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L@LC@C'ikcl @ivI s c 0 N@ s I t-i f,c)s T o r r 1C F E.0 X 7 E 4 r, 1,1A L'IE 0 W. W I 53707-754.r, FINAL REPORT Roger G. Perkins, PhD 3M Toxicology Services Building 220-2E-02 St. Paul, MN 55144-1000 HWI Number: 40200468 Study Title: Acute Oral Toxicity Study of T-5898 in Rats (OECD Guidelines) Signed: Stev6n-M. Glaza C) Uate Study Director Acute Toxicology t ne 7 :e il F'@E S l@,l I L E L I \fE R Y: HWI Number: 40200468 Sample: T-5898 Acute Toxicology Steven M. Glaza Study Director Manager Steven R. Sorenson Study Coordinator Patricia Padgham In-life Supervisor Rose M. Bridge Report Supervisor Page 2 KEY PERSONNEL Laboratory Animal Medicine Cindy J. Cary, DVM Diplomate, ACLAM Supervisor Anatomical PathologY Thomas E. Palmer, PhD Anatomical Pathologist Deborah L. Pirkel/ Jack Serfort Supervisors Necropsy Anne Mosher Supervisor Pathology Data CONTENTS Paqe Key Personnel 2 Objective 3 Test Material 3 Test System 3 Procedures 4 Summary of Results 6 Discussion 13 References 13 Pathology Report 14 Appendix - Raw Data 15 HWI Number: 40200468 Sample: T-5898 Page 3 OBJECTIVE The objective of this study was to assess the acute oral toxicity produced when the test material is administeredby the oral route (gavage)to rats.' TEST MATERIAL Identification The test material was identified as T-5898 and described as a clear, lightyellow liquid. Purity and Stability The Sponsor assumes responsibility for purity and stability determinations (includingunder test conditions). Storage and Retention The test material was stored at room temperature. Any unused test material will be returned to the Sponsor after issuance of the final report according to Hazleton Wisconsin (HWI) Standard Operating Procedure (SOP). Safety Precautions The test material handling procedures were according to HWI SOPs and policies. TEST SYSTEM Test Animal Adult albino rats of the Crl:C[)O(SD)BRstrain were procured from Charles River Laboratories, Inc. and maintained at the Hazleton Wisconsin facility at 3802 Packers Avenue, Madison, Wisconsin. Animal husbandry and housing at HWI comply with standards outlined in the "Guide for the Care and Use of Laboratory AnimalS,,.2 The animals were separated by sex, housed in temperature- and humidity-controlledquarters, provided continuous access to Laboratory Rodent Diet@ #5001, PMI Feeds, Inc., and water, and held for an acclimationperiod of at least 7 days. The feed is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. Samples of the water are periodically analyzed by HWI. There were no known contaminants in the feed or water that would have interferedwith or affected the results of the study. HWI Number: 40200468 Sample: T-5898 Page 4 Ten male and 10 female acclimatedrats, weighing from 225 to 280 g, were assigned to two treatment groups of 500 and 5,000 mg/kg of body weight. Each dose level consistedof five male and five female rats. Animalswere group housed by sex and identified by animal number and correspondingear tag throughout the study.. Food and water were availablead 7ibitum, except for an overnightperiod before test materialadministrationwhen food, but not water, was withheld. If variationsfrom the requiredtemperatureand humidity conditions existed, they were documented and consideredto have had no adverse effect on the study outcome. Justificationfor