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InternatioRneaslearcahndDevelopmenCtorporation SPONSOR: COMPOUND: SUBJECT: 3M Company FM-3422 Ninety Day Subacute Rat Toxicity Study. Edwin I. Go,4a:ntha.1, Ph.D. Vice Plres3ean and Director of Research Collaborators: D. C. Jessup, Ph.D., Associate Director of Research R. G. Geil, D.V.M., Vice President and Director of Pathology N. D.-Jefferson, B.A., Acting-Director of Small Animal Toxicology F. A. Ruecker, D.V.M., M.S.1 Staff Pathologist Date: November 10, 1978 137-086 InternatioRneaslearcahndDevelopmenCtorporation I* Synopsis . ......... .0 Page 1 II* Compound. . . . . . . . . . . . . 0 . . . . . . . . . . . . 3 III. Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . 4 A. Method . 0 . . 9 0 . 0 . 0 a 0 # . 0 0 . 0 a 0 0 . . . . . 4 lo General Procedureo . . o . a 0 . 0 . . 0 . . 0 0 . . . 4 2o Compound Administration* o o o o o o o o 9 o * . o a 4 3o Observations . . . o o 0 . & a 0 . . . 0 . 0 0 . 0 0 5 4o Laboratory Tests o . . a t0 9 0 0 0 0 ..0 .0 0 5 a* Hematology o a o o o o o * o o o o & 9 . . 0 . . 0 5 b. Biochemistry . . o . o . . . 0 & . . 0 . . . o 5 c. Urinalysis . . . . . . 0 . 0 ...0 . . 0 5 d. Serum Samples . . . . . 0 . . 0 . * 0 .0 . 6 5. Statistical Analysis o 0 0 . 0 . . . . t . . 0 0 0 . 6 B. Results . . . . . o 0 0 . . 0 ...0 . . 0 6 1. General Behavior, Appear'ance-and Survival. o . o . 0 . 6 2. Body Weights o ol.,. . oo6.o 6 o o o * 8 3. Food Consumption o o o o o * o o o a o a a o a a o . o 8 4. Laboratory Tests . . . 0 0 . . 0 0 . 0 0 0 . . . . . . 9 a. Hematology . . . o . o .. .0 0 .* 0. 9 bo Biochemistry . . . . 0 . . * & 0 . 0 a . 0. 9 c. Urinalysis . . . . . . 0 0 a . * 0 a . . . . . . . 10 IV. Pathological Studies . . . . . . . 0 . 0 ..0 A. Methods . . . . . . . . . . 1. Gross Pathology. . . . 00 2. Histopathology . . . . 0 0 . . ......6 . B. Results . . . . . . . . . . . . . o . . . o 12 lo Gross Pathology and Organ Weights . . . . 0 12 2.' Histopathology . . . . . . . . . . 0 . . . . . . . . . 13 137-086 InternatiRoensaelarcahndDevelopmeCnotrporation Table No. TA BLE 0F C0N TENTS (Continued) Page 1. Group Mean Body Weights, Weight Ranges; and Survival 16 2. Individual Weekly Body Weights . . . . . . . . . . . . . 17-18 3. Mean Food Consumption . . . . . . . . . . . . . . . . . 19 4. T-test Comparison Between Means of Control and Treated Grou@s, Food Consumption . . . . . . . . . . . . . . . . 20 5. Means and Significance of Hpmatological Values . . . . . 21-22 6- 8. Individual H-matological Values . . . . . . . . . . . . 23-26 9. Means and Significance of Biochemical Values . . . . . . 27-28 10-12. Individual Biochemical Values . . . . . . . . . . . . . 29-32 13. Means and Significance of Urinalysis Values . . . . . . 33-34 14-16. Individual Urinalysis Values . . . . . . . . . . . . . . 35-41 17. Sl-.qry of Necropsy Observations . . . . . . . . . . . . . 42-43 18. Absolute and Relative Organ Weights . . . . . . . . ... 44 19. 20-21. Individual Organ Weights . . . . . . . . . . . . . . . . Histomorphologic Observations . . . . . . . . . . . . . 45 46-50 137-086 InternatiRoensaelarcahndDevelopinCeonrtporation Page 1 SYNOPSIS FM-3422 was fed in the diet at levels of 30, 100, 300, 1,000, 3,000 and 10,000 ppm to Charles River CD rats for 90 days. Five male and five female rats were initiated at each dosage level and in the control group. The rats were observed twice daily for overt signs of toxicity and mortality. Individual body weights and sex-group food consumptions were recorded weekly. Hematological, biochemical and urinalysis studies were conducted during the pretest period and at 1 and 3 months of study. All rats at the 1,000-, 3,000- and 10,000-ppm dosage levels died between days 9 and 29 of the study. Most of these rats exhibited one or more of the following signs of overt toxicity including: emaciation, altered posture, convulsions, reduced motor activity and/or increased sensitivity. Time-to-onset of signs of toxicity and length of life span decreased as the dosage level was increased. At the 30-ppm dosage level, neither changes in appearance nor deaths were noted for either male or female rats. Females had a slightly depressed weight gain when compared to the controls. With the following exceptions, laboratory test values were within the expected range: at 1 month, Y-glutamyl transpeptidase (Y-GTP) levels were slightly elevated for two males; at 3 months, Y-GTP values were elevated for three males. One male rat with elevated Y-GTP (I month) had a normal Y-GTP value at 3 months but slightly elevated plasma glutamic pyruvic and oxalacetic transaminase (PGPT and PGOT) values. Two male rats at the 30-ppm dosage level also showed slightly elevated blood urea nitrogen (BUN) values at 1 month of study. At the 100-ppm dosage level, only one rat (a female) manifested any behavioral or appearance change (excessive salivation, week 4). A reduction in body weight gain occurred with both sexes. Food consumption was depressed for the females. Laboratory values were within the expected range. 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 2 At the 300-ppm dosage level, an increased incidence of possibly compound-related signs was noted. Two females died after the collection of blood for clinicopathology. One male and one female had an accumulation of material around the eye(s) and/or nose, and one female had a dilated pupil. Group mean body weight and food consumption levels were significantly lower (p<0.01) for both males and females. At 3 months of study, erythrocyte counts, hemoglobin and hematocrit values for males and females at the 300-ppm dosage level were slightly lower when compared to the control values (statistically significant). Biochemical values showed some changes for alkaline phosphatase, PGPT, PGOT, Y-GTP and for BUN values for one or more rats of each sex at each sampling period. Compound-related gross liver lesions consisting of enlargement,@ accentuated lobulations, brown discoloration and gray/yellow/white areas of discoloration were observed in the 300-ppm group and to a lesser extent in the 100-, 1,000- and 3,000-ppm groups. Brown kidney discoloration was observed in the 300-ppm group, and stomach hyperemia/congestion and red/brown foci/hemorrhages were noted in some rats from the 1,000-, 3,000- and 10,000-ppm groups. A statistically significant liver weight increase in 100- and 300-ppm rats was considered compound-related. Compound-related, microscopic, liver lesions consisting of hepatocellular hypertrophy and hyperplasia, hepatocellular vacuolation, hepato'cellularnecrosis and hepatocellular and Kupffer cell accumulation of brown pigment were observed to varying degrees in all.treated groups. Compound-related, microscopic, kidney lesions consisting of tubular nephrosis, tubular proteinaceous casts, and intracellular accumulations of brown pigment and reddish brown hyaline droplets in tubular epithelial cells were observed in some rats from the 300-ppm group. 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 3 COMPOUND The compound was received from 3M Company, Saint Pault Minnesota on October 28, 1977 as indicated below: Label Description FM-03422 41-2700-3422-0 Lot 784/ Net-35 DR-1 off-white to tan waxy substance 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 4 III. CLINICAL STUDIES A. METHOD: 1. General Procedure: Thirty-five male (240-306 g) and 35 female (180-226 g) Charles River CD rats purchased from The Charles River Breeding Laboratories, Inc., Portage, Michigan were used in this study. The rats were distributed among the groups, based on a computer-generated table of random numbers. The rats were housed individually in suspended wire mesh cages and maintained in a temperature-, humidity- and light- controlled room. During the pretest period, rats were provided PurinaS Laboratory Chow-0and water ad libitum. During the test period, the rats were provided the appropriate test diet and water ad libitum. This study was initiated on November 4, 1977 with Groups I-VI (control, 100-, 300-, 1,000-, 3,000- and 10,000-ppm dosage levels). Group VII (30 ppm) was initiated on November 25, 1977 in accordance with an approved protocol modification. Surviving rats from Groups IVI were sacrificed on February 2, 1978. The study was terminated by sacrifice of the Group VII rats on February 23, 1978. 2. Compound Administration: The compound was mixed weekly with ground PurinaO Laboratory Chow4D (i.e., ground basal diet) to provide dosage levels of 30, 100, 300, 1,000, 3,000 and 10,000 ppm.. Five male and five female rats were used at each dosage level and in a control group. The control rats received the basal diet only on the same regimen as treated rats. Diet samples (100 grams each) were taken immediately after preparation of each diet and after 7 days standing in weeks 1 4 and 12. samples were frozen and subsequently shipped to th"e sponsor. The Diets were prepared in the following manner: an appropriate amount of FH3422 was dissolved in 15 ml of ACS grade acetone. The resulting 137-086 InternatioRneaslearcahnd DevelopmenCtorporation Page 5 solution was thoroughly mixed with 500 g of Purina* Laboratory ChowS in a Hobart blender to produce the premix. To provide the proper dosage levels',appropriate quantities of the premix were mixed with the ground basal diet using a twin-shell blender equipped with an intensifier bar. The diets were prepared weekly. 