Document N2n8ykq1ZvYwdZZDoBpe457yQ

BEST COPY AYAllABLE &R EaCi6EiIOV ED ,H Oral "--vngefinder Study of T-314 'CoC in Pregnant Rabbits >per Ituc;t '-iO.: Conduct *s At: Oosrng I'ariodStudy Dir Ctor: CS81RB0331 Safety Evaluation T.nborstory Sixer Labciatcties, Xnc. St. Paul, Minnesota July L6, 1981 to Srptember 4, 931 E. G. Gortner ii. G. Gcrtner Date Senior Research Technologist Animal Teratology Reproduction Study Director E. G. Lamprecht, DVM, PIC.' Date Research Veter-''.ary Pathologint 9n f& M. T. Case, DVK, PhD "//t / . U Date Manager, Pathology-Toxicology Safety Evaluation Laboratory 003074 1. Introduction This oral, rangefinder study-- was conducted to determine the upper dose level of T-3141CoC-- for a subsequent oral teratology study in rabbits. The study was sponsored by 3M Commercial Chemical Division, St. Paul, Minnesota and was conducted by the Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota. The study was conducted in accordance with the Safety Evaluation Laboratory's Standard Operating Procedures for such studies. The storage location for the raw data and a copy of the final report is maintained in the Safety Evaluation Laboratory's record archives. Methods Forty-eight sexually mature New Zealand White/Minikin derived female rabbits from Dutchland Laboratories, Inc., were used in the study. Each female was injected with 1 mg of pituitary luteinizing hormone via the ear vein before breeding. The does were then artificially inseminated with 0.5 ml of pooled diluted semen. The day of insemination was designated day 0 of pregnancy. Eight groups of 6 animals were dosed with T-3141CoC dissolved daily in distilled water at 300, 150, 100, 50, 25 or 10 mg/kg/day. There were two sets of compound administration groups. Concurrent control animals dosed at 0 mg/kg/day T-3141CoC in distilled water were present with both groups. All animals were dosed during days 6 through 18 of gestation by oral intubation with a syringe and rubber catheter using a constant dose volume of 1 ml/kg. The rabbits were housed individually in hanging stainless steel cages with wire mesh floors in a temperature and humidity controlled room. Purina Rabbit Chow and water were available ad libitum. The lights were on a 12 hour light/dark cycle. All animals were observed daily from day 3 of gestation until termination for abnormal clinical signs. Body weights were recorded on days 3, 6, 9, 12, 15, 18 and 29 of gestation and the rabbits were dosed accordingly. All surviving animals were euthanatized on gestational day 29 and each uterus, including its contents, was examined immediately to determine if the animal was pregnant. Results and Discussion First Group of Pregnant Rabbits (300, 150, 100 or 0 mg/kg/day T-3141CoC) Hie oral administration of T-3141CoC at doses of 300, 150 or 100 mg/kg/day resulted in compound-related deaths. All 300 mg/kg/day rabbits died within the first two days of dosing (Table 1). All 150 mg/kg/day rabbits died within the first four days of dosing. The two surviving 100 mg/kg/day rabbits were terminated on the fifth day of dosing after four rabbits had already died. The compound was very toxic to pregnant rabbits at levels of 100 mg/kg/day and higher. She resulting deaths occurred rapid enough to preclude body weight ^ Riker Experiment No. 0681RB0331 - FC-143 003075 2. effects, clinical signs and often necropsy findings. All of the dose levels used in the first group of pregnant rabbits were too high to be tolerated during a rabbit teratology study. Therefore, a second group of rabbits was dosed at lower compound levels. Second Group of Pregnant Rabbits (50, 25, 10 and 0 mg/kg/day T-3141CoC) The oral administration of T-3141CoC at doses of 50, 25 or 10 mg/kg/day did not result in compound-related deaths. One death in the 0 mg/kg/day group was due to an intubation error. No signs of either abortion or resorption were observed in the study. One 25 and one 0 mg/kg/day rabbit