o 11.89 148 4.2 1()9 8.4 10 206 8.15 5.30 158 5.11 112 8.1 15 165 7.94 4.78 153 5. t t]2 7.9 7364 11 7306 m 112 lit 7384 F 105 7385 F 12o Mean 117 y,/kg/tIaX: 18.0 23.) 24.2 19.1 21.2 970 693 539 1185 847 31) 36 171 8.15 5.20 150 4.3 106 6.9 39 19 148 8.05 5.42 154 4.9 110 6.6 30 15 141 8.70 4.85 152 5.8 111 7.5 40 13 153 8.00 4. 72 152 5.2 114 7.8 35 21 154 8.23 5.05 152 5.1 ]to 7.2 7363 ti 98 24.9 552 40 7458 m 97 22.5 732 40 7328 F 98 22.7 640 23 7383 F 124 20.0 /1130 31 tlealo 104 22.5 601 34 lq_.!!&/k&/day: 35 2 t9 9.40 4.62 161 6.3 118 6.9 43 1 Y, 9.05 4.32 151 4.9 to9 8.4 19 145 8.20 4.50 152 4.3 it) 5.4 37 132 8.0() 5.19 1511 5.2 113 7.2 34 158 8.66 4.66 155 5.2 113 7.0 7367 H 112 35.2 376 48 30 181) 6.20 4.70 157 6.0 110 6.6 7455 m 86 21.0 322 61 80 177 8.55 3.22 148 5.2 112 6.9 7382 F 104 25.2 400 83 43 16t 8.15 4.21 149 5.9 111 6.0 7387 F 185 22.8 360 45 23 179 8.55 5.0() 153 5.6 114 7.2 Mean 122 26.1 365 59 44 174 8.36 4.28 152 5.7 112 6.7 100 mg/kg/da : 7361 m Died. week 5 7456 m Died, week 2 7335 F I)it!tl,week 3 7381 F Died, week 4 137-091) Vi:-14 1: Niiiety Day Stil).ictiKtleiestiM-(iiiikeyTtixi(-ItyStil.1y. lii(lividii;BiIl(icliciniciVliitit-.-,;3 @loittltr. Monkey Nufnijer Sex Glite(iae H.U.M. mg/JOO in] mp/100 mt Alk. Plit)s. S. (:.0.'1'. s. (,.P..,r. (:Ili1)4@-i- 'rotiiI lnt'i istitto/i liltI' f,Il@ni;i terol 11rot e In AII)tjniiiiSt)tlliiesnluin ri,it- I'liotii)elial tifilts/i utitts/iiiinig/100 nit g/100 nit g/100 mi ni(@(1t/ nic(lI/ me(l/I mg/11)0 in[ S, C,)nt rol 7362 m 95 7365 m 77 7336 F 67 7386 F 86 Mean at 3 mt@kS,@,Lny: 41.9 17.4 33.1 18.1 27.6 7364 ti 7366 7384 F 7385 F Mean 10 -n&/kl/dU: 106 III 94 74 96 17.1 18.1 23.4 22.0 20.2 7363 m 7458 m 7328 F 7383 F tienn 30 _!ng.IkLLIly: 87 88 75 1()() 86 24.9 21.1 21.8 20.0 22.0 7367 m 7455 m Died, week 7 66 22.6 7382 F 7387 p Died, week 13 Died. week 12 mean 66 22.6 1()0mg/kg/tiay: 7361 H 7456 m Died, week 5 Died, week 2 7335 r Died, week 3 7381 F t)fed,week 4 604 744 766 1068 851 1092 594 432 tol 4 783 936 936 624 474 743 360 360 55 411 197 7.59 /1.99 150 5.5 114 5.6 47 3() 135 9.18 4.40 15t 6.1 113 8.1) 39 2to 39 27 150 8.31 177 7. 76 4.98 4.90 151 5.1 114 7. 