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Oral Rangefinder Study of T-2999Coc in Pregnant Rabbits
Experiment No.: Conducted At:
Dosing Period: Study Director:
0680PZ.0019
Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota
February 1, 1981 to March 13, 19
E. G. Gortner
E. G. Gortner
Date
Senior Research Technologist
Animal Teratology Reproduction
Study Director
E. G. Lamprecht, DVI4, PhD
L
Research Veterinary Pathologist
M. T. Case, DVM, PhD
D
Manager, Pathology-Toxicology
Safety Evaluation Laboratory
Introduction a
This oral raegefinder 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 Now Zealand Whit*/Kinikin derived female rabbits from Dutchland Laboratories, Inc., wereused In the study. Each female was injected with 1 mg of pituitary lut:einizing hormone via the ear vein before breeding. The does were then artificially inseminated with 0.5 uLlof pooled diluted semen. The day of insemination was designated day 0 of pregnancy*
Eight groups of 6 animals were dozod with T-2999CoC suspended daily in corn oil at 100, 75, 50, 25, 15, 12, 9 or 6 mg/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 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 wore outhanatized on either days 22 or 29 of gestation and each uterus, including its contents, was examined immediately to determine if the animlal was pregnant.
Results and Discussion
First Group of Aniinals
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 two higher dose levels and compound related deaths also occurred at the two lower dose levels. All dams at each compo=d dose level aborted or were in the process of resorbing their concoptuses (lable 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 were terminated at "station day 22 of a 29 day study. All of the done levels war* too high to be tolerated during a rabbit toratology study. Therefore, a second group of animals were dosed at lower dose levels.
Riker Experiment No. 068ORBOO19 FM-3924
2
Second Group of Animals
The oral administration of T-2999 CoC at doses of 15, 12, 9 or 6 mg/kg/day did not result in compound related deaths. 7he 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 consid ered 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 more pronounced in the T-2999CoC aniinals.
Conclusion
The objective of determining an upp@er 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.
Table 1
Oral Rangefinder Study of T-2999CoC in Pregnant Rabbits
Mean Body Weight Gain or Loss Of Pregnant Rabbits With Standard Deviations (9)
Group I Day
---------------------------------
-j_
0 mg/kg/day
loo mg/kg/day 75 mg/kg/day
2 7 i..E: 2 .1.fE"4--@4.
50 mg/kg/day 25 mg/kg/day
2 14 Group
2!-@-.
-84
7
tit-4.. 2 C-i.2
Day
-- - - - - - --- --- - -- - -- - - - - - - - - - - - - - - -- - - -
0 mg/kg/day 15 mg/kg/day
4 :LI @41
12 mg/kg/da y 9 mg/kg/day
-:14
6 mg/kg/day i4
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 mg/kg/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 Darrs Aborted or with Total Resorbed Conceptuses
0 6 6 6 6
1 1 1
a 30
Two of the three damis died before the end of the study.
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