Trước năm 1998, hướng dẫn kiểm tra quy định đánh giá độc tính phát triển quy định tiếp xúc từ ngày thai (GD) 6 (thời điểm cấy conceptuses vào nội mạc tử cung) để kết thúc organogenesis lớn (đóng cửa của vòm miệng thứ cấp), GD 15 cho loài gặm nhấm, và GD 18 (4) hoặc 19 (3) cho thỏ. | Fetal Skeletal Risk Assessment Issues 387 Fig. 2. New risk assessment risk management paradigm 2 . Prior to 1998 regulatory testing guidelines for developmental toxicity assessments specified exposure from gestational day GD 6 time of implantation of conceptuses into the uterine lining to the end of major organogenesis closure of the secondary palate GD 15 for rodents and GD 18 4 or 19 3 for rabbits. Current International Conference on Harmonization guidelines 20 have retained this duration of exposure. Recent EPA 11 21 FDA 6 and OECD 12 testing guidelines specify exposure beginning after implantation is complete or on the day of insemination see below and continuing until the day before scheduled sacrifice at term. This corresponds to GD 6 or 0 through 19 or 20 for rats GD 6 or 0 through 17 or 18 for mice and GD 6 or 0 through 28 or 29 for rabbits. The day vaginal sperm or a copulation plug is found rodent or mating is observed rabbit is designated GD 0. The rationale for starting exposures after implantation is complete is based on two possible confounding scenarios If the initial parent test material is teratogenic and the metabolite s is not and if metabolism is induced by exposure to the parent compound then exposure beginning earlier than implantation with concomitant induction of enzymes and enhanced metabolism will result in the conceptuses being exposed to less of the teratogenic moiety and the study may be falsely negative. If the test chemical and or metabolite s interfere with implantation then exposure prior to implantation will result in few or no conceptuses available for examination at term. However there are situations when initiation of exposure should begin before uterine implantation. These include the following For exposure regimens that are anticipated to result in slow systemic absorption . topical application subcutaneous injection or insertion of an osmotic mini-pump for continuous infusion or dosing via feed or water steady-state or .
