Document QkYbbB9kGa6ma5gJg0krBvLw7

A R Z 2 6 'G > Z & International Research and Development Corporation SPONSOR: COMPOUND: SUBJECT: 3M Company FM-3422 Ninety Day Subacute Rat Toxicity Study. 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., Staff Pathologist Date: November 10, 1978 137-086 001396 International Research and Development Corporation T A B L E OF C O N T E N T S I. S y n o p s i s ...................................................... Page 1 II. C o m p o u n d ...................................................... 3 III. Clinical Studies .............................................. 4 A. M e t h o d ................................................. 4 1. General Procedure..................................... 4 2. Compound Administration............................... 4 3. Observations ......................................... 5 4. Laboratory Tests ..................................... 5 m m m vo a. Hematology . . . b. Biochemistry . . c. Urinalysis . . . d. Serum Samples. . 5. Statistical Analysis ................................. 6 B. Results. .................................................. 6 1. General Behavior, Appearance and Survival............. 2. Body W e i g h t s ......................................... 6 8 3. Food Consumption..................................... 8 4. Laboratory Tests ..................................... 9 a. Hematology....................................... 9 b. Biochemistry.......................... 9 c. Urinalysis.......................................... 10 IV. Pathological Studies ......................................... 11 A. Methods............................................... 11 1. Gross Pathology................................... 11 2. Histopathology.......................................... 11 B. Results...................................................... 12 1. Gross Pathology and Organ Weights........................12 2. Histopathology.......................................... 13 137-086 001397 International Research and Development Corporation T A B L E OF C O N T E N T S (Continued) Table N o . 1. Group Mean Body Weights, Weight Ranges;and Survival , . 2. Individual Weekly Body Weights ......................... 3. Mean Food C o n s u m p t i o n ........................... , . . 4. T-test Comparison Between Means of Control and Treated Groups, Food Consumption ............................... 5. Means and Significance of HematologicalV a l u e s ......... 6- 8 . Individual Hematological Values ...................... 9. Means and Significance of Biochemical Values .......... 10-12. Individual Biochemical Values ........................ 13. Means and Significance of Urinalysis Values .......... 14-16. Individual Urinalysis Values .......................... 17. Summary of Necropsy Observations ...................... 18. Absolute and Relative Organ W e i g h t s .............. .. . 19. Individual Organ Weights ............................... 20-21. Histomorphologic Observations ........................ Page 16 17-18 19 20 21-22 23-26 27-28 29-32 33-34 35-41 42-43 44 45 46-50 137-086 001398 International Research and Development Corporation Page 1 I. 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: ema ciation, 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 (1 month) had a normal Y-GTP value at 3 months but slightly elevated plasma glu tamic 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 consump tion was depressed for the females. Laboratory values were within the expected range. 137-086 001399 International Research and Development Corporation Page 2 At the 300-ppm dosage level, an increased incidence of possibly compound-related signs was noted. Two females died after the collec tion 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 con sidered compound-related. Compound-related, microscopic, liver lesions consisting of hepatocellular hypertrophy and hyperplasia, hepatocellular vacuolation, hepatocellular necrosis 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 001400 International Research and Development Corporation Page 3 II COMPOUND The compound was received from 3M Company, Saint Paul, 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 001401 International Research and Development Corporation Page 4 111 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 lightcontrolled room. During the pretest period, rats were provided Purina Laboratory Chow and 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 Purina Laboratory Chow (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. The samples were frozen and subsequently shipped to the sponsor. Diets were prepared in the following manner: an appropriate amount of FM3422 was dissolved in 15 ml of ACS grade acetone. The resulting 137-086 001402 International Research and Development Corporation Page 5 solution was thoroughly mixed with 500 g of Purina Laboratory Chow 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: hemoglobin*, hematocrit^, total erythrocytes^, reticulocytes^ and total-* and differential leucocyte counts. b. Biochemistry: Biochemical studies included: fasting glucose^, blood urea nitrogen (BUN)^, plasma glutamic pyruvic transaminase (PGPT)^ and plasma glutamic oxalacetic transaminase activity (PGOT)^, plasma alkaline phosphatase activity^, y-glutamyl transpeptidase (y-GTP)**, creatinine phosphokinase^ and calcium**. 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, pH^ and specific gravity; qualitative tests for 137-086 001403 International Research and Development Corporation Page 6 protein^, glucose^, ketones^, bilirubin^ and occult blood^; 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 consump tion (weeks 1-13), hematological, biochemical and urinalysis parame ters 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 Torrie^^ using Dunnett's^ 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 1 month; one at 3 months) without any signs of overt toxicity having been noted. One male had an accumula tion 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 001404 International Research and Development Corporation Page 7 All rats at the 1,000-, 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 Inc. sensi- tivity Red material 1 (eyes) Red material (nose, mouth) Yellow material Pupillary dilation Excessive salivation 1 1 ' 3 1 1 6 10 48 11 35 2 1 22 2 10,000 ppm 10 10 7 1 2 Survival after 3 months of compound consumption was as follows: Treatment Group No. Surviving/No. Initiated MALE FEMALE Control 30 ppm 100 ppm 300 ppm 1,000 ppm 3,000 ppm 10,000 ppm 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 001405 International Research and Development Corporation Page 8 2. Body Weights (Tables 1-2): 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 Average Food Consumption (grams/rat/day) MALE FEMALE Control 30 ppm 100 ppm 300 ppm 27.6 27.2 27.4 24.2 19.9 19.3 18.6 15.1 137-086 001406 I International Research and Development Corporation Page 9 4. Laboratory Tests (Tables 5-16): a. Hematology: Hematological values for rats at the 30- and 100-ppm dosage levels at 1 and 3 months of study and for rats at the SOOyppm 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-GTP levels (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 signifi cantly lower (p<0.05) when compared with the control group mean. One male rat (3-month sampling) had a slightly elevated PGPT (154 units/ml) and PGOT (299 units/ml); this rat had had a slightly ele vated 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 (1 month) plasma alkaline phosphatase levels were elevated for all females (statistically signi ficant at p<0.01 when the group mean was compared with the control 137-086 001407 International Research and Development Corporation 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 001408 International Research and Development Corporation TV. PATHOLOGICAL STUDIES Page 11 A. METHODS : 1. Gross Pathology: After completion of the compound administration period, all sur viving rats were sacrificed by CO^ inhalation and necropsied. The spleen, liver, kidneys and brain were weighed and representative tissues were collected in buffered neutral 10% formalin.