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oo . Attachments to Letter to Perfluoroctane C. Auer dated May Sulfonate Studies 4, 2000 ARYG-013 7 Repeated-Dose Toxicity 1) Ninety-Day Subacute Rhesus Monkey Toxicity Study, with Fluorad Fluorochemical Surfactant FC-95, International Research andDevelopment Corporation, Project No. 137-092, December 18, 1978. a) Study Report b) Aborted Study: Ninety-Day Subacute Rhesus Monkey Toxicity Study, with Fluorad Fluorochemical Surfactant FC-95, International Research and Development Corporation, Project No. 137-087, January 2, 1979. 2) Ninety-Day Subacute Rat Toxicity FC-95, International Research and Study, with Fluorad Fluorochemical Surfactant Development Corporation, Project No. 137-085, November, 1978. 3) 104-week Dietary Chronic Study and Carcinogenicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS: T-6295) `Study Number 6329-183. In progress. in Rats, Covance Laboratories Inc. a) Summary Report - Week 53 undated b) d"aLtievderApSrliilde5,Re2v0i0e0w,r"elaMyairngvitnheCraesseulttosoJfoahnnBiuntdeenpheonfdfeanntdhiAsntodpraethwolSoegaiccat review of liver slides from the study. ) Second Draft Cell Proliferation Report, Pathology AssociatesInternational, August 24, 1999. [final interim report, to be incorporated in finalreport] d) Study Report of Determination of Cyanide Insensitive Palmitoyl-CoA oxidation in samples from 3M Environmental Laboratory - Covance Studies 6329-183 and 6329-212, Centre For Xenobiotic Research, University of Dundee, Biomedical Research Center, Study Number XR0108, February 18, 1999. 4) Range-finder: 4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys, Covance Laboratories Inc., Study Number 6329-222 4) UPenrafulduiotreodocDtraanfet SFuilnfaolniRcepAocritd, 4Po-tWaeseskiuCmapSaslutl(ePTFoOxSic;itTy-6S2t9u5d)y iwnitChynomolgus Monkeys, Covance Laboratories Inc., Study Number 6329-222 (draft not complete). 002029 . : Attachments to Letter to C. Auer dated May 4, 2000 Perfluoroctane Sulfonate Studies : b) Cell Proliferation Report, 4-Week Capsule `Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys, Covance Laboratories Inc., Study Number 6329-222 (draft to be. incorporated in final report) ) Protocol ~ Analytical Study, Quantitative Analysis of Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys Following Administration of a 4-Week Capsule Toxicity Study, 3M Environmental Laboratory, AMDT-041598.1 d) Memorandum from Marvin Case, regarding histopathology review of liver tissue in Covance Study 6329-222, July 27, 1998 5) 26-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS: T-6295) in Cynomolgus Monkeys, Covance Laboratories Inc., Study Number 6329-223. In progress. a) Undated report covering the 26-week dosing phase and one year of recovery. b) John Butenhoff, " Dose-Setting Cynomolgus Monkeys," dated Rationale for July 29, 1998 Six-Month Chronic and followup Aug. Oral Study 3, 1998. in ) Fecal Urobilinogen Analysis, Chemistry Group, Test Code: Mayo 8308. Clinic, Porphyrins and Nutritional i) Summary Report from Dr. Joseph P. McConnell, dated March 16, 1999. if) General information from Mayo Clinic, Porphyrins and Nutritional Chemistry Group on Urobilinogen Analysis, dated January 14, 1999. iii) Individual animal urobilinogen lab reports (raw data) from Mayo Clinic, Porphyrins and Nutritional Chemistry Group. d) Pathology Report (Ancillary Study), Electron Microscopic Evaluation of Liver in Cynomolgus Monkeys, Pathology Associates International, Study No. EM99.76, July 13, 1999. ) Pathology Review, Marv Case to Andrew Seacat, dated July 22, 1999 relaying the results ofa histopathology reviewofslides. 