Document xdL8xX7ngN6pa4xv0KZEKNjgb

Oral Rangefinder Study of T-2999CoC in Pregnant Rabbits Experiment No. : Conducted At: Dosing Period: Study Director: 0680RB.0019 Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota February 1, 1981 to March 13, 1 E. G. Gortner E. G. Gortner Date Senior Research Technologist Animal Teratology Reproduction Study Director E G . Lamprecht, DVM, PhD D Research Veterinary Pathologist M. T. Case, DVM, PhD Manager, Pathology-Toxicology Safety Evaluation Laboratory 004182 Introduction This oral rangefinder study^ was conducted to determine the upper dose level of T-2999CoC-- 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 Sixty sexually mature Mew Zealand Mhite/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 oil of pooled diluted semen. The day of insemination ras designated day 0 of pregnancy. Eight groups of 6 animals were dosed with T-2999CoC suspended daily in corn oil at 100, 75, 50, 25, 15, 12, 9 or 6 ag/kg/day. There were two sets of compound administration groups. Concurrent control animals dosed at 0 mg/kg/day T2999CoC in corn oil 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 rere on a 12 hour light/dark cycle. All animals rere observed daily from day 3 of gestation until termination for abnormal clinical signs. Body weights rere recorded on days 3, 6, 9, 12, 15, 18 and 29 of gestation and the rabbits rere dosed accordingly. All surviving animals were euthanatized on either days 22 or 29 of gestation and each uterus, including its contents, was examined issnediately to determine if the animal ras pregnant* Results and Discussion First Group of Animals The oral administration of T-2999CoC at doses of 100, 75, 50 or 25 mg/kg/day resulted in compound and dose related deaths and signs of abortion. Over 50% of the females died at the tvro higher dose levels and compound related deaths also occurred at the tro lower dose levels. All dams at each compound dose level aborted or rare in the process of resorbing their conceptuses (1 able 2). Also all T-2999CoC groups had a negative body weight effect (Table 1). Because of the high death rate and compound related signs of abortion the animals rare terminated at gestation day 22 of a 29 day study. All of the dose levels ware too high to be tolerated during a rabbit teratology study. Therefore, a second group of animals rare dosed at lower dose levels. - Riker Experiment Mo. 0680RB0019 - FM-3924 004183 f] I | : 2 Second Croup of Anl-- 1 The oral administration of T-2999 CoC at closes of 15, 12, 9 or 6 mg/kg/day did not result in compound related deaths. The three deaths In the 9 mg/kg/day .group were due to noncompound related events of intubation error, broken back or pneumonia. One surviving female in each of the 15, 12, 9 and 0 mg/kg/day groups aborted or was undergoing resorption (Table 2). However, these abortions and resorptions were not considered to be compound related. Abortions or resporptions did not occur in the 6 mg/kg/day group. All dose groups including the control group had reduced body weight gain at some point during gestation (Table 1), but generally it was store pronounced in the T-2999CoC animals. Conclusion The objective of determining an upper dose level for an oral rabbit teratology study was met with the second group of animals. The results suggest that the 15 mg/kg/day dose level would be an appropriate high dose in a rabbit teratology study as there was the toxic effect of reduced body weight gain and absence of compound related deaths. A majority of the conceptuses were maintained throughout pregnancy at the 15 mg/kg/day dose level. 