* 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. His topathology: Microscopic examination of fixed hematoxylin-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 mammary 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 &0 1 4 S International Research and Development Corporation Page 12 B. RESULTS: 1. Gross Pathology (Table 17) and Organ Weights (Tab l e s 18-19) : 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 lOO-.and 300-ppm groups were considered compound related with male rats more severely affected: Dosage Level Organ (ppm) Sex Weight Change P< Liver 100 M 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 P< 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 001410 International Research and Development Corporation 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 sit uated 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 in flammatory 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 Gomori's 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 associ ated proteinaceous cast formation and intracellular accumulation of brown pigment and reddish-brown hyaline droplets (protein) in tubular epi thelial 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 renal parenchyma or indirectly 137-086 001411 International Research and Development Corporation 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 examination. Lesions observed in other tissues were not considered compoundrelated but were interpreted as spontaneous in origin. 137-086 International Research and Development Corporation 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 Zg, 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 II, 6/60 Micro Methodology. 8 . Photovolt PV4, Photovolt Corporation. 9. Multistix (Ames Reagent Strips). 10. Steel, R. G. D. and Torrie, J. H. (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 001413 IM IV'. /I-2700-IA22-0 Ninety Day Siihaentc Htil T ox lefly Study. TAIII.K Week .>1 St ndv Croup Mean Body W e ig h ts, Cram a; W eight R an g es; and S u r v i v a l . Menu Hoilv U l. Cot ro i W<' l|.|it Ranges Khi v i va 1 Mr.in Body Ul . 30 ppot WH 1.1 Rangea Surv 1va 1 Mean Hiily U l. 100 i.j.1 Ut-1Kilt S u rRanges v iv a l Mt'iin Body Wt . 100 |>|ini Ut-lKlil S u rRanges iv .ll 1 .0 0 0 pim Mrim Hotly U H lilll S u r 1" . Ranges v i v a l 3 ,0 0 0 ppm Mean Body Ur 1Kill Sh i U t. Ranges v iv a l | 0 L0I}|| ppm Mean Body Weight S u lUl . Ranges vi va 1 HACKS: -i 0 >n 2SO-2HO 5/6 260- 106 6/6 1 K 1 2`I0 - 160 6/6 ;> m 110-163 4/5 1 141 102-396 5/5 4 177 160-416 5/6 S 194 186-428 5/5 f> 419 404-4 66 5/5 7 H 4t ,2ri95 414-464 4/5 442-600 5/5 67 1 464-612 5/5 in 6 7/ 460-621 5/5 11 6<)7 4 79- 619 6/5 i > M l 446-644 5/5 i i SOI 4 /4 -6 4 / 5/5 IKHAI.IKK: i un 0 :>n 2i 222211,, /, 2 II 2 1** r> 2AH h 267 7 _'< * H 21.6 ') 2HS Kl 776 1f 279 17 :k s 1 1 2HI 196-210 200-218 216-240 218-218 206-246 226-266 227-266 26 1-280 246-278 246-290 264-106 248- 108 268-106 267-118 'SH- 120 5/5 5/5 5/5 4/5 5/5 5/4 5/5 5/5 5/5 4/4 4/4 4/4 4/4 4/5 4/4 242 248 2*11 ih 165 161 197 426 414 454 4/0 480 481 Vit 491 198 200 208 225 219 226 241 266 254 261 267 271 271 270 269 219-246 240-254 282- 106 114-361 346-400 316-400 373-435 400-464 410-467 421-494 436-518 442-515 446-516 448-546 454-538 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 185-224 180-226 190-211 204-254 212-264 204-252 222-268 240-294 225-281 217-291 240-294 24 7-100 247-101 246-101 240-100 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 262 248-272 5/5 291 279-104 5/5 326 102-140 5/5 148 320-370 5/5 341 300-168 5/5 379 154-398 5/5 393 356-416 5/5 422 388-447 5/5 427 396-466 5/5 446 407-490 5/5 463 422-500 5/5 459 418-505 5/5 474 428-522 5/5 487 434-3VI 3 0 482 414-534 5/5 195 202 210 211 224 216 219 217 237 216 254 240 245 248 248* 190-204 190-210 200-220 201-218 214-210 208-222 214-225 230-242 212-242 228-247 248-262 215-252 219-252 240-260 219-254 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 261 250-272 2/7 264-288 119 308-316 321 294-348 147 128-382 351 326-189 340 102-394 371 340-426 372 346-414 389 353-436 405 372-452 393 165-430 412 381-456 414 384-445 192** 342-414 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 200 194-206 207 199-220 212 20 0-2 30 2(H) 187-214 202 164-224 202 188-219 209 186-230 222 210-218 222 212-218 219 206-233 241 210-258 222 210-240 210 212-248 211 218-248 22/** 201-241 5/5 5/5 5/5 5/5 5/5 5/5 4/5 4/5 4/5 4/5 4/5 4/5 4/5 4/5 1/5 259 270 261 226 214 201 209 190 157 157 252-262 261-276 246-282 218-243 204-220 5/5 5/5 5/5 5/5 3/5 0/5 190-214 194-224 174-206 147-168 142-168 5/5 5/5 5/5 5/5 5/5 0/5 255 279 194 204 211 149 240-278 21t1iUl --2:**1)'2 5/5 5/5 5/5 0/5 188-212 205-220 142-164 5/5 5/5 5/5 0/5 249 :(( M2 205 215 240-256 259-280 156-168 5/5 3/5 2/5 0/5 194-214 200-226 5/5 5/5 0/5 j SS #2 22 e 001414 I W MK*. *S Ign I I Ie nnl I v i l i t i i i e n l 111;11 C o n t r o l g i o u p mean, p 0 . 0 fi. * "Mj'.ni I irniii I y <11 I l<1 <`il I Ilian Con I t <*I g m t i p im.iii, |<0 . (>I . P9 OQ fD FM-3422 41-2700-3422-0: N'in e tv Day S u b acu te Rat T o x ic ity S tudy, e 17 TABLE In d iv id u al Weekly Body W eights, Grams. GRNToar.ot up, Sex - i P r e te s t0 1 2 3 4 5 6 W7eek ot'8Studv 9 10 11 12 13* C o n tro l: 7777733333999996666635214 MMMM>1 222225556840000 225649 223580106 233339001404640 333321417500 363 333334092324668 433331766661809 433332888868648 444400118480 456 444442161246482 444444445245 500 444545167642208 444456762681305 444558780359229 449986 555401450 444554987072844 7777733333999996666779680 FFFFF 212211901906406 222220111084830 222223221442600 222223112305888 222224404160648 222223524295858 222222566373622 222225577843820 222227765488460 222224674954660 230844 322606846 232227086448508 322220575957898 232221869584887 232229269528028 30 ppm: 7777766666222223333334521 MMMMM 224420 222443396 222225454540240 232229088963620 332440 333161418 433330447576048 433330583480602 443333278754233 444440610484080 444446152179200 444492474416 436 444455853188646 445453495284 473 444547693428466 445584406388 493 455438508426 476 7777766666222223333496780 FFFFF 111129899257224 121128099200686 221220090360166 222222022554034 222223135632404 222222022504682 222223244652818 222224766940004 222225552827531 222223556947941 222476460 226934 222237467070800 222234767079503 222237466043681 222236477070000 100 ppm: 7777733333999997777751423 MMMMM 222224676528868 222329780349948 333330342228080 333337644200800 333334663048860 333339959524478 444331007568856 444433404872082 446464 443209826 444444092657036 544442360926600 444455291035358 544452642125708 544 444574338546 454456342349448 7777733333999997777867980 FFFrF 211110999948400 221220100950600 222222011002800 222221100155853 224 222223218024 222222101228512 222221121275464 223442 222334700 222224334328220 222224323375854 222224565582480 222223453372750 222224544332598 222224644428900 254 222244534839 300 ppm: 7733998821 777333999888543 M MHMM 226642 222657820 222227886724846 333333100266888 323934 333241180 333336282382086 333338524399658 333330954074632 433332644865300 433331865444426 443330357826320 443331597922424 443331378627050 444335029867513 432834 443419569 444331104847280 7777733333999998888998760 FFFFF 222110009946840 222120912029300 222203400 220008 122218100974205 122261024824 204 221119981145893 2D2113928i8026ed 222213310800 222231128226 222231024363 222253438400 222221417020 222234218262 222234135880 2D22403i138ed 1.000 ppm: 77773333999999992431 73995 >MMMM1 222226566620200 222227777616031 228626 222456684 222222412203880 DD2201ii48eedd 220 DDDiiieeeddd 7777733334999909999096780 FFFFF 211220919042406 222211219044242 211109976444 ISO 111114655578588 111116446686280 DDDDD iiiiieeeee ddddd 127-0S6 Terminal 001415 FM-3422 41-2700-3422-0: TABLE 2. C ont. GR arot up, No. Sex P re te st -1 0 3 .000 ppm: 7777744444000000000051432 MMMMM 222226457428060 222226978842116 7777744444000000001078906 FFFFF 221122 221008288 222112440 220145 10.000 ppm: 7777744444000001111124153 MMMMM 222225445568000 222225866699400 7777744444000001211167890 FFFFF 221091424 221040 222221002265066 BESTCOPYAVAIlABIE g Page 18 Ninety Day Subacute Rat Toxicity Study. In d iv id u a l Weekly Body W eights, Grams. 