Document 4J39Y6qvjJYe0EaYgGaNzXY5R

: ARz26 -02% International Research and Development Corporation SPONSOR: 34 Company COMPOUND: FH-3422 SUBJECT: Ninety Day Subacute Rat | Toxicity Study. | vEidcveinPr1.esiGdoljdaecntahnadl, Ph.D. Directordf Research | Collaborators: D.DiC.recJtesosrupo,f PRhe.sDe.a,rchAssociate R.anG.d DGieirle,ctoDr.V.oMf.,PaVtihcoelogPyresident .ofD. `SJmeaflflerAsnoinm,alBT.oA.x,icAocltoignyg Director F. SAt.affRuePcaktehro,logDi.sVt.M., M.S. Date: November 10, 1978 137-086 01396 [I | International Research and DevelopmentCorporation | TABLE OF CONTENTS !! To SYBOPELS + titi aaaee.1Page IL Compound + keke eae . TIL. Clinfeal Studfes + ov vou vas enn enn... 4 | Ac Method tui iee,.4 1. GeneralProcedure. ve vv vss atti... 4 i 2. Compound AdmIn{ s+ +tvr4atut.i.uoan.... 4 3. OBSETVARIONS + + si 4 a iiiiuii.uaa....5 i 4 Laboratory Tests . . uuu. .ia.........5 ' b8.. HBelAocLhOeLmOiBsYtryovoiv.v .w.v .s.t..a.t..u.e.......5.5 dc.o SeUtrnuamlySsaimsples.oo. .. .+............................&5.. 5. Statistical ANalySis + vv vv tea eat... 6 Be Results. oot iti a. . 6 1. General Behavior, Appearance and Surv.i.v.a.l... 6 2. BodyWelghts eet iiaiiiai......8 3. Food COMSURPELON + + 4 + suk tui a uaa...8 Ge Laboratory Tests ee asi iiu.aaa..... 9 ba.. HBleomcahteomliosgtyry. iLiu.i.a.i.i...i...............99.. Co Urinalysis ov vv aii.10 IV. Pathological Studfes + + vv a uuu tua uu ua... OL | LETT 1. GrossPathology. + vv vv vv vue usu u uss, 11 2. BiStopathology ve vest u.uu. aaa... 11 Be Results tote iiu aie, 12 1. Gross Pathology and Organ Wei..g.h ..t..s.... 12 2. BISEOPAtMOlOBY + + + a ta tutu. aaa... 13 137-086 601397 - [I | International Research and Development Corporation | nto re. 1 TABLE OF CONTENTS T(TContimued Page 1. Group Mean Body Weights, Weight Ranges; and Survival . . 16 | 2. Individual Weekly Body Weights . . . . . ........ 17-18 3. Mean Food Consumption . . ............... 19 4. TGr-otuepsst,CoFmoopdarCiOsnoSnUBBPeEtiwOenen .Me+an+s +o.f .Co.ntrol4.an.d .Treuatued. 20 5. Means and Significance of Hematological Values . . . . . 21-22 9. Means and Significance of Biochemical Values . . . . . . 27-28 | 10-12. Individual Biochemical Values . . . .......... 29-32 ! 13. Means and Significance of Urinalysis Values . ..... 33-3 | 14-16. Individual Urinalysis Values . . . . . ......... 3541 if 17. Sumary of Necropsy Observations . . . . . . ...... 42:43 i 18. Absolute and Relative Organ Weights . ......... 4 ! 19. Individual Organ Weights . . . . . ........... 4s ; 20-21. Histomorphologic Observations . . . .......... 46-50 i | i| 137-086 601398 | | International Research and Development Corporation | Page 1 | 1. synopsis and Five female sats vse itiated at each dosage devel snd 1 toe F-34022 vas fed fn the diet ac levels of 30, 100, 300, 1,000, 3,000 and 10,000 ppm to Charles River CD rats for 90 days. Five male | tcoonxtircoiltygraonudp.sortTahleltrya.ts wIenrdetviodbusaelrvebdodytwwieceighdtasilyandforsexo-vgerrtouysigfnosodof consumptions were recorded weekly. Hematological, biochemical and | urinalysis studies were conducted during the pretest period and at 1 and 3 months of study. i All rats at the 1,000-, 3,000- and 10,000-ppa dosage levels died between days 9 and 29 of the study. Most of these rats exhibited one i k or more of the following signs of overt toxicity including: ema- elation, 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-ppa 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 i expected range: at 1 month, Y-glutamyl transpeptidase (Y-GTP) levels were slightly elevated for two males; at 3 months, Y~GTP values were i elevated for three males. One male rat with elevated Y~GT? (1 month) had a normal Y-GTP value at 3 months but slightly elevated plasma glu- tamic pyruvic and oxalacetic transaainase (PGPT and PGOT) values. Two male rats at the 30-ppm dosage level also showed slightly elevated blood urea nitrogen (3UN) values at 1 month of study. At the 100-ppn 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 601399 ] | International Research and DevelopmentCorporation | Page 2 | 56 the 30-ppn dons Level an tncressed Ecidence of porsthty | compound-related signs was noted. Two females died