004184 Table 1 Oral Rangefinder Study of T-2999COC in Pregnant Rabbits Mean Body Weight Gain or Loss of BEST COPY AVAILABLI Pregnant Rabbits With Standard Deviations (g) Group I ________ Day 1 0 mg/kg/day 100 g A g / d a y 75 g A g / d a y 50 ag/kg/day 25 mg/kg/day 4 rw-. -1 2 .24. 3 4 s*. v 62. 4 00 8 23 - 1 8 7 --It'S* -1 2 3 -1 1 6 34. 1* 71. 8 24. 6 43. --;* -1 8 6 -153 -146 1.0. 7 36. 2 22. 1 78. 0 11 - 1 7 6 --*36 -1 2 8 2 ?. 1 43. 2 6 ?. 1 I*' 2S. 6 -184 -8 4 --76 24. 5 62. 2 56. 4 20. 2 23. 3 Group II ________ Day 6 3 1.;: 10 16 28 0 g/kg/day 15 g A g / d a y 12 g A g / d a y 9 mgAg/day 6 gAg/day !;-3.'I '~ s --6 12 i t ., fl 45. 1131. j:. --b2 01. 2 32. 1 40. 6 41 0 203 02. 1. 66. V 66 --13**: - 6 5 -1.1 42 226 25 36. ? 66. 3 20 1 48. 3121. 6 110 - 1 4 3 -1.01 --f -4 4 ' 160 88. 6 64. 2 34. 4 70. 8dL62. 2 64. 1 ? 'l --5 6 -2 2 20 11 242 26. 7 t>. 8 4 S'. Ci 70. 6 2 ? . 1112. 004185 4 Table 2 Oral Rangefinder Study of T-2999COC in Pregnant Rabbits Death and Reproduction Results Dose Group 0 mg/kg/day 100 mg/kg/day 75 mg/kg/day 50 mg/kg/day 25 mg/kg/day 0 mg/kg/day 15 mg/kg/day 12 mg/kg/day 9 mg/kg/day 6 mgAg/day Number Pregnant 6 6 6 6 6 6 6 5 6 5 Number Died 3 6 4 2 1 1 0 0 3 0 Number of Dams Aborted or with Total Fesorbed Conceptuses 0 6 6 6 6 1 1 1 a 30 -- Two of the three dams died before the end of the study. 004186 Appendix I Oral Rangefinder Study of T-2999COC in Pregnant Rabbits Individual Body Weights (g) and Mean Body Weights With Standard Deviation for Pregnant Rabbits 5 BEST COPY AVAILABLI Day___________________ S' 12 15 18 U I'iu.'kli/L'I-iV I'Ub 14j.b- Nib HI 6 Nib N1 B 13 z 1689 159 5962 139 2229 160-- 2 5 8 3 li >' 2 2 1 8 178 2133 1 6 9 1- 1 6 1 9 2332 2276 2246 2194 2568 2393 2226 2178 2158 2145 1649 8-- 8 2 2 9 1 225>9 ci 2111 0 i"'" 8 8-- 6 6 2 1 9 5 223 r* 222.1 2167 262 3 1953 H t M N 2 1 8 9 21.93 2 1 6 5 2 8 7 1 217 4 2161 '] fill DLV323. 1312. 8314. 224?. 4129. 2182. 9 *L t* 9 12 15 1 188 Nij.-'KG.'Dm Ulb 161 2836 2829 i860 1659 -- 0 016 162 1866 1887 1744 1582 1475 1358 1B 163 2312 247? .-*-i<\ 2159 61 -- 0 01B 164 20O1 2815 1827 11*i't* 8'- 8 Olb 179 3 3*6 --^d.'L`2l 2922 2731 2634 0 01b 188 06 2636 1895 1757 1378 0 MEMN c-*7 2286- 26198 1928 1893 1358 ST FIN. DEV439. 7514. 8454. 7443. 2643. -- Died 004187 Appendix I (Continued) Oral Rangefinder Study of T-2999CoC in Pregnant Rabbits Individual Body Weights (g) and Mean Body Weights With Standard Deviation for Pregnant Rabbits SSL 9 12 IS 18 i''t Mu.'Pu/'QHY Pi 8 Pit P18 Plb Pub PIE: ;l65 166 i ii*y 1 2104 1954 1777 1421 1269 1126 0a 0a 1 67 J- c* 1 9 7 4 1 8 2 6 1 6 9 8 1 6 0 7 168 t'* t'' 2 0 9 5 1 964 0* 0 18 a 1820 1737 1557 1255 182 0 * 0 0 0 0 1 PicHP 2 0 6 8 2 0 7 1 1 8 8 5 1 7 5 2 1 5 4 0 1 4 8 1 7 Hi-4. L>EV263. 8271. 4278. 5285. 6290. 2178. 