each had necropsy findings of abortion or resorption. A body weight loss occurred in all three compound levels between days six and nine of gestation. The loss in body weight coincided with clinical signs of either no or few stools indicating the rabbits were off feed. The body weight changes of all three compound levels between days six and nine of gestation were significantly different from the 0 mg/kg/day group (Table 2). The compound-treated rabbits recovered from the initial weight loss caused by compound administration and by day 18 of gestation were gaining more body weight than the 0 mg/kg/day group. Conclusion The objective of determining an upper dose level for an oral rabbit teratology study was met with the second group of rabbits. The results suggest that the 50 mg/kg/day dose level would be an appropriate high dose in a rabbit teratology study because a toxic effect of body weight loss occurred in the absence of compound-related deaths. 003076 Table 1 Oral Rangefinder Study of T-3141CoC in Rabbits Death by Gestational Day Dose Group 0 mg/kg/day 300 mg/kg/day 150 mg/kg/day 100 mg/kg/day 6 7 8 9 10 11 12 13 14 15 29 0 0 0 1- 0 0 0 0 0 0 0 0600 0000000 0022 2000000 10 1 1 10 0 0 0 0 1/6 6/6 6/6 5/6 0 mg/kg/day 50 mg/kg/day 25 mg/kg/day 10 mg/kg/day 0 1^ 0 0 00 0 0 0000 0000 00 0 0 0 0 0 000 0 0 0 0 00 0 0 0 0 0 00 0 0 0 0 0 1/6 0/6 0/6 0/6 r- Intubation error -- Animal broke back and was terminated from study CO Table 2 Oral Rangefinder Study of T-314lCoC in Rabbits Mean Body Weight Gain or Loss DRV 6 9 12 15 18 29 0 mg/kg/day 28 14 31 58 24 157 STfiN. DEV 41. 1 25. 4 49. 6 49. 6 34. 3 98. 4 50 mg/kg/day 47 -68* 23 36 55 219 STRN. DEV 18. 0 37. 4 52:. 8 89. 9 96. 9 45. 3 25 mg/kg/day 36 --108-- -7 60 73 213 STRN. DEV 15. 4106. 4118. 1 78. 4 47. 1 91. 5 10 mgAg/day 54 -31-- 12 13 37 188 STRN. DEV 23. 6 62. 6 28 72. 8 20. 5 62. 7 4. -- Significantly lower than the control (Dunnett's t test p <0.05) 003078 Appendix I Oral Rangefinder Study of T-3141CoC in Rabbits Individual Body Heights (g) and Mean Body Heights Hith Standard Deviations DAY 2 6 9 12 15 16 29 0 MG/KG/DAY NIB 2147 2355 2396 0 0 0 0 8 NIB 2148 2102 2170 2156 2155 2202 2235 2348 NIB 2149 2177 2127 2180 2278 2209 2319 2362 NIB 2150 2469 2495 2516 2585 2704 2687 2961 NIB 2162 2457 2511 25 2 2522 2618 2636 2881 NIB 2164 2174 2205 2204 2191 2187 2263 2271 MEAN 2289 2317 2316 23^46 2404 2428 2585 STAN. DEV159. 2170. 8186. 5195. 7241. 2216. 0208. 5 5. DAY 3 6 9 12 15 18 29 50 MG/KG/DAY 01B 01B 01B 01B 01B 01B 2151 2152 2153 2154 2165 2166 1985 2574 2595 2118 2523 1878 2036 2632 2643 2163 2588 1891 1975 2589 2501 2110 2545 1821 2010 2627 2527 2029 2595 1889 1920 2622 2560 2204 2685 1901 1780 2707 2684 2299 2756 1993 2029 2955 2893 2463 3029 2162 MEAN 2279 2326 2257 2280 2315 2370 2589 STAN. DEV322. 4335. 5329. 8337. 5355. 2413. 9431. 7 003079 -Appendix I (Concluded) Oral Rangefinder Study of T-3141CoC in Rabbits Individual Body Weights (g) and Mean Body Weights With Standard Deviations DRV 3 6 9 12 15 18 29 25 MG/KG/DRV P1B P1B P1B P1B P1B P1B 2155 2156 2157 2158 2167 2168 1929 2106 1725 2149 2080 2900 1972 2141 1753 2210 2098 2926 1903 2102 1715 1927 2071 2727 1951 2103 1681 1745 2014 2901 2088 2142 1707 1941 1973 2982 2055 2164 1816 1984 2121 3051 2286 2458 2037 2205 2393 3087 M E R N 2147 L1S s 2074 2066 2126 2199 2411 STRN. DEV399. 8397. 8348. 4439. 5442. 7435. 2362. 6 6. DRV 3 6 9 12 15 18 29 10 MG/KG/DRY Q1B Q1B Q1B Q1B Q1B Q1B 2159 2168 2161 2162 2169 2170 1699 2123 1804 2141 2585 2088 1746 2206 1825 2221 2630 2135 1766 2058 1841 2168 2620 2117 1772 2049 1844 2200 2603 2175 1834 1951 1887 2271 2542 2233 1879 1969 1938 2320 2595 2237 2089 2222 2153 2532 2669 2400 MEAN 2073 2127 2095 2107 2120 2156 2344 STRN. DEV310. 4317. 7301. 8298. 0275. 1277. 6228. 3 0-03080 BEST COPY AVAU ABLE UI5TRIKUTJON LIST M. T. Case E. G. Gortner (original + 1) E. G. Lamprecht W. C. McCormick -* K. D. Griffith * F A. bel (5) 003081