after the collec elon of blood for clinicopathology. One male and ome female had an | accuaulation 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 lover (p<0.01) for both males and females. I vAatlu3esmonftohrssaolfesstuadnyd, feemrayltehsroactytetheco3un0t0s-,ppahedmoosgalgoebinlevaenld vheermeatosclriigthtly ; i lower when compared to the control values (statistically significant). Blocheaical values showed some changes for alkaline phosphatase, i PORT, PGOT, Y-GTP and for BUN values for one or more rats of each sex at each sampling period. Coapound-related gross liver lesions consisting of enlargement, accentuated lobulations, brown discoloration and gray/yellow/white | areas of discoloration vere observed in the 300-ppm group and to a lesser extent fn the 100-, 1,000- and 3,000-ppm groups. Brown kidney discoloration vas observed in the 300-ppm group, and stomach . hyperenta/congestion and red/brovn foct/hemorrhages were noted in some rats from the 1,000, 3,000- and 10,000-ppm groups. A statistically | ssiidgenriefdicacnotmpoluinvde-rrewleaitgehdt. inCcormepaosuendi-nre1l0a0teda,ndmi3c0r0o-spcponpirca,tslivavsercon- 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 {n tubular epithelial cells were observed in some rats from the 300-ppm group. 137-086 01400 | International Research and Development Corporation | Page 3 | mn. conpomp y | on The compound vas received from 3M Company, October 28, 1977 as indicated below: Saint Paul, Mimmesota Label Description | FM-03422 41-2700-3422-0 Lot 784/ Net-35 DR-1 off-white to tan waxy substance | 137-086 601401 I | | 1 I 1 | | | ! i | International Research and Development Corporation Page 4 renton mabe, Ta sare vere move Stan le III. CLINICAL sTuprEs A. METHOD: I. General Procedure: Thirty-five male (200-306 g) and 35 female (180-226 g) Charles RTiavc.e,r PCoDrtraagtes, pMuircchhiagsaend vferroem TuhseedChtnarltehsisRistvuedry.BreeThdeingsacLsabvoerraetories, distributed among the groups, based on a computer-generated table of mesh cages and maintained in a temperature-, humidity- and light- controlled room. During the pretest period, rats were provided Purine Laboratory Chow and water ad libitum. During the test p1iebriicoudn,, the rats were provided the appropriate test diet and vater ad This study was initiated on November 4, 1977 with Groups I-VI (control, 100, 300-, 1,000-, 3,000- and 10,000-ppn dosage levels). Group VII (30 ppm) was initiated on November 25, 1977 in accordance with an approved protocol modification. VI were sacrificed on February 2, 1978. Surviving rats from Groups IThe study was terminated by sacrifice of the Group VII rats on February 23, 1976. 2. Compound Aduinistration: The compound vas mixed weekly with ground Purina Laboratory Chow (1.e., ground basal dtet) to provide dosage levels of 30, 100, 300, 1,000, 3,000 and 10,000 ppa.. 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 F 3422 was dissolved in 15 ml of ACS grade acetone. The resulting 137-086 601402 | International Research and DevelopmentCorporation | Page 5 I 5. Biochestsery: | solution vas thoroughly aixed with 500 g of Purina Laboratory Chowd 4a 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 vere prepared weekly. 3. Observations: i ! 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 sbnormal condition existed. Individual body weights and food consuaptions 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 vere obtained for analysis from all surviving rats. Food and water were withheld during sample collection. a. Hematology: Hematological studies included: hemoglobial, hematocrit, total erythrocytes, reticulocytes and totald and differential Leucocyte counts. I nitrogen (8UNB)i%o,chepmliacsmaal gsltuutdaimeisc ipnycrluudveidc: trfaansstainmginagsleuco(sPeGSP,T)Sblaonodd urea plasna glutanic oxalacetic transaminase activity (PGOT)S, plasma alkaline phosphatase activity', Y-glutamyl transpeptidase (y-GTP)S, creatinine phosphokinase' and calciund. Alkaline phosphatase values from the pretest (baseline) period were not measured because of fnterference by the anticosgulant. c. Drinalysts: Urinalysis included description of color and appearance; measurement of volume, ph? and specific