Inhalation Dosimetry Modeling with Decamethylcyclopentasiloxane in Rats and Humans

Abstract

Decamethylcyclopentasiloxane (D(5)), a volatile cyclic methyl siloxane (VCMS), is used in industrial and consumer products. Inhalation pharmacokinetics of another VCMS, octamethylcyclotetrasiloxane (D(4)), have been extensively investigated and successfully modeled with a multispecies physiologically based pharmacokinetic (PBPK) model. Here, we develop an inhalation PBPK description for D(5), using the D(4) model structure as a starting point, with the objective of understanding factors that regulate free blood and tissue concentrations of this highly lipophilic vapor after inhalation in rats and humans. Compared with D(4), the more lipophilic D(5) required deep compartments in lung, liver, and plasma to account for slow release from tissues after cessation of exposures. Simulations of the kinetics of a stable D(5) metabolite, HO-D(5), required diffusion-limited uptake in fat, a deep tissue store in lung, and its elimination by fecal excretion and metabolism to linear silanols. The combined D(5)/HO-D(5) model described blood and tissue concentrations of parent D(5) and elimination of total radioactivity in single and repeat exposures in male and female rats at 7 and 160 ppm. In humans, D(5) kinetic data are more sparse and the model structure though much simplified, still required free and bound blood D(5) to simulate exhaled air and blood time courses from 1 h inhalation exposures at 10 ppm in five human volunteers. This multispecies PBPK model for D(5) highlights complications in interpreting kinetic studies where chemical in blood and tissues represents various pools with only a portion free. The ability to simulate free concentrations is essential for dosimetry based risk assessments for these VCMS.

Evaporation of decamethylcyclopentasiloxane (D5) from selected cosmetic products: Implications for consumer exposure modeling

“…This value is slightly larger than the corresponding default parameter in Reddy's dermal PBPK model for D5, which is 0.0055 min −1 and 0.011 min −1 for men and women, respectively (Reddy et al, 2008). The discrepancy may result from the fact that the PBPK model was developed based on human in vivo data (Plotzke et al, 2002), whereas our estimations were derived from in vitro experiments with porcine skin.…”

Methyl Siloxanes in Environmental Matrices around a Siloxane Production Facility, and Their Distribution and Elimination in Plasma of Exposed Population

“…As previous studies indicated that inhalation F uptake for D4 and D5 was about 0.1 due to their low blood/air partition, 16,17 our study selected 0.1 as inhalation F uptake for cyclic compounds (D4−D6). Due to lack of specific F uptake for linear compounds, 1.0 was selected as F uptake for L3−L16.…”

“…Several groups have measured methyl siloxane concentrations in human plasma in controlled human exposures, such as the reports on octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) concentrations in plasma after 1-h exposures via inhalation (122 and 153 μg/L for D4 and D5, respectively.) 16,17 However, to our knowledge, there are no reports on methyl siloxane concentrations in the plasma of general or highly exposed populations in P.R. China or other countries.…”

Utility of trichloroisocyanuric acid in the efficient chlorination of silicon hydrides

“…The resulting 14 C-labeled siloxanes (for example, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, hexamethyldisiloxane, poly(dimethylsiloxanes) of various viscosities, etc.) are routinely utilized as tracers in environmental and toxicological investigations [2][3][4][5][6][7][8][9][10].…”