Document xzYQJbJ8KJ2e6MvGQ4aRMqdry

Experiment No.: Conducted At: Dates Conducted: Conducted By: Acute Oral Toxicity Screen with T-2574CoC in Albino Rats RECEIVED OCT - @ 1979 31 TOXICOLOGY 0979AR0037 Safety Evaluation Laboratory Riker Laboratoriest Inc-t St. paul, minnesota August 6, 1979 to September 6, 1979 i? -L@L, I D. M. Markoe, Jr. Laboratory Technician 7@ Date dc: M. T. Case K. L. Ebbens (2) F. D. Griffith w. c. mccormick K. L. Ebbens, BS Senior Toxicologist Study Director Date summary An acute oral toxicity screen with T-2574CoC was conducted from August 6, 1979 to September 6, 1979 at Riker Laboratories,-Inc., St. Paul, Minnesota using male and female albino rats ranging in body weight from 203 to 300 grams. The test article was administered by gastric intubation at dosage levels of 5,000 and 1,000 mg/kg body weight with mortalities of 10/10 and 0/10 noted respectively. The untoward behavioral reactions which occurred during the study generally consisted of diarrhea, hypoactivity, lethargy, urinary incontinence and unkempt appearance with the onset of the reactions occurring from two hours to seven days post dose administration. All reactions subsided by day seven or death precluded recovery. Autolysis precluded gross tissue evaluation of the animals from the 5,000 mg/kg dose group with the exception of one male which had hemorrhagic lungs while necropsy of the animals from the 1,000 mg/kg dose group revealed no visible lesions. The approximate oral LD50 of T-2574CoC is between 5,000 and 1,000 mg/kg in fasted male and female albino rats. Introduction a was to approximate The objective of this study the acute oral LD50 of T-2574CoC in fasted male ,and female albino rats. The study was initiated at St. Paul, Minnesota on August 6, 1979 and completed Riker Laboratories, Inc. on September 6, 1979. The raw data generated by the Study Director and final report are stored in the conducting laboratory's archives. Riker Toxicity Experiment No.: 0979AR0037, Test Method 605A 2. method and Results ratsa were used in this test. young albino All animals were held under quarantine for several days prior to test:Lng.with only animals which appeared to be in good health and suitable as test animals at the initiation of the study used. Ttle rats were housed in suspende@, wire-mesh cages in temperature b and humidity controlled rooms and permitted a standard laboratory diet@--,pus water ad libitum except during the 16 - 20 hour period immediately prior to gastric intubation when food was withheld. The rats were administered the test article at two dosage levels. All doses were a ministered at a constant volume of 20 ml/kg into the stomachs of the rats using a hypodermic syringe equipped with a ball-tipped intubating needle c After gastric administration of the test-.article,the rats were returned to their cages and observed for the following 14 days. initial, day one, seven 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, technical personnel involved in the study, composition characteristics, and Quality Assurance statement are contained in Appendices I-IV. a Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts Ralston Purina Laboratory Chow, Ralston Purina, St. Louis, Missouri Popper and Sons, Inc., New Hyde Park, New York TABLE 1 ACUTE ORAL TOXICITY SCREEN with T-2574CoC ALBINO RATS Mortality, Necropsy and Body Weight Data Dose (mg/kg) Sex Animal Number Individual Body Weights (g) Test Day Number: 0 1 7 14 -Number DeadNumber Tested 5,000 m 9RI1167 288 (5 Days) - 5/5 9Rlll68 250 - (8 Days) 9Rlll69 300 (6 Days) - 9Rlll7O 287 (7 Days) - 9Rlll7l 281 (7 Days) F 9RlO266 220 (5 Days) 5/5 9RlO267 224 - (3 Days) 9RlO268 261 - (7 Days) 9RlO269 244 - (6 Days) 9RlO270 264 - (4 Days) - 1,000 m 9Rl2376 231 239 273 302 0/5 9Rl2377 216 218 196 250 9Rl2378 203 221 219 266 9Rl2379 224 245 273 305 9Rl2380 239 256 280 317 F 9Rl2408 223 240 250 244 0/5 9Rl2409 208 226 213 224 9Rl2410 214 232 221 232 9Rl2411 216 227 238 230 