Document XO7xk3z9460k21gmXQ749nBmd

Acute oral Toxicity Screen with T-3066CoC in Albino Rats 01981 Experiw.nt No.: Conducted At: Dates Conducted: Conducted By: 0981AR0146 Safety Evaluation Laboratory R:Lker Laboratories, Inc. St. Paul, Mirmesota April 2, 1981 to May 14, 1981 X. D. O,Malley,IBS Advanced Toxicologist Study Director Date Reviewed By: dc: M. T. Case K. L. M:@bms F!''-D.Griffith W. C. McCo=ick -L. Ebbms, BS Date Supervisor, Acute Toxicology Su=ary The acute oral toxicity screen with T-3066CoC was conducted from April 2, 1981 to May 14, 1981 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rats ranging in body weight from 157-289 grams. The test article was administered by gastric intubation at dosage levels of 5,000 and 500 mg/kg body weight with mortalities of 7/10 and 0/10 respectively. untoward behavioral reactions were noted only in the 5,000 mg/kg dose group animals and consisted of hypoactivity, lethargy, prostration and diarrhea. The onset of the reactions occurred from 120 minutes to I day post dose and all reactions subsided by day 4 or death precluded recovery. Body weight gains were noted in all an'-Is which survived the 14 day study period. Necropsies performed at termination of the study revealed no visible lesions among the surviving animals while hemorrhage of the gastrointestinal track or lungs were noted in all animals which died acutely. The approximate LD50 of T-3066CoC is less than 5,000 mg/kg and greater than 500 mg/kg in fasted male and female albino rats. Introduction f The objective of this study was to approximate the acute oral LDSO of T-3066CoC in fasted male and female 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 Young albino rats_a_ 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 b and humidity controlled rooms and permitted a standard laboratory diet plus water ad libitum e=ept during the 16 - 20 hour period immediately prior to gastric intubation when food was withheld. Groups of five male and five female rats were administered the test article at preselected dosage levels. The doses were administered at a constant volume of 10mi /kg directly into the stomachs of the rats using a hypodermic c syringe equipped with a ball-tipped intubation 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, composition characteristics, and Quality Assurance statement Appendices I - IV. contained in a Charles River Breeding Laboratories, Inc., Wilmington, mA Ralston 12,x=inaTa ratory Chow, Ralston Purina, St. Louis, Missouri Popper and Sons, Inc., New Hyde Park, New York a Dose (mg/kg) Sex Animal Number 5000 M lR2612 lR2613 lR2614 lR2615 lR2616 5000 P IR2595 lR2596 lR2597 lR2596 lR2599 TABLt': 1 ACUTE ORAL TOXICITY SCREEN - MAINO RATS with T-3066COC mortality, Necropsy and Body Weight Data individual Body Weights (g) Test Day Number: N=tber Dead 0 14 iiumber Tested 246 267 .289 266' 263 234 238 219 239 232 (1 Day) 5/5 (1 Day) (4 Days) (1 Day) (1 Day) (2 Days) 2/5 (2 Days) 252 290 272 500 M lR4113 239 320 0/5 lR4114 227 319 lR4115 235 310 lR4116 228 332 lR4117 213 295 500 F lR4051 166 218 0/5 lR4052 167 213 lR4053 160 192 lR4054 158 191 lR4055 157 205 3. Percent Dead 100 40 0 0 Note: Figures in parenthesis indicate time of death. 1 The test article was aa-inistered as a suspension in cottonseed oil/ The acute oral LDSO is less than 5000 mg/kg and greater than 500 mg/kg in fasted male and female albino rats. Necropsy Necrapay of the animals which died acutely revealed hmorrhagic gastrointestinal track o lungs while no visible lesions were noted upon necrapsy of the an4mals which survived the 14 day observation period. Table 2 ACUTE ORAL TOXICITY SCREEN - ALBINO MTS with T-3066CoC Sunmry of Reactions Reactions Done Sex nolkg Minutes 1-30 60 120 observation Periods Number Affected/Number Dosed Days 1 2 3 4 5 6 7 a 9 5000 H Hypoactivity - - - Prostration - - Diarhhea - 1/5 - 1/1 1/1 1/1 0/1 0/1 - - 5000 r Hypoactivity - Lethargy - Prostration - - 1/5 0/3 3/3 0/3 4/5 3/3 0/3 1/5 0/3 - - 500 m No significant reaction 500 F No significant reaction No significant reactions *Total death APPENDIX PROTOCOL Riker Experiment I Number: 7.EST: kc.