Document Jrj7GYG80OQRg8pNBV4E1LxOr

Experiment ]No.: Conducted At: Dates Conducted: Conducted By: Reviewed By: Acute Oral Toxicity Screen with T-3493 in Albino Rats 0884AR0010 FFLC131l@00 1984 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota December 30, 1983 to January 13, 1984 D. M. Markoe, Jr., BS Toxicologist Stuay Director Date K.- D. O'Malley, BS Senior Toxicologist Acute Toxicology Date dc: M. T. Case K. L. Ebbens P. D. Griffith W. C. McCormick Summary The acute oral toxicity screen with T-3493 was conducted from December 30, 1983 to January 13, 1984 at Rike.r Laboratories, Inc., St. Paul, Minnesota using male and female albino rats ranging in body weight from 227-272 grams. The test article was administered by gastric intubation at a dosage level of 5,000 mg/kg body weight with no mortalities noted during the 14 day observation period. Diarrhea was noted in two males on day one and had subsided by day three and alopecia was noted in one female on days five through nine, inclusive. Body weight gains were noted in all animals at the end of the study. Necropsies performed at termination of the study revealed no visible lesions. The approximate oral LD50 of T-3493 is greater than 5,000 mg/kg in fasted male and female albino rats. Introduction The objective of this study was to determine the acute oral LD50 of T-3493 in albino rats. This study is not regulated by the Pbod and Drug Administration's Good Laboratory Practice Regulation of 1978, although the standard operating procedures of this laboratory adhere to the general principles of this regulation. The raw data generated by the Study Director and the final report are stored in the conducting laboratory's archives. 2. Method and Results Young albino a rats were used in this test. All animals were held under quarantine for several days prior to testing with only animals which appeared to be in good health and suitable as test animals at the initiation of the study used. The rats were housed in suspended, wire-mesh cages in temperature and humidity controlled roams and permitted a standard laboratory b diet plus water ad libitum except during a 16-20 hour period immediately prior to gastric intubation when food was withheld. .The rats were administered the test material at a single dosage level. All doses were administered directly into the stomachs of the rats using a c hypodermic syringe equipped with a ball-tipped intubating needle After gastric administration of the test article, the rats were returned to their cages and observed for the following 14 days. Initial, seven day and final body weights, mortalities (Table 1) and adverse reactions (Table 2) were recorded. A necropsy was conducted on all animals that died during the study as well as those euthanatized at the end of the 14 day observation period (Table 1). The protocol, principal personnel involved in the study, composition characteristics and Quality Assurance statement are contained in Appendices I - IV. a Charles River Breeding Laboratories, Inc., Wilmington, MA Ralston Purina Laboratory Chow, Ralston Purina, St. Louis, HO Popper and Sons, Inc., New Hyde Park, NY 3. TABLE 1 ACUTE ORAL TOXICITY SCREEN ALBINO PATS with T-3493 Mortality, Necropsy, and Body Weight Data Doses (mg/kg) Sex Animal Number Individual Body Weights (g) Test Day Number: 0 7 14 Number Dead 14umber Tested 5,000 m 3R7970 246 289 302 0/5 3R7971 256 302 322 3R7972 254 299 323 3R7973 272 312 350 3R7974 240 262 279 5,000 F 3R7896 238 252 266 0/5 3R7897 254 263 278 3R7898 227 245 257 3R7899 243 267 282 3R7900 251 288 303 Percent Dead 0 0 The test article was administered as a suspension in cottonseed oil. The acute oral LD50 is greater than 5,000 mg/kg in fasted male and