Document 0JOkrKx8BwZZwq6dko3BxxoaM

(Fl"l HAZLETONLAMCP%MUWIMAMPAE=C-W&Q.C Chemic&aBl[oM*diSccailencDeisvision 3301KINSMAN BLVD.- P.O.BOX 7S" - MADISON,WISCONSISN37'0-7PHONE(ON2)41-"T0lTLX7039MMAZRALMDS UD CE FINAL REPORT JAN 2 71988 3M 0 /COLO POR,ER G. MINNESOTA TnxICOLOGY ST. PAUL, PERKINS MINING & SERVICES MN 55101 MANUFACTURING COMPANY SAMPLE NUMBER: SAMPLE ENTERED: REPORT PRINTED: 70905392 09/23/87 01/21/88 SAMPLE: T-4101 PIJRR-HASE ORDER NUMBER: T837389-410 753 ENCLOSED: ACUTE ORAL TOXICITY STUDY IN RATS (OECD GUIDELINES) Key Personnel Method Summary Individual Pathology Reference5 Pathology Report Raw Data Appendix Comments SIGNED: STEVEN STUDY ACUTE M. GLAZA DIRECTOR TOXICOLOGY DATE WHAZLC%CN L*00%WOMIM &%AN9MCA, 01,C 33ol KINSOAAN BLVD. - P.O.BOX 7545 MADISON, WISCONSIN Chemical & BloModicalSciences Division S3707 - PNOME (OW 241-"71 - TLX 703956 MAZRAL MOB UD SAMPLE NUMBER: 70905392 SAMPLE: T-4101 PAGE 2 KEY PERSONNEL Acute TowicolocU Steven M. Glaze Study Director Calvin L. Horton Group Leader Support Services Sharon L. Howery Report Coordinator DualitU Assurance Debra Curley Arndt Manager Anatomical Patholog!e Thomas E. Palmer, PhD Anatomical Pathologist Robert Salava Senior Section Supervisor Dennis Hoffman Group Leader Necropsy Anne Ptesher Group Leader Pathology Data LaboratorNi Animal Veterinarian Cindy J. Cary, DUM Diplomats, ACLAM L@T)HAZLETON L^moncmcpas ApAracA. w,.r- 3301 KINSMAN BLVD. - P.O. BOX 7545 o MADISON, WISCONSIN Chemical A SioModical Sciences S3707 - PHONE (" 2414471 - TLX 703M MAZRAL Division MOS UD SAMPLE NUMBER: SAMPLE: T-4101 70905392 PAGE 3 OECD ORAL SCREEN Objective: To determine the acute oral toxicity produced when a test material is administered by the oral route (gavage) to rats according to the Organisation for Economic Cooperation and Development's Guidelines for Testing Chemicals. Test Material: T-4101 Physical De5cription: Purit5) and Stability: Storage and Rmtention: Safety Precautions: Clear, yellow liquid Sponsor as5umes responsibility for purity and stability determinations. The test material was stored at room Any unused material will be discarded to HLA Standard Operating Procedure. Normal handling procedures were used to HLA Standard Operating Procedure. temperature. according according Test Animal: Young adult albino rats of the Sprague-Dawley strain were procured, separated by sex, maintained in group cage5 in temperatureand humidity-controlled quarters, provided continuous access to Purina Rodent Chow and water, and hold for an acclimation period of at least 7 days. Animal husbandry and housing at HLA comply with standards outlined in the "Guide for the Care and Use of Laboratory Animal5". If variations from the prescribed environmental conditions existed, they were documented and considered to have no effect on the study outcome. No contaminants were expected to have been present in the feed or water which would have interfered with or affected the results of the study. Acclimated animals were chosen at random for the study. Test animals were housed by sox in groups of five and identified by animal number and corresponding ear tag. Food and