1 2 3 4 5 6 W7 eek o f 8Study 9 10 11 12 13* 122117189046280 DDDDDiiiiieeeeeddddd 111116444448662 DDDDDiiiiieeeeeddddd D1DD156iii68eeeddd DDiieedd DDDDD iiiiieeeee ddddd 137-086 Terminal 001416 Page 19 001417 FM-3422 41-2700-3422-0: TABLE 3. Week of Study Control 8/ g/ rat kg/ day day Ninety Day Subacute Rat Toxicity Study. Mean Food Consumption 30 PP1" g/ g/ rat kg/ day day 100 PP" g/ g/ rat kg/ day day 300 ppm g/ g/ rat kg/ day day 1.000 ppm g/ g/ rat kg/ day day 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 23.3 26.1 26.9 28.1 32.0 29.9 27.2 27.3 26.9 26.9 27.0 27.5a 29.8 75.0 78.7 78.9 74.6 81.1 71.3 63.4 60.0 56.9 56.4 54.3 53.8a 59.5 26.7 28.9 27.6 23.9 27.4 26.9 25.1 25.8 27.6a 28.8 29.4 28.2 27.2C 91.9 87.4 75.6 66.0 69.0 63.2 57.9 56.8 58 *7b 59.9b 60.9 56.9 55.5C 26.3 27.4 25.2 27.6 30.9 29.8 27.2 27.7 27.1 25.3 26.6 27.3a 27.4 80.6 78.7 73.5 72.8 78.7 70.5 63.7 62.1 58.5 55.0 56.2 56.0a 56.8 25.4 25.8 26.0 24.9 24.8 27.0 24.5 24.4 24.3 22.4 23.2 25.3a 17.1 79.5 80.5 74.9 70.9 73.0 72.7 65.7 62.7 60.1 57.0 56.2 61.0a 43.7 17.3 13.6 13.8 17.8 18.6 21.0 20.5 23.7 21.4 19.4 18.9 19.7 18.0 18.8 20.63 19.7 78.9 82.4 90.8 85.6 95.7 80.3 73.9 71.8 69.2 65.5 67.5 12.t 68.8 20.6 20.8 20.7 16.3 19.3 19.5 17.1 17.9 20.4a 18.2b 21.1 18.7 19.9C 99.2 92.4 86.4 72.1 79.6 73.5 67.2 68.6 76.4a 67.2b 77.4 69.1 73.9C g ^Nine-day food consumption Five-day food consumption Six-day food consumption 17.3 18.7 19.4 18.7 21.6 20.7 20.1 17.4 19.2 15.5 18.3 19.3a 15.5 82.2 88.6 86.5 86.5 98.8 87.2 84.6 73.8 75.7 64.6 74.6 77.7a 62.6 16.2 15.7 15.5 15.4 15.7 17.6 14.9 14.9 15.2 12.5 14.1 15.8a 13.4 76.3 78.4 76.7 76.2 75.2 79.2 66.9 68.2 63.1 56.5 61.3 68.0a 59.2 9.6 7.8 11.6 65.8 60.2 64.5 50.5 50.2 73.9 3.000 PPm g/ g/ rat kg/ day day 6.1 31.5 3.8 25.3 10,000 ppm g/ g/ rat kg/ day day 0.9 5.3 FM-3422 41-2700-3422-0: Ninety Day*.-Subacute Rat Tonicity Study, TABLE 4. T-test Comparison Between Means of Control and Treated Groups, Food Consumption. Study Wek 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. 001418 FM-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 5. MALES: Means and Significance of Hematological Values. Hematology Study Month Control 30 ppm 100 ppm Erythrocytes, 106/cmm Hemoglobin, g/100 ml Hematocrit, % Leucocytes, 10^/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 1 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** 11.33 14.45** 9.11 o 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. 001419 FM-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 5. Cont. FEMALES: Means and Significance of Hematological Values. Hematology Study Month Control 30 ppm 100 ppm Erythrocytes, 10 /cmm Hemoglobin, g/100 ml Hematocrit, % Leucocytes, 10^/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 6.41 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 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 2 0 0 1 0 0 0 3.5 2.7 2.0* *Significantly different from Control group mean, p<0.05. **Significantly different from Control group mean, p<0.01. 001420 23K S T C O P A m W E ^ FM-3422 41-2700-3422-0: TABLE 6. NCRuraomt ubpe,r Sex E1c0ry^y/ttcehssraoa gg/1Hlo0e0mb ionml Ninety Day Subacute Rat Toxicity Study. Individual H em atological Values - P re te st. HceSmr iatto- 1e0L3ve/tucecasom- SNe ge.u cNr ooDn -hSielsg . Lcymy tpehso Epohsiinlso A Mc yotneos pBha si los1. R ectyicteuslo C o n tro l: 7777733333999996666623143 MMMMM 5665....87474884**** . 5.56* 11111 54575 .....23030 4445416654 1180980.....1285175247 111164269 01000 8898841802 11032 0 0 0 0 0 00000 48845.....53302 Mean 6.08 15.4 46 9.39 14 0 85 1 0 0 6.1 7777733333999996667679806 FFFFF 66656 .....57385 76217 ***** 11111 54545 .....46486 4444467558 11U8560.....7870142931 1198699 00000 8988914090 1 2 0 2 0 0 0 0 0 0 00000 4.4 2.7 1.1 4.7 0.7 Mean 6.41 15.2 46 10.50 12 0 87 1 0 0 2 . 7 30 00a : 77776666222233334132 76235 MMMMM 66566.....1002271437***** 1111124645.....49986 45 44435578 1111153150.....2114916848 2331355530 00000 7678655550 0 2 0 0 0 0 0 0 0 0 00000 44 ..61 445 ...608 Mean 5.95 14.9 44 13.19 28 0 72 0 0 0 4 .6 7777766666222223334397806 FFFFF 663 ...368 449 *** 56 ..86 14 ** 11111 44756 .....88473 4444417727 11198505.....0816133302 1422264240 00000 8577747356 1 0 0 1 2 2 1 0 02 00000 44 ..50 4.0 6.1 3.6 Mean 6.2 6 1 5.8 45 11.75 25 - 0 73 1 1 0 4 . 4 100 pom: 77773333999977771243 73975 MMMMM 55555 .....98528 71557 ***** 1111145434.....97882 4444448662 11188103.....5202565716 11131398 00000 8998871096 1 0 02 0 0 0 0 0 0 00000 . 48 . 7n 3.9 32..03 Mean 5.69 14.7 45 10.33 11 0 88 1 0 0 3 .8 7777733333999997777878960 FFFFF 5666 ....8154 1711 **** 6.76* 1111135566.....55439 4444472798 165671.....0438119459 121154069 00000 8889792504 1 2 1 1 1 0 0 0 0 0 00000 40233.....75840 Mean 6.33 15.5 47 7.38 15 0 84 1 0 0 2.9 300 snm: 77773333999988884132 73985 MMMMM 65665.....2079079179***** 1111165567.....53732 4444459679 11199232.....1065342261 1465 109 00000 8998995303 12 1 1 1 0 0 0 0 0 00000 1 31 ..71 46 ..95 *.3 Mean 6.03 1 6.2 47 11.33 9 0 90 1 0 0 6 .: 7777733333999998889896780 FFFFF 5666....88384439**** 6 .44* 11111 65668 ..... 46383 4 54447276 189881.....9216516603 111156809 00000 83883486 81 22 5 0 1 00000 00000 4>. 6> 3.2 34 .. 61 Mean 6.47 16.7 48 9.29 14 0 84 0n 5.5 137-086 *T* Polychromasia 001421 KS COPY AVAllAB`4 ,f FJ!-3422 41-2700-3422-0: X inecy Day S ubacute S at T o x ic ity S tudy. 7A31.E 6. Cor*I. Individual K esacoiogic a l Values - P re te st. GSXaurconubpe,r Sex ElOcryyc/tchemsroo - gg/H1lo0eb0raicnm- l Rcermi ca to - 1Lc0vJe/cucecnsom- SXege.u tXrooon-hSielsg. Z ' Lcyymtpehso* Epohs iinl se - Mc votneoss Basot a iVl s Recrvictue slo - Z I 1.000 7777733333999999999954231 MMMMM 54665.....6909298871***** 1111164653.....38281 4444369659 111180322.....6895989909 11270067 00000 9997940330 00000 00000 00000 2565.....53363 Mean 5.79 15.3 45 11.81 12 0 88 0 0 0 5.2 7777734333990999909976890 FFFFF 655...498492*** 66 ..34 07 ** 1111155654.....97405 4544457270 1197700.....4619667189 1122181844 01000 8887703426 01323 00000 00000 43113.....52008 Mean 6.20 15.5 46 9.18 19 0 79 2 0 0 2.7 3.000 ;3om: 7777744444000000000045231 MMMMM 56556.....5119065361***** 11111 65545 ..... 97668 4444568606 11167203.....7363191316 11143079 00000 8899893614 00 2 1h 00000 00000 455 4 ...#0102 2.0 Mean 5.76 15.7 47 10.05 11 0 88 1 0 0 4 .1 7777744444000000010079086 FFFFF 56665 .....24288 57803 ***** 11111 34555 .....59820 44447465 45 111191200.....4385142156 1190979 00000 8999913101 00000 00000 00000 46223.....77505 Mean 6.13 15.3 45 10.86 11 0 39 0 0 0 3.9 10,000 ootn: 77774444000011113421 74015 MMMMM 5556 ....9954 3542 **** 6.13* 1111 5566 ....4786 16.2 4444598972 1118101....56071240 10.01 1125869 00000 3899983120 2 1021 00000 00000 45215.....92731 Mean 5.99 16.1 49 10.38 10 0 89 1 0 0 3 .8 7777744444000001111267980 FFFF F 65565.....9193138083***** 1111145555.....72882 4444477626 98867 .....32176 55868 2111114990 000 0 1 8888718519 001 0 1 000 000 00 00 42224 .....39180 Mean 6.10 15.3 46 3.14 17 0 83 0 0 0 3.2 237-086 *i-i- P olychrom asie 001422 BESTCOPY AVAIIABIIage 25 fm-3 4 2 2 41-2 700-3422-0: N inety Day S ubacute Rat T o x ici ty S tudy. TABLE 7 In d iv idu al H em atological Values - 1 Month. RNGuaromtubper Sex E ry th ro - 1 c 0 v 6 /tcems o gg/1Hl0oe0bnlonm- l Hce*rmiatto- 10Lc^ve/uctencsjom- SN%ege.u tNroopnZ-hSielsg. Lcyvm*trpehse- Epons iinl so - Mc votneos- p3 'ansicl s- R ctvi*ctteusle - C o n tro l: 7777733333999996666651243 MMMMM 66677 .....59313 39165 11115765....2440 16.5 4445597711 11109901.....8569195180 1115866 00000 8988981490 2 li0 1 00511 00 000 323S...0S6 2.3 Mean 6.87 16.1 49 10.43 9 0 89 1 1 0 2 .6 7777733333999996676697068 FFFFF 67676 .....08382 48531 11111 46665 .....79839 4445561791 1186067.....5351772621 . 