-.tt- ;PONSOR: 3m :ONDUCTED BY: Safety Evaluation Laboratory, 'EST ARTICLE: 'ONTROL ARTICLE: ROPOSED STARTING/COMPISTION DATE OF TEST: EST SYSTEM AND SOURCE: Ra@-, :'hpr;.ris Sax: t-1F, Number: Weight Range: 2"..j-30--7 Riker Laboratories, 4./:--- 7/"1 Division Inc., St. Paul, Minnesota BJECTM: :ETHOD: The objective of this test will be to characterize the acute kirt" toxicity of the test article in albino rits P-ts were selected as a test system for reproducibility of response, historical use, ease in handling and general availability. The animals will be housed in stainless steel suspended wire mesh cages in temperature and humidity controlled rooms duringbboth the-quarantine and test a periods, with food:- and water offered ad libitum-. Each animal will be identified by color coding, according to the laboratory's standard operating procedure, which will correspond to a card affixed to the outside of the cage. A single dosage of 5.00'% mg/kg will be administered each animal, however, if this dosage level does not adequately characterize the toxicity of the test article, additional animals will be administered the test article at supplemental dosage levels. Any additional dosage levels will be documented and filed with this protocol. The test article will be administered to the animals in the form received from the sponsor. After administration of the test article, the animals will be returned to their cages and observed for any untoward behavioral reactions for the following 14 days. Initial and final body weights will be recorded. A gross necropsy which will include, but not be limited to, heart, lungs, liver, kidneys and general gastrointestinal tract will be conducted on all animals which die during the conduct of the test as well as the animals surviving the test period. Any gross abnormalities which are observed during the conduct of the necropsy will be recorded with specific mention to the organ and/or site observed. The acute median lethal dose (LDSO) of the test article will be calculated, if possible, using a probit analysis method at the end of the observation period. All raw data and the final report will be stored in the Riker Laboratories Archives, St. Paul, Minnesota. Purina Laboratory Chow, Ralston Purina, St. Louis, MLssouri Except -luri-).-a 16-@@r.*-icu:p:fri-od imme-.2iatelv pricr to Cos.i-n7 fo:@d will be w+thnc.-lC-. Sponsor Form19171.16-PWO '/S@u-djyDirector Date C*@,r,O%V,v 2. 3. 4. S. 6._ 7. APPENDIX I (Conclucte-VAmendkiont to Protocol I't L KZI-E C,@7 @m:-Lia :Az VIA M-+LQ stiady Direethr 6. At-1.. A Date Study Director ID&te sti3dy D@rcv!*,.Oc Date study Director DiLto Study Director T- Study Director Date Date Study Director Date Ltaft Director Data APPENDIX 11 Principal Participating Personnel Involved in the Study Name G. E. Hart K. D. Olf4alley,BS K. L. Ebbens, DS G. C. Pecore Plunction Laboratory Technician Acute Toxicology Advanced Toxicologist Study Director..._ Supervisor Acute Toxicology Supervisor hn4mal Laboratory APPMMIX 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. APPMIX -TV Ouality Assurance Statement This study is not reguated.by the Good Laboratory Practice RLgulation of 1978 and therefore a statement signed and prepared by the Quality Assurance group is not applicable. This study was,'hwever, audited by the-Quality Assurance group. in addition to the data audit, differe*nt significant phases for studies underway in the Toxico:Logy Laboratory are inspected weekly on a recurring cycle, and the facilities are examined by Laboratory Quality Assurance on a three month schedule.