Document MDwKLk5XXe8n42JdJ8xrG3Zj

SEHR . 0800-373 T6320) ead ARG-- 0966 arial L867 HeCBI 1 REPORT Twenty--eight--day Repeated Dose Oral Toxicity Study of Sample D-1 in Rats (BMR143C) ? 8VepEa-oGrs 000811805N Ss EG t Bio-Medical Research Laboratories Co., Ltd. EEE -- ral em11 oosess REPORT Twenty--eight--day Repeated Dose Oral Toxicity Study of Sample D-1 in Rats (BMR143C) --TRANSLATION- lg February 16, 1993 Bio-Medical Research Co., Ltd. Laboratories 005294 PREFACE BY TRANSLATOR - HM. Femi 005295 CONTENTS - STATEMENT ON GLP CERTIFICATION StonATURE. GENERAL MATTERS Title / Study Nusber / Purpose / GLP Applicaiton / Testing Guidelines / Sponsor / Testing Facilities / Responsible Porson / Dates in the Study / Retention of Records and Samples sunary MATERIALS AND METHODS 1. Test Substance 2. Preparation of the Dosing Solution 3. Laboratory Animals and Resson for Choice 4. Antal Housing 5. Identification of Anizals 6. Identification of Cages g 7. Test Procedures 7-1 Dose levels and reason for selection 7-2 Nusber of animals 7-3 Route, frequency. and duration of administration 7-4 Mothod of adainistration 7-5 Grouping @ 005296 8. Parasoters assessed - 81 General condition Clinical signs / Body weight / Food consumption 5-2 Laboratory tests Hosatology / Biochanistey / Urtnalysis 83 Pathological exastnaiton Necropsy / Organ weight 8-4 Histological examination | 5. Statistical Analysts sesuurs 1. ortaltty 2. Clinteal signs 3. Body Hotght 4. Food Consumption 5. Hematological Findings 6. Biochentcal Findings 7. Uetnalysis 8. Pathological Findings 5-1 Organ weight 8-2 Macroscopic Endings at necropsy 6-3 Histological findings DISCUSSION AND concuusIoN FIGURE AMD TABLES (Group moan date) Figure 1. Changes in moan body weight un - 005297 Table 1. Group incidence of clinical signs - Table 2. Body weight Table 3. Food consumption Table 4. Hematology (in connection with REC) Table 5. Hematology (in connection with WAC) Table 6. Clinical chemistry Table 7. Urinalysis Table 8. Organ weight (Absolute) Table 9. Organ weight (Relative) Table 10. Group incidence of macroscopic findings Table 11. Group incidence of microscopic findings APPENDICES (Individual data) Appendix 1. Clinical signs Appendix 2. Body wolght Appendix 3. Food consusption Appendix 4. Hematology (tn connection with REC) Appendix 5. Hematology (in connection with HEC) Appendix 6. Clinical chemistry Mppendix T. Urinalysis Appendix 8. Organ weight (Absolute) Appendix S. Organ weight (Relative) Appendix 10. Macroscople findings Appendix 11. Microscopic findings Appendix 12. Microscopic findings (for the organs showed gross lesions) PHOTOGRAPHS (Histological findings) Photos 1-4 ain 005298 STATEMENT ON GLP - Title Tenty-sight-day Repeated Dose Oral Toxicity Study of Sample D-1 in Rats Study Nusber : BMRLESC The said study has been conducted in compliance with the "GLP Standard for Industrial Chemicals" tn Japan (1384, amended 1988). (signature) (bate) Signed February 16, 1993 (skoto Tonnichi) General Manager Bio-Medical Research Laboratories Co.. Ltd. an N 505299 CERTIFICATION _ Tite Tuenty-oight-day Ropeated Dose Oral Toxicity Study of Sample D-1 in Rats Study Nusbor : BMRIASC Having audited the final report, I, the undersigned, assure that the study has boen conducted In compliance with Japanese "GL? Standard for Industrial Chemicals". and accosplished ith the protocol and appropriate standard operating procedures of the testing facility, and the report has been prepared exactly based on the experimental results. (signature) (date) Signed February 16, 1993 (Yutaka Kesbora) Quality Assurance Unit Bio-Medical Research Laboratories Co.. Ltd. Dates of Inspection Object Dates of Inspection to Protocol 1992. 6.23 1902.7. 3 1982. 7.7 Testing Procedures| qq 5. 4 1952. 8.18 Records, Raw Data 1992.12.17 Final Report 1993. 2.18 Dates of Study Director 1892. 5.23 1992.7. 3 1992.7. 7 1992. 8. 4 1992. 8.20 1992.12.17 1993. 2.16 Report to Mansgement 952. 6.23 1992. 7.3 1982. 7.7 1902. 8. 4 1992. 8.20 1992.12.17 1993. 2.16 TM 005300 SIGNATURE = Title: Study No.: Tuenty-eight-day Repeated Dose Oral Toxicity Study of Sample D-1 in Rats BMRI43C Tho sald study has been conducted under the responsibility of the undersigned, and this report has been prepared so ss to reflect whole study correctly. (signature) (ate) Signed February 16, 1993 (tichio Otsuka) Study Director Bio-Medical Research Laboratories Co., Ltd. vn) 005301 GENERAL MATTERS - 1. Title Twenty-oight-day repeated dose oral toxicity study of Sample D-1 in rats 2. Study Number BHR143C 3. Purpose To investigate toxicological potentiel of the test substance. Sample D-1, through serial oral adainistration to rats for 28 days. It was intended to meet Japanese legal regulation for industrial new chemical substances. 4. GLP Application The study was conducted in cospliance with the Japanese "GLP Standard for Industrial Chemicals (1584, amsended 1988) 5. Testing Guidelines The testing methods conformed to the Japanese "Guidelines for Screening Toxicity Testings of Chemicals" (1988). 6. Sponsor Suaitono 3M Co. Ltd. 3-8-8. Minani-hashimoto, Segamthara, Kanagawa, Japan (Responcible Person) Nobushige Hurakant Manager, Techaical Department, Cheatcals Division -1-- 005302 7. Tostiog Facilities - Key Facility Bio-Medical Research Laboratories Co.. Ld. 3079 Susugaya, Kiyokawa-aura, Akoh-gua. Kanagawa. Japan Partial Contributor (81004 Biochemical Examination) @ Koshino Laboratory, Mitsubishi-Kesel Institute of Toxicological and Bavironsontal Sciences (4) 14, Sunayasa, Hasski-aachi, Keshima-gun, Ibaraki, Japan #)The conpany nase has altered to Mitsubishi Chealcal Sofoty Institute. (i1stopathological Specimens Preparation) @ Hora Pathological Research Kinoaine, Hayasa, Tuge-aura. Yassbe-gun, Nora. Japan (Histopathological Exantation) @ Hatano Research Institute. Food and Drug Safty Conter 728-5 Ochiai, Hadono-city, Kanagawa. Japan 8. Responsible Parsons (Ciseled figure after the nase indicates each belonging facility cited above.) Gonoral Manager Hakoto Temnteht, @ Study Director Michio Otavka, General Participants Hiroyuki Tshit, @ Toto Iehtkova, Osomu Tanaks, Quality Assurance Hikiko Kananabe, () Tutska Kasbara, --2= 005303 Partial Participants - (esponstble to biochentcal detoratnation) Noto Toyota, @ (Responsibie to histopathological speciaans separation Toshing Tatami, @ iractor for histopathological exsaination Shinsuke Yoshisura, @ (Participant to histopatholoical exaaination) Funte Kashi, ! 9. Dates in the Study (astiation of the study) sane 22, 1032 (nsaals racoption) sety 1, 1032 (dsinsatation period) Hate July 6 ng. 2, 1992 "pomsle- suty 7 = dug. 3, 1992 (Toraination of observation, blood sampling and necropsy) RT-- rg. 3, 0m "Female, natn groups hog 4, 1032 "Hale, ecovery groups- ag. 1. 1032 "Female, recovery groupa- avg. 10, 2032 (Conplatson of the stay) Fob. 16, 1033 10. Retention of Records and Samples MI documentation rocords and samples (including specimens) of the Study sce retained in the archives of Bioedical Research Laboratories Co.. Led. for 10 yaacs after the completion of the study As to furthes retention, it will ba decided on consultation ith the sponsor and the contactor. a- 005304 "suMMaRy - 1. Semple 0-1 vas acainistered to both sexes of rots with doses of 0.1, 1, 10, and 30 mg/kg for 28 days. A group of rats given the venicle (olive ofl) sions was included ss the control. Besides the main groups for monsecovery study. o satellite grow for 4-day recovery study wes added to each of the highost dose and the control groups. 2. No death occurred throughout the adsinistration poriod. One male of the 30 S/S group. however, dled during the recovery period: the death was considered to bo caused by the test substance. 3. No sbmorsal clinical signs were fod fn all rats of the control (including those for the recovery stody) and the 10 mg/kg or lover dose Sroups throughout the whole of the observation period. In the 30 mg/kg Grow. however, such signs ss the followings wero oberved during the adatnistration and the recovery periods: reduced spontansous acvemsnt, tonicClostc convulsion, lying or crouching, bradspncs of cyameats. salvation, rodsish salivation, brown urine, loss of hair, and cont staining. These were considered to bo cased by tho test substance 4. Body weight goin was supprossed during tho adeinistration period in beth males 0d females of the 30 mg/Kg group from the second wesk and ater: the suppression continued throughout the recovery period. 5. Food consumption was suppressed during the administration pariod in beth sales and fomales of the 30 na/kg grow fron the second wok and afters it tended to return during the recovery period. ovever 6. Hematological examination at the end of the administration period revealed 005305 dacransed hesoglobin concentration fn sales of the 10 and 30 mg/kg groups and raduced prothrosbin tise in females given 30 xg/kg. Moreover, at tho end of the recovery period. the followings were still detected in the 30 mg/kg Soup: docrasse of erythrocyte count and hematocrit, shortening of prothrosbin tie, snd incresse of levkocyte count, in males: decrease of hesoglobin concentration and mean corpuscular hemoglobis concentration, shortening of activated partial throsboplastin tims. and incresse of mean corpuscular volume, in females. 7. Blochenical examination revealed the the folloxings st the end of the administration period: decrease of GOT in females of the 1 mg/kg and higher dose grows: fncrease of albuain in females of the 10 mg/kg and higher dose groups: increase of GPT and chloride, and dacrosss of total cholesteral fn Both sexes, dacraase of total protein snd increase of alkaline phosphatase and of A/G ratio fn sles. fncrese of urea nitrogen in fomales, all these in the 30 =g/kg group. At the and of the recovery period. the followings ere observed in the 30 /k group: deceesss of triglyceride and incrosse of A/G ratio, in males: incranse of ures nitrogen. total protetn. albusin, and calcium. and decrease of glucose and triglycerides, in fomales. Besides, reddish change of serum was recognized in both sexes with the 10 25/45 or higher dose sain groups. and fn tho 30 mg/kg recovery group. 8. By urinelysis, scidic Shift in both sexes and decrease of protein in females woro noted in the 30 xa/kg grow ducing the adsinistration period. Acidic shift rensinad tn sales during tho recovery period. 9. As for absolute organ weight, tho sdsinistration resulted in increase of the liver weight in both sexes of the 10 xg/kg or higher dose groups and decrease in the kidueys weight of males given 30 mg/kg. After the recovery --5= 005306 period, increase in the liver of both sexes and decrease in the kidneys of foxales were still noted in the 30 mg/kg group. Relative organ welght increased In the liver of both sexes of the 10 mg/kg or higher dose and increased in the kidneys in females of the 10 mg/kg or higher doso. After the recovery period, Increase fn the liver of both sexes and increase in tho kidaoys of fomales remained in the 30 mg/kg group. 10. Autopsy for the male died during the recovery period revealed atrophy and dark reddish patch in the thymus, hemorrhage and tarry contents in the stomach, tarry contents in the small intestine, and grayish patch in the aver. In the scheduled necropsy at the end of the adainistration period, the following findings were dotected by macroscopic examination: dark reddish change in the liver of females receiving 30 =g/kg: grayish dot or patch and hypertrophy in the liver and blackish change fn the Kidneys in males given 30 mg/kg: dark reddish change, yellowish change, grayish patch, and hypertrophy in the liver of fosales rocolving 30 mg/ke. The examination at the end of the recovery poriod revealed grayish patch. dark reddish change, and hypertrophy In the liver of both sexes of the 30 8/kg dose. 11. Histopathological examination at the ond of the sdainistration period revealed dose-dependent changes ss eosinophilic degeneration in centrilobular hepatocytes and swelling in the liver in males of the 1 mg/kg or higher doses and in females of the 10 mg/kg or higher dose. Other findings: focal necrosis in hepatocytes in both sexes given 30 mg/kg and in males given 10 mg/kg: somewhat remarkable fatty degeneration in peripheral lobule In males receiving 30 wg/ks. No obnorsal change was detected in the heart, kidneys, spleen. adrenals. brain, and testes or ovaries -- 6 -- 005307 At the end of the recovery period. eosinophilic degeneration in centri- lobular hepatocytes turned slighter; swelling in the liver, however, did mot racover in both sexes given 30 mg/kg. and focal necrosis also remained. In case of one male given 30 mg/kg and died during the recovery period, In addition to tho same changes as found in the liver of the main groups. the followings were dotected: hemorrhagic foci in the brain, ulcer and hemorrhage in the glandular stomach, and congestion and hemorrhage in the thysus. : 12. Judging from the sbove, the toxicological mo-cbserved-effect level (NOEL) of the test substance, Sample D-1, was considered to be 0.1 mg/kg for both =ale and female rats. -7= 005308 MTERIALS AND METHODS - 1. Test Substance 1-1 Nose (Chontcal Nose) (broviation) 1-2 Structural formula 2-{N-Ethyl-N-per(C-1l-8u)sourl fooanyllaknynol] athyl acrylate Semple D-1 C, Hy | I CpFy $0, N=CH, CH, 0-C--CH=CH, (Composition) 1-3 Holocular weight 14 Lot nusbor 1-5 Appearance, 16 purity 1-7 Strage conditions (a ranges froa 1 to 6) about T8% for n= cosponent, about 21% for n=1-7 cosponents. 625 101 (supplied by the sponsor) Asbor-colored waxy solid. 