Document ZJGaVJ2Z3Gxgmore9ppeZvDRY

JEFFERSON MEDICAL COLLEGE of THO,MAS JEFFERSON UNIVERSITY DanielBaugh Institute Departmentof 4nafomy Officeof the Directorand Chairman December 7. 1983 Philadelphia1,9107 (215)928-7820 Mr. William C. McCormick, III Toxicology Services, Medical Department 220-2E 3M Center St. Paul, MN 55101 Dear 14r.McCormick: I have received the draft report of T3351 from Dr. Wetzel and after careful review find it to be a clearlyexplainedstudy. It is a state-of-the-art safety evaluation for developmentaltoxicity. The data demonstrate severe maternal toxicity is evident both during and after treatment at both 5 and 10 mg T3351/kg/da and that the higher dosed group was the more severely affected. Their food intake was reduced and, not only did the dams not gain weight normally, actual maternal weight losses occurred in both these treatment groups. Numerous clinical signs of maternal distress and even hair loss were observed. There were directly related reductions in fetal body weights from these ill dams. However, for such ill mothers and small fetuses, the 5 mg group showed fewer skeletal delays than one might expect in such severely stressed mothers. No signs of either maternal or developmental toxicity occurred in the low dose group. In short, at dose levels severely maternally toxic and even lethal, T3351 exerts only a relative few of the adverse effects on the conceptus one would expect. At a dose level below that producing maternal death, but numerous other signs of maternal toxicity, there were only minor effects on the rate of Ietal development and, at the all importantmaternally nontoxic dose level.,embryonic and fetal development were absolutely normal. This study clearly illustratesthe safety of the test substancefor the conceptus. The mother appears more vulnerable to T3351 than the conceptus and one would conclude that as long as exposures are kept below adult toxic levels, embryonic development would also not be affected. This study of T3351 makes a clear statement of a no effect level and fetal safety. You have gone the extra mile and are to be congratulated for your Page 2 William C. McCormick December 7, 1983 high motivation. I cannot envision a customer or a regulatory agency being confused by, or having reservations regarding, this data base clearly establishing T3351 to not represent a developmental hazard to the conceptus. Sincerely, E. @luarshaI J son, Ph.D. Professor a d hairman Director, Daniel Baugh Institute EKJ:amf cc Dr. Lawrence T. Wetzel, Ph.D. Department of Toxicology Hazleton Laboratories America, 9200 Leesburg Turnpike Vienna, VA 22180 Inc.