1211117080 00000 8888791295 4 2001 00001 00000 32232.....03520 Mean 6.86 16.1 49 9.86 15 0 84 1 0 0 2.6 30 ova: 7777766666222223333345321 MMMMM 66777.....5411484246* 11111 57565 .....12656 4455573920 111191010.....9286227163 1128999 00000 8889913800 0011 04003 00000 11 .^822 ..39 Mean 6.95 16.0 50 10.78 11 0 87 1 1 0 2 .2 7777766666222223334397806 FFrFF 66666 .....24554 65735 1111156665.....51009 4555581000 186845.....9456354620 211133006 00000 8388997460 00101 00000 00000 12111.....79930 Mean 6.45 15.9 50 8.77 12 0 88 0 0 0 1.8 100 oom: 77773333999977773421 73975 MMMMM 66667 .....77503 89848 11111 65665 .....59406 4444557861 11169751.....7834860649 1210679 00000 8899799238 10211 00001 o0000 23322.....43130 Mean 6.71 16.1 47 12.25 11 0 88 1 0 0 2 .6 7777733333999997777887690 FFFFF 66766 .....26966 45171 1111156656.....58913 4445558180 1167850.....6342719685 111153086 00000 8898754379 03113 00002 00000 2 . 4* 222...145 Mean 6.82 16.1 48 9.70 12 0 86 2 0 0 2.3 300 od d : 77773333999988883412 73985 MMMMM 6666 ....8482 5493 * 6.40 1111155566.....59104 4544588721 1111123455.....7188752730 1110556 00010 8999954034 10101 001 n 0V000 2.8 2323....8104 Mean 6.56 15.8 49 14.45 7 0 91 1 U 2.S 7777733333999998898869078 Mean FFFFF 66666 .....94755 58740 6.65 1111175556.....72535 16.0 4445472786 48 111190134.....3548023838 11.85 14s2986* 00000 0 999898149280 212 02i 00001 00o 00 00 2.0 422 ...153 137-086 *Repeat determ ination. 001423 KSicimvflWf FM-3422 41-2700-3422-0: 7A3LZ S. GRluarmot ubper, Sex ElOcrOyy/ctteShCsrDo gg/1Hl0oe0bnionm- l Minety Day Subacute Rat Toxicity Study. Individual H em atological Values - 3 Monchs. Hce5mr iatto loLcVvetucecmsoa- SM*ege.utNrooDnX-hSielsg. LcymyXtpehso- EpohsXiiniso Mc yotneos pBha si ol s Control : 777773333399999666665213 V MSMM' 87777.....0654852630 1111156756.....45386 4555581020 11195101.....4746750362 111146266 00000 8988824207 1 0y 002 00Q 2O C2 00 Mean 7.69 16.3 50 9.79 13 0 85 1 10 7777733333999996676697068 TFF FF 77777 .....63773 52560 1111166565.....82786 4445568700 199268.....7103088660 112110267 00000 8898778733 10101 00201 00000 Mean 7.56 16.2 48 9.08 13 0 85 1 10 30 com: 77776666222233333412 76235 MMMMM 77767 .....19435 91882 11111 46544 .....52149 4454477640 111192102.....4113975526 1111193930 00000 8888769670 41110 92 000 00000 Mean 7.3 0 1 5.0 47 11.21 15 0 84 1 0 0 77777666662222233433S9076 FFFFF 67677.....6473549133 11111 55564 .....28957 4444575990 198771.....0539412680 2230997 00000 8788779969 20212 002 40 00000 Mean 7.14 15.6 48 8.85 14 0 84 1 10 100 oom: 7777733333999997777741523 MMMMM 77777.....3924756700 1111165565.....73745 4444488888 11188143.....1449775661 11211657 00000 8898729828 04213 00001 00000 Mean 7.64 1 5.9 48 11.35 12 0 86 2 0 0 7777733333999997778778906 FFrF F 67777 .....92119 41280 1111156655.....98810 4444494886 144660.....7426198763 2111156913 00000 8887727194 22 062 Q 0001 00000 Mean 7.27 15.9 47 6.47 17 0 81 2 00 300 odo: 7777733333999998838854321 VMM MM 66667.....8358475380 11111 35354 .....93868 4444415472 187891.....4643772700 1130897 10000 9998914020 0010i. 001* 0 0000r. Mean 6.31 14.7 44 9.11 9 0 90 1q 7777733333999998968890786 "rr F ; D6667....i4790e476d8 11115445....1090 44445553 Mean 6.3 1 14.8 45 8897....39654553 14978 001 0 8.62 10 0 89885552 87 31UX Q G 02 oJ 0 y , r C'*tS n2 . ! 232 ...860 2.6 *.0 3323 ....4070 3.0 12233.....26458 Z.9 42333.....31103 3 3 i t 2233....4870 2 .S 2O2 ..73 32 .. 3S 2.7 3.4 3333....745S 3.6 -- 222 ...710 2.0 37-OS6 001424 FM-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 9. MALES : Means and Significance of Biochemical Values. Biochemistry Study Month Control 30 ppm 100 ppm Glucose, mg/100 ml B.U.N., mg/100 ml y-G.T.P., Sigma units/ml C.P.K.b , 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 3 ^Statistical analyses not conducted on the pretest values. C.P.K. - Creatinine phosphokinase Significantly different from Control group mean, p<0.05. Significantly different from Control group mean, p<0.01. 001425 FM-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 9. Cont. FEMALES: Means and Significance3 of Biochemical Values. Biochemistry Study Month Control 30 ppm 100 ppm Glucose, mg/100 ml B.U.N., mg/100 ml y-G.T.P., Sigma units/ml C.P.K.b , Sigma units/ml Alkaline Phos., int'l units/I 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 a ^Statistical analyses not conducted on pretest values. C.P.K. - Creatinine phosphokinase + = Not measured due to anticoagulant interference. *Significantly different from Control group mean, p<0.05. **Significantly different from Control group mean, p<0.01. 001426 FM-3422 41-2700-3422-0: TABLE 10. NGRuaromt ubpe,r Sex mGgl/1u0c0oseml C ontrol: 77773333999966664123 73965 MMMMM Mean 7777733333999996666776890 FFFFF Mean 30 ppm: 77776666222233334231 76235 MMMMM Mean 777666222333786 7766223490 FFFFF Mean 100 ppm: 7777733333999997777752413 MMMMM Mean 7777733333999997778797806 FFFFF Mean 300 ppm: 77773333999988884312 73985 MMMMM Mean 7777733333999999888889067 FFFFF Mean 6777795555 74 10989757500 89 4567751625 62 8665673076 67 9798751002 82 8889974790 89 8867775126 76 110098955913 97 mBg./10.N0 . ml Ninety Day Subacute Rat Toxicity Study. Individual Biochem ical Values - P re te st. Sigmy-agu. tn .ipts./m l uCSn.Piigt.msK/a.m* * l Aui kinn.i ttsP'/lhmols . 1111125382.....03800 02111 14.2 1 1111174868.....74320 11111 16.9 1 11 16 .. 72 111 255...300 2 2211 14.0 2 111 1 91355.....64500 11121 12.9 1 1111152122.....34330 251101 12.7 6 1111196533.....52250 11221 15.5 1 1111140322.....75800 11111 12.6 1 1111122525.....06000 21021 13.3 1 16352953 25 153533 6 221144058 16 1295865 13 - 104433 5 74687 6 1272733 10 45465 5 ********** AA AA AA AA AA 211222844850168 216 111117133421187 140 AA AA AA AA AA AA AA AA AA AA AA AA AA AA AA AA AA AA AA AA P .G .O .T . u innitts'/lm l 111470415 14976 133 11111122977006 114 8898674463 83 18809781408 88 11110304952249 116 111110121251700 115 11110140921753 112 1110229983000 106 P.G .P.T. u innitts'/lm l 111799974330 113 11110824570 90 103 8867711052 74 8666716002 68 108892740 111 95 10999989600 97 10999959000 95 10999923360 95 Page 29 Cmlailetcqei/urm 111190000.....82182 10.2 11199000.....55020 9.8 88577 .....13498 7.5 . 88777.....54116 7.7 111 09930 .....72819 10.7 1 99990 .....74581 9.7 11 99900 .....25541 9.7 1 99909 .....41296 9.6 *Creatinine phosphokinase **Alkaline phosphatase not measured due to anticoagulant 001427 FM-3422 41-2700-3422-0: TABLE 10. C ont. NGRuaromt ubpe,r Sex mGg/l1u0c0oseml 1,000 ppm: 7777733333999999999951324 MMMMM Mean 7777734333909999099990786 FFFFF Mean 3,000 ppm: 77774444000000001243 74005 MMMMM Mean 7777744444000000010098067 FFFFF Mean 10,000 pom: 7777744444000001111145123 MMMMM Mean 7777744444000001111278690 FFFFF Mean 89971329 102 89 111099875337 99 8877777588 81 110089922739 97 8987714868 83 84 109975008 89 mBg./U10.N0 . ml Ninety Day Subacute Rat Toxicity Study. Individual Biochem ical Values - P re te st. Sigm-aGu.Tn.iPe.s /m l uCSn.Piigt.msK/am.* * l Auiiknn.i ttsP'/lhmols . 