99% or above Stored at oon temperature 2. Praporation of Dostag Solution 21 vahteto oive 11 22 Procedure Roquired amount of the test substance as weighed and suspended homogeneously in the vehicle sentionad sbove. The dosing solution wes divided lato daily batches and stored in a refrigerator at 41C until Just before use. 2:3 Frequency of preparation The dosing solution wes prepared once a Wook, because the stability of the test substance in the mixture for eight days was contirsed in Japan Food Research Laboratories (Tokyo) by --8-- 005309 our request - 3. Laboratory Animals and Reason for Choice The anisals used were SPF Crj:CD(SD) rats of both sexes. They wers purchased fron Charles River Japan, Inc. (195 Shimo-furusawa, Atsugi, Kanagawa, Japan) at four weeks of age on July 1, 1992. After five (sale) or six (Fomale) days of acclimatization, animals that apparently healthy and showed normal weight gain were selected for the study at five weeks of age. They were grouped to bo unifora for the mean body weight based on the last weighing during the acclisatization. The weight ranged from 132 to 151 g for males snd 121 to 141 g for females at the initiation of administration. Reason for choice: Having appropriate nature for laboratory amimals and being bred under good gonotic and microbial control, this species and strain are widely used in toxicological studies: our testing facility. besides. has accusulated back ground data on this animal. 4. Antsal Houstng Five or two (during or after the acclimatization, respectively) snimals of the same sex were housed together in a stainless steel wire mesh cage of the hanging type (26x38x18 cm). The onisal care room was a barriered facility that was autosatically controlled to keep the following conditions: Temperatura 1 22-28 : Huntdity i 30 - 108 RH Vemtilation : 13 times/hour (all fresh air) Lighting + Light /dark cycle of 12 hours (Lights on 6:00 to 18:00) A little deviation of tespersture and humidity occurred during the animal kesping: it was. however, judged not to affect to the reliability of the study. The diet was WF pelleted food for laboratory snimsls (Oriental Yeast Co. --9-- 005310 Ltd.) and drinking water was tap water subjected to filtration and UY seradiation. Animals were allowed access to food and:water ad 1ibitus except for fasting from the evening before necropsy. Analysis of the ingredients and microbial contaatnation of the diet was perforssd by the manufacturer and toxic contaminants were examined by Japan Food Research Laboratories (Tokyo) at tho manufacturer's responsibility. The quality of the tap ater was periodically examined by Atsugi Public Health Conter by our request These data were checked and stored by us. Cagos were replaced with freshly autoclaved ones once a week. 5. Identification of Animals Bach aniaal was identified by marking a nusber on the tail with a saturated alcoholic solution of picric acid. To ldentify the dose group to which each anisal belonged, a colored mark was painted on the tail with an oil-based folt-tip pen 6. Identification of Coges Bach cage was identified with an attached card on which the study nusber. abbreviated nase of the test substance, dosage. and individual animal nusber wore listed. 7. Tost Procedures The testing methods conforsed to the Jopaness `Guidelines for Screening Toxicity Testing of Chemicals * (asended on Decenber 5. 1386) 7-1 Dose levels and reason for selection Prior to the principal study, preliainary dose-finding studies ranged betwoen 4 and 14 days in adainistration period wes performed with such doses 35 20, 40, 50. 100, 200, 500, and 1000 mg/kg. each in a few (these to five) male and female rats. It resulted death of more then half number of rats in -- 10 -- 005311 1000 =g/kg for 18 days repeated administration; suppression of body welghi gain was observed {n 40 mg/kg dose, though nono of changes found in 20 mg/kg dose. Hence, the highest dose was decided at 30 3g/kg in the principal study and the lower doses were set ot 10 sg/kg. 1 mg/kg. and 0.1 mg/kg for both sexes. A group of rats given the vehicle alone was included as the control. 7-2 Nusbor of snisals Forty-two rats of each sex were used. 7-3 Route, frequency, and duration of adainistration Adatnistration was porforacd via the oral route, once a day for 28 days. 7-4 Method of sdainistration The dosing mixture was intubated directly Into the stomach via a plastic gavage tube. The voluse adsinistored wos 1 al per 100 of body weight based . on the most recent weight data. 7-5 Grouping. Four dose groups mentioned above and the control group were set. Besides, to monitor the reversibility of amy toxic effects, satellite groups were added to the control and the highest dose groups for a 14-day recovery study. Grouping by|Dose|GrMoainwps'h| Recovery Groups (+2) dose levels, (Sex and Nusbor of animals) Control 0 [nate & female, 6 rats each [male & female, 6 rats each Lowest dose 0.1 [male & female, 6 rats each Intoracdiate-1| 1 | male & fomale, 6 rats each Intersediate-2| 10 [male & female, 6 rats each Highest dose | 30 [male & female, 6 rats each [male & female, 6 rats each Total [| [eeteoametcoats.ca0 ch [mato somata. cars each "11 -- 005312 (1) Animals were necropsied on the next day of the last adainistrateion. (42) Antsals were nocropsied insediatoly after the recovery period was over. Note, Individual animal nusber. Each animal was musbored with four-digit figure. First digit, Dose grows: 0. the control group 1 the loxest dose group 2, the intesediate-1 group a. the intesedtate-2 group a the highost dose group Second digit, Sexes: 1 sales 2 fonales Third and fourth digits, individual animal of main or recovery groups: 01-05. animals of the main groups 07-12, sntaals of the recovery groups 6. Parameters Assessed 8-1 General condition 8-1-1 Clinical signs The. appearance, behavior. and excreta of every anisal were observed daily throughout the adainistration and the recovery periods. 81-2 Body weight Every animal was weighed with an electric balance at the cossencemsnt of the adainistration, once a week thereafter. 81-3 Food consumption Leftover food from oach cage was weighed on day 0 and once a week thereafter. and the daily overago consumption per animal was calculated for esch group. 8-2 Laboratory tests 8-21 Homatology Blood samples were collected from the inferior vema cava under ether anesthesia just before the scheduled time of sacrifice. Blood sampling was - T2 005313 done under mon-fasting condition. The hematological parameters determined are listed below. The anticoagulant used was othylenediamtnotetrascotic acid dipotassius salt (EDTA-2K), except that 3.13% sodiua citrate was used to deteraine the prothrosbin tise and the activated partial throsboplastine time. Paranters Hothod TI) Leukocyte count (BC) Electrical resistance method (2) Erythrocyte count (R80) Electrical resistance method (3) Platelet count (PLT) Eloctricel rosstance method (4) Hemoglobin concentration (gh) Photo-electric colorisetry (5) Hematocrit (Het) Pulse detection method (6) Moan corpuscular voluse @CV) Calculated fron (2) and (5) (1) Mean corpuscular hemoglobin (HCH) Calculated from (2) and (4) (8) Mean corpuscular hemoglobin concentration (MCHC) Calculated from (4) and (5) (9) Differential loukocyte count Glosa-stained smear (10) Prothrombin tise (1) Quick's one-stage test (1) Activated partial throsbo- plestin tins (PTT) Activated cofaroplastin method Insturuments (-(8) : Automatic coll counter. Sysmex model CC-180A, TOA Medical Electronics Co.,Ltd. + Optical microscopy (10)-(11) Blood cosgulator, Model KC-1, Amelung Co.,Ltd. mong these data, PT and APTT of one malo in the recovery group (animal fo. 0111) were missing owing to cosgulation at blood sampling. On the other hand, reticulocyte counting was added in the mein groups after sequential staining with now methylene blue process and May-GruemwaldGiemsa process, bocause anemia was suspected in aniaals of this group. 8-2-2 Biochemistry The residual blood sample was lot stand at room tesperature for 30 min and J 005314 then centrifuged at 3000 pa for 10 in to separate serus. The serus, being frozen to <20 \C. was sent to Kashima Laboratory of Mitsubishi-Kasel Institute of Toxicological and Environmentel Sciences for biochemical exaaination. Paramotors examined were as follows: _-- @e ) ToPtaarlapsrootteerisnm Bluree t's methoWdoth--od--r, (@) Mbuatn Bromocresol green method @) A/G ratio Calculated froa (1) and (2) 4) Glucose Enzymatic UV-spectrophotosstry (Hoxokinase-GE-PDH) (5) Teiglycorides Enzymatic method (LPL-GK-GIPO-POD) (8) Total cholesterol Enzymatic method (CES-CO-POD) (1) Uren nitrogen Enzymatic UV-spectrophotosstry (Urease-GLDH) (8) Creatinine Jato mothod () Caletun o-Crasolphthalein complexons method (10) Inorganic phosphorous Phosphosolybdate-UY spectrophotosetry an cor (asm UV spectrophotoetry-rate method (Modified SSCC) az) er (mn UV spectrophotometry-rate method" (Nodified SSCC) an eer 7 ~Glutasyl-p-nitroanilide substrate method (Modified SSC) (14) Alkaline phosphatase (ALP) p-Nitrophenyl phosphate substrate method 15) Sodium Ton selective electrodes method (16) Potassiva Ton seloctive electrodes method an chloride Ton selective electrodes method Instrusent: Automatic analyser (Hitachi 736-10 type) 82-3 Urinalysis Fresh urine was collected from all animals at six or seven days before the completion of adanistration, and four or five days before the end of the recovery period. (In each of two successive days. the former and the latter days wero for male and for female respectively.) These were tested for the following parameters. -- 14 -- 005315 Er n e vnn a)s)? Parameter Method - +mot smi oL aosn ee I t im iL itrI mt n L B I DiT rrT rermem mprenrialtein S F imeei T m Se--o s I --e CII On -- cnwtL tnse i re o-------- miCrenLLseiim i 1.15 1 C SIL LIIT kat seer mresoSTe n 4 tt 005316 Mditional histological survey was conducted to the following cases in which any macroscopic changes were observed at the necropsy: lung in one case (anteal no. 0105), kidaeys in tno cases (animel nos. 1103, 2102). sad testes in one case (animal no. 0111). Concerning the dead animal which occurred during the recovery period in ome male (animal no. 4109), histologicel survey was perforsed in the typical seven organs and In thyaus and stomach, the lstter two were additional because of the macroscopic changes found at the necropsy. In this animal, tarcy intestinal contents were found botween duodenum and ileus at autopsy: however, preparation of the specimen and histological examination were mot pertorsed because of post-mortes autolysis AIL through the histopathology, histological specimens were prepared in Nara Pathological Research, whereas the microscopic exasinstion was carried out in Hatano Research Instituto of Food and Drug Research Center, both at our quest. 9. Statistical Analysis For metrical data, homogeneity of variance ssong all groups was first tested by Bartlett's method. Then the homogeneity of all group mesns wes tested by one-way layout analysis or Kruskal-Wallis H-test, dopending on whothor the group variance was homogeneous or not, respectively. When group means were significantly hotorogonoous and each group had the same number of data Stns, differences in mean values between any group and the control were tested by Dumett's multiple range test or Dumett's rank sus test, sccording to whether the group variance was homogensous or mot. respectively. When group means were heterogeneous and the musber of data iteas in each group was unequal, the above-mentioned procedures wer replaced by Scheffe's multiple range test or Schoffo's rank sus test, rospectively. Armitage's chi-squared test wes used to assess discrete data such as urinalysis findings - 16 -- 005317 RESULTS - 1. vortatey ALL rats survived to tho ond of administration periods during the recovery pariod, however, one male given 30 mg/kg dod on day 32 (siz. day 4 of secavery 2. 4) Each day throughout the study is indicated with such way os tho day of comsencesent of the adaiaistration is named "day 0 * ; and the next day of the last adainistration (viz. dey 28). that is the first day of recovery period, is expressed as "day 0 of recovery * 2. Clinical Signs (Table 1. snd Appendix 1 2-1 During tho administration period Yo abnorasl sigs were noted In all Fats of the control and the 10 mg/kg or lower dose grows. With rats receiving 30 mg/kg (inclusive of the cacovery group), however. the following ndings ware detected: Salivationr--a considerable musber of snisals of both sexes. in the latter Rolf of adainisteation period: and fn one male on day 0. basidos: Redden salivation---in a fow sales and females, occasionolly: Tontcrclonic convulsion, lying. bradypnea--in ono sale on day 26; Reduced spontaneous movement. clonic or tonic-clonic convulsion, lying or crouching. bradypaen of cyamosie-r-in one and tro females on day 20 and tron day 25 to 21, sospactively: Lass of haie and coat staining---in threo snd one famales cospactively en doy 17 and ator. 2-2 During the rocovery pariod Yo sbrorssl signs oppeared in both males and females of the control group us oll a5 in tho administration period. In case of the male given 20 cs 005318 g/kg and dled during the recovery period, reduced spontaneous movement. lying. bradypnes. reddish selivation and brownish urine were found on day 31 (viz. day 3 of recovery), then died on the next day. Loss of hair found in' females of the 30 mg/kg group during the administration period lasted until the tersination of the recovery period, whereas the coat staining in one female disappeared after day 34 (viz. day 6 of recovery). 3. Body Welght (Fig.1, Table 2, Appendix 2) 3-1 During the adatnistration period Body weight gain in the 10 g/kg or lower dose groups was similar to that of the control throughout the adainistration period. Significant supprossion of wolght gain, however, appeared in both males and Females receiving 30 ng/kg (rats of the recovery group inclusive) from neck 2 and after 3-2 During the recovery period The above-mentioned supprssion of weight gain during the administration period lasted until the end of recovery period. 4. Food Consumption (Table 3, Apondix 3) 4-1 During the adaintstration period Food consusption in the 10 mg/kg or lower dose groups was similar to that of the control throughout the adainistration period. Significant suppression of the consumption, however, was observed in both sexes receiving 30 s5/ks (rats of the recovery group inclusive) from wesk 2 and after. 