gravity; qualitative tests for 137-086 6061403 | | International Research and Development Corporation i Page 6 ! proteind, glucose?, ketones?, bilirubind atcroscoptc exaatnation of the sediment. and occult blood?; and | d. Serum Semples: i Serun 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. i 5. Statistical Analysis: ! ALL statistical analyses compared the treatment groups with the control group, by sex. Body weight (at 13 ueeks), food consump ton (weeks 1-13), hematological, biocheaical and urinalysis parame ters at 1 aad 3 months, and absolute and relative terminal organ weights vere 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 Torrtel using Dunnett's! multiple comparison tables to Judge significance of differences. 5. mEswTs: I. General Behavior, Appearance and Survival: At the 30- and 100-ppa dosage levels, one male (30 ppa) had an accumulation of red matertal around the right eve from week 11 co week 13; one feaale (100 ppa) exhibited excessive salivation and rales during week 4. No other rats at these dosage levels manifested any stgns of toxicity. At 300-ppa dosage level, an increased frequency of possibly compound-related signs were noted. Tuo 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 accumsla- t10n of red materfal acound 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 Lo i International Research and Development Corporation | Page 7 } ALL rats at the 1,000-, 3,000~ and 10,000-ppn dosage levels dled prior to the scheduled sacrifice. Most deaths occurred following i 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), aceu- | aulatton of yellow material (anogenital region), dilation of the right ! pupil and excessive salivation and rales. The incidence of these | findings vas as follows: Observation Control 30 No. of 100 Rats/3O00bservat1i,o00n0/Dosage3,0L0e0ve--l _10,000 } ---- Pe pom ppm pen pom ppm EnAlatc.taptoisotnure : Red. motor act. 64 108 1100 1 1 7 CoInncv.ulsseinosnis- 32 5 Redtivmiaetyerfal 1 1 3 1 | Red(emyeast)erial 1 2 2 1 Yel(lnooswe,matmeoruitahl) 2 2 . Pupillary dilation 1 1 Excessive salivation 1 i follows: Survival after 3 months of compound consumption vas as Treatment Group Contr3o0lppu 100 ppa 1,030000 ppppmm 103,,000000 ppppaa NoM.ALSEurviving/No. s5l/s5 5/5 o5f/s5 oo/r5s IFnEiMtAiLaEted s5//s5 35//55 0o//s5 o/s 137-086 { 01405 International Research and Development Corporation rage 8 2. Body Weights (Tables 1-2): Changes 1n body weight vere stailar for male rats at the 30- ppm and 100-ppm dosage levels when compared with control male rats. Female rats ac the 30-ppn dosage level showed slightly lower gains in body weights and female rats at the 100-ppm dosage level showed moderately lover gatns in body weight when compared with control i female rats. Male and female rats at the 300-ppa dosage level showed markedly lover 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-ppn 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: G(%rodupiffMeeraenncBeodyfrWoemigChotnst,rolg) Treatment Group MALE FEMALE Co3n0trpoplm s9o11 (- 2.0) 228669 (- 5.9) : 310000 ppppma 482 (- 3.8) 392 (-21.8) 28 (-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 pc0.0l. Treatment Group Co3n0trpoplm 310000 ppppmm ACvoenrsaugmeptiFoonod WE(grans/rat/daFyE)MALE 22770.26 1199..93 27.4 2.2 18.6 1500 137-086 001406 |. ! i | | ! | i ! , ! 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 dosage levels at 1 and 3 months of study and level at 1 month of study vere within for the rats at the 300-ppm expected range. The 3-month erythrocyte counts, hemoglobin and hematocrit values for male and female rats at the 300-ppn dosage level were slightly lover (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. Blochentstry: With the exceptions of the following findings, all biochea- Leal values were within the expected. range. At the 30-ppm dosage level (l-month sampling period), two male rats had slightly elevated Y-GTP levels (9 3-month sampling, one of these Y-GTP levels vas units/ml/rat). still elevated At and the two other males had elevated Y-GT? levels (10 units/al/rat). The group Bean Y-GT? level for male rats at the 30-ppm dosage level was signifi- cantly lower (p<0.05) when compared