3. Observations: The rats were observed twice daily for overt signs of toxicity and for mortality. Detailed observations normally were recorded weekly; daily observations were recorded whenever a specific abnormal condition existed. Individual body weights and food consumptions were recorded weekly during the pretest and treatment periods. 4. Laboratory Tests: Once during the pretest period and at 1 month and 3 months of the study, blood (orbital sinus puncture technique) and overnight urine samples were obtained for analysis from all surviving rats. Food and water were withheld during sample collection. a. Hematology: Hematological studies included: hemoglobinl, hematocrit2, total erythrocytes3, reticulocytes4 and total3 and differential leucocyte counts. b. Biochemistry: Biochemical studies included: fasting glucose5, blood urea nitrogen (BUN)S, plasma glutamic p'yruvictransaminase (PGPT)5 and plasma glutamic oxalacetic transaminase activity (PGOT)5, plasma alkaline phosphatase activity5, Y-glutamyl transpeptidase (y-GTP)6, creatinine phosphokiaase7 and calcium8. Alkaline phosphatase values from the pretest (baseline) period were not measured because of interference by the anticoagulant. c. Urinalysis: Urinalysis included description of color and appearance; measurement of volume, pH9 and specific gravity; qualitative tests for 137-086 InternatioRneaslearcahnd DevelopmenCtorporation Page 6 protein9, glucose9, ketones9, biiirubin9 and occult blood9; and microscopic examination of the sediment. d. Serum Samples: Serum samples were obtained for all surviving rats at 13 weeks of study. The samples were pooled by sex and group, frozen and subsequently shipped to the sponsor. 5. Statistical Analysis: All statistical analyses compared the treatment groups with the control group, by sex. Body weight (at 13 weeks), food consumption (weeks 1-13), hematological, biochemical and urinalysis parameters at 1 and 3 months, and absolute and relative terminal organ weights were compared by analysis of variance (one-way classification), Bartlett's test for-homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and TorrielO using Dunnett'sll multiple comparison tables to judge significance of differences. B. RESULTS: 1. General Behavior, Appearance and Survival: At the 30- and 100-ppm dosage levels, one male (30 ppm) had an accumulation of red material around the right eye from week 11 to week 13; one female (100 ppm) exhibited excessive salivation and rales during week 4. No other rats at these dosage levels manifested any signs of toxicity. At 300-ppm dosage level, an increased frequency of possibly compound-related signs were noted. Two females died shortly after the collection of blood (one at I month; one at 3 months) without any signs of overt toxicity having been noted. One male had an accumulation of red material around the left eye and nose. One 'female rat had an accumulation of red material around the right eye and another female had a dilated right pupil (weeks 5 and 6). 137-086 InternatiRoensaelarcahndDevelopmeCnotrporation Page 7 All rats at the 13- 000-, 3,000- and 10,000-ppm dosage levels died prior to the scheduled sacrifice. Most deaths occurred following manifestation of one or more of the following signs of overt toxicity: emaciation, altered posture (hunched back), reduced motor activity, convulsions following handling, increased sensitivity to outside stim- uli, accumulation of red material (right eye and mouth or nose), accu- mulation of yellow material (anogenital region), dilation of the right pupil and excessive salivation and rales. The incidence of these findings was as follows: No. of Rats/Observation/Dosage Level Observation Control 30 100 300 1,000 3,000 PPM PPM PPM PPM PPM Emaciation Alt. posture Red. motor act. Convulsions Ind. sensi- tivity Red material 1 1 3 (eyes) Red material 1 (nose, mouth) Yellow material Pupillary dilation 1 Excessive salivation I 6 10 4 8 1 1 3 5 2 1 2 2 2 10,000 PPM 10 10 7 1 2 Survival after 3 months of compound consumption was as follows: Treatment Group Control 30 ppm 100 ppm 300 ppm 1,000 ppm 3,000 ppm 10,000 ppm No. Surviving/No. Initiated MALE FEMALE 5/5 5/5 5/5 5/5 5/5 5/5 5/5 3/5 0/5 0/5 0/5 0/5 0/5 0/5 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 8 2. Body Weights (Tables_IM2j: Changes in body weight were similar for male rats at the 30- ppm and 100-ppm dosage levels when compared with control male rats. Female rats at the 30-ppm dosage level showed slightly lower gains in body weights and female rats at the 100-ppm dosage level showed moderately lower gains in body weight when compared with control female rats. Male and female rats at the 300-ppm dosage level showed markedly lower gains in body weight. The group mean body weights at 13 weeks of study were significantly lower for the females (p<0.05) at the 100-ppm dosage level and for male and female rats (p<0.01) at the 300-ppm dosage level when compared with control rats. Rats at the 1,000-, 3,000- and 10,000-ppm dosage level showed moderate to marked losses of body weight prior to death. The group mean body weights (and the percent difference from the-control group) at 13 weeks of study were as follows: Treatment Group Group Mean Body Weights, g (% difference from Control) MALE FEMALE Control 30 ppm 100 ppm 300 ppm 501 491 2.0) 482 3.8) 392 (-21.8) 286 269 (- 5.9) 248 (-13.3) 227 (-20.6) 3. Food Consumption (Tables 3-4 Group mean average for food consumption consistently declined as the dosage level was increased. Mean differences for the 300 ppm group (males and females) when compared with the control were sta- tistically significant at p<0.01. Treatment Group Control 30 ppm 100 ppm 300 ppm Average Food Consumption (grams/rat/day) MALE FEMALE 27.6 27.2 27.4 24.2 19.9 19.3 18.6 15.1 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 9 4. Laboratory Tests (Tables 5-16): a. Hematology: Hematological values for rats at the 30- and 100-ppm dosage levels at I and 3 months of study and for rats at the 3007PPM dosage level at 1 month of study were within the expected range. The 3-month erythrocyte counts, hemoglobin and hematocrit values for male and female rats at the 300-ppm dosage level were slightly lower (statistically significant) when compared with the control values. All other hematologic values, at 3 months of study, for rats at the 300-ppm dosage level were within the expected range. b. Biochemistry: With the exceptions of the following findings, all biochem- ical values were within the expected-range. At the 30-ppm dosage level (1-month sampling period), two male rats had slightly elevated Y--GTPlevels (9 units/ml/rat). At the 3-month sampling, one of these Y-GTP levels was still elevated and two other males had elevated Y-GTP levels (10 units/ml/rat). The group mean Y-GTP level for male rats at the 30-ppm dosage level was significantly lower (p<0.05) when compared with the control group mean. One male rat (3-month sampli*ng)had a slightly elevated PGPT (154 units/ml) and PGOT (299 units/ml); this rat had had a slightly elevated Y-GTP level at 1 month which had declined by 3 months. Two male rats at the 30-ppm dosage level also showed slightly elevated blood urea nitrogen values at 1 month of study. At 100-ppm dosage level all biochemical values were within the expected range and showed no changes that could be attributed to the compound. At the 300-ppm dosage level (I month) plasma alkaline phosphatase levels were elevated for all females (statistically significant at p<0.01 when the group mean was compared with the control 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 10 group mean). The group range for these values was 210 to 291 units/ml. One of these females also had an elevated PGOT (480 units/ml) value and an elevated PGPT (360 units/ml) value. Two male rats (at 1 month) had slightly elevated Y-GTP values (13 and 16 units/ml). At 3 months, three males and one female had elevated plasma alkaline phosphatase levels (227-281 units/ml). The group mean difference for these males was statistically significant when compared with the control mean. One male rat had a slightly elevated PGPT reading of 204 units/ml at 3 months. At 1 month of study, two female rats at the 300-ppm dosage level showed a slight and moderate increase in BUN. At 3 months of study, the BUN values for male rats at the 300-ppm dosage level generally were slightly higher than those of control male rats. The group mean blood urea nitrogen values for male rats at the 300-ppm dosage level was significantly higher (p<0.01) than the control male rats at 3 months of study. c. Urinalysis: No changes considered to be related to compound were seen in the urinalysis studies. 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 11 IV. PATHOLOGICAL STUDIES A. METHODS: 1. Gross Pathology: After completion of the compound administration period, all sur- viving rats were sacrificed by CO2 inhalation and necropsied. The spleen, liver, kidneys and brain were weighed and representative tissues were collected in buffered neutral 10% formaliu.* The adrenals, thyroid/ parathyroid and pituitary were weighed after fixation. Liver samples, obtained from all of the rats at terminal sacrifice, were frozen and subsequently shipped to the sponsor. Rats which died during the study period were necropsied as above with the exception that organ weights were not taken. 