4-2 During the recovery poriod The suppression in females of the 30 mg/kg group lasted ono more week after the finish of the adsinistration. -- 18 -- 005319 5. Hematological Findings (Table 4 and 5. Appendix 4 and ) - 5-1 At the ond of the adainistration period Hematological examination with animals of the mafn groups performed on the scheduled cacropsy-day revealed the following changes: decreased hemoglobin concentration In males of the 10 sg/kg and higher dose groups Saduced prothronbin tins in females receiving 30 mg/kg. 5-2 At tho end of the recovery period Mtor-racovery examination with animals of the 30 mg/kg recovery group ceveslod the following changes: In males, decrease of erythrocyte cout, hemoglobin concentration, and hematocrit, shortening of prothrosbin tise, and tncresse of lskoeyte count: in females. ducresse of hesoglobin concentration snd sesn corpuscular hemoglobin concentration. shortening of activated partial throsboplsstin tise, and increase of mean corpuscular volume. 6. Blocheateal Findings (Tablo 6. Appendix 6) 6-1 at tho and of tho administration period The exsainstion with saisals of the main grows resulted in decrense of GOT in females of the 1 mg/kg and higher dese grow. and increase of albuntn in also females of the 10 mg/kg and higher dose groups. Moraovar. In the 30 ng/kg group. the Following changes were significant: increase of GPT and of chlorids, and decresse of total cholesterol, all these fa both sexes: dacronse of total protein and faceesss of alkeline phosphatase and of MG ratio, all these in males; and increase of ures nitrogen in fonates. In addition, reddish changa of serus was visually recognized in tro males (anisal nos. 3102, 30 snd in one female (anisal mo. 3205) given 10 "/kg. and 1a five males (animal nos. 4101, 4102. 4103, 4105. 4108) ond in 11 females given 30 ng/kg. K [PU 005320 6-2 At the end of the recovery period Significant changes detected in the 30 mg/kg recovery group were as follows: lowering of triglycerides and increase of A/G ratio in males: increasa of urea nitrogen, total protein. slbuain. calcius, inorganic Phosphorous and sodius, and docreaso of glucose and triglycerides, all those in females. And besides, reddish change of sorus was recognized in four males (animal Bos. 4108, 4110, 4111, 4112) and in threo femsles (animal nos. 4207, 4210, 21). 7. Urtnalysts (Table 7, Appendix 7) 7-1 During the adainistration period The exaatnation perforsed with rats (Inclusive of the recovery group) ome Weck before the end of adainistration period resulted in the following changes: pi shift to alkaline side in males of the 1 mg/kg and 10 mg/kg groups and in females receiving 0.1 ag/kg: pH shift to acidic side in both sexes rocolving 30 =g/kg: decrease of occult blood in males recelving 30 m8/kg: decrease of protein in females receiving 30 sg/kg 7-2 During the recovery period Shift of pH to acidic side was noted in males of the 30 mg/kg recovery Foup in the oxaatnation conducted one week befora the end of the period 8. Pathological Findings 8-1 Organ weight (Table 8 and 3: Appendix 8 and 9) 8-1-1 Absolute organ weight 1) At the ond of the adainistration period With the animals of the main groups, liver weight (increased in both males -- em -- 005321 and females of the 10 mg/kg sad higher dose grows: wheres weigh decreased in Kidneys of males snd ovarles of females. both in the 30 we/k croup. 2 At the ond of the recovery poriod Changes noted in the 30 mg/kg Tocovery group were os follows: incresse of the Liver weight in both sexes; Increase in the testes of sales; decrasse a the kidueys. 10 the adranals and in the ovaries, all theso of fomales. 6-1-2 Relative organ weight 1) At tho and of the adatnistration period Increase of liver weight found in the sbsolute weight ith the 10 mg/kg ana higher dose groups as also detected fn the relative weight in both sales and females. In addition, the followings wero observed: incresse in tho brain of both sexes receiving 30 ag/kg: incresse in the adrenals and tho testes of sales receiving 30 =y/k: increase in the Kidneys of females siven 10 ng/kg and higher dose. 2) At the end of the recovery poriod Changes detected in the 20 xg/ky recovery group were as follows: increase in the liver and the brain of both sexes: increase In the testes of sales Increase tn the Kidneys of females. 8-2 Macroscopic tindings at necropsy (Tsblo 10; Appendix 10 and 12) 8-21 Hacroscople Findings in tho desd animal Autopsy on the male died during tho recovery period (animal no. 4108) cevealed the following changes: ateophy and dock reddish patch in the tho small Intestine: grayish patch ta tho liver 8-2-2 Macroscopic findings at scheduled necropsy a 005322 Gross pathological findings observed were listed below. - 1) At the end of the adainlstration period Males of the 30 mg/kg group---greylsh dot or patch in the liver and hypertrophy of the liver, in all six rats; blackish change in tho Kidneys and dark reddish chango {n the adrenals, in one rat. Females of the 30 mg/kg group---dark reddish change. yellowish change and grayish patch in the liver, in four, one and one rats respectively; hypertrophy of the liver, in all six rats: pyelectasis in the kidneys of ono rat. Femsles of the 10 mg/kg group---dack reddish change in the liver in one sat. Othors----graysh patch in the kidnoys of one male of the 1 mg/kg groups pysloctasts in the kidneys of ono sale of the 0.1 ng/kg group: cyst in the kidneys and dark reddish patch fn the lung, cach in ono male of the control group. 2) At the end of the recovery period Males of the 30 ag/kg group---graylsh patch and dark reddish change, and Bypertrophy in the liver, all these in tno rats Females of the 30 mg/kg group---dark reddish change and grayish patch. and hypertrophy in the Liver, in five, one, and one rat respectively. Others----atrophy of tho testes in one mala of the control. 8-3 Histological findings (Table 11; Appendix 11 and 12) 8-3-1 Histological findings in the dead anisal Histopathological examination with the male died during the recovery Poriod (animal no.4109) revealed the following findings: eosinophilic dogoneration In contrilobular hepatocytes. focal necrosis and peripheral fatty change in the liver; dilated tubules in restricted part of the -- 22 -- 005323 kidneys: hemorchagic foc! in the brain: ulcer and hemorrhage in the glandular stomach; congestion and hemorrhage fn the thysus. No abnormality was obvsorved in the heart, spleen, adrenals and testes. 8-3-2 Histological findings at scheduled necropsy Histological findings observed were listed below. 1) At the end of the adatnistration period tiver In centrilobular hepatocytes, cytoplasa appeared to be granular and eosinophilic, and swelling was recognized in all sales and females of tho 30 mg/kg group: in the 10 mg/kg group. the similar changes. though slightly, wero found in all males; and in fosales, either the swelling or eosinophilic change was observed in four rats even slighter in incidence and intensity than in male; in the 1 mg /kg group. the similar change was slighter in intensity and Incidence then in 10 mg/kg group. (Photo 1 and 2. Focal necrosis in hepatocytes was found in five males and two females of the 30 ng/kg group. and in two males of the 10 mg/kg group. The necrosis as found also in one male of the control. Fatty change in peripheral lobule xas remarkable in males of the 30 mg/kg group (Photo 4): In females, however, the incidence and intensity was siatlar to that in the control. Localized fatty change was also observed in one male of the control. Microglanulosa was found in a fox males and females of all groups. though clear difference in incidence and intensity was mot noticed between each dose group and the control group. @ Heart No abnormalities were found except extremely localized myocardinal dogoneration in two male of `the control group. -- 23 -- 005324  Spleen = No abrorsalities were found except extramedullary hematopofesis in three Bale of the control group. @ Kidneys Regenerated tubules were found in both males and females of the 30 mg/kg and the control groups though no difference in incidence and intensity botueen two groups wes noted. Other findings: dilated tubules in one male of the control; infiltration of lymphocytes in the interstitial tissue in one male of the 30 mg/kg group and threo male and female of the control: dilation of pelvis in two males and fn one female of the 30 mg/kg group. Adrenals, brain and testes or ovaries No abnormalities were observed. 2) At the end of the recovery period Liver Contrilabular hepatocytes were eosinophilic and showed swelling fn all mals and females given 30 ng/kg. As compared to tho main group animals, eosinophilic intensity turned slighter in both sexes: however, the intensity of swelling was siailar to that in the main group. Focal necrosts in hepatocytes was found fn three males and two females of the 30 g/kg group. though none In the control. Other findings: fatty change in poriphoral lobule and microglanulons were Observed, tho former was somewhat definite in males given 30 mg/kg. the latter, however, no difference was found with the control. @ oart Very slight myocardial fibrosis was found in one male of each of the 30 mg/kg and the control group, and myocardial degeneration was found fn one female of the cotrol. No other abnormal findings were noted. Spleen No sbnoraal findings were found except extramedullary hematopoiesis in one -- 24 -- 005325 2ale of each of the 30 g/kg and control groups. - Kidneys Rogonerated tubules were found in both sexes of every groups infiltration of lymphocytes tn interstitial tissue as observard in one male and in two fomalo of the 30 g/kg and the control group. respectively: very slight chronic nephropathy as found fn ome male given 30 mg/kg. No other [rT T---- Testes No sbnorsal findings were noticed except atrophy in one male of the control group. Adrenals, brain and ovaries o abaoeaalities wore observed. 5) Histological findings for gross pathological abnormalities Swelling of cytoplasa of centrilobular hepatocytes and focal mecrosis were found corresponding to the macroscopic findings of hypertrophy and grayish patch, respectively. 25 -- 00532 DISCUSSION AND CONCLUSION - Mejor findings obtained through repeated oral sdainistration of the test substance to rats for 20 days were sussarized below. Those changes were considered to be affected by the test substance. \roriod Bxoatnetion Findings Dose g/kg) Clinical signs (1)reduced spontaneous movement bradypna, nesta, salivation, convulsion; sup- Pression of body weight gain and food consusp- tion death occurred(numberof the animal) Homatologieal findings=----inclination to anemia, abnorasl change of blood cosgulation Slochenical Findings--Kbnoras] changes In 1ipids, protein, and in enzymes of in electolytes Urinalysis (acidic urine a sale, fi [sasinisiration J 7 female recamery 0 = ` = 0 ` = ` = Organ woight---changs In sbiolute eight of The Laver: change in relative weiogfhthte Tver and Kid neys scroscople findings greyish dot or patch and hypertrophy fn the Liver Histological Findings such changes 83 eosinophil 1c swelling and focal neccosis in the Liver, fatty change ipneripheral lobule = . oe ` = ` = . -" 1) Observation during each of the sdsinistration aad the recovery pociod. (+) Exonination one neck before each end of the administration snd the recovery pariod. Tho other examination was practised at each end of the administration 30d the recovery period. ~ 26 -- 005327 [Changes suggesting relation with the liver] ts Among the changes detected. decrease of serus cholesterol was remsckable. Though the mechanisn of the reaction fs mot clear, it fs generally accepted that cholesterol is produced through synthesis in the liver and absorption of lipid fn the intestine and fs controlled through accumulation in tissues, conversion into encrgy and excretion from the body. As decrease of total protein end increase of A/G ratio in males or increase of albuain in fosales wore found, considering the comnoction eaong protein and lipoprotein and cholesterol, influence of the test substance on globulin or effect to decrease lipoprotein was suggested: hence, for the reduction of serus cholesterol, concern of the liver was suspected. Lowering of triglyceride found in both males and females of the 30 mg/kg recovery group was also considered to. be affected by the test substance; because the same tendency was observed in the main group though statistically insignificant and the facts that the test substance was suspected to affect to lipids as mentioned above. Moreover, changes in enzyses relating to the liver. increase of the liver weight such macroscopic findings in the necropsy as grayish dot/patch and hypertrophy, and histopathological pictures such ss eosinophilic swelling and focal necrosis in centrilobular hopatocytes which were considered to bo connected with the macroscopic findings, all thess changes suggested that the test substance affected to the liver parenchysa. Mditional changes suggesting relation with the liver were shortened prothrombin tise in females of the 30 ag/kg main group and in males of the seme dose of the recovery group, shortened activated partial throsboplastine tise in females of the 30 mg/kg recovery group. Changes of calciua and glucose observed in females of the 30 mg/kg recovery group. though not found in the main group. were a little remarkable comparing with level of physiological variation, and connection with the adainist- -- 27 -- 005328 ration of the test subst vas prosusnd. . Ghenges seppesing swiation with othe orgs] 1+" to tho inceensn of Leukocyte count observed In the 30 musk secovery Grow, the sechanisn vs uncles: the sm tendency. Bower, van motions in the sain grow hough statistically fosigeificant. Theretors the connection with th test substance was svected. For the incresso of ren nitrogen found In females given 30 mgs in bon the xan and the recovery groups. wes aot clans shecher tho charge sas coved by dogrdation of protets or by sxcretion disturtence fn the Kidneys: hover, consideriag such facts 33 the incrbuse of chloride tn both exes of the 50 ng/kg nein grow nd the Incronse of th Kidaors ight 15 fonaien of the 10 25k ox higher dose man grovps and of the 30 w/e rocoary group, effect of the test substance to She kidneys sas pected, Shough no histological changes ore found. 