with the control group mean. male rat (3-month sampling) had a slightly elevated PGET (154 One units/al) 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 Tats at the 30-ppn dosage level also showed slightly elevated blood urea nitrogen values at 1 month of study. At 100-ppa dosage level all biochemical values were within the expected range and showed no changes that could be attributed to the coupound. At the 300-ppm dosage level (1 month) plasma alkaline Phosphatase levels were elevated for all females (statistically signi- icant at p<0.01 when the group mean was compared with the control 137-086 01407 [International Research and Development Corporation Page 10 group mean). The group range for these values was 210 to 291 units/al. One of these females also had an elevated PGOT (480 units/al) value and an elevated BGT (360 units/ml) value. Tvo male rats (at 1 month) had slightly elevated Y-GTP values (13 and 16 . units/ul). 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/al at 3 months. At 1 month of study, two female rats at the 300-ppa dosage level showed a slight and moderate increase in BUN. At 3 months of study, the BUN values for male rats at the 300-ppa 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-ppa dosage level was significantly higher (p<0.01) than the control male rats at 3 months of study. c. Urtnalysts: No changes considered to be related to compound were seen 1n the urinalysis studies. { 137-086 i 601408 International Research and Development Corporation IV. 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 veighed and representative tissues ; were collected in buffered neutral 10% formalin.* The adrenals, thyroid/ ! parathyroid and pituitary were veighed 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 mot taken. 2. Histopathology: Microscopic examination of fixed hematoxylin-eosin stained parat- in sections was performed for all rats in the control and 30-, 100-, 300-ppm dosage levels. The following tissues were examined: aadorretnaals mamoary gland nerve (with muscle) bbornaein (vith segment of cervical spleen pancreas eyecsord attached) bpornoestmaatrer/uotwer(ussternum) dheuaordtenu(nvith coronary vessels) salivary gland spinal cord (lumbar) !| 1jleejuunnum sptiotnuaicthary kciodlooenys ttheysrtoetsd/ovaries lLuinvger uparriantahryyrobtldadder thymaunsd any other tissue with abnormmaelsietniteesr.ic lymph node In addieion, livers from rats in the 1,000-, 3,000 and 10,000-ppm dosage levels were processed and microscopically examined. E *Eyes fixed in Russell's fixativeE . -- 137-086 01409 International Research and Development Corporation Page 12 B. REsuLs: 1. Gross Pathology (Table 17) and Organ Weights (Tables 18-19): Compound-induced, gross, liver lesions were observed in all 300- Pm 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/vhite 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 Lestons were observed in the stomachs (hyperemia/congestion, red/brovm 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 vere considered compound related with male rats more severely affected: organ Dosag(eopmL)evel Sex Weight Change p< Liver 310000 MM aabbssoolluuttee,, rreellaattiivvee increase increase 0.01, 0.01 0.0L, 0.01 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 KBirdanienys TPhiytruoittda/rPyarathyroid Dosage Level (ppm) Sex Weight Change p< 130000 MM rreellaattiivvee ifnaccrreeaassee 00..0055 300 MF rreellaattiivvee iinnccrreeaassee 00..0051 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 1,000- ppm groups and increased nusbers of hepatocytes (hyperplasia) in the | 3,000- and panlobular 10,000-ppm groups. These in distribution with more alterations were liver involved as centrilobular to the dosage level | increased. A very slighe-tommoderate facrease In cytoplasate vacuoles vis , observed in the livers of the 100- and 300-ppm groups. The vacuoles i contained 1ipid (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- aad ! 