3 153 5.1 [()9 1).1 45 31 165 8.21 4.82 151 5.5 III 6.9 41 28 39 33 39 31 43 29 41 164 7. 72 126 8.09 t 32 8.93 142 8.21 141 8.24 5.09 5.52 4.91 4.97 5.12 153 5.8 112 151 5.5 11)9 153 5.2 ltz 155 6.() 114 154 5.6 112 7.0 5.3 6.5 6.4 6.) 42 /,Z 38 3t 30 25 30 37 35 34 194 8.44 139 9.71 155 7.93 128 7.62 154 8.43 5.61 4.69 5.27 5.11 5.17 16/1 7.0 119 159 6.2 112 156 4.8 110 159 5.8 113 159 6.0 114 8.() 9.0 5.6 6.5 7.3 88 40 24fl 5.52 2.00 150 5.9 113 5.0 88 46 240 5.52 2.0() 150 5.9 113 5.0 137-090 FC-1 43: TABLE 12. Urinalysis VOIJIMP, mi pH Specific Gravity Ninety Day Subacute Rhesus Monkey Toxicity Study. Page 25 Month of Study Means and Significance of Urinalysis Values. Control 3 mg/kg/day 10 mg/k",/day 30 mg/kg/day 1 35 3 71 33 51 94 51 1 8.5 8.5 8.1 3 8.3 7.6 8.2 1 1.028 1.026 1.026 3 1.018 1.015 1.024 41 40a 8.1 6.6a 1.026 a 1.031 137-090 'Value not used in statistical analysis due to only one animal surviving. 'RANI.E 13. Grotil), Mooik(!y miledier Sex Niiii@ty1).iyStil@.i(-iHiittee-iiiKqtiikey'roxicity Sttitly. Vo Itime in( liitlivititUir;liit;iiy-iVl;siltie.46)titi-o1l. (:olor .111(i sl.e4.. Alilicir. lilt Grav. 0(*ciiI L Pr(itelit(;titeoqeBI-)od Kett,iies cy(eh Frytlirc)-1-'Ii. Trililt!(:;il. cytes (:ellfiUrites I'llo!;.Oxi I Coiitrot: 7362 m 7365 m 7136 F 7386 F -3 -.&!L!k RI t--.Ix1: 7364 @l 7366 m 7384 F 7385 p "call 10 m lk&tday: 7363 7450 m 71?8 F litil F Mt-aii 30 I%/k&/,tiiy: 7'J67 N 7455 H 7382 F 7397 F He.itis l(p mg/kg/day: 7361 m 7456 N 7335 F 7381 F 10() 28 Z7 70 56 25 25 215 35 75 20 50 35 35 35 20 35 20 48 3t 2t 25 25 40 28 I'S-cj 7.6 1.010 m 1.3-el 7.2 1.1)37 N lls-c 7.0 1.036 N I'S-cl 8.4 t.023 m 1.6 t.027 I'S-ci 7.8 t.032 N I.S-cl 7.2 1.035 N I-S-C 8.3 1.026 N LS-el 8.3 1.020 N 7.9 1.028 I.S-ct 7.7 1.020 N LS-el 7.5 1.036 N LS-cl 7.8 1.036 N LS-cl 8.2 1.02o N 7.8 1.(128 I'S-ct 7.1 1.050 N LS-cl 6.8 1.030 N LS-cl 7.t) 1.055 N I,S-c 1 6.2 1.030 7. *1 1.041 LS-cl 7.6 t.035 N I.S-cl 7.1 1.042 N I.S-t-l 7.2 1.041 N LS-cl 8.1 1.042 N 7.5 1.040 N tr N m 11 ti t-i- N lot N p ()CC 1-3 F 0,:C - occ ()CC (,(.c occ oce ()C(l N tr N N tr N N N N N N N oce F 0(7c F F ()CC F 0(,(. u(IC t)CC oce - "cc F (]CC N tr N N tr N - - oce p F - Oct-' F ()CC F N tr N - - 1-3 F occ 11 N 3t - - oce oce olle - N tr ti - 1-3 1-3 ot@c "cc 4)CC N tr N - 1-3 1-3 .)CC r - N N N - - 1-3 p "cc - of,C F (@CC ($CC N tr ti N tr 3# N tr It N 1+ 1.