2. Histopathology: Mcroscopic examination of fixed h-Atoxylin-eosin stained paraf- fin sections was performed for all rats in the control and 30-, 100-,@ 300-ppm dosage levels. The following tissues were examined: adrenals mqmmary gland aorta nerve (with muscle) bone spleen brain (with segment of cervical pancreas cord attached) prostate/uterus eyes bone marrow (sternum) heart (with coronary vessels) salivary gland duodenum spinal cord (lumbar) ileum pituitary jejunum stomach colon testes/ovaries kidneys thyroid liver parathyroid lung urinary bladder thymus mesenteric lymph node and any other tissue with abnormalities. .In addition, livers from rats in the 1,000-, 3,000- and 10,000-ppm dosage levels were processed and microscopically examined. *Eyes fixed in Russell's fixative. 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 12 B. RESULTS: 1. Gross Pathology (Table 17) and Organ Weights (Table.s--T8-19): Compound-induced, gross, liver lesions were observed in all 300- ppm rats which survived to terminal sacrifice. The lesions occurred singly or in combination and consisted of liver enlargement, accentuated lobulations, diffuse brown discoloration and gray/yellow/white areas of discoloration. Male rats appeared to be more severely affected. Similar, but less severe, liver lesions were observed in some rats from . .- the 100-, 1,000- and 3,000-ppm groups. Additional compound-related gross lesions were observed in the stomachs (hyperemia/congestion, red/brown foci/hemorrhage) of some rats in the 1,000-, 3,000- and 10,000-ppm groups and kidneys (brown discoloration) of some rats from the 300-ppm group. Statistically significant increases in absolute and relative liver weights in the 100-.and 300-ppm groups were considered compound related with male rats more severely affected: Dosage Level Organ (ppm) Sex Weight Change P< Liver 100 absolute, relative increase 0.01, 0.01 300 m absolute, relative increase 0.01, 0.01 F relative increase 0.05 other statistically significant organ weight variations observed in the 100- and 300-ppm groups were not accompanied by morphologic change and the biological significance of the variations is not known: Organ Kidneys Brain Thyroid/Parathyroid Pituitary Dosage Level (ppm) Sex Weight Change 100 m relative increase 0.05 300 m relative increase 0.05 F relative increase 0.05 300 m relative increase 0.01 300 m relative increase 0.05 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 13 2. Histopathology (Tables 20-21): Compound-induced microscopic alterations were observed in the livers from all treated groups and consisted of a very slight to marked enlargement (hypertrophy) of hepatocytes in the 30-, 100-, 300- and 1,000ppm groups and increased numbers of hepatocytes (hyperplasia) in the 3,000- and 10,000-ppm groups. These alterations were centrilobular to panlobular in distribution with more liver involved as the dosage level increased. A very slight-to-moderate increase in cytoplasmic vacuoles was observed in the livers of the 100- and 300-ppm groups. The vacuoles contained lipid (as verified by staining with oil red 0) and were situated in a centrilobular to midzonal location. Focal to multifocal coagulative hepatocellular necrosis of very slight-to-marked severity was observed in the 300-, 1,000-, 3,000- and 10,000-ppm groups. The lesion appeared to be primarily centrilobular to midzonal in location and there was a minimal amount of associated infl atory infiltrate. Increased intracytoplasmic accumulations of brown pigments in hepatocytes and sinusoidal macrophages (Kupffer cells) were observed primarily in livers from the 300-ppm group. Selected examples were stained for iron content using the Gomorils iron stain. Pigment in the Kupffer cells stained positive for iron while hepatocellular pigment was negative for iron. Kidney lesions were observed in most rats of the 300-ppm group and consisted of a very slight-to-marked tubular nephrosis with associated proteinaceous cast formation and intracellular accumulation of brown pigment and reddish-brown hyaline droplets (protein) in tubular epithelial cells. The brown pigment was positive for iron as verified by the Gomori's iron stain. Mineralization of luminal tubular debris was observed in some rats. Whether the lesions developed as a result of a direct toxic effect of the compound on the ren-alparenchyma or indirectly 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 14 as a result of compound-effect on the liver with subsequent overload of the kidneys'with bile and/or products of red blood cell breakdown could not be determined from histological exa-ination. Lesions observed in other tissues were not considered compoundrelated but were interpreted as spontaneous in origin. 137-086 InternatioRneaslearcahndDevelopmenCtorporation Page 15 References 1. Coulter Hemoglobinometer, Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 2. Microhematocrit, John B. Miale, 3rd Ed., 1967, The C. V. Mosby Company, p. 1154. 3. Coulter Particle Size Counter, Model ZB, Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 4. Gradwhol's Clinical Laboratory Methods and Diagnosis, Frankel and Reitman, Editors 6th Ed., 1963,.The C. V. Mosby Company, p. 1132. 5. Technicon Auto Analyzer 6/60 Micro Methodology. 6. Sigma GGTP Procedure Bulletin #545. Sigma Chemical Co., St. Louis, Missouri. 7. Micro Auto Analyzer 11, 6/60 Micro Methodology. 8. Photovolt PV4, Photovolt Corporation. 9. Multistix (Ames Reagent Strips). 10. Steel, R. G. D. and Torrie, J. R. (1960), Principles and Procedures of Statistics,-McGraw-Hill, New York, N. Y. 11. Dunnett, C. W., New Tables for Multiple Comparisons With a Control, Biometrics, Sept. 1964. 137-086 1111--14*2@4'1-.!7110-@1422-1): Nilld!IY I)IlySoil)4(!klieKill Tioxii.ity St.tolly. !;Iisti-e wi (:tioritoi1 %III killit-.Vt#vival 30 "I-fill U.-41y Wi- IallI wi Stirvivill Wiviglits, 4.riomti; Weit-,Iit Ritoigt-a,. not(i Sterviv4ii. )0(111 himly W4-iglit Stir- Wi Riksirat" vivill lkmiv Weirfil SisrWi . R.Iligo-O ,Iv;il lkmly Wi,I1-.IIo StirR.illl-.4-1v4ival Ikidy Wt-iglt4 Wt. MisteRi-H ?IA 77 III .1 141 4 177 5 3114 1,140 to2l) 8 455 if f17i 111 477 11 4111 IP 'sI I it 'pill FP.'FIAI.F.S: 2%11-281) 2')Ill-imb @P-041-14(1 *1(12-396 Ifif@-416 384-426 404-456 414-464 442-SON) 454-%12 to71)-% it) 49ft-544 4/4-541 5/5 '.@S/ S/S %/S 5/5 5/5 5/5 S/5 5/5 %/$ 5/5 ')/5 rb/5 5/5 S/5 242 219-246 5/5 262 148 241@-254 S/S 291 I'll 2112-'106%/is 326 '111 314-361 5/5 348 165 346-400 5/5 343 '161 336-400 5/5 379 1117 373-435 5/5 393 426 4(Wl--464 5/5 422 434 41(1-467 5/5 427 454 42J-494 5/5 446 41(l 436-518 5/5 463 48(1 442-535 5/5 459 483 446-536 5/5 474 491- 448-54f, 5/5 487 491 4S4-538 5/5 4112 248-212 5/5 2(o'l 250-272 'j/% 259 252-262 5/5 255 279-*$ll4 5/5 217 264-288 S/@ 2741 261-27h %/$ 279 *1112-'140 %/% '119 3418-136 5/') 26'1 246-282 5/5 194 1211-370 -)/5 321 294-348 5/5 226 218-243 5/5 100-168 5/5 347 328-382 5/5 214 204-220 3/5 154-398 5/5 351 326-IR9 5/5 0/5 356-416 5/5 340 102-394 5/5 388-447 5/5 37t 340-426 S/S 396-466 5/5 372 346-414 5/5 4(17-4911 5/5 389 353-436 5/5 422-SIND 5/5 44)5 372-4S2 5/5 418-SO5 5/5 391 165-4311 S/5 428-522 5/5 412 383-456 %/S 434-544 31 @i 414 3H4-445 5/5 414-534 5/5 392** :142-414 5/5 240-278 2(11-:111'o 17#j-Z 12 1 1 196-21(1 5/5 19R 185-224 5/5 195 191)-21)4 5/5 ZIKJ 194-206 5/5 2(11 1911-214 5/5 204 188-212 11 211 Zim)-218 5/5 2(Ml 1911-226 5/5 202 1911-210 5/5 21)7 199-220 %/S 2419 194-224 5/5 213 205-22(1 1 22(. 21fi-2411 t/5 21M 19(1-211 5/5 210 200-220 S/i 212 21)0-230 5/5 190 174-206 5/5 149 142-164 2 .1 22(t 219-218 5/5 225 2fM-254 S/5 211 24)3-2 1N 5/5 2(W) 187-214 5/5 157 147-168 5/5 2-11 2116-2/16 5/5 239 212-264 5/5 224 214-23(1 5/5 202 164-224 5/5 157 142-168 5/5 2'141 27'i-Z'ii S/S 226 21)4-252 5/5 216 2118-222 5/5 202 188-219 5/5 0/5 24H 227-266 5/5 243 222-268 5/5 219 214-225 5/5 2409 186-230 4/5 767 251-2811 5/1 26b 240-294 5/5 237 230-242 5/5 222 2111-238 4/5 7 *21,'l 246-27H 515 254 225-281 5/5 237 212-242 5/5 222 212-23R 4/$ It 2(.4 245-290 %/S 2(11 237-2111 5/5 23(t 228-241 5/5 219 24)0-233 4/5 41 'Par) "-1.4-*Ioh r,/r, 267 241@-294 5/5 254 248-2(,2 5/5 241 2-10-258 4/5 III 7, 2411-11111 5/5 211 247--lfM) 5/5 2441 2'1%-252 5/5 222 2111-240 4/5 11 Z74 2'10-'111-i %/-i 17-1 247-1(13 5/5 245 219-252 5/5 2111 212-24H 4/5 Zr,7--liO 5/', 2141 746-'Ifll 5/5 24H 741)-2641 5/5 2'13 218-248 4/5 2411-'(M) 5/5 2411* 7.'11)-2%4 r,/% 221** 2411-741 I/S I IV 111114-11-111 111.111441111$..1 1.