Document ZJ5gOarpJqO1jgLbb0LRZ0ny0

v> g E H fi. 0800-373 m & ~0368 REPORT T w e n t y --e i g h t --d a y R e p e a t e d D o s e O r a l T o x i c i t y S t u d y o f S a m p l e D --1 i n R a t s ( BMR 1 4 3 C) & EPA-OTS 000811805N ooaaiiaosN c_ o orC. G~ j /\) - cr. ( ' r 'i rrj ' L1* :-iv B i o --M e d i c a l R e s e a r c h L a b o r a t o r i e s C o. , L t d. li10W R M HWI9B97 ! iity\ 005293 | vJ REPORT T w e n t y --e i g h t --d a y R e p e a t e d D o s e O r a l T o x i c i t y S t u d y o f S a m p l e D --1 i n R a t s (BMR143C) -TRANSLATI0N- Pura frea life F e b r u a r y 16, 1 9 9 3 B i o --M e d i c a l R e s e a r c h L a b o r a t o r i e s C o . , L t d. 005294 P R E F A C E BY T R A N S L A T O R This is a total translation of the original report in Japanese language. On this work, I have paid close attention to transfer the real facts and the correct meaning in the text, confirming scientific matters to the original auther, the study director Mr. Michio Otsuka. April 23, 199T Translator Makoto Tennichi General Manager Bio-Medical Research Laboratories Co., Ltd. 005295 VJ STATEMENT ON GLP CERTIFICATION SIGNATURE CONTENTS GENERAL MATTERS Title / Study Number / Purpose / GLP Applicaiton / Testing Guidelines / Sponsor / Testing Facilities / Responsible Person / Dates in the Study / Retention of Records and Samples SUMMARY MATERIALS AND METHODS 1. Test Substance 2. Preparation of the Dosing Solution 3. Laboratory Animals and Reason for Choice 4. Animal Housing 5. Identification of Animals 6. Identification of Cages 7. Test Procedures 7-1 Dose levels and reason for selection 7-2 Number of animals 7-3 Route, frequency, and duration of administration 7-4 Method of administration 7-5 Grouping (i) 005296 8. Parameters assessed 8-1 General condition Clinical signs / Body weight / Food consumption 8-2 Laboratory tests Hematology / Biochemistry / Urinalysis 8-3 Pathological examination Necropsy / Organ weight 8-4 Histological examination 9. Statistical Analysis RESULTS 1. Mortality 2. Clinical Signs 3. Body Weight 4. Food Consumption 5. Hematological Findings 6. Biochemical Findings 7. Urinalysis 8. Pathological Findings 8-1 Organ weight 8-2 Macroscopic findings at necropsy 8-3 Histological findings DISCUSSION AND CONCLUSION FIGURE AND TABLES (Group mean data) Figure 1. Changes in mean body weight (ii) 005297 Table 1. Group incidence of clinical signs Table 2. Body weight Table 3. Food consumption Table 4. Hematology (in connection with RBC) Table 5. Hematology (in connection with WBC) 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 weight Appendix 3. Food consumption Appendix 4. Hematology (in connection with RBC) Appendix 5. Hematology (in connection with WBC) Appendix 6. Clinical chemistry Appendix 7. Urinalysis Appendix 8. Organ weight (Absolute) Appendix 9. Organ weight (Relative) Appendix 10. Macroscopic findings Appendix 11. Microscopic findings Appendix 12. Microscopic findings (for the organs showed gross lesions) PHOTOGRAPHS (Histological findings) Photos 1-4 (iii) 005298 V S T A T E M E N T ON GL P Title : Twenty-eight-day Repeated Dose Oral Toxicity Study of Sample D-l in Rats Study Number : BMR143C The said study has been conducted in compliance with the "GLP Standard for Industrial Chemicals" in Japan (1984, amended 1988) . (Signature) (Date) Signed (Makoto Tennichi) February 16, 1993 General Manager Bio-Medical Research Laboratories Co., Ltd. (iv) 005 29 9 CERTIFICATION Title : Twenty-eight-day Repeated Dose Oral Toxicity Study of Sample D-l in Rats Study Number : BMR143C Having audited the final report, I, the undersigned, assure that the study has been conducted in compliance with Japanese "GLP Standard for Industrial Chemicals" , and accomplished with 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 Kambara) Quality Assurance Unit Bio-Medical Research Laboratories Co., Ltd. Dates of Inspection Object Dates of Inspection Dates of Report to Study Director to Management Protocol 1992 6.23 ,1992 7. 3 1992 6.23 1992 7. 3 1992 6.23 1992 7. 3 1992 7. 7 Testing Procedures 1992 8. 4 1992 7. 7 1992 8. 4 1992 7. 7 1992 8. 4 '1992 8.18 1992 8.20 1992 8.20 Records, Raw Data 1992 12.17 1992 12.17 1992 12.17 Final Report 1993 2.16 1993 2.16 1993 2.16 (v) 005300 V SIGNATURE Title: Twenty-eight-day Repeated Dose Oral Toxicity Study of Sample D-l in Rats Study Ho.: BMR143C The said study has been conducted under the responsibility of the undersigned, and this report has been prepared so as to reflect whole study correctly. (Signature) (Date) Signed February 16, 1993 (Michio Otsuka) Study Director Bio-Medical Research Laboratories Co., Ltd. (vi) 005301 GENERAL MATTERS 1. Title Twenty-eight-day repeated dose oral toxicity study of Sample D-l in rats 2. Study Number BMR143C 3. Purpose To investigate toxicological potential of the test substance, Sample D-l, through serial oral administration 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 compliance with the Japanese "GLP Standard for Industrial Chemicals" (1984, ammended 1988). 5. Testing Guidelines The testing methods conformed to the Japanese "Guidelines for Screening Toxicity Testings of Chemicals" (1988). 6. Sponsor Sumitomo 3M Co., Ltd. 3-8-8, Minami-hashimoto, Sagamihara, Kanagawa, Japan (Responcible Person) Nobushige Murakami Manager, Technical Department, Chemicals Division 005302 1 7. Testing Facilities Key Facility Q Bio-Medical Research Laboratories Co., Ltd. 3079 Susugaya, Kiyokawa-mura, Aikoh-gun, Kanagawa, Japan Partial Contributor (Blood Biochemical Examination) 0 Kashima Laboratory, Mitsubishi-Kasei Institute of Toxicological and Environmental Sciences (*) 14, Sunayama, Hasaki-machi, Kashima-gun, Ibaraki, Japan *)The company name has altered to Mitsubishi Chemical Safety Institute. (Histopathological Specimens Preparation) 0 Kara Pathological Research Kinoraine, Hayama, Tuge-mura, Yamabe-gun, Nara, Japan (Histopathological Examination) 0 Hatano Research Institute, Food and Drug Safety Center 729-5 Ochiai, Hadano-city, Kanagawa, Japan 8. Responsible Personnel (Circled figure after the name indicates each belonging facility cited above.) General Manager Study Director General Participants Quality Assurance Makoto Tennichi, Michio Otsuka, Hiroyuki Ishii, Naoto Ichikawa, 0 Osamu Tanaka Mikiko Kawanabe, Yutaka Kambara, 005303 2 Partial Participants (Responsible to biochemical determination) Naoto Toyota, (jjj) (Responsible to histopathological specimens reparation) Yoshimi Tatsumi, () (Director for histopathological examination) Shinsuke Yoshimura, 0 (Participant to histopathological examination) Furaie Kawashima, 0 9. Dates in the Study (Initiation of the study) June 23, 1992 (Animals reception) July 1, 1992 (Administration period) -Male- July 6 - Aug. 2, 1992 -Female- July 7 - Aug. 3, 1992 (Termination of observation. blood sampling and necropsy) -Male, main groups- Aug. 3. 1992 -Female, main groups- Aug. 4, 1992 -Male, recovery groups- Aug. 17, 1992 -Female, recovery groups- Aug. 18, 1992 (Completion of the study) Feb. 16, 1993 ' 10. Retention of Records and Samples All documentation records and samples (including specimens) of the study are retained in the archives of Bio-Medical Research Laboratories Co., Ltd. for 10 years after the completion of the study. As to further retention, it will be> decided on consultation with the sponsor and the contractor. - 3- 005304 V* SUMMARY 1. Sample D-l was administered to both sexes of rats with doses of 0.1, 1, 10, and 30 mg/kg for 28 days. A group of rats given the vehicle (olive oil) alone was included as the control. Besides the main groups for nonrecovery study, a satellite group for 14-day recovery study was added to each of the highest dose and the control groups. 2. No death occurred throughout the administration period. One male of the 30 mg/kg group, however, died during the recovery period; the death was considered to be caused by the test substance. 3. No abnormal clinical signs were found in all rats of the control (including those for the recovery study) and the 10 mg/kg or lower dose groups throughout the whole of the observation period. In the 30 mg/kg group, however, such signs as the followings were observed during the administration and the recovery periods: reduced spontaneous movement, tonicclonic convulsion, lying or crouching, bradypnea or cyanosis, salivation, reddish salivation, brown urine, loss of hair, and coat staining. These were considered to be caused by the test substance. . 4. Body weight gain was suppressed during the administration period in both males and females of the 30 mg/kg group from the second week and after; the suppression continued throughout the recovery period. 5. Food consumption was suppressed during the administration period in both males and females of the 30 mg/kg group from the second week and after; it tended to return during the recovery period, however. 6. Hematological examination at the end of the administration period revealed 4 00S3QS decreased hemoglobin concentration in males of the 10 and 30 mg/kg groupsT and reduced prothrombin time in females given 30 mg/kg. Moreover, at the end of the recovery period, the followings were still detected in the 30 mg/kg group: decrease of erythrocyte count and hematocrit, shortening of prothrombin time, and increase of leukocyte count, in males: decrease of hemoglobin concentration and mean corpuscular hemoglobin concentration, shortening of activated partial thromboplastin time, and increase of mean corpuscular volume, in females. 7. Biochemical examination revealed the the followings at the end of the administration period: decrease of GOT in females of the 1 mg/kg and higher dos groups; increase of albumin in females of the 10 mg/kg and higher dose groups; increase of GPT and chloride, and decrease of total cholesterol in both sexes, decrease of total protein and increase of alkaline phosphatase and of A/G ratio in males, increase of urea nitrogen in females, all these in the 30 mg/kg group. At the end of the recovery period, the followings were observed in the 30 mg/kg group: decrease of triglyceride and increase of A/G ratio, in males; increase of urea nitrogen, total protein, albumin, and calcium, and decrease of glucose and triglycerides, in females. Besides, reddish change of serum was recognized in both sexes with the 10 mg/kg or higher dose main groups, and in the 30 mg/kg recovery group. 8. By urinalysis, acidic shift in both sexes and decrease of protein in females were noted in the 30 mg/kg group during the administration period. Acidic shift remained in males during the recovery period. 9. As for absolute organ weight, the administration resulted in increase of the liver weight in both sexes of the 10 mg/kg or higher dose groups and decrease in the kidneys 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 females were still noted in the 30 mg/kg group. Relative organ weight 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 dose. After the recovery period, increase in the liver of both sexes and increase in the kidneys of females 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 liver. In the scheduled necropsy at the end of the administration period, the following findings were detected by macroscopic examination: dark reddish change in the liver of females receiving 30 mg/kg; grayish dot or patch and hypertrophy in the liver and blackish change in the kidneys in males given 30 mg/kg; dark reddish change, yellowish change, grayish patch, and hyper trophy in the liver of females receiving 30 mg/kg. The examination at the end of the recovery period revealed grayish patch, dark reddish change, and hypertrophy in the liver of both sexes of the 30 mg/kg dose. 11. Histopathological examination at the end of the administration period revealed dose-dependent changes as 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 mg/kg. No abnormal 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 centrilobular hepatocytes turned slighter; swelling in the liver, however, did not recover in both sexes given 30 rag/kg, and focal necrosis also remained. In case of one male given 30 mg/kg and died during the recovery period, in addition to the same changes as found iri the liver of the main groups, the followings were detected: hemorrhagic foci in the brain, ulcer and hemorrhage in the glandular stomach, and congestion and hemorrhage in the thymus. 12. Judging from the above, the toxicological no-observed-effect level (NOEL) of the test substance, Sample D-l, was considered to be 0.1 mg/kg for both male and female rats. 7 005308 M T E R I A L S AND METHODS 1. Test Substance 1-1 Name (Chemical Name) 2-[N-Ethyl-N-perfluoroalkyl(C-l-8)sulfonylamino] ethyl acrylate (Abbreviation) Sample D-l 1-2 Structural formula C2 h5 O I II c n F 2n+l S 0 2 N - C H 2 C H 2 0 - C - C H = C H 2 (n ranges from 1 to 8) (Composition) about 7835 for n = 8 component, about 21% for n = l - 7 components. 1-3 Molecular weight 625 1-4 Lot number 101 (supplied by the sponsor) 1-5 Appearance Amber-colored waxy solid 1-6 Purity 99% or above 1-7 Strage conditions Stored at room temperature 2. Preparation of Dosing Solution 2-1 Vehicle Olive oil 2-2 Procedure Required amount of the test substance was weighed and suspended homogeneously in the vehicle mentioned above. The dosing solution was divided into daily batches and stored in a refrigerator at 4 until just before use. 2-3 Frequency of preparation The dosing solution was prepared once a week, because the stability of the test substance in the mixture for eight days was confirmed in Japan Food Research Laboratories (Tokyo) by - 8- 00S309 our request. 3. Laboratory Animals and Reason for Choice The animals used were SPF Crj:CD(SD) rats of both sexes. They were purchased from Charles River Japan. Inc. (795 Shimo-furusawa, Atsugi, Kanagawa, Japan) at four weeks of age on July 1. 1992. After five (male) or six (female) 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 be uniform for the mean body weight based on the last weighing during the acclimatization. The weight ranged from 132 to 151 g for males and 121 to 141 g for females at the initiation of administration. Reason for choice: Having appropriate nature for laboratory animals and being bred under good genetic and microbial control, this species and strain are widely used in toxicological studies: our testing facility, besides, has accumulated back ground data on this animal. 4. Animal Housing Five or two (during or after the acclimatization, respectively) animals of the same sex were housed together in a stainless steel wire mesh cage of the hanging type ( 2 6 x 3 8 x 1 8 cm). The animal care room was a barriered facility that was automatically controlled to keep the following conditions: Temperature : 2 2 - 2 6 IQ Humidity : 30 - 70% RH Ventilation : 13 times/hour(all fresh air) Lighting : Light /darkcycle of 12hours (lights on 6:00 to 18:00) A little deviation of temperature and humidity occurred during the animal keeping: it was, however, judged not to affect to the reliability of the study. The diet was MF pelleted food for laboratory animals (Oriental Yeast Co., 00S310 Ltd.) and drinking water was tap water subjected to filtration and UV irradiation. Animals were allowed access to food and- water ad libitum except for fasting from the evening before necropsy. Analysis of the ingredients and microbial contamination of the diet was performed by the manufacturer, and toxic contaminants were examined by Japan Food Research Laboratories (Tokyo) at the manufacturer's responsibility. The quality of the tap water was periodically examined by Atsugi Public Health Center by our request. These data were checked and stored by us. Cages were replaced with freshly autoclaved ones once a week. 5. Identification of Animals Each animal was identified by marking a number on the tail with a saturated alcoholic solution of picric acid. To identify the dose group to which each animal belonged, a colored mark was painted on the tail with an oil-based felt-tip pen. 6. Identification of Cages Each cage was identified with an attached card on which the study number, abbreviated name of the test substance, dosage, and individual animal number were listed. 7. Test Procedures The testing methods conformed to the Japanese "Guidelines for Screening Toxicity Testing of Chemicals " (amended on Decenber 5, 1986). 7-1 Dose levels and reason for selection Prior to the principal study, preliminary dose-finding studies ranged between 4 and 14 days in administration period was performed with such doses as 20, 40, 50, 100, 200, 500, and 1000 rag/kg, each in a few (three to five) male and female rats. It resulted death of more than half number of rats in 10 005311 1000 mg/kg for 14 days repeated administration; suppression of body weight gain was observed in 40 mg/kg dose, though none of changes found in 20 mg/kg dose. Hence, the highest dose was decided at 30 mg/kg in the principal study and the lower doses were set at 10 mg/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 Humber of animals Forty-two rats of each sex were used. 7-3 Route, frequency, and duration of administration Administration was performed via the oral route, once a day for 28 days. 7-4 Method of administration The dosing mixture was intubated directly into the stomach via a plastic gavage tube. The volume administered was 1 ml per 100 g 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 any toxic effects, satellite groups were added to the control and the highest dose groups for a 14-day recovery study. Grouping by Dose Main Groups(*l) Recovery Groups(*2) dose levels (mg/kg) (Sex and Number of animals) Control 0 male & female, 6 rats each male & female, 6 rats each Lowest dose 0.1 male & female, 6 rats each Intermediate-1 1 male & female, 6 rats each Intermediate-2 10 male & female, 6 rats each Highest dose 30 male & female, 6 rats each male & female, 6 rats each Total male & female,30 rats each male & female,12 rats each - 11- 005312 (*1) Animals were necropsied on the next day of the last a d m i n i s t r a t i o n . (*2) Animals were necropsied immediately after the recovery period was over. Note. Individual animal number. Each animal was numbered with four-digit figure. First digit, Dose groups; 0, the control group 1, the lowest dose group 2, the intemediate-1 group 3, the intemediate-2 group 4, the highest dose group Second digit, Sexes; 1. males 2, females Third and fourth digits, individual animal of main or recovery groups; 01-06, animals of the main groups 07-12, animals of the recovery groups 8. Parameters Assessed 8-1 General condition 8-1-1 Clinical signs The appearance, behavior, and excreta of every animal were observed daily throughout the administration and the recovery periods. 8-1-2 Body weight Every animal was weighed with an electric balance at the commencement of the administration, once a week thereafter. 8-1-3 Food consumption Leftover food from each cage was weighed on day 0 and once a week thereafter, and the daily average consumption per animal was calculated for each group. 8-2 Laboratory tests 8-2-1 Hematology Blood samples were collected from the inferior vena cava under ether anesthesia just before the scheduled time of sacrifice. Blood sampling was - T2 005313 VJ done under non-fasting condition. The hematological parameters determined are listed below. The anticoagulant used was ethylenediaminetetraacetic acid dipotassium salt (EDTA-2K), except that 3.13* sodium citrate was used to determine the prothrombin time and the activated partial thromboplastine time. Parameters (1) Leukocyte count (2) Erythrocyte count (3) Platelet count (4) Hemoglobin concentration (5) Hematocrit (6) Mean corpuscular volume (7) Mean corpuscular hemoglobin (8) Mean corpuscular hemoglobin concentration (9) Differential leukocyte count (10) Prothrombin time (ID Activated partial thrombo- plastin time (WBC) (RBC) (PLT) (Hgb) (Hct) (MCV) (MCH) (MCHC) (PT) (APTT) Method Electrical resistance method Electrical resistance method Electrical resistance method Photo-electric colorimetry Pulse detection method Calculated from (2) and (5) Calculated from (2) and (4) Calculated from (4) and (5) Giemsa-stained smear Quick's one-stage test Activated cefaroplastin method Insturuments (l)-(8) : Automatic cell counter, Sysmex model CC-180A, TOA Medical Electronics Co.,Ltd. (9) : Optical microscopy (10)-(11) : Blood coagulater, Model KC-1, Amelung Co.,Ltd. Among these data, PT and APTT of one male in the recovery group (animal no. 0111) were missing owing to coagulation at blood sampling. On the other hand, reticulocyte counting was added in the main groups after sequential staining with new methylene blue process and May-GruenwaldGiemsa process, because anemia was suspected in animals of this group. 