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T C) C-isYi C)Y-al -,@.Angef 4,iider St.;icl;i of T-314 in ;?.cecjnar.-F,4-a@b,bits ".-CoC At: Do.-,ing '--ar--od- .Idy Director: OSSIRB0331 Safety T,,tboratory St. Paui, MznLesota L6, 1981 to SLziptember 4, '.931 E. G. Gor-@@TEar G. G--rtner SeL4-or Reseal--ch Technologist X-iL-talTeratol-igy Reproduction Studl- 1:--'-rec--or Date E. G. Lamp:@echt, DVM, oate Research Veter4.np-i-y .0.7tthol.cgi!4t i';.T. Case, PhD @=nzger, Patholocy-Toxicology Safety Eval-x,-ation Laborator-@y, Date introduction a Th oral rangefinder study was conducted to determine the upper dose level of T-i3l4lCoC!@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 IAboratory's Standard Cperating 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 I 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-3l4lCoC 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-3l4lCoC 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 I 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 ligbt/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, IS 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-3l4lCoC) The oral administration of T-3l4lCoC 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. The resulting deaths occurred rapid enough to preclude body weight a Riker Experiment FC- 14 3 No. 0681RB0331 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 Pre$Mant Rabbits (50, 25, 10 and 0 mg/kg/day T-3l4lCoC) The oral administration of T-314ICoC 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. Dose Group 0 mg/kg/day 300 mg/kg/day 150 mg/kg/day 100 mg/kg/day 0 mg/kg/day 50 mg/kg/day 25 mg/kg/day 10 mg/kg/day 6 7 0 0 0 6 0 0 JL!l 1 Table 1 Oral Rangefinder Study of T-3l4lCoC in Rabbits Death by Gestational Day Gestational Day 8 9 10 11 12 13 14 15 29 0 12@ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 JLa 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 a Intubation error Animal broke back and was terminated from study 4. Table 2 Oral Pangefinder Study of T-3l4lCoC in Rabbits Mean Body Weight Gain or Loss DFRY :L2 :L5 :LS 29 -------------------------------------------- 0 mg/kg/day STRN. DEV 50 mg/kg/day STFKN. DEV 25 mg/kg/day STAN. DEV 10 mg/kg/day @@fRN. DEV 28 14 31 58 24 157 4:1.1 25.4 49.6 49.6 34.3 98. 4 47 -68A 23 36. 55 2:L9 IS. 0 --,7.452.8 89.9 96.9 45.3 36 -IOE:L -7 E,0 73 21l :15. 41:18. 1 78.4 47. :1 9:1.5 54 -lit 1-.1 13 37 iss 2:,.(E 62. -E.2E..Ci 72.8 2C4. 5 62. 7 significantlylower than the control (Dunnett'st test p < 0.05) S. Appendix I Oral Rangefinder Study of T-3l4lCoC in Rabbits Individual Body Weights (g) and Mean Body Weights With Standard Deviations DAY 3 6 9 :12 :L5 :18 29 -------------------------------------------------- 0 MG/KG/DAY N:LB NIB NIB NIB NiS NIB 2147 2148 2149 2150 2163 2164 2355 210a 211@7 246.9 2457 2174 2396 2170 2:127 2495 2511 2205 0 2:156 2180 2516 2522 2204 0 2:155 2278 2585 2522 2191 0 2202 230-q 2704 2618 2187 0 2235 2319 2687 2636 2263 0 2348 236r-L' 2961 2SE:l 2a7l MEAN 2289 2317 2316 2a46 2404 2428 STAN. DE%.-'15,c-i. S:ISE..5:11--057.241. 221L;. 2585 5 DAY 3 6 9 :12 :L5 :Le 29 ------------------------------------------------- 50 MG/KG,,IDRY OiB C)IB D:LB OiB OIB 018 2151 2152 2153 2154 2165 2166 1985 2574 2595 2118 2523 1878 2036 2632 2643 216a 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 246a 3029 2162 MEAN 2279 2326 2257 2280 2315 2370 2589 STRN. DEV322. 4335. 5329. 8337. 5355. 24:L3. 943:1. 7 6. Appendix I (Concluded) Oral Ungefinder study of T-3141coc in Rabbits indiviailn'Body weights (g) and Mean Body Weights With Standard Deviations DFIY 3 6 9 :L2 :15 :18 29 - -------------------------------------------------- 25 MG/KG/DAY PIS 2155 1929 1972 1903 1951 2ee8 2055 2296 PIS 2156 2100 2141 2102 2103 2142 2164 2458 PIS 2157 1725 1753 1715 1681 1707 1816 20a7 PIB 215e 2149 2210 1927 1745 1941 1984 2205 PIB 2167 2080 2098 2071 2014 1973 2121 2393 PIB 2168 2900 2926 2727 2901 2982 3051 3087 MERN 2147 2183 2074 2066 2126 2199 2411 STRN. DEV399. 8397. 8--<48.44--<9.5442. 7435. 2362. 6 DAY 3 6 12 15 18 29 -------------------------------------------------- 10 MG/KG/DRY QiB QIB QI.B OLB Q:LB QIB 2159 2160 2161 2162 2169 2170 1699 2123 1904 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 2220 2595 2237 2099 2222 2153 2522 2669 2400 MERN 2073 2127 2095 2107 2120 2156 2344 STRN. DEV310. 43:17.7301. 8298. 0275. 1277. 6228. 3 I)IS'I'RIJRUTJC)NI,ISU' 1,1.1,. Case E. G. Gcrtiier (c)rjqi.nal + 1) E. G. Lamprecht W. C. McCorni.-i--e*@.F. D. Griffith F. A. Ubel (5)