Species Selection Historically,rats have been used as a representativeof a rodent species and are preferredby various regulatoryagencies. PROCEDURES Preparationand Administrationof Test Material The undilutedtest material was administeredby gavage using a bulk density determinationof 1.13 g/mL to determinethe dose volume for each dose level. An individualdose was calculatedfor each animal based on its fasted body weight. Reason for Route of Administration Historically,the oral route has been the route of choice for administeringa known amount of test material. Observations Clinical observationsand mortality checks were conducted at approximately1, 2.5, and 4 hoursaftertest materialadministration.Additionalclinical observationsand twice a day mortalitychecks (morningand afternoon)were conducteddaily thereafterfor 14 days. Body weights were determinedbefore test materialadministration(Day 0). Additional body weights were determinedat Day 7, at terminationof the experimentalphase (Day 14), or at death when survivalexceeded 1 day. HWI Number: 40200468 Sample: T-5898 Page 5 Pathology At terminationof the experimentalphase, survivinganimals were euthanized. All animals, whether found dead during the study or euthanized,were subjected to an abbreviatedgross necropsy examination and any abnormalitieswere recorded. After necropsy,the animals were discarded and no tissues were saved. StatisticalAnalyses No statisticalanalyseswere required by the protocol. Location of Raw Data, Records, and Final Report The raw data, records,and a copy of the final reportwill be retainedin the archives of HWI in accordance with HWI SOP. HWI Number: 40200468 Sample: T-5898 Page 6 SUMMARY OF RESULTS Test Animal: Albino Rats - Crl:CDO(SD)BR Source: Charles River Laboratories, Inc., Portage,MI Date Animals Received: 01/14, 01/28, 2/04, and 02/25/94 Experimental Start Date: 02/22/94 ExperimentalTermination Date: 03/23/94 Estimated Oral LD50 Male - Between 500 and 5,000 mg/kg of Body Weight Female - Between 500 and 5,000 mg/.kgof Body Weight Animal Number C29181 C29232 C29184 C29234 C29190 Mean C27615 C28047 C28043 C28070 C28050 Mean Individual Body Weights (g) Day 0 Weight Day 7 Weight Gain* Day 14 Weight Gain* Males (500 mg/kq) 267 224 -43 319 52 274 302 28 382 108 253 284 31 354 101 280 312 32 390 110 257 289 32 353 96 266 282 16 360 93 Females (500 mg/kq) 241 228 -13 261 20 230 225 -5 255 25 225 180 -45 (131)8 - 232 207 -25 239 7 238 225 -13 250 12 233 213 -20 251 13 Gain from the Day 0 body weight. Value in parentheses is the body weight at the time the animal was found dead. Superscript number indicates day of death. This number was not considered when calculating the mean. Not applicable. HWI Number: 40200468 Sample: T-5898 Page 7 Animal Number C28621 C28613 C28598 C28619 C28625 Mean C28099 C28117 C28118 C28104 C28120 Mean Individual Body Weights (g) Day 0 Weight Day 7 Weigh Gain* Day 14 Weight Gain* Males (5,000 mg/kq) 269 (203)7 271 (228)3 266 t 267 (215) 271 (234)2 269 - Females (5,000 mg/kq) 246 (209)5 250 (235)2 267 (23!B3) 267 (23,5)2 255 (225)2 257 - Gain from the Day 0 body weight. f Animal was found dead on the day of dosing. No body weight required. Value in parentheses is the body weight at the time the animal was found dead. Superscript number indicates day of death. This number was not considered when calculating