8-2-2 Biochemistry The residual blood sample was let stand at room temperature for 30 rain and TO 005314 then centrifuged at 3000 rpm for 10 min to separate serum. The serum, being frozen to "20 c , was sent to Kashima Laboratory of Mitsubishi-Kasei Institute of Toxicological and Environmental Sciences for biochemical examination. Parameters examined were as follows: Parameters Method (1) Total protein Biuret's method (2) Albumin Broraocresol green method (3) A/G ratio Calculated from (1) and (2) (4) Glucose Enzymatic UV-spectrophotometry (Hexokinase-G6-PDH) (5) Triglycerides Enzymatic method (LPL-GK-G3P0-P0D) (6) Total cholesterol Enzymatic method (CES-CO-POD) (7) Urea nitrogen Enzymatic UV-spectrophotometry (Urease-GLDH) (8) Creatinine Jaffe method (9) Calcium o-Cresolphthalein complexone method (10) Inorganic phosphorous Phosphomolybdate-UV spectrophotometry (11) GOT (AST) UV spectrophotometry-rate method (Modified SSCC) (12) GPT (ALT) UV spectrophotometry-rate method'(Modified SSCC) (13) 7 -GPT j -Glutamyl-p-nitroanilide substrate method (Modified SSCC) (14) Alkalinephosphatase (ALP)p-Nitrophenyl phosphate substrate method (15) Sodium Ion selective electrodes method (16) Potassium Ion selective electrodes method (17) Chloride Ion selective electrodes method Instrument: Automatic analyser (Hitachi 736-10 type) 8-2-3 Urinalysis Fresh urine was collected from all animals at six or seven days before the completion of administration, and four or five days before the end of the recovery period. (In each of two successive days, the former and the latter days were for male and for female respectively.) These were tested for the following parameters. 1 4- - 005315 Parameter pH, Occult blood, Protein, Glucose, \ Ketone bodies, Urobilinogen, Bilirubin / Method Paper test, MULTISTIX (Miles-Sankyo Co.,Ltd.) 8-3 Pathological examination 8-3-1 Necropsy and macroscopic examination On the next day of the last administration, all survived animals except those assigned for the recovery test were sacrificed for necropsy after blood sampling; whereas for animals of the recovery groups, the necropsy was held on the scheduled day just after the recovery period was over. After careful investigation for any macroscopic abnormalities, the following organs were removed and fixed in 10* neutral buffered formalin: brain, pituitary, eye ball, (with Harderian glands), thyloid (with parathyloid), heart, lungs, liver, kidneys, spleen, adrenals, stomach, testes or ovaries, urinary bladder, and right femur (with bone marrow). 8-3-2 Organ weight The following organs were weighed before fixation, then the relative organ weight (ratio of organ weight to body weight on the day of necropsy) was calculated: brain, liver, kidneys, adrenals, and testes or ovaries. 8-4 Histological examination From the following fixed organs of all rats in the control and the highest dose (30 mg/kg) groups, histological sections of paraffin-embeded specimens were cut and subjected to hematoxylin-eosin staining, then histological changes were surveyed: heart, liver, spleen, kidneys, adrenals, brain, and testes or ovaries, (typical seven organs) The survey of the liver was expanded to animals of the other dose groups since some chages were found in case of 30 mg/kg dose group. - 15 - 005316 V Additional histological survey was conducted to the following cases in which any macroscopic changes were observed at the necropsy: lung in one case (animal no. 0105), kidneys in two cases (animal nos. 1103, 2102), and testes in one case (animal no. 0111). Concerning the dead animal which occurred during the recovery period in one male (animal no. 4109), histological survey was performed in the typical seven organs and in thymus and stomach, the latter two were additional because of the macroscopic changes found at the necropsy. In this animal, tarry intestinal contents were found between duodenum and ileum at autopsy: however, preparation of the specimen and histological examination were not performed because of post-mortem autolysis All through the histopathology, histological specimens were prepared in Nara Pathological Research, whereas the microscopic examination was carried out in Hatano Research Institute of Food and Drug Research Center, both at our quest. 9. Statistical Analysis For metrical data, homogeneity of variance among all groups was first tested by Bartlett's method. Then the homogeneity of all group means was tested by one-way layout analysis or Kruskal-Wallis H-test, depending on whether the group variance was homogeneous or not, respectively. When group means were significantly heterogeneous and each group had the same number of data items, differences in mean values between any group and the control were tested by Dunnett's multiple range test or Dunnett's rank sum test, according to whether the group variance was homogeneous or not, respectively. When group means were heterogeneous and the number of data items in each group was unequal, the above -mentioned procedures were replaced by Scheffe's multiple range test or Scheffe's rank sum test, respectively. Armitage's chi-squared test was used to assess discrete data such as urinalysis findings. - is - 005317 RESULTS 1. Mortality All rats survived to the end of administration period; during the recovery period, however, one male given 30 mg/kg died on day 32 (viz. day 4 of recovery *). *) Each day throughout the study is indicated with such way as the day of commencement of the administration is named "day 0 " ; and the next day of the last administration (viz. day 28), that is the first day of recovery period, is expressed as "day 0 of recovery " . 2. Clinical Signs (Table 1, and Appendix 1) 2-1 During the administration period No abnormal signs were noted in all rats of the control and the 10 mg/kg or lower dose groups. With rats receiving 30 mg/kg (inclusive of the recovery group), however, the following findings were detected:' Salivation-- a considerable number of animals of both sexes, in the latter half of administration period; and in one male on day 0, besides; Reddish salivation-- in a few males and females, occasionally; Tonic-clonic convulsion, lying, bradypnea-- in one male on day 26; Reduced spontaneous movement, clonic or tonic-clonic convulsion, lying or crouching, bradypnea or cyanosis-- in one and two females on day 20 and from day 25 to 27, respectively; Loss of hair and coat staining-- in three and one females respectively, on day 17 and after. 2-2 During the recovery period No abnormal signs appeared in both males and females of the control group as well as in the administration period. In case of the male given 30 1 7- - 005318 -v-J mg/kg and died during the recovery period, reduced spontaneous m o v e m e n t s lying, bradypnea, reddish salivation 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 termination of the recovery period, whereas the coat staining in one female disappeared after day 34 (viz. day 6 of recovery). 3. Body Weight (Fig.l, Table 2, Appendix 2) 3-1 During the administration period Body weight gain in the 10 mg/kg or lower dose groups was similar to that of the control throughout the administration period. Significant suppres sion of weight gain, however, appeared in both males and females receiving 30 mg/kg (rats of the recovery group inclusive) from week 2 and after. 3- 2 During the recovery period The above-mentioned suppression of weight gain during the administration period lasted until the end of recovery period. 4. Food Consumption (Table 3, Apendix 3) 4- 1 During the administration period Food consumption in the 10 mg/kg or lower dose groups was similar to that of the control throughout the administration period. Significant suppres sion of the consumption, however, was observed in both sexes receiving 30 mg/kg (rats of the recovery group inclusiv) from week 2 and after. 4-2 During the recovery period The suppression in females of the 30 mg/kg group lasted one more week after the finish of the administration. -18- 005319 5. Hematological Findings (Table 4 and 5, Appendix 4 and 5) 5-1 At the end of the administration period Hematological examination with animals of the main groups performed on the scheduled necropsy-day revealed the following changes; decreased hemoglobin concentration in males of the 10 mg/kg and higher dose groups; reduced prothrombin time in females receiving 30 mg/kg. 5- 2 At the end of the recovery period After-recovery examination with animals of the 30 mg/kg recovery group revealed the following changes: in males, decrease of erythrocyte count, hemoglobin concentration, and hematocrit, shortening of prothrombin time, and increase of leukocyte count; in females, decrease of hemoglobin concentration and mean corpuscular hemoglobin concentration, shortening of activated partial thromboplastin time-, and increase of mean corpuscular volume. 6. Biochemical Findings (Table 6, Appendix 6) 6- 1 At the end of the administration period The examination with animals of themain groups resulted in decrease of GOT in females of the 1 mg/kg and higher dose group, and increase of albumin in also females ofthe 10 mg/kg andhigher dose groups. Moreover, in the 30 mg/kg group, the following changes were significant: increase of GPT and of chloride, and decrease of total cholesterol, all these in both sexes; decrease of total protein and increase of alkaline phosphatase and of A/G ratio, all these in males; and increase of urea nitrogen in females. In addition, reddish change of serum was visually recognized in two males (animal nos. 3102, 3103) and in one female (animal no. 3205) given 10 mg/kg, and in five males (animal nos. 4101, 4102, 4103, 4105, 4106) and in all females given 30 mg/kg. - n-9- - 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; increase of urea nitrogen, total protein, albumin, calcium, inorganic phosphorous and sodium, and decrease of glucose and triglycerides, all these in females. And besides, reddish change of serum was recognized in four males (animal nos. 4108, 4110, 4111, 4112) and in three females (animal nos. 4207, 4210, 4211). 7. Urinalysis (Table 7, Appendix 7) 7-1 During the administration period The examination performed with rats (inclusive of the recovery group) one week before the end of administration period resulted in the following changes: pH shift to alkaline side in males of the 1 mg/kg and 10 mg/kg groups and in females receiving 0.1 mg/kg; pH shift to acidic side in both sexes receiving 30 mg/kg; decrease of occult blood in males receiving 30 mg/kg; decrease of protein in females receiving 30 mg/kg. 7- 2 During the recovery period Shift of pH to acidic side was noted in males of the 30 mg/kg recovery group in the examination conducted one week before the end of the period. 8. Pathological Findings 8- 1 Organ weight (Table 8 and 9; Appendix 8 and 9) 8-1-1 Absolute organ weight 1) At the end of the administration period With the animals of the main groups, liver weight increased in both males - 005321 and females of the 10 mg/kg and higher dose groups; whereas weight decreased in kidneys of males and ovaries of females, both in the 30 mg/kg group. 2) At the end of the recovery period Changes noted in the 30 mg/kg recovery group were as follows: increase of the liver weight in both sexes; increase in the testes of males; decrease in the kidneys, in the adrenals and in the ovaries, all these of females. 8-1-2 Relative organ weight 1) At the end of the administration period Increase of liver weight found in the absolute weight with the 10 mg/kg and higher dose groups was also detected in the relative weight in both males and females. In addition, the followings were observed: increase in the brain of both sexes receiving 30 mg/kg; increase in the adrenals and the testes of males receiving 30 mg/kg; increase in the kidneys of females given 10 mg/kg and higher dose. 2) At the end of the recovery period Changes detected in the 30 mg/kg recovery group were as follows: increase in the liver and the brain of both sexes; increase in the testes of males; increase in the kidneys of females. 8-2 Macroscopic findings at necropsy (Table 10; Appendix 10 and 12) 8-2-1 Macroscopic findings in the dead animal Autopsy on the male died during the recovery period (animal no. 4109) revealed the following changes: atrophy and dark reddish patch in the thymus; hemorrhage and tarry contents in the stomach; tarry contents in the small intestine; grayish patch in the liver. 8-2-2 Macroscopic findings at scheduled necropsy 005322 Gross pathological findings observed were listed below. 1) At the end of the administration period Males of the 30 mg/kg group greyish dot or patch in the liver and hypertrophy of the liver, in all six rats; blackish change in the kidneys and dark reddish change in 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 one rat. Females of the 10 mg/kg group-- dark reddish change in the liver in one rat. Others-- graysh patch in the kidneys of one male of the 1 mg/kg group; pyelectasis in the kidneys of one male of the 0.1 mg/kg group; cyst in the kidneys and dark reddish patch in the lung, each in one male of the control group. 2) At the end of the recovery period Males of the 30 mg/kg group-- grayish patch and dark reddish change, and hypertrophy in the liver, all these in two 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 the testes in one male of the control. 8-3 Histological findings (Table 11; Appendix 11 and 12) 8-3-1 Histological findings in the dead animal Histopathological examination with the male died during the recovery period (animal no.4109) revealed the following findings: eosinophilic degeneration in centrilobular hepatocytes, focal necrosis and peripheral fatty change in the liver; dilated tubules in restricted part of the 2 2-- -- 005323 kidneys; hemorrhagic foci in the brain; ulcer and hemorrhage in theglandular stomach; congestion and hemorrhage in the thymus. No abnormality was obvserved 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 administration period Q Liver In centrilobular hepatocytes, cytoplasm appeared to be granular and eosinophilic, and swelling was recognized in all males and females of the 30 mg/kg group; in the 10 mg/kg group, the similar changes, though slightly, were found in all males; and in females, 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 than in 10 mg/kg group. (Photo 1 and 2). Focal necrosis in hepatocytes was found in five males and two females of the 30 mg/kg group, and in two males of the 10 mg/kg group. The necrosis was found also in one male of the control. Fatty change in peripheral lobule was remarkable in males of the 30 mg/kg group (Photo 4); in females, however, the incidence and intensity was similar to that in the control. Localized fatty change was also observed in one male of the control. Microglanuloma was found in a few males and females of all groups, though clear difference in incidence and intensity was not noticed between each dose group and the control group. (D Heart No abnormalities were found except extremely localized myocardinal degeneration in two male of the control group. -- 23 -- 005324 VJ (D Spleen No abnormalities were found except extramedullary hematopoiesis in three male of the control group. 0 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 between two groups was noted. Other findings: dilated tubules in one male of the control; infiltration of lymphocytes in the interstitial tissue in one male o f .the 30 mg/kg group and three male and female of the control; dilation of pelvis in two males and in one female of the 30 mg/kg group. 0 Adrenals, brain and testes or ovaries No abnormalities were observed. 2) At the end of the recovery period Q Liver Centrilobular hepatocytes were eosinophilic and showed swelling in all males and females given 30 mg/kg. As compared to the main group animals, eosinophilic intensity turned slighter in both sexes; however, the intensity of swelling was similar to that in the main group. Focal necrosis in hepatocytes was found in three males and two females of the 30 mg/kg group, though none in the control. Other findings: fatty change in peripheral lobule and microglanuloma were observed, the former was somewhat definite in males given 30 mg/kg, the latter, however, no difference was found with the control. (D Heart 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 in one female of the cotrol. No other abnormal findings were noted. 0 Spleen No abnormal findings were found except extramedullary hematopoiesis in one - 24 - 005325 v male of each of the 30 mg/kg and control groups. 0 Kidneys Regenerated tubules were found in both sexes of every group; infiltration of lymphocytes in interstitial tissue was observerd in one male and in two female of the 30 mg/kg and the control group, respectively; very slight chronic nephropathy was found in one male given 30 mg/kg. No other abnornmalities was found. (D Testes No abnormal findings were noticed except atrophy in one male of the control group. (g) Adrenals, brain and ovaries No abnormalities were observed. 3) Histological findings for gross pathological abnormalities Swelling of cytoplasm of centrilobular hepatocytes and focal necrosis were found corresponding to the macroscopic findings of hypertrophy and grayish patch, respectively. -25- 005326 V* D I S CUS S ION AND C O N C L U S I ON Major findings obtained through repeated oral administration of the test substance to rats for 28 days were summarized below. Those changes were considered to be affected by the test substance. m: male, f: female \ Period Administration Examination Findings \ Dose \ (mg/kg) 0.1 1 10 30 Clinical signs (*1)-- reduced spontaneous movement, bradypnea, anemia, salivation, convulsion; sup- in pression of body weight gain and food consump- f tion death occurred (number of the animal) Hematological findings-- inclination to anemia, id m abnormal change of blood coagulation f Biochemical findings-- Abnormal changes in lipids, m protein, and in enzymes or in electolytes fff Urinalysis (*2)-- acidic urine m f Organ weight-- change in absolute weight of the mm liver; ff change in relative weight of the liver and kid- mm neys ff Macroscopic findings-- greyish dot or patch and m hypertrophy in the liver f Histological findings-- such changes as eosinophil- m ra m ic swelling and focal necrosis in the liver, fatty change in peripheral lobule ff ra Recovery 30 ra f m (1) ra f ra f ra m f ra f ra f ra f (*1) Observation during each of the administration and the recovery period. (*2) Examination one week before each end of the administration and the recovery period. The other examination was practised at each end of the administration and the recovery period. -- 26 -- 0 S 3 2 7 >w> [Changes suggesting relation with the liver] Among the changes detected, decrease of serum cholesterol was remarkable. Though the mechanism of the reaction is not clear, it is generally accepted that cholesterol is produced through synthesis in the liver and absorption of lipid in the intestine and is controlled through accumulation in tissues, conversion into energy and excretion from the body. As decrease of total protein and increase of A/G ratio in males or increase of albumin in females were found, considering the connection among protein and lipoprotein and cholesterol, influence of the test substance on globulin or effect to decrease lipoprotein was suggested; hence, for the reduction of serum 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 enzymes 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 as eosinophilic swelling and focal necrosis in centrilobular hepatocytes which were considered to be connected with the macroscopic findings, all these changes suggested that the test substance affected to the liver parenchyma. Additional changes suggesting relation with the liver were shortened prothrombin time in females of the 30 mg/kg main group and in males of the same dose of the recovery group, shortened activated partial thromboplastine time in females of the 30 mg/kg recovery group. Changes of calcium 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 administ- - 21 - 005328 ration of the test substance was presumed. [Changes suggesting relation with other organs] As' to the increase of leukocyte count observed in the 30 mg/kg recovery group, the mechanism was unclear; the same tendency, however, was noticed in the main group though statistically insignificant. Therefore the connection with the test substance was suspected. For the increase of urea nitrogen found in females given 30 mg/kg in both the main and the recovery groups, it was not clear whether the change was caused by degradation of protein or by excretion disturbance in the kidneys; however, considering such facts as the increase of chloride in both sexes of the 30 mg/kg main group and the increase of the kidneys weight in females of the 10 mg/kg or higher dose main groups and of the 30 mg/kg recovery group, effect of the test substance to the kidneys was suspected, though no histological changes were found. As to reddish change of serum recognized visually in both sexes of the 10 and 30 mg/kg groups, sometimes y -GTP activity does not change apparently when reddish serum was caused by hemolysis. In this case of the study, however, the relation among the reddish serum andhemolysis and y -GTP was unclear. [Changes considered not to be related to the test substance] The following changes were considered not to be related to the effect of the test substance. Changes of inorganic phosphorous and sodium observed in females of the 30 mg/kg recovery group were unconnected to the test substance, because the magnitude of the changes was within limit of physiological variation and the changes were not found in the main group. In urinalysis, significant decrease of occult blood was recorded in males of the 30 mg/kg main group; it was, however, considered to be apparent, - 28 - 00S329 because one case of occult blood occurred In the control accidentally, hence the change was detected statistically. Urine pH shifted to alkaline side with the administration in males receiving 1 and 10 mg/kg and In females receiving 0.1 mg/kg; the change, however, was not dose-dependent, and the change was considered not to be related to the test substance, therefore. Weight Increase of the brain and the testes and decrease of the ovaries were observed In males or females given 30 mg/kg In both the main and the recovery groups; no histological findings, however, were detected. Therefore, the changes were considered to be apparent caused by decrease of the body weight and to have no toxicological significance. As for the macroscopic changes in the adrenals found in males or females given 30 mg/kg, no histological findings were detected; they were judged to have little toxicological significance, therefore. Concerning any other changes such as gross pathological findings having no dose dependency and no histologocal findings except above-mentioned incidents, they were judged to be unconnected with the test substance. [Conclusion] As mentioned above, significant response was found in the liver by administering the test substance to both sexes of rats with 1 mg/kg or higher dose. Whereas none of response was observed in the 0.1 mg/kg group with both male and female. Therefore the toxicological no-observed-effect level (NOEL) of the test substance. Sample D-l, was concluded to be 0.1 mg/kg for both male and female of rats. -- 005330 F I G . U R E S A N D T A B L E S (Group Mean Data) 005331 *%r. S S t u d y No. BMR143C Male E 'C X O CD <-* C . O CD g Ferna1e F i g . 