111193728.....87000 11111 14.1 1 1111126282.....02000 11111 14.0 1 1111102722.....24900 11121 12.9 1 1111158555.....30000 11221 15.7 1 1111164454.....57737 11122 15.2 1 1111175555.....73330 10211 15.7 1 113100108 14 1111765 8 154877 8 1138875 10 - 5 85a8 7 11150297 11 AA AA AA *A*A ** A*A* AA AA ** A****A** AA *A*A AA AA **** AA A**A AA AA AA AA AA P u in.Gniet.sO'/1.mT . l 111111322145334 122 11111201770515 106 1112903930826 110 1110109981302 101 11110022958600 110 111112000265580 113 P.G .P.T. u innitts'/lm l 10999980900 95 7999768380 87 1110029922300 101 11111139074502 112 112599963603 112 111115120394025 126 e 30 Cmlailetcqei/urm 11190090.....73730 10.0 1199900.....36061 9.7 1199900.....89520 9.9 1 1 99900 .....77183 9.9 11199000.....79220 10.0 1199900.....75381 9.9 *Creacinine phosphokinase **Alkaline phosphatase not measured due co anticoagulant 001428 Page 31 FM-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 11. In d iv id u al B iochem ical V alues - 1 Month. i NGRuarmot ubper, Sex mGgl/1u0c0oseml mBg./U10.N0 . ml Sigmya-Gu.Tn .iPts./m l uCSn.Piigt.mKs /a.m* l Aui kinn.i ttsP'/lhmols . P .G .O .T . u innitts'/lm l P u i.nnGiet.sP'/.1mT . l Cmlailetcqei/urm C o n tro l: 1i 77773333999966662341 73965 MMMMM i Mean : ! 777333999666786 7733996790 FFFFF Mean 30 ppm: i1 f 7777766666222223333354132 MMMMM Mean ! 7777766666222223333497680 FFFFF Mean 100 ppm: ! 7777733333999997777712543 MMMMM Mean ; I 7777733333999997778798607 FFFFF I Mean 300 ppm: !] 77773333999988884321 73985 MMMMM Mean 7777733333999998888078960 FFFFF Mean 110099928966 100 111110312252400 118 11110000982520 101 11111211914010 109 111110000158227 107 111110200088520 109 1099626 10932 98 111110011025481 108 11111 42816 .....70780 14.6 111 758 ...703 11 15..73 15.6 1131340542.....96744 21.6 12111 40765 .....17450 16.7 11 52 ..00 111 455 ...733 14.5 11111 49928 .....72833 16.9 1221171457.....77036 19.3 11253 88601 .....66040 28.9 01 01 1 1 01111 1 99223 5 22222 2 0 1011 1 00000 0 1136222 7 01011 1 4111153254 111118649762424 1112129961033 5443715268 899 ...474 98 ..50 20 172 109 50 9.0 94997 10988921640 110286824604 4245484122 88989 .....81762 8 91 91 41 8 .9 12 111687 195 111194557593 108 11111274780 42 44432556 1 99990 .....48465 11 170 107 42 9.7 1111187550 11130938280 111 11115203903532 4464398298 199392.....26849 15 116 121 49 10.0 111030S4 211111936932225 119019938490 4443328296 98887.....35659 9 179 101 41 8 .6 227577 10499738862 7879684560 4443322803 88889.....75264 10 83 79 39 8 .7 1111133452 11114631745878 11999973630 6755577732 887 ...740 89 ..62 13 128 98 61 8 .4 11179089 222226259175210 4118388975006 3114656770065 98399.....52281 13 249 196 160 9 .0 137-086 *C reatinine phosphokinase 001429 FM-3422 41-2700-3422-0: TABLE 12. NGRuarmot ubpe,r Sex mGg/l1u0c0oseml C o n tro l: 7777733333999996666653241 Mean 7777733333999996666776890 Mean 30 opm: '77776666222233331234 76235 Mean 7777766666222223433380976 Mean 100 ppm: 77773333999977774231 73975 Mean 7777733333999997778767908 Mean 300 pom: 77773333999988881234 73985 Mean 7777733333999998988880967 Mean MMMMM FFFFF MMMMM FFFFF MMMMM FFFFF MMMMM FFFFF 112241 111232490 126 111113423015526 128 111112212345400 123 111114232405500 132 111111112247936. 120 111112110124728 115 111111132085190 119 D11111100i633e0d 108 N inety Day Subacute R at T o x ic ity Scudy. Individual Biochem ical Values - 3 Months. mBg./U10.N0 . ml Sigmya- gu. tn .ipts./m l u CSnii.gPtms./Kam. *l Aui kinn.i ttsP'/lhmols . 11111 73757 .....99052 0 00 00 16.3 0 1121183970.....89698 01101 18.2 . 1 1111153736.....19190 1100290 15.2 6 11217618....4113 12.9 01121 17.2 1 1121191788.....62101 00001 18.8 0 2221134409.....29659 10011 20.6 1 2222203253.....11111 00010 22.7 0 21218914....9548 0051 21.2 2 1100899 11113492456000 9 126 93866 4685959911 7 69 48633 113499948441 5 112 111115003 10895780167 10 82 257757 211111316139620 10 148 66757 4864947929 6 68 1110896 212122574771740 9 214 111159 12108197014 9 148 P u i.nGni t.tsP'/l.mT . l 5433325492 40 2223379013 28 1453743 3598 66 3233382704 32 4453323061 40 4223338481 33 124087629848 116 166459660 83 Pu i.nGni t.tOs'/l.mT . l 1118382013206 104 1111109900140 101 2111908986951 140 112069998256 98 1111008984860 101 8998732820 85 110189739122 93 188995491 115 Page 32 Cmlailetcqei/urm 1111101111.....96293 11.4 11111 11110 ..... 01968 11.3 . 1111110011.....52630 10.9 11111 10111 .....18452 11.2 11111 00110 .....87536 11.0 11111 01100 .....89869 11.2 11111 01111 .....81900 11.2 1111 1211 ....3130 11.4 137-086 *C reatinine phosphokinase 001430 FM-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 13. 0 MALES : Means and Significance of Urinalysis Values. Urinalysis Study Month Control 30 ppm 100 ppm Volume, ml 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 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. 001431 FM-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 13. Cont. FEMALES: Means and Significance3 of Urinalysis Values. Urinalysis Study Month Control 30 ppm 100 ppm Volume, ml 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 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. 001432 1422- 0 ; N iii ty Day S iih a n ito Hat T o x l r l t y S L u d y , ore l-: BEST COPY AVAILABLE Page 35 Ii II : i ; i Sfi i !Sw Ow I 5 5: li 11 5 3 5S ?! X X - X X x x x x ^ - Itili 11111 x^ 3 3v v* vi v * S Ss m u 3? ' i ' > i . 1 1 7t T i i X `- i. X X X - X X X X v. ' = i ; i I V3 3V ^ 3- 3V. * 3 1V VI g * o3 v8> * 3vi 3vi V3 8V 3V I I i i r i i 1 11 1 1 3V V3 1 1 1 3 1 1 1 X X X X X X X U. 11111 till' 11111 5 " VV is XXX s 3 3 3Vi W V V v. v Vi V g" r = 1 3V 3- 3v. 3v> 1 3V . 1 1I 11 3 1 1 i i i! ll il n_ i i! C as I1 il ; li! ` <>11 I I I I I u v. I I I i I lll|| Itili III s- - Z Z < 50 II i! 5C O* S C OS C C 3 C C - N.a: e e si ^(e*lIreS UmeIeN ^e- e f 1se rC tsNC <O vP-. 1I ae ?e Cs Os Ca Cs Os sC sO sC Cs Os c>e -- rff * w*^ y*<n nC -*X C O C C O |l|i SSS5 i|II| g ngl !gggj I- c o c c e C C 3 */* -- y ?m y cocco ccccc fZ y* e u- x r* r* ****,,- c o c c o --ceco rs C C X y -- n - --' e v. -- 3i- -- j- Z X X X X ti. V- la. Vu z z z ^ u- " i- ' s S S S S S S S S S s ? : - = =3t---^ri:--s<c ; ; 2 zi .J' E 5 lE5 E E = - 2 2 2 2 2 2 2 2 2 2 1 1 ! :i I j: \ ! 1i ?_i_ t1! i i I I It I I Z - -XXw J i l l/. < ^ vI:l-- csitci!u iiiiiii *2 j I" - li Ufii H x iiii Z -- M-- 001433 il ji i| 1 li I t? |!:: I'M-Vi 22 'il 2700-1422-0: TABI .It I A. lrmip f Hat Number S Volitine ini Cu lo r and Appear. 1(10pput: 7m i 7 I`i82 7 1983 73*184 7 l `)H'i M M M M H 71*186 71987 7 1*188 7 1*18*1 71*1*70 F F F F F J f000 ppm: 7 1*7*11 71*7*12 71*1*11 7 19*7/. 71*1*7*) 1 M M M 11 71*1*76 7 1*1*77 7 1*1*18 7 l*7'l'l 74000 F F F F F 1,00(1 ppm: 74001 74002 74001 74004 7400*) M M M M M 74006 74007 740011 7400*7 74010 F F F F F 4 .0 I.S-C1 5.0 S-C 2 .0 I.S-C 6 .0 I.S-C 6 .5 I.S-C 5 .0 S -c l 1 .0 I.S-C 5 .0 I.S-C 1 .5 1.S-C 4 .0 I.S-C 1 .0 I.S-C 6 .0 I.S-C 4 .0 1.S-C 3 .5 I.S-C 8 .0 I.S-C 1 .0 I.S-C 2 .0 l.S -cl 4 .5 S-C 1 .0 I.S-C 2 .5 I.S-C 6 .5 I.S-C 4 .0 I.S-0 1.0 s-i: 6 .0 I.S-0 8 .0 i.s-o 1 .0 s-<: 1.0 n s-c i 6 .0 I.S-C 2 .0 DS-c 1 1 .0 I.K-C N inety Day Subacute Hat T n x lc lty S tudy. In d ivid u al llrln a ly u is V alues - I 'r e le s t . S p e c. T o ta l filu - B i l l - O ccu lt Ke- I.eneo- K r y t lir o - E p l. Amor. T r ip le C a l. U ric A cid Bac pll C r a y . P r o t e in c o se r u b ili Blood to n e s c y t e s cytes C e lls U rate s Pints. Ox. C r y s t a ls lo r la C a sts 6 .5 1.033 N N N N N occ F F 7 .5 1.035 N N N N N (ICC - occ F- -M 6 .8 1.035 N N N N N ** - occ occ F- - H 7 .0 1.010 N N N N N" - - occ F- - M 8 .5 1.024 N N N N N" - - occ K- -M 7.9 1.027 N N N 31 N- 1-3 1-3 F F_ - M 6 .5 1.034 N N N N N" occ -F F- - F 6 .9 1.023 N N N N N- - - occ occ - - F 6 .9 1.029 N N N 2+ N - - - occ occ - - H 7 .0 1.023 N N N N N- CC - occ F- - F 7.2 1.026 N N N tr 7.0 1.026 N N N tr 7 .0 1.028 N N N tr 7.1 1.035 N N N N 7.7 1.027 N N N N N" N NNN - - occ occ - - - occ F - - - occ occ - occ - occ F - - occ occ F- 7 .8 1.033 N N