<Il.fll F4-3422 41-2700-3422-0: TABLE Group, Pat No. Sax Pratest -1 0 Ninety Day Subacute Rat Toxicity Studv. Individual Weekly Body Weights, Grams. Page 17 Week of Studv 1 2 3 4 5 6 7 8 9 10 11 12 73-* Concrol: 73961 @l 73962 1%1 73963 %1 73964 m 73965 m 73966 r 73967 F 73968 F 73969 F 73970 F 254 259 304 325 338 371 388 418 422 445 468 465 482 496 474 250 264 306 310 344 368 386 410 418 445 462 460 479 498 492 250 250 290 317 302 360 386 408 414 442 454 463 '-85 500 488 260 281 314 340 326 369 384 404 426 444 470 478 502 515 504 280 306 340 363 396 416 428 456 464 500 512 521 539 544 547 196 208 222 225 240 239 253 272 264 264 284 274 279 288 292 210 218 234 230 246 255 266 280 278 290 304 308 305 318 320 204 214 240 238 244 248 262 278 278 276 306 285 297 298 298 210 213 220 218 206 228 22' 254 250 245 268 260 258 164 262 196 200 216 218 218 225 23@ 253 246 246 -164 248 258 257 258 30 ppm: 76231 m 76232 x 76233 m 76234 m 76235 m 76236 F 76237 F 76238 r 76239 F 76240 F 242 252 290 340 374 382 422 448 452 476 486 494 494 508 506 240 250 293 324 358 358 383 408 420 444 454 458 472 483 482 243 254 306 361 400 400 435 464 467 494 518 535 536 546 538 246 244 282 318 346 336 373 400 410 421 436 442 446 448 454 239 240 286 314 347 340 374 410 419 436 458 473 468 493 476 185 180 190 204 212 204 222 240 225 237 240 247 247 246 240 192 196 206 223 234 220 241 264 253 254 266 270 269 268 270 192 198 206 225 250 226 248 270 257 269 274 268 275 274 270 197 200 206 220 233 228 235 260 252 254 263 270 270 263 267 224 226 231 254 264 252 268 294 281 291 294 300 303 301 300 100 Dom: 73971 m 272 304 340 370 348 392 416 447 466 490 Soo 505 522 544 534 73972 m 258 288 328 348 366 398 408 442 444 466 490 495 517 536 528 73973 m 248 279 320 340 " 300 357 375 402 402 423 436 423 440 445 444 73974 M- 268 294 338 360 368 394 408 430 428 445 466 453 465 478 469 73975 m 266 289 302 320 334 354 356 388 396 407 422 418 428 434 434 73976 F 73977 r 73978 F 73979 F 73980 r 194 205 210 215 224 222 225 242 242 247 204 210 220 215 228 208 217 234 238 233 190 190 200 203 214 211 216 230 232 234 190 206 212 218 230 22 224 240 240 235 198 200 .108 205 222 215 214 237 232 228 262 252 248 260 254 254 240 252 248 248 250 237 239 1-40 239 258 235 245 249 253 248 237 243 2!,2 244 300 Dom: 73981 m 73982 @i 73983 m 73984 m 73985 m 73986 F 73987 F 73988 F 73989 r 73990 F 264 282 328 333 360 359 356 380 384 402 412 412 427 .28 414 262 264 308 294 328 326 307 340 346 353 372 365 383 384 342 272 2",6 316 310 336 345 343 365 364 380 394 377 401 (,16 407 250 274 308 321 328 338 302 343 352 372 394 380 395 399 388 268 288 336 348 382 389 394 426 414 436 452 430 456 443 410 204 220 220 214 224 213 222. '@30 226 223 240 227 232 235 238 206 213 230 202 218 219 230 238 238 233 258 240 248 248- 241 198 202 204 200 202 194 186 210 212 214 234 212 226 230 Died 194 199 200 195 164 195 198 210 212 206 230 210 212 216 203 200 200 208 187 204 188 Died 1.000 1)1)m: 73991 m 73991 x 73993 m 13994 x ,3995 m 252 270 282 243 Died 260 '-73 266 220 Died 260 261 258 218 218 Died 262 276 264 228 204 Died 260 271 246 220 220 Died 73996 r 7399,- F 73998 F 73999 F 74000 F 192 202 194 155 160 Died 190 194 174 158 142 Died 214 224 206 168 168 Died 206 212 194 147 168 Died 204 214 ISO 1.38 146 Died 11-7-066 FH-3422 41-2700-3422-0: 4inety Day Subacute Rac Toxicity Study. Page 18 TABLE 2. Cont. individual Weekly Bodv Weights, Grams. Group, Rat Pretest Week of Study No. Sex -1 0 1 2 3 4 5 6 7 9 10 11 12 13* 31000 opm: 74001 m 74002 x 74003 x 74004 m 14001 M 256 286 176 Died 240 261 200 Died 278 294 212 Died 262 281 198 Died 240 272 184 Died 74006 F 212 220 164 Died k 74007 F 212 214 148 Died 74008 F 208 214 146 Died 74009 F 188 205 142 Died 74010 F 202 214 146 Died 10,000 Epm: 74011 m 74012 m 74013 14 74014 m 74015 m 240 264 Died 256 259 Died 250 280 168 Died 250 260 156 Died 248 269 Died 74016 F 202 216 Died 74017 F 214 226 Died 74018 r 194 205 Died 74019 F 214 226 Died 74020 F 200 200 Died 137-086 *Term:Lial FM-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 3. Mean Food Consumption. Week of Study Control 30 ppm 100 ppm 300 ppm 1,000 ppm 3, g/ g/ 8/ g/ g/ g/ g/ g/ g/ g/ g/ rat kg/ rat kg/ rat kg/ rat kg/ rat kg/ rat day d.ay day day day day day day day day da3 MALES: 1 2 3 4 5 6 7 8 9 10 11 12 13 FEMALES: 1 2 3 4 5 6 7 8 9 10 11 12 13 137-086 23.3 75.0 26.7 91.9 26.3 80.6 25.4 79.5 17.3 65.8 6.1 26.1 78.7 28.9 87.4 27.4 78.7 25.8 80.5 13.6 60.2 26.9 78.9 27.6 75.6 25.2 73.5 26.0 74.9 13.8 64.5 28.1 74.6 23.9 66.0 27.6 72.8 24.9 70.9 32.0 81.1 27.4 69.0 30.9 78.7 24.8 73.0 29.9 71.3 26.9 63.2 29.8 70.5 27.0 72.7 27.2 63.4 25.1 57.9 27.2 63.7 24.5 65.7 27.3 60.0 25.8 56.8 27.7 62.1 24.4 62.7 26.9 56.9 27 58. 27.1 58.5 24.3 60.1 26.9 56.4 28:8 59.9 25.3 55.0 22.4 57.0 27.0 a 27.5 29.8 54.3 a 53.8 59.5 29.4 29.2 27.2c 60.9 56.9 c 55.5 26.6 27.3 27.4 56.2 56.,a 56.8 23.2 25.3 '17.1 56.2 61 oa 43.7 17.8 18.6 78.9 82.4 20.6 20.8 99.2 92.4 17.3 18.7 82.2 88.6 16.2 15.7 76.3 78.4 9.6 50.5 3.1 7.8 50.2 21.0 20.5 90.8 85.6 20.7 16.3 86.4 72.1 19.4 18.7 86.5 86.5 15.5 15.4 76.7 76.2 11.6 73.9 23.7 95.7 19.3 79.6 21.6 98.8 15.7 75.2 21.4 80.3 19.5 73.5 20.7 87.2 17.6 79.2 19.4 73.9 17.1 67.2 20.1 84.6 14.9 66.9 18.9 71.8 17.9 68.6 17.4 73.8 14.9 68.2 19.7 69.2 20.. 76. 19.2 75.7 15.2 63.1 18.0 65.5 18 2 67.2 15.5 64.6 12.5 56.5 18 8 67.5 21.1 77.4 18.3 74.6 14.1 61.3 20:e 72.? 18 7 69.1 19.P 77.7a 1,.8a 68.,a 19.7 68.8 19:9P 73.9c 15.5 62.6 13.4 59.2 a b Nine-day food consumption Five-day food consumption c Six-day food consumption FM-3422 41-2700-3422-0: Ninety Day,:..SubacutRea.t Toj;icityStudy. TABLE 4. T-test Comparison Between Means of Control and Treated Groups, Food Consumption. Study Week Sex Control 30 ppm 100 ppm 1-13 m 27.6 F 19.9 27.2 19.3 27.4 18.6 Page 20 300 ppm 24.2* 15.1* 137-086 *Significantly different from Control group mean, p<0.01. FM-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 5. MALES: Means and Significance of Rematological Values. Hematology Study Month Control 30 ppm 100 ppm Eryttrocytes, 10 /cmm Hemoglobin, g/100 ml H-.qtocrit, % Leuc cytes, 109 /cmm Neutrophils, % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % Reticulocytes, % Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 6.08 6.87 7.69 15.4 16.1 16.3 46 49 50 9.39 10.43 9.79 14 9 13 85 89 85 1 1 11 0 1 1 0 0 0 6.1 2.6 2.6 5.95 6.76 7.30 14.9 16.0 15.0* 44 50 47* 13.19 10.78 11.21 28 11 15 72 87 84 0 1 1 0 1 0 0 0 0 4.6 2.2 2.9 5.69 6.71 7.64 14.7 16.1 15.9 45 47 48* 10.33 12.25 11.35 11 11 12 88 88 86 1 1 2 0 0 0 0 0 0 3.8 2.6 2.8 Page 21 300 ppm 6.03 6.54 6.81** 16.2 15.8 14.7** 47 49 44** li.33 14.45** 9.11 9 7 10 90 91 89 1 1 0 0 1 1 0 0 0 6.1 2.8 3.6** 137-086 *Significantly different from Control group mean, p<0.05. **Significantly different from Control group mean, p<0.01. F*-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 5. Cont. FEMALES: Means and Significance of Rematological Values. H,-Tnqtology Study Month Control 30 ppm 100 ppm Eryttrocytes, 10 /cmm Hemoglobin, g/100 ml H-atocrit, % Leucgcytes, 10 /t-mm Neutrophils, % Lymphocytes, % Eosinophils, Monocytes, Basophils, % Reticulocytes, % Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 6.41 6.86 7.56 15.2 16.1 16.2 46 49 48 10.50 9.86 9.08 12 15 13 87 84 85 1 1 0 0 1 0 0 0 2.7 2.6 3.0 6.26 6.45 7.14 15.8 15.9 15.6 45 50 48 11.75 8.77 8.85 25 12 14 73 88 84 1 0 1 1 0 1 0 0 0 4.4 1.8 3.3 6.33 6.82 7.27 15.5 16.1 15.9 47 48 47 7.38 9.70 6.47 15 12 17 84 86 81 1 2 2 0 0 0 0 0 0 2.9 2.3 2.7 Page 22 300 ppm 6.47 6.65 6.81* 16.7 16.0 14.8* 48 48 45* 9.29 11.85 8.62 14 7* 10 84 92 87 -2 1 20 0 1 0 0 0 3.5 2.7 2.0* 137-086 *Significantly different from Control group mean, p<0.05. **Significantly different from Control group mean, p<0.01. Page 23 41-2700-34.72-0- TABLE 6. Group, Rat '.lumber Sex Erythrocvces 106/c= He=globin S/100 al Ninetv Day Subacute Rat Toxici" Studv. Individual R4kaatological '.Islu*s Prates,. Hematocrit Loucocvtas 103/c= Noutrachils Seg. Non-Seg. 'ymphoc@tes Eosinophils Monocvt*S Basochils Reticul@c,:,tes Concral: 73961 M 5.78* 15.2 45 9.82 14 1 84 1 0 0 3.2 73962 m 5.94* 14.3 46 10.25 9 0 90 1 0 0 8.5 73963 m 6.78* 17.0 51 10.17 12 0 as 0 0 0 4.3 7,3964 m 6.44* , U.3 46 8.17 16 0 el 3 0 0 8.3 73161 4 5,1(,* 1,5*0 1,54 16 0 81 2 0 o i,o M&an 6.08 15.4 46 9.39 14 0 85 1 0 0 6.1 73966 p 6.32* 14.6 45 6.03 19 0 so 1 0 0 4.4 73967 F 5.81* 15.4 45 10.79 9 0 89 2 0 0 2.7 73968 F 6.57* J/A.8 46 11.1.1 6 0 94 0 0 0 1.1 73969 F 6.57* 15.6 48 15.92 is 0 so 2 0 0 4.7 73970 F 6.76* 15.4 47 8.74 9 0 91 0 0 0 0.7 1,4*an 6.41 15.2 46 10.50 12 0 87 1 0 0 2.7 30 Pam: 76231 x 6.01* 14.9 45 15." 25 a 75 76232 m 6.27* 13.6 47 10.98 33 0 65 76233 m 5.04* 12.4 38 13.16 30 0 70 76234 m 6.23* 14.8 45 15.n 35 0 65 76235 x 6.17* 16.9 43 11.18 15 0 es an 5.95 14.9 13.19 28 0 72 76236 F 6.89* 16.3 47 15.03 ILO 0 57 76237 F 6.34* 15.7 47 9.10 26 0 73 76238 F 5.64* 14.8 42 8.62 24 0 76 76239 F 5.31* 14.8 41 15.13 24 0 75 76240 F 6.64* 17.4 47 10.85 12 1-0 94 %I"n 6.26 15.8 45 11.73 25 0 73 100 ovm: 0 0 0 4.6 2 0 0 4.1 0 0 0 5.i 0 0 0 .0 0 0 0 '-.6 0 0 0 4.6 1 2 0 4.0 0 1 0 4.3 0 0 0 4.0 1 0 0 6.1 2 2 0 3.6 1 1 0 4.41 73971 m 5.55* 13.8 42 13.36 13 0 86 1 0 0 4.7 73972 m *5.97* 15.8 46 10.03 13 0 97 0 0 0 --.2 73973 m 3.25* 14.2 46 11.21 9 0 91 0 0 0 i.9 73974 x 5.81* 14.9 48 8.56 8 0 90 2 0 0 3.0 73975 m 5.87* 14.7 44 8.27 11 0 89 0 0 0 2.3 Mean 5.69 14.7 45 10.33 11 0 88 1 0 0 3.8 L 73976 F 5.81* 13.5 42 11.19 23 0 74 1 0 0 4.7 73977 p 6.17* 16.3 49 6.34 16 0 82 2 0 0 0.5 73978 r 6.51* 15.5 47 6.01 10 0 89 1 0 0 2.8 73979 F 6.41* 15.4 47 7.85 14 0 85 1 0 0 3.1, 139110 F 6*76* 16*9 48 5.49 9 0 go 1 0 o 3.0 %um 6.33 15.5 @L7 7.38 15 0 84 1 0 0 2.9 300 pvz: 73981 m 5.97* 15.7 47 12.62 14 0 85 1 0 0 11.1 73982 m 6.09* 17.2 49 13.56 5 0 93 2 0 0 3.7 73983 m 6.27* 16.5 49 12.31 6 0 93 1 0 0 -.9 73984 m 6.09* 16.3 1,6 9.02 9 0 90 1 0 0 6.5 73985 x 5.71* 15.3 45 9.14 10 0 89 1 0 0 @. 3 Mean 6.03 16.2 47 11.33 9 0 90 1 0 0 6.1 73986 F 5.84* 15.6 46 9.10 15 0 83 2 0 0 -.6 13987 r 6.33* 16.3 47 8.91 10 0 88 2 0 0 2.2 73988 F 6.89* 16.8 46 8.63 9 0 86 5 0 0 3.2 "3989 r 6.84* 18.3 52 11.56 16 0 84 0 0 0 3.1 73990 F 6. 16.4 /A7 S.@16 is 0 al 1 0 0 4.6 Mmm 6.47 16.7 48 9.29 14 0 84 2 0 0 3.3 1-37-086 *1-@-Polvchromasia u1 Page 24 ni-34:2 41-27CC-341--'-O: 7-:L3LE 6- Con:. Group, Rac .Number Sax Er.