1s to radish hangs of sorun sacegnized visually In both sees of Che 10 100 30 wy/g. groups. sumetines 7 GTP sctieity dons not change pperently "hen reddish sexun was covses by hessizsis, Tn this casn of the study. bovever, the elation among the seddish serum and heseiysts and 7 GIF en Chases considered not to bo relat to the test substance) Tho totioning changes wore considered ot to bn elated fo he affect of Changes of inorganic phosphorous and soften chaeved fn Femsies of the 30 A ---- senitate of the chosgen wes within Tiatt of ghysiologient wavtecion wna tTohewcehiamnigyeastew,erestngouttifocuanndt idnectcheessmeainofgrocucp.lt blood was recorded fn sales of tho 50 ng/g main grow: i was, Hoxeer, considered to be opparont, = as 005329 because one case of occult ores 13s ating wes detected statisti blood occurred in the control scotdentally, Trims o shifisd tn allolie se Wh te ststeleiestion in wales sooateing 2 ant) 0 waste and 0 Seles TRSNTING Bk tHE toe Changes however, was not dose-dependent. and the change was considered ot to be A-- Noight fackonse of the brain and the testes and docrosss of the ovaries wero abssevad fn males oF fanales given 0 ng in both the mein and the recovery grows: no histological findings. however. vere detected, Therefore, the chasges were comidoret to bu sppesent cwused by dootorns of tho body weight and to have no toxicological sigaiticance hs for the macroscopic changes in the adrenals found In sales o fomsios 2ivsn 35 sari, 70 istslegtont Strings wate deteisnts HRY We Julget o have Little toxicological sigaiticonce, tharos. Conconiog any othr changes such as gross pathological findings having 20 toon Supontancy ab me Mrslogwsl Gnbinsn vast dvmeseeiored nctdenta. hey vere fudged to bo unconnected with th test substance {onctuntons Me `nontioned shove, significant response was found in the lives by snintstering the test substance to both sexes of rats with 1 s/he or Miho dose. Hnorons none of response was cbserved fn the 0.1 mg/kg group [a Soosptoce, the snmiootogiesd sporsessisattun faved ED oF the ast hatasen, agin, Bets wou COSTAE 48. D0 Gob SETHE. S00 WHER 284 O08 ---- ES 005330 FIGURES AND TABLES (GroupMean Data) 005331 w= s5 = vdy = [---- 3 om ` 150 pT Study No. BMRI43C rate riE d ge FIE Pa alleeR A wr. ge Mainistration ----i-- Recovery ---- 7 1A%53 Daye after comercsnent of treated . g5 = FE PE) 833 om 150 pT @ Forala Pa TEE k =r F n aeomersem " Aministration ------+ Recovery ----+ 7 14 2 2 E @ Daye after commencement of treated Fig. 1 Cfheamnagleesraitns mdeaunrinbgody28 wdeaiygshtofoformaalle and a14dmdianyisstrraetcioovneryofpeSraimopdl.e D-1 and CBms + Rims imo AlBmk X Bra 005332 - " a8 8 a fr Sihebe EEeIA na Sot ce SLE es asthe sommo rs tier coment /cevstion of \restaent t SliSET INNIS Rau S Enns Bn RG uw am --_-- |T , ): : i un nT Tw mss ` i ast FH adhe Me Te no tei e t--se ars--su--ss sor mee Rennhmefa= ` = EaEmme e a tomas SA h tin arI ds E ' ar SHtIEie Fyre Bun r ' e-- i| A CSS TE TT TTT en . 8 288 i me aon ot elonhe- Groreup peaen vata stnvo. mniasc ` _-- bse tre Tatars' Bere 01 wwie t Vecks atte comencennt ceretion of srenteent -- ow SwA oowm. m B\ omn2F r oswlr f oCsmm wm mom m m moomm ' Gimme gen oo:n aomn' do mwm:op,ny: om.t : : , | Tene Hgen\ooomW: aoomm| oomms: oomay ae : oS 10 mks 44 Mean 5.0. & ww wSmEOsw Em THEmw 8 n 13 5.8 5 201 8.8 s 257 u.2 5 mmee 305 19.s6 343 0.5 mmeew gaeese ame T Sr er S mE dg es ea } 3 1 Tbe 2. Body weight - Group sean values Study No. BARISC TestarticlSeex 5 SFaemmpallee 0-1 _etre Wit: g bose level Veeks after consencesent/ cessation of treataent _C o r ' 2 5 m 1 sn on Omaske 5He5aW 140 iz a1015 iz 1119i9z 1a8:i73z 1285i57z 22614 2a7 0d mefke tseia;nW 3129o 2103s 10m5 81s 12015 Lae eSba.nW 153165 31167 1129i2 1a572s 12519d5 $ 0am tSenN 51590 71691d 0185` 152:043 1214 8 & wma p55e.ni 31i:mz 715i08z 7mi2ze 7mi8ezwn 10u:i9zsw 0t:5dse 1ms3ga TT STIR GnTerent fro esntrel ElGe Wy pL 5 : ` |. |,i ie aon rostecaonsds gptio|ne - GSroiubpieeaonn values Str vo. omresc ` b--s_e--reve esa ster concent cessation of wWiit: sevens vwAheats _-- EE Laf>rCwm m m om ' Si ER lw mWm ommo dwt m| m| mme tomamom om3 ome3 , trpEi ONme$ i3 s wa | s wwgm3 } 0a3 3 $s Was s gienesn 5 omeE m ws nae3 g8 wma SMenioo1m5.4t m5t8t 4 t15.34 W12.|74om20.4$ }2.2 : i He aep Food consSgemion- Greoumpimean values Study vo. ouaac ` -_-- Testarticie Sle on nit akskinimsait/ony bose tevet Veeks atte comenceseat/ cessation of treatacnt r _ e : 1 2 3 a Ss 6/2 t a seoi i E : EiE EE i oTmE? mp3 , Cli gseni ooBa: amme3 of mai mpa3 | te fen 0 ma ona ae ov i5.0. 3 2.35 Wane gen pr 31.55 ws 1017 3 0.79 wa ag $S$ * 88 was i$.0. 1.03 smenhoone 3 0.81 07 3 0.36 omladr osttim Nstew r uss msg i: TST ny iT ier frgerl We o TRS 3 7 -------- i 1 toTseeer omAs Clans tale 8@ Wake 88Bown TT Goocmlo) mSmWheeoms tSenioospme5 pSeOnW WoEm` bSaneogom0 wSniosyom: Seay Ger Toe ane HTeemstatarotlicSle-ecGrogSmTieaatnmeevaplts nial ied on scheble (3 vcs) cWoE"m.D MoM (OK) ae) mre eK) ewma oanlgo aE3i 83daa mteeo oweom3 aa7Ros a a @ w mo wTay3 ewie@ 3maao ao35 meom3 moawr3 epmasr maad` aM5 OBaSw% mUem5 ewea.e osw ksE s mfa mTeea fal xco p 3 study fo. mRitzc wchooueente) MNT ee eo pTleerSCioomt gwwso bwezo B meo Wwe" hma1` MwpoT mRas &Bme3 P meo ROwa5 S megs B= oemg5 oxa` mBEss = 3 sPgE o7z ogom o oxa 5 :| i _--_-- i. _evel-- Wane TT aSSs s24 The 4-n-2 HTeemsattaolrtPiocell-e"Gro SmewTaaantpvealu0e-s1 animals killed on schedule (Recovers) aCmmlt Oo) mcGonIe.D Bom OK) we) GmD ee (Kalcmooen)e FF TR Um E s0eoE sd5 oR0 a@ 2S 2i mom0 mi0ko wmke5 tSniomeW3e epRas w MLeE5r 2m230 omnas wLas: omms3 Sica Geren TrewGora alee 50S + Hp om 9 eo oonnss omna5s Stodybo. old em Ge SsieecaTonnt em eh aios 3=Ty i15B23 a s i ewemt5dreo reaTea oes sur we ` we TTTmTomeen TRrrmHam dEmon| cm Ee eS rmc emeee----on ----wm --m--e -- =) owM wBnF T oGT moooN lG Bs 0m ma 8 H 7 aan w w m me h ooamafo aw=l) rmm eone wma weonmoe WSTTo2h2 GlwmowBn oseOmREeoMd mmMRe eonma Wmremg oRmoma meweoymews eh dE pomegd oaa BE ww WoodOTE fme olws ow a megHoomamowmmeeeowwg owmde enoa 2a8GoE wn mWoeOT S mM mrWomss o0S ommaeg woademommee mwael omwaae aaa " g SD.o T ot s.S 6aa t0.43n owsat2e.r8-- 5ae -- 15 -- 118 -- 192te --nsond --021a-- t 20-- 2df* 2.8 1 Te 4f-2 Stuy do. mI HTeemsattaorlotgiycSle-ceGrosp sSeFiemnmpavllaeelu0e-1s. t -_-- Mnisa1s led on schedule (Recovers) eovseel _-- ncCoetE) cW o"m. EwoD o ) ow GD WIC (%) ocPulaie te.let FT eo NT se aRetteiccuolot- Omhs tsen0towsmsg o1l 7 TW TR Um Ew Se eT g1a@ 23 o0m2 wLsi uwws omns oIses 323 Davie stehn" mo3m4 onme5s owie5 s5555 B@@esBT ammew mmsa omiw p1aas ioes 5o 5s s 58 uw i Tie semen Henstolons5=,Gr8oup sTeaen values Stuy No. amiaac . _-- TanTh ieesatM tsartkicile ee.d one schSesuur lee Gphye weeks)leles ttoosee Gcwoiemta) mGepSshit:ferentisaetmecmoa tuendt of hlaenuakocytes hCiXeof total counted hs colts om : ome S tenW ak5i SuTni adsi os1 ofio 00o: 2:. , Stans ten i 1o0a8%: 8o`r a:: ofo& 1i' of0 23i` : Lads wteniean1i 3wwi ais ofi0 ofi' of@0 13:: a8 Werks p5e5an nwen: p5e:5l fe0): 0.03o 10| 0.0@0 28:5 g T wus penW W1Yi e e P5i: e2i. 0dt: m 0p3o od0@ 035 i | Tele seme2 Study no. BARIAIC HTeeasattolaorgtyicSle- xe Grou1 p mMeaalnevalues Sample pot ` _-- Anieals'kiiled on schedule (Recovery) DToesvee.t cCowuIent0e) cLylmeDhsiofrferentisaelpmecnoNtueenudttroofphiBllaesnudkocytes Bo(vi3neo:f ais totalBascaorunted shite ceHlonle)s: Mores Omeske HSe.n i 13593 s a055 8 o1l 0.350 0.s00 0.400 185o i 0 weke e55a;ni 1e 1%3 wa3 Les5 [x3:1 0.00s 0.00 5 5.25 .: I# StCaAtistical analysis aIsposA sibic. LE or a ry E -- s 2 1 | Tle Sof. Stay No. omRIAsC HeTmeasttolaorgtyiScel-xeGrou1p mSeMauonmnlavetalpu-e1s ` T --_-- Animals killed oR n schedule Ch weeks) Dofesveer cCovuiInctCA) cLylnegDshiofrferentisaelmecnNotueenudttroofphiBllaesnudkocytes Eho(isl%iengo-f totalhBaiccooe-unted ceTolnolo)is. . Omsk eoayn W 10:75 350 n1ls0 0881 0.0o0 0.00 2.s08 ' Ol mfg HBooan i 01.011` aar a0g7 0.08s [>0 0.050 2531 . Pade Ms5e.n0 ul55 awa5 13015 0.s80 0.085 0.so0 13s2 a8 0k eSa;nW 2535 aat 215o 0.40 0.s50 0.`00 75 0 m/ke MSe5ann 15.355 08 358 0.40 0.4s0 0.00 245 TS een E ii -_-- Dtoesveel Ome Hoeyan Wake Mpeeani TE Tbe 5-f-2 HTeeasattoalrotriycSel+xe"Grou1"p sSe"Faaenmmlavleealpuets Animals killed on schedule (Recovery) IcwoneAt ) cLyytmepDshiof-ferentisaelmmecnNoteueundttroopfhiBlafenoudkocytes pEh(oislXisno-f 58955 6a3@ 53s9 E15e1] 2938 2i2si ShUsaT wes wee 0.8s0 1381 0.40 [30 s Study No. totalhBiactgoosu-nted 0.0so 0.s0 mHRI3C celTolnosoi") al5 19` a8 a 15 ' i . vo | Te Gone ClTiensitcaarlticcShleaesistr y S-luGperoluep sean 0-1 values Animal ki ed on scho(d4avelckes) Studylo. BRI ` t=e] ar WH er an par aun we aun nEiUtdreodgen Crtinin Guess Gud Ged cThoall. ew cTreirgtldytae Ome site.n L&` Y]P8y 00]0mm3d nIaR ooxs 5 00g o5s mx2 Olan eoyn n 960d 51 Q 000 0 me8m o 2n0g8 o0x53 1n5g03 i a5s u5g5 | 3 tana pSeTni aald 0355 000 m Ar n18a0 oonsa 9104 5 3C) weo 2" Dune sie,nW 3a9g aa2i 000` mw2ms 2n8ai oobs o 8102 wl aw 388 own Spain 9n8 wSz H s 000 s anwae w uigk o0.n5 a 41%0 s 20[EY5 CT SStatiT stical aSmiyseis imosrsiobiec. 5s5 is pl : i iwietnysrms i ore Se sn vo : m e i= Bohr eoR ww TieE wwn E=Bbie wwnn wwnn ewwn : 2 sa. 0.09 0.146 0.1 0.30 0.8 0.9 0.33 14 rE ; S own om sont zee wo wo ow an me Tbe 6en-3 CTleisnticaarltichcSelneoistteyS-MGuarllueep0m-e1anvalues Anina1s ile on schesle (covers) Studyto. ERIC | tleoveel an OT rr Wad) AP aun GiUtrmodren Cabin Gus we Gu Tcooll. ean Tcornitdg ay Omi tan 5.0.W 5 d7 2 .8 0.o0 my5.2@ 7 242 05 0.05 3 us 5.94 ES uid 3 5.0 i Mahe stien & 8n5 s wi s 000 5 wmd3oonssd5 ooms 5 u1y5 s ou z s ao2 s s StaTtistSicaRl amGiiyteeie imfprosoimbcloen.tol woe FTpO aS a e i vo {: He eonea incl misty -Gram ssnvats Sayto. woe . iTaettanWiuS lsd on se hSelse Gomer) biT eo--w_-- T wT Qeein n wan lAGe OGe lnde simrne eWn kawn wouo n . owA pSmooedsw wsossMN o1m0ME V owmeMeW)oofPr GMwnm4ag wE anel o ewom \ owe gSeniemamEoM wiw Mdimn'e d1aeg OsBeeg w1%m faFnel a T SeTaso R 28a & 6 {i Te 8eF-1 CTliensitcaarlticcShleeexaistr y -FeGmraoluep Suple mean 0-1 values nies Killedonschedl(e4 seeks) Stay do. BRIG toesveel an wn OT aun rE awn WP aun nGiWtrahogen Gat Gus ed ewe GoTolal.ln cTreilgay ey Ome eSabn n 8C0d3 3z5d ofo ` mwz5 n1g% 5 o0n5 5 71%3 i 053 i I2x} d ` OlseSnoi 50o 4x8s 000s mwme 3phas o0m65 o1p05 652 s 0z4 o ` Take sie.n 7w4` u 229 of0 mwims zi o0e5d 833s s5is 622i Owe esanWhowsasn 3a20 3 000 msa imis ` oonso 113S5 arldy 229 o 2aaa R was eSTTn.0 eyaSSH GTfmrMeoO le0 mme0 smios w 0o6ss , m1esd 5x5d 8 a7o @ i THe 6-fo2 Studyho. BRIG ClTiensitcaarlticcShleesiFstr y S-Grireaompullpee sean 0-1 values --_ AisaKi ed onsche-- dule (1 vecks) -- DToosweel _-- wpTroWatein Abin wan aAtGlo Glow Gi) Epword:e)ic GD x Ga) a Gen) Omics tSmti ooo8mG oamm 01mmm v7 WP TD ea wn o5i4s igka 0nmp o4m1 01%0 3 Olwis MSan"hoosmss oaiws oism o9k5 10%7 s oms o1l5 2pe 5 Take SMeen 0ad8 iums oLjmo o] ooas ogdg s5 1mw2 o1i ` r10g1 o 8 Dwi bsan0hoo69 ciaesn's ooomm o9k1 o7n s5 U1s2 oal1i s r1ag a&a Wwk Sfehm 8 5 01m0m i oailse oiiw 3 oad9 ogme o nwoo d4n d 10838 0s TST dierentfrcon onvtateolTp 5 HT pT s s5 2 : | )' voli Te apes CllTeienitiacsarltHicceSteSssniant| sS-icemrhmoietc shperonvearse)s sue muse sooae GGT wow rm Cann aGuimrEe Get Geese an awn foaimin m oGilrym owhe bSmi Esom@ ow i wd` ooamn` Hom BOw s moo: aa` Lea5 i mks SMeanhom6E1i owy2: a0@ go387: 2HR0M.T14 TT S AeR fr tr al Fp 0.6 . m1@24em51: o1w:8 4 ` 5 Sista amir cre, $ g&8 " i in tay sn. oon EP tose T level frotein tio wa) an frost ee TeE w Bio wn ww an Gerd) Gad) GED GE) (ab) $0. 0.288 0.122 0.081 0.16 0.50 0.8 0.i2 12 EL rr a Sw 7.508 4n@ LW 2s git ls a3 105 8s ga = : | ` Co ' we Toner [ffrEoRrcIeSa-- | Bee-- su to. omic . h oxtUEla dmoal Bion Jfi oerwd ce wan ten Gwin ". TCh 00 MmBRLOnL0A0tU0B9iI2S0T0L1Ir RS00l0 S0S1S0R0ER B- 0o000800e 1 TBemn a 000t 6s 10e 115s0s 0ess P E e IIee S rAenet LLiiLo to ER EveRnRuP as R0 E auP g) 0 B 680000 mRO000 R80000008: 600006000 noo 0210 50 mo 00000 42g 6000 tsa 0 TTFE TO-- TG--ST---- Werte--S-- e -------- 500s0s;ss}t: 8 a rtA Tom on te 47 ts, 1 pn, ------ aaa Co ; Tle 7-n-2 Urine - Grog sen values Sat to. BRI . I5 svteasrilceseroc"omecaSeneeetoonf trestent Recovery) otoee eiEnlns aioll bliin Gaofleeitshey cs wan Protein Guin) " AO OLL2AE-HIBD ZN = SISNEN 010505 2 M010 29060657087085s 6800001sa1000i0so0s 50000 40010500005000 so 50 vo ots see 0000050 os 0 05 32t3a0o o0|o ++: SSigtneiiftilcaeentTlayEmdiaTffrrereeinofsTriormtlcoenST,trol3valu,de4re,p0S0. r a& * Co i Tle 7-f-1 UTreisntaalrytsiicslSe-oGrrtoupSsieFmaenpmllveealu0e-s1. 3 vee after comencencnt of treataent Stuyto. BRI . olseeer x rEgaeanin oBiloedl Bilirubin inedtioense Cewity Glucsse wan Protein Caan) ": oGm 0 MIm GELL0Z0A0e B0SWC2R0s I0M0U12s C0B0B0Ns 0T30T 0T S0ST O 01e 2-- 100-- 005i 0--0201---t 12-- 100 0e zm 80r 6.57.07a 5r808e5 1 10 660000 420006000 51000 88000022200 600024000 60 50 00 0000240 o 000015 00100a1s3s 3+s)l 0 $ 6060000 51000 600033000 00 0015, 50 0000240 G0 ay 10000 T520012000102000 20 0003540 " oFm i;SSitmatie ifsitcicaanltTyaEmdiiyfTsfeirraeenitspforsCosnibScloeIn.tr,ol BT dere,BTSere value, 4; 0.05. $8 p01. & 315g 0 8 a&8 aJ # Lo i Tle 1-F-2 Urinalysis Gra san values Sty o. mit . StTeRtISaGsr co|mecSinEt EoF reataent Recov.ery i. tee x urba einti- Sat win ertg Glity Glocose wan Protein 7 woo GAO IL2AZESRIBY Zn = S500 - oles x TB I0 06.06.5 701.58085 S 2 8P80E 000020 400 0050603 0082000 001500 00 06 0000 00100 34220006 00 00 000 1 130 5s0 ,! -- : Stati-- sticalTaEnaTysise-- iossiTCbSeIT. -- dente, -- TS -------- aS2 a8 7 !i Tele gene Organ weigShte(Atbsolutael)e= Group mean values Study No. BARIAIC ` T _-- r TAneisstaalrstikcilleled on schSeadputlee Cph1vece ks) _ Dose level F@A)V B@aiv n L@iv'er v K@ids w A[dr)enals Tv estes Ome BeaonW 23501 oLiere L1.i65 o2l.13i o 5s0i.e5 o2e.0s0 d Od mek 5ean " sai9g o1de` 98Lsists o2l.5e5 s satss o3i.1s4 | : Late SeTn w3T19 5 oLdast 1Lias s e2i.2n0 2s.i95 l3i.s1ts0 3S Wan 5MeanW w3s13i oLoom5 Lsiema s o2n0od wsisi o5i.0s1 A8a sm hS5e0n;i w2ea oLeemrs 32a0m H o2mam asies ` o3d.0s8 s TT #75 FSETiTgnificantlymdiwfferent fron control value , #4 ; pe0.01. % AE { | The 8-n-2 Study No. BHRIASC OTregsatnarwteiicglhSete(xA:bsoluMtSeaa)lm-epleGrp-o1up mean values, ` _---- Aninais killedT on schedulT e (Recovery) _ F Dose level F(AV s@rin Uvew r K@idneys (Aadr)enals T@estes , Oman sMie.anW 3a8d9 o2d0s55 1L3e57 o2s.4t1 B5i.s1 o2d.1a1 Washes Mbeoadn W 8H5+ o2l0s wLees e o2las s7t.3s1 o3i.l3? 