N tr N- - - F occ - 8 .2 1.030 N N N 1+ N 3-5 1-3 - occ occ - 7 .0 1.032 N N N 1+ N - 1-3 occ F M- 6 .2 1.074 N N N N 6 .9 1.027 N N N N N- N- occ occ occ occ - - occ occ - -F -M -H -F -M _N -M -H -P -F occ7 .0 1.029 N N N N N- - - occ occ7 .0 1.035 N N N N N" OCC - o cc7 .0 1.041 N N N N N- - o cc7 .0 1.031 N N N N N- - - occ occ7 .5 1.025 N N H N N- - - F- - M -- H F- - H F- - F -M occ7 .0 1.044 N N N N N- -F F_ _M - 38 .0 1.040 N N N 11 N- -F F- _ M occ6 .8 1 .028 N N N N N- - - F- _ F o r r7 .9 1 .0 1 6 N N N 2+ N- 1-3 - F -_ M occ8.1 1.024 N N N tr N -F F- - H BESTCOPY AYIIABLE 001434 117-086 1 r - Trace 1F - Troc** lo s 1J j*hl :m - S l i t t i l i tu m oderate li -- M oderate Al - Marked S - S i row I.S - l.lttht St row l)S 1.Am - D\. o1lr'kIil SI row Amber DAiw - Dork Ami*r c l - Cloudy C - C lear N - Nega 1 1ve \Fs - Few D im lcd M - Many H - Haro o cc - O c c a s ioiwi - None seen 0D0> (D to CT> FM-'1422 41-2700-1422-0: TABLE 14. ('out. Croup, C o lo r Rat VoJ urne and Number Sex ml A p p ea r. Ninety Day Subacute Rat Tuxfclty Study. individuai Urinalysis Values -Pretest. S p e c . T o t a l G lu - Hi 11- O c c iil t Ke L e u co E r y t h r o K|>1. Amor. T r i p l e C a l . U r i c A c id B ac I'll C r a v . P r o t e in cim e rub 1n Blood to n e s c y t e s cytes C e lls U rates P lius. Ox. C r y s t a ls t e r ia (tasi s II), 000 'iiTM: 7401 1 M 5 .0 I.S-C 7 .0 1.026 N N N N N occ F M 74012 M 1 .0 S-cl 4 .5 1.046 N N N N N- occ 1-3 K occ - - H 7401 1 M 2 .0 s-c 6 .5 1.044 N N N i+ N- (ICC - occ H- - M 74014 M 7 .0 I.S-C 6 .9 1.028 N N N N N- 1-3 - occ F - -F 740 |S H 5 .5 1.S-C 7.0 1.033 N N N tr N- - -F F- - H _74014 F 0 .5 S-<:1 7.1 1.043 H NN 2+ N 1-3 occ F _ _ M 7401 7 F 2 .0 I.S-C 6.2 1.038 N N N N N- - - occ occ _ - F 7401H F 2 .0 I.S-C 6 .2 1.044 N N N N N- - - occ F- - F 74014 K 1.0 1-S-cl 6 .8 1.035 N N N tr N- occ - occ F- -M 74020 F 2 .0 1.S-C 6.1 1.038 N N N N N- 1-3 - occ F - - F 001435 tol r - T ra c e 11 - Trace m11 Il t 21 - S lip ,til to m oderate 11 - M oderate 41 - Moikcd S - Straw 1.S - M plu S tra w I.ADS - Dark Straw iii - 1.1ititi Amber DAiii - Dark Amber c l - Cloudy t; - G le a i N - N egative F - Few 1. - lead ed M - Many R - Rare occ - OiM'aulonal - = None seen LZ tS*aa$3r BEST COPYAVAUABU 38 C e lls U rate s Phon. Ox. C r y s t a ls le r ia C asts cyteB S p e c . T o t a l (In - B i l l - O c c u lt K c - l.e u cu - K r y t lir o - F .p l. Amor. T r i p l e C a l . U r i c Ac I 'I Itao- I 1I I I till Itili I as i I I IIIII IIIII I I I I I Ix I I I t I I u I as I I I auSfeSKfeSb SbChSfeXZ scasasi 0 5 0 0 0 9000 l i t i oo9 yy0 1 u0(J 0uu 0yu Itili ec oc I I I - u m my lOiB uOt i mt l tm u0 l l I ate I I IItII IIIII IIIII zzzzz zzzz zzzzz UOy u0U !!5 ;> !==-- = * = I I 1I I I I C ra y . P ro te in coac ru liin Blooil tone cy te a pll zzzzz z zzzzz zzzzz z zzzzz zzzzz zzzzz irt0t/0<ii9AinO0i<oc iio nno*eoN^ecoos n O zi S C C ^ O O r. xC r*m o tn m NO>0 yuy U Vi Vi Vi - V5 9 V5 w Vi 9 in y V3 a. c c s C tn. s 00 c m rsx w-l <r rt -- {N xT X zzzzz >i - N 'J 0 fofi *o No Mo rot O tn O i xC xC n* xC Ps 0ro* 4er-. 0otn xC 00 n. uy ggy V i CO cn sc gj y COV i VJ o -- o o xn - O xn xn c -- N pa pa -- C s -- -- n ZZZZZ Z Z Z Z Z i. b. b. b. b. V-0xC nsS5'nSO'^sCiC,* P*x P^ipx* Pv, p*. 5 N^ s?O C r**, T C* V- V- -" - fx-* P-rrx-. 3oZ;ji fo-t|, - N f* ^ 4rnMCp<xN. 4?rf**sf.|i4rPv***|f4Mf!x". i NS ? C hNC* NCN CNft C>!NCNN-c s 2 o - I3r-s- 1Sj: i5 jc- <--s-t < jue *x:;5 vI. I-cI -IisIi --; * V i aVI Vi <3 <S v--* ZSC*i5 : -j - .5 w 5 u ----w --i--* " zZ A". , i 1l t1 ; - - pa p'n5 . "905 ! 001436 Appear. Volume noil C o lo r ml Niimlicr Sex Cnm p, Kol BESTCOPY AVAIIABtf O3 CW --X 001437 FM- 1422 41-2700-1422-0: N inety liny Suhncntc Rat T o x ic ity Sludy. TAHI.K I*. C o n i. In d iv id u a l U rln a ly n lti Value - 1 Month. (IrtMip, Rat Nniuher Sex Volurn* ml C o lo r mit! Appear. S p e c. T o ta l C l li 8111I'll O ra v . P r o t e in co se r u liin Re l.euco- E ry th ro - E p l. A m ir. T r ip le C o l. U ric A rid Har tane cy tea ey te C e l In lir a ten PIioh . O x. C r y n t a ln t e r la CSlH 100 ppm: / V i 71 M J. n s-.:l 7.0 1.065 N N N N 73972 M 6 .0 s-c 8 .2 1.050 H N N t r 73973 II 7 .5 S-<1 6 .3 1.035 N N N N 71*774 M 5.0 S-C 7.0 1.045 N N N N 739/5 M 1.5 S -c l 6 .2 1.055 H N H N 71*7/6 F 2 .0 s-c 6 .2 1.075 N N N N 71977 F 2 .0 s-c 6 .2 1 .0 8 0 N H H N 7197 K 3 .5 s-c 6 .0 1 .0 5 0 N N N N 719 79 F 3 .0 118-c 1 7 .0 1.055 N N N N 739811 K 3 .5 s-c 6 .2 1.040 N N N N )00 ppm: N HNN- N- N_ NNNN- ot:c - occ occ 1-3 CICC occ occ occ - F o c c OCC 1 -3 OCC - occ occ occ .. occ occ F occ F occ occ occ F H occ HF. F_ F- OCC MF occ occ occ - _ _ _ - _ _ _ - H H H M _ H- H M . _ M_ H M- _ _71981 M 1.5 S-cl 5 .5 1.090 N N H N 2+ - occ occ occ occ F_ _73982 M 2.0 S-cl 6 .0 1.080 H N N N 1+ - - _ occ H_ _ F _ _7198 1 M 2 .5 S -c l ' 5 .0 1.065 N N N N 2+ - occ occ F F_ M 71984 M 8.5 S -c l 6 .2 1.040 N N N N N- - occ F F F M 73985 M 5.0 O S-d 7 .0 1.058 N H H H H- - occ occ M- - H- 71*781. F 4 .0 71987 K 1.0 / P>HH K 5 .0 1 .07 PUP) F 7 .0 / PUMI K S -c l 7.2 1.040 N N N N S-C 6 .0 1.060 N N N N s-c 6 .8 1.036 N N N N s-c 6.7 1.031 N N N N s-c 5.5 1.065 N N N N N_ N- N- N N -- - occ occ occ occ K_ F_ - occ occ occ -o cc 1-3 o c c o c c _ occ occ F_ M _ M_ _ _ M M _ _ M_ I 1/ UHI, Code: 1r - T ia re 211\ T ra re lu llj'Jtt - S I ip.hi lo m o derale H Modrait' 41 - Marked S - Si raw I.S - I J ) ;lil S i raw US - Mark SI raw I.Aiti - 1.11*li 1 Amher UAm - Uark Amher c 0l -- lC'Iloeuadry N - Ne)*al Iv e 1 - Frw 1. - lead ed M - Many K - Ilare ore - O rraslo nal ft VO FM-1622 AI - 2 /Oil- 1422-0: N inety Day Stilm cute Rat T o x ic ity S tudy. TAIII.K Hi. 1rulIv 1ilu aI U r i n a l y s i s V a lu e s - 3 M onths. Croup, lUt Number Sex Vo 1umo ml C o lo r and Appear. Spec, T o ta l filll- B i l i O ccu lt Ke Leuco F.rytliro- E |) i. A n ar. T r ip le G a l. U ric Acid Bac pll G ra v . P r o t e in COBU ru b in B lend to n e s c y t e s cytes C e l l s U ra te s Plios, Ox. C r y s t a ls t e r ia Gant s ('.o n triij: 73*161 h 6 .0 I.S-C 6 .9 1.038 N N N tr N 73*)(.2 h 5 .0 IIS-c 1 7.8 1.050 N N N 2+ N - 7 W ill M 6 .0 I.S-C 6 .5 1.068 N N N N N- 71966 ii 6 .5 I.S-C 6 .2 1.066 N N N tr N- 73965 M 6.5 s - c 6 .9 1.053 N N N t r N- 73966 F 1.0 l>S-rl 7.3 1.088 tr N N 2+ N _ 7 1*3#7 F 1 .0 S-C 6 .0 1.096 N N N N N- 73908 F 6 .5 1.S-C 5 .9 1.060 N N N tr N- 73969 F 1 .5 I.S-C 6 .0 1 .0 6 2 N N N N N- 73*170 F 0 .0 10 ppm: 762 31 ii 5 .0 I.S-C 6 .0 1 .0 6 0 N N N N 762 12 M 5 .0 S-cl 6 .0 1.055 N N N N 76271 M 2.5 S-C 6 .0 1.072 N N N N 762 16 II 3 .0 S -c l 6. B 1.052 N N N N 76231 11 3.(1 S-c 1 6 .8 1.065 N N N N NNNN N- 76216 F 1 .0 D S-cl 6 .3 1.096 N N N N IS - C76217 F 1 .0 5.1 1.088 N N N N F762 III 0.0 F7621*1 1.0 IlS-c 1 8 .0 1.086 1+ N t r 2+ F76260 1.5 S-c 1 7 .8 1.070 N N N N NN- N N- occ occ occ occ F occ - occ - F F - 1-3 - F F - occ - F F - - occ M F _ occ - F M - - - occ F - - occ occ F - occ 1-3 1-3 occ 1-3 occ 1-3 occ occ occ occ occ 1-3 occ occ occ F F OCFC _ - F occ - FF- F H- HH FF- FM F H- ii - M- ii - F- F- H_ - M- F- F- - F_ - M- F- II - II _ II - F- H - ii - 001438 I1/-OHf. Code: t r - Truro If - Trace m slig h t 21- - S l i g h t to m oderate UH\ - M o derate Marked S - Straw LS - l.lg lit Straw 1)S - h a rk S tra w I.Am - L ig h t Amber DAn - Mark Amber c l - Glnudy G - C lear N - NcgatIvo F - Few L" MH - Many Haro nor - O ccasional 0 Seen S assg; d 0f0l> o V H -W 1 2 41-2700-V22-0: TABLE 16. Cont. (I (Ul|>v Rat Vo 1ume NhiuIh1!' Sox Ml C o lo r and Appear. N inety Day Subacute Rat T o x ic ity S tudy. I n d iv id u a l l l r l t i a l y s i Va l e a - 3 Hont lia . . HurS p u e. T o ta l d u n u 1 - O c e u lt K e - Le uco E r y t h r o K p l. Amur. T r i p l e C a l U r ie A c id pH C r a v . F ro to In ron e r u liln It load tniicM cyte* cyte C e