-thro- Hamcglabit 106/c= ililoo 1,000 Dec: 73991 %1 73992 x 73993 x 73994 x 73995 m %lean 73996 F 73997 F 73998 F 73999 F 74000 F Mean 3,000 v=: 74001 .4 74002 m 74003 m 74004 x o4005 x @taan 74006 F 74007 11 7400a F 74009 F 74010 F Mean 10,000 om: 74011 x 74012 x 74013 m 74014 x 74013 x M.,@ 74016 F 74017 r 74018 r 74019 r 74020 F M"n 4.98* 6.08* 6.21* 5.97* 3.69* 5.79 3.99* 5.82* 6.44* 6.47* 6.30* 6.20 5.13* 5.96* 6.01* 5.56* 6.15* 5.76 3.80* 6.25* 5.a3* 6.47* 6.28* 6.13 5.93* 5.55* 6.42* 5.94* 6.13* 5.99 6.18* 6.13* 5.90* 5.93* 6.38* 6.10 13.8 15.1 16.2 16.8 14.8 15.3 13.0 14.3 15.7 16.4 15.9 15.5 15.7 15.6 14.6 15.8 16.9 15.7 14.8 13.2 11.0 15.5 13.9 15.3 15.7 16.8 16.6 15.4 16.2 16.1 13.2 13.2 14.7 15.8 15.8 15.3 Ninety Day Subacute Rat Tox4-city Scudv. Individual He=tological Ha=tocric Lauca- cvtas 103 C= Neutrochils St$. Non-Set. z L@mphocytes Zosinophils @!oncC%Icas Baso-zhils 39 8.89 10 0 90 0 a 0 45 11-@.99 27 0 73 0 0 0 49 13.50 6 0 94 0 0 0 46 1-1.99 7 0 93 0 0 0 46 10.68 10 0 90 0 0 0 45 11.81 12 0 as 0 0 0 43 10.91 11 0 86 42 7.18 24 0 74 47 10.69' 28 0 72 50 7.67 14 0 83 47 9.46 is 1 so 3 0 0 2 0 0 0 0 0 3 0 0 1 0 0 46 9.18 19 0 79 2 0 0 46 13.31 9 0 91 46 12.63 7 0 93 48 6.31 14 0 84 46 10.16 13 0 86 30 7.79 10 0 89 47 10.05 11 0 as 0 0 0 0 0 0 2 0 0 0 0 1 0 0 1 0 0 145 10.16 9 0 91 0 0 0 46 11.32 9 0 91 0 0 0 10.53 10 0 90 0 0 0 47 12.81 7 -0 93 0 0' 0 45 9.44 19 0 al 0 0 0 45 10.86 11 0 89 0 0 a 47 11.70 6 0 92 2 0 0 49 11.61 a 0 91 1 0 0 52 8.32 9 0 90 1 0 0 48 10.04 12 0 so 0 0 0 49 10.01 15 0 83 2 0 0 49 10.38 10 0 89 1 0 0 46 9.28 19 0 81 0 0 0 46 8.18 21 0 79 0 0 0 42 6.76 14 0 85 1 0 0 47 7.65 19 0 81 0 0 0 47 a.85 10 1 as 1 0 0 46 8.14 17 0 83 0 0 0 cvt*S 3.3 6.6 2.3 6.3 3.3 S.., 4.2 3.8 3.3 1.0 1.0 2.7 3.1 4.0 5.0 4.2 2.0 4.1 3.3 4.7 6.5 2.7 2.0 3.9 5.1 5.7 1.3 2.2 4.9 3.8 2.8 4.9 2.1 2.3 4.0 3.2 '37-086 Poly,:hromasia Page 25 P.-34Z2 1-1-2700-3422-0: &ABLE Group, Ra". Number So-% En-throcvtes 10@/c= Howglobin 2/100 ml Ninety Day Subacuze &at ToxicicY StudY- I-,di%,idual Hamcological %?glues 1 @louth. Hanatocric I-sucoc0vtas 3/cm Soutroohils Seg. Non-Ses. % Lmphocytes Easi.-io- @iono- ph4is c@-tes Basephils c c*ltas Concrol: 73961 m 6.31 15.0 47 9.55 6 0 91 2 0 3.0 73962 m 6.53 15.2 47 10.89 11 0 as 1 0 0 73963 x 7.35 17.4 51 11.98 15 0 84 1 0 0 -.8 73964 m 7.16 16.4 51 9.61 6 0 89 0 5 0 73965 m 6.99 16.3 49 10.io a 0 90 1 i 0 Z.3 Mean 6.87 16.1 49 10.4@3 9 0 89 1 1 0 :.6 73966 F 6.88 15.9 47 6.32 20 0 75 1. 1 0 Z.0 73967 F 7.35 16.7 49 8.57 is 0 82 0 0 0 2.3 73968 r 6.83 16.9 51 10.56 10 0 89 1 0 0 2.5 73969 F 7.04 16.8 51 16.71 17 0 81 2 0 0 3.1- 73970 F 6.21 14.3 46 7.12 11 0 89 0 0 0 3.0 .M"U 6.86 16.1 49 9.86 15- 0 54 1 0 0 2.6 30 *vm: 76231 m 7.14 15.6 49 11.66 is 0 so 2 0 0 1.8 76232 m 7.46 16.5 52 10.23 9 0 90 1 0 0 76233 m 6.58* 15.6 so 11.27 12 0 83 1 0 2.9 76234 m 6.44 15.2 47 10.81 9 0 91 0 0 0 2.3 76235 m 7.12 17.1 53 9.92 9 0 88 0 3 0 2.. Mean 6.95 16.0 50 10.78 11 0 87 1 1 0 2.2 76236 F 6.57 16.1 50 5.64 20 0 80 0 0 0 1..0 -,6237 F 6.53 15.9 50 8.46 13 0 86 1 0 0 @.9 76238 T 6.4,5 16.0 50 6.52 13 0 87 0 0 0 2 .3 76239 F 6.45 16.0 51 14.30 10 0 89 1 0 0 1.7 76.140 r 6.26 1.5.5 0 8.95 6 0 94 0 0 0 1.9 lean 6.45 15.9 50 8.7," 12 0 88 0 0 0 1.8 100 cam: 739-il m -6.78 16.0 51 15.1-4 6 0 93 0 1 0 2.1 73972 m 6.79 15.6 47 9.36 21 0 78 1 0 0 3.3 73973 m 6.38 16.5 48 16.80 7 0 92 1 0 0 3.0 73974 m 6.58 15.9 45 11.89 9 0 89 2 0 0 2.L 73975 x 7.04 16.4 46 7.76 10 0 89 1 0 0 2.3 .Uan 6.71 16.1 47 12.15 11 0 88 1 0 0 2.6 f 73976 F 6.65 15.5 45 17.75 13 0 84 3 0 0 2.4 73977 F 6.91 16.9 51 10.26 15 0 85 0 0 0 73978 r 7.24 15.8 48 6.68 6 0 93 1 0 0 .7733997890 FF 66..6671 1166..31 4580 85..3419 1180 00 8779 13 02 00 2@..5,. @Aan 6.82 16.1 48 9.70 12 0 86 2 0 0 ;.3 300 pom: 73981 m 6.23 15.1 47 14.70 5 0 93 1 1 0 2.8 73982 m 6.89 16.0 51 15.87 5 0 94 1 0 0 2.41 73983 x 6.83* 16.4 52 15.83 6 0 94 0 0 0 3.0 7,3984 m 6." 15.5 48 12.75 11 1 85 1 2 0 3.1 73985 m 6.40 15.9 48 13.1'-! 10 0 90 0 0 0 -^.a Mean 6.36 15.8 49 14.45 7 0 91 1 1 0 2.8 .73986 r 6.48 15.7 1.7 13.83 9 0 90 1 0 0 :.o 73987 F 6.54 15.5 46 14.08 a 0 89 2 1 0 Z.-@ 73988 F 6.30 15.5 47 9.33 6 0 92 2 0 0 .1.3 73989 F 6.77 16.3 48 11.52 1.1 0 88 0 0 0 4.1 73990 r 6.95 17.2 52 10.48 4* 0 94 2 0 0 2.3 %W an 6.65 16.0 48 11.85 9 0 91 1 0 0 7 137-086 *Repeat determination. Page 26 Groui), Rat Number Sa2c Erythroc,-tes 100/c= Hem*glabin g/loo ml \Lnecy Day Subacuce Rat Taxicicy Study. IndividualliamatologicalValu*s 3 Months. Hamatocrit z Laucocvtes ol/c= N*utroohils Sag. Non-Seg. 'b Lymphocvt*S Eosine:hi'-s @:orc- BasoC1.1tas p@-ils :4 c *.t* s Co-itrol: i-3961 m 7.56 16.6 50 Ll.72 12 0 87 0 0 2.1- i3961- x 7.43 16.5 51 11.43 6 0 94 0 0 0 Z..@ i-3963 m 8.05 17.3 52 10.66 16 0 80 i 3 0 Z.6 73964 m 7.80 15.8 50 9.45 14 0 82 2 2 0 3.0 3965 x 7.62 15.4 i.8 5.70 16 0 82 2 0 0 2.8 M.Aan 7.69 16.3 so 9.79 13 0 85 1 1 0 2.6 73966 r 7.32 16.2 48 6.36 22 0 77 1 0 0 :.9 73967 F 7.76 15.6 47 8.00 16 0 83 1 0 0 3.1. 73968 F 7.75 16.8 50 9.78 7 0 93 0 0 0 3.0 73969 F 7.65 16.8 50 12.06 11 0 87 1 1 0 3.0 73970 F 7.30 15.7 46 9.18 10 0 as 0 2 0 2.7 NMean 1 7.56 16.2 48 9.08 13 0 85 1 1 0 3.0 30 opm: 76231 m 7.48 14.5 46 11.12 19 a so 1 ell 0 2.3 76232 m 7.38 14.9 47 9.45 10 0 89 0 1 0 3.4 76233 m 6.52 14.1 44 12.35 19 0 77 4 0 0 2.8 76234 m 7.91 16.2 so 12.17 13 0 86 1 0 a 3.-' 76235 m 7.19 15.4 47 10.96 13 0 86 1 0 0 '-.6 Mean 7.30 15.0 47 11.21 15 0 84 1 0 0 "..9 7,6236 r 7.53 15.9 49 7.36 9 0 89 2 0 0 I.j 76237 F 7.33 16.5 so 8.52 23 0 76 1 0 0 3.S 76238 F 6.64 14.7 45 7.40 20 0 77 2 i 0 3.0 6239 r 7.49 15.8 49 n .98 9 0 89 2 0 0 2.3 76240 F 6.71 15.2 47 9.01 7 0 89 0 4 0 3.1 Mear. 7.14 15.6 48 8.85 14 -0 64 1 1 0 3.3 100 vm 73971 x 7.85 13.3 43 13.71 16 0 82 2 0 0 2.2 73972 m .,7 15.5 48 8.15 11 0 88 1 0 0 !-.7 73973 m 7.20 15.7 48 11.47 5 0 92 3 0 0 3.8 73974 m 7.96 16.7 48 14.96 7 0 89 4 0 0 3.0 73973 m 7.40 16.4 48 8.46 21 0 78 0 1 0 2.-' 1.4"n 7.64 15.9 48 11.35 12 0 86 2 0 0 2.8 73976 F 7.18 15.0 44 10.17 11 0 87 0 0 2.3 73917 F 7.24 16.8 48 6.26 19 0 79 0 0 2.7 739@8 F 6.92 15.1 46 4.79 13 0 81 6 0 0 2.; 73979 F 7.11 15.9 48 6.63 26 0 74 0 0 0 3.i 73980 F 7.90 16.8 49 4.48 15 0 82 2 1 0 -@.S .Mean 7.27 15.9 47 6.47 17 0 81 2 0 0 2.7 300 @ym: 73981 m 6.38 13.6 47 11.70 7 1 92 0 0 0 3.4, 73982 m 6.35 13.9 42 8.67 10 0 90 0 0 0 3.7 73983 m 6.87 15.3 45 9.32 8' 0 91 0 1 0 3.5 73984 m 7.4,0 14.8 44 @.47 13 0 94 1 2 0 3.1- 739e5 %1 6.53 13.8 41 8.40 9 0 90 0 C. B.S 1.tear. 6.31 14.7 141, 9.11 9 0 90 V^ - 0 3.6 '!3986 F 6.96 15.0 45 9.63 9 0 85 3 3 0 '-.7 13967 F 6.44 14.0 43 8.34 7 0 92 1 0 73988 7.08 14.9 45 7.55 a i 83 73989 F 6.77 15.16 45 8.95 14 0 85 i 0 0 73990 :)iad Mean 6.81 14.8 45 8.62 10 0 87 z 1 0 :.o FM-3422 41-2700-3422-0: TABLE 9. MALES: Ninety Day Subacute Rat Toxicity Study. a Means and Significance of Biochemical Values. Biochemistry Study Month Control 30 ppm 100 ppm Glucose, mg/100 ml B.U.N.9 mg/100 ml y-G.T.P., Sigma units/ml b C.P.K. Sigma units/ml Alkaline Phos., int'l units/1 P.G.O.T., int'l units/1 P.G.P.T., int'l units/1 Calcium, meq/liter Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 74 100 126 14.2 14.6 16.3 1 1 0 25 20 9 172 126 133 109 104 113 50 40 10.2 9.0 11.4 62 101 123 14.0 21.6 15.2 2 5 6* 16 11 5* 216 170 112 83 107 140 74 42 66 7.5 9.7 10.9 82 107 120 12.7 14.5 18.8 6 1 0 5 9 10 179 148 116 101 101 95 41 40 10.7 8.6 11.0 Page 27 300 ppm 76 98 119 12.6 19.3 22.7** 1 7 0 10 13 9 128 214** 112 98 93 95 61 116* 9.7 8.4 11.2 137-086 a Statistical analyses not conducted on the pretest values. b C.P.K. - Creatinine phosphokinase *Significantly different from Control group mean, p<0.05. **Significantly different from Control group mean, p<0.01. FM-3422 41-2700-3422-0: TABLE 9. Cont. FEMALES: Ninety Day Subacute Rat Toxicity Study. Means and a Significance of Biochemical Values. Biochemistry Study Month Control 30 ppm 100 ppm Glucose, mg/100 mi B.U.N., mg/100 ml y-G.T.P., Sigma units/ml b C.P.K. Sigma units/ml Alkaline Phos., int'l units/1 P.G.O.T., int'l units/1 P.G.P.T., int'l units/1 Calcium, meq/liter Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 89 118 128 16.9 15.6 18.2 1 1 1 6 8 7 + 91 69 114 91 101 103 41 28 9.8 8.9 11.3 67 109 132 12.9 16.7 17.2 1 2** 1 13 15 10 140 116 82 88 121 98 68 49 32 7.7 10.0 11.2 89 109 115 15.5 16.9 20.6 1 0 1 6 10 6 + 83 68 115 79 85* 97 39 33 9.7 8.7 11.2 Page 28 300 ppm 97 108 108* 13.3 28.9 21.2 1 1 2 5 13 9 + 249** 148 106 196 115 95 160 83 9.6 9.0 11.4 137-086 a Statistical analyses not conducted on pretest values. b C.P.K. - Creatinine phosphokinase + - Not measured due to anticoagulant interference. *Significantly different from Control group mean, p<0.05. **Significantlydifferent from Control group mean, p<0.01. F.4-342241-2700-3422-0: TABLE 10- Group, Rat I,qumber Sax Glucose mg/100 al Iinecy Day Subacute Rat Toxicity Study. Individual Biochemical Values Pretest. B.U.N. mg/100 ml y-G.T.P. sigma uuits/mi C.P.K.