the mean. Not applicable. HWI Number: 40200468 Sample: T-5898 Page 8 Individual Clinical Signs Animal Number Observation C29181 C29232 C29184 C29234 C29190 Appeared normal Thin appearance Appeared normal Appeared normal Appeared normal Soft stool Appeared normal Hour 1.0 L. 5 A-0 I I I A A Males (500 mg/kq) 0( - Females (500 mg/kq) C27615 Appeared normal if Red-stained face Thin appearance Alopecii - rear quarters C28047 Appeared normal C28043 Appeared normal Red-stained face Hypoactivity Thin appearance - - - - - - - - - Hunched posture - - - Aggressive behavior - - - Found dead - - - C28070 Appeared normal C28050 'Appeared normal Red-stained face Condition existed. Condition not evident. Day A a @LO 11 12 13 14 1( f/ - HWI Number: 40200468 Sample: T-5898 Page 9 Individualclinical Signs (Continued) Animal Number C28621 C28613 C28598 C28619 C28625 Observation Appeared normal Red-stained face Hypoactivity Found dead Appeared normal Red-stained face Hunched posture Red nasal discharge Staggered gait Hypoactivity Dyspnea Miosis Found dead (afterclinical observation) Appeared normal Miosis Hypoactive Clear nasal discharge Found dead Appeared normal Red-stained face Hypoactivity Found dead Appeared normal Red-stained face Dark-stained urogenital area Found dead Hour 1.0 2.5 4.0 1 2 3 4 5 6 Males (5,000 mg/kq) -- Condition existed. Condition not evident. Day a LO 11 12 13 14 HWI Number: 40200468 Sample: T-5898 Page 10 IndividualClinicalSigns (Continued) Animal Number Observation Hour 170 L. 5 4.0 Day 5 6 7 8 9 10 Ll L2 13 14 Females (5,000 mo/kq) C28099 Appeared normal Red-stained face Miosis Hypoactivity Found dead C28117 C28118 Appeared normal Soft stool Yellow-stained urogenital area Red-stained face Lacrimation Hypoactivity Found dead Red-stained face Dark staining around eyes Hypoactivity Yellow-stained urogenital area Found dead - - - - - - - - - - - - - - - r, f/ C28104 Appeared normal Red-stained face Yellow-stained urogenital area Staggered gait Hunched posture Found dead (afterclinical observations) C28120 Appeared normal Red-stained face Hunched posture Hypoactivity Miosis Found dead (after.clinical observations) o( Condition existed. - Condition not evident. HWI Number: 40200468 Sample: T-5898 Page 11 Individual Pathology Comments Dose Level: 500 mg/kg of Body Weight Animal Test Day Number Sex Died Sacrificed Necropsy Observation C29181 m - 14 No visiblelesions. C29232 m - 14 No visible lesions. C29184 m - 14 No visible lesions. C29234 m - 14 No visible lesions. C29190 m - 14 No visible lesions. C27615 F - 14 There is alopeciaon both hind limbs, 60 x 35 mm. C28047 F - C28043 F 8 14 No visiblelesions. - Due to the animal being cannibalized the spleen,pancreas,left kidney, duodenum, jejunum, ileum, cecum, colon were not found at necropsy. C28070 F 14 No visiblelesions. C28050 F 14 Each horn of the uterus is filled with a clearfluid HWI Number: 40200468 Sample: T-5898 Page 12 Individual Pathology Comments Dose Level: 5,000 mg/kg of Body Weight Animal Test Day Number Sex Died Sacrificed Necropsy Observation C28621 m 7 - No visiblelesions. C28613 m 3 - No visiblelesions. C28598 m 0 - There is red ocular discharge in both eyes. C28619 m 5 C28625 m 2 - There is a tan, moist abraded area on the dorsal cervicalregion, 15 x 10 MM. - The perianalregion is stained yellow. There is red nasal discharge. The