002030 Attachments to Letter to Perfluoroctane SCu.lAfouneartedaStteuddiMesay 4, 2000 ) Laboratory Report, Interim Report of Preliminary Data for 26 Week Capsule `Toxicology Study with PFOS in Cynomolgus Monkeys, 3M Environmental Laboratory, Report No. FACT-TOX-030, dated March 29, 1999. Evaluation Laboratory, Riker Laboratories, Inc. Experiment No. 170RR023, 3M 6) Two Week Oral Rangefinding Toxicity Study of T-2509CoC in Rats, Safety Reference no. T-2509.3 (FC-99 New Formula, L-4509, 25 % diethanolamine salt of perfluorooctanesulfonate in water), February 25, 1980. 7) [Submitted under claimofConfidentiality] 5 adler a ras -- Sly 21-4 ! ry Ey a a PFas ogi omidbill | alaacer 002031 International Research and Development Corporation SPONSOR: conpouND: suBJECT: 3M Company Fluorad Fluorocheaical Surfactant FC-95 TNoixniectiyt-yDayStuSduyb.acute Rhesus Monkey VEidcweinPr1.esiGdobJndeentahnadl, Ph.D. Director f Research Collaborators: D.DiC.recJtesosrupo,f PRhe.sDe.a,rchAssociate R. G. and DGeiirle,ctoDr.V.oMf.,PatVhiocleogPyresident J.Las.rgeMeharniinmga,l TPohx.iD.c,oloDgiyrector of Date: December 18, 1978 137-092 002032 International Research and Development Corporation TABLE OF CONTENTS To SYMOPSLS tut i ieee. Page 1 TL ComPOUmd 4 tutu uaa. 3 TIL. Clinfcal SEWdfes + vv vv vv vitae tea... 4 Ac MeERod Lie. 4 1. Gemeral Procedure. . vv vue utii...... 2. Compound AdmANi+S+ +trvaut.iuuoun.... 4 3. OBSEIVAELONS + uuu aii... 5 4. Clinical Laboratory Tests. + + vow vou. . 5 ab.o HeBmoactheomliosgtyry.....s.t..a.ii...i.i.....i........... cd. StUraitniasltyisciaslAnoalvyosisi.ii........................ 6 Bu Results vv tiiae eae. 6 I. General Behavior, Appearance and Survi.v.a.l... 6 FOJ TY I dcoo S LS mu gg l c/ ovk .ik .g .ug Lil L/ .iLdd i l.a a L.y .yl. l.. 87 2. Body Welghts ovo vei iuuii ae a.. 8 3. Laboratory Tests. a. eu. a.......... 8 ab.. TOhnreeMeoMnotnhthofsotfhtehSetuSdtyud.y.+ + .v..o.u.s.......... 8 9 IV. Pathological Studies + + saat itt i ate. . 10 AcMethods. ov vue, 10 1. Gross Pathologye vv eves ve vv unnue. 10 2. HiSO+P + A vvt sth taO uulao a.g.y. 10 Bu Resultse vot vmmin sie. 1 1. Gross Pathology andOrganWei.g.h.t..s.... II 2. Histo +p +ea vst eihsaoiil tiuoag any a. 1 137-092 002033 International Research and Development Corporation TABLE OF CONTENTS Continued) Table No. Page 1. Individual Body Weights + + ov ves eta... 13 2. Means and Significance of Hemtalogical Values . . . . . 14-15 3-5. Individual Hematological Values + + + + vv ov. 16-18 6. Summary of Mean Biochemical Values. + + + + + +4... 1920 7-9. Individual Biochemical Values + + + + + +44 +... 