* Sig= units/al Alk. Phos. int'l units/ml control: 73961 m 75 12.0 2 73962 m 75 15.3 1 73963 m 69 13.8 1 73964 m 75 18.0 0 73965 m 75 12.0 1 mean 74 14.2 1 73966 F 90 18.3 1 73967 F 87 16.2 1 73968 F 105 18.0 1 73969 F 90 17.7 1 73970 p 75 14.4 1 Mean 89 16.9 1 30 ppa: 76231 m 75 16.2 2 76232 m 51 11.7 1 76233 m 66 12.3 2 76234 m 72 15.0 2 76235 m 45 15.0 1 4ean 62 14.0 2 76236 F 57 15.0 1 76237 r 66 13.5 2 76238 p 87 15.0 1 76239 r 63 9.6 1 76240 F 60 11.4 1 Mean 67 12.9 1 100 opm: 73971 m 72 11.4 1 73972 x 90' 12.3 1 73973 x 75 12.0 0 73974 m 90 15.3 1 7391@5 x 81 12.3 25 Xean 82 12.7 6 73976 F 99 19.2 2 73977 F 90 16.5 2 73978 F 87 13.5 1 73979 F 84 13.2 1 73980 F 87 15.0 1 Mean 89 15.5 1 300 cam: 73981 x 81 10.5 1 73982 m 66 12.0 1 73983 M 87 14.7 1 73984 m 72 13,8 1 73985 m 75 12.0 1 YA= 76 12.6 1 73986 p 99 12.0 0 73987 F. 81 15.6 2 73988 p 105 15.0 2 73989 F 93 12.0 1 73990 F 105 12.0 1 Mean 97 13.3 1 5 12 69 3 35 25 5 15 3 3 3 6 L5 288 24 141 20 246 14 225 8 180 16 216 a 138 5 147 6 171 25 ill 19 132 13 140 4 4 3 3 10 5 7 4 6 7 8 6 7 22 3 17 10 4 6 5 4 5 5 P.G.O.T. int'l units/al P.G.P.T. int'l units/ml 105 144 171 96 147 133 96 120 117 117 120 114 93 84 87 84 66 83 108 78 90 el 84 88 105 132 102 99 144 116 117 105 120 120 ill 115 ill 147 105 93 102 112 90 120 120 93 108 106 90 117 174 93 93 113 120 105 114 87 90 103 81 72 75 al 60 74 81 66 60 60 72 68 87 102 84 90 ill 95 99 90 96 108 90 97 90 105 90 99 90 95 90 93 96 102 93 95 Page 29 Calcium meq/ liter 10.2 10.8 10.1 10.2 9.8 10.2 10.2 10.0 9.5 10.0 9.5 9.8 8.3 5.8 7.4 7.9 8.1 7.5 8.1 7.1 7.6 7.4 8.5 7.7 9.9 9.8 10.1 10.2 13.7 10.7 9.4 10.1 9.5 9.8 9.7 9.7 9.5 9.5 10.1 9.4 10.2 9.7 9.2 9.9 10.1 9.6 9.4 9.6 137-086 *Creatinint phosphokinase **.41kalinephosphatase not measured due co ancicoagulant F.4-3422 41-2700-3422-0: TABLE 10. Cont. Groups Rat Glucose Number Sax mg/100 ml 1,000 opm: 73991 m 73992 m 73993 x 73994 m 73995 m Mean 73996 F 73997 r 73998 F 73999 F 74000 p .lean 3,000 ppa: 74001 m 74002 m 74003 x 74004 m 74005 m '40an 74006 F 74007 F 74008 F 74009 F 74010 Mean 10,000 Pam: 74011 m 71-012 x 74013 %1 74014 m 74013 m %lean 74016 F 71-017 F 74018 p 74019 F 74020 F kan 99 93 81 72 102 89 87 117 105 93 93 99 78 78 75 87 87 81 99 102 87 93 102 97 78 78 96 81 84 83 84 105 90 78 90 89 Ninety Day Subacute Rat Toxicity Study. Individual Biochamir-al Values Pretest. B.U.N. mg/100 mi t-G.T.P. Sigma units/al C.F.K.* Sigma units/ml klk. Phos. int'l units/al 9.0 1 11 17.7 1 10 13.8 1 8 12.0 1 30 18.0 1 10 14.1 1 14 16.2 1 11 12.0 1 5 18.0 1 6 12.0 1 11 12.0 1 7 14.0 1 12.0 1 12.9 1 4 12.0 1 7 17.4 2 7 10.2 1 15 12.9 1 8 15.0 1 5 15.0 2 18 15.0 1 8 15.3 2 13 18.0 1 7 15.7 1 10 16.5 2 5 14.7 1 8 14.7 1 8 15.3 1 5 14.7 2 8 15.2 1 7 15.3 1 12 15.0 0 7 17.7 1 9 15.3 1 10 15.3 2 15 15.7 1 11 P.G.O.T. int'l units/ml 123 135 114 123 114 122 ill 75 105 120 117 106 96 108 132 123 90 110 102 108 93 ill 90 101 105 126 120 90 108 110 120 108 105 105 126 113 Page 30 P.G.P.T. int'l units/ml Calcium maq/ liter 90 99 90 108 90 95 90 78 93 78 96 87 120 93 90 102 102 101 102 135 90 114 117 112 126 93 153 96 90 112 135 114 120 102 159 lj6 9.7 10.3 9.7 10.3 10.0 10.0 10.1 9.6 9.6 10.0 9.3 9.7 10.0 10.2 9.5 9.9 9.8 9.9 9.7 9.8 10.1 9.7 10.3 9.9 10.2 10.0 10.2 9.7 9.9 10.0 9.3 9.8 9.7 10.1 10.5 9.9 137-096 *Creatinine phosphokinage **Alkaline phosphataso not measured due co anticoagulant FM-342241-2700-3422-0: TABLE 11. Group. R&t Glucose Number Sex mg/100 ml Ninety Day Subacute Rat Toxicity Study. Individual Biochanic&l V&luts 1 .4onch. B.U.N. =a/loo ml Y-G.T.P. Sigma units/al C.P.K.* Sig= units/al Alk. Phos. intli units/mi Control: 73961 x 96 11.7 1 73962 %1 102 18.0 0 73963 m 96 14.7 1 73964 x 108 16.8 0 73965 m 99 12.0 1 %lean 100 14.6 1 73966 F 120 15.0 1 73967 F 120 18.3 0 73968 F 132 17.7 1 73969 F 114 15.3 1 73970 F 105 11.7 1 Mean 118 15.6 1 30 ppm: 76231 m 90 14.7 2 76232 m 102 14.4 3 76233 m 108 30.9 9 76234 m 105 32.4 9 76235 m 102 15.6 2 4&an 101 21.6 5 76236 F 90 20.7 2 76237 F ill 17.4 2 76238 F 120 15.o 2 76239 F 114 16.5 2 76240 F ill 14.1 2 Mean 109 16.7 2 100 ppa: 73971 m 108 12.0 0 73972 m 105 15.0 1 73973 x 102 15.3 0 73974 m 102 14.7 1 73975 x 117 15.3 1 Xean 107 14.5 1 73976 F 120 19.8 0 73977 F 108 18.3 0 73978 F 108 14.7 0 73979 F 105 19.2 0 73180 F 102 12*3 0 Mean 109 16.9 0 300 ppm: 73981 m 102 24.3 13 73982 m 96 17.7 2 73983 .4 96 15.6 16 73984 m 93 21.0 2 73985 m 102 17.7 2 Xaan 98 19.3 7 73986 F ill 20.4 1 73987 r 105 18.0 1 73988 F 108 51.0 0 73989 F 102 18.6 1 73900 F 114 36.6 0 .4a&n 108 28.9 1 14 192 43 162 15 174 15 186 12 144 20 172 9 90 4 96 9 102 7 84 9 81 8 91 12 195 7 133 11 195 16 159 147 170 10 90 is 138 15 138 17 102 15 ill 15 116 8 132 10 213 10 162 13 192 4 195 9 179 7 48 5 96 7 93 22 108 7 72 10 83 12 168 13 78 14 135 13 144 15 117 13 ize 10 291 8 210 9 267 19 225 17 252 13 249 P.G.O.T. int'l units/m.1 93 126 ill 93 120 109 84 84 102 120 66 91 108 120 114 78 117 107 123 150 132 105 93 121 108 93 99 90 114 101 78 84 75 96 60 79 117 96 93 93 90 98 87 480 96 135 iso 196 Page 31 P.G.P.T. int'l unitsllml Calcium meq/ liter 42 8.7 51 9.4 78 9.4 36 9.5 45 8.o so 9.6 42 8.6 42 9.1 48 8.7 51 9.2 24 8.8 41 8.9 42 9.4 45 9.4 42 9.6 36 10.5 45 9.8 42 9.7 48 9.6 69 9.Z 48 9.9 42 8.8 39 12.4 49 10.0 42 8.6 48 9.3 39 8.5 36 8.9 42 7.5 41 8.6 42 8.5 48 8.4 42 8.7 30 9.2 33 8.6 39 8.7 72 8.7 57 8.0 57 7.4 63 8.6 57 9.2 61 8.4 66 8.5 360 8.8 75 9.2 147 9.1 150 9.2 160 9.0 137-066 *Creatinine phosphokinase Fm-342241-2700-3422-0: TABLE 12. Group, Rat Glucose Number Sex mg/100 al Control: 73961 m 73962 m 73963 m 73964 m 73965 m 4e&n 73966 F 73967 F 73968 F 73969 F 73970 F Mean 30 Dpm: '76231 m 76232 m 76233 m 76234 m 76235 x 4ean 76236 F 76237 F 76238 F 76Z39 F 76240 F @aan 100 ppm: 73971 M 73972 x 73973 x 73974 m 73975 m .4ean 73976 r 73977 F 73978 r 73979 F 73980 F 4aan .300 pom: 73981 m 73982 M 73983 x 73984 m 73985 m Xean 73986 F 73987 p 73988 F 73989 F 73990 F .4ean 121 124 120 139 124 126 125 131 145 132 106 128 114 120 124 125 130 123 125 125 140 130 140 132 126 114. 117 119 123 120 122 112 114 117 108 115 120 118 131 109 115 119 103 113 100 116 Died 108 Ninety Day Subacute Rat Toxicity Study. Individual Biochemical Values 3 .4onths. B.U.14. mg/100 mi y-G.T.P. Sigma units/ml C.P.K.* Sig= unitsltl A.Lk. Phoo. int'l units/ml 15.5 0 17.2 0 17.0 0 17.9 0 13.9 0 16.3 0 19.6 0 18.8 1 20.8 1 17.9 0 13.9 1 18.2 1 13.9 10 13.9 10 15.1 2 17.1 9 16.0 0 15.2 6 21.1 2 18.1 1 16.3 1 17.4 1 12.9 0 17.2 1 18.1 1 18.1 0 17.0 0 19.6 0 21.2 0 18.8 0 23.2 1 24.6 1 19.9 1 20.5 0 14.9 0 20.6 1 23.1 0 20.1 1 22.1 0 23.1 0 25.1 0 22.7 0 21.4 1 18.9 0 24.8 0 19.5 5 21.2 2 10 140 8 120 9 135 9 140 10 96 9 126 6 91 9 65 8 89 a 51 6 49 7 69 3 144 6 94 3 134 4 98 a 91 5 112 10 77 11 100 10 91 3 56 15 88 10 82 5 3.12 25 160 7 116 7 139 7 213 10 148 7 44 6 99 6 82 7 67 5 49 6 68 6 227 Li 151 a 270 10 147 9 274 9 214 9 114 11 107 11 281 5 90 9 148 Page 32 P.G.P.r. int'l units/ml P.G.O.T. intli units/ml Calcium meq/ liter 32 39 45 34 52 40 31 29 20 33 27 28 33 47 154 39 58 66 34 30 32 37 28 32 43 50 31 36 42 40 43 34 31 28 28 33 78 142 89 204 68 116 50 46 166 69 83 82 106 L20 81 133 104 94 90 101 110 110 101 85 106 299 91 118 140 95 128 102 96 69 98 100 104 88 96 118 101 92 83 90 88 72 85 81 103 92 119 72 93 91 89 184 95 115 11.6 11.2 11.3 11.9 10.9 11.4 11.1 11.0 11.9 11.6 10.8 11.3 10.6 10.2 11.3 11.5 11.0 10.9 11.2 11.1 11.5 10.8 11.4 11.2 10.6 10.7 11.5 11.3 10.8 11.0 10.8 10.6 11.9 11.8 10.9 11.2 10.8 11.1 11.0 11.9 11.0 11.2 11.3 11.3 11.0 12.1 11.4 137-086 *Creacinine phosphokinase F*-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 13. a MALES: Means and Significance of Urinalysis Values. Urinalysis Study Mouth Control 30 ppm 100 ppm Volume, mi PH Specific Gravity Pretest 1 3 Pretest 1 3 Pretest 1 3 3.8 5.9 5.2 7.1 6.7 6.9 1.032 1.050 1.047 6.2 1.7** 3.7 7.0 6.5 6.3 1.036 1.076* 1.057 5.4 5.0 6.6 7.4 6.9 6.6 1.032 1.050 1.051 Page 33 300 ppm 4.7 4.3 6.8 7.3 5.9 6.1* 1.031 1.067 1.045 137-086 a Statistical analyses not conducted on pretest values. *Significantly different from Control group mean, p<0.05. **Significantly different from Control group mean, p<0.01. FM-3422 41-2700-3422-0:. TABLE 13. Cont. FEMALES: Ninety Day Subacute Rat Toxicity Study. a Means and Significance of Urinalysis Values. Urinalysis Study Month Control 30 ppm 100 ppm Volume, mi pH Specific Gravity Pretest 1 3 Pretest 1 3 Pretest 1 3 3.4 2.9 2.0 7.0 5.8 6.3 1.031 1.057 1.071 4.2 1.2 1.1 6.9 7.3** 6.8 1.037 1.065 1.084 1.8 2.8 3.8 6.9 6.3 6.4 1.036 1.060 1.044 Page 34 300 ppm 4.1 4.4 3.9 7.0 6.4 6.3 1.027 1.046 1.043 137-086 a Statistical analyses not conducted on pratest values. *Significantly different from Control group mean, p<0.05. **Significantly different from Control group mean, p<0.01. Ito. Nigic-t1y).iy K;ltTd)Xlt.-ISltyaltly. laielividlto;lilrloijilytilVriilii4,ti ViaIliam- iiii.1 tx Aielottrji Sibee. rtiI it1 If- blif- itil (:riov. Prot c Iit cutie risl)iit Kilkltl Ko- lattit!tt- Frytllro- Vpl Anwir. 1'r11-11- (:iIt. eyilm cyti-to (:0 1 In ttrat t-m lllitili. Ox. 7 '110(11 7.1 1.043 N N N - 1*11)112 5---1 7.7 1.028 N n N I N - i slil.'l 11 2.fi 1.4i-(: 6.8 1.034 N u N N N - 7'11)filo ti 6.11 I.S-t: 6.7 1.026 N N N tr I illl.5 ti 5.(l 8-4-1 7.0 1.031 N N tr F 1.() 1.8-(: 7.6 1.022 N N N Lr r 1.(1 1.8-(: 6.9 1.034 N N I II)flm F 1).(1 6.9 1.024 N N N N r 2.5 7.2 1.(136 N N N tr N F 1.5 6.5 1.037 N N N m N - 7.0 1.4-(: 7.3 1.034 N N N tr N - 5.() 1.4-(: 6.6 1.037 N N N k N ?1 6.4) 8-..l 7.4 1.1)35 N N N I+ N 1412'116 @l 1. 4) 8-4-1 7.0 1.042 N N N tr N 19.2l'i I.S-i-l 6.9 1.031 N N N tr N 7(12'111 s-(: 6.7 i.ola N N I'#. N 1-%-(: b.S 1.048 N N N N S-471 7.1 1 .04(1 N n N 1.1 N 7.1 1.()27 N N N N 7.1 1.014 N N N N Ilifif ti 2.41 N-l' 6.9 1.04H N N N N i ti 6.4) "-I: 1.0 1.029 N N N N N ti ($.(1 118-4-1 0.1 1.1127 N N tr N ti B.Ii I's-1: 6.9 1.1126 N N N N S-4:1 7.9 1 .4)'14) N N 4'r N 7 1')/11 8-1: 6.8 1 .(Y,2 N N Is+ N 11)/H F N n N r N 1.8-(: 1-.4 1.036 N N 1.8-(: 6.5 1.026 N N N N N F 1.11 li.