1 Changes in mean body w e i g h t o f male and female rats during 28 days of oral a d m i n i s t r a t i o n of. Sample D-l and 14 days recovery period. a 0 mg/kg + a. i rng/kg o 1 mg/kg A 10 mg/kg X 30 msKkg 1 005332 cccsoo Sex Kale Table 1- Group incidence of clinical signs Test article : Sample D-l Sex : Male Study No. B1IR143C Dose level Clinical signs (g/kg) Days after commencement / cessation of treatment 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 /0 29 30 31 32 33 34 35/7 42/14 0 No abnormality observed______'12 .................... -............................................... >12 6 .............................. >6 0.1 No abnormality observed 6 .................. ..>6 1 No abnormality observed 6 ................. .. >6 10 No abnormality observed 6 ................. 30 Seduced spontaneous movement ..>6 1 Tonic-clonic/Clonic convulsion 11 Lying 11 Crouching Salivation 1 222255532343 Reddish salivation Reddish snivel 11 1 Bradypnea Cyanosis 11 Brownish urine 1 Loss of hair Coat staining No abnormality observed 11 1 2 ................................ > 12 10 10 9 10 7 7 7 9 10 9 7 8 12 6 6 6 5 5 ......... -......... >5 Death 1 i I 4 Sex Female Table 1~F Group incidence of clinical signs Test article : Sample D-l Sex : Fenale Study No. BXH143C Dose level Clinical signs (mg/kg) Days after commencement / cessation of treatment . 0 1 2 3 4 5 6 7 8 9 10 il 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 t l M /Qj>29 30 31 32 33 34 35/7 No abnomality observed 12 0.1 No abnormality observed 6 ........................ 1 No abnormality observed 6 ........................ 10 No abnormality observed 6 ........................ 30 Seduced spontaneous movement Tonic-clonic/Clonic convulsion Lying Crouching Salivation Reddish salivation Reddish snivel Bradypnea Cyanosis Broinish urine Loss of hair Coat staining No abnormality observed 12 111 >12- 6 ........ >6 -.>6 21 12 2 121 2 21 22345221 3 11 >11 11 11 8 6 6 5 5 4 7 5 7 7 4 8 2 >! 2222 2 2 hi) iM il i " >3 - >3 Death CO CO Table 2 - li Body weight - Group mean values Sex '. Male Test article : Sample D-l Study No. BMR143C Unit : g Dose level Weeks after commencement/ cessation of treatment 0 1 2 3 4 5/1 6/2 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean 143 204 260 307 342 361 S.D. 5.6 8.8 12.2 15.4 21.8 26.8 N 12 12 12 12 12 6 Mean 143 207 269 320 359 S.D. 4.6 6.6 16.7 24.7 31.8 N66666 Mean 144 206 265 314 349 S.D. 4.2 7.1 9.9 13.2 17.7 N6 66 6 6 Mean 143 201 257 305 343 S.D. 5.8 8.8 14.2 19.6 24.5 N66666 Mean 143 193 239 U 272 ** 290 n 315 * S.D. 3.7 7.0 10.2 14.5 16.2 13.4 N 12 12 12 12 12 5 * . Significantly different from control value , * ; p<0.05 , ** 4 p<0.01. 389 34.4 6 341 * 18.5 5 005335 Table 2F Body weight - Group mean values Sex : Female Test article Sample D-l Study No. BMR143C Unit : g Bose level Weeks after commencement/ cessation of treatment 0 1 2 3 4 5/1 6/2 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean 130 166 193 217 237 S.D. 5.4 8.1 13.1 16.5 18.6 N 12 12 12 12 12 Mean 129 164 189 212 227 S.D. 3.4 2.3 5.0 9.6 10.5 N66666 Mean S.D. N 131 167 192 217 235 6.6 13.7 14.2 15.2 15.9 66666 Mean 130 161 185 203 214 S.D. 5.9 7.9 9.8 13.4 14.4 N66666 Mean 130 158 171 ** 176 ** 185 ** S.D. 3.9 7.0 7.2 7.8 10.9 N 12 12 12 12 12 * : Significantly different from control value , H ; p<0.01. 5 264 20.7 6 195 ** 9.9 6 277' 24.8 6 208 i 14.5 6 005336 Table 3-M Food consumption - Group mean values Sex : Male Test a rtic le : Sample D-l Study No. BMR143C Unit : g/Animal/Day Dose level Weeks after commencement/ cessation of treatment 1 2 3 4 5/1 6/2 0 rag/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean S.D. N 16.8 0.85 6 19.1 0.92 6 18.9 0.77 6 16.8 1.27 6 21.8 1.26 3 23.0 0.75 3 Mean S.D. N 18.0 1.26 3 20.6 1.88 3 20.2 2.96 3 18.8 2.52 3 Mean S.D. N 17.0 0.75 3 19.3 0.57 3 18.1 1.00 3 17.3 0.65 3 Mean S.D. N 16.6 1.25 3 18.3 1.61 3 19.5 2.77 3 17.8 2.63 3 Mean S.D. N 15.4 0.72 6 15.8 *t 0.68 6 15.3 * 0.36 6 12.7 * 0.64 6 20.4 2.46 3 21.2 2.12 3 * : Significantly different from control value , * ; p<0.05 . : p<O.Oi. 6 005337 Table 3-F Food consumption Sex : Test article : Group mean values Female Sample D-l Study No. BMR143C Unit : g/Animal/Day Dose level Weeks after commencement/ cessation of treatment 1 2 3 4 5/1 6/2 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean S.D. N 13.8 1.15 6 13.1 1.36 6 13.9 1.50 6 12.7 1.42 6 19.4 0.20 3 20.0 0.35 3 Mean S.D. N 13.7 0.40 3 12.6 0.80 3 13.4 1.42 3 12.4 1.12 3 Mean S.D. N 14.0 2.35 3 12.3 1.55 3 12.9 1.07 3 11.9 0.79 3 Mean S.D. N 12.7 1.10 3 11.5 0.81 3 11.2 0.75 3 9.7 0.36 3 Mean S.D. N 12.9 0.78 6 10.3 * 0.72 6 8.1 U 0.82 6 8.0 ** 1.09 6 14.3 * 1.51 3 15.4 1.97 3 % Significantly different from control value , * ; p<0.05 , ** ; p<0.01. 7 005338 005339 Table 4- M- l Hematology - Group mean values Sex Male Test article I Sample D-l Animals killed on schedule (4 weeks) Bose level RBC HB count cone. (xlOVmin3) (g/dl) Ht (% ) MCV (//m3) MCH (pg) 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean S.D. N 735 46.0 6 14.2 0.39 6 47.3 2.66 6 65 19.3 2.9 1.02 66 Mean S.D. N 698 33.7 6 14.0 0.18 6 46.7 2.74 6 67 20.1 1.0 0.91 66 Mean S.D. N 737 38.8 6 14.0 0.43 6 47.2 3.21 6 64 19.0 1.9 0.69 66 Mean S.D. N 728 31.4 6 13.4 0.33 6 46.2 2.15 6 64 18.4 2.4 0.80 66 Mean S.D. N 700 53.3 6 13.3 0.85 6 46.1 3.30 6 66 19.1 1.5 1.01 66 * : Significantly different from control value , 4 ; p<0.05. 8 MCHC (% ) Platelet count (xlOVmm3) PT (sec) 30.0 1.66 6 30.1 1.54 6 29.7 1.34 6 28.9 1.20 6 29.0 1.63 6 96.6 12.88 6 93.8 10.51 6 103.7 18.92 6 103.7 11.79 6 89.9 6.76 6 14.3 0.59 6 14.0 0.44 6 14.0 0.31 6 13.9 0.30 6 14.4 0.29 6 Study No. BMR143C t APTT (sec) Reticulo cyte count (%o) f 16.4 1.16 6 16.7 1.57 6 15.5 1.60 6 15.6 1.26 6 18.1 2.29 6 26 3.9 6 29 5.3 6 28 2.1 6 27 5.6 6 20 5.0 6 Table 4 - M- 2 Hematology - Group mean values Sex : Male Test article I Sample D-l Animals killed on schedule (Recovery) Study No. BMR143C Dose level RBC HB count cone. (xlOVmm3) (g/dl) Ht (%) MCV (/im3) MCH (ps) MCIIC (% ) Platelet count (xlOVmm3) PT (sec) APTT (sec) Reticulocyte count (%o) ' 0 mg/kg 30 mg/kg Mean S.D. N 798 54.4 6 14.1 0.39 6 45.5 2.82 6 57 17.7 31.0 2.2 0.88 1.44 666 Mean S.D. N 717 * 22.6 5 12.7 ** 0.50 5 41.6 * 1.68 5 58 2.2 5 17.7 0.67 5 30.4 1.15 5 * : Significantly different from control value , $ ; p<0.05 , ** ; p<0.01. 88.4 16.90 6. 95.5 11.28 5 13.8 0.11 5 13.4 * 0.47 5 16.0 0.79 5 15.2 1.28 5 25 4.9 6 31 6.2 5 005340 I ,9 Dose level i RBC HB count cone. (xl0+/mm3) (g/dl) Table 4 - F- 1 Hematology - Group mean values Sex : Female Test article Sample D-l Animals killed on schedule (4 weeks) Ht (% ) MCV (tm3) MCH (pg) MCHC (% ) Platelet count (xloVmm3) PT (sec) Study No. BMR143C APTT (sec) Reticulocyte count '(%>) f 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean S.D. N 705 51.2 6 13.3 0.43 6 42.8 3.36 6 61 18.9 2.5 1.00 66 Mean S.D. N 691 25.2 6 13.6 0.18 6 42.0 1.40 6 61 19.7 3.4 0.66 66 Mean S.D. N 701 52.0 6 13.3 0.29 6 41.3 1.79 6 60 19.4 2.3 1.09 66 Mean S.D. N 716 35.6 .6 13.7 0.30 6 43.8 2.06 6 61 19.2 2.7 0.96 66 Mean S.D. N 722 54.6 6 13.0 0.49 6 43.1 2.95 6 60 18.0 1.5 1.16 66 ** : Sc :ignificantly different from control value , It ; p<0.01. 10 31.3 1.70 6 32.4 1.24 6 32.2 1.19 6 31.4 1.00 6 30.1 1.92 6 115.7. 15.64 6 103.1 12.27 6 107.9 6.81 6 105.9 13.81 6 103.2 11.39 6 14.3 0.20 6 14.3 0.46 6 14.2 0.57 6 14.0 0.42 6 13.4 It 0.21 6 14.0 1.64 6 14.8 1.19 6 15.7 1.66 6 15.2 0.99 6 14.6 2.12 6 22 3.1 6 22 2.9 6 22 2.5 6 21 2.1 6 20 2.8 6 005341 Table 4 - F- 2 Hematology - Group mean values Sex ' Female Test article : Sample D-l Animals killed on schedule (Recovery) Dose level RBC HB count cone. (xlO4/mm3) (g/dl) Ht (% ) MCV C M m 3) MCH (pg) MCHC (% ) Platelet count (xlOVmm3) PT (sec) 0 mg/kg 30 mg/kg Mean S.D. N 715 24.6 6 13.7 0.28 6 43.1 1.68 6 60 19.2 31.8 2.3 0.38 1.12 666 Mean S.D. N 678 33.3 6 12.6 n 0.29 6 42.7 1.62 6 63 * 1.3 6 18.7 0.61 6 29.6 n 0.80 6 I Significantly different from control value , * ; p<0.05 , ** ; p<0.01. 93.8 13.44 6 110.3 17.87 6 13.5 0.37 6 13.1 0.46 6 Study No. BMR143C APTT (sec) Reticulocyte count (%>) ? 15.5 1.62 6 12.3 n 1.35 6 24 3.3 6 25 2.6 6 005342 11 Table 5 - M- 1 Hematology - Group mean values . Sex '. Male Test article . : Sample D-l Animals killed on schedule (4 weeks) Study No. BMR143C Oos,e level 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg WBC count (xl02 /mm3 ) Differential count of leukocytes ( % of total counted cells ) Lympho- NeutrophiIs Eosino- Baso- Mono- cytes Segmented Band Phils phi Is cytes $ Mean 88 86 8 1 0 0 6 S.D. 22.6 5.7 3.2 0.5 0.5 0.0 2.9 N666666 6 Mean 106 87 8 0 10 4 S.D. 24.8 5.7 3.9 0.5 1.2 0.0 2.2 N66666 6 6 Mean 118 88 8 0 1 0 3 S.D. 23.3 4.3 3.1 0.4 0.5 0.0 1.3 N666666 6 Mean 97 85 10 0 1 0 5 S.D. 17.4 5.6 3.5 0.0 1.0 0.0 2.8 N666666 6 Mean 137 86 9 10 0 5 S.D. 65.5 2.8 2.4 0.8 0.0 0.0 3.0 N666666 6 $ : Statistical analysis impossible. 12 005343 Table 5 - M- 2 Hematology - Group mean values Sex Male Test article : Sample D-l Animals killed on schedule (Recovery) Study No. BMR143C Dose level 0 mg/kg 30 mg/kg WBC Differential count of leukocytes ( X of total counted cells ) count Lympho- NeutrophiIs Eos ino- Baso- Mono- (xl02/mm3 ) cytes Segmented Band phi Is phi Is cytes $ $-- Mean 97' 85 11 0 0 0 5 S.D. 13.9 6.5 6.1 0.5 0.0 0.0 1.8 N66666 6 6 Mean 126 n 87 8 1 0 0 5 S.D. 11.6 4.6 1.8 0.5 0.0 0.0 3.2 N5 55 55 5 5 * : Significantly different from control value , ** ; p<0.01. $ : Statistical analysis impossible. i i 4 005344 13 Table 5 - F- 1 Hematology - Group mean values Sex I Female Test article Sample D-l Animals killed on schedule (4 weeks) Study No. BMR143C Dose level 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg WBC Differential count of leukocytes ( % of total counted cells ) count Lympho- Neutrophils Eosino- Baso- Mono (xlO2 /mm3 ) cytes Segmented Band phi Is phi Is cytes $ Mean 75 86 10 1 0 0 3 S.D. 10.8 3.0 2.1 0.8 0.0 0.0 2.0 N666 66 6 6 Mean 101 88 7 0 0 0 4 S.D. 30.7 4.7 4.0 0.5 0.4 0.0 2.5 N666 66 6 6 Mean 86 88 10 0 0 0 2 S.D. 21.9 4.4 3.7 0.5 0.5 0.0 1.3 N666666 6 Mean 85 89 5 0 0 0 5 S.D. 22.3 3.1 2.1 0.4 0.5 0.0 1.7 N666666 6 Mean 77 87 8 0 0 0 5 S.D. 15.6 4.4 4.8 0.4 0.4 0.0 2.4 N666666 6 $ : Statistical analysis impossible. 14 005345 Table 5 - F- 2 Hematology - Group mean values Sex : Female Test article : Sample D-l Animals killed on schedule (Recovery) Study No. BMR143C Dose . level 0 mg/kg 30 mg/kg WBC count (xlOVmm3) Differential count of leukocytes ( % of total counted cells ) Lympho NeutrophiIs Eosino Baso- Mono cytes Segmented Band phils phi Is cytes $ Mean 85 86 9 0 1 0 5 S.D. 23.9 6.3 5.3 0.4 1.3 0.0 3.1 N666666 6 Mean 86 91 ' 5 0 0 0 4 S.D. 18.1 2.3 2.2 0.4 0.4 0.0 1.9 N666 66 6 6 $ : Statistical analysis impossible. 005346 15 Table 6 - M- 1 Clinical chemistry - Group mean values Sex : Male Test article : Sample D-l Animals killed onschedule (4 weeks) study No. 6MR143C Dose level GOT OU/I) GPT <IU/I) r -GTP (IU/1) ALP (IU/1) Urea nitrogen (mg/dl) $ 0 mg/kg Mean 68 30 0 711 12.4 S.D. 7.0 4.6 0.0 129.3 1.62 N66666 0.1 mg/kg Mean 65 30 0 677 10.6 S.D. 9.0 5.1 0.0 84.9 2.18 N66666 1 mg/kg Mean S.D. N 71 31 8.1 4.5 66 0 734 0.0 127.7 66 13.3 2.34 6 10 mg/kg Wl CO 30 mg/kg Mean 65 34 0 780 12.4 S.D. 3.9 3.2 0.0 130.2 2.56 N66666 Mean S.D. N 73 53 U 0 1191 n 14.1 9.5 13.2 0.0 243.7 1.93 66666 * I Significantly different from control value , ** ; p<0.01. $ : Statistical analysis impossible. 16 Creatinin Glucose (mg/dl) (mg/dl) 0.5 0.00 6 0.5 0.05 6 0.5 0.04 6 0.5 0.05 6 0.6 0.12 6 140 9.4 6 150 10.5 6 140 6.9 6 142 9.0 6 142 11.5 6 Total chol. (mg/dl) 58 6.9 6 57 3.5 6 49 4.3 6 38 11.1 6 9n 2.0 6 Trigly ceride (mg/dl) 49 18.2 6 55 11.8 6 60 28.6 6 48 28.0 6 21 9.6 6 Table 6 - M- 2 Clinical chemistry - Group mean values Sex : Male Test article : Sample D-l Animals killed onschedule (4 weeks) Study Ho. BMR143C Dose level Total protein (g/dl) Albumin (g/dl) A/G ratio Calcium (mg/dl) Inorganic phos. (mg/dl) Na (mEq/l) 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean S.D. H 6.51 0.212 6 3.98 0.125 6 1.58 0.110 6 9.8 0.46 6 10.2 0.70 6 Mean S.D. N 6.38 0.166 6 3.96 0.103 6 1.63 0.076 6 9.8 0.28 6 9.5 0.98 6 Mean S.D. N 6.22 0.190 6 3.84 0.079 6 1.63 0.149 6 9.8 0.31 6 9.5 0.72 6 Mean S.D. N 6.20 0.099 6 3.93 0.146 6 1.74 0.141 6 9.8 0.30 6 9.3 0.82 6. Mean S.D. N 6.01 ** 0.368 6 4.01 0.166 6 2.04 ** 0.264 6 9.4 0.54 6 10.0 3.06 6 $ 1 Significantly different from control value , p<0.01. 17 142 0.5 6 142 0.4 6 142 0.8 6 142 0.9 6 144 1.9 6 K (mEq/l) 4.1 0.08 6 4.0 0.08 6 4.2 0.20 6 4.3 0.33 6 4.2 0.35 6 Cl (mEq/l) 102 2.2 6 102 0.8 6 103 1.2 6 104 1.4 6 106 n 1.3 6 005348 Table 6 - M- 3 Clinical chemistry - Group mean values Sex : Male Test article l Sample D-l Animals killed onschedule (Recovery) Study No. BMR143C Dose level 0 mg/kg 30 mg/kg GOT CIU/I) GPT (IU/1) r-GTP (IU/1) ALP (IU/1) Urea nitrogen (mg/dl) * Mean 85 34 0 613 18.7 S.. 12.7 4.5 0.0 65.2 2.42 N66666 Mean S.D. N 76 44 6.5 10.1 55 0 716 0.0 105.4 55 21.8 3.61 5 * : Significantly different from control value , 44 ; p<O.Ol. $ .' Statistical analysis impossible. Creatinin Glucose (mg/dl) (mg/dl) 0.5 0.05 6 0.5 0.08 5 148 5.9 6 152 12.8 5 Total chol. (mg/dl) 50 14.1 6 29 11.3 5 Trigly ceride (mg/dl) 85 45.0 6 10 4.2 5 005349 18 Table 6 - M- 4 Clinical chemistry - Group mean values Sex Male Test article : Sample D-l Animals killed on schedule (Recovery) Study No. BMR143C Dose level Total protein (g/dl) Albumin (g/dl) A/G ratio Calcium (mg/d1) Inorganic phos. (mg/dl) Na (mEq/l) K (mEq/l) Cl (mEq/l) 0 mg/kg 30 mg/kg Mean S.D. N 6.42 0.167 6 3.85 0.056 6 1.50 0.072 6 9.6 0.28 6 8.7 0.18 6 Mean S.D. N 6.57 0.288 5 4.14 0:195 5 1.70 * 0.109 5 9.7 0.08 5 8.9 0.63 5 i ` Significantly different from control value , t ; p<0.05. 141 4.2 1.5 0.28 66 142 4.2 1.1 0.20 55 104 1.5 6 106 2.5 5 005350 19 Table 6 - F* 1 Clinical chemistry - Group mean values Sex : Female Test article Sample D-l Animals killed on schedule (4 weeks) Study No. BMR143C Dose level GOT (IU/1) GPT (IU/1) r-GTP (IU/1) ALP (IU/1) Urea nitrogen (mg/dl) Creatinin Glucose (mg/dl) (mg/dl) 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean 80 23 0 472 11.9 S.D. 8.0 3.5 0.4 65.2 1.33 N66666 Mean 70 25 0 419 13.2 S.D. 5.0 4.8 0.0 84.6 3.41 N 6 6 6 .6 6 Mean S.D. N 60 ** 7.4 6 20 2.9 6 0 437 13.1 0.4 82.1 2.89 666 Mean S.D. N 60 n 12.5 6 24 3.2 6 0 451 13.5 0.0 81.8 2.59 666 Mean S.D. N 56 n 4.1 6 36 U 7.2 6 0 0.0 6 590 170.9 6 18.0 U 3.43 6 *4- * SC Uignnificantly different from control value , ** : p<0.01. 20 0.5 0.04 6 0.6 0.08 6 0.5 0.06 6 0.5 0.04 6 0.5 0.05 6 133 7.6 6 140 22.0 6 143 8.3 6 135 11.7 6 126 15.0 6 Total chol. (mg/dl) Trigly ceride (mg/dl) 58 10.5 6 57 6.2 6 59 5.1 6 48 8.1 6 25 U 5.1 6 24 4.9 6 28 9.4 6 30 6.2 6 21 2.9 6 20 4.7 6 TSCSOO Table 6 - F- 2 Clinical chemistry - Group mean values Sex : Female Test article : Sample D-l Animals killed onschedule (4 weeks) Study No. BMR143C Dose level Total protein (g/dl) Albumin (g/dl) A/G ratio Calcium (mg/dl) Inorganic phos. (mg/dl) Na (mEq/l) 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean S.D. N 6.63 0.173 6 4.18 0.060 6 1.72 0.099 6 9.4 0.15 6 8.4 1.09 6 141 0.8 6 Mean S.D. N 6.61 0.320 6 4.19 0.154 6 1.74 0.095 6 9.8 0.59 6 9.7 1.01 6 141 0.9 6 Mean S.D. N 6.45 0.335 6 4.15 0.125 6 1.82 0.191 6 9.6 0.18 6 8.7 0.31 6 141 1.2 6 Mean S.D. N 6.91 0.255 6 .4.42 * 0.143 6 1.77 0.072 6 9.7 0.35 6 7.9 0.73 6 142 1.5 6 Mean S.D. N 7.01 0.327 6 4.59 44 0.140 6 1.90 0.143 6 9.9 0.49 6 8.6 0.93 6 142 1.1 6 t : Significantly different from control value , * : p<0.05 , 44 ; p<0.01. 21 K (mEq/l) 4.1 0.27 6 4.5 0.58 6 4.4 0.48 6 4.1 0.45 6 4.9 0.72 6 Cl (mEq/l) 104 0.5 6 102 1.4 6 104 1.9 6 106 1.2 6 106 4* 1.5 6 005352 Table 6 - F- 3 Clinical chemistry - Group mean values Sex Female Test article : Sample D-l Animals killed on schedule (Recovery) Study No. BMR143C Dose level 0 mg/kg 30 mg/kg GOT (IU/1) GPT (IU/1) r-GTP (IU/1) ALP (IU/1) Urea nitrogen (mg/dl) $ Mean 71 30 0 323 17.3 S.D. 8.8 7.7 0.0 63.4 2.55 N66666 Mean 61 30 0 387 24.1 ** S.D. 10.6 5.9 0.0 52.4 2.99 N6 6 6 6 6 4 : Significantly different from control value , *4 ; p<0.01. $ : Statistical analysis impossible. Creatinin Glucose (mg/dl) (mg/dl) 0.6 0.05 6 0.6 0.04 6 150 6.9 6 126 U 9.6 6 Total chol. (mg/dl) 61 10.1 6 51 7.3 6 Trigly ceride (mg/dl) 48 31.1 6 18 n 2.4 6 csesoo 22 I Table 6 - F- 4 Clinical chemistry - Group mean values Sex .* Female Test article 1 Sample D-l Animals killed onschedule (Recovery) Study No. BMR143C Dose level Total protein (g/d1) Albumin (g/dl) A/G ratio Calcium (mg/dl) Inorganic phos. (mg/dl) Na (mEq/l) K (mEq/l) Cl (mEq/l) 0 mg/kg 30 mg/kg Mean S.D. N 7.02 0.286 6 4.34 0.142 6 1.62 0.064 6 9.6 0.16 6 7.3 0.54 6 140 0.6 6 Mean S.D. N 7.50 * 0.379 6 4.72 ** 0.204 6 1.70 0.123 6 10.2 ** 0.19 6 8.1 * 0.31 6 141 ** 0.4 6 * : Significantly different from control value , * ; p<0.05 , ** ; p<0.01. 4.1 0.12 6 4.3 0.39 6 105 1.2 6 105 1.0 6 005354 23 Table 7 - M- 1 Urinalysis - Group mean values Sex : Male Test article t Sample D-l 3 weeks after commencement of treatment Study No. BMR143C { Dose level N Urobilinogen (EU/dl) Occult Blood Bilirubin Ketone bodies (mg/dl) Glucose (g/dl) Protein (mg/dl) pH > (mg/kg) 0.1 1 2 4 S 8 - TR 1+ 2+ 3+ - 1+ 2+ 3+ - 5 15 40 8 0 - 0.1 0.25 0.5 S I - TR 30 100 300 6.0 6.5 7.0 7.5 8.0 8.5 3 ': 0 12 12 0 0 0 0 9 2 0 0 1 12 0 0 0 1 10 1 0 0 12 0 0 0 0 0 2 10 0 0 1 0 4 1 6 0 I 0.1 66 0 0 00 5 10 0 0 6 00 0 04 110 60 000005 1 0 0002401 u* 1 66 0000 5 100 0 6000 05 100 60 0000042 0 000042 * 10 660000 60000 6000 06000 60 0000042 0 000 150 ** 30 12 12 0 0 0 0 12 0 0 0 0 12 0 0 0 0 8 2 2 0 12 0 0 0 0 0 1 9 2 0 2 1 4 4 1 0 ~ : Negative, TR : Trace, 1+ : Slight, 2+ : Moderate, 3+ : Severe $ : Statistical analysis impossible. * : Significantly different from control value , I ; p<0.05 , ** *, p<0.01. 005355 24 Table 7 - M- 2 Urinalysis - Group mean values Sex : Male Test article : Sample D-l 5 weeks after commencement of treatment (Recovery) Study No. BMR143C Dose' . level N Urobilinogen (EU/dl) Occult Blood Bilirubin Ketone bodies (mg/dl) Glucose (g/dl) Protein (mg/dl) pH f (mg/kg) 0.1 1 2 4 S 8 - TR 1+ 2+ 3+ - 1+ 2+ 3+ - 5 15 40 ^ 8 0 .