4 | 3 s TR T TEe E e 3 5 s s : #3 Sianiticantly different fron control value , 3 p<0.05 , 4 } pe0.01. a8 348 I" [a i Tbe wep Organ veight (Absolute) - Group mean values Study Yo. BARISC _-- ATensitaalrstikcillSeleexd ont oscmSheaadtmuleee (gitveeks) Dose evel --_-- F[O5VC B@in C Uber W K@idneO ys [W h2aremls Qaunarles Ome beaen 0 w23a0 5 1od.e8r5 o8u.{1n]0 1o.l6i2ns 0s.i1e a8i5.ss7 0.1 mere eSainW was4 1o.s(7s49 o8d.6m5i 1o.i6e1 56.583 Bl.i1g Pate siea;ni 92355 10.9d1o o9.k01i o1do7ro a. s s2i.l0 a8S mk tSe5n0 W21As0 odLeess o 0sasm a s o1ki0e 082.185 853.38o =Q wah ptoeyn i 9M5 w ` oLdee ( ondas e o1lsa s55i.e0 725.10 38 TE #73 SigE nificanmtlyeaifeferent fros control value , #4 1 peo.ol. Wo ` , i . Codi | The sof-2 Suty No. BARIGSC TAOneriszgtsaanlrswteiKicigllSheltedREbosnolsuctha Seea)daull=ee G(0r.Ro1eucpovseerasn) values . T _-- he; bose level --_-- FEV maT in UneP K@iesW wpanres w ovaries Cure sHeoni aCeA& eam dim3 olino as` s Wake 5e5a;ni wH el3 eowedns oafsmtsteo oliifssste sfotis eom s e |,i #3 SaR niticTantlyEdifferent fron control value , 4 3 p<0.05 , 48 7 pe0.01, a28 88& a 4 1i || Te sono "Organeeilght WGaeitastve percentage of boty eighstty u o. smtinac , nfefrntalrStictlieSl'lhed on epSciehtte {n4tveoks) Soe tere --_-- F@E!E win lve lees GMriesmts Teme . omhs Sgenhv omewrm: oomms oahmms Goe. 18wss 5o%ms Clams gSenialem: aslls oehwh Moln: gg tem mm ese ae om B5R3s 5ogs ss gg i . 3 sioon: ol: ohi Sls : 5 & wwh gsmihoesan: beEn dwtsw Jolno pIes 8 wns esnioosmsa GwRYw` w mettn SoEm` TTEmme Mmasrse hLeege #2Significantly different fron control2 value , 3 p<0.05 , 4 1 50.01. o 1 Tbe 9-m-2 Study no. BARINC Organ weight (etative : percentage of body veizht) ATensitsslasrtikcilSleelxed on| scmShaaemldpellee (0-R1ecovery) Dose level _-- F6B)V brain Une Kidneys A[darteimnls Testes . Oke Msehan " s8d0 o 00.053 5 o3.R48 s o0l.d0s0 1L5.i41 o0.m70s 0 se M5e5ani BH503e 000s%st osmow 5 oolms 2156.s2 o0.m00s 35 ` : ST r#7E SignifimcCantly different fron control value , 5 p<0.05 , #4 ; peo.01, 2& 28 5 i Tbe 9rd Study vo. BaRI3C O=rGgraonupweitgahnt (vaRieuleastive percentage of body weight) TAensitnaiasrtkiicllSeeegxoin scShpieemdmpuallteee (04-1veeks) Dose level _-- F(E&V erin Liver Kidneys Awdorhem"ls GOviaoriseys Ouse esia.nN W23A0 006.8m0 3o.d8i1w o0b.7i0 22..728 aa83. OL mirke oMeradn W W2E1` 000.1s5 5 3e.l0i1m o0.g11d 226:.850 230.00 aSS tem sei.wW B2S5d 0obmm e3d.8n5 o0b.7i15 2257.36 pnea5 LSd mse stie;nW WaA1 o0.b0s7 oLds8H o0lsm w 22.5a 33.x0 Washes esia.nv 0m5oe 0068 H eTsa m o0bsm u w2.a50 p5e.d0 TT +3 SiPanEiTcEantlwy diefferent fro contol value , 48 5 3.01. ` . ' ` Co ' 1 ] ie area Org sigh tsi ecg of bd subs wlan) to. ore : ie e ot e tort t e E&G e R twin eUwe EEbeUslee ry[deattee teO]iDn own WweAoonan? SoRwtI Samm soyw: mme3onsns| 0 masks MWean; OM2$048 o0m.e9i04 a6g.0e804% a0m.e768 2m5.pi9 3o3.m0} ;|i 3g Li tn ---------- &gg i Et g a EEnHmRR. Fyn sp s $8ee9dg8is35e ob 0bdE0 e g i0 Er l 0 E0 gt 2o i1i o o r9 s0p oo8ga i Fu NEE. PRE RESELL shop : Wn S h0 0 e0 e% t b90on8 e s ae383 a8&3 8 "ioe 99000 1 i ry $E188 TEiEs 18388 21193 13118 A Hemme 13393 I1E3E8E83 }, es 8g&8 8 60000 60000 i tte oie tie crim TT Sm Tet avneiSelre1 ew Studymdo.esmitre . Wetoermions 13999 934908 24288 93i0g 131i En. 0000 60000 coon zines sabes un onto ffiEr oRc. a Ee rity 8&gg 8 4 00 0 0 2EE1R1EE0]1 cCoovuease $0000 sou Iii3EiiEisEs . Scoovoeon 60000 vo + Bo w eea e eSapte 5] 1e reerr rSimndyosc t EE. FREE BERD BREED gia : fry cooos boose soooa oozio o Earneores 60r08030 1008382%0 6i0308080 $vo80869080 | BReeEpEeT . BE3Ei3Ri9Ei9Ed9 4Gi1Rt8Ei8Es8D: BR24EE0O8R0EE0 3EB1MR0RE0EE0 0 ti 60000 50000 60000 60000 "emit 60000 30000 60000 60000 Iisa 50010 50000 a 33 vo v etsof Feti 1a lsehei e ri, i LL et Sinntir $$08081103 sora $to3o1o33 sg Be eormiteouyi. & 2g TS To 10----0-- 00 oe . ! ! ; t APPENDICES (Individual Data) 005372 TCaitnisctlicpsiieeg:etS lLIdeLiv0id1at EGTp BmaRiinTte 0123 4s SCexaTeaYecREAMom an RStotyne tossn aours we 2S1o0r 0 iiinsd SCSIoIIITIIIIIIIIIIIIIIIIIIIoIIoIIoIoIIGnIuaunCanT auWanHuaEEnaaaSnaRndnR: i|| kiis] S CI II II II II IIII IITII IaNaI I sQaQI I aUnAI I uYaI I aenRI I aEl: an Cittttisssseeiogmuoiwae gS --m -- m8 a 0T:eTonei-mcaoisis/bCleonricectomlsin, LY Line. St: Sifvation 1S : Rtdch salvation. 8 Brads, & vod t . ceGgTeTtosnpo1E1l1on -- I a = a AT d russ ane . [ $ wWT oTE r aTeT e TS T g . we ow #ii: . wA ooo E : L B0h ee onsrc,Te Toricn<lcitccoms, 11 re, 1 Ble il, 0: rn . ag g , \ ClinicaSloSpiopts -1I1n-di1vidual I TestartSicelxe. +Spaepmtlee D1 Study YoBan Gag aber 012345C Ts NURBUEBIBAN RAUNT t _-- Female josit -- sat -_-- = +oaboraality observed | aS a3 [Ea i TCeslt iarcticllsoepiep:s-Sa1mnpv2leiDd1ia RE EeEr erssiFm enle L Stat toPBrErLT) ` wr Se RR aont CTLIIILIIIIIIIIIIIIIILIoIoIIoImlugSllCaMaulgmuluoluueols mie 2 as Serer TL aa . rond SS eIIIIIII IIIIIhIuInI SInIuiIsgsnIGaIllIuaIsl as on S Se et ete. uuBpuMBUBBstBMRUBUUEBEEEYY | a CII III GeReaRaREwaaRnS ` nawr oe SIIIIIIIIIIIIIIIII w ellHSl _e -- w BL:ttteidcdlehdSspolntaineouvsCsa1evteGnrsia,mTosC:,1nT:ieLocslsico/fClbainirc,5ssiosnitons,tLaY:inLy.-i+ng.o8h:oCardouichiiyngs,eSr1v+edSelimtion I$] 33 : i TeCtiatcieclpSeie"pnstS-p1nl7ti5vi1cual Gang) mamher ow--mo-- wn-- SSSexA ele SS Us S36 su 8SADA 4/124/13 2A ` rele E Imoet U MUU WE oLou WLWU oa L ioamws o-I UooUWC ouou o0 uou oW 0 TWTo T2 T uTlT 2 dn LE: Lossof air, :Conttae,-: osors cerned. | a8 JJ8 i Aopendix 2-H - 1 Body weight = Individual values Study No. BMRLASC ` Dose leSveelx 1"5 Saalmeple Del 0 me/ks [er aRnaimmmaelr o Meeks atler commencement cessation of treatment 1 2 3 sn 2 : o00l11o00r23 11133296 2is3s 262489 136 252 a2031 301 335148 xx53 534 88 ` 000111000456 11144s0s 202078 21 22674 313289 75 327 555727 8858 570 Ks ` 000111000788 Tr18id1g 222001780 2i2556733 203501009 55302119 a3ou0sr3 30i6s85s xxx333 oooiuiiiez 1113s52 ais1s 198 225618 30708 250 308 332074 Bp 3S254 78 337444 xx55 do xs a9SW Memn si1s3 ie 2050s ie 122:620 iz 138047 iz as8z is 26306815 poasst 5 8Sw Ries on sonedue 5 o: i Mppentix 2-2 Body velahtLa= Individust values Stuy to. muniasc .` bose level Samle dt 01 make tse amnimea Veeks after commencement' cessation of treatment : : 5 ` on an : 1H110a81 Hat iwir 323006 Hie i pii iisnns it i om51eEs Ha | HHooet iis ii iin iiw fSiE . e5anW i1a: 20B7Y: W 260: ay a0: 42%50: WR eee a8 3 2 Co i Appendix 2 - K-23 Body weight - Individusl values Stuay No. BuRLaC , Dose levSeelx i"atSaemple del 1 me/ke nit cg ARunsihmearl o Vegks after commencement cessation of treatment 1 2 3 4 sn 2 : 222111000003 1113308 201s9o07 262265845 2533106s8 033056s4 xxks88 | 11000645 i11i7s 3ihn0e5 222577488 a33n0s f33r75i60g KKs5 3' N5e5a;nW 1i4z& 2E0a0 WATEa eee 2o6'5s` 1a2nei f2its 2a8 & 3 [a] i Appendix 2 -N- 4 Bog welghy = Indivigust values Study No. BMRLASC . Dose level : Sample D1 10 me/ke niece aRnuismhaelr o Weeks after conmencenent/ cossation of treatment 1 2 a . sn oe : a331100023 111543738 111953683 242254528 220089 280 234216 x85 320 k5 i f3i10t4 3106 1145s0 17 210348 282532 ht) Zo 3p0d1 308 333438809 111533 ` MBeyan% sl14s3s 20a0s. 2f5e7t` 3105.88s pr2ie43d ETRE eee 98& 2& 9 vod i hovendin owes Body weigh - Individual values Stay No. mumiezc , bose evSeel "HSemie ot 30 marke units saainnt o Veeks ater commencement! cessation of tresteent : : . ` on wn . iiwoenr dion 111508 Hi 1ii0n3 ise 2i333 iiiimn MHm200EEE15 , pdiiio]er iin iiid He iii i i3i iiinn i in RimEE 200 iat 0 5E26Ex5 : iiiien o Hii IEiHBHiie fiii% hE Fiii on iiin BS iiis on 2i00 h201E58 5i g g =FWWw 5wen 31%0 21% fi2t20 iwEe wm fi2e0s0 i2i33 wm A3ais: mE iwhu: 5KST eKaidT.Ted on schedule - 10 vol t Mependix 2 Fon Body weight - Individual values Stuy to. mL : bose levEeRl Sample ol 0 meskes wits g fiAsnitmeald o Veeks after comsencensnt/ cessation of treatment 1 2 ) ` on or . oCGoazaoooons iTMi1 iii1ie6 11H15i051 iimin Ha20eE1s Bek | GGGiaaooo Sion iii i ii15e ii iiise iiio sat i i3 ii s00 37 384 H225E18 \ GGGioits g om iii iH 3iie fe 1if0o0e in iii sor iBiid isieat i HiiEE 37k eS 8@ em 12i0t 1b6ii6z a1i1 1fnihr 12%i7t 20610: 2ari TET -------- n Co i penaix 1-pe2 Body weightSay= tndiividuest vaiues stay ve. mmiisc . Dose level Sele oi ot make wie | we Veeks : after comsenceneat/ 2 cessation . of trentoent ` on on Hii12oee0td1 111i2%0 ia i iii15e9 iat 11i1i0%s i1ii0e i HHHReRxs \ rd i fi ii kd mHEi . baweyfaln p1ise: i104i o1ns: o uz an27: RR se g 2&4 N ood i pendix zpos BeyDosveelethesSneetx~ InL1divOigeuSantSdva0tues Stuy do. mamncac een ` Aenimalro Weeks : after commencencnt : cessation a of trestommy4 [ , fii2i20)1 1iimh hi16ea2 1ii7 2s0od0 ` on H225i15 or E32H08 ii15d2 iiiit iiion i3sno2f i iHBHeEid ex i . -- bwieoaFan re-- B1e1: -- 15167i7 --Wu10-- 2: f-- ndri -- 12%25: ---- 82 g&a 1 Co i i Appendix 2 Fd Body elght - Individual values Study No. BURLATC . Dose leSveelx "4 FSeammaprlee D1 10 mek [a \ Necks after commencement/ cessation of treatment Nuaber o 1 2 5 ` sn 2 . 33s22200015 121122888 11156%0 111968365 202i1r38s 22i12e68 xxx85a ' 32332i000564 111333068 1iis6e9 111988197 220020388 22222213 Kxx888 | M50e5a;nW a1i3s0` 1ls6` WRT a eee a8 @3 a1888s 215004 3 i214i 1" Cod i Apendix 2 -F <5 Body velght = Individual values Study No. BMRLAC Dose level : Sample D-1 30 me/ke unt RAanmibmearl Weeks ater commencenent/ cessation of treatment 1 2 3 4 sn 2 | i4220021 i203 113310 127 i11s56160 1117812s4 111788908 111997448 K8x885 | do0a0es1 1113335836 11i68s80 i173 172 117757 152 2i0sl4 xx3s 191 %8 i"1222000780 111322198 1h186e70 1i167s77s 111668112 111765890 1i19s%4s 2i20s01o8 xkK5s5 So$ 1ua1nn0 111252042 1h8t9 157 i1n59 178 1h8i 175 116580 157 11897 212 i2s133 kKss 254 88 @) --meem------130------158------mn ------178 ------ 185 ----r 198 ees 208 SEW 3i3z 7i0z 2ie 8iz 10i9z be]5 1s8 BTR en whee 15 vo} i [TH Food consumptSaion - Iandlievidust values stuay vo. anvaac : sore towel | Samsle bi 0 merke Unit = a/aninat/oay cage Vecks aster commencssent/ cessation of treataent Number 1 2 a . sn 6/2 P PPs ooomsmwee mwpieEtdd B Bere enRi10di.3 anMww wma , ffmm wy hd f wo w mFsH . g ghwm m ama: aama: awe: iteus: mteas so s g mrwr ewmrem. w------------------------------------------ . 1 vo : Avpendix 3-H Food consusption ~ Individual values Study No. BuRLISC . Dose levSeelx': Saalmeple Dl 0.1 masks Unit: /animal Day cNaomgbeer Weeks after comsencement/ cessation of treatment ' 2 3 sn oz . 231 i117s6.s88 20is..2 28 117.s5 4 211a88.71 NnNAwA i MBeyan~ 1i8i.s03 20a.s63 2202.9253 2180.283s ` We alee Sas &&3 1 Co y Appendix 3 Meg Food consusptSeixo'n: = IMnadliovidual values Study No. BuRLaaC . _-- Dose level | Sample D1 1 mike BIL: e/animal say te:enim cNaumgbeer --_-- Weeks after commencement/ cessation of treatment 1 2 a ` on 2 . _--231 1118677.a03 1i198s..1s8 11187.11 111776.563 nNnMA i MSe5a0nW 01177.803 0197.33 1p8.c1 2 o1l7.833 ` WN amar etated a8 g 18 vo i Moendix| one Fond consueption - Individual values Stay to. igo , " Dose levseal | aSalmple D1 10 m/e Unit: a/ntmat/oay wCaakgee Veeks atter camsencement/ cessation of trsataent : : . ` on on . i+3 w1w6.ee1 pu17lu1 m i16:.0 di15.0 wW"w ` w5eainW 10.0 3 t1.a03 m 15.8: ya1a3 \ -- TR ------ &g g8 Co i Ncsabgeer ' :3: 1f155n i:: j[otiHs] 5ea5nw o16i.4 8 We ew &a Menai 3 He Food consumption = individual values sway vo. Lac .` Dose loSveen's| Shaalmeple bl 30 mere unit + animalony Veoks after commencement/ cessation of treataent 2 5 ` sn on : i11i4.s9 111845.51 11n2.y8 wa" ' 111051 1115546 ijiate] p0otn 2li0.es2 b1e5.d8: b15e.9o p1e2.t7i 2i0.43 niaa 3 0 [ i Appendix 3 Fe Food consumption = Individual values Study No. BuRLAC | Dose levSeelx':| FSeammapllee Dl 0 mike Unit: /Aninal/Day cNaumgbeer Meeks after commencement/ cessation of treatment 1 2 3 " sn oe . 1zi 1110220.764 11i23.01s 1118220.143 1113.00288 nNNmAA ' i` fri13est 1i12400l43 11f88t fr1e3t3 12 1199..26 2300.140 jot fed : H5o5a5n 1i5i.s8` 1l9i.e1s 1l3i.o9 j2i.t7 7100.43 s20e.03 8 RT No animal existed a8 8 | Appendix 3 -F-2 Food consumption - Individual values Stuay No. BURLASC . Dose levSeelx':| SFaemmpallee D1 0.1 mg/kg Unit: g/Animal/Day Nucmabgeer Weeks after comsencement/ cessation of treatment 1 2 a ` sn rz : 215 11133.0 nB12el7 1110230.}s1 11i2.e%1 nNaaa ' 5M5e(5a];n o1r2i.g7H B1x2.63 1i.43 1V2i.z43 ` WT Re wR ee a3S 28$ . 2 vo} i ceaoe ) i3: ii1 bseeaWnu p1r0s3 New &284 &8 Mvenaix aE ea Food consumpt(ionR-AInHdivNidual values Stuy No. Lec . Dose level} Semple D1 1 marie Unit: g/animal/oay Werks after comsenconent/ cessation of treatment 2 s ` sn oz 2 fj1ii0.t5 i[15a7l i1120 jwWny \ a193 i1.03 a13 . n Co } Appendix 3-4 Food consumption = Individual valves Study No. BURL Dose leSveelx': FSeammapllee Dl 10 merke Unit: g/Animal/Day Nucmabgeer Weeks after commencement/ cessation of treatment 1 2 5 ` sn oz ` 321 ix12s.d8 1n120e8 1ni0.0s42 10o90l.1d6 kNaAA | H5(e5a5}n 1t2i.o73 o1u.s5t3 01..283 0l93.673 . WT Wo SRT eed 8a 23& u Co i Aovendix 3 -F 8 Fond consumption = Individual values Study No. BuRLASC ` Dose levSeelx': SFeemmpallee D1 30 marks Unit: g/Animal/Day cNaumgbeer Weeks after comsencement/ cessation of treatment 1 2 3 4 sn oz . 