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Acute Oral Toxicity Screen with T-3065COC in Albino Bats a S iV' ,$ ^ < sj u v-^V Kxpr'ri.incnt No. : Conducted At: Dates Conducted: Conducted By: 0981AR0145 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota April 2, 1981 to April 16, 1981 ICO K. D. O'Malley, BS Advanced Toxicologist Study Director s7y/?7 Date Reviewed By: de: M. T. Case K. L. Ebbens F. D. Griffith W. C. McCormick dssX*s^. K. L. Ebbens, BS Date Supervisor, Acute Toxicology 001202 1. Staminar y 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 t :*"!TM.'' survived the 14 day observation period. Necropsy of the animals performed 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 LD50 of T-3065CoC 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 LD50 of T-3065CoC 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 principals of this regulation. The raw data generated by the Study Director and the final report are stored in the conducting laboratory's archives. 001303 2. Method and Results Young albino 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 rooms 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 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 re corded. 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. $ jTCharles River Breeding Laboratories, Inc., Wilmington, MA -- Ralston Purina Laboratory Chow, Ralston Purina, St. Louis, Missouri -- popper and Sons, Inc., New Hyde Park, New York 00i*>Q4 TABLE 1 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-3065COC Mortality, Necropsy and Body Weight Data Dose -- Animal (inej/kq) Sex Number 5,000 M 1R2607 1R2608 1R2609 1E2610 1R2611 Individual Body Weights (g) Test Day Number: Number Dead 0 14 Number Tested 274 293 289 279 287' (5 Days) 377 (1 Day) 373 (2 Days) 3/5 5,000 F 1R2590 1R2591 1R2592 1R2593 1R2594 235 241 231 233 209 274 281 275 275 251 0/5 3 Percent Dead 60 0 i t -- 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 fema albino rats. Necropsy Necropsies performed upon termination of the study revealed no visible lesions, however, necropsy of the animals which died acutely revealed hemorrhagic gastrointestinal tracts and hemorrhagic lungs (one incidence). OOJ.^05 Reactions Dose rcgAg 5000 Sex F Hypoactivity Diarrhea TABLE 2 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-3065COC Summary of Reactions Observation Periods ______________________ .________ Number Affected/Number Dosed Minutes_____ _____________________________ Days 1-30 60 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 - -- --- 5/5 5/5 0/5 5/5 0/5 5000 M Hypoactivity Diarrhea Lethargy - - -- - 2/5 -- 4/4 3/3 1/3 0/3 4/5 0/3 1/4 0/3 No significant reaction (-) o o H fw O CT v V ..I-r.\ 4.V-ik-0r.lt' Hiker1.Experiment Number t v- >,t\sria5?^v5!!------------------------ e s s s i >/( -AV - ir v i VX*** H APPENDIX I :v^:'v'*i*r>7&`^owf1-.w--:*<s- PR0TC5C0ir~ JEST.:/ At-M'-f >) 1 `IV.y-ifi 1-y SP6NS0R: 3M tfftftcTslal f-hemicals CONDUCTED BY: Safety Evaluation Laboratory# Riker Laboratories ,'"Inc.,-St.v Paul,r;Minnesota TEST ARTICLE! T~3(feSCoC ' ^'" ^': :'v -- '--- ',' " " : ; ..- . . . . . . Vt-_ * r,.-;.*,*;I.!:..;:-.,,.. ; CONTROL ARTICLE: PROPOSED STARTING/COMPLETION DATE OF TEST; -7ni -v/m- TEST SYSTEM AND SOURCE : Kl,,,. t;i.iv.'.lo;-, River. YV'oodiv.'f J.,nbo;"iitorQB, Ino,/ W..1linington, MA ;'. Sex: H,r Number: W e i g h t Range: -'GU-iiOO m. ...... ;. ,.. ... .... ...,,.. . : . v!*1* " * ^ ?:.-v>,-'/; ;, .-v K;;.-viii:v; ......MW%0&&, OBJECTIVE: The objective of this test'will'be to'characterise';the^acu't'e'1^ MBm i&fei- toxicity of the test article in"albino ,rats`' lintsr-t^were-selectea:iais`Jva^tV- .-. .-RV.- . . ...; .|V- . . . . . ' . .-'' ``` '. - ' ;. {' '"iT !*`i " ''n -y * - , > f v ^ry-.-i' > * ., n'TTv. test * ` " ` ... and METHOD: ^ by vcoiorjt^dxngp^acc^ which willcorrespond t o a dosage of ' (i)Q mg A g will be^administered jeach'animal, howeverPtif this -t vi dosage level does not adequately characterize the toxicity ofthe?test^article^kV; additional animals will be administered the test article at supplemental dosage levels ; *Any additional dosage levels'will bedocumented 'and"filed^wlt^^this^-f7;^ protocol. The test article will be administered'to the animals inthelform received from the.: sponsor. animals ..will be returnedhavioral reac tions'T for th fol lowing 1 4 'days/7'] initial' a n d '-finalt body'weights will be recorded. A gross necropsy which will include* but not be limited to, . heart, lungs, liver, k i d n e y s and general gastrointestinal'tract w i l l Jae' con-"' duc t e d o n all animals wh i c h die d u r i n g the conduct- o f the test as w e l l cas the animals surviving the test period. A n y gross- abnormalities which are" observed . dur i n g the conduct of the n e c r o p s y w i l l be recor d e d w i t h s p e c i f i c 'm e n t i o n to i-r '- the org a n and/or site observed. T h e acute m e d i a n lethal dose {LD50) o f the - test article w i l l be calculated, if possible, using a probit analysis m e t h o d li t the end of the observation period. All raw data and the final report will r be stored in the Riker Laboratories Archives, St. Paul, Minnesota. Form 1fi]71-1S*WO APPENDIX II Principal Participating Personnel Involved in the Study Name G- E. Hart K. D. O'Malley, BS K. L. Ebbens, BS G. C. Pecore Function Laboratory Technician Acute Toxicology Advanced Toxicologist Study Director Supervisor Acute Toxicology Supervisor Animal Laboratory 001208 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 Quality Assurance Statement 8 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 bn a three month schedule. 10