$ $ 0 660000 2 400 0 600 0 15000 30 6 5 0 0 0 0 4 0 0 1 0 5 0 0 0 0 5 0 0 0 - 0.1 0.25 0.5 S I - TR 30 100 ^300 6.0 6.5 7.0 7.5 8.0 8.5 $ 6 0 0 .0 0 0 2 4 0 0 0 0 1 2 3 0 ** 50 0000050 0 023000 -- : Negative, TR : Trace, 1+ : Slight, 2+ .* Moderate, 3+ : Severe $ : Statistical analysis impossible. : Significantly different from control value , U ,' p<0.01. 005356 S 25 #4 Table 7 - F - 1 Urinalysis - Group mean values Sex : Female Test article *. Sample 0-1 3 weeks after commencement of treatment Study No. BMR143C { 'Dose level N Urobilinogen (EU/dl) Occult Blood Bilirubin Ketone bodies (mg/dl) Glucose (g/dl) Protein (mg/dl) pH f (mg/kg) 0.1 1 2 4 S 8 -- TR 1+ 2+ 3+ - 1 + 2 + 3+ - 5 15 40 S 8 0 - 0.1 0.25 0.5 S I -- TR 30 100 300 6.0 6.5 7.0 7.5 8.0 8.5 ** $ 0 12 12 0 0 0 0 10 2 0 0 0 12 0 0 0 9 3 0 0 0 12 0 0 0 0 0 2 10 0 0 0 1 3 3 4 1< *} 0.1 66 00 0 0 4 20 0 0 6 00 0 5 100 0 6 0 0 0 00 2 4 0 0 0 0 0 1 3 24 1 660000 22200 6000 24000 6 0 0 0 00 1 5 0 0 0 0 13 2 0 10 66 0 0 00 5 10 00 6 00 0 33 0 0 0 6 0 0 0 00 2 4 0 0 0 11 12 1 ** ** 30 12 12 0 0 0 0 7 3 2 0 0 12 0 0 0 10 2 0 0 0 12 0 0 0 0 3 5 4 0 0 3 16 2 0 0 - : Negative, TR '. Trace, 1+ : Slight, 2+ *. Moderate, 3+ 1 Severe $ : Statistical analysis impossible. * : Significantly different from control value , * ; p<0.05 , ** p<0.01. 005357 t 26 Table 7 - F - 2 Urinalysis - Group mean values Sex : Female Test article Sample 0-1 5 weeks after commencement of treatment (Recovery) Study No. BMR143C Oose level N Urobilinogen (EU/dl) Occult Blood Bilirubin Ketone bodies (mg/dl) Glucose (g/dl) . Protein (mg/dl) pH f (mg/kg) 0.1 1 2 4 8 - TR B 2+ 3+ - 1+ 2+ 3+ - 5 15 40 8 0 - 0.1 0.25 0.5 S I - TR 30 100 S300 6.0 6.5 7.0 7.5 8.0 8.5 Y~ $$ i 0 680000 32 0 10 60 00 600 00 6 0 0 0 0 1 3 2 0 0 0 0 12 3 0 30 6 6 0 0 0 0 2 4 0 0 O' 6 0 0 0 6 0 0 0 0 6 0 0 0 0 0 4 2 0 0 0 1 3 110 -- *. Negative, TR : Trace, 1+ '. Slight, 2+ '. Moderate, 3+ : Severe $ : Statistical analysis impossible. O O C/l CO cn oo 27 Table 8 - M- 1 Organ weight (Absolute) - Group mean values Sex Male Test article : Sample D-l Animals killed on schedule (4 weeks) Study No. BMR143C Dose level F.B.W (g) Brain (g) Liver (g) Kidneys (g) Adrenals (mg) Testes (g) 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean S.D. N 351 22.0 6 1.96 0.117 6 13.60 1.180 6 2.43 0.156 6 50.5 3.19 6 Mean S.D. N 359 31.8 6 1.98 0.094 6 14.50 1.194 6 2.55 0.257 6 54.3 4.90 6 Mean S.D. N 349 17.7 6 1.94 0.045 6 13.88 1.459 6 2.26 0.170 6 52.9 3.71 6 Mean S.D. N 343 24.5 6 1.94 0.078 6 16.93 ** 1.179 6 2.39 0.101 6 49.5 5.14 6 Mean S.D. N 292 n 17.6 6 1.97 0.072 6 20.36 ** 2.228 6 2.11 n 0.084 6 50.4 4.15 6 F.B.W I Final body weight i : Significantly different from control value , ** ; p<0.01. 28 2.99 0.265 6 3.14 0.196 6 3.14 0.194 6 3.01 0.189 6 3.08 0.250 6 005359 Table 8 - M- 2 Organ weight (Absolute) - Group mean values Sex I Male Test article I Sample D-l Animals killed on schedule (Recovery) Study No. BMR143C Dose level F.B.W <g) Brain (g) Liver (g) Kidneys (g) Adrenals (mg) Testes (g) 0 mg/kg 30 mg/kg Mean S.D. N 389 34.4 6 2.05 0.051 6 13.57 1.768 6 2.47 0.151 6 53.1 6.85 6 2.74 0.942 6 Mean S.D. N 341 * 18.5 5 2.02 0.058 5 20.66 t* 1.693 5 2.40 0.157 5 51.5 7.31 5 3.38 * 0.117 5 F.B.W : Final body weight * : Significantly different from control value , * ; p<0.05 , ** ; p<0.01. 005360 29 I Table 8 - F- 1 Organ weight (Absolute) - Group mean values Sex *. Female Test article i Sample D-l Animals killed on schedule (4 weeks) Study No. BMR143C Dose level F.B.W (g) Brain (g) Liver (g) Kidneys (g) Adrenals , Ovaries (mg) (mg) 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean S.D. N 230 17.4 6 1.85 0.067 6 8.76 0.471 6 1.62 0.177 6 60.1 5.46 6 Mean S.D. N 227 10.5 6 1.79 0.054 6 8.65 0.679 6 1.61 0.162 6 59.8 6.93 6 Mean S.D. N 235 15.9 6 1.91 0.069 6 9.07 0.852 6 1.67 0.081 6 62.6 7.79 6 Mean S.D. N 214 14.4 6 1.85 0.063 6 10.58 U 0.973 6 1.70 0.109 6 60.8 8.01 6 Mean S.D. N 190 n 9.5 6 1.83 0.064 6 13.78 t* 0.816 6 1.50 0.126 6 55.6 6.28 6 F.B.W T Final body weight * : Significantly different from control value , ** ; p<0.01. 30 83.7 10.13 6 83.7 7.86 6 92.0 15.11 6 75.8 8.53 6 62.6 ** 7.57 6 005361 Table 8 - F-2 Organ weight (Absolute) - Group mean values Sex Female Test article : Sample 0-1 Animals killed on schedule (Recovery) Study No. BMR143C Dose level F.B.W (g) Brain (g) Liver (g) Kidneys (g) Adrenals (mg) Ovaries (mg) 0 mg/kg 30 mg/kg Mean S.O. N 277 24.8 6 1.93 0.074 6 9.09 1.122 6 1.78 0.100 6 70.8 12.55 6 89.7 9.96 6 Mean 208 n 1.86 S.D. 14.5 0.131 N 6 .6 1 F.B.W : Final body weight * : Significantly different from 12.46 n 0.574 6 control value 1.59 * 0.146 6 , * ; p<0.05 54.0 * 7.39 6 68.5 6.22 6 , p<0.01. ** 005362 31 Dose level F.B.W (g) Table 9 - M- 1 Study No. Organ weight (Relative : percentage of body weight) - Group mean values Sex I Male Test article '. Sample D-l Animals killed on schedule (4 weeks) Brain Liver Kidneys Adrenals (xlO'3 ) ' Testes BMR143C 005363 0 mg/kg 0.1 mg/kg 1 mg/kg. 10 mg/kg 30 mg/kg Mean S.D. N 351 22.0 6 0.56 0.037 6 3.88 0.197 6 0.69 0.026 6 14.5 1.55 6 0.86 0.094 6 Mean S.D. N 359 31.8 6 0.55 0.066 6 4.04 0.210 6 0.71 0.018 6 15.3 2.70 6 0.88 0.071 6 Mean S.D. N 349 17.7 6 0.56 0.037 6 3.97 0.272 6 0.65 0.060 6 15.2 1.03 6 0.90 0.057 6 Mean S.D. N 343 24.5 6 0.57 0.043 6 4.98 ** 0.611 6 0.70 0.060 6 14.5 1.10 6 0.88 0.075 6 Mean S.D. N 292,** 17.6 6 0.68 ** 0.048 6 6.97 ** 0.475 6 0.72 0.035 6 17.3 * 1.54 6 1.06 ** 0.112 6 F.B.W : Final body weight * l Significantly different from control value , * ; p<0.05 , 32 : p<0.01. Dose level F.B.W (g) Table 9 - M- 2 Study No. Organ weight (Relative : percentage of body weight) - Group mean values Sex ' . H a l e Test article : Sample D-l Animals killed on schedule (Recovery) Brain Liver Kidneys Adrenals (xlO-3) Testes BMR143C 0 mg/kg 30 mg/kg Mean S.D. N 389 34.4 6 0.53 0.044 6 3.48 0.160 6 0.64 0.056 6 13.7 1.82 6 0.70 0.231 6 Mean S.D. N 341 * 18.5 5 0.59 * 0.030 5 6.06 ** 0.482 5 0.70 0.029 5 15.2 2.67 5 0.99 ** 0.069 5 F.B.W .' Final body weight I .' Significantly different from control value , * ; p<0.05 , ** ; p<0.01. 00S364 33 Dose level F.B.W (g) Table 9 - F- 1 Study Ho. Organ weight (Relative percentage of body weight) - Group mean values Sex : Female Test article Sample D-l Animals killed on schedule (4 weeks) Brain Liver Kidneys Adrenals (xlO"3 ) Ovaries (xl0~3) BMR143C 005365 0 mg/kg 0.1 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg Mean S.D. N 230 17.4 6 0.80 0.037 6 3.81 0.198 6 0.70 0.043 6 26.2 2.76 6 Mean S.D. N 227 10.5 6 0.79 0.053 6 3.81 0.148 6 0.71 0.042 6 26.4 2.89 6 Mean S.D. N Mean S.D. N 235 15.9 6 214 14.4 6 0.81 0.047 6 0.87 0.055 6 3.85 0.237 6 4.95 H 0.255 6 0.71 0.043 6 0.79 n 0.015 6 26.6 2.73 6 28.4 2.54 6 Mean S.D. N 190 ** 9.5 6 0.96 ** 0.034 6 7.24 ** 0.321 6 0.79 ** 0.053 6 29.2 2.50 6 F.B.W ! Final body weight * I Significantly different from control value , ** ; p<0.01. 34 36.4 4.28 6 36.9 2.90 6 39.3 6.90 6 35.4 3.23 6 33.0 4.37 6 Dose level F.B.W (g) Table 9 - F-2 Study No. Organ weight (Relative '. percentage of body weight) - Group mean values Sex : Female Test article *. Sample D-l Animals killed on schedule (Recovery) Brain Liver Kidneys Adrenals (xlO-3) Ovaries (xlO'3 ) BMR143C 0 mg/kg 30 mg/kg Mean S.D. N. 277 24.8 6 0.70 0.059 6 3.28 0.157 6 0.64 0.035 6 25.6 4.10 6 Mean S.D. N 208 ** 14.5 6 0.90 ** 0.047 6 6.00 n 0.358 6 0.76 U 0.033 6 25.9 2.43 6 F.B.W : Final body weight : Significantly different from control value , ** *, p<0.01. 32.5 2.25 6 33.0 3.18 6 99CS00 35 ^ _____________________ Table 10-M.F Group Incidence of aacroscopic findings Test article : Saaple D-l 0 f8an Findings Period : Set : Dose level (ag/kg) : Nuaber of anlaals : _________________________ 23 days__________ ________________ M a l e P eaale 15 071 1 TO JO 0 0.1 1 10 30 66666 66666 Thyaus Dark reddish patch Atrophy Lungs Dark reddish patch Liver Scatterring of greyish dot/patch llypertrophy Greyish patch Dark reddlsh change Ycllovish change kidneys Cyst Pyelectasls Greyish patch Blackish change 00000 00000 10 00 0 00000 00000 00000 00005 00006 0000 1 00000 00000 10 0 0 0 0 1000 00 100 00001 0 0 0 00 o. 0 0 0 6 00001 00004 00001 00000 0 00 1 00000 00000 Adrenals Dark reddish change 0000 1 00000 Stoiach Tarry contents/lleaorrhage 00000 00000 Testes Atrophy 00000 Study No.BMR143C ________ Recovery______ Hale Peaale 0 30 15 Tff 65 66 Dead anlaal Male 30~ 1 00 00 00 00 00 00 1 1 0 01 02 02 02 00 00 00 00 00 00 00 10 00 01 01 05 00 00 00 00 00 00 00 1 0 0 0 0 0 0 0 0 0 1 0 9CS00 or 005368 Table Ll-H Group Incidence of ticroscoplc findings Sex : Male Test article : Saaple D-L (23days) Dose level Findings Grade : 0 ag/kg (n-6) : - + +4 Hi 0. 1 a;g/kg (n-6) - + i+ Hi 1 ag/kg (n-6) - + + W Hi Liver aicrogranuloaa focal necrosis focal fatty change peripheral fatty change swelling of centrilobular hpatocytes eosinophilic change in centrilobular hpatocytes Heart ayocardia! degeneration ayocardlal fibrosis Spleen extraaedullary heaatopolesis Kidneys regenerated tubules dilated tubules inflltratlon of lyaphocytes dilation of pelvis -chronic nephropathy Adrenals abnoraali ty Brain abnoraality Testes atrophy 04 200 5 0 10 0 50 100 60000 60000 60000 4 2000 60000 32 100 3 120 0 50 100 3 2 10 0 60000 60000 60000 60000 60000 06000 60000 60000 5 1000 60000 60000 04 200 60000 60000 4 2000 33000 24 00 0 - : N e g a t i v e . : V e r y s l l g h t . + : S l i g h t , H- : M o d e r a t e . Hi : S e v e r e 10 a.g/kg (n-6) - + H- HI Study No.BMR143C 30 ag/kg (n-6) -+ Hi 03300 40200 60000 22200 0 150 0 0 12 3 0 03300 104 10 60O00 12 2 10 0024 0 00060 60000 60OO0 60O00 3 12 00 60O00 5 10 00 4 0200 60O00 60OO0 60000 60000 005369 Table 1L-F Group incidence of aicroscoplc findings S*6X * p69316 Test article : Saaple D-l (2Sdays) Dose level Findings Grade : .: 0 ag/kg (n-6) -+ HI 0..1 ag/kg (n-6) -+ Hi 1 ag/kg (n-6) -+ Hi Liver icrogranuloaa focal necrosis focal fatty change peripheral fatty change swelling of centrilobular hepatocytes eosinophilic change in centrilobular hepatocytes Heart yocardial degeneration nyocardial fibrosis Spleen extraaedullary heaatopoiesis Kidneys regenerated tubules dilated tubules infiltration of lyiphocytes dilation of pelvis chronic nephropathy Adrenals abnoraality Brain abnoraality Ovaries abnoraality 150 0 0 60000 6 00 00 22200 60000 60000 60000 60000 60000 32100 60000 32 100 60000 6 00 00 60000 60000 60000 0 5 10 0 6000 6 0 00 0 0 24 0 0 60000 6d000 24 000 60000 60000 32 100 60000 6 00 00 : Ne ga ti ve . : V e r y s l i g h t . + : S l i g h t . 4t : M o d e r a t e . Hi : S e v e r e * Study No.BMRH3C 10 ag/kg (n-6) - + tt HI 30 ag/kg (n-6) - + tt HI 05 100 60000 60000 22200 24 0 0 0 24 0 00 13 110 4 0200 60000 3 120O 00 150 00060 6000O 60O00 60000 33000 60000 60000 50 100 600O0 60000 60000 60000 Sex Dose level Findings Grade Liver icrogranuloia focal necrosis focal fatty change peripheral fatty change swelling of centri lobular hepatocytes eosinophilic change in centrilobular hepatocytes Heart yocardial degeneration yocardial fibrosis Spleen extraaedullary heaatopoiesis Kidneys regenerated tubules dilated tubules infiltration of lyaphocytes dilation of pelvis chronic nephropathy Adrenals abnoraallty Brain abnoriality Testes atrophy Ovaries abnormalIty Table ll-R-1 Croup incidence of ilcroscopic findings Test article : Saiple D-l (Recovery) : _________________ Hale : 0 ag/kg (n-6) 30 ag/kg (n-5) : + HI - + tt HI 13 20 0 6 000 0 60000 60000 60000 60000 60000 5 1000 5 100 0 33000 60000 60000 60000 60000 60000 60000 5'0 0 1 0 0 14 00 20300 50000 21200 00050 00320 50000 4 1000 4 1000 4 1000 50000 40 100 50000 4 1000 50000 50000 50000 005370 - : N e g a t i v e , : V e r y s l l g h t , + : S l i g h t . 4t : M o d e r a t e . Hi : S e v e r e 0 ig/kg (n-6) -- + 4f w 06000 60000 60000 4 1100 60000 60000 5 1000 60000 60000 24 00 0 60000 4 0200 60000 60000 60000 60000 60000 Study NO.BMR143C 30 ig/kg (n-6) -+ HI 13 200 4 0200 60000 50 100 0 024 0 00600 60000 60000 60000 5 1000 60000 60000 60000 6 0000 60000 6 00 00 6 0000 005371 Table li-R-2 I n ci de nc e of a l c r o s c o p l c find in gs In d i e d m a l e rat (32 day) Test article : Sample D-l Findings Sex Dose 1eve1 Grade : : : Male 30 mg/kg (n-T T - + + tt Hi Liver Eosinophilic change In centrllobular hepatocytes Swelling of centrilobular hepatocytes Focal necrosis Peripheral fatty change Kidneys Dilated tubules Brain lleaorrhaglc foci Stomach Ulcer and hemorrhage In glandular stoiach Thymus Congestion Hemorrhage Heart No abnormality Spleen No abnormallty Adrenals No abnormality Testes No abnormal 1ty 000 10 00 0 10 000 10 00 100 00 100 00 100 00 100 0 0 100 00 100 10000 10 0 0 0 10000 10 0 0 - : Negative. : Yery sllght.+ : Slight. 4+ : Moderate. HI : Severe Study No.BMR143C ( 4 I f A P P E N D I C E S (Individual Data) 005372 Appendix 1-M-l Clinical signs - Individual Test article : Sample D-l _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Sex : Male_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Study No.BMK143C Sex Dose level Animal Days after commencement _ _ _ _ _ _ _ _ _ (mg/kg) number_ _ _ _ _ _ _ _ _ 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 0101 0| ------ -- -------------------------------------- - - - -------- -------- -- ________________ 0112________________________________________________ ___________________________________ 1101 0.1 1 ---------------- ------------------- ------ ---------------------------------------------------- ------------------- ------------------- ------------------- ------------------- - - ______________ 1 n o 6 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ;_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 2101 1 ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Hale 2106 3101 10 i. ------------------- ------- ------- ------- -- ----------- -- --------- _ _ _ _ _ _ _ _ _ _ _ _ _ _ 31Q6_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 4101 4102 - - - - - - - - - - - - - - - - - - - - SA SA SA S A - S A SA S A - __________________________ 4103 - - - - - - - - - - - - - - - - SA SA SA SA SA SA SA SA SA SA SA - 30 4104 - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - 4105 4106 4107 SA- - - - - - - - - - - - - - - - - - - - - - - - - - - - _____________________________ _-_____'____________s^_._ _ _ _ _ _ _ _ 4108 - - - - - - - - - - - - - - - - SA SA RS - SA SA SA SASA SA SA SA- 4109 - - - - - - - - - - - - - - - - - - S A - SA SA S A - - - TC E S - LY BP 4110 - - - - - - - - - - - - - - - - - - - - S A SA S A - - - - - 4111 4H2 ------------ '--------------- ------------------------------------- TC : Tonic-clonic/Clonic convulsion, LY : Lying, SA : Salivation. RS : Reddish salivation, BP : Bradypnea, - : No abnormality observed. - 005373 1 Appendix l-M-2 , Clinical signs - Individual Test article : Sample D-l _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Sex : Hale _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Study Wo. BMR143C Sex Dose level Animal Days after commencement/cessation of treatment _ _ _ _ _ _ _ _ _ (mg/kg) number 28/0 29/1 30/2 31/3 32/4 33/5 34/6 35/7 36/8 37/9 38/10 39/11 40/12 41/13 42/14 0107 0 i -------------- ______________ 0U2____________________________________________________________________________ 4107 4108 4109 - - - RII DD Hale 30 TC LY BP RD ' BU 4H0 4111 - - - - - - - - - - - - - - - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 4112_ _ _ _ _ _ _ _ - --- -- --- RH : Reduced spontaneous movement, TC : Tonic-clonic/Clonic convulsion, LY : Lying, RD : Reddish snivel, BP : Bradypnea, BU : Brownish urine, DD : Death, - : No abnormality observed. 005374 o Appendix 1-F-l Clinical signs - Individual Test article : Sample D-l _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Sex : Female_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Study No. BMK143C Sex Dose level Animal Days after commencement _ _ _ _ _ _ _ _ _ Cmg/kg) number_ _ _ _ _ _ _ _ _ 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 0201 01 ------ -------- -- ------------------------------------------------------------ ______________ 0212____________ 1201 Female 0.1 1 1206 ------------------------------------------------------------------ 2201 1l ----------------------------------------------------------- ------- 2206 3201 - . 10 i ------------------------------------------------------------------ 3206 - : No abnormality observed. , 005375 O Appendix l-F-2 Clinical signs - Individual Test article : Sample D-l _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Sex : Female_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ;_ _ _ _ _ _ _ Study No. BMR143C____ Sex Dose level Animal Days after commencement ________ (mg/kg) number_ _ _ _ _ _ _ _ _ 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 4201 - - - - - - - - - - - - - - - - S A - - S A S A - S A - - S A SA - 4202 -------------- - - -------- -- ------------- ------------------- _ _ _ _ _ 4203 - - - - - - - - - - - - - - - - - - S A - - S A S A - R S - - R S - 4204 - - - - - - - - - - - - - - S A S A - - S A S A S A S A S A - SA - - S A RK TC CR CY Female 30 4205 _____________________________ 4206 - S A S A S A - - S A 4207 - - - - - - - - - .- - -- . - - - - LH LH Lfl LII LH LH LH LH LH LH LH LH SA SA SA SA 4208 - - - - - - - - - - - - - - - - - Lfl LH LH LH LH LH 111 LH LH Lfl LH LH SA 4209 - - - - - - - - - '- - - - - - - - LH LH LII LH LH LH LH LH LH LH LH LH 4210 - - - - - - - - - - - - - - - - - C S C S C S C S C S C S C S C S C S C S C S C S RH RM TC TC TC CR LY 4211 - - - - - - - - - - - - - - - - - _ _ _ _ _ - - - - - - - - - - - - - - - - - - - - - - - - - _ _ _ _ _ 4212 RH RM - - - - RH - TC TC _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ;_ _ _ _ _ _ _ _ _ _ _ CR LY RK : Reduced spontaneous movement, TC : Tonic-clonic/Clonic convulsion, LY : Lying, CR : Crouching, SA : Salivation, RS : Reddish salivation, CY : Cyanosis, LH : Loss of hair, CS : Coat staining, - : No abnormality observed. esoo 4 Appendix l-F-3 Clinical signs - Individual Test article : Sample D-l _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Sex : Female_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Study No, BMR143C Sex Dose level Animal Days after commencement/cessation of treatment (mg/kg) number 28/0 29/1 30/2 31/3 32/4 33/5 34/6 35/7 36/8 37/9 38/10 39/11 40/12 41/13 42/14 0207 0l 0212 4207 LH LH LH LH LH LH LH LH LH LH LH LH LH LH LH Female 4208 LH LH LH LH LH LH LH LH LH LH LH LH LH LH LH 30 4209 LH LH LH LH LH LH LH LH LH LH LH LH LH LH LH 4210 CS CS CS CS CS CS CS - - ---- 4211 4212 LH : Loss of hair, CS : Coat staining, - : No abnormality observed. 005377 005378 Appendix 2 - M - 1 Body wei ght - I n d i v i d u a l v a l u e s Sex Mal e Dose l e v e l : Sample D-l 0 mg/kg Study No Ani ma l Number 0 Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t m e n t 1 2 3 4 5/1 0 1 0 1 139 21 3 2 6 8 3 1 3 3 5 4 KS 0 1 0 2 142 196 2 4 9 291 3 1 8 KS 0 1 0 3 13 6 196 25 2 301 3 3 4 KS 0 1 0 4 1 4 0 2 0 7 2 6 5 3 1 8 3 5 2 KS 0 1 0 5 145 2 0 8 2 7 4 32 9 3 7 7 KS 0 1 0 6 14 8 21 5 2 7 5 3 2 7 3 7 0 KS 0107 146 210 263 300 329 345 0108 147 207 257 299 331 363 0109 151 206 263 319 361 401 0110 149 211 268 306 327 352 0111 132 185 231 275 304 324 0112 143 198 259 308 346 378 Mean S.D. N 143 5.6 12 KS K i l l e d on s c h e d u l e 204 8.8 12 260 12.2 12 307 15.4 12 6 342 21.8 12 361 26.8 6 BMR143C Unit : 6/2 365 405 : 438 : 374 344 : 410 : 389 34.4 6 Appendix 2 - M - 2 Body weight - I n d i v i d u a l v a l u e s Sex : Male Dose l e v e l : Sample D-l Study No. BMR143C 0 . 1 mg/kg Unit : g Ani ma l Number 0 Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t me n t 1 2 3 4 5/1 6/2 11 0 1 13 7 2 0 6 2 7 7 3 3 3 3 7 5 KS 1 1 0 2 14 0 2 0 0 2 4 4 2 8 8 321 KS 1 1 0 3 141 2 1 0 2 6 8 3 1 8 36 2 KS 1 1 0 4 146 199 2 5 4 2 9 3 32 1 KS 1 1 0 5 148 2 1 4 2 8 4 3 4 0 3 7 6 KS 1 1 0 6 148 2 1 4 28 5 3 4 7 3 9 9 KS Mean S.D. N 143 4.6 6 KS : K i l l e d on s c h e d u l e 207 6.6 6 269 16.7 6 320 24.7 6 359 31.8 6 005379 7 Appendix 2 - M - 3 Body weight - I n d i v i d u a i v a l u e s Sex : Male Dose l e v e l : Sample D-l 1 mg/kg Study No. BMR143C Uni t : g Ani ma i Number 0 Weeks a f t e r commencemen t / c e s s a t i on o f t r e a t m e n t 1 2 3 4 5/1 6/2 2 1 0 1 136 197 25 5 3 0 8 3 4 6 KS 2 1 0 2 143 20 6 2 6 5 3 1 5 3 4 5 KS 2 1 0 3 142 20 2 2 6 4 2 9 6 3 5 4 KS 2 1 0 4 146 20 3 2 5 4 311 32 1 KS 2 1 0 5 14 7 21 3 2 7 8 33 6 3 7 6 KS 2 1 0 6 14 7 216 2 7 5 3 1 8 3 5 0 KS Mean S.D. N 144 4.2 6 KS : K i l l e d on s c h e d u l e 206 7.1 6 265 314 349 9.9 13.2 17.7 666 t \ j i 005380 8 Appendix 2 M4 Body wei ght - I n d i v i d u a l v a l u e s Sex : Male Dose l e v e l : Sample D-l 10 mg/kg Study No. BMR143C Unit : g Ani ma l Number 0 Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t m e n t 1 2 3 4 5/1 6/2 3 1 0 1 135 196 24 5 2 9 3 3 2 6 KS 3 1 0 2 137 193 2 5 2 2 9 8 3 4 1 KS 3103. 