title: Embryo/fetal development studies with hydroxypropyl methylcellulose acetate succinate (HPMCAS) in rats and rabbits.
abstract: BACKGROUND
  Hoshi et al. [Hoshi et al. J Toxicol Sci 10(Suppl):187-255, 1985a,b,c,d] evaluated the potential for hydroxypropyl methylcellulose acetate succinate (HPMCAS) to produce developmental and reproductive toxicity in a series of studies that included rat and rabbit teratology studies, a rat fertility study, and a rat peri- and postnatal study. The authors concluded that there were no compound-related findings. In the cesarean-section phase of the rat teratology study, however, clubfoot was reported for 0.8, 2.1, 5.5, and 4.1% of fetuses in the control, 625, 1250, and 2500 mg/kg groups, respectively. There were no significant increases in external anomalies, but the apparent dose-related increase in clubfoot was not specifically addressed. In the rabbit teratology study, the number of litters evaluated (12-13 per group) was not consistent with current regulatory guidelines. Therefore, to definitively establish the potential of HPMCAS to produce developmental toxicity, embryo/fetal development studies were carried out in rats and rabbits.
  
  
  METHODS
  Groups of 20 pregnant Sprague-Dawley rats and New Zealand White rabbits were dosed with 0, 50, 150, 625, or 2500 mg/kg HPMCAS from gestational day (GD) 6-17 or GD 7-19 for rats and rabbits, respectively. Fetuses were collected by cesarean section and examined for external, visceral and skeletal development.
  
  
  RESULTS
  No developmental toxicity was observed as a result of HPMCAS exposure demonstrating that maternal HPMCAS exposure during gestation does not induce developmental anomalies. There were no findings of clubfoot or other limb anomalies in these studies at dose levels equivalent to those that were previously associated with a possible increase in clubfoot.
  
  
  CONCLUSIONS
  The conclusion of the earlier study indicating that treatment with HPMCAS at doses up to and including 2500 mg/kg did not produce developmental toxicity was confirmed with these studies. It is likely that the clubfoot noted in the earlier rat teratology study was a misdiagnosis or artifact.
authors.affiliation: Pfizer Global Research and Development, Building 274 MS 1260, Eastern Point Road, Groton, CT 06340, USA. gregg_d_cappon@groton.pfizer.com
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Cappon
authors.forename: Tammye L
authors.initials: TL
authors.lastname: Fleeman
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Rocca
authors.forename: Jon C
authors.initials: JC
authors.lastname: Cook
authors.forename: Mark E
authors.initials: ME
authors.lastname: Hurtt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003025:Clubfoot / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D008747:Methylcellulose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity
chemical_list: D013723:Teratogens; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose