Document Y9MDGR5Zb6zogpa70vRbRXgYK

Oral Rangefinder Study of T-299BCoC in Pregnant Rats Experiment No.: Conducted At: Dosing Period: Study Director: 06BORROO18 Riker Laboratories, Inc. St.-Paul, Minnesota January 20, 1980 to January 29, 1980 E. G. Gortner ezr!-27 4::f-.Icp . E. G. Gortner Date Senior Research Technologist Animal Teratology Reproduction Study Director gil., E. G. Lamprecht, DVM, PhD Date Research Veterinary Pathologist M. T. Case, DVM, PhD Manager, Pathology-Toxicology Safety Evaluation Laboratory Date Introduction This oral rangefinger xtudy! was conducted to determine the upper dose level of T-2998COC- for a subsequent oral teratology study in rate. The study was sponsored by 3m Commercial Chemical Division, St. Paul, Minnnesota 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 Thirty-six time-mated Sprague-Dawley derived female rats from Charles River Breeding Laboratory were used in the study. The animals were indiscriminately removed from the shipping boxes by Animal Care personnel and placed in the rack of cages from the left to right starting at the top and working down. Later the Study Director assigned dose groups by vertical rows. The rats were housed individually in hanging stainless steel cages with wire mesh floors and fronts in a temperature and humidity controlled room. Purina Laboratory Chow and water were available ad libitum. The lights were on a 12 hour light/dark cycle. The animals were observed daily from day 3 through day 20 of gestation for abnormal clinical signs. Body weights were recorded on days 3, 6, 9, 12, 15 and 20 of gestation and the rats dosed accordingly using a constant dose volume of 5 ml/kg of body weight. T-299SCoC was suspended in corn oil and administered daily by oral intubation at doses of 150, 100, 75, 50 or 25 mg/kg/day to groups of 6 rats on days 6 through 15 of gestation. A control group of 6 rats received only corn oil by oral intubation on the same days. On day 20 of gestation the rats were killed by cervical dislocation and each uterus, including its contents, was examined immediately to determine if the animal was pregnant. Because two previous teratology studies (Riker Experiment Nos: 0680TROOOB and 0680TRODIO) with chemically related compounds resulted in fetuses with teratogenic changes in the lens of the eye, a few fetuses were also taken at day 20 of gestation and examined for eye abnormalities. Blood samples from three rats in each dose group were taken before the first dose and at day 20 of gestation. Liver specimens were also taken from the same rats on day 20 of gestation. The plasma samples and liver specimens were frozen and submitted to the sponsor. Results and Discussion The oral administration of T-299SCoC at 150, 100, 75, So or 25 mg/kg/day to rats during the period of organogenesis (days 6 through 15 of gestation) did not result in any deaths. A toxic effect of reduced body weight gain occurred between days 6 and 9 of gestation in the 150 mg/kq/day dose group (Table 1). The two nonpregnant 150 mg/kg/day rats had a more severe effect on body a Riker Experiment FC- 14 3 No. 06BORROOIS 2. weight on day 9 of the study than the pregnant high dome dams (Appendix 1). They lost a considerable amount of weight and one was observed to have urinary incontinence on days 11, 12 and 13. The pregnant dams of the 100, 75, 50 and 25 mg/kg/day dose groups did not have abnormal clinical signs and gained weight at comparable levels to the 0 mg/kg/day group. Four fetuses were examined from each of four dams in the 150 and 25 mg/kg/day dose groups for eye changes. All of the readable fetuses sectioned had eye changes consisting of one or more of the following: large lens clefts, dark streak running one-half to three-quarters of the way through the lens or disorganized lens fibers (Table 2). The lens abnormalities occurred in the same location as those observed in the two previous teratology studies (Riker Experiment Nos: 0680TRODOS and 0680TROO10) on chemically related compounds. The abnormalities in this study appeared more pronounced than in the previous studies. In the previous studies, the teratogenic effect was a developmental eye abnormality which appeared to be an arrest in development of the primary lens fibers forming the embryonal lens nucleus; followed by secondary aberrations of the secondary lens fiber of the fetal nucleus. The same general morphological changes occurred in this rangefinder study with T-299SCoC. Conclusion The objective of determining an upper dose level for an oral rat teratology study was met in this study. The above results suggest that the 150 mg/kg/day dose level would be an appropriate high dose in a rat teratology study because of the toxic effect of reduced body weight gain. In addition to the toxic effect of reduced body weight gain, the teratogenic effect of lens abnormality was observed and is likely to be reproduced in a teratology study. 3. Table I oral Rangefincier Study of T-299SCoC in Precmant Mean Body weight Gains of Pregnant Rats With Standard Deviations (g) Rats Control 150 mg/kg/day 100 mg/kg/day 75 mg/kg/day 50 mgAg/day 25 mgAg/day Day ------------------------------- I 4 -4 :1 t- E, 7. :1Ci. @i Significantly higher than the control (Dunnett's t test p < 0.05) 4. 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