143 195 245 289 3 2 0 KS 3 1 0 4 145 , 198 2 5 3 301 3 3 5 KS 3 1 0 5 15 0 2 1 4 28 2 34 3 3 8 9 KS 3 1 0 6 14 7 2 1 0 2 6 4 3 0 8 3 4 5 KS Mean S.D. N 143 5.8 6 KS : K i l l e d on s c h e d u l e 201 8.8 6 257 14.2 6 305 19.6 6 343 24.5 6 005381 9 005382 Appendix 2 Body weight - I n d i v i d ua l v a l u e s Sex : Male Dose l e v e l : Sample D-l 30 mg/kg Study No Ani ma l Number 0 Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t me n t 1 2 3 4 5/1 41 0 1 1 4 0 193 2 3 7 2 7 3 3 0 0 KS 4 1 0 2 139 185 22 9 26 5 2 8 6 KS 4 1 0 3 14 4 2 0 0 2 5 4 3 0 0 321 KS 4 1 0 4 14 7 198 241 2 6 8 2 8 3 KS 4 1 0 5 143 19 0 231 2 5 6 2 6 9 KS 4 1 0 6 146 196 2 4 7 28 5 2 9 3 KS 4107 147 193 235 265 284 304 4108 136 189 233 268 291 311 4109 145 193 231 256 261 D 4110 138 180 228 263 284 308 .4111 142 194 238 271 292 315 4112 146 207 260 297 310 338 Mean S.D. N 143 3.7 12 KS : K i l l e d on s c h e d u l e D : Dead. 193 7.0 12 239 10.2 12 272 14.5 12 10 290 16.2 12 315 13.4 5 BMR143C Unit : g 6/2 3 2 6 KS 3 3 6 KS 331 KS 3 4 0 KS 3 7 3 KS 341 18.5 5 I Appendix F-1 Body weight - I n di v i d u a l v a l u e s Sex : Female Dose l e v e l : Sample D-l 0 mg/kg Study No, BMR143C Unit : Ani ma l Number 0 Weeks a f t e r commencement/ c e s s a t i on o f t r e a t me n t 1 2 3 4 5/1 6/2 0 2 0 1 1 2 8 162 191 211 2 2 8 KS 0 2 0 2 123 151 17 7 193 2 1 4 KS 0 2 0 3 131 16 0 181 2 0 7 22 1 KS 0 2 0 4 1 4 0 17 8 2 0 8 2 3 5 2 6 4 KS 0 2 0 5 128 1 6 4 186 2 0 7 2 2 7 KS 0 2 0 6 131 165 18 7 2 1 4 2 2 7 KS 0207 138 178 222 255 279 304 325 0208 131 168 201 222 237 254 265 0209 129 168 188 214 237 256 264 . 0210 128 171 200 228 243 261 270 : 0211 133 171 196 220 244 262 278 : 0212 121 156 179 201 225 245 257 ; 005383 Mean S.D. N 130 5.4 12 KS K i l l e d on s c h e d u l e 166 8.1 12 193 13.1 12 217 16.5 12 11 237 18.6 12 264 20.7 6 277 24.8 6 Appendix 2 - F - 2 Body we i g ht - I n d i v i d u a l v a l u e s Sex : Female Dose l e v e l : Sample D-l Study No. BMR143C 0 . 1 mg/kg Unit : g Ani ma l Number 0 Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t me n t 1 2 3 4 5/1 6/2 12 01 1 2 4 15 9 188 2 1 0 2 2 4 KS 1 2 0 2 12 5 . 165 1 8 0 196 21 2 KS 1 2 0 3 132 165 192 21 9 23 5 KS 1 2 0 4 130 1 6 4 192 2 2 2 24 2 KS 1 2 0 5 12 8 165 19 4 2 1 7 2 2 7 KS 12 0 6 132 163 189 2 0 7 2 2 2 KS Mean 129 164 189 212 227 S.D. 3 . 4 2 . 3 5 . 0 9 . 6 1 0 .5 N6 6 6 6 6 KS : K i l l e d on s c h e d u l e { 005384 12 00S385 Appendix 2 - F - 3 Body weight - I n di v i d ua l v a l u e s Sex : Female Dose l e v e l : Sample D-l 1 mg/kg Study No. BMR143C Uni t : Ani ma l Number 0 Weeks a f t e r commencement/ c e s s a t i o n of t r e a t me n t 1 2 3 4 5/1 6/2 2 2 0 1 121 152 177 2 0 4 2 2 5 KS 2 2 0 2 12 8 157 184 2 0 5 2 2 6 KS 2 2 0 3 130 15 7 18 0 201 2 1 6 KS 2 2 0 4 132 171 20 2 2 2 8 2 4 0 KS 2 2 0 5 13 4 185 21 3 2 3 7 2 5 9 KS 2 2 0 6 141 18 0 198 22 5 2 4 6 KS Mean S.D. N 131 6.6 6 KS : K i l l e d on s c h e d u l e 167 13.7 6 192 14.2 6 217 15.2 6 235 15.9 6 13 a i ,4 Appendix 2 - F - 4 Body wei ght - I n d i v i d u a l v a l u e s Sex : Female Dose l e v e l : Sample D-l 10 mg/kg Study No. BMR143C Unit : Ani ma l Number 0 Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t m e n t 12 3 4 5/1 6/2 3 2 0 1 125 156 185 2 0 3 2 1 6 KS 3 2 0 2 125 16 4 193 2 1 8 2 2 5 KS 3 2 0 3 125 149 166 17 8 18 6 KS 3 2 0 4 1 3 0 159 189 2 0 8 2 2 1 KS 3 2 0 5 136 169 187 2 0 3 2 1 2 KS 3 2 0 6 1 3 8 169 191 2 0 8 2 2 3 KS Mean S.D. N 130 5.9 6 KS : K i l l e d on s c h e d u l e 161 7.9 6 185 203 214 9.8 13.4 14.4 666 005386 14 Appendix 2 - F - 5 Body weight - I n d i v i d u a l v a l u e s Sex : Female Dose l e v e l : Sample D-l 30 mg/kg Study No. BMR143C Unit : g Ani ma l Number 0 Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t m e n t 1 2 3 4 5/1 6/2 4 2 0 1 131 1 6 0 17 4 179 1 7 8 KS 4 2 0 2 13 0 156 169 18 0 1 9 4 KS 4 2 0 3 12 7 151 172 186 1 9 4 KS 4 2 0 4 136 16 8 18 4 179 2 0 4 KS 4 2 0 5 133 162 173 17 7 181 KS 4 2 0 6 135 159 172 182 191 KS 4 2 0 7 129 1 5 7 167 162 175 1 9 4 20 1 KS 4 2 0 8 12 8 144 158 161 169 18 8 1 9 9 KS 4 2 0 9 131 1 6 0 17 7 181 19 0 196 2 0 8 KS 4 2 1 0 129 159 171 169 1 6 8 18 3 1 9 3 KS 4 2 1 1 122 149 159 175 186 19 7 2 1 3 KS 4 2 1 2 134 167 175 179 18 7 21 2 2 3 4 KS 005387 Mean S.D. N 130 3.9 12 KS : K i l l e d on s c h e d u l e 158 7.0 12 171 176 7.2 7.8 12 12 15 185 10.9 12 195 208 9.9 14.5 66 Appendix 3 M 1 Food consumption - Individual values Sex : Male Dose level : Sample D-l 0 mg/kg Study No. BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t m e n t 1 2 3 4 5/1 6/2 1 17.8 2 17.0 3 16.9 4 17.4 5 16.1 6 15.5 20.4 19.2 19.6 19.1 18.5 17.7 18.6 19.6 19.6 17.6 19.2 18.5 16.3 18.8 17.4 15.0 17.1 16.4 NA NA NA 20.6 23.1 21.6 22.3 23.8 23.0 Mean S.D. N 16.8 0.85 6 NA : No animal e x i s t e d . 19.1 0.92 6 18.9 0.77 6 16.8 1.27 6 21.8 1.26 3 23.0 0.76 3 005388 16 I Appendix 3 - M - 2 Food consumption - I n d i v i d u a l v a l u e s Sex : Male Dose l e v e l : Sample D-l 0 . 1 mg/kg Study No. BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t me n t 1 2 3 4 5/1 6/2 1 17.8 2 16.8 3 19.3 20.2 18.9 22.6 19.5 17.6 23.4 18.1 16.7 21.6 NA NA NA Mean S.D. N 18.0 1.26 3 NA : No animal e x i s t e d . 20.6 1.88 3 20.2 2.96 3 18.8 2.52 3 00S389 17 Appendix 3 - M - 3 Food consumption - Individual values Sex : Male Dose level : Sample D-l 1 mg/kg Study No BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i on o f t r e a t m e n t 1 2 3 4 5/1 6/2 1 16.3 2 16.9 3 17.8 18.8 19.1 19.9 Mean S.D. N 17.0 0.75 3 NA : No animal e x i s t e d . 19.3 0.57 3 18.1 17.1 19.1 18.1 1.00 3 17.3 16.6 17.9 17.3 0.65 3 NA NA NA 005390 18 I Appendix 3 - M - 4 Food consumption - I n d i v i d u a l v a l u e s Sex : Male Dose l e v e l : Sample D-l 10 mg/kg Study No BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t m e n t 1 2 3 45/1 6/2 1 15.7 2 16.0 3 18.0 17.1 17.6 20.1 16.9 19.1 22.4 15.9 16.7 20.8 NA NA NA Mean S.D. N 16.6 1.25 3 NA : No animal e x i s t e d . 18.3 1.61 3 19.5 2.77 3 17.8 2.63 3 T6CS00 19 I Appendix 3 - M - 5 Food consumption - Individual values Sex : Male Dose level : Sample D-l 30 mg/kg Study No BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t m e n t 1 2 3 4 5/1 6/2 1 14.8 2 15.8 3 15.8 4 15.1 5 14.5 6 16.4 14.9 16.3 16.4 15.2 15.4 16.4 14.7 15.6 15.3 15.6 15.0 15.4 12.8 12.8 11.7 13.7 12.5 12.8 NA NA NA 17.8 22.7 20.6 20.2 19.7 23.6 Mean S.D. N 15.4 0.72 6 NA : No animal e x i s t e d . 15.8 0.68 6 15.3 0.36 6 12.7 0.64 6 20.4 2.46 3 21.2 2.12 3 005392 20 Appendix 3 - F - 1 Food consumption - Individual v a lu e s Sex : female Dose l e v e l : Sample D-l 0 mg/kg Study No. BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t m e n t 1 2 3 4 5/1 6/2 1 12.4 2 14.7 3 12.6 4 14.8 5 14.9 6 13.4 12.1 13.6 11.4 14.9 14.3 12.4 12.3 15.1 12.4 15.6 15.1 13.1 11.2 13.8 10.8 14.3 13.3 12.9 NA NA NA 19,6 19.2 19.4 20.4 20.0 19.7 Mean S.D. N 13.8 1.15 6 NA : No animal e x i s t e d . 13.1 1.36 6 13.9 1.50 6 12.7 1.42 6 19.4 0.20 3 20.0 0.35 3 005393 21 Appendix 3 - F - 2 Food consumption - Individual values Sex : Female Dose level : Sample D-l 0.1 mg/kg Study No. BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i on o f t r e a t me n t 1 2 3 4 5/1 6/2 1 13.3 2 14.1 3 13.6 11.8 13.4 12.7 12.1 14.9 13.1 11.4 13.6 12.1 NA NA NA Mean S.D. N 13.7 0.40 3 NA : No animal e x i s t e d . 12.6 0.80 3 13.4 1.42 3 12.4 1.12 3 005394 22 Appendix 3 - F- 3 Food consumption - I n d i v i d u a l v a l u e s Sex : Female Dose l e v e l : Sample D-l 1 mg/kg St udy No. BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i o n o f t r e a t m e n t 1 2 3 4 5/1 6/2 1 11.6 2 14.1 3 16.3 10.5 12.9 13.4 11.7 13.1 13.8 11.0 12.2 12.5 NA NA NA Mean S.D. N 14.0 2.35 3 NA : No animal e x i s t e d . 12.3 1.55 3 12.9 1.07 3 11.9 0.79 3 { 005395 23 i Appendix 3 - F - 4 Food consumption - Individual values Sex : Female Dose level : Sample D-l 10 mg/kg Study N o . BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i on o f t r e a t me n t 1 2 3 4 5/1 6/2 1 12.6 11.9 2 11.6 .10.6 3 13.8 12.1 11.2 10.4 11.9 9.6 9.4 10.1 NA NA NA Mean S.D. N 12.7 1.10 3 NA : No animal e x i s t e d . 11.5 0.81 3 11.2 0.75 3 9.7 0.36 3 005396 24 Appendix 3 F - 5 Food consumption - Individual values Sex : Female Dose level : Sample D-l 30 mg/kg Study No. BMR143C Unit : g/Animal/Day Cage Number Weeks a f t e r commencement/ c e s s a t i on o f t r e a t me n t 1 2 3 4 5/1 6/2 1 12.0 9.6 7.9 6.9 NA 2 13.4 11.3 8.5 9.6 NA 3 13.4 10.6 9.0 8.6 NA 4 11.9 9.8 6.6 8.5 14.1 14.6 5 13.7 10.7 7.9 6.8 12.9 13.9 6 13.2 9.5 8.4 7.6 15.9 17.6 Mean S.D. N 12.9 0.78 6 NA : No animal e x i s t e d . 1,0.3 0.72 6 8.1 0.82 6 8.0 1.09 6 14.3 1.51 3 15.4 1.97 3 005397 25 Appendix 4 - M- 1 Hematology - Individual values Sex : Male Dose level : Sample D-l 0 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Animal Number 0101 0102 0103 0104 0105 0106 Mean S.D. N RBC HB count cone. (xloVmm3) (g/dl) 774 14.6 780 13.8 681 13.7 775 14.6 695 14.2 705 14.0 735 46.0 6 14.2 0.39 6 Ht (% ) 50.5 50.6 44.4 45.6 47.3 45.6 47.3 2.66 6 MCV (yUffl3) 65 65 65 59 68 65 65 2.9 6 MCH (pg) 18.9 17.7 20.1 18.8 20.4 19.9 19.3 1.02 6 MCHC (% ) Platelet count (xloVmm3) PT (sec) 28.9 . 27.3 30.9 32.0 30.0 30.7 84.8 104.6 102.6 115.4 88.2 83.7 13.8 14.1 14.1 13.8 14.9 15.2 30.0 1.66 6 96.6 12.88 6 14.3 0.59 6 APTT (sec) Retculocyte count (%o) 14.7 16.1 17.0 16.7 15.8 18.1 26 29 18 27 28 26 16.4 1.16 6 26 3.9 6 005398 Appendix 4 * M- 2 Hematology - Individual values Sex Male Dose level : Sample D-l 0.1 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C Animal Number 1101 1102 1103 1104 1105 1106 Mean S.D. N RBC HB count cone. (xIOVmm3) (g/dl) 765 14.1 683 13.9 689 13.9 675 13.8 679 14.3 696 14.1 698 33.7 6 14.0 0.18 6 Ht. (% ) 52.2 46.0 45.4 44.8 46.1 45.6 46.7 2.74 6 MCV (tin3) 68 67 66 66 68 66 67 1.0 6 MCH <Pg) 18.4 20.4 20.2 20.4 21.1 20.3 20.1 0.91 6 MCHC (% ) Platelet count (xlOVinm3) FT (sec) 27.0 30.2 30.6 30.8 31.0 30.9 106.1 78;2 88.3 91.0 94.7 104.7 14.9 13.9 13.9 14.0 13.8 13.7 30.1 1.54 6 93.8 10.51 6 14.0 0.44 6 APTT (sec) Reticulocyte count (%o) 15.5 15.7 15.4 16.4 19.4 17.6 26 26 21 33 32 35 16.7 1.57 6 29 5.3 6 005399 27 Appendix 4 - H - 3 Hematology - Individual values Sex : Male Dose level : Sample D-l 1 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Animal Number 2101 2102 2103 2104 2105 2106 o i Mean Q S.D. ON RBC HB count cone. (xlOVinin3) (g/dl) 681 13.2 733 14.0 794 14.1 764 14.3 719 13.8 728 14.4 737 38.8 6 14.0 0.43 6 Ht (% ) 42.3 46.3 51.9 47.7 46.2 49.0 47.2 3.21 6 MCV ( /xm3) 62 63 65 62 64 67 64 1.9 6 MCII (pg) 19.4 19.1 17.8 18.7 19.2 19.8 19.0 0.69 6 MCHC (% ) Platelet count (xlOVmm3) PT (sec) 31.2 30.2 27.2 30.0 29.9 29.4 97.4 92.1 134.7 112.7 105.4 79.8 13.9 14.2 14.1 14.1 14.4 13.5 29.7 1.34 6 103.7 18.92 6 14.0 0.31 6 APTT (sec) Reticulocyte count (%>) 13.0 14.7 15.8 16.7 17.6 15.4 27 25 30 30 26 27 15.5 1.60 6 28 2.1 6 28 i Appendix 4 - M- 4 Hematology - Individual values Sex M a l e Dose level : Sample D-l 10 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C An ima1 Number 3101 3102 3103 3104 3105 3106 Mean S.D. N RBC HB count cone. (xloVmm3) (g/dl) 681 12.8 714 13.6 737 13.5 756 13.3 713 13.7 766 13.2 728 31.4 6 13.4 0.33 6 lit. (% ) 43.4 45.1 49.6 45.4 46.2 47.6 46.2 2.15 6 MCV (Aim3) 64 63 67 60 65 62 64 2.4 6 MCH (pg) 18.8 19.0 18.3 17.6 19.2 17.2 18.4 0.80 6 MCHC (% ) Platelet count (xIOVmm3) PT (sec) 29.5 30.2 27.2 29.3 29.7 27.7 97.5 111.8 84.3 115.5 100.9 111.9 14.4 13.9 13.6 13.8 14.0 13.6 28.9 1.20 6 103.7 11.79 6 13.9 0.30 6 APTT (sec) Reticulocyte count (%o) 14.8 14.4 14.7 17.2 17.1 15.1 25 30 23 31 34 19 15.6 1.26 6 27 5.6 6 005401 29 i i ,4 Appendix 4 - M- 5 Hematology - Individual values Sex : Male Dose level : Sample D-l 30 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Animal Number 4101 4102 4103 4104 4105 4106 Mean S.D. N RBC HB count cone. (xIOVmm3) (g/dl) 647 13.1 665 12.5 702 13.0 725 12.9 667 13.6 792 14.9 700 53.3 6 13.3 0.85 6 Ht (% ) 44.1 43.8 45.9 48.4 43.0 51.6 46.1 3.30 6 MCV (m3) 68 66 65 67 64 65 66 1.5 6 MCH (pg) 20.2 18.8 18.5 17.8 20.4 18.8 19.1 1.01 6 MCHC (% ) Platelet count (xloVinm3) PT (sec) 29.7 28.5 28.3 26.7 31.6 28.9 92.1 88.1 96.0 96.3 78.0 89.1 14.4 14.8 14.6 14.2 14.0 14.2 29.0 1.63 6 89.9 6.76 6 14.4 0.29 6 APTT (sec) Reticulocyte count (%>) 15.0 20.4 15.7 18.4 20.2 19.1 14 21 22 14 21 27 18.1 2.29 6 20 5.0 6 30 I i f Appendix 4 - M- 6 Hematology - Individual values Sex I Male Dose level : Sample D-l 0 nig/kg Animals killed onschedule (Recovery) Study No. BMR143C Animal Number RBC Ills count cone. (xlOVmm3) (g/dl) Ht (% ) 0107 0108 0109 c* 0110 0111 ! 0112 s"'. O Ci Mean S.D. N 790 728 798 896 784 791 798 54.4 6 14.5 13.4 14.2 14.3 13.8 14.1 14.1 0.39 6 45.0 40.4 46.6 48.2 45.2 47.7 45.5 2.82 6 CL Not measured because clotting. MCY (m3) 57 55 58 54 58 60 57 2.2 6 MCH (pg) 18.4 18.4 17.8 16.0 17.6 17.8 17.7 0.88 6 MCIIC (% ) Platelet count (xlOVmm3) PT (sec) APTT (sec) Reticulocyte count (%>) 32.2 33.2 30.5 29.7 30.5 29.6 71.4 97.0 71.0 97.6 80.2 113.1 13.8 14.0 13.8 13.8 CL 13.7 17.3 16.2 15.3 15.9 CL 15.5 22 30 22 24 20 32 31.0 1.44 6 88.4 16.90 6 13.8 0.11 5 16.0 0.79 5 25 4.9 6 31 Appendix 4 - M- 7 Hematology - Individual values Sex : Male Dose level : Sample D-l 30 mg/kg Animals killed on schedule (Recovery) . Study No. BMR143C i Animal Number RBC HB count cone. (xloVmm3) (g/dl) 4107 4108 4109 4110 4111 o 4112 0/T 743 688 D 718 703 735 Q Mean A S.D. N 717 22.6 5 : Dead. 12.7 11.9 12.5 13.2 13.0 12.7 0.50 5 Ht (% ) 43.8 39.6 41.5 42.7 40.5 41.6 1.68 5 MCV 59 58 58 61 55 58 2.2 5 MCH (pg) 17.1 17.3 17.4 18.8 17.7 17.7 0.67 5 MCHC (% ) Platelet count (xlOV i t im 3 ) PT (sec) 29.0 30.1 30.1 30.9 32.1 82.8 112.7 96.0 88.6 97.4 13.3 13.7 13.7 12.6 13.6 30.4 1.15 5 95.5 11.28 5 13.4 0.47 5 APTT (sec) Reticulocyte count (%o) 14.2 14.3 15.8 14.6 17.2 31 34 22 31 39 15.2 1.28 5 31 6.2 5 > i j 32 i rf Appendix 4 - F - 1 Hematology - Individual values Sex : Female Dose level I Sample D-l 0 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Animal Number 0201 0202 0203 0204 0205 0206 Mean S.D. N RBC HB count cone. (xlOVmm3) (g/dl) 720 13.2 777 13.7 658 13.3 635 12.6 727 13.4 714 13.8 705 51.2 6 13.3 0.43 6 Ht. (% ) 44.5 46.3 40.6 37.6 41.8 45.7 42.8 3.36 6 MCV (/im3) MCI! (pg) 62 60 62 59 . 57 64 18.3 17.6 20.2 19.8 18.4 19.3 61 18.9 2.5 1.00 66 MCHC (% ) Platelet count (xlOVmm3) PT (sec) 29.7 29.6 32.8 33.5 32.1 30.2 117.7 142.0 95.2 107.5 120.4 111.4 14.3 14.4 14.6 14.2 14.0 14.3 31.3 1.70 6 115.7 15.64 6 14.3 0.20 6 APTT (sec) Reticulocyte count (%>) 15.9 13.6 11.8 12.9 15.9 14.1 22 24 26 18 19 24 14.0 1.64 6 22 3.1 6 005405 33 i Appendix 4 - F - 2 Hematology - Individual values Sex : Female Dose level : Sample D-l 0.1 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Animal Number 1201 1202 12031204 1205 1206 Mean S.D. N RBC HB count cone. (xloVmm3) (g/dl) 720 13.5 693 13.5 644 13.4 699 13.9 698 13.7 693 13.5 691 25.2 6 13.6 0.18 6 Ht < % ) 40.7 40.8 42.6 41.3 42.3 44.4 42.0 1.40 6 MCV (Atm3) 57 59 66 59 61 64 61 3.4 6 MCH (pg) 18.8 19.5 20.8 19.9 19.6 19.5 19.7 0.66 6 MCHC (% ) Platelet count (xloVmm3) PT (sec) 33.2 33.1 31.5 33.7 32.4 30.4 101.4 97.6 124.0 87.7 99.1 108.6 14.7 14.5 14.5 13.4 14.2 14.2 32.4 1.24 6 103.1 12.27 6 14.3 0.46 6 APTT (sec) Reticulo cyte count (%>) 17.0 14.5 15.1 14.0 14.4 13.7 24 18 26 21 20 22 14.8 1.19 6 22 2.9 6 005406 34 i ,4 Appendix 4 - F - 3 Hematology - Individual values Sex : Female Dose level : Sample D-l 1 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Animal Number 2201 2202 2203 2204 2205 2206 Mean S.D. N RBC HB count cone. (xlOVmm3) (g/dl) 726 13.7 708 12.9 724 13.5 634 13.2 768 13.1 643 13.3 701 52.0 6 13.3 0.29 6 Ht <% ) 42.6 40.6 44.0 40.7 41.3 38.8 41.3 1.79 6 MCV (/um3) 59 57 61 64 61 60 60 2.3 6 MCH (pg) 18.9 18.2 18.6 20.8 19.3 20.7 19.4 1.09 6 MCHC (%) Platelet count (xIOVmm3) PT (sec) 32.2 31.8 30.7 32.4 31.7 34.3 106.3 115.6 113.6 111.1 102.7 97.9 13.9 14.2 14.8 13.2 14.4 14.6 32.2 1.19 6 107.9 6.81 6 14.2 0.57 6 APTT (sec) Reticulocyte count (%o) 13.1 16.8 15.1 14.7 17.1 17.3 22 25 21 24 21 18 15.7 1.66 6 22 2.5 6 005407 35 I i Appendix 4 - P - 4 Hematology - Individual values Sex : Female Dose level : Sample D-l 10 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Animal Number 3201 3202 3203 3204 3205 3206 Mean S.D. N count cone. (xloVmm3) (g/di) Ht (% ) 685 14.0 44.0 759 l3.b 43.4 /64 14.1 47.4 700 13.4 41.0 693 13.5 ' 43.4 695 13.9 ,43.8 716 35.6 fa 13.7 0.30 6 43.8 2.06 6 HCV (/m3) 64 57 62 59 63 63 61 2.7 6 MCH (pg) 20.4 17.8 18.5 19.1 19.5 20.0 19.2 0.96 6 MCHC (% ) Platelet (xloVmm3) PT (sec) 31.8 31.1 29.7 32.7 31.1 31.7 31.4 1.00 6 88.0 111.0 123.3 93.7 117.7 101.9 105.9 13.81 6 14.3 14.2 14.1 13.5 13.5 14.5 14.0 0.42 6 APTT Reticulo* (sec) C(%>)Unt 15.3 14.0 15.2 14.3 15.4 16.8 15.2 0.99 6 22 21 25 20 19 20 21 2.1 6 i 005408 36 I 4 005409 Appendix 4 - F - 5 Hematology - Individual values Sex : Female Dose level : Sample D-l 30 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Animal Number RBC HB count cone. (xloVmm3 ) (g/dl) 4201 4202 4203 . 4204 4205 4206 778 649 763 713 666 761 13.9 12.9 12.8 12.7 12.5 12.9 Mean S.D. N 722 54.6 6 13.0 0.49 6 Ht (% ) 44.7 39.6 46.6 42.5 39.9 45.5 43.1 2.95 6 MOV. (urn3) 57 61 61 60 60 60 60 1.5 6 MCH (pg) 17.9 19.9 16.8 17.8 18.8 17.0 18.0 1.16 6 MCHC (% ) Platelet count (xloVmm3 ) PT * (sec) 31.1 32.6 27.5 29.9 31.3 28.4 95.6 97.3 117.9 . 101.7 90.4 116.4 13.7 13.5 13.3 13.3 13.5 13.1 30.1 1.92 6 103.2 11.39 6 13.4 0.21 6 APTT (sec) Reticulocyte count (% o) 16.6 15.2 11.4 16.9 14.6 13.0 16 21 22 19 19 24 14.6 2.12 6 20 2.8 6 { Appendix 4 - F - 6 Hematology - Individual values Sex : Female Dose level : Sample D-l 0 mg/kg Animals killed onschedule (Recovery) Study No. BMR143C Animal Number 0207 0208 0209 0210 0211 0212 Mean S.D. N RBC HB count cone. (xlOVmm3) (g/dl) 713 13.9 727 13.6 683 13.4 755 14.1 699 13.4 713 13.7 715 24.6 6 13.7 0.28 6 lit (% ) 42.1 42.0 41.1 44.4 43.2 45.6 43.1 1.68 6 MCV (jUffl3) 59 58 60 59 62 64 60 2.3 6 MCH (pg) 19.5 18.7 19.6 18.7 19.2 19.2 19.2 0.38 6 MCHC (% ) Platelet count (xl0*/mm3) PT (sec) 33.0 . 32.4 32.6 31.8 31.0 30.0 112.4 90.8 88.3 99.8 72.5 99.1 13.3 14.0 13.3 13.2 13.9 13.2 31.8 1.12 6 93.8 13.44 6 13.5 0.37 6 APTT (sec) Reticulocyte count (%o) 15.7 17.8 13.0 14.5 16.1 15.9 25 19 28 23 23 27 15.5 1.62 6 24 3.3 6 005410 38 < f i Appendix 4 - F - 7 Hematology - Individual values Sex .' Female Dose level : Sample D-l 30 mg/kg Animals killed on schedule (Recovery) Study No. BMR143C Animal Number 4207 4208 4209 4210 4211 4212 Mean S.D. N RBC 118 count cone. (xloVmm3) (g/dl) 666 12.5 700 12.6 641 12.2 653 12.6 732 13.0 678 12.9 678 33.3 6 12.6 0.29 6 Ht (% ) 41.4 44.6 41.2 41.2 44.4 43.3 42.7 1.62 6 MCV (/im3) 62 64 64 63 61 64 63 1.3 6 MCH (pg) 18.8 18.0 19.0 19.3 17.8 19.0 18.7 0.61 6 MCHC (% ) Platelet count (xl04/mm3) pi (sec) 30.2 28.3 29.6 30.6 29.3 29.8 114.4 138.9 85.4 105.3 101.4 116.5 13.4 13.8 13.2 12.8 13.0 12.5 29.6 0.80 6 110.3 17.87 6 13.1 0.46 6 APTT (sec) Retculocyte count (%o) 13.5 12.8 12.0 13.8 10.2 11.5 27 27 23 26 21 27 12.3 1.35 6 25 2.6 6 005411 39 \ Ani ma l Number 0101 0102 0103 0104 0105 0106 Mean O O C/ S.D. N b* Appendix 5 - M - 1 Hematology - Individual values Sex : Male Dose le vel : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) Study No. BMR143C WBC D i f f e r e n t i a l c ount o f l e u k o c y t e s ( % of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eos i no- Baso Mono ( x l 0 Z/mm3 ) c y t e s Segmented Band phi Is phils cytes 69 83 9 1 1 0 6 83 91 7 .1 0 0 1 119 90 4 1 0 0 5 63 90 6 0 0 0 4 80 , 77 13 0 1 0 9 111 82 10 0 0 0 8 88 86 8 1 0 0 6 22.6 5.7 3.2 0.5 0.5 0.0 2.9 666666 6 An i ma1 Number 1101 1102 1103 1104 1105 1106 Mean S.D. N Appendix 5 - M - 2 Hematology - Individual values Sex : Male Dose l e v e l : Sample D-l 0 . 