10,000-ppm groups. The lesion appeared to be primarily centrilobular to midzonal in location and there was a minimal amount of associated in- flamatory tafiltrate. Increased intracytoplasaic 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 | Kuptfer cells stained positive for iron while hepatocellular pigment was negative for iron. Kidney lesions vere 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 : Pignent 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 vas 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 mot considered compoundrelated but were interpreted as spontaneous in origin. 137-086 01412 International Research and Development Corporation Page 15 References . 1. HCioaulletaehr,HeFmloogrlidoab.inometer, Coulter Electronics, 590 W. 20th Street, i 2. MCoimcpraonhye,matpo.cr1i1t5,4.John B. Miale, 3rd Ed., 1967, The C. V. Mosby \ 3. WC.ou2l0ttehr PSatrreteitc,leHiSailzeeahC,ounFtleorr,idaM.odel Zg, Coulter Electronics, 590 ,i 4. RGeriatdmwahno,l'sEdiCtloirnsica6lthLaEbd.o,rat1o9r63y,MeTthehodC.s aV.ndMDoisabgynoCsoimsp,anyF,ranp.kel113a2n.d 5. Technicon Auto Analyzer 6/60 Micro Methodology. i 6. MSiisgsmoaurGiG.TP Procedure Bulletin #545. Sigma Chemical Co., St. Louis, 7. Micro Auto Analyzer II, 6/60 Micro Methodology. 8. Photovolt PV4, Photovolt Corporation. 9. Multistix (Anes Reagent Strips). 10. SSttaeetli,stiRc.s,G.McD.Graawn-dHiTlolr,rieN,ewJ.YorHk., (1N.960Y)., Principles and Procedures of 11. DBuimonmeetttr,icsC,. WS.e,pt.New196T4a.bles for Multiple Comparisons With a Control, 137-086 601413 Rm aSim g g= 2 5 =3 ,i =o : Po"; To Er ----,DETTE bfiramleim.ene 1s rr yr rears B era wPreysent etee sof Scud , BB TfEaeeI w BBmoommREEowmDomoDommoomm aow woowmoowwmm owowws omowwomooowm Bwmoaowmm [mTM BmeOra lORBoOmB SoBOmRBRmmRooommmBomOwoBeRmoomB mm mEoowoEmmom SwoowmoL awoMmwomm Rmodmommpom owBommom:E COEMhRaorpORMRmOMMBRolB OeE BoBm oMlMoommBoEoommoommomommooommoomooommm oowmwoowEoomowmogwom [- H WyLi OMmog mOB a BomeoMom pom OE OR BON E a owmBoDa wBm Dhw8m Emueonm3wm emooe@osonw@e omE wme onooE wsoomueEomwe PoH wgrOoBmow ERD ob oBwoRReomoommeBoomonBmmoomnoommmmmooommmmmoomdmemoomommomoommmoommomoe oaywmmoomwmwoomaoumwsoombwe m HliiPREspopmommomm dom eomg om EoE om E oa Rom ERwER I nWWRoOxlLM OBMmRB oomwOB Wl oBR BD R B BMueooBDmwB e RooweM mBooE wmmBoRomoues@soworuoomoowe@eeomm womwo ooguomeooomsmmmoommmom oomdue uosww TWBB TeiooIoO rrl RoE owl DoBoE mmRRoB oR Nm EomomE omRmoom ommS wOomEomE wBwoomR wmmooEomoaommmooR wmDomoEmomEooommBomoE omERSdommeoSomwooSm CObB TBayEBBmM omR ER Rom B Rom OB omRe BRwooREw ooomBwRooOwmREomSmoowomS owomm@oonoEw o@mompoonas WBELIORM OOMB B meI r RmoDm D oMOmmoEMoomW RmOoWoommB omEoMommmBooommmooEmmoDomomzomommomeoonmpRoomeozm oRoomonBo poEBBRROELI BOOBRR BOOBB pRRooowmmoRommooonmmooomMowmomoommoomm omoom m oEaooo | WeeYeEE mom om ow we aMi noolrooEmsooDR oom omom oa, om ou mmL LtmoirI rToCBBm2oEE8mEom EEonomoBRmoE EammER ooRwe mEEomySne sane P22 210t0-a2i2-n01 f Stoacy Dey d Subacuce Raac Tosmie.tsydSBeiudEyS .ST N Page 18 | mez oe todividual veekly ody Weignee, Grome. fw [rao d sJe CT m prS aca JS T J J y o e A i ofJ see at , SE | 2,000 ope: oTo w PoodMeomo X Xo b aom1be ddwobe bboiiedes uMeosn Hmo mmm dbms bbiees b| onHmeoews Hop rf + oommmsr Fis ozo bdoes iiweEs ls buoiseee bie {oe Fod om ie a |, ooHmmoeem xx Emaoeo |Hoe ls He jLooemHeyaw PFro oomaGemi EHoRle Me o Imme hbbiie oe ikeo iosi bis 1aow5ee bbbiilse mi bes | t37enms 60141 S mdz>.re2700-342201 MMeineoty wDMaeySanSuFbhoaocduteCeonRy meautmpTheotxotney.ttysSecusd.. eoeFk. 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Subacute Rat Toxicity Study. { TABLE 4. _-- of ControTl-teansdt TCroemaptaerdisoGnrouBpest,weeFnoodMeaCnosnsumption. Te | WSeteukdy --- Sex Control 3m 0 ppo m. T10e0 pmpm | 1-13 u F 2179..69 21970.32 1287..64 Page 20 300 eppma 215..21%% ii i | || -_-- 137-086 #significantly different from Control group mean, p<0.0l. 001418 . F_M---3422 41-2700-3622-0: Ninety Day Subacute Rat Toxicity Study. | B-_L--E 5. MALES: Means and Significance of Hems atologicals Values. |gg -- Hematology Study Month Control 30 ppm T100m ppm | Erythrocytes, Pretest 10%/cam 1 6.08 6.87 | 3 7.69 , Hemoglobin, | 8/100 m1 Pretest 15.4 1 16.1 3 16.3 , Hematocrit, | z Pretest 46 1 49 3 50 Leucgeytes, { 10%/com Pretest 9.39 1 10.43 3 9.79 ! Neutrophils, z Pretest 1 4 9 3 13 {{ Lympho7cytes, Pret1est 8859 ' 3 85 | { Eosinophils, z Pretest 1 1 1 3 1 ' Monocytes, z Pretest 