Document 93QxMbOyvorNYda9XeKMYwJXq

Acute oral Toxicity Screen with T-3065COC in Albino Rats No.: Coliclucted At: I)ates Conducted:. Conducted By: 0981AR0145 Safety Evaluation Laboratory .-Riker Laboratories, Inc. St. Paul, Minnesota April 2, 1981 to April 16, 1981 X. D. O'Malle3?1 BS Advanced Toxicologist Study Director Date Reviewed By: dc: M. T. Case K. L. Ebbens F. D. Griffith W. C. McCorimick X. L. Ebbens, BS Data-.., Supervisor, Acute Toxicology.'. Summary An acute oral toxicity screen with T-3065CoC was conducted from April 2, 1981 to April 16, 1981 using male and female albino rats ranging in body weight from*209-293 grams. The test material was administered by gastric intubation at a dosage level of 5,000 mg/kg body weight with mortalities of 3/10 noted from day 1 to day 5 post dose administration. Diarrhea, lethargy and hypoactivity were the untoward reactions which were noted from 120 minutes to day four and body weight gains were noted in all animals which sur,vived the 14 day observation period. Necropsy of the animals perfor=d upon termination of the study revealed no visible lesions while hemorrhage of the gastrointestinal tract and lungs were noted in the animals which died acutely. The LDSO of T-306SCoC appears to be greater than 5,000 mg/kg in fasted male and female rats. Introduction The objective of this study was to approximate the acute oral MSO of T"306SCoC in fasted albino rats. This study is not regulated by the Food and Drug Administration's Good Laboratoxy Practice Regulation of 1978, although the standard operating procedures of this laboratory adhere to the general principals 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 ratss 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. and h=idity The rats were housed in suspended, wire-mesh cages in temperature b controlled ro=s and permitted a standard laboratory diet;@-plus water ad libitum except during the 16 - 20 hour period immediately prior to, gastric intubation when food was withheld. Five male and five female rats were administered the test material at a preselected dosage level. All doses were administered at a constant volume of 10 ml/kg directly into the stomachs of the rats using a hypodermic c 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 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, compos*ition characteristics, and Quality Assurance statement are contained in Appendices I IV. a ECharles River Breeding Laboratories, Inc., Wilmington, MA - Ralston Purina Laboratory Chow, Ralston Purina, St. Louis, Missouri E-Popper and Sons, Inc., New Hyde Park, New York Doso Animal -(ing/kg)So.),Number 5,000 M lR2607 lR2608 lR2609 lR2610 lR2611 '.VABLL 1 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-3065CoC Mortality, Necropsy and Body Weight-Data Individual Body Weights (g) Test Day Number: Number Dead 0 14 Number Tested 274 (5 Days) 3/5 293 377 289 (1 Day) 279 373 287' (2 Days) 5,ooo r IR2590 235 274 0/5 lR2591 241 281 lR2592 231 275 lR2593 233 275 lR2594 209 251 3. Percent Dead 60 0 The test article was administered as a suspension in cottonseed oil. The approximate oral LD50 appears to be greater than 5,000 mg/kg in fasted male and femal albino rats. Necropsy Necropsies performed upon te=-lnation of the study revealed no visible lesions, however, necropsy of the animals which died acutely revealed hemorrhagic gastrointestinal tracts and hemorrhagic lungs (one incidence). Reactions Dose Sex mg kg 5000 F Hypoactivity Diarrhea 5000 m Hypoactivity Diarrhea Lethargy TABLE 2 ACUTE ORAL TOXICITY SCREEN ALBINO RATS with T-3065CoC Summary of Reactions Minutes 1-30 60 120 Observation Periods Number Affected/N=ber Dosed Days 1 2 3 4 5 6 7 8 9 5/5 5/5 0/5 5/5 0/5 - - 4/4 3/3 1/3 0/3 2/5 4/5 0/3- - - - 1/4 0/3 - - No significant reaction it.LXer-Experlme-nt NLInIDer: ApPnP(F.y=NroDIrX I spbNS(DR: CONDUCTED 3M BY: Safety Evaluation TEST ARTICLE: T- CONTROL ARTICLE: PROPOSED STARTING/COMPLETION DATE TEST SYSTEM AND SOURCE: Lc-Lboratory, Riker OF TEST: La-boratories, I Inc.