1 mg/kg Animals k i l l e d on s c h e d u l e (4 weeks) Study No. BMR143C WBC D if f e r e n t ia l count of leukocytes ( v. of total counted c e l l s ) coun t Lympho- Neutrophils Eosino- Baso- Mono- ( x l Oz /mm3 ) c y t e s Segmented Band ph i 1s Phils cytes 120 82 15 0 0 0 3 86 88 6 ' 1 0 0 5 94 80 9 1 3 0 7 126 93 6 0 0 0 1 135 93 4 0 0 0 3 73 83 10 0 1 0 6 106 87 8 0 1 0 4 24.8 5.7 3.9 0.5 1.2 0.0 2.2 6666666 41 005414 Ani ma l Number 2101 2102 2103 2104 2105 2106 Mean S.D. N Appendix 5 - M - 3 Hematology - Individual values Sex : Male Dose le v el : Sample D-l 1 mg/kg Animals k i l l e d on s c h e d u l e (4 weeks) Study No. BMR143C WBC D i f f e r e n t i a l c ount o f l e u k o c y t e s ( % of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eos i no- Baso- Mono- ( xl O2 /mm3 ) c y t e s Segmented Band Phils phils cytes 104 95 3 0 1 0 1 109 89 7 0 0 0 4 162 89 8 0 0 0 3 121 87 9 0 1 0 3 116 82 12 1 0 0 5 96 86 10 0 1 0 3 118 88 8 0 1 0 3 23.3 4.3 3.1 0.4 0.5 0.0 1.3 6666666 Ani ma l Number 3101 3102 3103 3104 3105 3106 Mean S.D. N Appendix 5 - M - 4 Hematology - Individual values Sex : Male Dose le v e l : Sample D-l 10 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) Study No. BMR143C WBC D i f f e r e n t i a l c o unt o f l e u k o c y t e s ( V. of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eos i no- ' Baso- Mono- ( xl Oz /mm3 ) c y t e s Segmented Band Phils Phils cytes 105 78 15 0 1 0 6 107 82 10 0 0 0 8 123 82 9 0 2 0 7 86 92 6 0 0 0 2 81 82 12 0 0 0 6 80 91 6 0 2 0 1 97 85 10 0 1 0 5 17.4 5.6 3.5 0.0 1.0 0.0 2.8 6666666 005415 43 Ani ma l Number ' 4101 4102 4103 4104 4105 4106 Mean S.D. N Append ix 5 - M - 5 Hematology - Individual values Sex : Male Dose l e v e l : Sample D-l 30 mg/kg Animals k i l l e d on s c h e d u l e (4 weeks) Study No BMR143C WBC D i f f e r e n t i a l c o u n t o f l e u k o c y t e s ( /. of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eos i no- Baso Mono CxlO2 /mm3 ) c y t e s Segmented Band phi Is phils cytes 245 91 6 0 0 0 3 108 85 7 0 0 0 8 104 88 9 2 0 0 1 112 84 8 1 0 0 7 66 85 13 0 0 0 2 184 84 9 0 0 0 7 137 86 9 1 0 0 5 65.5 2.8 2.4 0.8 0.0 0.0 3.0 6666666 005416 44 Ani ma l Number 0107 0108 0109 0110 0111 0112 Mean S.D. N Append ix 5M 6 Hematology - Individual values Sex : Male Dose l e v e l : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e (Recovery) Study No. BMR143C WBC D i f f e r e n t i a l count o f l e u k o c y t e s ( % of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eos i no- Baso- Mono- ( x 10* / mm3 ) c y t e s Segmented Band phils phils cytes 96 90 4 1 0 0 5 96 75 20 'o 0 0 5 117 90 5 1 0 0 4 78 79 14 0 0 0 7 106 90 8 0 0 0 2 86 83 12 0 0 0 5 97 85 11 0 0 0 5 13.9 6.5 6.1 0.5 0.0 0.0 1.6 66666 6 6 00S417 45 Appendix 5 - M - 7 Hematology - Individual values Sex : Maie Dose l e v e l : Sample D-l 3 0 mg/kg Animals k i l l e d on s c h e d u l e ( R e c o v e r y ) Study No. BMR143C Ani ma l Number WBC D i f f e r e n t i a l c ount of l e u k o c y t e s ( X of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eos i no- Baso Mono ( xlO* /mm3 ) c y t e s Segmented Band phi 1s phils cytes 4107 122 87 8 i 0 0 4 4108 134 86 8 i 0 0 5 4109 D 4110 107 83 7 i 0 0 9 4111 130 85 10 0 0 0 5 O 4112 135 95 5 0 0 0 0 r*. C-1 Mean 126 87 8 10 0 5 S.D. 11.6 4.6 1.8 0.5 0.0 0.0 3.2 00 N 5 5 5 5 5 5 5 D : Dead. i 46 i If Ani ma l Number 0201 0202 0203 0204 0205 0206 6O c/i Mean S.D. N Appendix 5 - F Hematology - Individual values Sex : Female Dose le v el : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) Study No. BMR143C \vBC D i f f e r e n t i a l count of 1 e u k o c y t e s ( % of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutroph i 1s Eos i no- Baso- Mono- ( xl Oz /mm3 ) c y t e s Segmented Band phi 1s Phils cytes 54 86 10 1 0 0 3 80 92 8 0 0 0 0 77 85 13 0 0 0 2 80 87 9 1 0 0 3 72 84 12 0 0 0 4 84 84 8 2 0 0 6 75 86 10 1 0 0 3 10.8 3.0 2.1 0.8 0.0 0.0 2.0 666666 6 Ani ma l Number 1201 1202 1203 1204 1205 1206 Ci JN Mean S.D. N Appendix 5 - F - 2 Hematology - Individual values Sex : Female Dose le v e l : Sample D-l 0 . 1 mg/kg Animals k i l l e d ons c h e d u l e ( 4 weeks) Study No. BMR143C WBC D i f f e r e n t i a l count of l e u k o c y t e s ( v. of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eos i no- Baso Mono (xlO^/mm3 ) c y t e s Segmented Band phi 1s phils cytes 143 86 9 0 0 0 5 58 94 3 0 1 0 2 129 82 12 1 0 0 5 . 96 93 5 1 0 0 1 86 89 3 0 0 0 8 92 85 11 0 0 0 4 101 88 7 0 0 0 4 30.7 4.7 4.0 0.5 0.4 0.0 2.5 6 66666 6 48 Ani ma l Number 2201 2202 2203 2204 2205 2206 Mean S.D. N Appendix 5 - F - 3 Hematology - Individual values Sex. : Female Dose le v e l : Sample D-l 1 mg/kg Animals k i l l e d ons c h e d u l e (4 weeks) Study No. BMR143C WBC D i f f e r e n t i a l c ount of l e u k o c y t e s ( % of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eosino Baso Mono ( x l 0 2 /mm3 ) c y t e s Segmented Band phils phils cytes 57 86 9 1 0 0 4 94 92 7 0 0 0 1 108 87 10 0 1 0 2 112 81 15 0 1 0 3 77 86 13 0 0 0 1 70 93 5 1 0 0 1 86 88 10 0 0 0 2 21.9 4.4 3.7 0.5 0.5 0.0 1.3 666666 6 4 TZSOO 49 i i ,4 Ani ma l Number 3201 3202 3203 3204 3205 3206 Mean S.D. N Appendix 5 - F - 4 Hematology - Individual values Sex : Female Dose l e v e l : Sample D-l 10 mg/kg Animals k i l l e d ons c h e d u l e ( 4 weeks) Study No. BMR143C WBC D i f f e r e n t i a l count o f l e u k o c y t e s ( % o f t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eos i no- Baso Mono ( xl O2 /mm3 ) c y t e s Segmented Band phi 1s phils cytes 117 92 103 87 61 90 67 89 89 92 70 84 41 6 0 60 60 20 80 00 00 00 10 00 10 3 7 4 4 6 7 85 89 5 0 0 0 5 22.3 3.1 2.1 0.4 0.5 0.0 1.7 666666 6 i 1 005422 50 i , Ani ma l Number 4201 4202 4203 4204 4205 4206 O o in Mean & S.D. i\j N Co Appendix 5 - F - 5 Hematology - Individual values Sex : Female Dose l e v e l : Sample D-l 30 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) Study No. BMR143C WBC D i f f e r e n t i a l c ount o f l e u k o c y t e s ( % of t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutrophils Eos i no- Baso Mono CxlO*/mm3 ) c y t e s Segmented Band phi 1s phils cytes 78 89 6. 0 0 0 5 66 83 i 1 0 0 9 83 ' 89 7 0 0 0 4 104 87 7 0 1 0 5 60 92 5 0 0 0 3 71 80 18 0 0 0 2 77 87 8 0 0 0 5 15.6 4.4 4.8 0.4 0.4 0.0 2.4 6666 66 6 51 Ani ma l Number 0207. 0208 0209 0210 0211 0212 C o C/T Mean S.D. i\) N Appendix 5 - F - 6 Hematology - Indi vidual value's Sex : Female Dose l e v e l : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e ( Re c o v e r y ) Study No. BMR143C WBC D i f f e r e n t i a l count of 1 e u k o c y t e s ( % o f t o t a l c o u n t e d c e l l s ) coun t Lympho- Neutroph i 1s Eos i no- Baso- Mono- ( x 1 02 / mm3 ) cy t e s Segmen ted Band Phils Phils cy tes 69 82 4 1 2 0 11 92 94 2 0 0 0 4 5 4 87 9 0 0 0 4 114 82 13 0 0 0 5 72 91 7 0 0 0 2 109 77 16 0 3 0 4 85 86 9 0 1 0 5 23.9 6.3 5.3 0.4 1.3 0.0 3.1 6666666 i 52 I i f Ani ma l Number 4207 4208 4209 4210 4211. O o 4212 /T 0 C/7 Mean S.D. N Appendix oF/ Hematology - Individual values Sex : Female Dose l e v e l : Sample D-l 3 0 mg/kg Animals k i l l e d on s c h e d u l e (Recovery) Study No. BMR143C 07 H- CO 07 07 WBC D i f f e r e n t i a l count o f l e u k o c y t e s ( % of t o t a l c o u n t e d c e l l s ) count Lympho- Neutrophils Eos i no- Baso- Mono- ( X10z t mm3 ) c y t e s Segmented Band .Phils Phils cytes 105 92 3 1 0 0 104 88 6 0 0 0 84 88 5 0 1 0 76 93 4 0 0 0 88 91 8 0 0 0 57 93 2 0 0 0 86 91 5 0 0 0 18.1 2.3 2.2 0.4 0.4 0.0 666666 07(0^ Appendix 6 - M- 1 CI in icaI chem is try - Ind iv iduaI va Iues Sex : MaIe [lose level : Sample D-l 0 mg/kg Animals killed on schedule (4 weeks) Study No. BNR143C i Animal Number 0101 0102 0103 0104 0105 0106 Mean S.D. N GOT (IU/1) 80 70 60 64 65 71 68 7.0 6 GPT (IU/1) 37 26 33 26 31 26 30 4.6 6 r -GTP (IU/1) 0 0 0 0 0 0 0 0.0 6 ALP (IU/1) 739 667 859 642 841 518 711 129.3 6 Urea nitrogen (mg/dl) Great ini n (mg/dl) Glucose (mg/dl) 11.2 0.5 134 13.4 0.5 129 14.8 0.5 153 12.2 0.5 138 12.6 0.5 150 10.2 0.5 137 12.4 1.62 6 0.5 0.00 6 140 9.4 6 Total chol. (mg/dl) 57 52 58 67 63 48 58 6.9 6 Triglyceride (mg/dl) 59 37 81 32 41 43 49 18.2 6 005426 Append ix 6 - M - 2 Clinical chemistry - Individual values Sex Male Dose level : Sample D-l 0 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C Animal Number 0101 0102 0103 0104 0105 0106 Mean S.D. N Total protein (g/dl) 6.36 6.34 6.63 6.68 6.27 6.78 6.51 0.212 6 Albumin (g/dl) 4.07 3.92 4.00 4.04 3.75 4.08 3.98 0.125 6 A/G ratio 1.78 1.62 1.52 1.53 1.49 1.51 1.58 0.110 6 Calcium (mg/dl) 9.5 9.3 10.6 9.6 9.9 9.9 9.8 0.46 6 1norganic phos. (mg/dl) Na (mEq/l) 9.4 9.8 10.8 10.0 11.2 9.7 142 143 143 142 142 142 10.2 0.70 6 142 0.5 6 K (mEq/l) 4.0 4.1 4.1 4.2 4.0 4.1 4.1 0.08 6 Cl (mEq/l) 103 105 101 99 100 101 102 2.2 6 , Animal Number 1101 1102 1103 1104 1105 1106 Mean S.D. N GOT (IU/1) 65 77 69 61 66 50 65 9.0 6 GPT (IU/1) 29 31 38 26 30 23 30 5.1 6 Append i\ 6 - M- 3 Clinical chemistry - Individual values Sex I Male Dose level : Sample D-l 0.1 mg/kg Animals killed on schedule (4 weeks) Study No BMR143C r -GTP (IU/1) 0 0 0 0 0 0 0 0.0 6 ALP (IU/1) 822 666 713 577 618 666 677' 84.9 6 Urea nitrogen (mg/dl) Greati ni n (mg/dl) Glucose (mg/dl) 11.8 13.2 10.1 11.5 10.4 6.8 0.4 0.5 0.4 . 0.4 0.5 0.5 136 138 157 149 159 159 10.6 2.18 6 0.5 0.05 6 150 10.5 6 Total cho 1. (mg/dl) 62 58 59 57 53 53 57 3.5 6 Triglyceride ( m g / d 1) 71 59 41 61 56 41 55 11.8 6 005428 56 I 005429 Appendix 6 - M- 4 Clinical chemistry - Individual values Sex 1 Male Dose level : Sample 0-1 0.1 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Animal Number 1101 1102 1103 1104 1105 1106 Mean S.D. N Total protein (g/dl) 6.29 6.67 6.21 6.31 6.48 6.33 6.38 0.166 6 A 1bum in (g/dl) 3.95 4.16 3.93 3.90 3.90 3.89 3.96 0.103 6 A/G ratio 1.69 1.66 1.72 1.62 1.51 1.59 1.63 0.076 6 Calcium , (mg/dl) 1norganic phos. ( mg/ d1) Na (mEq/l) 9.6 9.9 10.1 9.8 9.9 9.3 9.3 9.0 10.4 8.8 10.9 8.4 142 142 142 142 142 141 9.8 0.28 6 9.5 0.98 6 142 0.4 6 K (mEq/l) 3.9 4.1 4.1 4.0 4.0 4.0 4.0 0.08 6 Cl (mEq/l) 102 103 101 101 101 101 102 0.8 6 57 { Appendix 6 - M - 5 CI ini caI chem istry - Ind ivdual vaIues Sex Ma Ie Dose level : Sample D-l 1 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C Animal Number 2101 2102 2103 2104 2105 2106 Mean S.D. N GOT (IU/1) 66 87 69 67 66 70 71 8.1 6 GPT (IU/1) 26 36 34 33 30 25 31 4.5 6 r -g t p (IU/1) 0 0 0 0 0 0 0 0.0 6 ALP (IU/1) 705 923 537 806 727 703 734 127.7 6 Urea nitrogen (mg/dl) Creatinin (mg/dl) Glucose (mg/dl) 11.3 11.1 12.3 12.6 16.8 15.5 0.5 145 0.5 129 0.5 143 0.5 136 0.5 139 0.4 148 13.3 2.34 6 0.5 0.04 6 140 6.9 6 Total chol. (ing/dl) 46 56 52 44 49 48 49 4.3 6 Triglyceride (mg/dl) 41 43 54 39 113 72 60 28.6 6 005430 58 I Appendix 6 - M- 6 Clinical chemistry - Individual values Sex : Male Dose level : Sample D-l 1 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C , An im a 1 Number 2101 2102 2103 2104 2105 2106 Mean S.D. N Total protein (g/dl) 6.18 6.36 6.35 6.07 6.43 5.95 6.22 0.190 6 A 1bum in (g/dl) 3.88 3.92 3.82 3.93 3.77 3.74 3.84 0.079 6 A/G ratio . Calcium (mg/dl) 1.70 1.61 1.51 1.84 1.42 1.69 9.4 9.8 9.9 9.8 10.2 9.4 1.63 0.149 6 9.8 0.31 6 1norganic phos. (mg/dl) Na (fflEq/l) 8.7 9.0 10.1 10.3 10.1 8.9 142 141 141 142 143 141 9.5 0.72 6 142 0.8 6 k (mEq/1) 4.2 4.4 4.0 4.0 4.5 4.2 4.2 0.20 6 Cl (fllEq/l) 104 103 101 103 101 103 103 1.2 6 005431 59 . Animal Number 3101 3102 3103 3104 3105 3106 Mean S.D. N GOT (IU/1) 65 66 69 58 67 62 65 3.9 6 OPT (IU/1) 40 33 32 34 33 31 34 3.2 6 Appendix 6 - H - 7 Clinical chemistry - Individual values Sex Ma l.e Dose level : Sample D-l 10 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C r -g t p (IU/1) 0 0 0 0 0 0 0 0.0 6 ALP (IU/1) 988 755 682 797 615 841 780 130.2 6 Urea nitrogen (mg/dl) Great in in (mg/dl) Glucose (m g/ d 1) 12.8 0.5 131 14.8 0.5 142 14.9 0.5 145 11.0 0.4 145 12.8 0.5 155 8.1 0.4 132 12.4 2.56 6 0.5 0.05 6 142 9.0 6 Total chol. (mg/dl) 26 35 37 29 54 49 38 11.1 6 Triglyceride (mg/dl) 65 30 60 17 89 25 48 28.0 6 005432 60 i Appendix 6 - M- 8 Clinical chemistry- Individual values Sex : Male Dose level 1' Sample D-l Animals killedon schedule (4 weeks) Study No. BMR143C 10mg/kg Animal Number 3101 3102 3103 3104 3105 3106 Mean S.D. N Total protein (g/dl) Albumin (g/dl) 6.29 6.05 6.28 6.16 6.15 6.29 ' 4.15 3.84 4.05 3.94 3.75 3.87 6.20 0.099 6 3.93 0.146 6 A/G ratio 1.94 1.74 1.82 1.77 1.56 1.60 1.74 0.141 6 Calcium (mg/dl) 10.2 9.9 9.9 9.7 9.8 9.3 9.8 0.30 6 1norganic phos. (mg/dl) Na (mEq/l) 9.2 10.8 8.8 8.9 9.6 8.5 143 143 141 142 142 141 9.3 0.82 6 142 0.9 6 K (mEq/l) 4.1 4.8 3.9 4.2 4.6 4.3 4.3 0.33 ,6 Cl (mEq/l) 104 104 102 105 102 105 104 1.4 6 005433 61 . Animal Number 4101 4102 4103 4104 4105 4106 Mean S.D. N GOT (IU/1) 81 77 76 61 62 83 73 9.5 6 OPT (IU/1) 46 57 46 47 43 78 53 13.2 6 Appendix 6 - M- 9 Clinicalchemistry - Individual values Sex ' Male Dose level : Sample D-l 30 mg/kg Animals killed onschedule (4 weeks) Study No., BMR143C r -OTP (IU/1) 0 0 0 0 0 0 0 0.0 6 ALP (IU/1) 1639 1243 1036 1179 940 1111 1191 243.7 6 Urea nitrogen (mg/dl) Creatinin (mg/dl) Glucose (mg/dl) 15.1 15.8 13.7 10.4 14.9 14.5 0.6 0.5 0.5 0.5 0.5 0.8 139 144 127 140 137 162 14.1 1.93 6 0.6 0.12 6 142 11.5 6 Total chol. (mg/dl) 10 9 12 6 10 9 9 2.0 6 Triglyceride (mg/dl) 15 13 22 15 20 39 21 9.6 6 005434 62 r . Animal Number 4101 4102 4103 4104 4105 4106 Mean S.D. N C/l CO 01 Appendix 6 - M- 10 Clinical chemistry - Individual values Sex M a l e Dose level *. Sample D-l 30 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C Total protein (g/dl) 6.06 5.87 6.28 5.45 5.87 6.51 6.01 0.368 6 Albumin (g/dl) 3.94 3.97 4.06 3.91 3.86 4.32 4.01 0.166 6 A/G ratio 1.86 2.09 1.83 2.54 1.92 1.97 2.04 0.264 6 Calcium (rag/dl) 9.3 9.1 9.9 8.8 9.1 10.2 9.4 0.54 6 1norganic phos. (mg/dl) Na (mEq/l) 8.8 8:3 8.9 9.0 8.7 16.2 142 142 143 144 143 147 10.0 3.06 6 144 1.9 6 K (mEq/l) 4.1 4.1 4.7 3.7 4.3 4.5 4.2 0.35 6 Cl (mEq/l) 107 104 105 107 107 105 106 1.3 6 63 Appendix 6 - M- 11 Clinical chemistry - Individual values Sex : Male Dose level '. .Sample D-l 0 mg/kg Animals killed on schedule (Recovery) Study No. BMR143C ( An ima 1 Number 0107 0108 0109 0110 0111 0112 Mean S.D. N GOT (IU/1) 85 77 80 110 76 81 85 12.7 6 GPT (IU/1) 28 30 37 36 40 33 34 4.5 6 r -GTP (IU/1) ALP (IU/1) 0 718 0 578 0 621 0 542 0 652 0 564 0 613 0.0 65.2 66 Urea nitrogen (mg/dl) Creat ini n (mg/dl) Glucose (mg/dl) 22.6 19.9 16.0 16.4 18.6 18.6 0.5 0.5 0.5 ' 0.4 0.5 0.4 145 152 158 144 145 143 18.7 2.42 6 0.5 0.05 6 148 5.9 6 Total chol. (mg/dl) 44 52 77 40 41 43 50 14.1 6 Triglyceride (mg/dl) 144 72 135 39 76 43 85 45.0 6 005436 64 t 4 Append i\ 6 - M- 12 Clinical chemistry - Individual values Sex '. Male Dose level : Sample D-l 0 mg/kg Animals killed onschedule (Recovery) Study No. BMR143C Animal Number 0107 0108 0109 0U0 0111 0112 Mean S.D. N Total protein (g/dl) 6.43 6.23 6.59 6.65 6.34 6.30 6.42 0.187 6 Albumin (g/dl) A/G ratio 3.82 3.77 3.89 3.90 3.91 3.82 1.46 1.53 1.44 1.42 1.61 1.54 3.85 0.056 6 1.50 0.072 6 Calcium (mg/dl) 10.0 9.7 9.8 9.4 9.3 9.4 9.6 0.28 6 1norganic phos. (mg/dl) Na (mEq/l) 8.7 143 8;8 142 8.6 140 9.0 142 8.6 142 8.5 139 8.7 0.18 6 141 1.5 6 K (mEq/l) 4.0 4.3 4.5 4.2 3.8 4.5 4.2 0.28 6 Cl (mEq/l) 105 105 104 104 105 101 104 1.5 8 005437 65 I '! ,4 Appendix 6 - M- 13 Clinical chemistry - Individual values Sex M a l e Dose level Sample D-l 30 mg/kg Animals killed on schedule (Recovery) Study No. BMR143C Anima1 Number GOT (IU/1) 4107 4108 4109 4110 4111 4112 78 86 D 74 71 70 Mean S.D. N U : Dead. 76 6.5 5 GPT (IU/1) 36 42 37 44 61 44 10.1 5 r -GTP (IU/1) 0 0 0 0 0 0 0.0 5 ALP (IU/1) 792 852 681 671 586 716 105.4 5 Urea nitrogen (mg/dl) Creatinin (mg/dl) Glucose (mg/dl) 24.4 21.7 26.1 19.6 17.1 0.4 0.5 0.6 0.5 0.4 141 171 159 141 150 21.8 3.61 5 0.5 0.08 5 152 12.8 5 Total chol. (mg/dl) 22 28 19 48 27 : 29 11.3 5 Triglyceride (mg/dl) 14 15 9 8 5 10 4.2 5 005438 66 i Appendix 6 - M- 14 Clinical chemistry - Individual values Sex : Hale Dose level 1 Sample D-l 30 mg/kg Animals killed on schedule (Recovery) Study No BMR143C Animal Number Total protein (g/dl) 4107 4108 4109 4110 4111 4112 6.08 6.81 D 6.70 6.70 6.57 Mean S.D. N D I Dead. 6.57 0.288 5 Albumin (g/dl) A/G ratio Calcium (mg/dl) 3.80 4.13 4.24 4.25 4.26 1.67 1.54 1.72 1.73 1.84 . 9.7 9.8 9.8 9.7 9.6 4.14 0.195 5 1.70 0.109 5 9.7 0.08 5 1norganic phos. (mg/dl) Na (mEi|/l) 8.3 143 9.4 141 9.4 140 9.4 142 8.2 142 8.9 0.63 5 142 1.1 5 K (mEq/l) 4.1 4.5 4.1 4.3 4.0 4.2 0.20 5 Cl (mEq/l) 109 108 103 104 106 106 2.5 5 005439 67 Appendix 6 - F - 1 Study No. BMR143C Clinical chemistry - Individual values Sex ' Female Oose level : Sample D-l 0 mg/kg ifl Animals ki Iled on schedule (4 weeks) Animal Number 0201 0202 0203 0204 0205 0206 Mean S.D. N GOT (IU/1) 75 67 87 79 88 83 80 8.0 6 GPT (IU/1) 20 26 25 25 23 17 23 3.5 6 r -GTP (IU/1) 0 0 0 1 0 0 0 0.4 6 ALP (IU/1) Urea nitrogen ( mg/ d1) Creatinin ( mg/ d1) Glucose (mg/dl) 364 431 534 473 525 507 11.3 10.7 14.2 12.1 12.4 10.7 0.5 0.6 . 0.5 0.5 0.5 0.5 137 130 143 131 137 121 472 65.2 6 11.9 1.33 6 0.5 0.04 6 133 7.6 6 Total chol. (mg/dl) 48 74 54 53 69 52 58 10.5 6 Triglyceride (mg/dl) 22 29 22 20 21 32 24 4.9 6 005440 68 I Appendix 6 - F - 2 Clinical chemistry - Individual values Sex l Female Dose level '. Sample D-l 0 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C Animal Number 0201 0202 0203 0204 0205 0206 Mean S.D. N Total protein (g/dl) 6.52 6.87 6.63 6.38 6.76 6.62 6.63 0.173 6 Albumin (g/dl) 4.23 4.24 4.20 4.08 4.15 4.20 4.18 0.060 6 A/G ratio Calcium (mg/dl) 1.85 1.61 1.73 1.77 1.59 1.74 9.1 9.5 9.4 9.5 9.4 9.5 1.72 0.099 6 9.4 0.15 6 1norganic phos. (mg/dl) Na (mEq/1) 7.4 141 7.0 143 8.0 141 9.4 141 9.2 141 9.5 141 8.4 1.09 6 141 0.8 6 K (mEq/l) 4.1 3.8 3.7 .4.1 4.3 4.4 4.1 0.27 6 Cl (mEq/1) 104 104 104 104 103 103 104 0.5 .6 005441 69 005536 TABLE 4 EYE IRRITATION TEST - ALBINO RABBITS with T-3494 Examination Tissue Period Cornea(D-A) 1 Hour Iris Conjunctiva (RSD) Total 3B2037 0 ____________ RESULTS________________ ANIMAL NUMBERS 3B2036 3B2035 3B2040 000 00 0 0 4(2-0-0) 4(2-0-0) 4(2-0-0) 2(1-0-0) 44 4 2 Cornea(D-A) 1 Day Iris Conjunctiva (RSD) Total 0 0 0 0 0 0 2(1-0-0) 2 0 0 2(1-0-0) 2 0 0 0 0 Cornea(D-A) 2 Days 0 0 0 0 Iris 00 0 0 Conjunctiva 00 0 0 (RSD) Total 0 0 0 0 Cornea(D-A) 3 Days 0 0 0 0 Iris 00 0 0 Conjunctiva 00 0 0 (RSD) Total 0 0 0 0 Cornea(D-A) 7 Days 0 0 0 0 Iris 00 0 0 Conjunctiva 00 0 0 (RSD) Total 0 0 0 0 i____________ B6r ?nm m 3B2039 0 0 4(2-0-0) 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3B2038 0 0 2(1-0-0) 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Means 0.0 0.0 3.3 3.3 1 0.0 0.0 0.7 0.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -- ~ " 1. '= 5536 Appendix' 6 - F - 3 Clinical chemistry - Individual values Sex Female Dose level : Sample D-l 0.1 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C Animal Number 1201 1202 1203 1204 1205 1206 Mean S.D. N COT (IU/1) 74 64 64 76 71 68 70 5.0 6 GPT (IU/1) 32 23 25 29 19 22 25 4.8 6 r -GTP (IU/1) 0 0 0 0 0 0 0 0.0 6 ALP (IU/1) 409 504 362 540 366 331 419 84.6 6 Urea nitrogen (mg/dl) Great!nin (mg/dl) Glucose (mg/dl) .17.0 0.7 126 10.6 0.5 140 16.7 0.5 136 14.9 0.5 182 9.9 0.5 120 9.9 0.6 134 13.2 3.41 6 0.6 0.08 6 140 22.0 6 Total chol. (mg/dl) Triglyceride ' (mg/dl) 55 24 56 24 58 36 59 43 67 17 48 26 57 28 6.2 9.4 66 005442 70 Appendix 6 - F - 4 Clinical chemistry - individual values Sex : Female Dose level I Sample D-l 0.1 mg/kg Animals killed on schedule (4 weeks) Study No. BNR143C Animal Number Total protein . (g/d 1) Albumin ( g /d 1) 1201 1202 1203 1204 1205 1206 6.85 6.08 6.61 6.46 6.63 7.00 4.39 3.94 4.19 4.16 4.14 4.30 Mean S.D. N 6.61 0.320 6 4.19 0.154 6 A/G ratio 1.78 1.84 1.73 1.81 1.66 1.59 1.74 0.095 6 Calcium (mg/dl) 9.9 9.1 10.1 10.8 9.6 9.5 9.8 0.59 8 1norganic phos. ( mg / d 1) Na (mEq/l) 9.9 8.9 9.9 11.4 9.5 8.5 141 142 140 142 140 141 9.7 1.01 6 141 0.9 6 K (mEq/l) 3.9 4.3 4.4 5.5 4.7 4.0 4.5 0.58 6 Cl (mEq/l) 102 105 102 102 101 102 102 1.4 6 005443 Appendix 6 - F - 5 Clinical chemistry - Individual values Sex Female Dose level : Sample D-l 1 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C Animal Number 2201 2202 2203 2204 2205 2206 Mean S.D. N GOT (IU/1) 62 66 65 67 51 51 60 7.4 6 GPT CIU/I) 20 16 20 22 23 16 20 2.9 6 r -GTP (IU/1) 0 1 0 0 0 0 0 0.4 6 ALP (IU/1) 491 504 534 377 342 372 437 82.1 6 Urea nitrogen (mg/dl) Creatini n (mg/dl) Glucose (mg/dl) 17.7 14;1 13.0 13.6 10.6 9.5 0.5 0.5 0.4 0.6 0.5 0.5 . 156 148 133 136 142 142 13.1 2.89 6 0.5 0.06 6 143 8.3 6 Total chol. (mg/dl) 69 57 59 54 58 58 59 5.1 6 Triglyceride (rag/d1) 32 32 32 35 33 18 30 6.2 6 00S444 72 i 'l Appendix 6 - F - 6 Clinical chemistry - Individual values Sex : Female Dose level Sample 0-1 1 mg/kg Animals killed on schedule (4 weeks) Study No. BMR143C \nimal lumber 2201 2202 2203 2204 2205 ' 2206 Mean S.D. N Total prote in (g/dl) 6.48 6.08 6.02 6.86 6.68 6.58 6.45 0.335 6 Albumin (g/di) 4.17 4.11 4.01 4.38 4.11 4.11 4.15 0.125 6 A/G ratio 1.81 2.09 2.00 1.77 1.60 1.66 1.82 0.191 6 Calcium (mg/dl) 9.6 9.9 9.5 9.8 9.5 9.5 9.6 0.18 6 1norganic phos. (mg/dl) Na (mEq/l) 8.5 140 8:8 143 9.3 141 8.7 140 8.4 142 8.7 142 8.7 0.31 6 141 1.2 6 K (mEq/l) 4.4 5.2 4.4 4.0 3.8 4.4 4.4 0.48 6 Cl (mEq/l) 102 106 104 103 103 107 104 1.9 6 005445 73 005446 t Animal Number 3201 3202 3203 3204 3205 3206 Mean S.D. N GOT (IU/1) 65 52 66 79 50 46 60 12.5 6 Appendix 6 - F - 7 Clinicalchemistry - Individual values Sex *. Female Dose level : Sample D-l 10 mg/kg Animals killedon schedule (4 weeks) Study No. BMR143C GPT (IU/1) r -GTP (IU/1) 24 21 , 27 28 24 20 0 0 0 0 0 0 24 0 3.2 0.0 66 ALP (IU/1) 567 361 531 429 382 436 451 81.8 6 Urea nitrogen (mg/dl) Creatinin (mg/dl) Glucose (mg/dl) 17.4 0.6 122 11.1 0.5 149 13.7 0.5 148 14.0 0.5 136 14.7 0.5 126 10.2 0.5 127 13.5 2.59 6 0.5 0.04 6 135 11.7 6 Total chol. (mg/dl) 36 58 46 44 48 56 48 8.1 6 Triglyceride (mg/dl) 21 19 25 17 23 23 21 2.9 6 Animal Number 3201 3202 3203 3204 3205 3206 Mean S.D. N Appendix 6 - F - 8 Clinicalchemistry- Individual values Sex : Female Dose level : Sample D-l 10 mg/kg Animals killed onschedule (4 weeks) Study No. BMR143C Total protei n (g/dl) 6.68 6.84 7.14 6.58 7.21 7.03 6.910.255 6 Albumin (g/dl) 4.35 4.34 4.52 4.24 4.64 4.40 4.42 0.143 6 A/G ratio 1.87 1.74 1.73 1.81 1.81 1.67 1.77 0.072 6 Calcium (mg/dl) 9.6 9.2 10.2 9.5 9.9 9.5 9.7 0.35 6 1norganic phos. (mg/dl) Na (mEq/l) 7.0 141 7.6 140 7.9 143 8.0 141 9.2 144 7.6 142 7.9 0.73 6 142 . 