Assessment of Hydroxypropyl Methylcellulose, Propylene Glycol, Polysorbate 80, and Hydroxypropyl- Delta b-Cyclodextrin for use in developmental and reproductive toxicology studies

BACKGROUND: A series of studies were conducted to assess Polysorbate 80 (PS80), Propylene Glycol (PG), and Hydroxypropyl- Delta *b-Cyclodextrin (HP Delta *bCD), when compared with Hydroxypropyl Methylcellulose (MC) in developmental and reproductive toxicology (DART) studies. METHODS: In the rat fertility study, 20mg/kg MC, 10mg/kg PS80, 1,000mg/kg PG, 500mg/kg HP Delta *bCD or 1,000mg/kg HP Delta *bCD were administered orally before/during mating, and on gestation Day (GD) 0-7, followed by an assessment of embryonic development on GD 14. In the rat and rabbit teratology studies, the doses of MC, PS80, PG, and HP Delta *bCD were the same as those in the fertility study. In these teratology studies, pregnant females were dosed during the period of organogenesis, followed by an assessment of fetal external, visceral, and skeletal development. RESULTS: In the rat fertility and rat teratology studies, PS80, PG, and HP Delta *bCD did not exhibit toxicity, when compared with MC. Similarly, in the rabbit teratology study, there was no PS80 or PG-related toxicity, when compared with MC. However, individual rabbits in the 500 and 1,000mg/kg HP Delta *bCD groups exhibited maternal toxicity, which included stool findings, decreased food consumption, and body weight gain. Furthermore, one rabbit each in the 500 and 1,000mg/kg HP Delta *bCD groups exhibited evidence of abortion, which was considered secondary to maternal toxicity. CONCLUSIONS: Although HP Delta *bCD was not well tolerated in rabbits at doses of 500 and 1,000mg/kg, PS80 and PG were comparable to MC and should be considered for use in developmental and reproductive toxicology studies. Birth Defects Res (Part B) 89:504-516,2010. ? 2010 Wiley-Liss, Inc.