female rats. Necropsy Necropsies performed upon termination of the study revealed no visible lesions. Reactions Dose mg/kg 5,000 Sex m Diarrhea 5,000 F Alopecia TABLE 2 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-3493 Sumary of Reactions Minutes 1-30 60 120 Observation Periods Number AffectedINumber Dosed Days 1 2 3 4 5 6 7 a 9 2/5 1/5 0/5 1/5 1/5 1/5 1/5 1/5 0 APPENDIX I PROTOCOL 0 8 3 4A:r"l0 0 RikerExperiment No.: TEST: SPONSOR: Acute Oral Toxicity 3M Com-arcial Chemiails CONDUCTED BY: SafetyEvaluationLaboratory,Riker Laboratories,Inc.,St.Paul,Minnesota TEST ART ICLE: T-3493 CONTROL ARTICLE: PROPOSED STARTING/COMPLETION TEST SYSTEM: ALj3100 SOURCE: DATE OF TEST: c -r) Sex: Number: 5,.; 'WeightRange: 20J-iOO Pra-Ls Division OBJECTIVE: METHOD: The objecfivoefthistestwillbe tocharacterizteheacute Oral toxiciotfythetest articlienalbino ra,.s .- -P,-.Its- were selectedas a testsystem forrepro- ducibiliotfyresponse,historicuasle,ease inhandlingand generalavailability. The animalswilble housed instainlesssteelsuspendedwiremesh cages intemperatureand humidity controllerdooms duringboththequarantneand testperiodsw,ithfood-and waterofferedad libitumt. Each animalwillbe ldenfifibeyd colorcoding,accordingtothe laboratorys'tsandardoperatingprocodurs,whichwilclorrespondtotheanimalnumbers on a cardaffixetdotheoutsideofthecage.A single dosage of -r,00;)mgtkg willbe administereedach animal,however,Itthisdosage leveldoes not adequatelycharacteriztehetoxicitoyfthetestaruclea,ddloonalanimalswillbe administeretdhetest arficlaetsupplementaldosage levelsA.ny additionadlosage levelswillbe documented and filewdith thisprotocolT.he testarticlweillbe administeretdotheanimalsintheformreceivedfromthesponsor, afterwhich theanimalsvwllbe returnedtotheircages and observedforany untowardbehaviorarleacflonsforthefollowin1g4days.Initiaanld finablody weightswilble recorded.A grossnecropsywhich willIncludeb,utnot be limitetdo;heart,lungs,liverI,ddneysand generalgastrointesfitnraalctwillbe conductedon allanimalswhichdieduringtheconductofthetestas wellas theanimalssurvivintghe testperiod.Any grossabnormalitiewshich areobservedduringtheconductofthenecropsywillbe recorded%(itshpecifimcenflontothe organ and/orsiteobserved.Allraw data generatedby the study directoarnd thefinalreportwillbe storedinthe RikerLaboratorieAsr'chive,St.Paul,Minnesota. 1 Pudna LaboratorCyhow, RalstonPudna,St.Louis,Missoun Foov ISE. t'Jt'i-i4t4r-E, For- 4, le, LA. -"I Sponsor a- .0.7i.A-Cmjn Date Study Director ;-7 Date 6. APPENDIX II principal Participating i?ersonnelInvolved in the Stud Name D. M. 14&rkoe,Jr., BS K. L. Ebbens, BS K. D. O'Malley, BS G, C. Pecore Function Toxicologist Study Director supervisor Toxicology Testing Senior Toxicologist Acute Toxicology Supervisor Animal Laboratory 7. APPENDIX III Ccmposition Characteristics This study it not regulated by the Good Laboratory Practice Act of 1978 and therefore information pertaining to composition characteristics is not applicable for inclusion in this study. APPENDIX IV Quality Assurance Statement This study is not officially regulated by the Good Laboratory Practice Regulation of 1978, and therefore a statement signed and prepared by the Compliance Audit department is not applicable. The standard operating procedures of this laboratory does adhere to the general principles of this regulation. The Compliance Audit dftzartment does inspect different significant phases for studies underway in t@@.eAcute Toxicology Laboratory on a recurring cycle, and.the facilities are examined on a three month schedule. in addition a select number of Research & Development studies are routinely picked at random from the Archives by the Compliance Audit department for review.