Metabolism of 14C-octamethylcyclotetrasiloxane ([14C]D4) or 14C-decamethylcyclopentasiloxane ([14C]D5) orally gavaged in rainbow trout (Oncorhynchus mykiss).

Critical factors (uptake, distribution, metabolism and elimination) for understanding the bioaccumulation/biomagnification potential of Octamethylcyclotetrasiloxane (D4) and Decamethylcyclopentasiloxane (D5) siloxanes in fish were investigated to address whether these chemicals meet the "B" criteria of the Persistent, Bioaccumulative, and Toxic (PBT) classification. A metabolism study was conducted in rainbow trout whereby a 15mg [14C]D4/kg bw or [14C]D5/kg bw as a single bolus oral dose was administered via gavage. Of the administered dose, 79% (D4) and 78% (D5) was recovered by the end of the study (96-h). Eighty-two percent and 25% of the recovered dose was absorbed based on the percentage of recovered dose in carcass (69% and 17%), tissues, bile and blood (12% and 8%) and urine (1%) for D4 and D5, respectively. A significant portion of the recovered dose (i.e. 18% for D4 and 75% for D5) was eliminated in feces. Maximum blood concentrations were 1.6 and 1.4µg D4 or D5/g blood at 24h post-dosing, with elimination half-lives of 39h (D4) and 70h (D5). Modeling of parent and metabolite blood concentrations resulted in estimated metabolism rate constants (km(blood)) of 0.15 (D4) and 0.17day-1(D5). Metabolites in tissues, bile, blood, and urine totaled a minimum of 2% (D4) and 14% (D5) of the absorbed dose. The highest concentration of 14C-activity in the fish following D4 administration was in mesenteric fat followed by bile, but the opposite was true for D5. Metabolites were not detected in fat, only parent chemical. In bile, 94% (D4) and 99% (D5) of the 14C-activity was due to metabolites. Metabolites were also detected in the digestive tract, liver and gonads. Approximately 40% of the 14C-activity detected in the liver was due to the presence of metabolites. Urinary elimination represented a minor pathway, but all the 14C-activity in the urine was associated with metabolites. Clearance may occur via enterohepatic circulation of metabolic products in bile with excretion via the digestive tract and urinary clearance of polar metabolites.

Elemental Impurities in Pharmaceutical Excipients.

Control of elemental impurities in pharmaceutical materials is currently undergoing a transition from control based on concentrations in components of drug products to control based on permitted daily exposures in drug products. Within the pharmaceutical community, there is uncertainty regarding the impact of these changes on manufactures of drug products. This uncertainty is fueled in part by a lack of publically available information on elemental impurity levels in common pharmaceutical excipients. This paper summarizes a recent survey of elemental impurity levels in common pharmaceutical excipients as well as some drug substances. A widely applicable analytical procedure was developed and was shown to be suitable for analysis of elements that are subject to United States Pharmacopoeia Chapter <232> and International Conference on Harmonization's Q3D Guideline on Elemental Impurities. The procedure utilizes microwave-assisted digestion of pharmaceutical materials and inductively coupled plasma mass spectrometry for quantitative analysis of these elements. The procedure was applied to 190 samples from 31 different excipients and 15 samples from eight drug substances provided through the International Pharmaceutical Excipient Council of the Americas. The results of the survey indicate that, for the materials included in the study, relatively low levels of elemental impurities are present.