Document 2Je0B1jZ4O2ExjNBGq9d7dvM5

Acute Oral Toxicity Screen with T-3066COC in Albino Rats Experiment No.: Conducted At: Dates Conducted: Conducted By: 0981AR0146 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota April 2, 1981 to May 14, 1981 K. D. O'Malley/BS Advanced Toxicologist Study Director 041 Reviewed By: f de: M. T. Case K. L. Ebbens P.* D. Griffith W. C. McCormick r K. L. Ebbens, BS Date Supervisor, Acute Toxicology 000361 1. 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 1 day post dose and all reactions subsided by day 4 or death precluded recovery. Body weight gains were noted in all animals 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 them 500 mg/kg in fasted male and female albino rats. Introduction f The objective of this study was to approximate the acute oral LD50 of T-3066CoC in fasted male and female albino rats. This study is not regulated by the Food and Drug Acbninistration'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. 000362 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 dietplus water ad libitum except during the 1 6 - 2 0 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 10 ml /kg directly into the stomachs of the rats using a hypodermic syringe equipped with a ball-tipped intubation needle--c . 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 are contained in ^Appendices I - IV. a -- Charles River Breeding Laboratories, Inc., Wilmington, MA -- Ralston Purina Laboratory Chow, Ralston Purina, St. Louis, Missouri -- Popper and Sons, Inc., New Hyde Park, New York G0363 TABLE 1 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-3066CoC Mortality, Necropsy and Body Weight Data a Dose -- Animal (mq/kg) Sex Number Individual Body weights (g) Test Day Number : Number Dead 0 14 Number Tested 5000 M 1R2612 1R2613 1R2614 1R2615 1R2616 5000 F 1R2595 1R2596 1R2597 1R2598 1R2599 246 267 289 266 ' 263 234 238 219 239 232 (1 Day) (1 Day) (4 Days) (1 Day) (1 Day) (2 Days) (2 Days) 252 290 272 5/5 2/5 500 M 1R4113 1R4114 1R4115 1R4116 1R4117 500 F 1R4051 1R4052 1R4053 1R4054 1R4055 235 227 235 228 213 166 167 160 158 157 320 319 310 332 295 218 213 192 191 205 0/5 0/5 f 3. Percent Dead 100 40 0 0 Note: Figures in parenthesis indicate time of death. -- The test article was administered as a suspension in cottonseed oil / The acute oral LD50 is less than 5000 mg/kg and greater than 500 mg/kg in fasted male and female albino rats. Necropsy Necropsy of the animals which died acutely revealed hemorrhagic gastrointestinal track lungs while no visible lesions were noted upon necropsy of the animals which survived the 14 day observation period. 000364 Table 2 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with T-3066COC Summary of Reactions Reactions Dose gAg Sex 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 5000 M Hypoactivity Prostration Diarhhea 1/1 1/1 * 1/1 0/1 - * 1/5 0/1 - - * 5000 F 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 Riker Experiment Number: r r> APPENDIX I t 7EST: SPONSOR : 3M CONDUCTED BY: Tc V PROTOCOL BEST COPY AVAILABLE 5. Co-^o-cinl Chemicals_______________________________________________ Division Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota 'EST ARTICLE: T-SOoC'-Pl ____________________________________________ ________ ______________ ONTROL ARTICLE : ;;/ _________ ___________________________________ __ __________________ ROPOSED STARTING/COMPLETION DATE OF TEST: 4/:. - 7/l_______________ ___________________ EST SYSTEM AND SOURCE: Ra\_, ::h?rlos '.i',,er Sroedir." LaJv-rPtrri-os, 'limingtou, '\ Sex: K,F Number: 5," Weight Range: 2'. -.'-300 ~r BJECTIVE: The objective of this test will be to characterize the acute or;.' ________ toxicity of the test article in albino rats Pto w ere selected as a test system for reproducibility of response, historical use, ease in handling and general availability. ETHOD: 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 foocF- 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 ' m g/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 con ducted 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 (LD50) 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. f -- Purina Laboratory Chow, Ralston Purina, St. Louis, Missouri b. Except durin-* a 16-2C heur period iirur.edi&tely prier to dosing when food will be withnelc. Sponsor C-- J . A . K ' d . . *^/V '{/%-(- V 1' O * oL jl- Date/ '/ Stiudy Director (j -/Jyi Form 19171-16# W O * ***" GOOSifc i-idk. Ijvi^ ovri^v APPENDIX I (ConciucTT*! aan^-- nt to Protocol 1 6. 0x^ jl- <A.sayW w^ffi!tc9 .rka-- ifiQ - ..'Bit) -- . . V L j ^ r O x n ^ - W ^ c C U fv.y\ >rVk^,~ ^ Lu.cPc^-------- 1\^Q<eV\r,OOo>\/ 5A/7iT Study Director Date 2.___________________________ ______________________ _ Study Director Date 3. 1 Study P\rcc;.cx Date 4. Study Director Date Study Director Date f 7 8 Study Director Date Study Director Date itudy Director Date 000967 APPENDIX II Principal Participating Personnel Involved in the Study Name G- E. Hart K. D. O'Malley, BS K. L. Ebbcns, BS G. C. Pecore Function Laboratory Technician Acute Toxicology Advanced Toxicologist Study Director-. Supervisor Acute Toxicology Supervisor Animal Laboratory 7. 1 000968 APPENDIX III Composition Characteristics 8 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. ( 000369 APPENDIX IV Quality 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. / 000370