water were available Xd libitum throughout the study, except for an overnight period just before tm5t material administration whom food, but not water, was withheld. Reason for Species Selection: The rat is the animal classically used due to its small size, ready availability, and large amount of background data. Method: Five male and five female rat5 weighing used for each dose level. The study con5isted (0.50 and 5.0 g/kg). from 200 to 298 g were of two do3a levels Preparation and Administration of Test Material: An individual dose was calculated for each animal based upon its fasted body weight and administered undiluted by gavage. The do5a volume of the test material varied per dose level based upon an average bulk density of 1.13 g/ml. HAZLETON i.@@ AtoLwpcA. wr- 3301 KINSMAN BLVD. - P.O. BOX 7545 * MADISON, WISCONSIN Chemical & SloM@dical Sciences Division S3707 o PHONE 1608)241447'1 o T" 703M HAZRAL MOS UD -RAMPLE NUMBER: SAMPLE: T-4101 70905392 PAGE 4 OECD ORAL SCREEN (CONTINUED) Reason for Route of Administration: a known quantity of test substance historically. This is the method for administering and has been the route of choice Observations: The animals were observed for clinical signs and mortality at 1, 2.5 and 4 hours after test material administrationand daily thereafter for at least 14 days. All animals were weighed just before test material administration, at 7 days and at study termination (or at death). Pathology: At study termination surviving animals were euthanatized. Animals which died on study or outhanatized at study termination were subjected to a gross necropsy examination and abnormalities record". Following necropsy, animals were discarded and no tissues were saved. Statistical Methods: Other than average body weights, no other statistical method was performed. Location of Raw Data and Final Report: The raw data and a copy of the final report will be retained in the archives of HLA. (EHAZLEMON LAMCPcxphm Ap.,L-or-A. *4-- Chemical& BloM*dicalSciencesDivision 33oi KINSMAN BLVD. - P.O.BOX 75" MADISON, WISCONSIN S3?07 - PHONE INM 24J."?l - TLX 70=W MAZRAL MOS UD C;AMPLE NUMBER: SAMPLE: T-4101 70905392 PAGE OECD ORAL SCREEN SUMMARY (CONTINUED) Test Animal: Albino Rats Sprague-Dawley strain Source: Charles River Laboratories, Inc., Portage MI Date Animals Received: 09/08, 09/28, 10/12, and 10/26/87 Method of Administration: Oral Gavaga Date Test Started: 10/16/87 Date Test Completed: 11/20/87 Estimated Oral LD50: Male - Between 0.50 and 5.0 g/kg of body weight Female - Between 0.50 and 5.0 g/kg of body weight Oose Level (g/kg) Male 0.50 5.00 Fmmals 0.50 5.00 Average Initial Body Weights (g) Day 7 Terminal 266 340 370 278 --- --- 203 230 237 2ae 166 232 Mortality (Number Dead/Number Dosed) 0/5 5/5 0/5 4/5 CLINICAL SIGNS (No. of Animals Affected) Hours 1.0 2.5 4.0 DaUs 1 2 3 4 5 6 7 8 9 10 11 12 13 14 DOSE LEUEL: 0.50 g/kg Males Appeared Normal 5 5 5 5 5 5 5 5 5 5 5 5 93 5 5 5 5 Females Appeared Normal 5 5 5 5 55 55 5 55 5 5 5 5 5 5 (I!rHDAZLETON L*ACPCrMnS AAOWRCA. *,C- 3301 KINSMAN BLVD. - P.O. BOX 7$" - MADISON, WISCONSIN Chemical & BloMedical Sciences Division S3707 - PHONE (W$) 2414471 TLX 7OUSS MAZRAL UDS UD C;AMPLE NUMBER: 70905392 SAMPLE: T-4101 PAGE 6 OECD ORAL SCREEN (CONTINUED) CLINICAL SIGNS CContinued) (No. of Animals Affected) Hours 1.0 2.5 4.0 pays 1 2 3 4 5 6 7 8 9 10 11 12 13 14 DOSE LEUEL: 5.0 g/kg Males Appeared Normal 3 0 0 0 t 0 0 0 0 --- - - - - - Hypoactivity 2 5 5 5 5 5 3 1 0 -- - - - - - - Ataxia 0 0 5 5 0 5 3 1 0 --- - - - - Red-stained -- - - - - - face 0 0 0 1 4 5 3 1 0 - -- - - Pain reflex -- - - - absent 0 0 a 0 0 4 2 1 0 -- - - - Miagis 0 0 1 a 0 a a 0 0 -- - - - Yellow-stained -- - - - genital region 0 0 0 0 0 2 1 0 0 --- - - Death 0 0 0 0 0 0 2 2 1 --- - - Females Appeared Normal 3 0 0 0 00 00 0 00 0 1 0 1 1 1 Hypoactivity 2 5 5 5 3 3322 11 1 0 0 0 0 0 Yellow-stained genital region 0 1 1 53 33 22 11 1 0 0 0 0 0 Diarrhea Ataxia 1 1 1 1 000 0 00 00 0 0 0 0 0 0 1 5 5 133221 0 1 0 1 0 0 c Red-stained face Prostration Tremors 0 0 5 5 2 332 2 1 1 0 0 0 0 0 0 a 0 0 10 0000000 0 0 a a 0 0 0 0 10 00 00 0 0 0 0 0 0 0 0 Pain reflex absent 0 0 0 00 11 10 0 0 0 0 0 0 0 0 Cyanosis 0 0 0 1 0 000 0 a0 0 0 0 0 0 0 Dpiath 0 0 0 2* 0 0 0 1 0 1 0 0 0 0 0 0 0 Animals died following a.m. observations. le HAZLE%CN t-@ ".WP@CA. rC Chemicala elomodicalSciencesDivision 3301 KINSMAN BLVD. - P.O.BOX 7545 - MADISON, WISCONSIN S3707 - PHONE (ON)241-4471 TLX 703956MAZFTAL MDS UD SAMPLE NUMBER: 70905392 SAMPLE: T-4101 OECD ORAL SCREEN (CONTINUED) PATHOLOGY DOSE LEUEL: 0.50 9/kg of body weight Animal Ntimber Test Day Sax Died Sacrificed Necropsy Comments C03078 m C03074 m C03077 m C03076 m C03073 m C03245 F Cr)3243 F C03246 F C03244 F C03327 F - 14 - 14 - 14 - 14 - 14 - 14 - 14 - 14 - 14 - 14 ND visible lesions. No visible lesions. No visible lesions. No visible lesions. No visible lesions. No visible lesions. No visible lesions. No visible lesions. No visible lesions. No visible lesions. PAGE 7 anh WHAZLOMON LANCPUCTPWM AAO*Rir-A WI.C 3301KINSMAN BLVD. - P.O.BOX 7W 0 MADISON, WISCONSIN Chemical& SloMedicalSciencesDivision 53707 9 PHONE 1605)2414471 9 TLX 703956HAZRAL MOS UD (;AMPLE t4tJMF3ER: '70905392 .C;AMPLE: T-4101 PAGE 8 OECD ORAL SCREEN (CONTINUED) PATHOLOGY (Continued) DOSE LEUEL: 5.0 g/kg of body weight Animal Number Sew r-f)0544 m Test Day Died Sacrificed 4 Necropsy Comments Parianal stains - tan; ocular discharge (bilateral) - red and black, crusted; gastrointestinal tract (GI) - severely autolyzed. Cf)0542 m 4 Parianal stains - tan; ocular discharge (bilateral) - red and crusted; stomach - grandular mucosa diffusely red with multiple dark brown linear areas, 4 x 1 mm. COO%345 m 4 Perianal stains - tan; stomach glandular mucosap multiple dark brown linear areas, up to 3 x 2 mm. C00551 m 5 Perianal stains - tan; ocular discharge (bilateral) - red and crusted; stomach - glandular mucasa has two dark brown linear areas, both are 10 x 2 mm. C00548 m 5 Gi tract - very autolyzed. HAZLM%CN 3301 KINSIAAN BLVD. LAMICX%MWOFNM AAOWNC.A@ W4.