$ St., Paul,:: Hinnd,s,@otai@,, lnc.i ll:tllloingtoneKA. Sex: Number: 4A Weight Range: OBJEC,rIvE: METHOD: The objective of this test-,will-be to c aracter ze,.'the @-acu e toxicity'-p'f the test article in" ali@ino were-sel'664t-ed" test system for reproducibility- 'of response,,"historir-al,use-,.-.ease-,-@-iannld,-- and general availability The-: an,mals- will teMpera tu e,' I pe@ ric>ds b@e botii36d',,,in:.staiiilGiss@-,stieel-,ziuspended,r@fiisihj".""cage s it @,l-ii 3" ulIr-I@t t t h, b 6 ant n 1 ie@ by bol;r@@@c'o"d-3'-ng,a,c.cording -, @,to th 6 -@la ratol it@,-6 dard'@:operal which'will' correspond to a card --afikird,,to th a.:ou, @@A-@,tin dosage.of. /.kg will b6--'adminis-t@'e--:it-id.,"a-'.a'acihm' mg @h'-owever-t@ dosage.level does not adequa. t.ely I chaiac'teriz''6,,' ,1 additional aniraals will be, a dmin i'stered the test artic le at sii@pleme n tal @dosacje levels Any additional --do:@a ge -.-3:6V4iVwsi@ll ..be.-aocumented. and filed lw:Lth'@th2.s.,@,@ protocol. The test article'will be' aclini'nist_ered-'@to ek_animals n @l;he@-f6ii@ received',from the,.i@ponsor@,-,,A.fi er"-,@6cliiihistiiiti6ioff, the-,test'. animals viill be returned--to th ea."r'@ ca lR'es n towatd.4@@,be bavio"ra@i'@r-e'act@ion's--''ftohre.-fi6li-oitin4 -14 "::ti@al-body will be recorded A gross nelcropsy,-,whi'ch Wili@'i@cibde b,ut@not..rl@4@iii4iid,t heart,, l.ungs, liver, kidneys and'qenera gaistro ntestinal,",t.ra,ct;"iiiii ducted on all animals animals surviving the during the conduct of which die during the co-nduct-of th6 test as test period. Any gross-abnormalities@which the necropsy will be recoided with specific we as are'-observed'. mention @to@:l@-%*, the organ and/or site observed. The acute median lethal dose (LD50) -,of -t,h test article will be calculated, if possible, usir.ig a probit analy'sis-,'m thod;;".@.',, at the end of the observation period. All raw.data and the final rep'ort--,will-.- be stored in the Riker Laboratories A-ichives, St.- Paul,: Minnesota-.,-",.,,,-. p urina'-Laboratory Chow Ralston Purin'a, St.'.Louis )4issouri b a 1G.-.'tO liou% U.,c@ri6d ii-.anediately prior to dos inrj wIien Nqi 1. wit 4t Sponsor Dafte dY- Dii@@cto Form 19171-16-PWO 6. APPENDIX II Principal Participating Personnel Involved in the Study Name C, E. Hart K. D. O'Malley, BS K. L. Ebbensi, BS G. C. Pecore Function Laboratory Technician Acute Toxicology Advanced Toxicologist Study Director Supervisor Acute Toxicology Supervisor Animal Laboratory APPENDIX III Composition Characteristics This study is not regulated by the Good Laboratory Practice Regulation of 1978 and therefore information pertaining to composition characteristics is not applicable for inclusion in this study. APPENDIX IV ouality Assurance Statement This study is not regulated by the Good Laboratory Practice Regulation of 1978 and therefore a.statement signed and prepared by the Quality Assurance group is not applicable. This study was, however, audited by the Quality Assurance group. in addition to the data audit, different significant phases for studies underway in the Toxicology Laboratory are inspected weekly on a recurring cycle, and the facilities are examined by Laboratory Quality Assurance on a three month schedule.