Metabolism and disposition of [¹⁴C]-methylcyclosiloxanes in rats

Octamethylcyclotetrasiloxane (D₄) and decamethylcyclopentasiloxane (D₅) are low molecular weight cyclic volatile methyl siloxanes (cVMSs) primarily used as intermediates or monomers in the production of high molecular weight silicone polymers. The use of D₄ as a direct ingredient in personal care products has declined significantly over the past 20 years, although it may be present as a residual impurity in a variety of consumer products. D₅ is still used as an intentional ingredient in cosmetics, consumer products and in dry cleaning. Persons who may be exposed include occupational exposure for workers, and potential inhalation or dermal exposure for consumers and the general public. Because of the diverse use, especially of D₅, and the potential for human exposure, a comprehensive program was undertaken to understand the kinetics, metabolism, enzyme induction and toxicity of D₄ and D₅ in rats following relevant routes of exposure. Physiologically based pharmacokinetic (PBPK) models utilizing these studies have been reported for D₄ and D₅ in the rat and human following dermal and inhalation exposures, with the oral uptake component of the model being limited in its description. Data from high dose oral studies in corn oil and simethicone vehicles and neat were used in the D₄/D₅ harmonized PBPK model development. It was uncertain if the inability to adequately describe the oral uptake was due to unrealistic high doses or unique aspects of the chemistry of D₄/D_5. Low dose studies were used to provide data to refine the description of oral uptake in the model by exploring the dose dependency and the impact of a more realistic food-like vehicle. Absorption, distribution, metabolism and elimination (ADME) of D₄ and D₅ was determined following a single low oral gavage dose of ¹⁴C-D₄ and ¹⁴C-D₅ at 30 and 100mg/kg body weight (bw), respectively, in a rodent liquid diet. Comparison of the low vs. high dose oral gavage administration of D₄ and D₅ demonstrated dose-dependent kinetic behavior. Data and modeling results suggest differences in metabolism between low and high dose administration indicating high dose administration results in or approaches non-linear saturated metabolism. These low dose data sets were used to refine the D₄/D₅ multi-route harmonized PBPK model to allow for a better description of the disposition and toxicokinetics of D₄/D₅ following oral exposure. With a refined oral uptake description, the model could be used in risk assessment to better define the internal dose of D₄ and D₅ following exposure to D₄ and D₅ via multiple routes.