23' 11125..04 iio9l.s6 i7ol.s9 al6ai.ss0 wniww i i` 11133s.72 1990'0ss7 iB7sy5 siiisss fr1152050 1i13.r16es : M55e5a;n] 01.27.B8b9 p10e.t3` px5.1 186.s0` pHoay5 1150.647 a 8o MIE mm enw a8 2 Co i -fm cwomcp om"5e Neer GIO) GAD ooloer m m Ewe 000s mw W7E 001100s5 ws wMo2 _-- ta50n. i w5o 5 0wmi Sayg 0 8 Mopendix 4--H1 HematologySe Individutaallevalues AnieDaolsse klielvleledon scShuemsillee (blveeks)0 me Study bo. BRIIC . . " no on (%) ue) GD HC pcloauntte,let pT (%) Gl) (se) LL cytecunt. GeO) wwes Ha 6 8 mm19 mi mo.;ys omnes 28 jos 1w3n.8 1 1871 mo Ixz i 6ans als w odmEa By m0o w7 Um42 1398 1815738 md 152 1 73 } 7 o2a68 4 29 xBS 0Le nwee g oMR35 11.61.84 5 3E3l 5 = ood i opens 4-2 Hebmaeteologlyevsee-lrIndiviSduHuaapllelvealutels 0.1 me niet lied onscaG4lseeeks) StuyYo. RIGS . Niambetr cGwmIctVE) cGonUew.D won CX) Ge) MKC GD (%) PCoeunl,e Give) MRT Roteelciouenst. Ge) (se) Ol nhmooe mm Bowy yn wm@oa & wmsia2 m%X o2 m mmeal MoMm9yy 1IIsdsa ==a | Hoet em m 3es uwar He ows Wr ss & wa@ils aX%0ss mworor mMmso1 ilaeded 525 J sg SfeBm wmrm` ouios 7zms to ooems mLids mmssl5 0wMos 6LE7 523s e28 7 Pal i Mopenix 4-3 HemtolonS=yx IntividHiaallevalves niDeossies Kllevieeld on sScahmepdllee (14 seeks)Laue StatyYo. BIAS . - ihmeir wcGocImpNA) cGoAwee.D woo (%) Ge) mC G9 (%) Pcloautnetlet GOED MT so) WT otReetcioluent eo) Oe) aa20ew0 oo@mm dwwloz ows sue s & mswmaiooomma2e owwmiaa wdomdae admsros =@zn ` o 2aa1e0ms1 mowmme ouIwssis adw7so CR m2r wmoyI dW+ewHdr dal dBie0rr1e 2z= | -- BgbSwN owemrs a wo wda2 Ld oemwo mLTMo wmer 0mdo5 L1555 2=0d @ Co i Aon 1-n-4 Voeivnsteoon0 esiohicdBbrisaeer4ssvet une sar, moc " Sro e oTt"t oo[3 nwovm. wo non Hac faFloairtedrmet wme Leuod ISh6ai ` w ddseeow mmommo esoE oprmsB oomoemomoycooo@@8 de mo om Eo o@ MMomwes EOIBmosm HDB MwWgsP woBB emD mwom we 23= Mom fr 3 | . se mo baw oa RoE OBO& 0% gJ S WwnhooodgmMEMomoaS s mmS ME aAwMs WfaN ogmms moamhj ommaS eR omS meawag 22g " i: denis 4-H-5 Hetmtoolaneytet- IntviSdialamteivealuv1es 0mie nels ied on schol 4 eck) StuyNo. BRIS . Njiemeir oGoncOtA) cGowAnseD WoW (KG WMC G0 (%) iMcvoeuenet)t mT 60 Go eiGteea)colnt ddw ews wTommos kmomesa wGwaes id mm de a & mewzss momm31s wmmi1o wWwaea mmBa1o @ is m1 m3 Wu: ja aau it i . BoD c dJmr e Wm -- NeI -- 8+%] -- &Go-- mi@s -- msse -- mmiore-- Mw12e -- tnwi -- etaa 8o2 steeanW m0si o13s.T3 a6.1 as@ l19o.s1 2L.00 e9mo onmao 418m.1@ 2 ` od + Jos 41-6 pra . emtaony- vid tus ninsees Wtoeenmtd on sSSeiaietseGshecoversyown eer -------------- Rmame cGw ome)mcGoEmD m 0) om Ge) A ep hc (5) aCmbawene)s mo eo ies NT ee fiBerSnee eetweet rset aaoere moowm onWdwEs BgE 1e0 B8og @mwse eee me ratet xmaF gmMau0 oph nae Eommse oo2zm ' SToauorrd oo=mmm m6 WEs & BBrr 880% B olmn RBa3 OBB4Ss wBe aIBws" Ma 332 | Erwmioodomoowsn eB (s1 dsi om08 mfe ommao omms5 o105 sox: ToT RSeTli an Co i dove 41-1 emtCooleofneyes-loIni1viSdilaatelvealvbees 0sue nats Kied on sclele Ghecovers) Studybo. DIAS ` nNaiomr cGwomtio cGownA"e.D WoW CK) Gd GD OC (6) Giaovneet) fT eo NT eo ea0el6sl)oet w ar om ow 0opdr 8m3s aomms owo@en amrs wBad uu2d EHu] i ooc d aioneommom' BowpEas Woowfss s8somowaswroo@owwlis Wwomdoe mdwrse lmisaa i52 ` a= --- 2 S bn" awhmg om&1S aUsm5 asz3 nadw5 oTmsa3 Wwms3 oommas 1B6m2: eadst ow a | ' dix 4-1 Hneitdeootseonityesec-todIionv| isdSaFeeltmRlueeeC4svel)owe stybo. gO , Niame Gcami cGoE Hm.D m0 Gm ww WK (6) wFainatee MAT eo eo oRiBeelScatne G@Goroom&om Bmo3B20T Wm3 Rs %o mBB3s BSm&1y agwna wwwias uwmseso2 J GGGyne Tmoeoso ommmeapoo7osgonooow. 0 BBms3e B@D3P oomwdis WwWesd E W ows Sa Bob | ghSmaosaomi oRms" 3m%eo ao3io fBmao WMsRs BMeEls omm3T W we4 l2 F8erm ------------------------------ 2aa Co ' hewis 4-7-2 etasooelatyesl=on"iv idSaelamlvtaeins omg Jains 1d on schle (3 seeks sitydo. wm ----mWener---- cGBoimCo--)o-- oGmmA.D--(--m %)eWGtad E GaD (M%C) R aAlamme)s Gmoo B eeTo RaBieee`)tcoemt mmwo oowwom mi @ mmmGss Bs @e@sre oBk omomswss ws 0 o% we mnmi2s x3 wowmaee @3 HoMwsi #3 mBB 1e0 Ra8 he 2 i mmws @ome mBEr #B3E 88 mwss %om4a wweis Wfad BH1e0 #B ' g SEEooom#i 8 ommei mTee aohwi oWeIo mfHeT Bm1R Mwesu ws ` 32 228a # [I | penx 4-3 HematologyS-oInd2ividFaelmavleas. AbnimoasleivTe1led on sScahmedpullee bGr8)ecks)1aye StuYyo BIOS . dRaibmelr wcGuIcnOtVE) cWon"eD. [a C6) no Ge G0 WC (6) PCloautnetlet Go) FT Ge) AT Rcyetteiocloou-nt (se) Oe) zmznnm mom wm 1zdsys waweeo somo0 mewmze wmcsrasoo d1ws3ass WMp2es Idphas xazl | womsst ewosow i3Gsmz m7adl & om@w37 @Wwiir umwirs #Md3saniargs 2ais ' 8a sthmi 2 3 mmp5 msoms wLmas -- 2@3 Lwa@d eee mLi2ss weeas 0m%25 1mGa5 225s tate ------ = Co i pendix Fa Stuy Yo. BRIE . HeDmoasteololegSvy-eolr Indi+ viSduFuaelmlavleaelu0es110 safiy nimi kiTied on schsule Ch veeks) -_-- Wmiamrl PcGsamlp o WconwUe.D WM (XD Ge) ME GD WC OK) wcPioaueenlt)et MNT so Ge) iRBeeteicwolnet _-- 7 TTT Wm asmaom Tm es oamwse aamnodd wow mi dio s 8 msmWis cmwa1sn amme3e wWWias 1l1ao @ mi @1 Wr ms ls Fza5 ' . T _wwe--s wosw mmss A wmosF aS 7 r ols W3s8 m ioesd 72is Pa Msahn oommee 0m1 m2%s5 261 0m%25 mLae wmas oweo o1Wa 22110 aES 7 8 = ol i rn 4-7-5 eomboileointP eionasR tSheBaseEhsvewan sane. mmec oSmo eowTi mmm mk oo wm wo amlfeyw mem ew eo SeWeShe @ om me wr ewamo omooke 1ouo2sw.m9os ooo@wwm.sse6 ow ma a1 ms m1 we ow ooo8wwa 19B mw.9oooo oag2s.z 6 opm9i.ho3 1BBh3.rr5 rohb15t2 mooa22 ;` WOW EE 8 moa om moma ggg h" wWnoodsom smeetu RfwMiw 3@ M meMpr o gm1 m v wC ahyr eonme r onmaE er moaa 23 Co t font 4-7-6 Styto. m0 emtoeny- Inivial values atnoieltioe1sn0t4 on cShBiemsilecEo(.ecovers)oun --_-- wiF _em--r cGBmCItO) cGom mADm ) mGe) GDW R(WKCO D GfofM oeety)e Eem Wm Teo aRaee)vceunlt ooonnx omemmso ooommweee oo6@me ao mo owlo Mi 8 oomwsmeyooommweee mMomaiy wr ows ma BmhsYa bs Bmo7rs hs o825m | w@ii --_-- mWs armi EomSC : oomH W woiwiW oowweo B Bbis BBbEaR B M8S F38 ` psaniomeom oonmao aio823i omm2o wlsi3 wweeu opms k8s 4o5w a2gSs S = Co | to 4-7-1 Sestolons Itividal vues iebserKieeotsanPEscSSlREsIE0(0hmers mas styto. R10 Ma cGB otecom mM 0 we hhc @ 60 aMaEae)s mo eo NT ee SfBhaSetaen Bmeeonooww Bo mmmsen ms oMmwers aio 4oom o@ wommose ms mmwiea fm`mmay ome ams BmB3Ya0 hs BpB Es Fo2z Bs x i $G2 ifGmsme Bwaioowow wowos mowss dfowss hfse hMid #& . og2 W Mw aom: EmBe3 mO1W MS@W W wr" W meo Wwso mpm " omns: 2xo B22 crr--------------t-- re-- m --_ 0 vg | Appendix 8-H -1 HemaDtooseloglyevse=el Ixn:dii viduSaaallmeplvealuDe1s 0 me/kg Animal Killed on schedule (4 veeks) Study No. BURLASC ANviimmbaelr cow(uaxne1t0'/ms) LyysepDshiof-ferentiSaelgmecnNoteuenvdttroopfniBliaesnudkocytes Bpho(it%lnsaosf|totalBwahsicoto-eunted celWGloesnos~) . a00t11o00r23 18a8 1aa 79i 111 1 0 .:1 i 000111000468 fiat0 7"50 1103` 05 1 0 54 ` 8ogs Mem W 2'as` 5a7s 5.2si 0.5s1 0.8o` 0.0o5 2.9g. 8Br ----------a gn 8 ot i Appendix 5-H 2 Stuay No. BURLASC . HemaDotsoelogtyevsoe-xl"Indi|viduMSaaallmeplveaiuDels 0.1 ma/ks Animals Killed on schedule C4 weeks) aNnuimmbaelr covuinct (x10%/mad) LcyysrpeDhsiof-ferentiSaelgmecNnoetuuentdtroopfhiBllaesnudkocytes Bno(is3li%engosf totalpBauscieossunted celvHloisneos.) ' 1i110o02r5 1i250 I"8 1s`5 1oi o3 o 733 ' o 1h0o4s eos 112=366 u55 1i 31 3s 351 : 5 = -o-oo [ es aW 2410088` aPe7l ` 3.95 ` 0.8o6 121 0.0o : 2.24` a Co i Mopendix 5 -M-a Stay vo. Bannaac . HaenmabitosoaelogatyieivseT=oledixn"odni visdcuahSaletlesw)uliveealuD(ea1sweeks) 1 mgrkg -_-- dNuimaelr --_ cGoviueenGt/m) iLylmpDehiafrferentisaelgmecKnoetuuentdtroopfniBliaennudkocytes mmo(irli%enaosf TTT hee hm wi totalBpaicsoeaunted Mh cel"slhesovne"n) ee : fpnoodrr 1i10s05?4 a55s fot iz 5 33:i o oo: i ooo o i1i 3 i | -- ffioot i5is _ 5a i= -- 01 i. -- 5o 58 a2&sg w5-- e5an m Ex1si -- 5os: al.` 0.`o00. `: o0v .00 133i = " Co i Appendix 8 M4 HemaDtosoeloglyevse-elxI"nd:ividuSaaailmeplvealuDe-s1 10 marke Animals Killed on schedule (4 veeks) Study No. BMRLATC aNniismbaelr cowuanet (10'/ms') LycsyipeDhsiof-ferentiSaelgmecNnoetuuentdtroopfhiBllaesnudkocytes Bpho(islt%snaosf totalpBahsicalorsunted ceHlGlrosineos) . -- TAR WP Me s31ait0o5r 111002872 27a 1i59 S101 i %2 ` o9o 0 21 5 o o8 72 i 3C _131--0058 aa s5i 2` P 9s ? 5 51 ` M5ean 2N wi57 ` si8s5 s al1s0 5 0.0o ` 10s1 0.0os 285s a% -- 8@ @ Co i pendix 5 oM-s Study No. BRIE HemaDtoosleogfyesve=erxI"nd:i viduSaaillmeivcalu0e-s1 30 meng Animals Killed on schedule (4 weeks) -- ee _aNnuimmbaelr c(ovxueincott/me) LySnytpeDhriaf-ferentisaelpsecnoNuieneuttdroopfniBliuesnudkocytes smoi(alt%enoorf total"hBaictoeorunted celNSloisnoe~) 7 TOMOO Wik Min me : aiho0e f12r0445 iaa od hts a `5 : 52oi 3o2 0oo o :3: 7 i iiotsd _-- 18a4 bi5 1: 3 oo 5o 7:7 ` a2e S nhemN 51.97` p5l: 249i 0.:: 0.0o: 0.0o` 1.05` g _-- rf } Appendix 5-H Study No. BMRLGSC . HemaDtosoeloglyevsee-lxIndi| viduMSaaallmeplvealu0e-1s 0 marke Animals Killed on schedule (Recovery) ANnoimmbaelr cGowua0net mm) LyGpChDoif-ferentiSaelgmNecenoutuentdtroopfhibllaesnudkocytes BBo(islienoof-|totaliBascyoorunted celeMlovsneos.) ' o10011000788 n93%r 92i% 2`5 1} ooo so 533 ' oooinnez 15508 5a Ph 12 o0 0 s 2:7 . MBXean% 139.793 aolssi o1l` 0.303 0.0o 0.s0o Le`` --_---- ee a98 2 E o}g i Appendix 5-H 7 Study No. BMRIAIC . HematologySe=x Indii viduMaallevalues AnimDaolsse Klielvelled oni schSeadmupllee D(R1ecovery)30 mg/kg ee ANnuimmbaelr cowuent (x10 /mw) LyysepDshiof-ferentiSaelgmNecenoututnetdroopfhiBllaesnudkocytes Bo( s%inoo-f Phils totalBacsoaunted while ceHlolsno-) cries ' a1l0o7s i103 1i2s2 5a .: 1i o o 4: ` o iSatyze i1s013s70 955% 1075 g 1 0 0 oo: : BAC osmehan i1e26 _-- w7e Ls. 0.5: 0.0o 0.0o a25 &N 5 5 5 s 5 5 5 ibe i Appendix 8 -F-1 HemaDtooseloglyevse-elxI"nd:ii viduFSaealmmapllveealuDe1s 0 mg/kg Animals Killed on schedule (4 weeks) Stay No. BNRLAIC . ANunmibmearl cCowiuanemt t) LynpDhiof-ferential coNuenuttroopfhillesukocytes ies Segmented Band Eo( sXinao.f|totalBascoorunted phils Phils celHlosnoete o00223000123 5574 52I 1130s 31 o o 332 i 000331000186 87a 555 25i 321 s s 3i: ` GB8D wemnm---- 7s ----8 ----10------1 ----o------ o ----3 88W 1013` 3%` 21. 08s 0.0 0.0 2.0 Tr ---------------- t Aopendix 5 -F-2 Stuay No. BuRLAGC ` HemDaotsoeloglyesve-el Ixn:dii viduSFsaelmmoallveealDu-e1s 0.1 Animals Killed on schedule (4 veeks) me/kg --- NAvuimmbaelr c(wxuaine0t'/ast) LcyysipeDshiof-ferentiSaelgnecNnoeiuuentdtroopfhiBllaesnwdkocytes hBo(isisnao-f totalPBhaicsloesrunted celHlosno~) : _-- eTWli oGtees 11220021 1203 Ir5 129 55%6 o3 2 1204 50 9 5 o 11 ooo! 0 o 52 5i i ` ao& --1i20e8 62 88 i3 05 0 84 8No h _se--ahnW 310071 7afH woi7 r 0.3`o 0.4io 0.05o 2.8g4 vdi  LS " Cy} 3202 103 87 6 0 0 7 i S ww a . . . \ . : 50 ` : r Aspendix BE -F-8 Study No. BMRLSC . HemaDtosoeloglyevsee=xl'indi1"1 viduSFaealmmapllveealuDeesl 30 m/ke Animals Killed on schedule (4 veeks) ANnuimmbaelr c(owxua1ne0t/ms) LyCrpiheDsoif-ferentiSaelgmecNnoetuuentdtroo|pfhiBllaesnudkocytes BPho isl%isngo-f totalBBhaicsloos-unted celHiloesnos-) ' i020o31r ii7 a81 75i o1 09 o0 55i ' B3h2oo0ts8 1i071 j5&r te{` o1o 0 333 . 8@o Mv ean 77 0x o rf 0 * . 0 o 0 5 a8 8 % 156s a` as` 0.4i 0.4` 0.0` 2.4s J SSSS 5 vy t Appendix 5 Fo 6 Study No. BuRLAC . HemaDtooseloglyevsoe-xl" Indii vidu"SaFaelmmpalvleaelu0e-1s 0 marke Animals Killed on schedule (Recovers) nNuimabelr couuscnt x10 /ma) LcyrsipeDhsiot-rerentiSaelgmNecenoutuentdtraopfhiBliaeanudkocytes Eo( s%inao-f phils total Bacsoo-unted Bhils celHlosno) Cries : 000332000807 5aa 5aa i5` 1 62 0 ntil ' o[0a3tr1t0 mi 165 s5ia 31$ oo 3 05 :zi | < ei -- s---- se------ a 8a s wea1n] Et8i a3si 5.33 odso 13s1 0.0o a105 Bo -------------------------- 52 Co i penx 5-ve7 Star ome . [ JUboLre T H1sI5o 1EpE BanEt--LW0 p MELoeGwhle ee BnETt eRd ELL OaT Differential count of leukocytes gB( aH% lof totalmminctEoedunted celcSloslIs)) ' PO w g ii om o85 i 82##" i 2 ai i 5 i):: i: :5::: 5 :::.: : ::.:: : ii.; , . Eggo oeomn=i v w| = ": r ai: c a.i r a.i E ed.: J: " Co t sensi 6m1 Clinsiocrael 1c6Sh5ai1atry -aSlIhneaisetdputal value.s n Animals killed on schedule (4 weeks) me stu to. meine . wiMnstouanr wr awn ram un Wr au Gableiden tee Gus ewan ewan TdGoellion tTGhereing om 0 n ao0l1oo0rs2 iH0 Ed28 0b1i0o5s bi8 u3 om oma es om o0omme867 o13w.s4 00 .5 B129 0 oBls 1m2.d6 HR 0.5 150 a5 ia52 i53 i 6] a51 v srh= es o0t d5d0 wdtomali ms s es : we : 850: ul"i 8&aFg - cc 8 = Co i Appendix 6-H 2 Stuy No. BHRIAIC ` Clinical cSheexmistriy =MaIlnedividual values Anistaolsse Klielvelled on schSeadmupllee 1 (4 we0eks)mg J nisl Naber pCroTtein GAD Gran ratio Cilcis phtonso.rzanic Ka x a GoD GRD GED GED GE) _-- TT TP ol01o0r2 66.:3301 0103 Gli S1.0027 00 LLegz 152 95:3s 10 x0.)4 108 111132 113 a2.0 a 11003s io} i o0l1s05 oles Gg6a8r 5 ia1o ton 1L5a8g ist ppxd by i01202 01 jir 12 i0 a 10509 101 ` GBQosneen Fl 6e.d5z1d o3.i0s8 o1i.5l8 0u..486 100..720 d 025 o4l.i1n 21032 yN -- Ed Co i rents any Clinieat inbeotc AtcLehernniaoehy Ssc-aihbnediiinetviodnutvevearuse0s mng swae. wnec wmi E Ge aun aun eo aun wr am a aGismsgen Cote awn Gwe aun TS Geemin h TGrae w w wno o o oow nwwo82R won oR so o omm m wo BB ni srooH wwer om om od wh ou i 8iai 8 0inaB o,, 5 woos 8 oom mw 8i agS S oww E w t A wi Wbo : gW t S wm et 0si aowt ow: 5t 8 5 Co t enix nea Stuy vo. mIRC . Clinical bore 1cev1 heelmistr y -SahrIannediicevid0ual-v1alu.es aanig anieets ATHied on schesmts Gh veeks) iNabter aTGtowsai'n Amen an aMtGh Glow ay sGehoErltDe en x Geen o ean : wh[HoeErR eeammoHEaiA eks LrS eR we he wR mm 0i13 i1nin i} pA bi2i io 0o8f io i [nesHESww Emo is tohe] iiizt iie jiio : Eaoni deimmot esfwi: oLmmti oemsi o2.i5o a 1: oe0o t1x0tt2i 8a 53 = [I + Amendiy 6-5 Study No. BRIG Clinical bose cSheosistry level i -maIlnedividual Sample 0-1 values lms Animals hile on schedule (4 vecks) -_-- Nmainbaelr ar UD wn UD con QU ae uD nGUitasrohgen Creatinin Glucose aad ead TGcooetla.il n Tcereiregllanye-" --T _-- T esTe Ge 20210013 oaw ist aot ar 5 000 9112055 11121s3 000.55 11is3 EH2] 0 a 128 05 fs it a I3] y 3 _m p21--d08 38 3 0 m013 m 11865s [2o1f iisn r IiHs] r 1713 5g eBaenW snl aass 0004 uam p15e.t3o b0e.d5o 51190 a19` o8ds 3aa8 5 Co t ends 60-0 Study no. BURG . Clinical bose lcehSveeelaistry =maIdnedividual Simple 0-1 values 1 wake Animals killed on schedule (4 veeks) _-- An-imal Nosber Tprootlein GAD Abin Gan) raAtiGo Glove Gua) pIhnoosr:ganic da GE) GE) x GED a GE) : 2210012 2108 [830 pd s3.i0z8 Siw 1La1t0 isi 0p.e0d eo 1059}10 1121a ii12 11o00t43 ' 2a210o01s6 wsoors 3ss0mu3 Ljiaest] 10av2is tfoxo'ts jr1ri2t hixes4} 1i100o3s . HSahni o6.q22 o3e.8m0o 1o.l6a3 9l.it8 4 ol5i5z 0182 o4.i2 210d3 eaS ~ TT -- a88 a [ i Avvendix 6-1-7 ClinVioctael lceShveelsoisftry -aIlnedividual Sample bl valves 10 mash Animals AiTied on schedule (i veeks) Study vo. BARISIC | ANnaibmearl ar GUD a GUD ara GUD Gud nGUirteeraolgen Creatinin Glucose Gea Gee) TcGooatla.dl d TcGerrialgdleny,- a3s0o02s stoi o@as 1 3@ st 00 s7a8s5 i11i.'s8s 0oo5Fs l1ii3s1z 1 110 of lis 23st 3a noo at3e10s8 aa