nonglandular mucosa of the stomach has.multipledark red areas, pinpoint and up to 1 mm in diameter. C28099 F 5 C28117 F 2 No visiblelesions. The perianal region is stained yellow. There is red nasal discharge. The nonglandular mucosa of the stomach has multiple dark red areas, pinpoint and up to 1 mm in diameter. C28118 F 3 C28104 F 2 No visiblelesions. The perianalregion is stained yellow. There is red nasal discharge. The nonglandularmucosa of the stomach has multipledark red areas, up to 3 x 1 m. The thymus has multipledark red areas, up to 1 mm in diameter. C28120 F 2 The perianalregion is stained yellow. HWI Number: 40200468 Sample: T-5898 Page 13 DISCUSSION The acute oral toxicity of T-5898 was evaluated in male and female rats when administered as a single gavage dose at levels of 500 and 5,000 mg/kg of body weight. Based on the observed mortality, the estimated oral LDS,for male and female rats was determined to be between 500 and 5,000 mg/kg. Clinical signs of toxicity included thin appearance, hunched posture, hypoactivity, Aggressive behavior, staggered gait, red-stainedface, clear or red nasal discharge, miosis, lacrimation,dark staining around eyes, dyspnea, soft stool, yellow- or dark-stainedurogenitalarea, alopecia (rear quarters),and death. All mortality occurredwithin 8 days of test material administration. Six of the 10 animals treated at 500 mg/kg exhibited body weight losses of 5 to 45 g during the first week of the study. Page 14 contains a pathology report by the study pathologist. REFERENCES 1. "Acute Oral Toxicity," Organisation for Economic Cooperation and Development's Guidelines for Testing of Chemicals, Section 401 (adopted May 12, 1981). 2. NIH PublicationNo. 86-23 (revised 1985). HWI Number: 40200468 Sample: T-5898 Page 14 PATHOLOGY REPORT There were 10 rats (fivemales and five females)each from dose levels of 500 and 5,000 mg/kg, necropsied. All animals given 5,000 mg/kg and one female from the group given 500 mg/kg died on test (DOT). The remainingsurviving animalswere euthanizedand necropsiedat the terminationof the study. The dose level, day of death, and gross observationsrecorded for each animal are in the IndividualPathologyComments that precede this report. At necropsy,most of the changes observedwere in the animals that died on test. Brown stains in the perianalregion and red nasal dischargewere indicativeof acute death. All other changes in these animalswere attributedto post mortem autolysis. The alopeciaand fluid filleduterinehorns observedin two of the females survivingto study terminationwere consideredincidentalfindings and unrelatedto the test material. There were no visiblelesionsin any of the remaininganimals in either group. Thom4TS Date Pathologist (40200468.lhm) 041194 HWI Number: 40200468 Sample: T-5898 APPENDIX Raw Data Page 15 PERSONNEL SIGNATURE SHEET ACUTE TOXICOLOGY HWI: q 0-0 Name Rose M. Bridge Job Title Report Supervisor Si nature Anthony Cass Cindy J. Cary, DVM Lab Animal Technician Lab Animal Veterinarian @Donna J. Clemons, DVM, MS Lab Animal Veterinarian John A. Disch Charles W.