l l s U r a te s PIlOH. Ox. C r y a t n lu l e r In C a s t s 100 779/1 M 1.0 1)8-1:1 6 .9 1.058 N N N N ft.71072 M 4 .0 S-cl 6 .0 1.074 N N N N 7 JO7 I M 11.0 LS-C 1 1.079 H N N N 71*774 M 7.0 l)S-t.l 6 .9 1.044 tr N N N 77071 M ft.O S-c t 7 .0 1.041 N N N N 7707ft F 0 .0 F f t.l N77077 2 .0 l)S-cl 1.057 N NN F7 1978 4 .7 IJS-c.l 6 .0 1.046 N N N H F N77079 <0.7 DS-e 1 7.5 1.038 N N 2+ 71980 i' 7 .0 I.S -0 6 .0 1 .0 3 6 N N N N 31)0 ppm: s - c73*mi H 7.7 5 .9 1.043 N N N N 1 .5 N77982 H DS-t: 1 6 .0 1.045 N NN M ft.O77081 S-cl 6.1 1.051 H N N H 6 .0 s-c N73984 H 6 .0 1.043 NNN M S-C77087 9 .0 6 .3 1.042 N N N N s -c7708ft F 2 .0 s -c7 JOB/ F 2 .5 s -c7 J988 F 5 .0 I-C N N73989 F ft.O 7 .0 1.056 N N N N 5 .8 1.058 N N N 2) 6 .2 1.033 N N N H 6.1 tl.026 N N 73`<JO F 0 Ititi N N - N N N -- N N N N -- NN H 2+ N --- N_ N0- N- 1-3 o-c- c - OCC HH occ F F - occ F - FF occ occ F __- 1--3 o -c c occ F F F F F occ F occ __ - -- ooooocccccccccc o cFc F F - o cF c F Oo Cc Cc F - occ - o-cc - _ oo cc cc - ooocccFccc H F ' OCFC _ - --- -_ - - - _ _ - m H K HM --- FF h F -- FF - H- FF - - M FFF- STCOPY AVAILABLE 001439 tr - Trace IJ - T ra ce tu n lig h L 21 - S l i g h t to m oderate II - Huile iti te 41 - Marked S - Straw I.S - L ig h t Straw DS - Dark S traw I.Am - L ig h t Author DAm - Dark Aiuher e l - Cloudy C - C lear N - N egative F - Few 1. - Loaded H - Many K - Rare ore - OecoHfonal - * 0 Seen OfaiQ> & Page 42 6a a o oo_ *4 001440 FM-3422 41-2700-3422-0: TABLE 17. Site Lesion Number necropaied No gross lesions External red-brown material, eyes/nose/mouth emaciation incomplete fracture, femur yellow material, anogenital region Lungs congestion red foci gray/yellow/whlte foci Liver congestion adhesions accentuated lobulations brown discoloration gray/yellow/whlte areas enlarged yellow mottling red foci Stomach hyperemla/congestion, mucosa red foci/brown areas/hemorrhages brown-red mucoid contents Spleen pale Mesenteric Lymph Nodes dark red Small Intestine red/black/brown contents Adrenals dark red Kidneys hydronephrosis brown discoloration 137-086 Ninety Day Subacute Rat Toxicity Study. Suranary of Necropsy Observations, Terminal Sacrifice and Deaths. Control MF Terminal Sacrifice___________ 30 MF 5 100 -EE" MF 300 .EES MF ____________________ Deaths 300 ppm F ppm MF 3.000 J2E" MF 55 35 55 24 55 51 53 00 2* 55 55 0 00 00 10.000 MF 55 01 1 1 32 3 2 12 1 1 14 1 1 21 2 1 12 21 1 1 11 *Died after blood collection. 22 1 21 32 13 24 33 21 11 1 1 1 21 1 1 1 FM-3422 41-2700-3422-0: TABLE 17. Cont. Site Lesion Uterus hydrometra Testes small Ninety Day Subacute Rat Toxicity Study. Summary of Necropsy Observations , Terminal Sacrifice and Deaths. Control MF Terminal Sacrifice 30 ppm MF 100 ppm MF 300 ppm MF 300 ppm MF Deaths 1.000 -EE5. 3.000 HE MF MF 10.000 ppm MF 2 1 Page 43 001441 137-086 *Dled after blood collection. KM-1422 41-2700-3422-0: Ninety Dtty Subacute Rat Toxicity Study. TAHI.K 18- Absolute (Crams) and Relative! (Z Rudy Weight) Organ Welglita. Terminal Sacrifice. Croup Sex Body Ut. g Spleen 8" Z l.lver 8Z Kidneys 8* Brain 8* Adrenals * mg ZxHT Conirol: M V 10 ppm; H K J IMI pjm: M K 100 ppm: M K 484 270 439 257 462 237 372 208 0.82 0.62 0.17 0.23 0.75 0.60 0.18 0.23 0.82 0.52 0.17 0.22 0.68 0.47 0.18 0.22 17.51 11.48 3.61 4.23 18.24 10.59 4.30 4.14 24.89** 11.67 5.37** 5.00 31.52** 15.01 8.51** 7.22* 3.75 2.36 0.77 0.88 3.66 2.46 0.86 0.96 4.24 2.15 0.91* 0.92 4.73 1.99 1.30 0.96 2.19 1.99 0.45 0.74 2.29 2.08 0.55 0.81 2.22 1.90 0.48 0.B2 2.17 2.04 0.59* 0.98* 61 1.27 77 2.88 63 1.46 80 3.12 55 1.19 75 3.17 76 2 .1 1 73 3.52 Tlijirold/ Pnjriitliyrold 8 Zxl 24 0.50 21 0.78 26 0.60 22 0.87 30 0.66 20 0.84 27 0.72** 17 0.81 T Unitary, mg ZxUr 15 0. 12 17 0.6 1 16 0. 15 17 0.67 15 0.32 16 0.6B 14 o . m* 13 0.64 3EST COPY AVAIlABLE 001442 I 17-Hilf ______ _________ _________________________________ ___________________ __ _ Croup wen r e l a t i v e organ w e ig h ts shown In t h i s t a b le wt'ii* r a i r u l a l r d by a v e ra g in g th e i n d i v i d u a l l y r a I n i l at **l r e l a t i v e org an w r l g h l s . * S Ig it if le a n t Iy d i f f e r e n t front c o n t r o l group moan, p<IM)*>. **SIgnlI leant Iy different from control group moan, p<0.0(. P ^ P' BEST Cflpy 001443 FH-1422 61-2700-1622-0: TABLE 19. Croup, Hal No Conlj'ol 71961 71962 71961 71966 71965 71966 71967 71968 71969 719 7 10 ppm: 76211 76212 762 11 76216 76215 76216 76217 76218 76219 7626 } ppm 71971 71972 71971 71976 71975 71976 71977 71978 71979 7198 100 ppm 71981 71982 71981 71986 71985 /71986 7198 71989 Sex H H H H H F F F F F M M H M H F F F F F H M H H M F F F F F M H M H M F F 117-086 Uiidy Ut. 8 Spleen 8 Ninety Day Subacute Hat Toxicity Study. Individual Organ Weights. Liver g Kidneys g Brain B 659 0.82 675 0.74 670 0.84 690 0.80 526 0.89 270 0.66 106 0.81 278 0.59 251 0.66 265 0.18 496 0.71 467 0.73 127 0.94 418 0.71 465 0.61 212 0.53 257 0.61 256 0.72 251 0.46 285 0.69 516 0.98 509 0.69 422 9.72 448 411 0.80 244 0.77 2)0 0.47 250 214 0.47 226 0.38 192 0.68 124 0.76 181 0.48 168 0.78 194 0.69 217 0.58 221 0.44 IH7 0.39 - Not avaiInhle --- 14.72 16.71 16.50 20.06 19.54 9.62 10.51 19.88 9.42 8. 18 1.56 1.42 1.85 1.92 1.99 2.47 2.18 2.21 2.10 2.45 20.76 12.60 21.11 18.86 17.85 10.08 10.85 9.74 10.95 11.35 3.75 3.48 4.05 3.56 3.44 2.28 2.53 2.33 2.48 2.68 29.15 24.28 22.81 _ 23.32 11.92 11.53 _ 11.40 11.81 4.43 4.66 4_.23 3.63 2.62 1.93 2.05 2.00 15.44 11.19 28.51 11.78 30.44 16.64 14.69 11.71 4.47 6.77 4.12 4.13 4.18 2. 15 2.02 1.81 ------------ --- 2.09 2.24 2.22 2.20 2.19 2.18 1.82 1.87 1.92 2.15 2.08 2.17 2.94 2.14 2.12 2.06 1.92 2.12 2.03 2.25 2.19 2.30 2.19 2.21 1.71 1.94 2.16 1.80 2.05 2.21 2.17 2.15 2.24 1.84 2.22 2.05 Adrenals 8 53 63 71 64 55 72 77 85 80 73 65 64 63 69 53 81 88 74 66 88 56 59 52 56 50 72 63 68 97 75 52 132 58 68 71 73 76 70 Thyroid/ Parathyroid 8 18 24 25 28 27 22 20 20 19 23 29 29 21 25 28 2 27 22 21 22 32 28 27 29 34 20 15 19 25 20 21 24 12 32 22 16 20 15 I'Rultnry "8 15 15 17 15 15 14 17 18 16 2 19 19 1 15 15 17 16 19 12 22 14 17 14 15 14 18 17 18 11 15 14 12 16 IS II 14 14 12 LSn' 001444 PM-3422 41-2700-3422-0: N inety Day Subacute Rat T o x ic ity Study. TA!.K 20. Illstomorplioiogic Observation. Control 30 ppg 100 ppm 300 ppm Tissue besIon S S X X X k K K K K X X X X X k feK Im K X X X X X iMKlxfE.fl X X X X X (MfMiMlMfM ou u 2z H0NOPOI 'wf 'OtO (nMMmhsiONotOf nstONnt vtOf>r*OO*O0ftfOt O <dfsntmfoxtM sw n^ o t o (rtsi NNH<o*)NNtnMNtooMtNNtnooNNtNntooNNhnmto NtNt^tnoo>NhnrtNo--osNNf0tntoQsoNNNtatnooWNt^otoo hNH*O.-.tNnn*.ON-.htm.tn-nf.thO.f*--.iitNOm.n*.ti | to | \ oo o t o sOntNnO tNhO tNnO tC<OO*>t N h- P> f> N h> I"'- K h> r i N Pt ^ (O tl O Ot O eOMCOCOCC1 (D CO 00 O ot p>r n rinpiO* Ot Ot Ot Qt OptiOptiOt pOit Opit P N h N h | s f * h h> P> l.lver lu'.hmtu|miubU liepatore Ilular vacuolatlon focal /muI d focal mononuclear Infiltrate - parenchymal focal/multifocal mononuclear Infiltrate - periportal l>lle duct proliferation liopatocellular hypertrophy hepatocellular accumulation of brown pigment focal chronic inflammation focal/ntil ti focal inflammatory Infiltrate - parenchymal focul/multlfocal hepatocellular necrosis mineralization of necrotic debris accumulation of brown pigment In sinusoidal macrophages (Kupffer cells) Brain focal lymphocytic infiltrate - meninges Cervical Spinal Cord 111 22 334 2 22 2 2 22 2 2 2 22 2 2 32 333 22 44434 33224 2 2334 3 2 55555 32 2223 2 2 2 44433 3 3 12 11111 11111 111 1 1 1 1 1 1 2 11111-1111 11111 11111 -111 --111 2 5 4 2 5 43 3 4 2 2 3 2 2 22 2 1111 11111 1111 l.iuitlwir Spinal Cord Peripheral Nerve Byes retinal remette - right eye i c t i u n .ti i opliy - h l l a t c r n l I'1tnl Iary cysL with ihicl-llke structures adjacent to cyst wall Tliiylrl itillilmihrinichlal re nt s Paral liyrolil Aili'eua I vacuolated cells - zona fasciculate Imal/um 11 1local mononuclear Infiltrate - zona fasciculata local conical degeneration diffuse mononuclear infiltrate - zona reticularis hypertrophy and hyperplasia of cortical epithelial cells - zona fasciculata 111-1 11--1 11111 11111 liiii u n i 11111 11111 11111 11111 i ili liiii X -1--1 11111 11111 11111 l i i i i i i 11 ill-1 11111 11111 11111 111 1 1 1 1 1 1l 1 11 11 1 i 1 1 l 11 1 11 11 11 1 I l l 1 I t 11 11 1 1 X X XX 11 11 l 1l 1 1 l1l 1 111 11 1 l 1 X 1 1 1 1111 XX i11 I1 1 1 1 1 1 1 1 lilil 1 I 1 I 1 I II 11l1 1 11 11111 11 1 1 11i 11 1 23 2 2 13 137-OHfi Code: x - condition present 1 - not remarkable 2 - very alight 3 - alight 4 - moderate *dled 5 - marked 6 - extreme - not available T3 0(QU rt> O' <Group, Rat 73961 73962 73971 73972 73973 73974 73975 73976 73977 73978 73979 73980 73981 73982 73983 73986 73987 7396S* 73990* BEST COPY AVAllABU 001445 Ft!-1422 41-2700-1422-0 Ninety liny Subacute Rat Tuxlclty Study. TAIII.E 20. Omit. Illstn m orplio log ic Olm crviit Io n s. TliiHue U k Ioii Control 30 PP ws litis: * M* U* Ut Mi Ma Id 1 2 <n *9 m 40 40 40 nOinOlnOi r- e-*C" 4400 I4'*vgoo 4<704o OfhO-v nrs OX tms ntOsi j<O*vi1 X X x X X In Im In IU nH nNnnr -t9ntn N4r0*NN40N40NM40NS40 40 |s flO04 O n r M i r> 4 MN>psN\>N>|psNiNftMfs 100 ppm *: * * at 1*41*41*41*41*4 300 ppm X X X X X 1*41*4(*41*4 Ut *9 *n 0<7040O0N nn n C7> I<C0s2O4 long perlbroiiclilal/perlbronchlolar lymphoid hyperplasia focal accumulation of alveolar macrophages atelectasis perivascular lymphoid infiltrate Interstitial Inflammatory Infiltrate Interstitial edema hemorrhage llenrL focnl/multlfocal mononuclear Infiltrate-myocardium focal/miil ti focal fibrosis focal mineralization - myocardium Aorta Silicon hematopoiesis hemosiderosis Mesenteric Lymph Nodes congest ion Thymus hemorrhage degeneration of cortical thymocytes Bone Marrow focili m yeloid h y p e rp la sia L-dCM.I 2 32 2 2223 2 2222 2 442 2 43223 34 23 43 322 2 2 3233 3 3 1 22 1 22 22 2 23 24 2 2 33 22 32223 1 23 2 211 2 3 23 3 2 1 1 11 32 32 2 2 2 1 1 lllll 222 1 111 1 1 111 11111 22 2 2 2 2 1 1 1 1 1 1 ill 1 1 1 11 2 32 23 3 1 1111 lllll 1 332 32 2 323 2 111 1 1 1 - 1 1 1 1 111 11111 2 111 1 1 1 1 1 1 1 111 1 1 1 1 1 j l 1 l 1 1 1 1 1 1 1 1 1 1 1 1 1 11 11 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 24 111 1 111 1 1 1111 lllll 32 1 1 1 1 1 1 11 1 1 1 1 1 1 1 11 11 2 111 1 1 1 - 1 l l 1 1- 11 11 23 3 111 1 1 1 1 1 1 1 1111 111 1, 2 Hone 11111 11111 11111 11111 11111 lllll 11111 11111 Salivary Claud focal /mul 11focal mononuclear Infiltrate St omacli Hiilimncoiinl In f Inimaatory I n f i l t r a t e fo c a l InfluiHMntury I n f i l t r a t e - neroaa nml11 f o c a l m ucosal n e c r o s is sulinnicosa I hemorrhage fo c a l d e g e n e ra i Ion and e a r ly m in e r a liz a t io n o f smooth m uscle - tu n ic a musco I a r t s congestion - mucosal v e s s e ls I17-OHh lllll 1111 2 lllll lllll lllll lllll lllll lllll 1111111111 111 1 1 111 1 1 1 1 l 1 1 1 1 1 l l l l l 3 2 3 2 11 3 2 Code: x - co n d itio n present 1 - not rem arkable 2 - very slig h t 3 - alight 4 - moderate *d!ed 5 - marked 6 - extreme - not available p> 09 to .o i i i 001446 KH-1422 A 1-2700-1422-0: TAIII.1C 2(1. C oni. Ninety Day Subacute Rat Toxicity Study. IIlatom orphologlc O bservations. C m ttrol______ __ ___ 30 ppm_________ ___________ 100 ppm __ _ 300 ppm T lsssu e hcalim F F s r .tiy .s ix yn , si s: lu u Ut , Ui u. u* Udsr y |l<|l4 th|ti (M t. y, r . Uslit tkr. Ua tXuo\ 0O0'Oo'- o N 00COocnvHAin(O-rftttmil rs V0 V ON fl ONOiOv Oi ONONOiOnOi 9 n r> n n nf*)n nmn nn nn1*1 |> nMs NN rss rs. rsi*. rl CNr>>IOOfs(Oo>O nnnno (vS3 NtANtiltNAtNil iNnrtirlinnntiltNil h>r*.nrsrs rstsh. h-is hnn 4 m NOfscoon tsMs Ms |s-Isrsts QiOsOnOnOnONONOnOnOn nnn n n n nn MsfsfsN rs. rsrsrsrs HN(O9 in |S ON COtOCOCO00 COU>CO ONONONONONOn rommmco rs ts|s |s rsrs rs |SIs Smffaoolccl aallIa mtveuuaHctoicnsuaellltflsi b r- oms iessentery l i l i l i i i i 11111 i i i i 11111 i i i i i 1 1 1i i i i l 1 Large lo le slln e (Colon) 11111 11111 11111 11111 11111 11111 11111 11111 P afffnfffoooooocccccccrueaaaanaslllll/s/mmopfIinfeuibtrilherltitvoyrIllaffspooosiebscccruuaatrwlllloaaipmrrtfhhiobaiinnenprodfdoalnasnupmaiccscerlmierenwiaaadarttiourtihcrIcynctduaefiuclilnallicsntrtfraiapIlrnttrerfaolatalrtmioefpmehraayttoiroyn I n f i l t r a t e 111 21 11 3x 3 11 22 111111 1 11 1 1 1 1 423 32 3 11 1 1 1 22 111 KidccshttffttiIhuuuuononyhyneibbbbpceccrstdtcyortaaaupueurhrkanlcalolllliie/aacaluitcnlmnscharrireteeceiceulplnnnmupllllhgunuptietreriaeoIlrpelpnoaoolafthpseheorlfrIirrheinrsccoanilrfgyarenlstalieilileailtuczossdlimlecesslmtdoeodumiweousbarhudsuiutssoellhabcrabydrrarrobriswsrbroitoensanpwgsflehneeimlnyttspeaerinrlagiaitnmntteeimeognend-mltorb-morrepaenntlrueeaubtllwsauhrli-talhlsruptuseaecobpesuiitlnhaorelia l 1 111 22 2 2 3 1 1111 2 33 1 1 11 222 2 2 x 3 2 23 3 5 33 2 A55 3 3 3 32 2 3334 222 3 3333 U rfioncaaryl mB loandodneurclear I n f i l t r a t e - tu n ic a m u sc u la rls 3 1111 11111 11111 11111 11111 11111 11111 11111 T estes 1111l 11111 1l11l 1 11 I I O vccfaoyyrcssiaettliiscc inocfovlraapmruiamsnaltubotrueyrusmaI n f i l t r a t e - p ara o v a ria n ad ip o se tis s u e 1l 1 X2 x 11 1 xx l1 1 xx 111 1 X C4 cr: i*" fn x1 -- cnootn drietmioanrkparbelese n t 23 -- svleirgyh ts lig h t 45 -- mmaordkeerdate *died 6- "- nseovt eraev a il a b le 0fl9> 00 FM-'1422 4 I-2700-3422-0: TAItl.K 211. i:.m t T isbsuusei ou l'ro s ta te focal Inflammatory Infiltrate alveolua multifocal Inflammatory infiltrate - alveolus interstitial mononuclear infiltrate lie u n is liydrometra Skeletal Muscle Mammary Clami hyperkeratosis - skin N liiuly Day Subacute Rat T u x ic lly St mly Il 1s tou orp lio ] a g l c O b s e rv a tio n . Control 30 ppm 100 pii 100pi S to U O (J U -fl U3 as T* * JC * H N n s r w x> O \ lO o ON On On ( lt |l |<4 |l4 |l O h i (O On O O vO NO N ON On On On On nnnn N f s h |n 33 * S3 S3 S3 U U* |4 |l4 fl h n n * io r i n <*i n M N N N rc n nO nO nO nO r r * N r s r> n/1 i A in tA tA h* N fs fs 35 JG X 35 S In In In lu In hH. NN N *J NIA t> OO f s COO fOn>* nC7N l> nOl sv|Cn7sN n0f s> hnOi. <ONnv hnO-i NnOi rOl 7S 53 SS T, t: U< (< M< COmOr nO0>O mCQO\ 0n004 Oc0o)\ NNMv h O N C O O i-C n n n nCO IO CO CO 04 Oi ON Oi Oi Oi rs i- h. |v i 1i 11 iiii 1 Ili 3 1l i 43 3 11111 iiii i m i 11111 iiiii iiii 1 11 xx iiii iiii Itili i i i i il ili iii-iiii- -i-i-iiiii iiiiiiiiii i 3 i i i i 2 ili 00144V I I /-Olili . Colle x - co n d itio n present 1 - not rem arkable 2 - very slig h t 3 - s i 1p.lii S4 - m oderate ' * d le d - marked 6 - ext reme - * not a v a ila b le g mmse* SRS* hd Cl) 09 ft) VO FM-3422 41-2700-3422-0 TABLE 21 Ninety Day Subacute Rat Toxicity Study lllstom orphologlc O bservations. 1 ,0 00 ppm____________ _________ 3 ,0 00 ppm______________ T issu e lesion i| o g M<9 o & as XX 58 HOOCr*O*'' cOOm'' r<-o. cOOo'' 0 OOo'' rr sn tmfOOsn'' Pm h Pm l>4 sOOnO '' rOO-s'' co 0OO0'' trso. OOO ''' tc-os o o srosi. L ivc oern g e stio n ahhhhfff oocoeeeepcmccccpppyuhaaaoaaammalllrtttg//roooaummhfelcccliasabueeeugtllllrlei(lllttooKuuullnffsllluooaaaipsoccrrrffaafhhvell byayr rhIpcponceueweferpolrntalpalrlmaotlsptoapm)iiscoghiaemynatloel runytl a irn In nf ei lctrroasties s in u s o i da l paren-' macro bh ei lpea tdouccetllpu lraorlifaecrcautmi ounlatio n o f brown pigm ent 433 55 45 4 4 3 22 2 33 44 45 43 44 xXXXS H CM ro s t *o oOooo ro^o ros*- sIoSi- o r% Srost. Pm Pm Pm fu f4 'O O fs. 00 OO O' o OH Osrsf. osrst. Osfst. osNr sOrst 3 4 43 3 22 2 2 4 43 3 454534 2 10,000 ppm a XX X irHH CHM rr ol sr lt m rH stOsi. Osrst. IsOSt. ors0. srOst. Pu Pm Pm Pm tHo rs rH CO i--1 OrH' OCM Osrsi. rOSst. Osrst. Osrst fOsst 4 23 2 4 3 23 4 4 5 4 001448 137-086 Codei x - condition present 1 - not remarkable 2 3 _- vs leirgyh ts lig h t 45 -- mmaordkeerdate -6 -- ns eovt earev a ila b le *ETls.-.- a?: JPv f*ru O(QD Uo i