sat 0 aais iaz oois jits swe a3 H5e5a.n0 5os38 332i 000s 17280i 21525.4 0.60.5d5 01:20 wil3o 1w0s 28a 88= o i somendix 6-8 Stay Yo. BHRIAIC . Clinical bose lcehvSeeelxsiste y- SMaaIlmnepdlievidbulal values 10 masks Aniils Killed on schedule Ci veeks) r------------------------------------------------------ iNambeir Tprootlein Gad GAlaani)n raWtiGo Glen wa) bnioosr:gmic ne GD GED x GRD a Gagan) ---- TTT -- SRY WA s33i100n13 sle6o2dg0 st sig 1Ts o5s mnILnt 10vw.os2 10[9'.xs2 $01 in ur 8 ar11d3 jix1s 12 i io1o0z0 fos i } 1006s sizs 3p7d 11566 oxsd 5i5d 1iia h3e 1f0o2s HSeoa,nW 05.260o oli3.93o 1ol.d7]s 0593.08Q o0li.z3i 0132 01..333 410go aSs 8&~ 0 vod i ei 6m sway vo. wien Cliieat ainbaolsse AlcevLTheerliststarnys-caShaitebnemiiveeid40u1ntseveakls3ue0s ag csreee---------------------------------------- D ewirm QWuaTaud auD n auurd GwGisedsen eeatenB mnde woawen e GaeemGtn|eGTTioramisg Haiio bit i40 a ii# ihe & i o o o m w mmemEskaEi e0e2es 83 wiim iE ole Md 82 iB 133 i 3Biso it cio # #Ocooo. oan 28A 8 .SN : .3noo rwr eiae ni roe ie so5ieee e:odman : MwaW: t S o i E w e i r Lp3sCommi a21@ &gs 2& w o i dovendix 6-10 Stuty vo. nmiaac , Clinical sninsaotrse KtceiSvheeernisaotnrs-ycahBaaItsnkeudiiievindGut4alveevkasls)ueos wpne T wT--ai.b_et--r E graiein an E alk GeT d Gs-- eoUrmsD wwmn Eatxned wGmaan d adoEeoossEe dda edEo a EaoMnmO waaTLERs am cf udedan iof iiee i51 w w wo ow u h ih i 11i051 ior woo i , \ de e eeS eimo rr i r8ee8eewooo erat eee i -- fSBwi osuomo okloii oaumi oef-- ro 30%E0tP P H m: o E h02: E1103i6 2 g2o 8 o Co i pena 80-1 : Clinical bose tcoShrceehxnistey S-anaaItnmediievid0u1al valves omg ninais Ailes on schedule (Recovers) sty to. wie afnoirmealr ar GUD a UD raw UD oa uD alCiUrasorlen Creatinin Glucose Ged Gea dTGhoeolli. n cTeerretaint g jaoior 5750 iisn oaaiito ilio i5oi 0a0 : o mnoe wme oo0sfs fwd jx 11155s1 hid i"& io 11n3o 5 :0 Wowsws o5t 11s Ba ji] SHoEani ai pr5s4i od.0 3as M7as o0.i5i s uss an55 el55 aS *&a w o t open 6H 12 Study ho. onereac . CalniinmsiaoctraeelAtceTUhveeElTsistoenysc-ihSeIesenubdtiievidCnuhtailcovveartsuyeos mg m rc-- s ------{-- rer ---- ------ -- o wwiem pTBrowDtein aeainn aMttGe tGeleO doGGses hoErrtDie ein Goexben Giaain : oa gwmenemEmioE ole. es woo M rE E ET Rdm T8i tao aE 8S FTIR TS 8 ww[oo A]113 1i10o63n Wwoo1o3d oiohs \ . e aie--Sm-- ooises-- ei -- 8eee-- wooeo ee-- oeio rSani oiew oaemso oLhei onmei otaiig ImHi od12" 1i0i8 &38 &g ws vol i g8ge " Cg t Suis to. wis . iewrse T1 h oh1rs aBceIBonsag -_-- SOEEE awRw ew emny aw Cl wwenn GBimo wwenn aewwnn eaen weoMoxmomwm ounmm , M O Hidem no ' . o oawmn ermowsoom wowosen ooommm ooann oommme ; gHBoEwEee ? EET t e2eeE 2eeesE 1semi 2 om: ? ---- or `' t Aentin 6-7-1 Stuyvo. Bneieac 0 CalninbiiocrtaelW1ciev3hfee0ersdisont rsy-otSreIiesnmumdiliycevidpGuitalveevkael)uegsang wNaibetr WW un Gund rm wn Wr Gun fGiUeeis. cet Gwe Geen ewe fdGoewmlin mTGeyoen osibmnyrh =8H 2#i0 sind 5 i o oW w m noomayan ? moi 00o8s 0 5wiar i #"5 3 BnFoH io, o sHinikc 8i c 8# s o6 s EA e od mc882ci#SO &8 .ia3 AB2 hean x80t 2+33i of0: aa2r2i n1e8: 0o.f5i T13Ei3 05s8i 52@ " Co t ] oentix GF2 Clinical bose lcehSveeelsxiste"7y = SraeImmnpadllieevid0u-a1l values 0 mpske Animals Milled on schedule C8 veeks) Study No. BARISIC Mnaismheir pTGrootelein Aisin Gan) raAtGio loi pohorsa: te x a Gua) Gi) GED GRD Gs) . o00a220013 5op.el5ad2 paEe2r20t eL1ay%s o0e1si 7702.04 j1ir 31fd 1oi0do4 i g 00o2200w15 pse6mt2 piLesd i113H1g peoodss xpoti 1H11i1 ioal 0ifoo3ls ` [BBoeSsathn o5i.53l owdse | i -- o1.w12 o0i.s0 L8o.y4 -- [xw3 0.0311 o1sg o d o 5 s w Co i Fi TRT] EEE| T CITr I TCIEEIE FCROEAE mets 6-103 r[ E HoTo ona cits ven , suo, ee Ww oWCE Tawmn daunn rar awmn ow aeunn WBwAelR weeeeunn Gaeowwne GwGlmno GmGeahd goimm 1ml2o0O2 noB 6m RB =3BF ps b 0 m m5E m0o4 mmo1o0w.swe6 em 0ow w.s5 oowo18m0 = 5o4o6&2x0 om oE2=R i BagwwwmeooB4mmAko a0 mdow owsoa oS woowmwe ooS owame ow mS.m.i --_-- th eF b pk s F ew i mg r ah ag i ; t Avpendia 6 Fg Stay No. BMRIAIC ' ClinDiocsael ecvSheeelxmistCE r-yTSriIemnmpdalileveid0u-a1l valves 0.0 Aniaals Killed on schedule (1 veeks) swske To Animal Tporetoatllein FAebsa riAtlGo waber GAD Gan) Gleivs pIhnoosr:ganicteeeaiestSxeeta. Gud Gawd) Ge) GED aE) . T _1120--012 s6osn p3et9 8178 o9.W t9 9#.09 TjrwDt3i.9hGR110025 ` o8 i1l2mm0is3 aso0sl iai1ne LI15an6 1fo0p1d h09e95] & os 700 30 is bd 55 11r2y 1a 5ii5 i l1loa0zf2 102 ` 2AEen s.01 sssemmm-- 4.10 1.7 5.8 so adm ost odds pet ee ene rPor 009 0a3s8 a102 C -_--i (] t 5 4 s n Co i Aventis 6-F-5 Study No. BNRIASC Clinical bose cSheexmistr-y reIsnadlievidual level Same 01 values Lage Aniuais kilied on schedule (i veeks) -_-- aNnaibmearl ar GUD or OUD row uD a Gud nGiUtrereaalgen Creatinin Glucose aa Gea) TcGooatla.nl n TcGererilpgaltny- T --_-- T SE Gey =n 22200013 aa 21it o nm of 7 01 s0soi h1iw5a0 0o05i5 1i15s18ss 85 0 si 15 ols iss st 2 25 3 aS mwws ssii ias E2A w0ss 0oss 1iz2 E5 s it e BAea-- n P Si& 74 22s 0.40 5 aai15 213 1d 0.06.85s 8u3s s5h0 532 4 _-- rt nu Co i Aentiy 6-6A Study do. BHRIIC ` ClinDiocsaellecvSheelmoisDtr y =FSeaImmnapdllieevidbulal values 1 g/kg Anils killed on schedule Ch veeks) -_-- iwembeir TpGorrtoatalebin Asin Coan) rato alc Gra) _F -- pIhnoosr:ganic a Ew) Ge) x se) a Gan) ` p22r100t12 ss0.o18z8 puaLtortl 202L00a00 W TWD Gn ee 5po.e56 8a9.35 11503 02 f1o02g i a20n01s8 [3exd iainm i1156n0s vooiss a11 tiliioz 81 i apsioal a f11o00s3d 107 ` eo C _Hsa--on o5d.1s5 o1i1s5 1o.i82 o9l.iB 6s o8l.1 0tz W ol0a0 e 1904 SSE o 5 s aain 5 Co i Ammendin 6 F< 7 Study bo. BRIESC ClinDiocsael lcehSveeelavisteEy - reImnadlievidual Sample bi values 10 mukg ! Animals killed on schedule (4 eeks) -_-- , ANnaibmearl wr (UD ar AUD ar GUD ar au aiGUtreeorlen Cratinin Glucose esa Gea) Tcgoolil.n TcGerrielgdleny.-t C _-- T WWDwb sa550200108 5aa2 a2al 5208 00 fsaooir niila 000.2s 1t2ifi2ss s5w] 0 Ei] io 05 130 u 22Bo i _F SS22--0005 5 ax 0 0ws F io1i7z 003 aiz1 i5 nt 8 -- C esabni 2@s3 522 0.0o0 si151 F 21335o 00..051 w1a335 a8i 221 aS 2. a n o i Awendix 6-8 Study No. RISC . Clinical Dose lceShveelmois"try -STirIemnmpdalileveid0ual1v1alu0es masks Anis ied on schedule (i veeks) Nn-aibmeir pTGortoAatleDin Alin wan raMtiGo Galcius Ga) AshlontoD:rsnic GRA x GRA a Ge) : F P3em r]Giohs a3isn Li17an 005.26 750 jr1r}g p3i.5]1 1oh0ig5d | oSmuam wTxaml piTata] iiiaseti 8oxsd) 8Tvi0i iiiiazt i3#s4 hhhiiid J ag -- Cr vw 7 SA SeEnW o0.a91g o0ll3 o1.m17o o5l.s13 o7.l9 11255 o0i1s p10e55 i Cod| Swventix 6-7-9 sue. omic Clinica nibnosae ivcteh3 eelsdistorny sc- SrheeEImsnRasdIiliEnsvid0Guh0alveevkasl)ueas0 agg re-- ee---------------------- ta mnienaet oE un auE n aun audA adirO lten ai wed ewan o eA in s --Gie-- Piiirnn oo 5o 5 ai FH fas 5 FH o o o oow m mmphWwdnEao os 88f 11it9 ih Lu5a oma 88 is i n#BiBo o, i EH EH] ow hE iaH 2 g SEStu% eT n &5: 3B5i edt}0 moswo T MmWei JoEs. 1428i PFY.ccmon.a` SO SS 0 i: pendix 57-10 Study vo. HRI . Clinical bose cSheexmistrCEy evel + TrIenmdailveidual Sample 0-1 values 30 mike Anigals Ailied on schedule (3 veeks) _-- sumibmeir TpGortoatDlein wasn Gan) ravteo Glove Gud) pEIhnoodsr:gDanic a GED x GED a Gs . _-- CT PP i12a200n31 77i.a01 i180e51 i1j.md80 100p.e05} i208 sist 030 La 01 o7o.ly0 llii1zzs 93 iio pipdn 1i10o07s8 81% io ' . $i220005 _-- w7o3 ais 2in 0uss 073s 11152 i8 iioor TC FW" esanWhed7.01 w1i.5d9 o1l.i9w0o ol5i.n0 o5.s6 0nt4 olai 9 i10s86 8&8 a rk [a] n Co i ends 6p su to. me Cahritwcoersse!MtceLiheeE)emistorh+ys-cSphdlRaiotvIleidGuhaeleowvievse)gs u reteset wmet We aun awn rm awn wr a AGuamdre cet owe awn ewe md elanam Gnhe Pa2 0iaa2t08 iEi|3 FF3HH20 om we os im x wm 0o omaommmo1B9m.d:9 0p s 86 pm m151 5%#8 88F55H ,i ja eeieee ieeorheeBYeee 8 etMDremeli eeei 2g horeHm Wuht 2a0r: W o : d m: W ms: oos: m om: ma: w : gFg -- Co i Awentin 8p ez Study vo. BHRISC . Clinbiocsael ecvSheeelnistrEy = TrIenmdailveidual Simple 0-1 values 0 masks Animals hiiied on schedule (Recovers) --- wNaibemr pTrootlein GAD owas Gan) rawiel _-- Glos Gua) pIhnoosr:zanic Ka CdD ees) i Get) a Gagan) ' WTOT tb Gem ooi02u0s1 77T.o0m0 p3iia 11165788 ong 7s is 156 0vp.1a8 90 7711s joH0o tio iia1o a 111000470 105 i . ooanilz awir ios --_-- 613 0va 778sRF i15i9 03 i1o0sd BR. Seha.nW o7d.0s42 oo3li0g o1i.6ei2] ol5e.0 o7's.3s ol1s0 ol5i1z 1107s5 ES--S-------------- 28a a ga LK od i Amendiy 67-3 Clinical bose lcevhSeeelaxistry = reImnadlievidual Samle 0-1 values 30 masks Animals Ailes on schedule (Recovers) Study No. BUKISSC Aanbimearl wr (WD or GUD rar GUD aw GUD nUirtreoagen Greatinin Glucsse Ged esd wad Tcootla.l Gein Tcreilgaly Gap T --_-- T WOW AD pi0wrne i3r a0 2pus i 000 aa0w 2 nai oo0i.ls8s i1is5i2z i5osw 0 22 oa ir 8 n i1i5 d i aim aa i 0 E38d5 a2ii 0ois 1iis 3%b inoto 2g -Hse5a.nW aaa 8 x6] 55o _-- 0.s0 C 525:547o 220(.]1 0:06.80 f s1is 7%51 2i4ss TY i wensin 6-7-1 Stuy ho. wnkitac . Cnliinsniocraael WbceivhSeeeelmdistornySs-crhReetnsanoCiilnsd0Cah1icovartyu)e0s g ee e rr-------------------- wN-aie TGportaaDlltin an Albumin aAttGe Gn Calcium sGIhnooirregnanic na Ged Gam a een t ddE dmwoooooowoTranaoEbadEms GIRR R RETlE o7id] nooo is i WR iiwt iii ii1l i 1110%%9 iH i i] , . z Gror oora n dm n im n w i a[HI reE 0 Jo8 a S FJtwi GeWmE. S OuEwi MoEa: of" L d wn`S ohisoS03s 8& " oi opendix 7M Urinalysiss-exin"dividuaalevalues Stuy No. BMRLAIC : 3 weDeoksse atfelveelr commencSehmmevnite 0of1 treatacCoatmg e e-- e-- r------ees---------- ANviimmbaelr UnraEogbe'ialic BOicoeudl Bilirabin KbSoeitiloenhre Glucose wen Protein pH gran . _-- we ee ooolooodr 00o1i :- olod oi : :-M : 15i : t a550 o0is 55 i aaolllooorse oooiii : ::: oon oi a : iii T13e0e 07500 i : 30 70 ' aoLoiooisne oooinn a on oi TIeeeee CC : i:: ::: : T33hee 5ii0oo i a0 -8 Nemative, +f SUgh +o: Moderate, er : Severe 5 vg i Aovendix Ton-2 Urinalysis = Individual valves Study No. mmLazc . 3 eDkosee A1FevLseSelr xc"om| menSacelimebenit o01t treatagohtt mae -_-- NAvuimmbaelr --_-- nUnrEeorba!inlic cBoiuat Bilirubin KbGeoetiolineesb Glucose war Te ee Proteln pn eween n1111o0625 o00.i1 1104 oi :-: :-: face C iis p. 2 S32o0 iTosso 5 os i _m 111106s--5 0oi :: p: = s : 3102 B5X5] ' 9 a = Negative, +: SIEM, ++ Moderate, vee: Severe aa i Co t Mevenaix To Mes Urinsiyats so=x!" natviduialle values Star vo. BuRLsgC ` 3 weDeoksse alfetveelr com|mencSeammepnlte vofi treatme1ntmpg _---- ANvoimmnaelr -- UnErogbeeni|ns oBelcounldl Bilirbin KfSeitohene TE Glucose wwean Proteln pn weaw n Hiio01 oo0tf1 isiot ooit :- :-2 f:reee : 1it ::- : : 2Hi0S a05 10 HH] , Hi at I : :: :: fHo b5i . 3:g g T = Negative, + T 1 SHEN, ++ 1 Noderate, ree: T Severe 3a wn vo i Mependix Tons UrinaiyeisC = naivH idsal values Stuy No. maniac , 5 weDeoksse aefvteelr commenSoiebminte ooft treatas1e0tmeske -_ Ndbeemr _-- Uweegbehnlaines iococunlt Bilinwin SKSeetaotDnse Glucsse wan Protein pn ewan p5i16081 pit oo0tt1 ot : :B- i:s ee ee :B- 13230 ohosdo . Sr Si_oes-- ooii : :: e i: ::: 15500 Booi ee . a8m = G Messtive + i SIEM ++ 5 oderate, vee Severe $a 5 Co | J rraeaiezet1s_e0-a!dcimsnttiiaSnllitnvdoeiu1nes reateean0dsee stuart. man ` 32 LE eR T "EE as seo men fjOoSeg, ower wan Fr wen , Pare 8 :::: :::: 4Ws{: :.:: : T35uH% 3 Tp3Jes]] ne , , da aa oa a8 :: a8 : :: : :{ : { : : f * ]fH 3EH0] 56.5 SF8 oo4uu1w09 on0oo.uu1 -::: :-:: 154t :-t fi % oies TT vegies + SH oe Moderate, ee 5 Severe " ) t AUorpiennadliyxsis se-TxInHdivEiduMaallevalues Study No. BNRLAIC 0 mE/KE . o 2b0o0s0e LfEeeEl) comi mencSeammepnlte Dofl treatment (Recovery) eNmwmer wnowgein i Bsleowodn mmm fGaoediatgenns Ghee wan Protein ot cagran) . Eran o107 0.1 -Trace -: 55 -:: 33Tr00ace a87l.'o0s i 00i11t0680o ooolll ohn ol TTrr-aaccee :: : Trace : 258 s ::: 3Tr30ace 7ii%ss oz oh TTL wegative, +; Slight, oo Noderate, ext i Severe aa8 a ii appendix Urinalysis TMT - individuNaaltevalues Study No. BNRLASC ` J Doosree tLEesVseEtxL CoiiG mencSeemernet nofa treatae8n0ts(RRecover? PR sogen Blond. BTtoaettehr Glucose wen Protein BH (gran . Moser Ean 0.1 - -: 5 -: 3300 77.0 i rfSe1os5st0 ho o0.a1 " -: -: 5& -- 3003 6.a5s lo 8 } apintt a8 ooin - TbiT vesetp.iiee, + : SH oe Noterate, wre ESET 323 i appendix Urinalysis TFC - Indi1 viduFaelmavlaelues Study No. DHRLAC ` 0 (Db0o5r8e AtSosVsoeexE comG mencSewmmelnet Doafd treatmentase Tm snogeenn Soiseodmy pune SoGtaerRersn Glucose ean Protein BH (mgran) ' Maver Ean 01 - -- s: :- 333000 s.8s0se i 0202200013 0304 oooill ::: : :-- 01 : --5- ::: 3033 5ailloo 5 30 - 7s \ 2oS S0w2e00e08r & os ooll oi ::T:race --: :-: - --- 3Tr30ace 30 77is0s 2Looooom ooolll ol --Trace --: :: -: Trace lo oh TT aepatives 6 stig oe Nedsrate, est SEVER 8 i - pendix TF Study No. BARLASC Urinalysisse-xIndiividuFSsealmmapvllaeeluDeosl 0.1 make ` 3 weDeoksse slietvealr com encenent of treatment NFumEer noEzeann Biosd btoaeterrsa aran egran 111223000123 o0o.il1 T::race --- ::- -:: - T3ra050ce 78as3s 30 0 : 80 i 111222000486 ooolli T::race -:: :8 :: Tr5ace 3 TL Negative, + SUELL +e: Moderate, wee 1 Severe 2ae 82 0 i J Urtnatyates- oIn"dividuFaelmavlaelues stay vo. BRIE LL . 2J 0 LU commencEementRof treatment Tmaml wVone mBloeend wenn TfWaAteSe, shee an protetn ot san : Ean 201 0o1l T- ae - :;: -:: h05e 5 wi1oo8 i i | ip1rnt oo aHeo oaoil i mj: e : ::: ::: ::: 55 iBe 25 TT weetiees Sant, es Noderate, oon Severe an v3 i Aependix To Fd Study No. BNRLAGC U5rivniDaeolnsyeesiAisclsvae-erl Ixnc:doim+vmiednuFcSaeaelmmmapellvneeatluDoef1s treatme1n0tmak . Neosmwer wnoegein l gBleotodt Bilimbin KbGeoetdorineaesh Glucose carn Froteln (gran 7 Eran S23h30o005 o0o.il1 :-- -:: -5: : :-: : 3TTrr0aaccee 88a.s80 30 80 i 333522000s16 oaoll :T:race ::: :5 :: 303 785 ' g a MM Negative, + Slight, + Moderate, eve 3 Severe 2@ " i Appendix TFS Urinalyste se- x IndividuFaelmalvealues 0 sg/ke Study No. BNRLAIC . 