title: Dietary Route of Exposure for Rabbit Developmental Toxicity Studies.
abstract: Dietary administration is a relevant route of oral exposure for regulatory toxicity studies of agrochemicals as it mimics potential human intake of the chemical via treated crops and commodities. Moreover, dietary administration of test compounds during a developmental toxicity study can deliver a prolonged and stable systemic exposure to the embryo or fetus at all stages of development. In this study, strategies were employed to optimize rabbit test material consumption via diet. Comparative toxicokinetic profiles of gavage versus dietary administration were evaluated in pregnant or non-pregnant New Zealand White rabbits for 2 novel agrochemicals with different plasma half-lives of elimination (sulfoxaflor, t½= 13.5 h and halauxifen, t½= 1 h). Dietary administration of sulfoxaflor resulted in stable 24-h plasma concentrations, whereas gavage administration resulted in a 3-fold fluctuation in plasma levels between Cmaxand CminDietary administration of sulfoxaflor resulted in a 2-fold higher nominal and diurnal systemic dose when compared with gavage dosing due to Cmax-related maternal toxicity following gavage. Results with the shorter half-life molecule, halauxifen, were more striking with a 6-fold diurnal fluctuation by the dietary route compared with a 368-fold fluctuation between Cmaxand Cminby gavage. Furthermore, plasma halauxifen was detectable only up to 12 h following gavage but up to 24 h following dietary administration. Finally, the presence of these compounds in fetal blood samples was demonstrated, confirming that dietary exposure is appropriate for achieving fetal exposure. Collectively, the results of these studies support the use of dietary exposure in rabbit developmental toxicity studies.
authors: *The Dow Chemical Company, Toxicology & Environmental Research and Consulting, Midland, Michigan, USA brhannas@dow.com.
authors: Bethany R
authors: BR
authors: Hannas
authors: *The Dow Chemical Company, Toxicology & Environmental Research and Consulting, Midland, Michigan, USA.
authors: Robert G
authors: RG
authors: Ellis-Hutchings
authors: *The Dow Chemical Company, Toxicology & Environmental Research and Consulting, Midland, Michigan, USA.
authors: Valerie A
authors: VA
authors: Marshall
authors: Dow AgroSciences, LLC, Indianapolis, Indiana, USA.
authors: Claire
authors: C
authors: Terry
authors: *The Dow Chemical Company, Toxicology & Environmental Research and Consulting, Midland, Michigan, USA.|Dow AgroSciences, LLC, Indianapolis, Indiana, USA.
authors: Alene A
authors: AA
authors: McCoy
authors: *The Dow Chemical Company, Toxicology & Environmental Research and Consulting, Midland, Michigan, USA.
authors: Shakil A
authors: SA
authors: Saghir
authors: *The Dow Chemical Company, Toxicology & Environmental Research and Consulting, Midland, Michigan, USA.
authors: Keith
authors: K
authors: Brooks
authors: Dow AgroSciences, LLC, Indianapolis, Indiana, USA.
authors: David
authors: D
authors: Eisenbrandt
authors: *The Dow Chemical Company, Toxicology & Environmental Research and Consulting, Midland, Michigan, USA.
authors: Edward W
authors: EW
authors: Carney
authors: Dow AgroSciences, LLC, Indianapolis, Indiana, USA.
authors: Richard
authors: R
authors: Billington
authors: Dow AgroSciences, LLC, Indianapolis, Indiana, USA.
authors: Reza J
authors: RJ
authors: Rasoulpour
mesh_terms: D000284:Administration, Oral; D016573:Agrochemicals / Q000633:toxicity*; D000818:Animals; D004032:Diet; D005260:Female; D005333:Fetus; D006207:Half-Life; D011247:Pregnancy; D011725:Pyridines / Q000097:blood / Q000633:toxicity; D011817:Rabbits; D013457:Sulfur Compounds / Q000097:blood / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*; D066007:Toxicokinetics
chemical_list: D016573:Agrochemicals; D011725:Pyridines; D013457:Sulfur Compounds; C560328:sulfoxaflor
keywords: developmental toxicity; guideline toxicity study; toxicokinetics