1 0 1 3 1 | Basophils, z Pretest 1 0 0 3 0 | ! Reefculocytes, Pretest z 1 6.1 2.6 3 2.6 5.95 6.76 7.30 14.9 1156..00% a" a50m 13.19 10.78 n.21 28 1 15 8712 8 01 1 0 1 0 0 0 46 2.2 2.9 5.69 6.71 7.64 1.7 1165..19 45 4g7x 10.33 12.25 1.35 un 1 12 8888 86 11 2 0 0 0 0 0 3.8 2.6 2.8 Page 21 300epmpm 66..5043 6.814% 16.2 1158..874% 47 4a9drx 11.33 14.45%% 9.11 7 10 921 8 11 01 1 00 62.81 3.6%% _-- 137-086 Significantly #*$ignificantly different different from from Control Control group group mean, mean, p<0.05. p<0.0l. 601419 3022 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 5. Conc. FEMALES: Means and Significance of Hematological Values. Hematology MSotnutdhy Control 30 pm 100 ppm ; Ertyprioceytes, Pret1est 66.84s1 : 3 7.56 Hesoglobin, Preest 15.2 8/100 m1 31 1166.21 | Hemato7crse, Pret1est i46 3i | Les10c%gecyaemes, Pret1est 190.a50 3 508 i Neocrozphtls, Pre1cest 1152 3 13 i Lymphozcytes, Pret1est 8a7 3 8s : Eosino2phils, Pret1est 11 3 1 Monocytes, Pretest ! z 31 01 {| Besop%nils, Pret1est 0 3 s6.i2s6 6.63832 710 727 15.8 15.5 1155..96 1156.s1 5us0 a4 i a 18.17757 57..3780 alas it 122s 1152 1% 0 a3 aa a a 1 21 1 2 1 01 0 0 00 | x Reticulocytes, Pret31est 322%.7 b3Lusb 222.30973 ! Page 22 300 pm 6s.l4e7s ois 16.7 116..800 ai use 190.8259 8.62 u7s 10 a52 a 221 0 01 o0 32Z.i75o 137-086 *"SSiiggnniiffiiccaannttllyy ddiiffffeerreenntt ffrroomm CCoonnttrrooll ggrroouupp mmeeaann,, ppe<00..0015.. C01420 . W I e T ETE e I hewSess ne Dy w Subacuce tac BESTCOPYAvanapi Tost sud. = ' perry aGown fSorne mBeene SndividualmVemsecolopeti enl Taloe ns < eFraes sesrs,. ses, bwewhto Glnee RSeeemomna Loeme feornme omemme ms Merion |! cSonlgreatsse aeimmodie em C Te S d PSr Y T FBo wE Bim T y ||| mmmeeexoxan oaemm mmees wxoo snwee WmBae8o0wow 0 uS Lo BgaEmm o3won ROB moo & 33 0P5B 5% PPooeeooss 3ouoans oa i ! as "new em ooxR 0 mJre reo m ewe A ws emAo 1mA o 8 5 Pooee iPoose aon o ow e | mmmeeerorrooammanmwel 8L&o BBuERm 4o% 888 80a% oio55 5 0oG iid suas Rom a m2 ow wm ou o ow ioe oan | i JaAneannxXox uoowsddomaEwoooanloWdasst ds wo wm ws 48B00s0 5 BwBBiaaR xa3O3R 8808 dm #0 53% 8 i os88 ao o 022 nwosu oid i i! mmyson roroesgsrh fre aw8ss 300Ww bsBmwRRowm o8o I n75 5 o a too1 o uas @ oo i , ddseo roaomamse saan em awhoo 450 was B488 RORSS onnom oo "5 i iooe 00 aodu Vor a | oo pon: i! T mwmowmkoodaamdeoumde pAmnooxoddea as o48w wBBwREBomOY d 80 &NEg) oo S oaw o8 p B e e 1s s s ioe 3e opai 0. 13 | mmmeasorroahostseoe oWwnyrs 4s a5 wuWamE OuaR ooop 8 on s toeos oo a iPoose o0aar mmpeeeeoorrrooeeondeeewoa#Wls 308o&o stMmno RB 5 5 503 %8 iiPooosse 8 oiidn | wes 200m: en ms ow ms 0 ie a | mmmmeemeoxdoxoddaaammme ooowwwBSmsa 3588ow me oyosmoo3 8 BBomaeOWwo N MW a3f) %w50sB iitooosss io 08 5nhdua 3 . |t mmaeesroroseos ooanwms:s wun 3 os8 o8w mgmoRuo H P ro os se ea n FiE orSE 0 us ii mmmeeearrroooooadnmahowlossn Suan "ner Fow ONR d E 0 %ON83 8 %s&s a an ao " ia ioo0se 33oown Teal : ----it-- ermetren-- remnrts ------------------er-- es 137-008 601421 n BESTCOPY AVAILRBIE, WEEB l.. SE RCE SSEEPRW ESRWOOW WOWT owwowmmur Nn To sms us mam uo " oso ax noe ee e ee. n JE 001422 BESTCOPY AVAILABLE... : -- | ) 7831 x Tae 15.6 a 11.66 18 80 2 9 1.2 oo 601423 = TRoeunst, drensizzeor nTnedSiivvnieidsuallDalMyeemSe socboalcoue pciecaFlace efaTievxeied cstr-y3e Sveeeurncr,.rs. Ge Hareins.e se EirSviiehmeee gmWeeenem Waebmetsto NLcoemeoSSLTTeeoc eYsnsE es. LtmepTerse S fses%hine oeiES lee ssenR n eorien mmmeee xxx g273ss6 mex Te wa13es ooHmns ask mdmiome oaem ooo6 si 18 oa 2 i5:: i [3oI 23 i1ofls1 es xe oan ne ome ws & os 5% 8 as om oo 2 a : : 3 fs 3 1 ne J mmmeoesees rrrooooramnmo me ro Tas aBas:n oo4as ss ex sm du3 oo0 ue ou 0 55n & oi1 5soo03 isllo2 i io 38 | mee roa on nw who wr Wh ho ow se 1m oo a oE 1 FE 7 0 ! 