title: Safety of PVAP and PVAP-T including a 90-day dietary toxicity study in rats and genotoxicity tests with polyvinyl acetate phthalate (PVAP).
abstract: The safety of PVAP was evaluated in a 90-day subchronic toxicity study in rats. Sprague Dawley Crl:CD(SD) rats were administered a dietary concentration of 0.75%, 1.5% and 5.0% PVAP for a minimum of 90days. There were no adverse effects reported. The no-observed-adverse-effect level (NOAEL) in the 90-day sub chronic study was the 5% dietary concentration, which corresponds to a dose of 3120mg/kg/day for males and 3640mg/kg/day for females, the highest level tested. PVAP is co-processed with titanium dioxide to produce polyvinyl acetate phthalate and titanium dioxide (PVAP-T). The chemical composition, physiochemical properties and specifications of PVAP-T are unchanged during manufacturing process based on various analytical studies. Therefore, the toxicological data that support the safety of PVAP can be used to support the use of PVAP-T as a pharmaceutical excipient. An independent expert panel evaluated the safety of PVAP and PVAP-T. Based on the toxicology study results, safety assessment and the estimated exposure assessment for PVAP and PVAP-T, the expert panel concluded that PVAP and PVAP-T could safely be used in drug products up to 829mg per day which was the estimated exposure provided to the expert panel for current applications of PVAP and PVAP-T.
authors.affiliation: Colorcon, Inc., 275 Ruth Road, Harleysville, PA 19438, USA. Electronic address: cdemerlis@colorcon.com.
authors.forename: C C
authors.initials: CC
authors.lastname: DeMerlis
authors.affiliation: Colorcon, Inc., 275 Ruth Road, Harleysville, PA 19438, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Schoneker
authors.affiliation: School of Medicine, Virginia Commonwealth University, Richmond, VA 23229, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Borzelleca
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods*; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D011145:Polyvinyls / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014025:Titanium / Q000493:pharmacokinetics / Q000633:toxicity; D059550:Toxicity Tests, Subchronic
chemical_list: D011145:Polyvinyls; C009495:titanium dioxide; C036125:polyvinylacetate phthalate polymer; D014025:Titanium
keywords: 90-Day study; PVAP; PVAP-T; Polyvinyl acetate phthalate; Polyvinyl acetate phthalate and titanium dioxide; Subchronic study