21-23 10. Summary of Mean Urinalysis Values + 4 + vv... 24-25 11-13. Individual Urinalysis Values. + + + vv vv uso. 2628 14, Necropsy ObServatioms vss vse uuu u a... 29 15. Absolute and Relative Organ Weights + + + + vv. 30 16. Microscopic OBSErvations. vv ve vv vv vss s.. 31-35 137-092 002034 International Research and Development Corporation Page 1 I. smopsrs age tFoluorrheasdusFmlounokreoycshemattcadlosaSguerfalcetvaenlts oFfO-09,5 w(adsistaidluliendiswtaetreerd obynlyg)ave 0.5, 1.5 and 4.5 mg/kg/day for 90 days. Two male and two female onkeys were initiated at each dosage level and also in the control 8roup. 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 frst and third month of the study. The monkeys treated at the 4.5-ag/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 activ ity 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-ag/kg/day dosage level had decreased serun cholesterol values and serus alkaline phosphatase activity. ALL monkeys at the 1.5-ug/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-ng/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 002035 International Research and Development Corporation Page 2 In the laboratory tests, there vas a decrease in the alkaline phosphatase activity and the concentration of inorganic phosphate in the serun at 3 months of study. ALL monkeys at the 0.5-ag/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 vas 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-ng/kg/day dosage level. Microscopically, the adrenals fron male and female monkeys at the 4.5-ug/kg/day dosage level had compound-related marked diffuse lipid depletion; the pancreas from male and female monkeys at the 4.5-ag/kg/day dosage level had compound~ related 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 002036 [International Research and Development Corporation Page 3 1m. compouwn The compound was received from 3 Company, Saint Paul, Mianesota ou October 24, 1977 as shown below: Label FFCl-u9o5rad3-1FSltuoocrkochNoe.nic9a8l-02S0u7r-f0a1c0t3a-n7t Lot 640 Net wt. 5 lbs. 2,2 kg. Description white powder 197-002 002037 International Research and Development Corporation Page 4 IIL. CLINICAL sTuDIss A. yETHOD: 1. General Procedure: Eight male (weighing from 2.35 to 3.55 kg) and eight female (weighing zom 2.70 to 3.75 kg) rhesus sonkeys were initiated in this study. The monkeys were purchased 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- 4ey- and light-controlled environment. Purinad Monkey Chowd was fed tulce each day and fresh apples wers fod 3 times a week. Water was available ad libitus. During the conditioning 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 treatment period. Complete physical examinations vers conducted by the staff veterinarian prior to initiation of compound administration. Only monkeys in good health were selected. This study wes initiated on February 16, 197. Terminal sacrifices were conducted on May 17, 1978. 2. Compound Adatnistration: At the end of the conditioning period the monkeys vere divided into four groups on a random Basis, so that the {aicial average body weights wera similar: Dosage Level (mg/kg/day) Number of Monkeys Yale Fesals 00.5(Control) 22 22 u1s5 22 22 137-092 002038 International Research and Development Corporation Page 5 The monkeys in the control group were previously emploged as the control group in an aborted 90 day study in monkeys on FC-95 (study 137-087). The test compound suspended in distilled vater, was aduinistered 7 days a veek by gavage. All doses were given in the same volume of water. This volune of distilled water vas 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 pharaacotoxic signs. Individual body weights were recorded weekly. General physical examinations were conducted fn the control period and monthly during the study. Food consumption vas estimated. 4. Clinteal 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 vere fasted overnight prior to the collection of blood and urine samples. a. Hematology: Hematological studtes tncluded: hemoglobinl, hematocrit? erythrocyte count?, total' and differential leucocyte counts, reticulocyte couat', platelet count', prothrombin timed and activated partial thromboplastin time' (APTT). Mean corpuscular hemoglobin, mean corpuscular voluse and mean corpuscular hemoglobin concentration were calculated. b. Blochenistry: Biocheatcal studies included: the determinations of fasting blood glucosed, blood urea nitrogenS, the activities of serus alkaline phosphatasef, serws glutamic oxalacetic a 002039 International Research and Development Corporation Page 6 transaninased, and serus glutamic pyruvic transaminase, and the concentrations of cholesterol, total protein', albumin, sodtul, potassiual, chloride?, inorganic phosphate', as well as the activities of Y-glutamyl transpeptidase!! and creatinine phosphokinasel?, ec. Urtnalysts: Urinalysis included: easurement of volume, pil3 and specific gravity; description of color and appearance; qualitative tests for proteinl3, glucosel3, ketones!3, occult blood!3 and aicroscopic examination of the sediment. 4. Statistical Analysts: 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, biochenical 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 une qual variances) as described by Steel and Torriel using Dunnett's15 qultiple comparison tables to judge significance of differences. B. RESULTS: 1. General Behavior, Appearance and Survival: There was no mortality in the control, 0.5= and 1.5-ag/kg/day dosage levels. Three monkeys at the 4.5-ng/kg/day dosage level died between week 5 and 6 of the study. The fourth monkey from this group was sacrificed in extremts in week 7 of the study. a. Control: The monkeys from this group shoved an occasional soft stool or diarrhea (slight to severe). For one day Monkey 7358 had 137-092 002040 International Research and Development Corporation 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 1n activity vas noted for Monkeys 7463, 7483 and 7504. 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 dlarrhea vere noted for this monkey, slight general body trembling and mucus in the stool was observed in week 12, as well as slight dehydration in veeks 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 fn 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 1 day each in weeks 1 and 3 and the decreased activity was observed in week 1 only. 137-092 002041 International Research and Development Corporation Page 4 4.5 ma/kalday: At 4.5 a/kz/day the monkeys showed apparent sigs of toxicity fn the gastrointestinal tract from the first to the second day of the study (anorexia and partial anorexia, emesis, black stool and/or dehydration fron slight to moderate). All had decreased sctivity from slight to severs. Before death they showsd marked to severe rigidity, convulsions, moderate generalized body trembling and finally prostracion. Monkey 7485 had petechial hemorrhages on the skin of the inguinal area, thorax and face and Monkey 7484 had pale gums after week 3 of the study. 2. Body Weights (Table 1): Changes 1a the body weights were siatlar for monkeys in the control and at the 0.5-33/x3/day dosage level. The male monkeys fn the 1.5-ng/kg/day dosage Level hada decrease in their body weight rom 3.15 kg at the beginning of the study to 2.93 kz at the end of the study and from 3.22 kg to 2.75 kg for the female monkeys. The change fn body weight for this group of aonkeys was mot statistically significan: from the control group. The monkeys at che 4.5-ng/kg/day dosage level showed a loss of the body weight ater 2 weeks of the study. Their average body weight decreased from 3.44 k3 at the beginning of the study to 3.23 kg (week 2) = 3.13 kg (eek 3) = 2.97 kg (seek 4) = 2.70 kg (week 5) for both sexes. At week and 7 of the study they died. There vas mo statistical evaluation of the body weights for monkeys at the 4.5ag/kg/day dosage level, Secause they were mot alive st week 13, when the statistics vers done. 3. Laboratory Tascs (Tables 2-13): 2. One Monch of the Study: At 1 moach of scudy there were no pathological changes in values for monkeys from the contol and 0.3-ma/ke/day dosage level. pre 002042 International Research and Development Corporation Page 9 At the 1.5-ag/kg/day dosage level only Monkey 7501 had a slight sdteucdrye.ase in the erythrocytes which was recovered in the third month of Both the male and female monkeys at the 4.5-ag/kg/day dosage level had low values for serum cholesterol which were statisti cally significance. Monkey 7484 had a decreased alkaline phosphatase activity (312 unit/1), serua 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 $.G.0.T. activity of male Monkeys 7484 and 7485 was in the highest expected normal range (11S units) the differences between these values and that of the control were mot 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). However, these monkeys had mo pathological increase of the blood glucose. b. Three Months of the Study: There vas a statistically significant decrease in the serum alkaline phosphatase activity for the male monkeys at the 0.588/kg/day dosage level and for two Monkeys, 7500 and 7501, at the 1.5 ug/kg/day dosage level. These latter monkeys also had a decreased values of serus potassium concentrations. Monkey 7501 at 1.5 mg/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 002043 International Research and Development Corporation Page 10 IV. PATHOLOGICAL STUDIES A. METHODS: 1. Gross Pathology: After completion of the compound administration period all surviving monkeys vere anesthetized with Sernylan*, exsanguinated and necropsied. At mecropsy the heart, liver, adrenals, spleen, pituitary, Kidneys, testes/ovaries and brain were weighed and representative tissues were collected in buffered neutral 107 formalin. Eyes were fixed in Russell's fixative. The thyroid parathyroid vas 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 perforned for all animals in the control and treatment groups. The following tissues vere examined; aadorretnaals esbroapihnagus egyaelslbladder hveearstse(lwsi)th duodenum tJleejuunnun ccoelcounm rectun coronary and any kLiidvneerys slaulaibvaarryspignlaalndcord skluinng psittoumiatcahry mreesternotpehraircyngleyamlphlnyomdpeh ttheysrtoeisd/ovaries mamnmoadrey gland ptahryamutshyroid nerve (vith muscle) trachea sppalnecerneas ttoonnsgiule prboosnet/abtoen/eutmearrursow (rib vuargiinnaary bladder Junction) tattoo other tissue(s) with lesions 137-092 *SPth.encJyoscelpihd,ineMisHsCoLur-i.BioCeutic Laboratories, Inc., 002044 International Research and Development Corporation Page 11 B. RESULTS: 1. 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/kg/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 granules. These microscopic findings were consid ered compound-related. No microscopic changes which vere 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/ kg/day dosage level were considered compound-related. 137-092 002045 International Research and Development Corporation References 1. HCioaulletaehr, HeFlmoorgildoab.inometer, Coulter Electronics, 590 W. 20th Street, 2. MCoimcpraonhye,satpo.cr1i1t5,4. John B. Yale, 3rd Ed., 1967, The C. V. Mosby 3. 5C9o0ulWt.er20PtahrtiSctlreeetS,izeHiaCloeuanht,er,FlMooriddeal. Zg, Coulter Electronics, 4. GReriatdmwahno,l'sEdiCtloirnsica6lthLaEbd.o,rat1o9r63y,MeTthheodCs. Va.ndMoDsibaygnoCsoimspanFyr,ankp.el 1a13n2d. 5. 2C0otuhlteSrtrePeatr,ticHliealeSaihz,e CFoluonrtiedra,. Yodel A, Coulter Electronics, 590 H. 6. General Diagaostics - Warner Chilcott Laboratories Revised April 1965. 7. G1e96n7e.ral Diagnostics - Warner Chilcott Laboratories Revised January 8. Technicon Auto Analyzer 6/60 Micro Wethodology. 9. Micro Auto Analyzer II, 6/60 Micro Methodology. 10. Atomic Absorption IL Yodel 353. 11. Signa Technical Bulletin 545, Signa Chem. Co., St. Louis, Missouri. 12. Signa Technical Bulletin 520, Sigma Chem. Co., St. Louis, Missouri. 13. Bilflabstix (Aves Reagent Strips). 14. Steel, R. G. D. and Torrie, J. H. (1960), Principles and Procedures of Statistics, McGraw-Hill, New York, N. Ya 15. DBuinonmeetttr,icsC,. WS.e,pt.New19T64a.bles for Multiple Comparisons With a Control, 137-092 + 002046 . SE am eT Eion rmmmmmmmomms* nns: s =og EB OiHBBBEHEEES -- g go g 2 e TT tt eT -- i{ sess: a --_-- 2, H--es_a--colosy EoyTcpeeacycas, HemTopoionbiant, emsgocee, PacTgoileees, Rectestocrees, PrPocshromsta Time, scpttsvaced 2.1.7. Lescoseeremes, wy sa,ie exac,io a - oacy-0ay Subacuce Mhesus Monkey Toxscsty Scady. --LES: asus Seay andtSpeotiticance of hBeemattolloneicdalVVaelueer , N0 oah Conecrwol O0dS muefiaaldayn LLSSuwssilkkalldesyy cons37ol iwoaan p5a.enr a3.s0e6 conc3Teal 1211.23 iJnvey} 11n2d2.3 Conc5Teal a53s % 337% Cone5ror I1r02s9 2160 i=nse conc37eal 0o0s13 38o33s oO01.i28 Conc37eal uuin uiiz kitu Gone37rat ii isz ai Cone51rat 71i.0.0509 1070.a08 s55z Goa7eol 3 an7 nn an@ Conc13eal 2755 5x= 21 Gonc3Tral x2 33 3u%n Page 14 44.5s syligidny osi!a i2ls7 3> i1I5n0 oL:zo iu:z 232 36=3z 9 nWn2 322 5562 -_-- 151-092 Tor svazianie w= n pTo r _-- [-- f---- ---- J -% -Tin AILABLE Te wat A oS-- = =1m ba+ HoHn 7 ow n " ct 34 * os wu 2 i 33 > wT-- ou .35 :HH 1v To3a"3 8352 iu3hy wT r k2 3z ;3 rage 15 +3 2 uw 0 a 7 A: 52 .3 Lt fWBoEGL WgEe ASDEWTEBaEr.NWRo afCRtEeEpDr -y FEe N eOgSU e OR lem me FALE Lihat wel Se mC mo Wwe we om moa mou I wm as ca ow om tm owe on g ae own on = ots ium os EB 3:5 Lm 2 eetwe Ve, TT ] BEEE, i Ean EETRa E EEeEe GeEr mEeERuEe wWEe SweE Aee HEESEERRE HIRREEIIEE BmoPr E Eoa Poy wme s Ge ome x EBOHE FOb OEE mazmo:n ogooxo r Boer mm am wos a 4 orp iotrE:or 2 ee mon oa g= worm = mous ow o HO0 wea " oF oak BE um oe oo foo: otniiB Venom ow TM gSL a mee Ty : ~ = 2 = g EF -- Ben 2 & _ == mseewanr iw wsiipg ams, Wns dn axnieat. -- Ee i _uo: i - BE AILABLE ,... ,, [ i R my o T en eves ir R--BSE eewne oswtain wsoewwssoawee ou 2 2 2 rl 17 az w=n w2z ral 2 2 2 --TML rg g8 a2zi aws3z "T2ye TM iimF i13" sia +i0 in 3 ix ow TM 12 4 i 8 PR i" 3 vt -- re-- ra 348 oit tie bwi s +;FctRin meTM t 3 3: s3 "i cwcsnose, mi =t 323 :3 iii s8: ty dr on er ee =e dew Sw son rape 2 ws costsi ii _---- Phs---- VsGamian pinesetonman, BESTCOPYAVAILABLE --- = iirsesoeom s Beosm eiycTsa tesrtr: ay ew ewe wis Gwe swe rg 7 i EH ra 3m - ue n 8 3 3 % -- a "2 -5 ee THon 1bo 1i2e isu -- 2 i" Ls v3 wr igy iws iHe "# oTMt 38 2" 3 3x ont oif :z p.S 35 om lTiyp sHi m a Te pemw i aTT ee we es ] Eon nr ERE CES RD ER see oe BFE SE SEED Santrots UOMO D os nw mde bd g gg5 =Ss = E S 8 y & TE BE ie RA WD LJDS NRG NTT I TRE mw oe o . . ; : eo we ER 354 = S= == 3 ree FY g * | emer BeSo DT | RET a WA wi ITN UE wii Uh UIE SUT DU I a `: a wa am am oz om se "w in : I. Lomond en au wose mr . " BE - ga E== 8 ' g= gSy ~ on : FC-95: TABLE 10. Urinalysis Vaollume, 8 SpGeracviiftiyc Ninety-Day Subacute Rhesus Monkey Toxicity Study. MALES: Summary of Mean Urinalysis Values. Study Month Comerol 0.5 mg/kg/day 1.5 mg/kg/day Cont1rol 3 Control 31 Cont1rol 3 3202 10 7.2 76..40% 1.1.002382 RET] 2 25 3 8.3 57..522 11..002277 1.0338 28 7"50 8.5 85..098 11..003201 1.024 Page 2 4.5 mg/kg/day 58 3868..44 11..00333 - 137-092 Significance not deternined due to only one value in the Control group. ~ = Not available 002058 FC-95: TABLE 10. Urinalysis Voallume, o Specific Gravity Nizety-Day Subacute Rhesus Monkey Toxicity Study. Cont. FEMALES: Summary of Mean Urinalysis Values. Study Month Control 0.5 mg/kg/day 1.5 mg/kg/day Cont1rol 3 Cont1rol 3 Comerol 31 2352 80 8.1 5.8 8.0 11..003321 1.021 1533 ES 7.9 5.5 5.0 11..002372 1.021 2280 "0 8.3 68..40 11.003218 1.025 Page 25 4.5 mg/kg/day 3203 8.8 6=.:5 11..002376 - 137-092 - = Not available 002059 | BEZ OPOI1E3 HHHEEEEgFL I IPLI 5HEE YEE D CG Borg EERL LPs LES 0 BOGEREEE LPP Lf a idl do B OTR EAB: (rr: BE 2: `lg s S= s = Q$ we HBoieam, =1m 88 oe H1:R 5 : LFoiE E onE RoE izg 3slagttars 2 " " =o - - = 5gJ E -Clear :2 ] Sn! . HE is Tou fob: omoboes fod B ow Gim flae. [EC 2 douse ss Rn * " z. BE BEEeet' : & BEST COPY AVAILABLE" * a_i SLLete. arr: oo gt eet y mai HEitovish atee Lestons x fxl ; Foxx ... ibiy wiente tare oo. - Mrephted . * TE te me (oF mi . . EE . . Ce Ey Hretencusted tobulactons SES pa x . . 