3 2b0osse lATeNverelco:mmencSeammepnlte Dof1 treatment Nmaseber Gnrogeenil Bolcoenmdt | Bilirwin Fbteohlaeotrneassn cheese eran Protein BH aaran) : Eran 200 01 :. -- :- -: TrTra5accee 77s.i00s ' prii25t0023 ooonih ios ol -:: Z:: Trace - -i: ::: : - 2Z Eg 7l8o alo - slo . o o m ai20o8 aa ooonln ol Tv:race :-: - ::5 ::: : - TTrr0aaccee 87000 2 7's aa[aaotnn ooil oi T--race :- -: -: Trace lo TL Negative, + SIIEhL ov Moderate, ses: Severe 0 i appendix Urinalysis -TIndFividuFaelmalvealues Study No. BNRLASC ` 4 Dn08e8 LTLeoxG bcommencSeamemnteotf treatee0ntRE(REecovery) Tm wenn Bgloowd mune bofodnaileese lucase wan Protein 7 ogra1) . Momer oEgena race - -: -- 3Tr0a-ce 887.0s0 i 0o0233000780 0o1l ooln :-" 010 - :-: - :-: --: T3rraa0ccee 7alsoo : , goootn a ooTnlT regeuiTvreasce+; SR: ve 0 ederate SE severe & i priemnaiiysetsa-dT"InFdivTiduhael avlalues Stay No. TRLIZC eee . J 0a 8 LTL TE colmeniSimniintt5e1 trentment (Reconerr) Tfemet wgeetn gseennde Rumen GLWeiUatedlrevrs protein 0 can : Ean pe 01 emee .:: .:- 2Bm0eee 5 oT3so0 i i 2~ piiltso! i bioothi oohn mf: eree:: ::: :: smheeee80 | o 55 TT emis + sian, oe edema se SOE a + appendix 8 M1 Study No. BARLAZC . orgapnorweeiTgohSotenx (Abosn1olsuctaSheael)mdepu=llee inDCd-41ivviedeukasl) 0veRtEuXesE niose W170 imal FirB) bra(in Livwer rd@neys ahearenals Testes Noaver 110012 3i5t4s 2l1.o900 1r133u.0t05s10 i2al.l3ts8e 5i810r.1s2 sa 323.00251 sor i 0S108 P2R mes 3SF3id4z 310 i211e9%s Zn 1Wi2s2 2 iileo pS0y4 Sp2t4 5 owe @8 wen 2325.10 o1r.9t8 1i3.s80. o2t.i4s8e5 S50i.s8 20.-20608 ` 3H] 5 ERLE a i pendix 8M1 Study No. BNRLASC t organn eweltgnStee(}RvsoslcuaSntetaeameupioIenma(i4avviedeurast) 0v-e1tunerek Joints MiTea on . J Brawin Live'r Kidneys Mr3e)nals Testes NNeuwmbeerr nou @) -- 7s 2.i0h8 1163.10288 222.57h08 ffrr0e2e.tt2 2i5.20o02 ptt i ijieoocst os 3322611 376 iiVsliao 11135..s8224 iss Vie 3B2n1 2 a 8so9la a3ra ` one wean 359 350 1.08 10.80 1.i94 20..258875 Pr4.5t0o 34 0.1980 8 so* ane5 0.094` . FET FT ody vein . or 3 Jpentix 8H Study No. BRAC . orgaI n welN MgEhSTtT_ee(aRtoosnalsuctaThet)eeaSu=eInN Cd4ivviedR eukasl) vases iS wee bm NpEl T pEarHenals Testes . fr r@aw 216 Les nMeees pira sii0.t0 2F.ai0to8 i 2p31e60t13 piHtae 325a 3 Ie[ hR hoo em adnise ppirds] 0 s5id3 pu3it5d] . 5q hos Ia wer 556 20 oLdosr r10e.s8 o2.p20: g52h.9. oai4s F F(e] E FT 2T S9o` --.---- . -- 0 i Appendix 8-H od Study No. DHRLC . orgabnorveettgehgSteerx(AbosnolsuctaSheeta)dmeui=leeInD(d4livviedeukasl) 1v0almuee/skE t oioat Mites mNiumnbaelr FiB Br(aHin Litvher idneys Atdoreenals Testes I : fb2S100r12 0 p2d6 1V11.e98z6 111778..2533 2.2 p4ec6t 12i6.2s3 56 25p.27ts8 ah ' e<o SuS10no8 3ios 333258080 bo j2$i0i0o7s iiiss7it50o01 p3rB5a H5e 3pist Ho 5 wean 21s3 0.1.69748e 1V6i.9n0 2o.ri3o0l0 [0t.t53 3o.i0s1s J FE*T FRAT Bo5d--y v--era-- 9" i popendtx, 87M Study No. BMRIC orgasnorweeifgenvSteerx (avosnolsuctaSheeen)mdepu=llee Inu(d4livviedeukasl) 3v0alnue/sN anit KiTied nNuianveer iFwB)V Brain Livwer r@neys Atdareenals Testes rheoszs 02508 1at0oh2t 125004..225230 pa2B.it0at2n 204 waswaeo Goa 233.i362020 Sioa ' o hhooota a236250 253 31i1i19o573 1ar8zts 5lpeog Se5l0o3 Ssiale : gues a A wen 12702 0.10.7927 20.a3n6sQ ol2d.s11os 5p0e.t45 30..20880s Nsw 5 FE TFT ody werent 100 i pendix 8-H Study No. BMRLAIC ` oJrnigo2sasiewseiKlgiehS1vteeTxrea(Abosn1 olsuctMhSeaea)tmdepui=leeInD(dR1ievciodvuearly)0vamleu/eksE aNnuimmbaelr FiBV Brain Liveeir Kid'neys Atraeenas Testes . o1001078 alio6ss 2pi.ao0ts7s 111235..045981 2.2p2le95 lez w6o8 850 23i.103w00 S21 i 0o011n01i00 a an a3ina aiZloonns i1l2e.s8z2 3le4r Waen oals . a 8Swe5n5 s3i8d9 2x.i08. 1h3e.87. o2t.i4s70 5p.t10 o2l.d1u40 or& FRAT-- Be5d -- Velen---- 101 | ppenatx 8 HT stay vo. mumLizE \ oarneiap22no8r5ewaA1l6I Ta55TCiobhgoslctSheaermdmu=ileeInnCdhriavciodvuearls)0valmueense . Tm T Eaw m{ha]e Une mC emos Rreas TWoe , I aiBoeR ome aw RomEa EmRo omeoa1.m95 2R0.R90 2E.5E6 dn ma 4W5.e0 ee Ed 2w.4w3 i awigoo 340 0g ewpwi aayn: aommt 3 FE Ta bME}eaanE| TnRy| eand: Bp: Dead 0 t Aopendix 8 Fo 1 Study No. BMRIAIC " oarngiaoDnaoslevselKlgienSTvteeTlxed(AbosnM1 olsuctrSheeae)nmdaput=lleeeInD(ad4livwiedeukasl)0vamleu/eKsE ` Riumsbaelr Fi)B Brwain Liwver Ki@dneys Atdareenals Owvaories , 000232000123 aia8nt 11i87s7se 888..1575383 11i.1e83s96 ett F5si 0e.e8 8% 92 w5.i2 957 580 ` 000131000458 pZabe7 1V197a6s a8i3o2 1pt7t 68201s1 Liwslre ` a@Swo esnhw6Ww 2S30 6 ord18875 v5i.7m6 oi1i6r2nH 6s0i.e1o 180..173H a3 OG & FETE Body vein 103 | Appendix 8 FC? Study No. BMRIAC orgabnolseveelKTgienSvlteeilxecdAbosn"1 olsuctFSheeae)mmdapul=lleeeInd(ad4livwiedeukasl) 0v.1alueess/ke ano NAniiambaelr fFrB Br@a'in Liver Kianeys Atdoreenals Owvearies 1120021 22142 1i.s8s8 sl7e75z 1iti4le3es s00s.3a5 79i8i3.t00 ass ' } POi1T220043 F2e5127 in iiiana 11 osBliaes iiiiessso 5Gn001a19 97521 ag Bee wnsm 1262.75 oR l01.8740 o05u.7698 o.1is62e p50d.0e T8.i1eG a sow 6 . re TFT body ETE wo | oe Jopendix $F ---- a\r2ae2en5eSwerEteVn2stIL(Aboho lscaaSh)eatdmue=lmeiIen(d4pivwiedeuakls1valaves Tm wa me womS M@aen WweP owvearies . I) 2i0n1 F2ls L1ia5s 5a5ss LiimnE iwaas an wR5.ae9 adel i p$fri os o Ho iiie i iFnheE ft i 1j1d%a pi[ti] pwith . a [aa 2283i J0a1: o5w.0e7: oLeorL 2a8ei a0d2.i0. 3& Fo vay Seo "oq 10s i Aependix 8 Fd Study No. BARLAC . oarngiaobnaolswseelMlgeinSviteeelxd(Abosn"1olsuctrSheaee)mdnpu=llaeeInD(d41ivwiedeukasl) 1v0alMuEeIsKE Nanuiambaelr FWwB) Br@a'in Liv@er Kiwdneys Aoderenals Owvearies . 3235000023 22h12d68 1i1.a9sn6 1i05s.100e06 11[.8819 17s 0aw2.li6 350 9n80l.s1 768 10.78 ' 333222000188 22i13z pV1isstte 1A0.o68 V1e7d 8il7o 77071 &E gwse eoan m [i2145 M 0.168853o 01.06.5783e or1i.o7s0s 5p0o.s80 755.8: = W FI-- R be-- dy w-- eight---- 108 i Jopentix SFE Study no. BAIAE oJrngiabDnoisSveeltMgoTnsSTteea)a(rAtbosn|olsuctFhSeeee)dmmup=llaeeInp(d4ivw3iedeukas0l) valmuaerske ` f mm eraw main wwer Kio wesog i Gwrer . ap0tos 11i TL[ aheo It wlaes vio nd 1jeus2tt] ie ff55o.o9 t6e 5fo6r.ee0d ffyr i iia22o00s81 fi2i04 vHEaE we 1i5a5 oe EX ggoemW P19e0: JE ei E oe` o1.d5e0: i55.n0: o62i.6 35 --T-- FT--Sed--ve-- oh -- wor i Lome M whe F 0211 278 199 8.81 1.78 7.7 83.6 i i i Appendix Bo FT Study No. BARLAC oArngioonnastewseiKJgeihSgteelrxe(Abosn1 olsuctFhSeeea)mmdapull=leee IDn(adRlievciodvuearly)3v0almuEe/skE . Raunsihmearl FwwB brawi)n Liver ia@neys Aader)enals Oavanries ppri42t07 2i20s080 i115an0 11132.050204 ied e1oatst ia 5Fp0i.dg1 80 o5i5se3 7s i ii"ariezt i2s14s3 2111l39o0s i12l0i38 ivilesr sosrs m7n g Mean 2108 1o.i8s6 1o2.s48 ol1d.5e9o sieeos 6l8i.z50 g 5 % Fe T m FT Sobed-- y VE-- TviEe R -- 2 100 i pore 11 Bens one a88 tv Appendix 9-H Study No. DARLASC oIrfgRaanivwiediigahSltev(xaRt:evleastivMeale percentage Sample Dal of body velght) 0.1 me/KE ` nioDaoisse lKeivlelred on+ schedule (4 veeke) animal FBV Brain iver Kidneys AGdiroensls Testes Number & 1101 a8 0.58 aazan oolme 1i3n.a9 o0ol.7os8 11oo0z3t 1108 333262112 o0l.s66 ois 376 0.51 aiian Los oomm o0..7702 iissiiss 1412.3 oollsa0 [x sis i Tos Mean 399 ole 359 0.55 0.43.1000 0.00.1181 21.57.03 0.00.18180 2o SO% sie eT 0.568o -s ` QT FT soa vera @& m i Appendix 9D Study No. BNRIAIC oOrfghainviweaitgahSltexv(aRleulTeastivMeale percentage Dose lover: Semple D-1 of body 1 me/ks velght) . anioais MiTied on schedule (4 weeks) RAnuismhaelr EiBV Brain Liver Kigneys GAdoren)sls Testes . 31221000152 3S148ss4 f00al.55d88 31L.i%2s3 o00l..e78s0 33 ol70 1111.2387 165 o00.l.8s52e0 ola i 2104 22110086 321 3706 alr 00185s1 4a236 05.8578 1184.77 00.19501 o sMeoan 73439` 0.06.3576o 034.70275 070.66880o 1157.623 e 0.06.09807 0 aa2 (] TTFET ody elEN 22 nz | Jovendix 9-H Say No. NRL organ velght (Relative : percentage of body velght) . CE JoDoise 1Koiv2Tgehah8oen scwhSaeatmdeoutlee v Ch ves0 ke) marke Tfm--raw man Uwe Gaon rtehegsi)s Tele . HS311o001 Sie pi2S2tt0o sis o0o.s5a6 on i5a.2]0 ih 20o18n8 oeno i1fe2 i1i2 o0finso a0d ' fSiie) iShs ooit Sihee oe i a 2 jweean 2a%0: o0.h57i o4f0. e0d.7e0: M1se: o0h.0m0: g Fm TFTew weeT . && 1 t Mpentin 9-HE J-- aongepnmoseelag1h01 t0S(RheleativwSeaamem: ipeerncaentage of 30 body velght) mee ` ais TEL oh sabes veer E HE T a) , p1ieo6 ia wpwoo ooooaut FOR T goSumE Heo5un1r on 1wiwses ws ohieiwwt 5 : iio ii oonn en oR fit 1a Jweeani 2 ane: mcen: oemm: ooemmt Hir.E: 1.08 : g22 Fw od wea 8& 1 i Appendix 9 = WG Study No. BMRLAC oOrfgraanivwieaiugahSltexv(aRleuleastivweane: percentage Dose level: Sample Dl of 0 body ma/XE weight) ` Anioas Ki1Tea on schedule (Recovery) RAnuismhaelr FiBV Brain Liver Kidneys Aidreensals Testes . o011i00s70 2di6aoss5 oo0ll.i5ea7 33S431h. o00..s68s37 3% 8.70 111330.0733 Pf0a.et8s3 180s 0.87 i shointzto 3ii7iy4s 0ooi.l5s1 p32e8 o0l.e7s0 118304 ooies o SMeoan f3r8e9t5 ou0.65a31o 3P.e4t80 0706.8664` i13i.7 P0.i70s @&gs eFavv r od-- y eet-- 31] ns i Appendix 9 Mo7 Study No. BuRLAC . OSrghaniwvelgant v(aRerluastive percentage of body weight) AnimDaolsse KleivlSelelexd on schSweaardmeupllee D(R1ecovery)"30 masks _TTT: aNnuimmbaelr Eap _-- Brain Liver Kidneys A1d5re%na)ls Testes : 4i1os0se7 3256 o0.z60 e5.r40 ol0.e6s8 i1s6.4 i1.l0o0 | a arnye 333731310 ol[0.si6s2 s6.8i61n27 ol00..677s80 j11i36..23 oi1l.os0ls7 } W _-- ee He55a;nWo 1a80u3: 0.05.3509s ot5i.s00: 0006.2790 -- 155.725 0-06.8030: 8Ga 0F : DeaF.E m wV y we -- @[4] ne co i Jovenain 87 F 1 say No. BAHIA oCrgEapnoisweeaitglehLsts a(NRuelsaticvphSeeeadnmunliepecero(c4tenvteaegkes)o0f body meine velght) ` A208 KTTha oh s fot) EE we i Ges SaiSniororn 2ioti Bi oooonhah Ii6o 6 0ooo.a7ti0 oh Paoosd i30 ai5Frei sh ` SGiGiooss 5Ed ooah Fae bt Fi 55 o yen 21290i 0.00 o o2i0e1o e0.d70s 150.0o 2i6.4t 8 &a FETT Sa eT ee 2 ur } Appendix 97 F 2 Study No. BMRIAIC ` oTrgaaniveaignnStexv(aRlevl1eastivpSeeansmi tepeerDc-e1ntage of body velEht) 0. me/kE Anib2oosse Tleveera on schedule (4 veeks) Nanaibmearl FiB) Brain Liver Kigneys AHdreenals Oovarhies 11220012 i23 o0ol.8sm2 23i.o8ss8 l0ol.e6r7 2257771.0 ffr3i0e.d8 2 383 i 111222000884 Vos 2aS3i75 i ooollisir0 33llpsee0st 0o0..77a83 awdi B 3 ; < dswwhm 10w022m57 00/0.6m1593 R ori2.d0s0 ou0.b7a120 e p20e.t4). Z26e.e86 s &2EvN er ww5 weet o ns i J Stuy No. ARLE organ wernt Relative percentage of body velgn) . EA2r1Le8 AK1i2TT,hhe7u1oeb sscpSheemnsisuttieee (4 veers)ene fTneetv)an wen be mess NTE OwGeIsS . fi2i1ns wmmHeoe eeoNomER S$wRnahoaoomemrm ow wEiiadd mose mwa1ht B4a i ffEiiooH F ooE o SE h L . goeI m BwEe: om : otmet eowm: mm ai Wma: 8B ga FFe Tv rm-- 1i appendix 8 Fd Study No. BARLASC oOrfgranivvieetgnnSltexv(aRleulieastivpeenalpercentage of 10 bed? ern) S8/KE JoiDootrse Me1i7n0 on scSheemdpullee u4l weeks) ' minal FB Brain Liver Kianeys AMdireensals Owvaori)es Nuaber 201 Ww) 26 0o.l0s1 s1l.035 o00l..15s80 2296.700 a230r3 Ws i 3332220004 o um 22i2s1se siz oloolsle4s ols Lihsaso pH oo[luxsrh friiiusttsd 3w5l2 ' g Se a em i 214 00..08878 o4r.a9s5s 00..17985 2p8o.t4. 336.a4s 8B W red` 6 --_-- J FrmeT vody veIEnt .3 120 i Appendix 9 =F 8 Study No. BMRLAIC . oOErgraanivwiealuganSltexv(aellu1aetsivpSeaesmas tlpeeerDc1entage of a0 body eign!) me/kE Anibooises KTielolred on schedule (4 veeks) Nanuiambaelr FBV -- Brain Liver We w) Kner Aadreensals Owvaorihes . ww 2i30012 1is8 o0o.nl5ts3 s.7j83t81 000...11725 fraoile4ad a7 a3a0i15s re i Sptaor0d8 o 4206 2is0i4 118911 o51ll.50s80 pT7e.rh8t3 0o0.l.1e59s8 i2o60e0 a0s7 ` g 52a w5ehan 159'0s 00..09364 ou7a.7214 ol00.s139os 2s.o2 T21a.00 s 4 o FTW FTe RRT Bo6dy NTE in t 32 83B appendix 9 =F Study No. BARLASC oOrgradn iwnelagnlStex(vRaelluaetsivpeona tpeercentage of boswetght) 0s Anhaoess MtieTsed on scSheemdpullee n(aRtecover) _ nial FBV Brain Liver vanes AMderennatls Owvaoringe name ber o207 Ir -- as - 0.59 -- 33.14086 -- o0.l5e9 -- 22te8ad oi Fel 25F2.6d1 380 i G0Sa32o0n00 23i66n61 is S00l.i778 33325742 Bae ooolllesess S2eo1lose 3s0s1 ` jSizs is 277 oat 0.70 3o.li2s8t 00..06348 2T5i.o65 22.a86 e5an] ale` 0.089 FT FTE wed Veen ARE 22 i FCT Study No. BNRLAIC <3n 2 appendix organ weight (Relative percentage of body Xelght) 38: OFafnroiaritevicK1ueiaoS1leeTtxevaaloun1esscpSheaemmdaputlleee oRtecovery)80 REIN FW Brain Liver rneys ABdreenhals Owveatri)es . mnNuisnbyear W tw 201 0.88 58.59s ole 0.s112 2i.r0o 323005.0078 2lpie0or1nt iat0 20i1s983 000...895608 0.5 5i.l20n032 0oo.il7re om ii5ll5os We 33383014s . pi1d 2a1n3 olse 8 5.00 0.76 225.a0 3pe.t0 K5eanW 2r0i8s5 00..09407os 0.388. 0.633. s 5 __ e FETy E Se e i , 2s i 3 re mero fiadiogs (1T8) pp 8. triknaa a eeSon e ie aa TTT TE to is . aairiege,of wens C oeorzizzaiiiiiiieisiiiiiziio iziziaizfiIiibibiiibiill i Tpnoeps cus pepe 25 32 CE CTeK avrie ie Leann RCC Wo 3 Se Elite C TIIe IiIeisi-iiisisi-izzziziziziiiziziiiiiiriaEriiiegls vodi Jett AE pags eon) A z 22 TW Hiya TE LLNLERN eo VR retin ster i eee pprrrziiizingdlitpr i1iiiiiizaarnieieiic | Rae t re Ts hae ne onam) on i eo e Te le CT ee es wis E3Fdy J gSB , i i ggi2s 3 pr SE LonmiDn iI ` SER A EERE He 211130 i g and nif Bples can eee ty ore wo S2s CT IE x r Xr CE A wwReRawuuns i aia ST IIIIIIIIIIIIIneemrTnn itll . Bes tii ` HE pe 222205 a ` ii 3: Sif, occoctrtt IIIIIIIIIID: "Ty iene TDIiIIoRRcetL JT TLL DLT TITID ILL. errr BIDE , : He PirIIIiIoR TIIIIIOCTILL ra To vo tv ent nme EE Ee 0 eEEr * " Swatiing of centrilobular besatoeries . me a 323329 eo Tr Cob EN wo Eee EEE Go ! ee ts Eers i 4 0 a 233 = CRa = pO51 Eo [; OE OE ms H EB Ea oL E n E , EEE ra w spon Arteria of erarish dotfpatch SE " wm Liver. wo SE cemems E EEE E Esemsn) , "gm Eh FEE - i| 2g2 on te EEps Apnendts LF vo g2 Sm E o-- _o S Tavene tsv a SoSma taa hE ie e H y nRE ee C [ea w - euw H p fEEnyEewe oEEaL fiAi EEEC E sereene e) e : Sh wu we ER a ED ove iE i rEt El EC E ee . wo frpFieamet a h TEiEr E EE Rt wE re rr a bl 2832 3 eneieeEsE Er oe s iome ee TT = w Sino = E EEE ee) BEom tie etobetar hesatocries(t) 'oe weowE Fa ERI ems I pe Meets) w ow &on - E RTs e _---- RE oS E t l Ee eS bee norm et , - pe - ne -- ER owe FREE 0 EE o) qe no ----" wih dus AiR BeTesbocri1ma stosle)16 -." - ao w EERE n TienTa mirhutar beetserten(t) ] rm 05500 oo oo. - PHOTOGRA PHS (Hisopathological Pictures) onE TEe R(e E AIfdoRs aSaRparEceRsd4 r fSeEaNirSea dPakna iE Li R Sat ] GaME iE g sHaE eii aA ltt SEIeb oSai aS re re e A ese Sela a AE Eh SERS Beos ad pb Er erly Ssenis ie Patan E wOeEE BERaGE ilIR LelnREE noa E R Se N n Aa Ee - to 005508 & | Shari Seg Tarra ; S5E:EPS iR n etE eE RE N G S EBAanREga s s 0 S ASaRhSel LR SEA eSLE sd Cpe Se] gPg T ES LaSlAAn EIENa SRR Se R In S Sa R pri aE y Se A RS P ES N So hR E nF e REE eR Stal Tir of satin sek given Twit. intent foe 400) Eaten xi R SS ARER e a S n S tit as li aR lnaa e Sa EE Ee SSe e ERe E R L0oEe RnTSe SSE Rlnye I sera eEEErSSanee EE AR RE E N SEAT Cae Ri TEP Catan = A TS TA ASeSte REe D ERNEST A-- Fartpharal fatty chang 1s found. RE x10 -2- 005509