- - P.O. BOX 7S4$ - MADISON, WISCONSIN Chemical & elom*dical Sciemes Division S3707 o PHONE (OW 241-4471 o TLX 703"6 MAZRAL MOS UD SAMPLE NUMBER: SAMPLE: T-4101 70905392 PAGE 9 OECD ORAL SCREEN (CONTINUED) PATHOLOGY (Continued) DOSE LEUEL: 5.0 9/kg of body weight (continued) Animal Number- coo9se Test Day Saw Died Sacrificed F I C009,76 F 1 r-00987 F ColOO95 F - 14 5 - Necropsy Comments Parinsum discharge .stomach material. stained brown; ocular (bilateral) - red; contains green semi-solid Perineum discharge parenasel stomach material. stained brown; ocular (bilateral) - red; discharge - red; contains clear, oily No visible lesions. Nasal discharge - red; parianal and inguinal stains - tan; stomach - glandular mucosa has multiple, dark brown linear areas, up to 4 x 2 mm. cno957 F 7 Stomach - glandular mucosa has multiple dark red linear areas, up to 3 x 1 mm. References: 1. Hitch., R.K., "Acute Oral Toxicity Study," Pesticide Assessment Guidelines., Subdivision F, Hazard Evaluation: Human and Domestic Animals, U.S. Environmental Protection Agency Office of Pesticide and Toxic Substances Series el-1, pp. 34-39 (November 1982). 2. 21 CFR 58 (United States Food and Drug Administration's Good Laboratory Practices Regulations for Nonclinical Laboratory Studies). 3. NIH Publication No. 85-23 (revised 1985). HLA LAB NO. 709Ob392 PATHOLOGY REPORT Acute Oral Toxicity PAGE 10 Ten rats (five males, five females)from eacn of two dose levels (O.@ and 5.U g/kg) were necropsied. Tne animals that died on test were refrigerated and necropsiedwithin 24 nours. usually tne same day. All surviving animals were euthanatizedand necropsied at the termination of the Study. The dose level. day of deatn and gross observationsrecordedfor eacn animal are on pages 7 to 9 of this report. The only recorded observationswere in those animals that died on test. The st(xnachcontainedmaterial of variable consistency and color which possibly representstest material mixed with ingesta. The gastric mucosa in some animals had focal red or brown linear areas wnich were possibly treatment related. All other observationswere consideredrelated to postmortemchange or incidentalfindingswhich were not related to treatment. - --Ll, " == .op ThomaS E Pathologist (1734mcs) / -;t /-slr Date Personnel Sigmture Sh*ot Acute Toxicology NLA Me BAK Job Title Sianaturo Becky Beckwith Sr. Lab. Animl Asst. Steve soloungy Lab. Animl Asst. kid Ken Bridges Sr. Lab. Animl AsSt. Pat Crary Sr. Lab. Animl AsSt. Shane Eith Sh" Frazier Lab Aninl ASST. Lab Animl Asst. Steven M. 61&2& group Load*r Molly Mbn Kevin Hamilton Admin. Clerk Lab. Animl Asst. Jeff Hicks Calvin Norton Sr. Lab. Animl Asst. are" L""r Sharon L. Mowry Administrative Asst. Sr"ory Johnson Lab. Animi Tech. Paul Krebs Waym ftdison Scott fteannell Lab. Animl Asst. section Soarviser Lab. Animl Tech. SMII*Y ftcannell Daim Conant Om ftvis M*in Olson Patricia Padohn Joseph J. Dom Michael fttzka Jam Paulson Jar* Polnow Lab. Animl Tech. Sr. Lab Animl Asst. Lab. Ani*mal Asst. Lab. Animal Asst. Team LmWer Lab. Animl Asst. Lab. Animl Asst. Sr. Lab.'Anial Asst. Lab. Animl Tech. @Pd.@ ;iim2 Omis S. Stainer Lab. Animl Tech. Ricb&eTlksing Paul& 6. vanw Ub. AnialASST. Administrative Asst. Albert Olson ftnpowr Jim Jirschole LTE Ben Haley Sr. Lab Animal Asst. Eileen M. McConnell Admin. Clerk Annette R. 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