@ oce - F occ - - occ F occ F 1-3 - Oct! oce - 1-3 ()CC occ 137-090 Code: tr - Trat-e 1+ - Trace to sliglit 2t - Sli@,,Iltt4imoderate 3@ - t$o(it-rnte 44 - @litki-ii S - St r;iw LS - l,igliSttriw I)S - I)-irkStraw I-Am - I.IglitAng),,r IlAtit- I)arkAiog,,-r N - Neg;itIve F - Few 1, M - @lany R - ltire (INS (?tiiltltlilt(y)sLte(ficteitt R(irnool Nt,ile"P(-Il I-*(1:4- 1: 'J'AIII.1E4 molikey Niosoel)rc Sex Vt.IIillil. iiii ct)lt)r ilied Alilicier. 1;11 Niii.!LyI)ilySiliactiteHilestitil,)IlkeTyoxicity Stilily. liidividis;UjrliiialysisValties I @14)iitli. %I)CC. 4)ct:toI I (;uav. t'rt)Lelil(;list'tws0e141@)ti ErytliroKet4illes cytl-ti cytes L'II) (;cIIs Urijteu u r 11)1c (;al A Ploos. I)xaI. Cry 7'J62 to 7365 to 7'136 F 7'186 p ti@,a-ll 55 1.5-C 8.5 1.021 N 31) I's-c 8.5 1.028 N 21) 1,5-(. 8.5 1.1133 N '14) L$-(@ 8.5 1.031) N N N N - N N N - N .11 N - 0 Lr N - 1-3 k)CC ()CC 4)(-,C F h 0 t: f F F oi:c F 7 J64 7161) it 2(1 2(1 I.S-C 8.8 1.(119 N I.S-C 8.5 1.036 N N N N N N - N - 738t, F 4(1 I)S-c1 8.0 1.021 If N 4 1- 2+ - 7')85 v 5() LS-c 1 8.5 1.()27 N N N N - 33 8.5 1.026 oce F ot*c F 11-12 - F - ()CC F m 0,'(' F F oce F oce @l 7 3f)3 @i 65 7458 to :J5 7328 7383 F 55 F 54) tiLall 51 -0)1.!E/kglii!y: 7'3bI ti N) 7455 to 3(1 7182 7187 F 60 F 45 Fk!jli 41 I.S-cl 7.5 1.()23 1.9-C 8.0 1.028 N 1.%-c 1 8.5 1.4)26 N I'S-cl 8.5 1.028 N 8.1 ).t)26 LS-C 7.5 1.024 14 I'S-cl 8.0 1.026 N I.S-c 1 8.3 1.022 N I'S-cj 8.5 1.032 N 9.1 1.026 N N N N - ote - F Dee to N - - occ occ N N N - 1-3 Dec occ N tr N - t)CC ()CC F Dec N N N N N N N N N N li N Dec oce oce - oce oce to F - F otle F F Oct: ()CC 7 )iIt ?I 7456 to 7335 F 7381 v I)IL-J,week 5 I)Ietl.week 2 I)Ietl,week 3 I)Ieti,week 4 137-OI)o (:title: t r - Trace + - Trace to uliglit 2I+ - Slit;ltt ti) 110(jeriite It - tiotit:riiie 44 - M;ei-ke,l S - St raw LS - 1,11;lttStraw I)S - Straw I.Aiii I.IglitAittlfk!r I)Aiii 1);iik A%%A,er Cl,itidy Clear N - Negativc- F - Few 1. - l.i)adeti M ttally R ltitre t@et-;jsl,)iial IINS - QuatitiLy iiot siilfic-Leiit lioril-l ",)rm;il - tl,)tieseetv Fc- 14 3: TABI,E 15. Grd)lop, Monkey Ntiniber Sex Ninety 1),iyStiliicute KlieFitis @li)iikt!1y'(ixi(,ItyStie(ly. Iiidlvi,lioUarliii.,Ilys(Vsaltief; 3 Mqititlis. Vo Itime mi and SI)ec. Al)lvear. lill Crav. Protein Orcillt (;Iticose Blood Ketones l@etico- E ry tItri)- I-'II.) T r11)1e Cal . cytes (*Ytes (:e114 I)rntes Vito-j. 4)xal. Cr Ct)nLro I 7362 7-365 m 7336 F 7386 v Ilean 3 7364 m 7366 m 73Rfo F 7385 v 110 40 05 5(1 71 50 150 125 5(1 94 I.S-C 8.2 1.012 N 1.8-cl 8.1 1.029 N I.S-C 8.2 1.015 N I.S-C 8.8 t.0 16 N 6.3 1.016 LS-C 6.0 1.020 N I.S-C 7.9 1.007 N LS-C 8.1 1.010 N ls-c B.5 1.021 7.6 1.015 N N N N m - 1+ - act F occ 1-3 F I)CC - F - N N tr - N jt N act 0('t@ F F u(IC F F F N N N N tr - N - F oce F occ - oce - N N N - occ F N tr n - ot,c 1-3 m F F F ti 73(@3 7458 pi 40 35 LS-C 8.0 1.027 N LS-el 8.7 1.022 7328 F 50 lls-c 9.0 1.029 N 73R3 F ?A) I'S-cl 7.0 1.019 N Mean 51 8.2 1.024 30_p.r.(ISt/dny_- 7'167 7455 ti Died, week 7 40 S-C 6.6 1.031 N 7382 7387 F Died, week 13 F Died. week 12 MLan 40 fi.6 1.031 100 73(il ti 7456 m [)led,week 5 Died, week 2 7335 lial 11 Died, week 3 F. Died, week 4 N N N N N N N N N - N - p oce oce F oce - N - ()CC occ F act - - (icc ()CC F N It N 1-3 oce F N OC(I 137-090 ck-)Ile: tr - 'Urilue 1+ - to .411glit 21-- Stigiet tt)nNi4lL@riite 34 - thitlt-r;itt- 4f - Markeql I.S Its I.Ain- St r;iw I.It'liStt I;tw 1);ir'Skt riiw 1.1gliL At%A,t-r I)Ani- 1).iikAisil)i!r N - Negative F - Few 1, - loiticti it - ttility It - Riri- I)N% - QiiaiiIiIy iiol stilf Ii@it,itt iii)i--inN(iriitat - N,,Iii- FC- 1-3: -A.BL-r1.6. oay -iubacute ;,hesus monkey Toxicitv Scudy. su.=narv f -,ross @;ecroosv I)bser-,ations. sacr4-@lica. Page 29 moe,@kz, @lav Site Las..,Or. Grozis 7.@:ernE, eve are= alopec4a d e.,ivd:,tea emaciatac red vaz@@nal d4-schar;e scab, zac4-al area Lunit mi"@e adhes'.ons dark red ye'@-lcw, @,;h4-te@aci .Iodu:es purple area ileart nemcrr:;aze, su.oendocardzal gela:@-lli--ed@-at, endocara-ai. atro-?hv ;@@des red&4-sh b'-ac'.i-n color .h-,mus atZC?nV Cav:L:.%, x x x x me,,ke/dav 10 30 '12, kiz!da-.' -'00 -mz da 'Z x x x xx x x '4 xx x x x x x x x xx x x x r-2d @@C4- -.)vlor4-nco-t4-on z-a'at4.-iousmacer4-a'-, ?crtion hemo--:@az,e, mucosa ,,i.lcers Smal- :ntest4.re ;reen4-sn-gray muco4-d material dark :ad/brou-n mucoid =ater4.a'@ --Iocdtinzed fluid 'oro;.*ir..,color ,:inges:4-cn,mucosa '-Ie,.to-,:@-.am2uec,osa -::e :n:,@st4-ne zon-.esz,'on, =uccsa =ucosa @ar@- reQ@-s',iblack oci ;e-.4m-s'z"- b'--oodstained contents x x x x xx x x x x -Died 3n Sc-.:dv FC -l@3: 16. Cont. Ninety Day Subacute Rhesus @!oriey -,Oxicitv Study. Summarv of @@ross Nc@roosv '@bservat4on$. Page 30 Si:e Pancreas 2c:essor@- svi-een 0 me/ke/dav o4 z! 3 me/kz,lda,@* '@O -ae,'k2;@4av 0 =iz, z.'da v 100 --cn k 2,,d a v ---- ---- --- @r=wn4-sh color accentuated lobuations granular surface yellowish aott'-inE .eddish yellow color K,'cne-is @-row-n;-sdhiscolaracion subcutaneous edema, abdomen s@ubcu=aneous hemorrhage, abdomen x x x x x x x x x x *D4@ed an Study F(:-14 3: 'I'Aill.1l7,., Pl-,iitey Ni#iigr,e rifice: 7Ili5 Ik-iiii 73 ih 7186 Plenil 7364 7166 flenit 7)84 7.185 Fle;ili lLq -M /ti.1y: 7361 745R Plea" 7128 7183 tlean .10 7455 Deation: 30 mgLkiL/--I@y: 7367 7182 7387 l(IO mg/kg/day: 7361 7456 7335 7381 137-0110 Ninety I)ilySioliaciiteklte,3,sstionkey romicity Stittly. Al-Fi(pliii(e(',ranitin)itilRelative (I B4)(ly14t.il..Ilt) 'I'ernillifil ;ex itg 9 I-v-re- 9 z 9 x-1-0 1. 2) 1.115 2.35 7.87 ll.(Il 11.20 11).13 79.15 2. 1tl 2.0(1 0.(.5 0.71 ().211 ().18 3.55 5.11 0.14 7/s.94 2. 12 0.68 4).19 1 to4 F :1.40 5.03 0.15 81s.79 2.49 - 3.50 3.87 (1.11 77.77 2.22 0.62 1)- I A 13. Ho 11).58 3.45 4.45 0.13 81.28 2.36 O.f@2;' ()*.Ig, 16.69 1). ti 4.10 4.67 11 91.4(1 2.23 0.77 ().19 Pi 2.65 1.87 0.07 63.17 2.,Ig 0.82 (1.31 IQ. 76 12.40 4). 3.38 3.27 ().09 77.29 2.31 0.8() 0.25 16.4)8 3.70 6.82 0.18 102.64 2. 77 0.78 0.21 p 3.45 2.94 ().09 67.25 1.95 0.5s ().16 1147..40t0o .1.58 4.88 ().13 84.95 2.16 0.67 t9 16.02 (1. m 3.80 2.39 0.()6 87.25 2.30 0.74 1).It) 16. f14 m 3.25 4.91 (1.15 82.30 2.5,1 0.67 ().Zi 16.54 3. 1)1 3.65 ().11 84.78 2.41 0.71 0.20 lh.(19 F 1.55 4.06 0.11 81.()() 2.34 0.66 ().19 15.32 F 1.70 3.99 11 Br,.:15 2.11 ().ftfi 0.21 1.1)(@ 6 3 4.1)1 11 8t,. 10 2. 12 0.76 0.21 0. it 2.40 3.5() 0.15 70.76 2.95 0.94 15 16. 