9Rl2412 214 229 233 241 3. Percent Dead 100 100 0 0 Note: Figures in parentheses indicate time of death The acute oral LD50 appears to be less than 5,000 mg/kg and greater than 1,000 mg/kg in fasted male and female albino rats. s The test article was administered as a suspension in cottonseed oil. Necror)sv indings: Autolysis precluded gross tissue evaluation of all animals from the 5,000 mg/kg dose with the exception of one male which had hemorrhagic lungs. Necropsy of the animals the 1,000 mg/kg dose group revealed no visible lesions. group from Dose (mg/kg) 5,000 5,000 1,000 1,000 TABLE 2 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-2574CoC Summary of Reactions Sex Reaction . M Hypoactiv ity Lethargy Salivation Unkempt Appearance urinary In- continence F Alopecia Ataxia Emaciation Hypoactivity Lethargy Unkempt Appearance Urinary Incontinence M Diarrhea Hypoactivity Unkempt Appearance F Diarrhea Unkempt Appearance Number Affected Number Dosed 5/5 1/5 1/5 5/5 5/5 1/5 1/5 1/5 5/5 3/5 5/5 5/5 2/5 1/5 5/5 2/5 5/5 Time of Onset Following Dose Administration 2 Hours 7 Days 7 Days 2 Days 1 Day 5 Days 4 Days 4 Days 2 Hours 4 Days 2 Days 1 Day 1 Hour 1 Day 1 Day 1 Hour 1 Day Cessation of !,Reaction b Following ,.Administration 7 Days Until Death Until Death Until Death 6 Days Until Death Until Death Until Death 6 Days Until Death .5 Days 4 Days 1 Day 2 Days 6 Days 1 Day 6 Days a Time indicates when first animal in the dose group exhibits the reaction Time indicates when no animal in the dose group exhibits the reaction APPENDIX I PROTOCOL Riker Experiment No. (-q--P)rqRoc)3i TF.ST: SPONSOR: 3M Company CONDUCTED BY: Safety Division Evaluation Laboratory, Riker Laboratoriet, inc., St. Paul, Minneso TEST ARTICLE: CONTROL ARTICLE: 1% I- PROPOSED STARTING/COMPLETION DATE OF TEST: 70 10 - -7-r- TEST SYSTEM AND SOURCE: OA&J-a. Sex: ttlow Number: m,@ Weight Range: -Zoc)-:3c%o OBJECTIVE: METHOD: The objective of this test will be to characterize the acute toxicity of the test article in albino 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 during both the quarant@ne and test periods, with fooc34 and water offered ad libiturr-. *Each animal will be identified by color coding, according to the laboratoryks standard operating procedure, which will correspond to a card.affixed to the 6utside of the cage. A single dosage of 5 C)C0) d.mg/kg will be administered to each animal. The test article 7w'-ilble administered to the animals in the form received from the sponsor, after which 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.C- 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. All raw data and the final report will be stored in the Riker Laboratories Archives, St. Paul, Minnesota. -9@ 1 Purina Laboratory Chow, Ralston Purina, St. Louis, Missouri I b C, u4a, ,Lu 61 eil Sponsor Date Stu D ectoit 7 Date tiq 447 5000, 2. 3. 4. 5. 6. 7. 8. Riker E,,cperiment No. APPENDIX I (continued) 6. Amendment@-to Protocol Study Director Study Director Date 4@6eed- 71q Date; Study Director Date Study Director Date Study Director Date Study Director Date study Director Date Study Director Date 7. AppENDiX-,i (concluded) Amendment to Protocol Note to the File, As of September1, 1979,Y,.L. Ebbenshas replacedY,.-D.o'Malleyas StudY Director. Y,. L. Ebbens APPENDIX II Name Technical Personnel involved in the Study Function D. m. Markoe, Jr., Acute Biocompatibility Laboratory Technician K. D. O'Malley, BS Advanced Toxicologist Technical Writer K. L. Ebbens, BS Senior Toxicologist Study Director G. C. Pecore Coordinator Animal Laboratory 9. APPENDIX 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. 10. APPENDIX IV Quality Assurance Statement This study is not regulated by the Good Laboratory Practice Act 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 Biocompatibility Laboratory are inspected weekly on a recurring cycle, and the facilities are examined by Laboratory Quality Assurance on a three month schedule.