Document QJLJRQG0Y8Xq85Dy0e4gpgw0R

Experiment No.: Conducted At: Dates Conducted: Conducted By: Acute Oral Toxicity Screen with T-2574COC in Albino Rats A M ifro ttH "r e c e i v e d OCT - 3 1979 3M TOXICOLOGY 0979AR0037 Safety Evaluation Laboratory Riker Laboratories, Inc., St. Paul, Minnesota August 6 , 1979 to September 6 , 1979 X? .LU ^- D. M. Markoe, Jr. Laboratory Technician *>//9/77 Date de: M. T. Case K. L. Ebbens (2) F. D. Griffith W. C. McCormick K. L. Ebbens, BS Senior Toxicologist Study Director Date 4374 1. 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 con sisted 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 hem orrhagic 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 be tween 5,000 and 1,000 mg/kg in fasted male and female albino rats. Introduction . .a The objective of this study-- was to approximate the acute oral LD50 of T-2574COC in fasted male and female albino rats. The study was initiated at Riker Laboratories, Inc., St. Paul, Minnesota on August 6 , 1979 and completed 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 437s 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. Hie 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. The rats were administered the test article at two dosage levels. All doses were administered 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^-. 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 recorde 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 char acteristics, and Quality Assurance statement are contained in Appendices I-IV. -- 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 004376 TABLE 1 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-2574COC Mortality, Necropsy and Body Weight Data a Dose -- Animal (mgAg) Sex Number Individual Body Weights (g) Test Day Number: Number Dead 0 1 7 14 Number Tested 5,000 M 9R11167 288 (5 Days) - 9R11168 250 - - (8 Days) 9R11169 300 - (6 Days) - 9R11170 287 - (7 Days) - 9R11171 281 -- (7 Days) - F 9R10266 220 - (5 Days) 9R10267 224 - (3 Days) 9R10268 261 - (7 Days) 9R10269 244 - (6 Days) 9R10270 264 - (4 Days) - 5/5 5/5 1,000 M 9R12376 9R12377 9R12378 9R12379 9R12380 F 9R12408 9R12409 9R12410 9R12411 9R12412 231 239 273 302 216 218 196 250 203 221 219 266 224 245 273 305 239 256 280 317 223 240 250 244 208 226 213 224 214 232 221 232 216 227 238 230 214 229 233 241 0/5 0/5 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, a -- The test article was administered as a suspension in cottonseed oil. Necropsy Findings: Autolysis precluded gross tissue evaluation of all animals from the 5,000 mg/kg dose group with the exception of one male which had hemorrhagic lungs. Necropsy of the animals from the 1,000 mg/kg dose group revealed no visible lesions. 004377 TABLE 2 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-2574COC Summary of Reactions Dose (mg/kg)___ Sex Reaction Time of Onset Cessation of Reaction Number Affected Following Dose-- Following Dose -- Time of Death Number Dosed Administration___________Administration_________Following Dose 5,000 M Hypoactivity Lethargy Salivation Unkempt Appearance Urinary In continence 5/5 1/5 1/5 5/5 5/5 2 Hours 7 Days 7 Days 2 Days 1 Day 7 Days Until Death Until Death Until Death 6 Days 5 - 8 Days 5,000 1,000 1,000 F Alopecia Ataxia Emaciation Hypoactivity Lethargy Unkempt Appearance Urinary In continence M Diarrhea Hypoactivity Unkempt Appearance F Diarrhea Unkempt Appearance 1/5 1/5 1/5 5/5 3/5 5/5 5/5 2/5 1/5 5/5 2/5 5/5 5 Days 4 Days 4 Days 2 Hours 4 Days 2 Days 1 Day 1 Hour 1 Day 1 Day 1 Hour 1 Day Until Death Until Death Until Death 6 Days Until Death -5 Days 4 Days 1 Day 2 Days 6 Days 1 Day 6 Days 3 - 7 Days SC>00 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 C^f-iRiker Experiment No. : 5. - au Kl.TEST: _______ Ar-UTg. O tt-At. *T~jtici*rV'- SPONSOR: 3M Company C aca t>eO,____________________ _______________,,___ Division CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories*, Inc., St. Paul, Minn -- rC -Jk n ! L B .TEST ARTICLE: ________________ !______________ :___________ CONTROL ARTICLE: r\g><\ <_______________________________________________ _ %-HQ j I d- ~1PROPOSED STARTING/COMPLETION DATE OF TEST: ^ _______________ OMxJl.iTEST SYSTEM AND SOURCE: o Wc ,{ ^ Sex: &Mf *r\, V Number: a, 5- g Weight Range:'^ 0 0 - 3 0 0 ^ .^ 5 OBJECTIVE: The objective of this test will be to characterize the acute t___________toxicity of the test article in albino yacts_________ * 'Rcdk were selected as a test system for reproducibility of response, historical use, ease in handling and general availability. METHOD: The animals will be housed in stainless steel suspended wire mesh cages in temperature and humidity controlled rooms during both the quarantine and test periods, with food-- and water offered ad libitum-- . Each animal will be identified by color coding, accord ing to the laboratory's standard operating procedure, which will QO Ocorrespond to a card affixed to the outside of the cage. A single dosage of d_.mg/kg will be administered to each animal. The test article 'will be administered to the animals in the form re ceived 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. 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 wilj. be stored in the Riker Laboratories Archives, St. Paul, Minnesota. -- Purina Laboratory Chew, Ralston Purina, St. Louis, Missouri do'~"vs*> _ J L ..J. rrrrfi) it rJxiSSaUA "fe -- ti . ...00 , . 7&< 004379 uj Sponsor &o+~2~cJL ifs-9 Date ' lO & t A A ( p / Study Director 1 ' J OU ^ otc*v /35/11 Date  f} ~Ftiker Experiment No. : APPENDIX I (continued) -- *---- Amendment to Protocol 6. l. Ut*-* c t w //rmn ZthitJjjjtf tot dr fkwX X jwp f //wy uvCu f J A J ? b (ajv4^ ( U /$ f.U' SL A o jC vrM R o k*. qM Z qt- c *J S (L m nU taacf O tiu w JL s SLO jy je l fr ... . . M ,--- .... . t Study Director s c 3 t3 C I n v o u M A thU lAJ-WlBs . ^ c A f l M 0 4T t u r ' r Z r W "ZJrJt Date O tflA stkJ) Study Director Date Study Director Date 4. Study Director Date 5. . - Study Director bate 6 Study Director Date 7. Study Director Date 8. 004380 Study Director Date Note to the File APPENDIX"! (concluded) Amendment to Protocol 7. As of September 1, 1979, K. L. Ebbens has replaced K- D- O'Malley as Study Director. 004381 Nane APPENDIX II Technical Personnel Involved ln the Study Function D. M. Markoe, Jr., K. D. O'Malley, BS K. L. Ebbens, BS G. C. Pecore Acute Biocompatibility Laboratory Technician Advanced Toxicologist Technical Writer Senior Toxicologist Study Director Coordinator Animal Laboratory 8. 43S2 APPENDIX III Composition Characteristics 9. 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. 004383 APPENDIX IV Quality Assurance Statement 10 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. 004384