8') 0. ti 2.10 . I5 1.45 0.07 75.33 3.51) 1.63 0.78 16.34 e- 3.()l 1-) 1 12.87 5.(12 1.74 0.77 11).03 ().B F 2.25 1.1)7 ().()9 8). 17 3.79 1. 2(1 ().51 1 m 2.40 1.6r, 11.07 /9.(12 3.29 1.59 ().66 ti 2.70 1.76 0.07 811.()H 3.1') 1./15 0.')4 21.Hfl ().9 r 2.05 2.49 0.12 711.28 1.62 1.03 1/1.77 (1.5 F 2.60 3.05 0.12 92.18 3.18 1.16 (0.)1.1550 1158..4200 0.77 (:r(wtil) in4-;iii relitiviWCI!,IoIF. slic)wii in ti,t@@ tlitit. l@Sigitifl(-,iitLlv tiffft@rt-itt fritnt (:(ttiietil irotil) 114*1;11.,Iilli..@II)tly 1111,-14,111 1141111 (:tllltr(ol I.,Ii@111Wflit-;IlI, III itll;ilyqi.%. w(-ie 1-y iverigitip fill, iii,livi.it F(:-14'1: tlijiiki!y 1'erniiii.Siiit:rlflce: 7'162 7'165 tll-;In 7136 7'111(, F tic,,Iil 7164 716(. F14!;Ill 7]Hlo 7 18') F tk-.Iii l(Iine/_k,p,/diiy: 7163 7458 ?k-ais 73211 F 7')Ri F Me.111 !ntl-kt;/A@!ay: 7455 ti I)eItliii: 30 ing/k-/t!.@y: 7367 7382 F 7387 p 100 ini-/_ko/Ld-il: 7361 ti 7456 Pi 7335 F 7381 F 137-01)0 AI)n4)liite -N1-11L-.0y-')-Y"--S1--1a1-'1-ItI-e -KI is tiwtnk.ey- -'I"xo1-c1-t-y--S t titIv iiiitRit.@IaLive (2 lio(lyW(@iglit)Orgiii Weiglits. Toriniiialc;.icrificenii(iI)eitilq. B4)(IY Wt. licarl itg 1'lri(yI,d/ Pariitliy!l@ti(i I,, z 9 7XIO 9 t 1.05 3.55 3.40 3.50 3.45 4.10 2.65 3.38 3.70 3.45 3.58 1. H() 3.25 3.53 3.55 3.70 .1.63 2.4f) 11.69 18. 17 14.93 15.30 14.75 15.()3 ().36 0.47 0.42 0.45 0.42 0.44 1fl.9() 12.70 15.8() 16.81 15.19 16.f)3 0.46 0.48 0.47 (1.46 0.44 0.45 15.11) 14. 14 t4.62 lt.85 11.69 11.77* (1.4o 0.44 1)./12 0.3) 0.32 0.32** l(I.5(i 0.4ti ].(151) 0.296 0.673 - 0.839 a (1.1119 0.32 0.()Il 0.20 11-.24 24a ().893 0.378 0.636 (1 694 ()*.543 0.619 0.22 1).14 0.18 0.19 0.16 0.17 1.211 0.488 0.85() 0.'#61 ().537 0.499 0.32 0.15 0.23 0.11 0.15 0.14 0.292 0.12 2.10 2.25 2.25 7,40 2.70 2.05 2.6() if).39 11.93 10.21 14.54 15.1)5 11.44 12.95 ().49 0.53 1).45 0.61 ().So 0.56 ().5(1 0.')12 1).543 0.845 0.25 0.24 0.38 (1.791 1).718 0.479 (J.417 0.33 0.27 0.23 0.16 (',rotipmc-aitret;itive t)rp;iiwielglits !ilo(lwiliii tliiq t;ifil(w@t@rt-itIvi orgiin w(,Iplits, Not 4ifff4-rc-ilftr(im (:oiiii-o1l,,rtiooiilv)oii.1) 0.115. ly tliff(-tvisfti4ifil lltq!lllllIeI,Illili;lfyqin. 11 (1.111. 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