1.5 6 K (mEq/l) 3.7 3.9 4.8 4.5 3.7 4.2 4.1 0.45 6 Cl (mEq/l) 105 106 107 105 104 107 106 1.2 6 005447 75 Appendix 6 - F - 9 Clinicalchemistry - Individual values Sex : Female Dose level : Sample D-l 30 rag/kg Animals killedon schedule (4 weeks) Study No. BMR143C Animal Number 4201 4202 4203 4204 4205 4206 Mean S.D. N COT (IU/1) 62 55 57 55 50 59 56 4.1 6 GPT (IU/1) 40 31 31 36 29 48 36 7.2 6 r -g t p (IU/1) 0 0 0 0 0 0 0 0.0 6 ALP (IU/1) 826 609 593 717 404 392 590 170.9 6 Urea ni trogen (mg/dl) Creati ni n (mg/dl) Glucose (mg/dl) 14.3 20.9 19.8 13.7 21.8 17.3 0.6 0.6 0.5 0.5 0.5 . 0.5 152 125 111 119 116 135 18.0 3.43 6 0.5 0.05 6 126 15.0 6 Total chol. (mg/dl) 24 23 34 21 20 27 25 5.1 .6 Triglyceride (mg/dl) 23 15 19 15 27 20 20 4.7 6 005448 76 f y Append ix 6 - F - 10 Clinicalchemistry- Individual values Sex : Female Dose level 1 Sample D-l 30 mg/kg Animals killed onschedule (4 weeks) Study No. BNR143C Animal "umber 4201 4202 4203 4204 4205 4206 Mean S.D. N Total protein (g/dl) 7.17 7.32 6.88 6.64 6.67 7.39 7.01 0.327 6 Albumin (g/dl) 4.61 4.68 4.53 4.36 4.56 4.77 4.59 0.140 6 A/G ratio 1.80 1.77 1.93 1.91 2.16 1.82 1.90 0.143 6 Calcium (mg/dl) Inorganic phos. (mg/dl) Na (mEq/l) 9.5 10.0 9.9 9.7 9.5 10.8 7.0 8.9 9.1 . 9.3 7.9 9.3 143 142 142 140 143 142 9.9 0.49 6 8.6 0.93 6 142 1.1 6 K (mEq/l) 4.4 4.7 4.2 5.5 4.4 6.0 4.9 0.72 6 Cl (mEq/l) 108 107 105 107 107 104 106 1.5 6 00544S 77 Appendix 6 - F - 11 Clinical chemistry - Individual values Sex : Female Dose level 1 Sample D-l 0 mg/kg Animals killed on schedule (Recovery) Study No. BMR143C Animal Number 0207 0208 0209 0210 0211 0212 Mean S.O. N COT (1U / 1) 57 75 71 66 78 81 71 8.8 6 CRT oo/i) 24 30 22 28 29 44 30 7.7 6 r -GTP (IU/1) 0 0 0 0 0 0 0 0.0 6 ALP (IU/1) 266 273 411 283 393 313 323 63.4 6 Urea nitrogen (mg/di) Great- ini n (mg/dl) Glucose ( m g/ d 1) 18.0 0.6 152 19.9 0.6 154 15.0 0.6 149 20.6 0.6 141 14.9 0.5 144 15.5 0.5 160 17.3 2.55 6 0.6 0.05 6 150 6.9 6 Total chol. (mg/dl) 76 56 65 66 54 48 61 10.1 6 Triglyceride ( m g / d 1) 104 65 29 35 26 28 48 31.1 6 005450 78 Appendix 6 - F - 12 Clinical chemistry - Individual values Sex : Female Dose level : Sample U-l 0 mg/kg Animals killed on schedule (Recovery) Study No. BMR143C Animal Number 0207 0208 0209 0210 0211 0212 Mean S.D. N Total protein (g/dl) 7.00 7.26 7.01 7.18 6.47 7.17 7.02 0.286 6 Albumin (g/dl) 4.35 4.41 4.42 4.38 4.05 4.40 4.34 0.142 6 A/G ratio 1.64 1.55 1.71 1.56 1.67 1.59 1.62 0.064 6 Calcium (mg/dl) 9.8 9.7 9.5 9.6 9.4 9.8 9.6 0.16 6 1norganic phos. (mg/dl) Na (fflEq/l) 7.1 140 6; 7 140 7.9 141 6.8 140 7.9 140 7.6 139 7.3 0.54 6 ' 140 0.6 6 k (mEq/l) 4.1 4.0 4.2 4.2 4.0 3.9 4.1 0.12 6 Cl (mEq/l) 104 107 106 105 106 104 105 1.2 6 005451 79 Animal Number 4207 4208 4209 4210 4211 4212 Mean S.D. N GOT (IU/1) 62 53 47 78 64 62 61 10.6 6 GPT (IU/1) 41 29 25 25 28 31 30 5.9 6 Appendiv 6 - F - 13 Clinical chemistry - Individual values Sex 1 Female Dose level : Sample D-l 30 mg/kg Animals killed on schedule (Recovery) Study No. BMR143C r -g t p (IU/1) 0 0 0 0 0 0 0 0.0 6 ALP (IU/1) 404 347 363 486 353 369 387 52.4 6 Urea ni trogen (mg/dl) Creatinin (mg/dl) Glucose (mg/dl) 29.2 0.6 132 22.5 0.6 141 22.6 0.5 123 26.2 0.6 117 22.2 0.6 116 21.7 0.6 129 24.1 2.99 6 0.6 0.04 6 126 9.6 6 Total chol. (mg/dl) 47 46 53 62 42 55 51 7.3 6 Triglyceride (mg/dl) 15 22 18 ' 17 17 16 18 2.4 6 00S452 80 Append ix 6 - F - 14 Clinical chemistry - Individual values Sex Female Dose level Sample D-l 30 mg/kg Animals killed on schedule (Recovery) Study No. BMR143C Animal Number 4207 4208 4209 4210 4211 4212 Mean S.D. N Total protein (g/dl) 7.63 7.51 7.24 8.18 7.12 7.34 7.50 0.379 6 Albumin (g/dl) 4.72 4.85 4.55 4.99 4.43 4.79 4.72 0.204 6 A/G ratio 1.62 1.82 1.69 1.56 1.65 1.88 1.70 0.123 6 Calcium (m g/d1) 1norganic phos. (mg/dl) Na (mEq/l) 10.2 8.2 141 10.4 7.9 141 10.4 7.7 141 10.3 8.1 141 9.9 8.6 141 10.1 8.2 142 10.2 0.19 6 ' 8.1 0.31 6 141 0.4 6 K (mEq/l) 4.7 3.9 4.1 3.9 4.2 4.8 4.3 0.39 6 Cl (mEq/l) 105 107 105 104 106 105 105 1.0 6 i 005453 81 I t f \ Ani ma l Number 0101 0102 0103 0104 0105 0106 0107 0108 0109 0110 0111 0112 Appendix 7 - M - 1 Urinalysis - Individual values Sex : Male Dose l e v e l : Sample D-l 0 mg/kg 3 weeks a f t e r commencement of t r e a t me nt Study No. BMR143C Urobi1i nogen (EU/dl ) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Occult Blood _ - +++ Trace Trace - Bi 1 i r ub in Ketone bodies ( mg/d1 ) 5 -5 - 15 -5 -5 -5 -5 -5 -- -5 -5 5 Glucose Cg/dl) _ - - - - - - - -- N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein Cmg/dl) 30 30 30 30 30 Trace 30 30 30 30 Trace 30 pH 7.0 8.0 7.5 8.0 7.0 8.0 8.0 7.0 8.0 6.0 7.0 8.0 454 82 Ani ma l Number 1101 1102 1103 1104 1105 1106 ^ Appendix 7 - M - 2 Urinalysis - Individual values Sex : Male Dose l e v e l : Sample D-l 0 . 1 mg/kg 3 weeks a f t e r commencement o f t r e a t me n t Study No. BMR143C Urobi1i nogen (EU/dl> 0.1 0.1 0.1 0.1 0.1 0.1 Occult Blood _ - Tr a c e - B i l i rub i n Ketone bodies (mg/dl) 5 -5 - 15 -5 - 40 5 Glucose (g/dl) - -- -- `. N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) 30 30 30 30 30 100 pH 7.5 8.0 8.0 7.5 8.0 8.0 in 83 Ani ma l Number 2101 2102 2103 2104 2105 2106 Appendix 7 - M - 3 Urinalysis - Individual values Sex : Male Dose l e v e l : Sample D-l 1 mg/kg 3 weeks a f t e r commencement o f t r e a t me nt Study No. BMR143C Urobi1inogen (EU/dl> Occult Blood 0.1 0.1 - 0.1 - 0.1 - 0.1 Trac e 0.1 "" B ili rubi n Ketone bod i es (mg/dl) a 15 -5 - 5 -5 -5 _5 Glucose ( g / d 1> - - - -- : N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) 30 30 30 100 100 30 PH 8.0 8.5 8.0 8.5 8.0 8.0 Ss&SQQ 84 I i f Ani ma l Number 3101 3102 3103 3104 3105 3106 Appendix 7 - M - 4 Urinalysis - Individual values Sex : Male Dose l e v e l : Sample D-l 10 mg/kg 3 weeks a f t e r commencement o f t r e a t me n t Study. No. BMR143C Urobi1 inogen CEU/dl) 0000 .... 1111 00.. 11 Occult B ood _ -, - B i1irub in Ketone bod i es (mg/dl) 5 -5 - 5 -5 -5 5 Glucose (g/dl ) _ - -- -- 1 N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) 30 30 100 30 100 30 PH 8.0 7.5 8.0 8.0 8.0 8.0 05457 85 Ani ma l Number 4101 4102 4103 4104 4105 4106 4107 4108 4109 4110 4111 4112 Appendix 7 - M - 5 Urinalysis - Individual values Sex : Male Dose l e v e l : Sample D-l 30 mg/kg 3 weeks a f t e r commencement o f t r e a t me nt Study No. BMR143C Urobi1inogen (EU/dl) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Occult Blood - - - - - B i 1i rubi n Ketone bod i es (mg/dl) _ 15 -5 - 40 -5 -5 -5 -5 -5 - 15 -5 T 40 5 Glucose ( g / d 1) - - -. - - - - Protein (mg/dl> pH 30 100 30 30 30 Trace 30 30 30 30 100 30 7.5 8.0 7.5 7.0 7.0 6.0 7.5 7.5 6.5 7.0 7.0 6.0 I N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Ss& f Q Q 86 Ani ma l Number 0107 0108 0109 0110 0111 0112 Appendix 7 M - 6 Study No Urinalys is - Individual va ues Sex : Male Dose l e v e l : Sample D-l 0 mg/kg 5 weeks a f t e r commencement o f t r e a t m e n t ( R e c o v e r y ) BMR143C lirobi 1 inogen (EU/dl) Occult Blood Bi 1 i r ub in Ketone bodies (mg/dl) Glucose (g/dl) 0.1 0.1 Trace - 0.1 Trace - 0.1 - - 0.1 Trace - 0.1 Trace 5 5-- 55 -' 5 -- : N e g a t i v e , + S l i g h t , ++ : Moderat e, + + + S e v e r e Pro t e i n (mg/dl) Trace 30 30 Trace 30 30 pH 8.0 7.5 8.0 7.0 7.5 8.0 Ani ma l Number 4107 4108 4109 4110 4111 4112 Appendix 7 - M - 7 Study No. Urinalysis - Individual values Sex : Male Dose l e v e l : Sample D-l 30 mg/kg 5 weeks a f t e r commencement o f t r e a t me nt ( Re c o v e r y ) BMH143C Urobi 1 i - nogen (EU/dl) Occult Bl ood B i l i rub in Ketone bod i es (mg/dl) Glucose (g/dl ) 0.1 0.1 D 0.1 0.1 0.1 f+ - - * 5 5- 5 5 -. 5 -- *. N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e D : Dead. Protein (mg/dl) 30 30 30 30 30 pH 7.0 7.0 6.5 6.5 7.0 Ani ma l Number 0201 0202 0203 0204 0205 0206 0207 0208 0209 0210 0211 0212 Appendix ,7 - F - 1 Urinalysis - Individual values Sex : Female Dose l e v e l : Sample D-l 0 mg/kg 3 weeks a f t e r commencement o f t r e a t me n t Study No. BMR143C Urobi1i nogen (EU/dl) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Occult Blood _ - - - - Trace - Trace B i1i rubi n Ketone bod i es (mg/dl) 5 -----5 -5 -- -- -- -- * Glucose (g/dl ) - ,-r - - N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) 30 30 30 30 30 30 30 30 Trace 30 30 Trace PH 8.0 6.5 8.5 8.0 8.0 8.0 7.0 7.5 7.5 7.0 7.5 7.0 Ani ma l Number 1201 1202 1203 1204 1205 1206 Appendix 7 - F - 2 Urinalysis - Individual values Sex : Female Dose l e v e l : Sample D-l 0 . 1 mg/kg 3 weeks a f t e r commencement o f t r e a t me n t Study No. BMR143C Urobi1i nogen CEU/dl) Occult Blood Bilirubin Ketone bod i es (mg/dl) Glucose (g/dl) 0.1 Trace 0.1 - - 0.1 - - 0.1 Trace - 0.1 - - 0.1 "" '- - 5 - -. -- : N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) 30 Trace 30 . 30 Trace 30 PH 8.5 8.5 7.5 8.0 8.0 8.0 { 005462 90 I ! Ani ma l Number 2201 2202 2203 2204 2205 2206 Appendix 7 - F - 3 Urinalysis - Individual values Sex : Female Dose l e v e l : Sample D-l 1 mg/kg 3 weeks a f t e r commencement o f t r e a t me n t Study No. BMR143C Urobili nogen (EU/dl) 0.1 0.1 0.1 0.1 0.1 0.1 Occult B1 ood Trace Trace - + + B i 1i rubi n Ketone bod i es (mg/dl ) _ -5 - - -0e* -5 5 Glucose (g/dl ) - - - "" : N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) 30 30 Trace 30 30 30 pH 8.0 8.0 7.5 7.5 7.5 7.0 Ani ma l Number 3201 3202 . 3203 3204 3205 3206 Cl cn Appendix 7 - F - 4 Urinalysis - Individual values Sex : Female Dose l e v e l : Sample D-l 10 mg/kg 3 weeks a f t e r commencement o f t r e a t me n t Study No. BMR143C Urobi1inogen (EU/dl) 0.1 0.1 0.1 0.1 0.1 0.1 Occult Blood Trace - B i 1i rubi n Ketone bodies (mg/dl> _ - 5' -5 -** 5 Glucose Cg/dl ) - - -- : N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) 30 Trace Trace 30 30 30 pH 8.5 8.0 6.5 8.0 7.0 7.5 92 Ani ma l Number 4201 4202 4203 4204 4205 4206 r> 4 2 0 7 o 4208 C/7 4 2 0 9 4210 4211 1 4212 Appendix 7 - F - 5 Urinalysis - Individual values Sex : Female Dose l e v e l : Sample D-l 30 mg/kg 3 weeks a f t e r commencement of t r e a t me n t Study No. BMR143C Urobi1 i - nogen (EU/dl) Occult Blood B i 1 i rubi n Ketone bod i es Cmg/dl) Glucose (g/d1) 0.1 + - -- 0.1 - - -- 0.1 - - 5 - 0. 1 - - -- 0.1 - - -- 0.1 Trace - -- 0.1 Trace - -- 0.1 + - - 0.1 - - 5- 0.1 - - -- 0.1 - - - 0.1 Trace - -- - I N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) Trace Trace 30 - 30 30 Trace Trace 30 - Trace pH 7.0 7.0 6.5 7.0 7.5 6.0 6.0 6.0 7.0 7.0 7.5 7.0 93 Ani ma l Number 0207 0208 0209 0210 O 0211 o 0212 in <&75 <75 Appendix i F-6 Study No Urinalysis - Individual values Sex : Female Dose l e v e l : Sample D-l 0 mg/kg 5 weeks a f t e r commencement o f t r e a t me n t ( R e c o v e r y ) BMR143C Urob i l i - nogen (EU/dl) Occult Blood B i1 irub in Ketone bod i es (mg/dl) Glucose (g/d1) 0.1 Trace - 0.1 - - 0 . 1 ++ - 0.1 - - 0.1 - 0.1 Trace -- --- - --** .` N e g a t i v e , + S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) Trace 30 - Trace Trace 30 PH 8.0 8.0 7.5 7.5 8.0 7.0 , 1 4 94 Ani ma l Number 4207 4208 4209 4210 4211 4212 Appendix 7 - F - 7 Study No. Urinalysis - Individual values Sex : Female Dose l e v e l : Sample D-l 30 mg/kg 5 weeks a f t e r commencement o f t r e a t m e n t ( R e c o v e r y ) BMR143C Urobi1i nogen (EU/dl) 0.1 0.1 0.1 0.1 0.1 0.1 Occult Blood Trace Trace Trace - Trace "" Bi 1 i r u b i n Ketone bod i es (mg/dl) -- -- - -- "" Glucose (g/dI ) --, - - - - N e g a t i v e , + : S l i g h t , ++ : Moderat e, +++ : S e v e r e Protein (mg/dl) PH 30 Trace Trace 30 Trace Trace .6.5 7.0 7.0 7.0 8.0 7.5 487 95 Appendix 8 - M - 1 Organ we i g ht ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Male Dose le v e l : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) Study No. BMR143C Ani ma l Number F.B.W (g> Brain <g) 0101 0102 0103 0104 O 0105 o'1 0 1 0 6 h-* CO 00 Mean S.D. N 354 318 334 , 352 377 370 351 22.0 6 1.90 2.00 1.77 1.95 2.03 2.11 1.96 0.117 6 F.B.W : F i na l body wei ght Liver (g) 13.07 12.17 13.50 12.92 14.52 15.42 13.60 1.180 6 Kidneys (g) 2.38 2.16 2.45 2.45 2.50 2.63 2.43 0.156 6 Adrenals (mg) 51.2 53.1 47.5 54.4 46.1 50.4 50.5 3.19 6 Tes tes (g) 3.01 3.23 2.54 3.07 3.24 2.84 2.99 0.265 6 96. Appendix 8 - M - 2 Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Male Dose l e v e l : Sample D-l 0 , 1 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) Study No. BMR143C Ani ma l Number F.B.W (g> Brain (g> 1101 1102 1103 1104 1105 1106 375 2.06 321 2.13 362 1.90 321 1.94 376 1.92 399 1.92 Mean S.D. N 359 31.8 6 1.98 0.094 . 6 F.B.W : Final body weight Li ve r (g) 16.05 13.25 13.55 13.52 15.24 15.37 14.50 1. 194 6 Kidneys (g) 2.75 2.19 2.60 2.27 2.71 2.78 2.55 0.257 6 Adrenals (mg) 52.2 55.6 50.4 63.4 53.9 50.3 54.3 4.90 6 Testes (g) 2.92 2.92 3.20 3.18 3.17 3.44 3.14 0.196 6 Appendix 8 - M - 3 Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Male Dose l e v e l : Sample D-l 1 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) Study No. BMR143C Ani ma l Number F.B.W (g) Brain <g> 2101 2102 2103 2104 2105 2106 .346 1.99 345 1.89 354 1.95 321 2.0 0 376 1.91 350 1.92 Mean S.D. N 349 17.7 6 1.94 0.045 6 F.B.W : Final body weight Liver (g) 14.63 12.98 14.84 12.15 15.90 12.75 13.88 1.459 6 Kidneys (g) 2.42 2.24 2.46 2.25 2.18 1.99 2.26 0.170 6 Adrenals ( mg ) 50.6 47.1 57.4 52.4 55.3 54.8 52.9 3.71 6 Testes (g) 2.85 3.10 3.04 3.15 3.40 3.30 3.14 0.194 6 Appendix 8 - M - 4 Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Male Dose le v el : Sample D-l 10 mg/kg Animals k i l l e d on sc h ed ul e (4 weeks) Study No. BMR143C Ani ma l Number F.B.W (g) Brain (g> 3101 3102 3103 3104 3105 3106 326 1.83 341 1.92 320 1.96 335 2.07 389 1.95 345 1.92 Mean S.D. N 343 24.5 6 1.94 0.078 6 F.B.W : Final body weight Liver (g) 17.23 18.33 17.38 17.50 15.01 16.10 16.93 1 . 179 6 Kidneys (g> 2.46 2.28 2.35 2.56 2.33 2.37 2.39 0.101 6 Adrenals ( mg ) 46.3 46.6 52.2 47.6 58.8 45.5 49.5 5.14 6 Testes (g) 2.78 2.84 3.23 3.11 3.18 2.91 3.01 0.189 6 Appendix 8 - M - 5. Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Male Dose le v e l : Sample D-l 30 mg/kg Animals k i l l e d ons c h e d u l e ( 4 weeks) Study No. BMR143C Ani ma l Number F.B.W <g> Brain <g> 4101 4102 4103 4104 4105 4106 300 1.92 286 2.11 321 1.97 283 1.97 269 1.92 293 1.93 Mean S.D. N 292 17.6 6 1.97 0.072 6 F.B.W : Final body weight Liver (g) 19.22 20.73 24.20 18.08 18.72 21.22 20.36 2.228 6 Kidneys (g) 2.02 2.16 2.'21 2.04 2.03 2.17 2.11 0.084 6 Adrenals (mg) 44.3 48,5 54.0 49.4 50.3 56.0 50.4 4.15 6 Testes (g> 2.62 3.30 3.26 3.03 3.21 3.06 3.08 0.250 6 Appendix 8 - M - 6 Organ we i g ht ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Mal e Dose l e v e l : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e ( Recovery) Study No * BMR143C An i mal Number F.B.W (g) Brain (g) 0107 0108 . 0109 0110 0111 0112 365 405 438 374 344 410 2.07 1.98 2.10 2.01 2.04 2.11 Mean S.D. N 389 34.4 6 2.05 0.051 6 F.B.W : Final body weight Liver (g) 12.43 13.98 15.91 12.82 11.18 15.12 13.57 1.768 6 Kidneys <g> 2.29 2.35 2.50 2.62 2.41 2.67 2.47 0.151 6 Adrenals (mg) 48.5 54.0 46.9 59.0 46.8 63.1 53.1 6.85 6 Testes (g) 3.00 3.36 2.89 3.24 0.85 3.12 2.74 0.942 6 Appendix 8-M i Study No BMR143C Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s ^ , Sex : Male Dose l e v e l : Sample D-l 30 mg/kg Animals k i l l e d on s c h e d u l e ( Recovery) Ani ma l Number F.B.W (g) Brain (g) Liver (g) 4107 4108 4109 4110 4111 4112 326 336 D 331 340 373 1.96 2.09 2.05 1.96 2.04 17.69 21.36 21.91 20.99 21.35 0 Mean S.D. N 341 18.5 5 2.02 0.058 5 F.B.W : Fi na l body we i ght D. : Dead. 20.66 1.693 5 Kidneys (g) 2.23 2.30 2.33 2.56 2.57 2.40 0.157 5 Adrenals (mg) Testes <g) 53.4 61.5 53.9 45.0 43.6 3.26 3.40 3.54 3.43 3.27 51.5 7.31 5 3.38 0.117 5 i i 4 102 I t4i Append ix 8 - F - 1 Study No BMR143C Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Female Dose 1e vel : Sample D-l 0 mg/kg * Animals k i l l e d on s c h e d u l e ( 4 weeks) Ani ma l Number F.B.W (g) Brain <g> 0201 0202 0203 0204 0205 0206 228 1.87 214 1.78 221 1.86 264 1.96 227 1.84 227 1.78 Mean S.D. N 230 17.4 6 1.85 0.067 6 F.B.W : F i n a l body wei ght Liver (g) 8.53 8.75 8.93 9.60 8.40 8.32 8.76 0.471 6 Kidneys . (g> 1.59 1.36 1.62 1.88 1.72 1.52 1.62 0.177 6 Adrenals (mg) 50.8 58.4 66.6 63.4 59.1 62.5 60.1 5.46 6 Ovaries ( mg ) 95.2 89.2 75.7 93.7 72.7 , 75,6 83.7 10.13 6 i G05475 103 I ( 4 1 Appendix 8 - F - 2 Organ we i g ht ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Female Dose le v el : Sample D-l 0 . 1 rog/kg Animals k i l l e d on s c h e d u l e (4 weeks) Study No. BMR143C Ani ma l Number F.B.W (g> Brain Cg) 1201 1202 1203 1204 1205 1206 224 1.83 212 1.85 235 1.81 242 1.72 227 1.81 222 1.73 Mean S.D. N 227 10.5 6 1.79 0.054 6 F.B.W : Fi na l body w e i g h t Liver (g) 8.57 7.83 9.52 9.41 8.38 8.18 8.65 0.679 6 Kidneys (g> 1.49 1.42 1.63 1.89 1.65 1.60 1.61 0.162 6 Adrenals ( mg ) 60.5 50.3 55.8 60.9 71.3 60.1 59.8 6.93 6 Ovaries ( mg ) 78.0 79.7 93.0 85.5 92.1 73.7 83.7 7.86 6 G05476 104 Appendix 8-F-3 Organ we i g ht ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Female Dose le v e l : Sample D-l 1 mg/kg Animals k i l l e d ons c h e d u l e ( 4 weeks). Study No. BMR143.C Ani ma l Number F.B.W (g) Brain <g> 2201 2202 2203 2204 2205 2206 07 Mean S.D. a- N 225 226 216 240 259 246 235 15.9 6 1.87 1.92 1.81 2.02 1.90 1.91 1.91 0.069 6 F.B.W : Fi nal body wei ght Liver (g) 9.55 8.39 7.95 9.33 10.32 8.85 9.07 0.852 6 Kidneys (g) 1.72 1.71 1.57 1.62 1.79 1.63 1.67 0.081 6 Adrenals (mg) 48.1 66.5 59.1 66.8 68.3 66.5 62.6 7.79 6 Ovaries (mg) 75.9 93.7 93.8 116.1 75.5 96.8 92.0 15.11 6 105 'i t4i 005478 Appendix 8 - F - 4 Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Female Dose le v el : Sample D-l 10 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) Study No BMR143C Ani ma l Number F.B.W (g> Brain (g) 3201 3202 3203 3204 3205 3206 . 216 225 186 221 212 223 1.96 1.83 1.77 1.86 1.84 1.82 Mean S.D. N 214 14.4 6 1.85 0.063 6 F.B.W : F i n a l body we i ght Liver (g> 10.04 11.96 9.06 10.75 11.01 10.68 10.58 0.973 6 Kidneys (g) 1.69 1.81 1.51 1.76 1.64 1.76 1.70 0.109 6 Adrenals (mg) 62.6 71.4 48.4 55.0 63.9 63.7 60.8 8.01 6 Ovaries (mg) 90.1 72.6 63.7 76.8 74.7 76.7 75.8 8.53 6 106 i 4 Appendix 8F 5 Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Female Dose le v e l : Sample D-l 30 m g / k g Animals K i l l e d ons c h e d u l e ( 4 weeks) Study No. BMR143C Ani ma l Number F.B.W (g) Brain (g) 4201 4202. 4203 4204 4205 4206 178 1.79 194 1.80 194 1.80 204 1.96 181 1.81 191 1.82 Mean S.D. N 190 1.83 9.5 0.064 66 F.B.W : F i n a l body we i g ht Liver (g> 12.25 14.65 14.18 14.04 13.81 13.73 13.78 0.816 6 Kidneys (g) 1.28 1.46 1.51 1.62 1.53 1.62 1.50 0.126 6 Adrenals (mg) 55.9 60.0 55.5 64.6 47.0 50.8 55.6 6.28 6 Ovaries (mg) 66.0 61.6 76.2 56.4 56.7 58.6 62.6 7.57 6 I 4 005479 107 i t4 Appendix 8 - F - 6 Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Female Dose le v e l : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e ( Rec o v e ry ) Study No. BMR143C Ani ma l Number F.B.W (g) Brain (g) 0207 0208 0209 0210 0211 0212 325 1.91 265 1.85 264 1.93 270 2.04 278 1.99 257 1.86 Mean S.D. N 277 24.8 6 i .93 0.074 6 F.B.W : Fi na l body we i ght Liver (g) 11.30 8.12 8.55 8.97 8.81 8.80 9.09 1.122 6 Kidneys (g) 1.92 1.63 1.72 1.84 1.78 1.76 1.78 0.100 6 Adrenals (mg) Ovaries (mg) 80.7 51.1 60.3 82.7 77.7 72.0 106.4 86.3 78.3 95.7 83.6 . 88.1 70.8 12.55 6 89.7 9.96 6 00S480 108 Appendix 8 - F - 7 Organ w e i g h t ( A b s o l u t e ) - I n d i v i d u a l v a l u e s Sex : Female Dose l e v e l : Sample D-l 3 0 mg/kg Animals k i l l e d on s c h e d u l e ( Recovery) Study No BMR143C Ani ma l Number F.B.W <g> Brain (g) 4207 4208 4209 4210 4211 4212 201 1.71 199 1.72 208 1.90 193 1.90 213 1.89 234 2.06 Mean S.D. N 208 14.5 6 1.86 0.131 6 F.B.W : F i n a l body we i g ht Liver (g) 11.92 13.04 12.90 11.64 12.40 12.85 12.46 0.574 6 Kidneys (g) 1.44 1.62 1.57 1.47 1.57 1.85 . 