Retrospective analysis on the tolerability of commonly used vehicle....

Retrospective analysis on the tolerability of commonly used vehicle/vehicle components in rat and rabbit DART Studies

Céline Pique Bernié 1, Coralie du Peloux 1, Eulalie Nicolas 1, Edward Marsden 1

1 Charles River Laboratories Safety Assessment, Lyon, France

Vehicles, commonly used for the formulation of test items in developmental and reproductive toxicology (DART) studies, can cause significant maternal and/or developmental effects that might interfere with the interpretation of study results and the evaluation of the potential toxicity of the test item.

We have performed a retrospective analysis on vehicles used in over 400 rat and rabbit embryo-fetal (prenatal) development studies (including dose range finding and preliminary studies) conducted in the past 10 years in the authors' laboratory. The most common “non-standard” vehicle/vehicle components included cyclodextrins (e.g. Hydroxypropyl-beta-cyclodextrin), polyethylene glycol (e.g. PEG400), propylene glycol, poloxamer (e.g. Kolliphor), methylcellulose, Tween 80, oil (e.g. corn oil), lipids (e.g. Labrafil and Labrasol), used to solubilize or stabilize the active substance or as thickening agents. Vehicle/vehicle components were rated as well-tolerated or non-tolerated, based on maternal and developmental effects. Vehicle intolerability was typically characterized by lower maternal body weight gain/loss and food consumption, and excreta-related findings such as mucoid feces and/or decreased fecal output. These maternal effects may result in abortion in rabbits and secondary developmental effects such as lower fetal body weight and delay in fetal skeletal ossification both in rats and rabbits. The key factors in determining tolerability of vehicle formulations were vehicle type, vehicle quantity/proportion if used in combination with other constituents, route of administration and species.

This retrospective analysis provides valuable information to share with Sponsors when initiating DART studies, such as the acceptable no-effect range for vehicle/vehicle components in rats and rabbits. Knowledge on these vehicle-related findings can be used to try and avoid unwanted effects that can complicate the interpretation of potential test item-related effects.

Keywords: Retrospective analysis, Vehicle, Tolerability, DART studies