Document znogvLzonzogrbZ4x0w4N493

Experiment No.: Conducted At: Dates Conducted: Conducted By: Reviewed By: Acute Oral Toxicity Screen with T-3494 in Albino Rats 0884AR0013 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota January 19, 1984 to February 2, 1984 D. M. Markoe, Jr., BS' Toxicologist Study Director Date ol alley, 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-3494 was conducted from January 19, 1984 to ftbruary 2, 1984 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rats ranging in body weight from 190-236 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 an day one and subsided by the day four observation. This response, however, would be expected using cottonseed oil as the vehicle at a constant volume of 20 ml/kg. 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-3494 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-3494 in fasted albino rats. This study is not regulated by the Food 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 a Young albino rate-l@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 rooms and permitted a standard laboratory diet-@pllus 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 at a constant volume of 20 ml/kg directly into the stomachs of the rats using a hypodermic syringe equipped with a ball-tipped intubating needles@. 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 b Ralston Purina Laboratory Chow, Ralston Purina, St. Louis, HO 1 Popper and Sons, Inc., New Hyde Park, NY TABLE 1 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-3494 Mortality, Necropsy, Adverse Reactions and Body Weight Data Dosea (mg/kg) Sex Animal Number Individual Body Weights (g) Test Day N=ber- 0 7 14 Number Dead Number Tested Percent Dead 5,000 5,000 M 4R411 4R412 4R413 4R414 4R415 F 4R432 4R433 4R434 4R435 4R436 231 285 317 234 297 339 216 263 288 213 268 303 236 285 323 207 251 265 191 216 232 190 224 218 205 241 255 199 234 251 0/5 0 0/5 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. Adverse Reactions Diarrhea was noted in all animals on days one through three, inclusive. APPENDIX I PROTOCOL RikerExperimentNo.: TEST: Aci.itOeral Toxicity SPONSOR: 3M CONDUCTED BY: SafetyEvaluationLaboratorysRikerLaboratoriesI,nc.,SL Paul,Minnesota TESTARTICLE: - T-34@14 CONTROLARTICLE: /V@,fi;@7-.PROPOSED STARTINGICOMPLETION DATE OF TEST: tZ::@ TESTSYSTEM: SOURCE: Vi@@-,Q, Sex: Number: 5 WeightRange: '/-,oo-3Lg)roans 4. Division OBJECTIVE: METHOD: The objectivoefthistestwillbe tocharacterizteheacute toxicitoyfthetest articlien albirio Rat-c; Tr@t- were selectedas a testsystem forrepro. ducibiliotfyresponse,historicuasle,ease inhandlingand generalavailability. The animalswillbe housed Instainlesssteelsuspended varemesh cages intemperatureand humidity controllerdooms duringboththe quarantineand testperiods,withfood#and waterofferedad libitubmEach animal willbe identifiebdy colorcoding,accordingto the laboratory'sstandardoperatingprocedure,which willcorrespondtotheanimal numbers on a cardaffixetdotheoutsideofthecage.A singif dosage of 5000 mgtkg willbe administereedach animal,however,ifthisdosage leveldoes nc adequatelycharacteriztehe toxicitoyfthe testarficlea,dditionaalnimalswillbe administeredthe tee articlaet supplementaldosage levelsA.ny additionadlosage levelswillbe documented and filedwit thispmtoool.The testarticlweillbe administeretdothe animalsinthe form receivedfromthe sponso afterwhich the animalswillbe returnedto theircages and observed forany untoward behavioralri actionsforthe followin1g4 days.Initiaanld finablody weightswillbe recorded.A grossnecropsywhi( willincludeb,ut notbe limitetdo;heart,lungs,liverk,idneysand generalgastrointestitnraalctwillI conductedon allanimalswhich dieduringtheconductof thetestas wellas theanimalssurvivintg testperiod.Any grossabnormalitiewshich are observedduringthe conductof the necropsywillbe cordedwithspecifimcention to theorgan andlorsiteobserved.Allraw data generatedby the stt directoarnd thefinalreportwillbe storedinthe RikerLaboratoriesA'rchive,St.Paul,Minnesota. 1 PurinaLaboratoryChow, RalstonPudna, St.Louis,Missouri DEPI l@' Sponsor Date Study Director Riker Experiment No. 0884AR0013 APPENDIX I (concluded) Deviations and/or Amendments-to Protocol 1. The weight range is extended to 190-300 gm to expidite the study. Study Director 1/19/84 Date 2. Study Director DaLte 3. Study Director Date 4. Study Director Date Study Director Date 6. APPENDIX 11 Principal Participating Personnel involved in the Stud Name D. M. markoe, Jro, 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. APPEIMIX III Composition Characteristics This study is 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. 8. APPENDIX IV guality 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 dt-.partmentdoes inspect different significant phases for studies underway in the Acute 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.