2 Day 12 13 18 5 0 f'Rj/Kii/DNV Qlfc Qlfc: Q1B Q1E: Qlfc: Qlfc: 169 170 171 172 182 184 1921 2072 2739 2197 2057 2507 1919 2123 2723 2202 2055 2526 1721 1915 2512 1997 1949 2404 156? 1918 2229 1924 1885 2294 0 a- 0 1790 1674 0- 0 1816 1714 1724 1562 2177 2041 M2 HP 2249 2260 2083 1986 1877 1748 S7RN. DEV311. 5204. 2207. 1285. 2202. 9205. 5 BEST copy AVAILABLE -- Died 004188 w Appendix I (Continued) 7 Oral Rangefinder Study of T-2999CoC in Pregnant Rabbits Individual Body Weights (g) and Mean Body Weights with Standard Deviation for Pregnant Rabbits 6 12 10 18 20 l-IG.-'Kij.'GhV hit I r_ 2141 2100 1040 1822 1710 1000 174 1728 1702 16 6 1624 1002 1477 kit 17 !; 2286 226:^ 2002 104-0 1844 1740 R1E 176 2022 24 2 108 1806 1704 1720 kit 18G 2066 216-6 1000 1840 1767 1722 R1E 1S6 2712 27*62 2**4 2226 0-- 0 MEHf-4 2160 2187 2602 1084 1724 1608 STftN. DEV323. 82 21. 0 28W. 42'2. y 112. 1118. 7 Day 12 18 0 M G , K / C'GV NIB NIB NIBNIB NIB N1B 010 516 017 518 526 176 2 10G 21.81 2184 182 8 1047 167 0 1760 8:1ji 2 -66 102 2 1020 1820 1822 2108 2189 1002 1916 1712 1720 ikl'wii 1 0 u 2* 19010 1841 1860 2170 206 1806* 1 9 2 2 17 4 6* 1 7 5 4 0*'-i 2 7 4 0 1018 1020 2ill 24x2 1846 1840 2 ir*6 6 246 MEfiN 282 2 2 0 0 6 200 0 20601 2 0 6 2 2 0ib' 2 2 2 7 8 ON. DEV422. 440. 6*2-r1!:-. 6 3-Si*. S. i^i ^ 20?. 74 21 6 BEST COPY AVAILABLE a Died 004189 Appendix I (Continued) Oral Rangefinder Study of T-2999CoC in Pregnant Rabbits Individual Body Weights (g) and Mean Body Weights With Standard Deviation for Pregnant Rabbits 6 8 12 18 18 1.* I'i1:.. h v IJ.I1: 61b' 61b 01B Oxb 1B 818 1872 1828 1822 1786 1842 1828 2617 826 clJLi2*r' 21 88 2688 1882 1.862 1872 182 V 821 1846 1872 1828 1718 1728 1686' 1878 t8--.*2--.2`i. 1876 1622 1872 1886 182? 1468 1764 1488 184 1478 1863 1830 21.82 1738 >1*J;*c* 1848 1868 187 1864 1882 2628 2268 MEAN 1881 1846 1817 1768 1808 180 2612 STAN. l>t'v`162. 61*2. 8182. 2172. 6188. 2171. 6184. 8 2*Z. 6 8 12 18 18 28 12 Mts/K/DHY PIE? P1B P1B PIE: Plb Plb 02-> 178 4 824 2171 828 1768 026 1686 828 1862 84 i-i 1 8 7 8 1821 2222 1867 1766 2638 1844 1753 2056 1721 1656 1886 1784 1817 1861 1610 1568 1823 1680 1764 1840 1601 16.06 1786 1678 1806 1884 1681 1642 1748 1776 2021 2185 1886 1721 2108 2182 MEAN 1877 1842 1818 1743 1721 1773 2068 S', AN. DEV172. 6166. 6142. 1148. 2128. 8118. 8201. 8 BEST COPY AVAILABLE 004190 Appendix I (Concluded) Oral Rangefinder Study of T-2999CoC in Pregnant Rabbits Individual Body Heights (g) and Mean Body Heights Hith Standard Deviation for Pregnant Rabbits Dajr 6 12 15 1 4 9 t'Ii.i, KLi. L1AV '.'.It: 'Jib Qlfc Gilt Ulb Qlfc !_27 24 69 2 5 9 8 \`0C-. .V. 2 0 2 9 2 8 7 2 529 1796 1884 528 1699 1779 54 1 26.i-4' 2 2 8 542 2848 2111 2512 1822 1796 1712 2845 2948 2 91 1783 1538 1688 2828 2888 2247 1981 1782 1871 1269 1272 1652 1756 8 B. 1 2751 2675 82686 1946 8 2768 HfcMN 217 9 2 2 9 8 2 1 4 8 2 8 2 8 I 9 6 0 ~1915 2 2 6 7 9iHN. Dfc.V501. 6497. 4486. 6476. 6542. 9474. 1429. 8 Day 6 12 15 18 6 Hij/KG/L'HV RIB RIB RIB RIB RIB 521 522 522 524 542 1828 1582 2878 1922 2278 1888 1698 2158 2827 2291 1742 1586 2898 1915 2276 1748 1558 1987 1928 2215 1752 1678 1911 1959 2262 1788 1966 1679 1898 1886 2216 1964 2899 2289 2564 MfcHN 1 9 2 8 2 8 8 9 1 9 2 2 1 8 8 8 1 9 1 2 1924 2 1 6 7 STAN. L-2V268. 4222. 4272. 4258. 8226. 8248. 8274. 6 BEST COPY AVAILABLE -- Died 004191