%-.1- 8.2 1.038 N N ($cc 1-3 - 1-3 I)CC ipee tbi!t: 4@4!t! 1-3 tire 41.*t* 1-3 4)Ct! r F r oce lit-(, IDCC F Oct. r Oct! oce occ tire oce F 4)Cd414-C p 4)CC live ore p glee oce 414.4, fied. I)CP iset- 04!4- F Oct. litit- d)c4, :::,*c 0 - .Cc F - face p lbet, r p F r F :::,e Hi r;lw To.jir4. 14) all litist 1.8 1.11-.IlSttriow 21 8111-111t4imul4li-ritit. 1).; litio-%ktiiiw If tbo4ii-ritit- lAm 1.1rlit Aolb4!r 41 I)An liiii-Akml,4-i- (:Istoitly 4!itr NI? 1.1-iIiI Va. llt-w 1. 1AD;kili.il H FLoily R Rilr.. st-i-it Pfl-1422 1.1-27110-'1422-0: HinL-ty I)ay StsbactiteRiotTcvxicit.ySttitly. 14. lostlividiontilvietalysinVnialem- 1'reletit. (:@flair Rif volinuf ilimi Sl)ttc. Tiptal Btil- 04-t!iittKe- lansen- Erytliro- Ei)i. Amor. w[ Al-lvt-iir. pli 4.rav. Preitelis come raibln Blood t4blit!nI!Yien cyten Cut In UrateR Trilile (.*iil. Pimps. ox. 731)81 4.0 I.S-cj 6.5 1.033 N N N N 711)82 11 5.0 N-C 7.5 1.035 N N 7 llld'i ti 2.() I-q-1: 6.6 1.035 R N N N 7'11)84 N 6.0 I.S-(: 7.0 1.010 u N N 7198,i to 6.% 1.8-C 8.5 1.024 N N N N 7'14)8(@ F 5.() S-c 1 7.9 1.027 N u 3+ F 1.11 1.4-(, 6.5 1.034 N N r %.() I.S-(: 6.9 1.023 N N v 1.5 1.11-C 6.9 1.029 N N N 2+ F 4.0 I-q-(: 7.0 1.023 N N N N - - N- u - m - N - N - N - N - N - fiec - 1-3 oce oce - fiec - oce oce occ - flee - oce 1-3 p - p - occ oce oce v oer - ()cc - 7'19411 3. 11 I.S-C 7.2 1.026 N N N tr 7191)2 N 6.0 1.8-(: 7.0 1.026 N N tr 73993 H 4.o I.S-(: 7.0 1.028 N N N tr N' - ace oce occ F oce nec 7*1994 ti 3.5 I.S-C 7.1 1.035 N N u 7 31)9 r, to 8.0 1.4-(: 7.7 1.027 N N ii - occ occ p N occ ace v 731)1)6 p 1.0 1.5-(: 7.8 1.031 N tr " occ - 7'11)97 p 2.0 1.9-cl 8.2 ' 1.030 N N N 1+ 3-5 1-3 ace acc - 714198 F 4.5 $-(: 7.0 1.012 N H N 1+ - 1-3 occ F N 119,19 r 1.() I-S-C 6.2 1.074 u m N N ace oce oce oce 744)4)0 r 2.5 I.S-C 6.9 1.027 ace occ 74(Xll ti 6.5 I.S-(; 7.0 1.029 N N N 74fN)2 H 4.() ls-c 7.0 I.OIS N N k N 7411(il H 1.11 8-(: 7.0 1.041 N N u N 74(H)4 m fi.11 lq-(; 7.0 1.03t N N N N 74(Nl$ pi 8.41 1.4-C 7.5 1.025 N N N N 144111(1 v i.11 s-t: 7.1) J.044 N N u N 141)(17 p 1.4) I)S-41! 8.0 1.()411 N N 3+ N 741111" v 6.0 1.4-4: 6.8 1.4)28 N N N 1410)-) r 2.1) 1).%-$1: 7.9 1.036 N N N 2+ N r 1.41 It;-(: 8.1 1.024 N N N i.r dice - I)CC 1-3 1-3 4sec - oce - occ occ - occ r - occ r - occ oce - r p - r r - oce F - v noll* - F r (4641e: ir If21 11 41 %1 lklit to ikpderiste t&o.l.-rztte ";irki-.1 1.8 11.1. lAm I)Am - I riow $I 1-iow It-irkSt riiw 0.1ilitAndit-i I)iirkAwlto!o- N - NeKat lvep - vttw 1. t.0161414-41 0 @lity R -,U;irt- dit-C - ()4:4-;Itilititill Nont. necii Ftl-'142241-27(XI-3422-4): Ninety Day Subacute Rat Toxicity Study. 14. ('atitt. Individual Uriiialysin Values - Pretest. (;rloiil). Rikt vo I time ol CADIor notil Alilicar. Spec. lill Grav. Total Protein Clis- Bill- Ocessit Ke- Letico- Brytliro- Kiii. cittie rubles Olcmd tooles cytes cytes Celle Amir. Dreten Triple (:at. Plion. Ox. 741111 5.0 IXD-C 7.(l 1.026 N N N 744)12 H 1.41 O-el 6.5 1.046 N N N N N - 14ol 'I H 2.0 $-(: 6.5 1.044 N N N 1+ N - 741114 n 7.() 6.9 1.028 N N N N n - ?/fill I ti 5.5 I.S-(: 7.0 1.033 N N m tr N - 741116 r 0.5 S-et 7.1. J.041 N N N 2+ - 1401? r 2.11 I.S-(: 6.2 1.018 N N N N N - 741118 r 2.0 I.S-C 6.2 1.044 N N N N - 741119 r 3.0 I.S-cl 6.8 1.035 N tr - 14(12(1 r 2.11 1.6-C 6.1 1.038 N N N - ()CC tocc 1-2 - 1-3 - oce 1-3 - oce p 1-3 v occ - ace m - ace IF - r p - ace p - oce occ - oce p - 4)CC F - occ p I'll-illit. IL@: ir - Triii-i- It - too 41 igiii 21 - Si ll;iitto) MHII!riott! :11- t4,fli-ti!rjol 41 - His ki-ol N - Straw 1-1;- I.IplllSerilw 1).% - IL-orkStraw lAw - 1.11%liiAmli4,r I)Am - I)iirkAtolit@r ..I (:Iflllcly N - Ntil-t,IiviLV - Ft-w 1. - latitili-ti N - H;lliy R - Rare t&)Iie Reen P'tl-'1424'1P-27(KI-1422-Ot Ninety nay Stibacute Rat Toxicity I;tiicly. VoiliscH- I Aiiiiii. Riot Hismi-itr St@x CAii4or Vt)lilaL. nivil mi Alipt-air. pit Spec. Crov. Total ('III- silt- Ocetelt Ko- letteo- EryLiert)-Viii. Amir. Protein etime reiiiinBii)i)tlttioun cyten cyted Celits Urates Triple ('iil. Plw)a. O)x. 71961 ti 8.11 S-c 1 7.2 1.045 N N N 1+ N 7'1962 ti 5.5 S-c 1 6.0 11.045 N N tr 7'1963 7.0 I)q-c1 7.5 1.045 N N I+ N 711)64 m 5.0 S-el 6.() 1.050 N N N tr N 7 19(o't 4.() n$-c 1 7.0 1.065 N N N 1.#. N 719(lb p 3.0 S-(. 6.0 1.055 N n N N 11967 v 1.5 8-C 5.5 1.080 N N N N 7'1968 r 2.11 S-(, 5.7 1.073 N N N N 7'1')f.1) v 4.0 8-C 6.0 t.040 N n N N 1'1970 r 4.0 S-el 6.0 1.038 N N N N N N N N - - oce - oce oce - oce - - occ 1-3 occ acc 1-3 occ oce oce - occ - oce oce - oce occ - oce p F F r p F r m H lice 76231 ti I.o IS-el 6.0 1.094 N N N N N - - 762:12 2.() Is-cl 6.3 1.084 N N N N N - R 1623's H 2.0 I)S-cl 7.0 1.072 N N N tr N - R 76234 2.0 15-cl 6.3 1.074 N N N N N - 7623'1 N 1.5 1)9-cl 7.1. 1.056 N N N N N - 762'lb r 0.() 7b2,l/ F (1.0 76111'1" p /6219 p 1.5 IS-el 6.9 1.070 I.S lis-4..l 8.0 t.076 N N N N tr N R 2+ N 0(*C 762411 p 3.0 S-4.1 7.0 1.050 N N N N N occ R - R - - R R R it occ it R li-illit. ir - Tr;et:u It - Tr.-i4-liottmilglit 21 - 1.1iniffit)widitrolle '11- Kwit-riett@ 4t - K-ii-keti 8 - Straw 1.8 - l.ii-lSitraw II.Ii- litorkStraw lAw - I.IKlotAWv(ir I)Aa- 1):erkAwlot!o, N - Negative F - Vi-w 1. - IAIII41041 Hit - Hilloy - R.Orl04-4-111;ltiil;ii f) Seen P'ti1-422 41-2700-'1422-0: .......... flinetyI)ay StilinctitkeiltTOXICILY SL&idy. lisdividitaIllrinalynisValties- I lfiiistit. C:i)lipr Ris I Vo Ilimf. ititel Spec. Total alte- bill- Orcilit Ku- l.eAjcf)g-rytitro- Bill. Amnr. Trjple ('al. Ni-x ml Alilit-itr. iiii (,rnv. Protelik cose risivin hicko)d tones cytes CyLen Celle tiraten Pli4its. Ox. /1971 3. It PS-el 7.0 t.065 N N - 714172 6.0 S-f: 8.2 t.050 N tv N - 73117'1 It 7.5 8-4.1 6.3 1.035 N N N N - 11914 5.(l S-(: 7.0 1.045 N N - 7'14)/S 3.5 S-el 6.2 1.055 N N N 0 N - 13916 v 2.0 8-C 6.2 1.075 N N 73917 p 2.() S-(: 6.2 1.080 m N N I't'17B v 3.5 9-C 6.0 1.050 N N 1*11179 F 3.() 1)4-ci 7.0 1.055 N N N N 3.5 B-C 6.2 1.040 N N N N - N - N - N - n - 73981 ti 3.5 S-el S.5 1.090 N N N 7'19112 H 2.0 S-el 6.0 1.080 N N N 711)81 2.5 B-t: 1 5.0 1.0fis N N 711)84 ?1 8.5 9-1-1 6.2 1.040 N N N N 731)ni 5.() 8)8-c.1 7.0 1.058 N N N 11981, F 4.o S-cl 7.2 1.04f) N r 1.() 8-(: 6.0 1.0fiO N N F 5.() 6.8 1.036 u N N it-pill) v I 6.7 1.031 u N N S-C 5.5 J.065 N N N 2+ - 1+ - 2+ - N - N - - - - - N - oce - Dec acc 1-3 occ oce occ oce oce oce - - (DCC OCC oce 1-3 occ - oce Dee occ - DC.C Dec p ace r Dec oce acc oce occ - oce occ p oce r occ oce oce Oct ove oce Gore occ 1-3 oce Dec. coce C)CC v r F occ m F occ - occ - oce - tice - r F F N - v - r - ace - oce - 8 - Striow I -,II .lot I..% - S114sw %liltiolOil mmis-ritio- I).% - I)ierkSi ritw liam I.Ii-,IeAimlit-r 40 tiisrk,-.1 IlAw I)iii-kAiml)i-#- 14 - No-l%;iIvf,p - P.-W 1. it plitily R R.Do-i- 00,otsttiliiii.1I t4o-4-it PH-*1422 41-2/iNl-:1422-0: Ninety I)aySullactiteRat TOX14:ity Stsitly. I'A$I.V 16. IndivititialtirtioalysinValuen - 3 Montlon. Rill Ntliolig.r%I!x VtoItwo mi 4:4)lor notti Alipeiir. Spec. pil Crav. Ttital ProLeJit etiou Bill- oct!tllt Ko- riobles 814-ad toeten lattit:o- Krytlero- cytes cytes Bpi. Cells Amor. Urates Triple Plion. (;a). Ox. (:ctsirtoil: 11961 6.11 6.9 1.018 N N N tr N - 119ts2 S.o lkq-6.1 7.8 1.050 N N N 2+ N - I 19(DI 114)64 ti 4.4) I.S-t* 6.5 1.048 pi 6.5 lq-(, 6.2 1.046 N m N N - N tr - 711)6'i 4.S 8-(: 6.9 1.053 N N tr N - I'l,166 v 1.0 us-el 7.3 1.088 tr N N 2-@ N - 1,141by F 1.0 S-C fi.0 1.094 N N u N x - 1,19too p 4.5 I.S-C S.9 1.040 N tv 1'1969 r 1.5 lq-c 6.0 1.062 N N N N - 7*14)711 p 0.0 occ oce 1-3 oce ace are ace - ace p itcc - r IF - r F - r p - oce m p - F oce r - oce occ F - 76231 ?1 71)212 N 76211 N 762'14 ti 7fi235 762'16 r 762'17 p 7(12IR r 7fiZ'19 r 1624(1 V 5.() S.1) 2.5 3.0 3.() 1.0 1.11 I).u 1.() I.s lq-c S-el S-C S-el S-el ls-c lis-4.1 3-c!i 6.0 fi.0 6.0 6.8 6.8 1.040 I.OSS 1.072 1.052 1.065 6.3. 5.1 1.094 1.088 8.0 7.3 1.084 t.070 N N N N N N m N N m N 1+ N x N N N N N N N N. N tr 2+ 9 N N - N - - N - - N - N - N - N - oce 1-3 1-3 occ 1-3 ace 1-3 occ oce occ ace occ 1-3 oce oce occ F F - r oce - r occ - r p - r m r p - v m - p N - 4:4.414!: ir - 1'riko,tl@ - Tral-4. tdl alislit 2@ - .1,11plit too widerate 'I# - ths,li!rjtie 4-1-- tl;bo-kq-tl S I-q Iiq IA* I)Am el %I rtw I.Igiat Striow lkei,k Striow I.Igist Aadser ltatrk Awlier C:14itidy Cleger NV1. Hk- Nt!ga i Ive Ft-w lAtiodtt4i FUsity Rare 0 Seen FN-lls22 /sl-27(X)-1422-11: TAIII.F1.6. (:4)oit. Ninety ljikyStilincestRoaL T4vxlclty Stakly. lndividienitiriiialyniVualties 3 Mmills. Rag Nolial.c.1- so!x VtlIliam- liff4i al Alvioi-;Ir. pol ....... ...... Spot!. Total Grov. Protein f:lu- Bill- (ILeglitKe-, Letwo- grytlirciK-iii. Amir. come reibin blo4oil tones cyten cyles COIIS UFBteS Trilile (:al PIK)R. I)x. 11911 5.1) 1)3-el 6.9 1.058 N N a N 7'11)72 4.0 S-el 6.0 1.074 Na N N N 711?)'1 if 11.41 Is-(: 6.1 1.039 N N N 1'1914 n 7.0 I)S-c.1 6.9 1.044 tr N N 7'197% Pi 6.0 S-cl 7.0 1.041 N N N a- N - N - 714)76 r 1).(1 7'1977 r 2.0 IJS-ci 6.1 1.057 N N N Na - 77"'11917)978 vr <40..s5 118-cl 67..50 11..003486 Na NN Nm N2+ a -- 7'1980 v 5.0 lq-(: 6.0 1.036 N N N N N - ")(al)ti)*: 73981 71902 7.5 S-C 5.9 1.043 N N a N 5.5 IA-el 6.0 1.045 a N N N /]Ojai ?1 6.0 S-4-1 6.1 1.051 0 N N N 71904 H 6.0 B-C 6.0 1.043 N a N N I'llini m 9.0 6.3 I.IMZ N N - m - N - 2+ - H. - 2.() S-C 7.0, 1.056 N N a- 711187 r 2.5 8-C 5.8 1.058 N N 21- N - 71988 v 5.11 S-C 6.2 1.033 N N N a a k- 739H9 r 6.