1.59 0.146 6 Adrenals (mg) Ovaries ( mg ) 50.1 53.7 45.7 53.0 53.6 67.7 61.8 59.3 72.7 73.6 71.2 72.1 54.0 7.39 6 68.5 , 6.22 6 i 005481 109 i t4 005482 Appendix 9 - M - 1 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e o f body w e i g h t ) - Individual values Sex : Male Dose le v e l : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) BMR143C Ani ma l Number F.B.W (g) Brain Liver Kidneys Adrenals Testes (xlO- 3 ) 0101 0102 0103 0104 0105 0106 354 318 334 352 377 370 . 0.54 0.63 0.53 0.55 0.54 0.57 3.69 3.83 4.04 3.67 3.85 4.17 0.67 0.68 0.73 0.70 0.66 0.71 14.5 16.7 14.2 15.5 12.2 13.6 0.85 1.02 0.76 0.87 0.86 0.77 Mean S.D. N 351 22.0 .6 0.56 0.037 6 F.B.W : F i na l body wei ght 3.88 0.197 6 0.69 0.026 6 14.5 1.55 6 0.86 0.094 6 no i 4 Appendix 9 - M - 2 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e o f body w e i g h t ) - Individual values Sex : Male Dose l e v e l : Sample P-1 0 . 1 mg/kg Animals k i l l e d on s c h e d u l e (4 weeks) BMR143C Ani ma l Number 1101 1102 1103 1104 1105 1106 F.B.W Cg) 375 321 362 321 376 399 Brain 0.55 0.66 0.52 0.60 0.51 0.48 Liver 4.28 4.13 3.74 4.21 4.05 3.85 Kidneys 0.73 0.68 0.72 0.71 0.72 0.70 Adrenals (xl0~3 ) 13.9 17.3 13.9 19.8 14.3 12.6 Testes ' 0.78 0.91 0.88 0.99 0.84 0.86 Mean S.D. N 359 31.8 6 0.55 0.066 6 F.B.W : F i n a l body wei ght 4.04 0.210 6 0.71 0.018 6 15.3 2.70 6 0.88 0.071 6 30Q548 111 005484 Appendix 9 - M - 3 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e o f body w e i g h t ) - Individual values Sex : Hale Dose le v e l : Sample D-l 1 mg/kg Animals k i l l e d on s c h e d u l e (4 weeks) BMR143C Ani ma l Number F.B.W <g> Brai n Liver Kidneys Adrenals (xlO~3 ) Testes 2101 2102. 2103 2104 2105 2106 346 345354 321 376 350 0.58 0.55 0.55 0..62 0.51 0.55 4.23 3.76 4.19 3.79 4.23 3.64 0.70 0.65 0.69 0.70 0.58 0.57 14.6 13.7 16.2 16.3 14.7 15.7 0.82 0.90 0.86 0.98 0.90 0.94 Mean S.D. N 349 17.7 6 0.56 0.037 6 F.B.W : Fi nal body wei ght 3.97 0.272 6 0.65 0.060 6 15.2 1.03 6 0.90 0.057 6 112 i Appendix 9 - M - 4 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e o f body w e i g h t ) - Individual values Sex : Male Dose le v e l : Sample D-l 10 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) BMR143C Ani ma l Number F.B.W (g> Brain Liver Kidneys Adrenals (XlO- 3 ) Testes 3101 3102 3103 3104 3105 3106 326 0.56 5.29 0.75 14.2 0.85 341 0.56 5.38 0.67 13.7 0.83 320 0.61 5.43 0.73 16.3 1.01 335 0.62 5.22 0.76 14.2 0.93 389 0.50 3.86 0.60 15.1 0.82 345 0.56 4.67 0.69 13.2 0.84 Mean S.D. N 343 24.5 6 0.57 0.043 6 F.B.W : F i n a l body wei ght 4.98 0.611 6 0.70 0.060 6 14.5 1.10 6 0.88 0.075 6 I 005485 113 I ! Appendix 9 - M - 5 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e of body w e i g h t ) - Individual values Sex : Male Dose l e v e l : Sample D-l 30 mg/kg Animals k i l l e d on s c h e d u l e (4 weeks) BMR143C- Ani ma l Number F.B.W (g) Brain Liver Kidneys Adrenals (XlO-3 ) Testes 4101 4102 4103 4104 4105 4106 300 0.64 6.41 0.67 14.8 0,. 8 7 286 0.74 7.25 0.76 17.0 1.. 15 321 0 . 6 1 7 . 5 4 0 . 6 9 1 6 . 8 1,. 0 2 2 8 3 0 . 7 0 6 . 3 9 0 . 7 2 1 7 . 5 1 ,. 0 7 2 6 9 0 . 7 1 6 . 9 6 0 . 7 5 1 8 . 7 1,. 1 9 2 9 3 0 . 6 6 7 . 2 4 0 . 7 4 1 9 . 1 1,. 0 4 Mean S.D. N 292 17.6 6 0.68 0.048 6 F.B.W : F i n a l body w e i g h t 6.97 0.475 6 0.72 0.035 6 17.3 ' 1.54 6 1.06 0.112 6 005486 114 Ani ma l Number F.B.W (g) Appendix 9 - M - 6 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e o f body w e i g h t ) - Individual values Sex : Male Dose l e v e l : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e ( Re c o v e r y ) BMR143C Brain Liver Kidneys Adrenals ( x l O -3 ) Testes 0107 0108 0109 0110 0111 0112 365 0.57 3.41 0.63 13.3 0.82 405 0.49 3.45 0.58 . 13.3 0.83 438 0.48 3.63 0.57 10.7 0.66 374 0.54 3.43 0.70 15.8 0.87 344 0.59 3.25 0.70 13.6 0.25 410 0.51 3.69 0.65 15.4 0.76 Mean S.D. N 389 34.4 6 0.53 0.044 6 F.B.W : F i n a l body we i g h t 3.48 0.160 6 0.64 0.056 6 13.7 1.82 6 0.70 0.231 6 4 005487 115 I i fi Appendix 9 - M - 7 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e of body w e i g h t ) - Individual values Sex : Male Dose l e v e l : Sample D-l 3 0 mg/kg Animals k i l l e d on s c h e d u l e ( Re c o v e r y ) BMR143C Ani ma l Number F.B.W (g) Brain Liver Kidneys Adrenals (x l0`3 ) Testes 4107 4108 4109 4110 4111 4112 326 336 D 331 340 373 0.60 0.62 0.62 0.58 0.55 5.43 6.36 6.62 6.17 5.72 0.68 0.68 0.70 0.75 0.69 16.4 18.3 16.3 13.2 11.7 1.00 1.01 1.07 1.01 0.88 Mean S.D. N 341 18,5 5 0.59 0.030 5 F.B.W : F i n a l body we i g ht D : Dead. 6.06 0.482 5 0.70 0.029 5 15.2 2.67 5 0.99 0.069 5 005488 116 ( i f 005489 Appendix 9 - F - 1 Study No. Organ we i g ht ( R e l a t i v e : p e r c e n t a g e of body w e i g h t ) - Individual values Sex : Female Dose l e v e l : Sample D-l 0 mg/kg Animal s k i l l e d on s c h e d u l e ( 4 we e ks ) BMR143C Ani ma l Number F.B.W (g> Brain Liver Kidneys Adrenals ( x l O "3 ) Ovaries (XlO'3 ) 0201 0202. 0203 0204 0205 0206 228 0.82 3.74 0.70 22.3 41.8 214 0.83 4.09 0.64 27.3 41.7 221 0.84 4.04 0.73 30.1 34.3 264 0.74 3.64 0.71 24.0 35.5 227 0.81 3.70 0.76 26.0 32.0 227 0.78 3.67 0.67 27.5 33.3 Mean S.D. N 230 17.4 6 0.80 0.037 6 F.B.W : F i na l body wei ght 3.81 0.198 6 0.70 0.043 6 26.2 2.76 6 36.4 4.26 6 117 i 4 Appendix 9 - F - 2 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e of body w e i g h t ) - Individual values Sex : Female Dose l e v e l : Sample D-l 0 . 1 mg/kg . Animals k i l l e d on s c h e d u l e ( 4 weeks) BMR143C An i mal Number F.B.W (g) Brain Liver Kidneys Adrenals <xl0'3 ) Ovaries ( x l O-3 ) 1201 1202 1203 1204 1205 1206 224 0.82 3.83 0.67 27.0 34.8 212 0.87 3.69 0.67 23.7 37.6 235 0.77 4.05 0.69 23.7 39.6 242 0.71 3.89 0.78 25.2 35.3 227 0.80 3.69 0.73 31.4 40.6 222 0.78 3.68 0.72 27.1 33.2 Mean S.D. N 227 10.5 6 0.79 0.053 6 F.B.W : F i n a l body we i ght 3.81 0.148 6 0.71 0.042 6 26.4 2.89 6 36.8 2.88 6 i 005490 118 i i t4 ! Appendix 9 - F - 3 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e of body w e i g h t ) - Individual values Sex : Female Dose l e v e l : Sample D-l 1 mg/kg Animals k i l l e d on s c h e d u l e (4 weeks) BMR143C Ani ma l Number F.B.W (g) Brain Liver Kidneys Adrenals (XlO-3 ) Ovaries (xlO~3 ) 2201 2202 2203 2204 2205 2206 225 0.83 4.24 0.76 21.4 33.7 226 0.85 3.71 0.76 29.4 41.5 216 0.84 3.68 0.73 27.4 43.4 240 0.84 3.89 0.68 27.8 48.4 259 0.73 3.98 0.69 26.4 29.2 246 0.78 3.60 0.66 27.0 39.3 Mean S.D. N 235 15.9 6 0.81 0.047 6 F.B.W : F i n a l body wei ght 3.85 0.237 6 0.71 0.043 6 26.6 2.73 6 39.3 6.90 6 005491 119 I it 005492 Appendix 9 - F - 4 Study No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e of body w e i g h t ) - Individual values Sex : Female Dose le v el : Sample D-l 10 mg/kg Animals k i l l e d on s c h e d u l e ( 4 weeks) BMR143C Ani ma l Number F.B.W Cg> Brain Liver Kidneys Adrenals ( x l O-3 ) Ovaries (xlO-3 ) 3201 3202 3203 3204 3205 3206 216 0.91 4.65 0.78 29.0 41.7 225 0.81 5.32 0.80 31.7 32.3 186 0.95 4.87 0.81 26.0 34.2 221 0.84 4.86 0.8 0 24.9 34 .8 212 0.87 5.19 0.77 30.1 35.2 223 0.82 4.79 0.79 28.6 34.4 Mean S.D. N 214 14.4 6 0.87 0.055 6 F.B.W : Fi na l body we i ght 4.95 0.255 6 0.79 0.015 6 28.4 2.54 6 35.4 3.23 6 120 i t * 6frS 0Q Appendix 9 - F - 5 Study No. Organ we i g ht ( R e l a t i v e : p e r c e n t a g e o f body w e i g h t ) - Individual values Sex : Female Dose le v e l : Sample D-l 3 0 mg/kg Animals k i l l e d on s c h e d u l e (4 weeks) BMR143C Ani ma l Number F.B.W (g> Brain Li v e r Kidneys Adrenals (XlO- 3 ) Ovaries (XlO'3 ) 4201 4202 4203 4204 4205 4206 178 1.01 6.88 0.72 31.4 37.1 194 0.93 7.55 0.75 30.9 31.8 194 0.93 7.31 0.78 28.6 39.3 204 0.96 6.88 0.79 31.7 27.6 181 1 .0 0 7.6 3 0 . 8 5 2 6 . 0 3 1 . 3 191 0 .9 5 7.1 9 0 . 8 5 2 6 .6 3 0 . 7 Mean S.D. N 190 0.96 9.5 0.034 66 F.B.W : Fi na l body wei ght 7.24 0.321 6 0.79 0.053 6 29.2 2.50 6 33.0 4.37 6 121 I 4 Appendix 9 - F - 6 St udy No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e o f body w e i g h t ) - Individual values Sex : Female Dose le vel : Sample D-l 0 mg/kg Animals k i l l e d on s c h e d u l e ( Re c o v e r y ) BMR143C Animal Number F.B.W <g> Brain Li ve r Kidneys Adrenals (xlO- 3 ) Ovar i es (XlO-3 ) 0207 0208 0209 0210 0211 0212 325 0.59 3.48 0.59 24.8 32.7 265 0.70 3.06 0.62 19.3 32.6 264 0.73 3.24 0.65 22.8 29.7 270 0.76 3.32 0.68 30.6 35.4 278 0.72 3.17 0.64 27.9 30.1 257 0.72 3.42 0.68 28.0 34.3 Mean S.D. N 277 24.8 6 0.70 0.059 6 F.B.W : Fi nal body weight 3.28 0.157 6 0.64 0.035 6 25.6 4.10 6 32.5 2.27 6 122 OO5 4 9 4 i 4 00S49S Appendix 9 - F - 7 St udy No. Organ w e i g h t ( R e l a t i v e : p e r c e n t a g e o f body w e i g h t ) - Individual values Sex : Female Rose l e v e l : Sample D-l 3 0 mg/kg Animals k i l l e d on s c h e d u l e ( Re c o v e r y ) BMR143C Ani ma l Number 4207 4208 4209 4210 4211 4212 F.B.W (fi) 201 199 208 193 213 234 Brain 0.85 0.86 0.91 0.98 0.89 0.88 Liver 5.93 6.55 6.20 6.03 5.82 5.49 Kidneys 0.72 0.81 0.75 0.76 0.74 0.79 Adrenals ( x l O-3 ) 24.9 27.0 22.0 27.5 25.2 28.9 Ovaries (xl0~3 ) 30.7 29.8 35.0 38.1 33.4 30.8 Mean S.D. N 208 14.5 6 0.90 0.047 6 F.B.W : F i na l body weight 6.00 0.358 6 0.76 0.033 6 25.9 2.43 6 33.0 3.18 6 4 123 <' ; 005496 Appendix 10-H Individual aaeroscopic findings Sex : Male Test article : Saaple D-l (28days) Study No.BHR143C Dose level : O ag/kg (01-) 0.1 ag/kg (11-) 1 g/kg (2L-) 10 ag/kg (31-) 30 ag/kg (41-) Findings Anlaal nuaber Lungs Dark reddish patch : 01 02 03 04 05 08 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 ----P Liver -Scatterring of greyish dot/patch Hypertrophy Greyish patch Dark reddish change Yellowish change ----------------------- -PPPP-P ----- -------------------PPPPPP ------- -- -- --- ----------P-- --------- -- -- ----- -- --- -------------- ______________________________ kidneys Cyst Pyelectasis Greyish patch Blackish change _p_______ -__-___-P -------------P--- ------- ------ _____________________________p Adrenals Dark reddish change Testes Atrophy - : No lesion.P : Present ------------------ ---- -------P ^ I i f 005497 Dose level Findings Aninai nuaber Lungs Dark reddish patch Liver >Scatterring of greyish dot/patch Hypertrophy Creylsh patch Dark reddish change Yellowish change kidneys Cyst Pyelectasis Greyish patch Blackish change Adrenals Dark reddish change -- : No lesion.P : Present 0 ag/kg Appendix Ifl-F Sex > pgiji 1Individual aacroscoplc findings 0 Test article : Saaple D-l (02-) 0.1 ag/kg (12-) (28days) 1 ag/kg (22-) Study No.BMR143C 10 ag/kg (32-) 30 ag/kg (42-) : 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 - P P P P PP P P- P P P- - P -- -- P- 4 I & 05498 Sex Dose level Findings Anlaal nuaber Lungs Dark reddish patch Liver Scatterring of greyish dol/patch Hypertrophy Greyish patch Dark reddish change Yellowish change kidneys Cyst Pyelectasls Greyish patch Blackish change Adrenals Dark reddish change Testes Atrophy - : No lesion.P : Present Appendix 10-8-1 Individual aacroscopic findings (Recovery) Test article : Saaple D-l Study No.BMRU3C : __________________ Hale_______ ' : 0 ag/kg (01-) 30 ag/kg Ul-) Feaale 0 ag/kg (02-j ; 30 ag/kg (42-) : 07 08 09 10 11 12 07 08 10 11 12 07 08 09 10 11 12 07 08 09 10 11 12 -PP-P--- P P--P- ______ ______ ______ _p____ _____P PPPPP_ ______ _____ -- --P- _____ ______ __ _ _ _ _ 4 I i f 00S499 Dose level (sg/kg) 30 Appendix 10-R-2 Individual Macroscopic findings In died aale rat (32 days) Sex : Male Test article : Saaple D-l Aiilaal nuaber Organ Macroscopic findings 4109 Thyaus Dark reddish patch Atrophy Stoaach Tarry contents lleaorrhage Liver Scatterring of greyish dot/patch Study No.BMRU3C I Appendix ll-M Individual alcroscoplc findings Sex * Mle Test article : Saaple D-l (26days) . . . .... Study No.BMRl43C Dose tevel : 0 Bg/fcg (0L-) 0.1 ag/kg (il-) 1 ag/kg (21-) 10 ag/kg (31") 30 ag/kg (4l-) Findings Anlial nuaber : 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 Liver alcrogranuloaa focal necrosis Tocal fatty change ' peripheral fatty change svelllng of centrilobular hpatocytes eosinophilic change in centrilobular hepatocytes Heart ayocardial degeneration ayocardlal fibrosis Spleen extraaedullary heaatopoiesis Kidneys regenerated tubules dilated tubules infiltration of lyaphocytes dilation of pelvis chronic nephropathy Adrenals abnoraallty Brain abnoraallty Testes atrophy +++ -+ -+ " -- ---++ --+----+ -- +-------- -+-- -- ~-- -- -- -- +1 -H +1 + f- + + + + 4; + + + + + + - ~ -- -- + -- + + + ff *-- ++ "" + + ff -- + + + + + ff ft + ff ff + - ff ff ft + + ft ft If 4f ff ff --+--+-- --- ------ + -- ** + *- - : Negative. : Yery slight.+ : Slight, ff : Moderate. 0S50i Appendix 11-R Individual aicroscoplc flndtngs Sex : Feaale Test article : Saaple 0-i (23days) Study No.BHR143C Findings Dose level Anital nuaber : 0 ag/kg (02-) 0.1 ag/kg 2-) 1 g/kg (22-) 10 ag/kg (32-) 30 ag/kg (42-) : 01 02 03 04 OS Ofi 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 01 02 03 04 05 06 Liver aicrogranuloaa focal necrosis -- + + -- '- +1 41 41 4 44 4 -- 4 4 ------ - focal fatty change peripheral fatty change --+ + 4++--- - 44 4 -- - 4-- 4 swelling of centrilobular hepatocytes + -- 44 44 44 4 44 44 eosinophilic change in centrilobular hepatocytes Heart 44 44 44 44 44 44 ayocardial degeneration ----------- -- ------ -- ayocardial fibrosis ---- "---- Spleen extraaedullary heaatopoiesls -- Kidneys regenerated tubules dilated tubules Infi1tration of lyaphocytes dilation of pelvis chronic nephropathy -- --+- ------ --- ---- +- ------------ -- --- ----------- --"------ ------4-- *** -- -- -- Adrenals abnoraality Brain abnoraal1ty Ovaries abnoraality -------- -- ---- -- - : Negative. : Very slight.+ : Slight, if : Moderate. Sex Dose level Appendix It-R-l individual alcroscoplc findings (Recovery) Test article : Saaple D-l : Male : 0 eg/kg (01-) 30 ag/kg (4L-) 0 ag/kg (02--) Feaale Study No.BMRl43C ............. 30 ag/kg (42-) Findings Aniaal nuaber : OT OS 09 10 11 12 07 OS 10 11 12 07 08 09 10 11 12 07 OS 09 10 11 12 Liver alcrogranuloaa focal necrosis focal fatty change ^peripheral fatty change swelling of centrliobular hepatocytes eosinophilic change In centrliobular hepatocytes Heart ayocardlal degeneration ayocardial fibrosis Spleen extraaedullary heaatopolesls Kidneys regenerated tubules dilated tubules infiltration or lyaphocytes dilation of pelvis chronic nephropathy Adrenals abnoraallty Brain abnoraallty Testes atrophy Ovaries abnormalIty +--+ --- -- - --- -- -- - ----- -- . -- "" -- -- -- -- ---- -- -- --- ----* -- ---- ------ --+---- ---- ----" . + + + 4" ++ - - + --++- 41 If If ff if + + + ft if ---- ---* -- ------- ---- - --+ - ++ --------+-- -- -- ------------ -------- ~ .-- --------+-- ---+----+ ++-- .- + - -- -- + + if + + if ff if ++++++ ----------- ------------------- ----------- -- - - - ft - - - -.- - - : Negative. : Yery slight.+ : Slight, ff : Moderate. i. ! t 005502 0SS03 Appendix ll-R-2 Individual Microscopic findings In died aale rat (32 days) Sex : Male Test article : Saaple D-l Dose level (ag/kg) Anlaal nuaber Organ Microscopic findings 30 4103 Liver Eosinophilic change In centrllobular hepatocytes Swelling of centrllobular hepatocytes Focal necrosis Peripheral fatty change Kidneys Dilated tubules Brain Stoaach lleaorrhaglc foci Ulcer and heaorrhage in glandular stoaach Thyaus Congestion Heaorrhage Heart No abnoraallty Spleen Adrenals Testes No abnoraallty No abnoraallty No abnoraal1ty + Slight, + + : Moderate ++ ++ ++ + + + + + + Study No.BHRU3C i I ,f 005504 Appendix 12-M Microscopic findings of the organs shoved gross lesion (28 days) Sex : Male Test article : Saaple D-l Study No.BMR143C Dose level (ag/kg) Anlsal nuaber Organ Macroscopic findings Microscopic findings 0102 Kidneys Cyst Dilated tubules(+) 0105 Lungs Dark reddish patch lleaorrhage(+) O.l 1103 Kidneys Pyolectasls Dilation of pelvls(+) 1 2102 Kidneys Grayish patch Bocal degeneration and calcification in tubules(+). regenerated tubules (+) and Infiltration of lyaphocytes(+) 30 4101 Liver Scattering of grayish dot Focal necrosis(+) Hypertrophy Swelling of centri lobular hepatocytes(+*) 4102 Liver Scattering of grayish dot/patch No abnoraality except for aicrogranuloaa ( ) . peripheral fatly change (*).eoslnophl1lc change in centri lobular hepatocy tes (+*) Hypertrophy Swelling of centri lobular hepatocyles(++) 4103 Liver Scattering of grayish dot Focal necrosls(+) Hypertrophy Swelling of centri lobular hepatocytes(+) 4104 Liver Scattering of grayish dot/patch Focal necrosls(+) Hypertrophy Swelling of centri lobular hepatocytes(++) 4105 Liver Grayish patch Focal necrosis(+) Hypertrophy Swelling of centri lobular hepatocyles(++) 4100 Liver Scattering of grayish dot Focal necrosis (+) Hypertrophy Swelling of centri lobular hepatocytes(+) Kidneys Dark reddish/Blackish dot No ahnoriali ty Adrenals Dark reddish/Blackish dot No abnoraality : Very slight , + : Slight, ++ : Moderate 1^9 I1 ! SOSSOO Appendix 12-F Microscopic findings of the organs shoved gross lesion (2S days) Sex : l-'eaale Test article : Saaple D-l Study No.BMR143C Dose level (ag/kg) Aniial nuiber Organ Macroscopic findings Microscopic findings 10 3206 Liver Dark reddish change 30 4201 Liver Dark reddish change 4202 4203 Liver Liver Hypertrophy Yellowish change Hypertrophy Dark reddish change 4204 4205 4206 Liver Liver Kidneys Liver Hypertrophy Dark reddish change Hypertrophy Dark reddish change Grayish patch Hypertrophy Pyelectasls Hypertrophy No abnoraality except Tor aicrogranuloaa ( ) . Swelling of centrilobular hepatocytes() and eosl-nophlllc change in centrilobular hepatocytes() No abnoraality except for alcrogranuloaa(++), eosi nophilic change in centrilobular hepatocytes (++) and focal necrosls(+) Swelling of centrllobular hepatocytes(++) Peripheral fatty change ( ) Swelling of centrilobular hepatocytes(++) .No abnoraality except for aicrogranuloaa ( ) eosinophilic change in centrilobular hepatocytes(++) and.peripheral fatty change(+) Swelling of centrilobular hepatocytes(++) No abnoraa! ity except for aicrogranuloaa ( ) and eosinophilic change in centrilobular hepatocytes(++) Swelling of centrllobular hepatocytes(+) No abnoraality except for eosinophilic change In centrilobular hepatocytes(++) No abnoraality except for eosinophilic change in centrllobular hepatocytes(++) Swelling of centrilobular hepatocytes(++) Dilation or pelvls(+) Swelling of centrilobular hepatocytes(++) : Very slight , : Slight, ++: Moderate Appendix i2--R Microscopic findings of the organs shoved gross lesion (Recovery) Test article : Saiple D-l Study No.BMRl43C Dose level (sg/kg) Anltal nuaber Organ Macroscopic findings Microscopic findings Male 0 - - 30 ... .-0111 4107 Testes Liver 4103 4109 * 4110 4111 4112 Liver Thytus Stoaach Liver Liver Liver Liver Atrophy Dark reddish change Grayish patch Hypertrophy Dark reddish patch Atrophy Tarry contents/lfeaorrhage Scattering of grayish dot/patch Hypertrophy Dark reddish change Grayish patch Atrophy(++) No abnormality except for swelling of centri lobular hepatocytes(++).and eosinophilic change in centri lobular hepatocytes(+) and tlcrogranuloia(+) Focal necrosis(+) Swelling or centri lobular hepatocytes(++) Congestion^) and heaorrhage(+) . No abnortallty Ulcer and hetorrhage in glandular stoiach(+) Focal necros!s(++) Swelling of centri lobular hepatocytes(++) No abnortality except for aicrogranulota(+). swelling of centri lobular hepatocytes(++) and eosinophilic change in centrilobular hepatocytes(++) Focal necrosis(+) Fetale 30 4207 4208 4209 4210 4211 4212 Liver Liver Liver Liver Liver Liver Dark reddish change Dark reddish change Hypertrophy Dark reddish change Dark reddish change Dark reddish change Crayish patch No abnoraallty except for ticrogranulota ().swelling of centri lobular hepatocytes(++) and eosinophilic change in centri lobular hepatocytes(+) No abnoraallty except to r ticrogranulota (). focal necrosls(+) and eosinophilic change in cent-rllobular hepatocytes(+) Swelling of centri lobular hepatocytes(+) No abnoraallty except for ticrogranuloaa(+).svel1Ing of centrilobular hepatocytes(+) and eosinophilic change in centrilobular hepatocytes(+) No abnoraallty except for ticrogranulota (}.swelllng of centrilobular hepatocytes(++) and eosinophilic change in centrilobular hepatocytes(+) No abnOraafity except for alcrogranuloaa(+).svel1ing of centri lobular hepatocytes(++) and eosinophilic change in centri lobular hepatocytes(+) Focal necroslsiO ; Very slight , + : Slight, ++: Moderate * : Dead aniaal 90SS00 * ossoo Pictures) P H O T 0 G R A P H S (Hlsopathological Photo.1 Liver of a male rat of control. (Animal No. 0103) Showing normal centrilobular region. H.E.stain X 180 Photo.2 Liver of a male rat given 30 mg/kg. (Animal No. 4105) Eosinophilic change and swelling of centrilobular hepatocytes are noted. H.E.stain x 180 1 05508 Photo.3 Liver of a male rat given 30 mg/kg. (Animal No. 4105) Focal necrosis is noted. H.E.stain X 180 Photo.4 Liver of a male rat given 30 mg/kg. (Animal No. 4106) Peripheral fatty change is found. H.E.stain X 180 2 005509