2da0e5nn0s: xoov rraN wwss o4w usmi o10 no0 den x em wi Wo oan ao *7 0`1 s io o0 f22asd + Wdesx xx ardss sdha boom spewoo1Booo %a ii [3 ifett se 7 mwyeror oonrsB mse 3ws omu0 um 1 oo a1%monsoo = 7% 1 oo te 2i FsE 0 pboss wndaaewsorrooroooaoedense aumwahn 48wo wsvsai B73 o40 57 3i: 5dFE os0 f5ii1) osm ae ome a ses wo " 1 PE 3 t E meoEwow EoarmE om EBB3300 EWoEww wE WwEEE3]. mow rw a Go as 30 5"2 2i5 o 3[E o3 i 5 2iii2 ie mno fie sean ne wl 4 mew wl ao ux on o nn o : [E 2 2 oo 2s : pmmeeso orrroaeam sworn mBwhlo ns wGoowa oa eoenwmo bo1on6oo esx 0 2"i % `3: 2[FEE 0 ii?3 3 oo 3 | maenr wreowsws 40 p ew eow ]o oam d : eFE 0 ain 0i 2m0m0e3e05:xow eexs nuse 0a ovwen w7 o3 meov sw m3 4 sw 8g 23pe 35 o [T I o o iu3n ts emes vansie wBaEd4 E Be 8508 "= 1i s iots iBd oss es wr ow pmeesr rPeosgs mHoo 44s su so sw e g so 0 o3%s . I ss 53 Fa I Hiu e B mef TopooSfeiand oiws a 83a3 iHS ii 5 FE 8 if+) os en ws es we wo " : re Pr 137uass I P3422 41-2700-3622-0; Ninety Day Subacute Rat Toxicity Study.eeePag: e 27 TABLE 9. MALES: Means and Significance of Biochemical Values. Blocheatstry NSoenucdhy Control 30 ppm 100 ppm 300 pp Glu5c8o/s1e0,0 m1 Prec1est 170%0 10612 1087 3 126 123 120 BUN, Precest 14.2 1.0 12.7 =g/100 ml 31 1164..36 2115.26 1184.s5 i G.1.2., Signa units/ml Pretest 1 11 25 61 j 3 0 or o 97% 119 12.6 219..7300 71 0 | crSixgu,a untcs/al Pret31est 22055 116Ey 105 11530 | Alkaline Phos., Pretest 216 ! int'l units/1 31 112762 11720 11789 p12r8 e .6.f0a.c1t.,Untes/1 Prete1 st 131039 18037 11o116 29% 3 104 10 101 9 P.Gt.aPe.T'.,ntes/1 Pret1est 11530 a7 9a5 9615 3 "0 6 "0 sr Camleeqt/uln,icer Prec1ast 109..20 97..57 108..76 89.47 3 1a 10:9 10 12 rv S-- s ---- IScacts-- tical -- analyse-- s not c-- onducte-- d on t-- he pret-- eset svalr eusst. r --__ #CS.iPg.nKi.ic~anCtrleyatidniifnfeerapnhtospfhrookminCaosnterol group mean, p<0.05. #*Significantly different from Control group mean, pe0.0L. 001425 R322 41-2700-322-0: Ninety Dey Subacute Rat Toxicity Study. TABLE 9. Cont. FEMALES: Means and Significance of Biochemical Values. Biochentatey HSoecahy control 30 pom 100 pou Glu2c8o/s1e0,0 m1 Pret51est 11o2188 115o02r9 1160s9 Bwuel.i60 a1 Pret5iest 111652.9 17126.1297 1w156.s.55 Lo ovsre, Pretest ' 1 1 | Sigma units/ml 31 11 128% 01 3 7 10 ` | c.p.kb, Pretest 6 13 6 Signa units/ml 1 8 15 10 i Alkaline Phos., Pretest 4 140 + int'l units/1 31 &91 5116 683 root, Pretest 1 a 11s N int'l units/1 31 10911 5121 a7s9t ror, Precest 103 @ 5 int'l units/1 51 =41 24" 39 | catetum, Pretest 5 77 5.7 meq/liter 51 8n.s9 210.0 8n.z7 Page 28 300 pou 11900788 221.83 1 21 ;5 13 + fr249%% 106 h19t6 55 160 5.6 n9.e0 3| 137-086 +SCt=a.t7Nio,stti-sceaaClsreeraaetndailnydisuneees ptohnoostapnhtcoiokcniodnsuagcsuteleadnton inptreertfeesrtenvcael.ues. *4"SSiiggnniitiiccaannttllyy ddiiffffeerreenntt ffrroonn CCoonnttrrooll ggrroouupp mmeeaann,, p5<00..005l.. 001426 Peaa2 41-2700-3422:0: perm aGrrou, Glucose Somber sex ai/i00al coneel: fmoie 23s efnecsteu4 7o sos " emmees F as5 | J me oF 37 ean " | mem PI oeeemnnwx &5 , edesm ou 7i Sean n aeynFeoF 5i5 a Tae E &2 soso o 1m0e0an0: x n oLmoemfnet xx 33 ws 4 i os a [omomee xof EH 5& ponesf 55 oan " , 20m0eoms: x a | JTmaremx 587 Toss 7 : os Pofheoiw f x s38 LLoomee r1 ow3 jo ES Ninety Day Subacute mac Toxicity Study. Tndividun biochemical Values - Precest. 30x. rG.t.e. SCirme Akfoefer agil00sl sigs snits/el ueitafal seitsfsl 1215.330s 2ii 11825% io 12 1 1fri13t] ii1 uwly ii 169 1 1187.2 :2i ifes] ii 10 2 fr11i.s]0 zi1 w5i6 1i ws 1 1e12x40] 511 1383 =i 127 . 11693.52 2ii 11335 i1 155 1 102.35 11 1r12ds0 1i 1 ns 1 11z365o 2i w5os ii Ba 1 o25 --- 33 -- 53s --33 - 5 iu1n 2108s i. is2so 1 ne 5`. 1h17i8 is2 mi 5 10 i"3 --13 -s :i -":3 - z7 -- 35 -- u " 1 5"5 -"-- i5 -n s FmOeOnT. unitaiml hm10nr Ww3 m i12306 1i2 me o=" 5a 1%078 aa a 11130028 15 us 10u125r m120 us rwml 1503 0 ue 1132300 138 106 PmOeRlT mice/sl mw2e 5i us in110280 0 isna a3 n &aa 7 1ao8r i5n 5s 3 125% or 1008 % ss 330% 1038 9s Page 29 csaieim liter 111000.182 1p0o 10.2 115010.s2 151s0 a". sp0sn a71s ns 57711s a7sa 1 1321s53 31012 10.7 w55i.5 557s 5.7 30.55 1S0l1i 102 0.1 0b91.r2 3a5 5 --_-- e"oCirleiaacliinnieaeospprhoascshaosreinamsoee sessured due to saticosgulece | m[ .utapti-- ons wHeaensy dBeysbecsesaee tooiesesseereXS0E0S1TUO7PFYRAVyOA TARRE. 5 aoSorTiee s Ft ree ee BE TEhee tsee wIiRn wien lelhite oSieNeLle eJlLe aJfte SWCD | 1,000pp: i ness " 16.2 1 por r nan : | T6000 NM i 12.0 1 u - . 3 - wm 0 10.1 wea 9 120 10.0 Do 20.000pee | C- nou : i , Wom as - n ----nn p. t tn mm rage 1 m Er eee BBoa soee SSEh SSBi.e sWeSlEmihe wSiELe aEiD wWlEie aRlDie } 73966 120 15.0 1 so | ne F 105 nr 1 9 %0 a" a 8.6 5 a 3 u Ey sa - rr ---- nnn 601429 Lo,Dd eOyET y --Ri -- Yhwwe ioeecey De ey Subacm uce tace Tosietsl y Seody.dwses Page 32 |b | oo . E ameer e.EGl. ucLose e A80Ex.so Totl tvidvi uiaelrSeieoshh enicalCSVirai lmxuees - 3al SkCahecrtsheSrh PToerdi n vTc oENoTr n ccums om Te wiPS SiwSmwie/a wwiiffee woiebld woiwl/ed waisfer Tide pmPeaea xx oomm fi15e.d5 2o Tew dn i 2 05: 5i0 i52 i0a wwie3 Bfee oom i3 : | mSaesa 0 1mma103 .o 0; i5 5: 1"6 i5 5% 1i "y 0 wion owai PTMeeee ep11 idbnwi fri0s]s i:{ |I 3 i :s3: iii5 352 1a5 wfirises sosa 1 wa ; o 7 i0o iulss 2an0mmoe wwowi nox on 1fux1s] 1003 i5s iwwi] e3e 1E0ad 11100033. pomunse wo B foi] 53 fo m 152 . :i 32 5m a5 i5 fnrs] Py 20 10s I wyaeorras PoE rm fo2113 2 i:i i 1ii0 1Fn0y S 5 %x3 i5a5s winia 7 5 fre] He ob saan im is na i 2 5 10 H " 2 H wd ni P-- oewmn x wm 1101 a: whoo in i : 335 iiwfim 3ia i10oF0] 1i100g.76 Pomomsm ov ii ofilx] :: Jo 1m 1s ;7 nis] 1 ue i% i3 i1o3 " 0 ul jPoE mwEhooorp iam iis2is whoop io 53ii `i7 ; HwaF G a3FA Fl 3n i0io. u iw Ter da i 3 | aan us 20.8 1 : 5 a = 10s ` 3 8 2 |e Fmrmexx admS fom1 [ome own mi oo{ i.: PFiYA Py 15u3t ii10e.8 PomToew x iosn Boii 22 aa 1I o 0S wil awi] a7s ii 5 ne us naz om Tmoww o11ramdie pinides 523 T Dawe Fp bii 3 $ ii5 3 io31r 1s6i0 o ] 1in 5 i313 ul saan 108 ns : 5a a us 1 1-2_7---088 Cesacinios promroriesee . F-3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 13. MALES: Means and Significance of Urinalysis Values. Urinalysis MSotnutdhy Control 30 ppm 100 ppm i, Voallume, !, oe Pret1est 3 Pret1est 3 || Specific Gravity Pret1est 3 53..89 5.2 67..71 6.9 1.1.005302 1.047 61.72a 3.7 67..50 6.3 1.1.003766% 1.057 5.4 56..60 7.4 66..69 11..005302 1.051 | i Page 33 300 ppm 47 46.38 7.3 5b.9i 1.031 11..004657 | | { 137-086 P*SStiagtniisftiiccaanltlyandailfyfseesrenntot fcroomndCuocntterdolongrporueptemsetanv,alupe<s0..05. Significantly different from Control group mean, p<0.0l. 01431 _F---3422 41-2700-3422-0: Ninety Day Subacute Rat Toxicity Study. TABLE 13. Cont. FEMALES: Means and Significance of Urinalysis Values. Page 3 cUrcinaclydscis Study MonichONContbrolBo. 30 ppmAO1i00sp.pm Volume, i al Pretest 1 3 PiE Pret1est 3 || Specific Graviey Pret1est 3 3.4 2.9 2.0 57..80 6.3 1.1.005371 1071 "122 1 62..934% 6.8 11..003675 1.084 21..88 3.8 66..39 6.4 1.1.00630 1.044 I30o0 lp.pm "as1 39 67..40 6.3 11..002676 1.043 i || | 137-086 *"SStiagtniisftiiccaanltlaynadliyfsfeesrenntot frcoomndCuocntterdolongrporueptemsetanv,alupe<s0..0S. **Significantly different from Control group mean, pe0.0l. 001432 Bes MU ah EL SO GO St me fen ee on ome se gg Ee Idn JR a-- = 88A LH SETimEmse JLnIiiE z: | mn wees g2a MRP WEI ODD YD Yow or E=BB 3 Be -- Mea dim. mem med g ; Bo an BIND LE i = g ==2 u3 = E & ----- te g Boafmem, Eia PET ee ee - @ i 8 : Bo time gm E 2 gg EE= & E = Swe TEER EEE DR em 5 || i o_o z 2 = - = E= B25 rem _--m fon mems, RBimielndu a PLO e--e -- So @ i SEE his i= : Bilwmumirrrg: oats: oz . EgB= = = S2 ay1 Tem rns Th FSTo 4 epe--TIS 2 a82 o BHoImaEL, mm RI ia ma Arbomn := -- . wE s. e reSsRE pert = a En mn : IEhE Tr 3133 3% ' Lo. tHe R . EEE SteBE m ernA a HE fH. \ : ETLos: 2go EEmWm. a: ae,: :z 2Eom 25 : | fo ee Tonten TW ey rye, is see TE p7 m er pp : -- p-- a ume -- upp gene : TT eg 3B [E-- i I 2g2a ae I t L lR e C-- e A TaOiRE g8 ===2 So Zr aos e i i &8:z Tron Fw wn vee me we a oe i : eo nm so pe 4 EmHob EL we oam oomm f8 ii ommrnoOFFE mOE EHae OEnmoao B"or oomm 2m da52 ii S mrm vop Eom a ose oo onmn o.m- in i. oo oe Ge oT Frere BeBe n g i i= = i PO=E= i " g x :& TT e ia nt ae ] BEES ammo EEE se en 0 greg, PEL my Toten weno, TTT Er Er TTEE Te TE Ta EE Eb or pa 1 LC OL a SO TT TT TAR TR nh 5 a he a B B I CE E EELn pia, ht 0 be . TTT TR rm ty ' a , it, VR : wT See mmm LE m mm Te TTTTTTRI I TI 5 tty st Cnn nan nnn an a= 3E Rho EEEEmmL SsmeT , T : . 1} gE . Br a Fever wn SAT Bray intiierate vened Mion. * CL, : aHT a Eo Vaepetitiaettiiaalecoelnlie sh Sea betin 4rtets tier rteoaeghronte. Mb ! > ain di nn ai Loa or = 3 pen g - = a ay = -- 2CRE 2 3: Tana Tha aan a E ea :, e eewe 0 romiimaeee ii g me | on . em iadete, TT ee Ee TM g<2 ggzz zEz 2 = 5 ery f B Er -- he Glggzap naan senanaaneg qesag inant Bere, Linn a. 0 : EE se tps ' : : g < E g Zz : z on Cot x cotton press 4 tre Ee EEL