() lq-c 6.1 4.026 N 7'1994) I)Itlll tice - 1-3 - - oce ace face r r oce r r v ace ace F bee - F oce r occ oce p ace ace p acc p 4)CC acc oce lice Occ F r oce F N oce oce v arc occ r acc ticc 4:4tdc tr - Triti-d- ii - rrn4..4.tit mi iglit 2# - !*.Ilgioi t4i ommltirate 'll- Phstiet-ilte 41 - thorki-41 8 - $I r;lw l.% - I.IKiit Hiriow Its 1)46lk Strisw lAs ItAm i:l 1; I.IKIitAinlit-r I)ioe-Akmlii,r y Nt-go tIVa. r - VL.W I. - 14ijecled H - H;lliy R - kitrtt 0 Sc-en FH-3422 41-2700-3422-Ot TABLE 17. Site Lesion Number necropoled No groan lesions External red-brown material. eyes/nome/mouth emaciation Incompletefracture, femr yellow material, anogenital region Lungs congestion red foci gray/yellow/whitefoci Liver congestion adhesions accentuated lobulations brown discoloration gray/yellow/whiteareas enlarged yellow mottling red foci Stomach ltyperemia/congastion.=coma red foci/brown areas/hemorrhages brown-red mocoid contents Spleen pole Hementeric Lymph Modes dark red Small Intestine red/black/brown contents Adrenals dark red Kidneys hydronephroxis brown discoloration 137-086 Ninety Day Subacute Rat Toxicity Study. Summary of Necropsy Observations, Terminal Sacrifice and Deaths. Control -Y Terminal Sacrifice 30 ppm F 100 PPE mF 300 ppm NF 300 ppa F 55 55 55 53 2* 35 2 '4 5 1 00 0 1,000 ppa HF 55 00 1 1 3 2 I 14 1 21 2 I 1 2 I 2 22 53 53 5 1 1 11 I 1 13 I I *Died after blood collection. 22 FH-3422 41-270G-3422-0: TABLE 17. Cont. Site Lesion Uterus hydrometra Testes small Ninety Day Subacute Rat Toxicity Study. Summary of Necropsy Observations, Terminal Sacrifice and Deaths. Control Terminal Sacrifice 30 pps r 100 ppe N r 300 ppa m F 300 ppm H F D 1,000 ppa m F 2 137-086 *Died after blood collection. P'ti-34224i-27(XI-3422-Ot Niowty Day Subacute Rat Toxicity Study. TANI.@. 18. Alsoolute (Grams) and Relative (2 Body Weigilt)Organ W*Igltto.Terminal Sacrifice. Body Wt. --- 51,ILI@tal- I,Lver Sex 9 9 Kidneys Brain Adrennis p mg 484 (1.82 0.17 17.51 3.61 270 -O.fiz 0.23 11.48 4.21 3.75 2.36 0.11 0.88 2.19 1.99 0.45 0.74 fil 1.27 24 77 2.88 21 N 439 0.75 0.18 18.24 4.30 3.66 0.86 2.29 0.55 63 1.46 26 p 257 0.60 0.23 10.59 4.14 2.46 0.96 2.08 0.81 80 3.12 22 462 1).82 0.17 24.89&6 5.37hit 4.24 0.91* 2.22 0.48 55 1.19 30 r 237 ().52 0.22 11.67 5.()0 2.15 0.92 1.90 0.82 75 3.17 20 Ft 372 O.fia 0.18 31.52** 8.51** 4.73 1.30 2.17 0.59* 76 2.11 27 208 1).47 0.22 15.01 7.22* 1.99 0.96 2.04 0.98* 73 3.52 17 ('.I*totsgup@not relsitive oritan weigisto milogwitlot filit.filitit-Wt-14*:;igistfIt-itittdliyfferent from catistrolgrinip **Signiitt:atitltyilfferttnftrim control grtitswiesiiii..<(1.01. liveriil%iltliltts-ltielivititizilly Ftf-'142241-27(K)-3422-0: - ------------ TAKI.F 19. Rilt M41. Sex lkuly Wt. 74961 H 71962 H 7'1963 m 73964 m 739fis H 73966 F 73,167 r 7396A r 73969 v 7197() v .I(kpl!m: 76211 H 7fi232 H 762'13 m 7fi234 N 76235 lfb2,lfi F 16217 f 762')R p 7fi2)9 v 7624(1 p !!IfP)ite; 719/1 7'1972 H ?1973 7'1974 H 73975 H 711176 r 71911 F 1*11)7R p I'll7)9 p 1110 lil!n; /'Iliml H 714)112 7'11)Hi H 7'14)84 7'198'i 459 0.82 475 0.74 470 0.94 490 0.80 526 0.69 270 0.66 304 0.81 278 0.59 253 0.66 245 0.38 496 4fil 327 438 465 2'12 257 256 253 285 0.73 0.73 0.94 0.71 0.63 0.53 0.61 0.72 0.46 0.69 516 0.98 509 0.69 422 9.72 448 - 413 0.80 244 0.77 230 0.47 250 - 214 0.47 226 0.38 392 124 )$'I 368 11)4 21Y 221 IR7 0.68 0.76 0.4n ().78 0.69 ().So 0.44 0.39 Nit iov;lilillwle Ninety Day Stibdctitkeat Toxicity Study. Individual orgaisWeigists. Liver Ki4litty!! Brain 14.72 16.71 16.50 20.06 19.54 9.42 10.51 19.88 9.42 4.18 20.76 12.60 21.11 18.96 17.85 10.4)8 10.85 9.74 10.95 it.35 29.15 24.28 22.bt 23.32 11.92 11.53 11.4t) 11.81 35.44 31. 19 28.51 11.78 3#1.44 16.64 14.ti9 I's.7 t 3.56 3.42 3.SS 3.92 3.99 2.47 2.38 2.2L 2.30 2.45 3.75 3.48 4.05 3.36 3.44 2.28 2.53 2.33 2.48 2.66 4.43 4.66 4.23 3.-63 2.62 1.93 2.05 2.00 4.47 6.77 4.12 4.13 4.18 2.15 2.4)2 2.09 2.24 2.22 2.20 2.19 2.18 1.82 1.97 1.92 2.15 2.08 2.17 2.94 2.14 2.12 2.116 1.92 2.12 2.03 2.25 2.19 2.30 2.19 2.-21 1.71 1.94 2.16 1.80 2.1)5 2.21 2.17 2.1% 2.24 l.R4 2.22 2.415 Adrenal@ 53 63 71 64 35 72 77 as so 73 65 64 63 69 53 al Be 74 66 Be 56 59 52 56 so 72 63 fig 97 75 52 132 so 68 71 73 76 70 Tityro tara-till mg Is 24 25 28 27 22 20 20 19 23 29 29 21 25 28 241 27 22 21 22 32 28 27 29 34 20 15 19 25 2(1 21 24 32 32 22 1(. 21) rc a %c o@ Oro, 31 pa in 4 ZM z cL -q-2 x as a@ 6n @R. F- a 91 SEL'D C n n OC 0 IL P4 ib fb pq to r3 2 c r n a c c -0 n .0111 *1 10 O@ r! 10 6 oc- .01 2 a a's -% Im- I rt 20 pt m o6 pt x w ow I- I- ow w w w w jo. ho 6; F4 Group. Rgtt Nu=bar Sax 73961 m 73962 x 73963 73964 73965 m 73966 F 73967 7396 F 73969 p 73970 F 762.31 It 76232 M 76233 N 76234 M 76235 m 76236 F 76237 F 76238 F 76D9 7 76240 F 73971 M 73972 M 73973 M 73974 N 73975 m 73976 F 73977 73978 73979 73980 n s 00- on go Ia Im L x 1 h& a- 61 LA 61 t4 V 73981 m 739a2 M 73983 m 73984 X A. 73985 ICZ 73986 F i 73997 p 73988* 73989 F 73990* RI-3422 41-27(XI-3422-ot TANI-E 21).(,.flat. IAIS I (all Ninety Day StsbactitoRat Toxicity Stiody. llistamorpliologic(Xvuervntions. Control )r mm3am P. I-. 9k P. k. 30 PER Z:v A x: x: su g% 'IN ok S.. xzzxz 100 PPO w gk w 1. @f c4 rt ' -n @o r- go m 0 ,p @D -0 %o @oo @o v AO %a r@ 0% th Ch 0. Ch ri fn mmm @4 c4 n A v% :3 in rn C4 fn 'D C4 C4 110,'PO@r@ %I.D- w r, so a.,o en n n 'o " " " 44 c, I0r@ Ira.1r@0 .1 110, .4 r4 en %t n r@ p@ r, P, r@ n' n' 'm n' r@ 11 r@ %a t, aro_ o@ t, I'. o@ c, 'an per Ibrcpncltii/tpter IliroitclIiolor lysplooldltyperplasia focal acciomsl*Lionof alveolar meroplieses atelectanin periveactilarlymplioldInfiltrate Interstitial Inflammatory Infiltrate Interstitial eclema fleart laical/miltifocalmonoiiuclear Infiltrate-myocardium fgocal/mmeitfiocal ti.brosto f4pcalwitterat[zatlost eyoi:ardium Aorta licantopoloole liesumideromis HL-saiitericl.yolwiMiodes eneii-enIton liemorritage tlenpnerationof cortical tlsymorytee (twiiimyclold hylverplasta e(lemn IUne salivary f;ljiolcl (#)(-iillrmittifomboii-ia(l"to@4!leI;ntfriltrate Ni 4mmicit uselimactitiIniflammatory liifiltrate feo4-alltifistarmatulrnytittrate - seroon wiltifol-al meccas&] alecrol@olof sid)met-tstilawlm)rrionge -legi!neratioaond early aiiieratizationof so"tlk MINS.le- tionicaweactilarls 1-4111nt.Inglloo- onscoval veomttls 1 2 32 2 2 22 4 32 2 3 3 2 2 2 2 2 22 2 2 2 22 23 2 442 34 23 3 233 2 2 3 24 2 43 3 2 2 3 3 3 I II 32 32 2 2 2 22 2 2222 2 I IIII II III I II 11 t1 111 1 1 1 1 1 1 1 1 2 32 23 3 I I I 1 11 1 1 332 32 2 323 2 1 11 11 11 1 1 2 2 1 1 1 11 11 11 32 II III I I I I 2 III II III t I I I I I I I 1 1. t I I I I 2 tII II I III I I IIII I III 3 I III I III 2 Code t x - ct)nditjonpresent I - not remarkable 2 - very alirlit 3 - aliglit 4 - okxlerate *died 5 - marked 6 - extreme not available Vtl-142241-27(XI-3422-fis TANI.P -01)4.:tigai. Ninety I)nyStalsocuteRat Toxicity Study. llistomorploologic Observattints. Control m X)r m W. I" w &4 #k 9. )r ;r :r X3 r. 4.14 s- su w )a xi r. r. r. w i. S. s.. A! Of I Iit - - --. m 4chth 0% z gq on 4n elt o ot ok m m dn in rb qq @4 C,4 91% -V 6n tn in ;3 N " ".a %a to @o %a %* r@ fn m #4 C4 @D w I, co a. !9 n C4 C4 C4 @D.D %D t, r% 1, H ot .0 4n P, 01 0% Ch Cn@ o@ et ri r@ t% @o@c a arllM 0. 0 ri n g. small littelitillil (4willvant!tillltinoesetitery tim:almilcoualfillrosto Larittl!iLentlio(e(:olon) llancreas focal perivascular and peridgictular lnfi.s@tory ftical/miltifocaslonanucl*sr infiltrate foctis of loylmrtropittail actuar calls fcm!iil loiterlabulac Inflammatory Infiltrate focal/wiltifocal fibrosis witio scipar stropliy f(teal fibrosis wjtlt pancreatic duct proliteratton inflitrote K141ioey focal/miltIfocal tubular regeneration aisbacl$Lleieplititis cyst 14scal acute lnfla@tory cliretaiticmpleritin infittrate canal ltilus toolpialairiapisromis tisickenitigof glomrular basement membrane wlth eosino- plilli(!protelanceous droplets toolitilaprroteinaceolim cast$ ttii)eelamrineralized del)rln in glmerular space lntracettiolar yellowisis brown pigment - tubular epitikelial Celle fietracelitilarraddialt brown i-Ilititeliatl!Clls liydrc)nupltronis ltyaline droplets - toolitilar lirliturySlitilder tim-aslkont)etiicilnefairltrate- tesitimcusscularis 2 I tII I III II II I 2 III II II II 1 II II 1 11 11 1 111 2 3 2 2 x 3 It I 2 22 2 3 x 3 I I II I 2 33 23 3 42 3 32 22 2 3 II 2 2 II 3 3 III t I III I III II I II II I III llvaIr&-a cystic oviarinn beirea focial ltiflammatory Infiltrate eyhllc corpus loiteum parn ovarian adipose tioutie I It I tt I x 2 x II I I III I xx xx III-Ila() 4;txle: x - condition present I - istitremarkrjtle 2 - very ollgl$L 4 - moderate *died 5 - marked 6 - severe not mvntlal)le t %c z alva c c 2 .9 pq 0 u 6J Group, IL&t Number Sox 73961 X 73962 73963 73964 73965 m F 73966 73967 73968 F 73969 F 73970 r 76231 m 76232 m 76233 76234 76235 76236 76237 F 76.138 r 76239 F 76240 r 73971 m 73972 m 73973 m 73974 73975 73976 73977 F 73978 r 73979 F 73980 F 73981 m 73982 73983 73984 M.11 739e5 m 739686 739 7 73988* F 73989 F i73990* z C,. IC x 01 0C,0, a .4 n 'a pr m a it. ev 05 SOL'A w -- zrw al P% 2* e3 c 0@ 0 0* n 0 0a 00 a "-SVDV n m n ei-0 m n ac 4r. a 0 a o=lb 10-10,000 P- M p@) one go alpoi 0 a m 0 10 0. I.- vl.b c0- r a b 'o o ir $I IM4 n n 00 0n n0 N 11 1".0 a" pt cr el n am Group, Rat Number Sax 73991 H 73992 N 73993 m 73994 Xx 73995 73996 73997 F 0' 0a a- 73998 a- 73999 F rv 74000 F na 74001 M 74002 N 74003 m 74004 M 74005 M 74006 F 74007 F 74008 F 74009 P 74010 F 0a a %4 74011 M 74012 M 74013 X 74014 M 74015 N a- 74016 F a 74017 F 74018 F 74019 P 74020 P