002063 Ey-- S amWo gene pe) r pe pe bjge ee BsEr ee~ fo A TE ER nme Ta TIN frp hn we a an freer no en a MII IIR ="3 i HEREIN RONDO ON NR ND OY LIN um am um om Ss BOM OM ER mM A mam a mar am aay moun iy = LL g 2 z 8 BEST COPY AVAILABLE TM ** woos see Sap ubssee seven Seay Ts Sse, Es Tere veario, Corl ogee ser bse omiee d$33] 1 BsEaEsF: BsoEcE:F Esiofsf. iE:iii:d Pfoghp tep atfetraatitm ae msaatnatrnye cSas eatnriiiseWscenN itEe Toy ews of ipod tattiesce 1a Treats EL i IE Ee iee iTi Seoen i enaeiteonsof tdsviduat iot sense sts ies 2 a > 5 . TT sas a 5 \ : : T ii3 aso oa TEfEeFboitnEe mdeEpmiaraisEionLoif Easc.Niepres Cogmmioes sn a sco apcheiten TaHele attamacory cuit ttiserces 1a dtineepaerernk cCursaetietrcees [rETHnaSlkaetmau cot taticrces SrRharma -- tte wren poicoentriatninomneaseeem s 312 s TT si 23s IJroEsEiEe s s . : : :: : s TTT sais esa Ts 1Yaas sta E IL6ceEEcmE. en BESTCOPY AVAILABLE -... . wen: T --_-- o Moe de Sete Manes Sse Tits sent. rear _2 - 00mm nce Swe Assim beer ee T=imsistuieoe n e 14]) eBaeTRRz3aezLEzyFeeeAEsi EsErFRnWp3rEi$egAgn3zeev3$i u15e3%is:: pWerETiet Rtp,erviiea, ross ov of ra a tras aoa a a : e =atterpr s sted es ; errFPr a ffTrapsratourt nweoproises s., aocltdl peoiftrTrsahiee,ersaSne:irrviaets sedsesces spe Ey ues tri: sass sia:33131: :asia sass 1aaa :an T ApmEnr a L eiteet nt soit , }; 3s ERhe -- s s cE oorEi T ewt eenee TT . TTT os op ntr heeoh y ELCAN s ss _=E--E--essI ere citTT S oT o T e atime ; =A r=Flyry cats tsscscn 1 T Gias a TT a eh rrETaommae]] AoSonewe en 1 s . s s 2s Ra memct auteaon of dntnst TIT TT .] Gia ram E reocttin onameses LPdEsLRm. RE4: Esmemae m senes BEST COPY AVAILABLE... ., reas: ins Say Subacute Shas okey Tost Ses. -- Ere ma------ Trevis-- tSe ear---- --------e Tfsuin d$h1 --TSSheualsmeiiser efsersesmiioenns11 mseesmeeete,ney A eeE e eleLatEeme.ry I iomiabimiodneatmimoanrst1esesecrotssnd ant cColIp]ES erEmhutE ismacsnarL ny ectist tsseideennreenast pSwlmleiS etestsmR eeeeimneTeTeIeedIhpsaeTvi nery jorpagri opchriinfvamatory cai tabicracn fFS on orseee R mp AE peetikvie. iny simmers ees So Eetiences E HFAime eEc i SeptLietIan ltlainatsin PA tHoaleSfiEneEaRtasImmaEsnor, cat ct stterces wmecrces wl5l I Sh mrLaIEin TT=ol test atticrsces ta WIE EI re dt brciias spots stsseraces we pogemmrme om oun B2R2E3E% s s: ar D: os : sia Tir imme fod iit FcEzgp . > Lise gsisiszs bse i3i3iE:D ... . s : a:xa anaes 13s 5 Te >s 3las ss :. 5 2a : TI . I .3 FI 5 3> A ss T ss ss ; Simem Ensen BEST COPY AVAILABLE -... s rors Tw acy Sy Sac Thru Bose Tose Sey Trevis esa Cool oie Lewes i Bl eras zzzs pias iii Fee econo trnate FaCleimctencs sites pscetion S aon aE nes rcs LSEAReTtEeR cai FiDonleL]ErSibEnteRaisIemEc, cat cus stones seston ofSf iiRtIreIrSheeNesiiL Set Pr i-- lEap macHorm y oT ceasgR ien 112mctontncrion Ee Tres satstcrces in seen P23: : 313s Taisen . 2731 : B TI sa ass aaa s > . 3s v. :: R i: : SE tock of nero ismrstncion ToHEmESnot EsytTnstsBnetiEsncrIciessaacmesusetde Hote Sled thers scons SeS[ErreaathhmeT aires.R EEE serene tn -- x-men goss Foam s : i: o:$s3 o1s 3} : se TT TT . ii an 1} a : : 3osgs 6:ese DIENER oe ross: = - BESTCOPY AVAILABLE -... 5; Winey ey Shanta Brus ener Txt Sein. S------ Col opmiwier Lssier s sg igtnion 35) zPIrEzSx SsEsEs:R EssEsE: iiEi:i Sra A oeeivgies tpeipsespaea camNisE. EI EL recute prep mELaEiEni neet e at sxsr . mpirtsi rere ug1 ee .5 s ss . g2%3 A :Tzrz .Ja.r rye r SeT SariTenhaeres eewe ymeion) eTis a ae aaat ST s> We wre pJEeoLomgLmgaer : GjioonrSmgne, 4SEm2mmu one 002069