-,Fritz Kari Garfoot Steven M. Glaza Lab Animal Caretaker Lab Animal Technician Lab Animal Technician Manager e:@w, oo.;OlrA qt@Z4. V-J(IH AeYA4- Kevin Grossman Jeff Hicks Sharen L. Howery Wa,yneA. Madison Doug McConnell Lab Animal Caretaker Lab Animal Technician Research Assistant Supervisor Lab Animal Technician C7 116e,@ A 1 -A Eileen McConnell Bud McDonald Staff Assistant Study Coordinator 0 -1 Albert oleson Lab Animal Caretaker Patricia Padgham In-lifeSupervisor Steven R. Sorenson Annette R. Turner Study Coordinator Staff Assistant Tamra L. Walker Staff Assistant Lana M. Weeden Staff Assistant tch &',Wd (7,am,4z4r Initia_ls -)@6 -ZD (G2/10-06-93) DOSE ADMINISTRATION/BOWWEIGliT/MORTALRIETCYORD HWI No.:1122ao. Study Type: Acute Oral Toxicity Test Material: 7--s-97.9 Dose Level: 5-OD (mg/kg) Dose Volume:__a.'&(mL/kg) Species/Source Strain: Syringe used/Size, d, Rat/Crl:CDOOR II Route of Adminis 41A Vehicle: InitiatedIn Date Received: iz@% .2-.25--,7Fyasted - Date/Time/Tech:3-oo-c79 -cc Savage Method use'd/Size:Ball-tippedstainlesssteel gavage needl Sex:(gl@rfema If.- Animal Number ca- Prefasted Body Weight (g) Dose Time/Tech: From 10.*00 To (7,2307 17/gy -17.29v- Technician Date - -L= Scale Used: MA Fasted Body Weight (g) Actual Dose (mL) Day7 BodyWeight(9) Day 14 Body Weight (g) Dead Body Weight (g) -247 273@ ol /a 01/01 cl =Y @0-'3'S3,a00 .7-Sg oied c,;57 0. /1 . ol /.t P-39 2a1 Ag -35@, erified by Irv XI:@-o&tr 3-1&1C-d--Za/-730 c:7 3-@93 1C1-.d' MA NA NA Sex:Male@ Animal Number Prefasted Body Weight (g) Fasted Body Weight (g) Actual Dose (mL) Day 7 Body Weight(g) Day 14 Body Weight (g) Dose T-ime/Tech:From 10,'0-5 To /0,'10 -7,dl59,OV-) goq:? &2Q 'o .2aS ;L3ol ;238 0.// 0 0.10 0,/o o.Io o,lo I@'te_ cI a47. NA c -7 3-7 COaal-730 Verifiedby-- Dead Body Weight (g) NA NA ER DIED/MMM DOSED) Study- av Hours 2 3 4 5 1; 7 8 9 111 11- 12 Sex 40H00o1u-ArMs4 AM PH AM PM AN PM AN PM AMN FM AM PM AM PM AMll I PH AM PM AM PM AM PM AM PM Al Male 9Isys A" Female 77,1 Technician Time NA IV.-lzyYs.O6L.-,v ift Date 13110 -Y/oly// 8@147 1 /Yi 911Y NA Not applicable. (02/10-18-93) 0/: e---? 7,A ljr.'749 VOW: -YS rn @.y5 LS li7y1"-55--Y--,i's @@5 oy C-:7 fi@-eIq IILI 4 AZ-h2/zl I I!//, Final data review by/Date: ni INDIVIDTICALLINICASLl HWI No.: &2aoy.@E Dose level: YOO.M,71kq TestmaterialT: -.,5-978 ,7@ Animal Number (Ei@fFemale Observation Appeared M7rmal Pre- ours dose1+12 20 u.-5 4 1 2 3 14 5 Study D@tv 67 8 9 -- 10 11 12 13 14 Appeared normal ADDeared normal gliq Appeared normal s*.oo/ c;z- ADReared normal i@o Technician Date /gp (026/09-22-93) -----4-- c 5? 31, NA C--? je" le, Housing of a Individ 77 L/ Group a by sex nician Date Surviving an submittedfo necropsy. Technician Date -7 Survivingan designatedf and discard. Technician Date &A NA &g ja A& &,g Y-1 j2-l-6]k(= C -Yx- NA Not appli -.( Condition AIAVA Condition C? 0- Found dea ra,31 Final data reviewby/Date: CLC INDIVIDUACLLINICASLl HWI Noe:qo;ZOOLI,4g Dose level: .5',O0o5!//fc, Test material: 97 w Male emale Animal NumberFobservation cg- rAp%p-eared normal @ i sbu@oed -,F=ce- 4aema Pre- Hours dose 1 2.514 11 Z273:241 5 ,,,- -,Met= It Api)earednormal S-;udy Da-v 6 7 8 19 110 11 12 13 14 E7- Appeared normal gle-sailvuln F-t-c-e- Cg- appeared normal lylo DDeare normal Time Technician Datei (026/09-22-93) L/ lz -,Z:2-..AZ/- La.22 r-i-c---Cl-7 Li 311-?, -@/1,@:/I@@/y? Housing of a Individ LZ Group a by se) Technician Date Surviving an submittedfo necropsy. Technician Date 51 Surviving an designated Technician Date LJA-c,IA -77 @5i NA Not appli Condition A16 Condition Found dea Finaldata review by/Date: ac DOSE ADMIMISTRATION/BO e WEIGHT/MORTALITY RECORD L HWINo.:@=Llz Study Type: Acute Oral Toxicity Test Material: 7- 5878 Dose Level: Sooo (m*g/kg) Species/Source Strain: Rat/Crl CDDBR Vehicle: 11114 Date Received: Route of Adminis InitiatedIn Fasted Date/Time/Tech: Dose Volume: -9-,4@g-(mL/kg) Syringe us,d/Size: -cc Gavage 14ethodused/Size: Ball-tippedstainlesssteel gavage needle Sex:@@emale AnimalNumber Prefasted Body Weight (g) Fasted Body Weight (g) Actual Dose (mL) Day 7 Body Weight (g) Day 14 Body Weight (g) Dose Time/Tech: From NII To 946117 aoo 'c 77/ /,.2 /.a15&wh F-O&Aof doaw-- D*-4d Ow e-7 Technician Date -LW Scale Used:4@D NA (DieA&y C2@ 7-- 1 -Verified by- Dead Body Weight (g) Sex:MalegEl Animal Number ol3Y Dose Time/TechF:rotn//,'5,YTol/.,Sg /cy- NA iw*NA NA NA Prefasted Body Weight (g) Fasted Body Weight (g) Actual Dose (mL) ay 0 y ight(g) Day14 Body Weight (g) IY44' F* e7- d,47 .2,(7a-515, C -7 1 Verified by- Dead Body Weight (g) c2 ;Z38 013-51 o-2@LG NA NA NA A MTK ITT (NLMM DIED/NLMM DOSED) Hours S udv Dav 2 3 A 11 5 61 8 9 11 11 12 Sex Male 0 - 4 AM PM JAM Y5 4yT5S IV PM A" PM AM PM AM I PM AM PN AM @PMH AM /WS /S PS' V6 f6 a Y-5 PM AN PH AN PH AN PM AM PM Al Female %r /CYI- 9@ YS %r M /-S- 915 Aq- Technician r@? Time MA NA Not applicable. (02/10-18-93) -LIS Final data review by/Date: /I-- INDIVID(JCALINICALSIGNS HWI No.:gjo-zoozl6g ptr- DoseIeve:lS&440,0m:zl.@o-Testmaterial: 4v dcv -4fiD@yFemale Animal Number Observation -Vi)-ep-a-re-d n or m a I Pre- fours Study Day dose 1 2.5 4 1 2 3 4 15 6 7 8 9 110 11 12 L3 14 c,OL- Appeared normal J P,2ce- e--lWi"CfiAgwp.. OL- Ve peaa=red normal v4! y V,e_ Ap eareT -no-r-m-aT Sft;Ae-,F4ace- .AIY nvl-o-- ---------- Appeared normal 6,1 Si@at"na-rvL.C'i!),ce-rt,.-r@ked4.13M,@0144@ 7) c, Time Technician Date (026/09-22-93) IZ v V"7 iz I V W.S//IV,ISe,Z-/Sl-AIAV/l@i/1..44Alm@ Al ;w C9-1 Housing of an Individu Group an by sex. Technician Date Survivingani submittedfoy necropsy. Technician Date Survivingani designatedfo and discard. Technician Date NA Not applic i Condition Condition Found,dead Finaldata reviewby/Date: Dose level: 5-,ooo,mv2,jkfo Test material: (!Ee:yFemale Animal urs Number Observation 5 GLINICAL SIGNS HWI Ho.: Studv D;iv 3 4 15 6 17 18 9 1011111213 14 -T-ec=nlcian Date ppy (OD50/09-27-93) HA Hot applic Condition Condition Found dead Final data review by/Date: /t@@ Dose level: Animal Malex@@@ Number Fobservation ApReared normal INDIVIDtIACLINICALSIGNS HWI No.: LIO;Loolli@8 age Test material: 7--.592R Pre- Hours Study D v dose 1 2.51 4 1 2 13 4 5 16 17 18 9 LO 11 12 13 14 -7 Ai)pearednor v' so 5-tool "W sft;f&.i AOReare ngrma L/ zkuck Apnpared normal oq Ad Cnep- DDear d normal, Re.d s-%-M- ...-,-A.J --@ ==. ie"-@@r7 -:,7-,77 L/ L/ V _Z pe,xd lq,.,Yo) Time Techni ian Date/717y (026/09-22-93) NA IS."s A!4AIA c, c Lit!@2 70 z@-Ti a@7L gLi Housing of a -M Individ V Groupa by sex Technician Date Surviving an submitted fo necropsy. Technician Date Surviving an designated f and discard. Technician Date NA Not appli Condition Condition Found dea Final data review by/Date-. K.;4 Dose level: or Animal NaleAEiia@ NumberiFobservation HMI No.:*20,0@Yd,? INDIVIDUACLLINICALSIGNS Test material: 7 -589 --ours 1 2.5 4 11 9 3 14 5 Study Day 6 17 18 9 10111112L3 L4 '6/ 7e-c7nic'ian Date 1,"V (OD50/09-27-93) row Not applica Condition e Condition n Found dead, Finaldata reviewby/Date: