Franzen A, Greene T, Van Landingham C, Gentry R. 2017. Toxicology of octamethylcyclotetrasiloxane (D4). Toxicol Lett 279 Suppl 1:2–22. DOI:10.1016/j.toxlet.2017.06.007.
Octamethylcyclotetrasiloxane (D4) is a volatile cyclic siloxane used primarily as a monomer or intermediate in the production of some silicon-based polymers widely used in industrial and consumer applications and may be present as a residual impurity in a variety of consumer products. A robust toxicological data set exists for D4. Treatment-related results from a chronic inhalation study conducted in rats are limited to mild effects on the respiratory tract, increases in liver weight, increases in the incidence of uterine endometrial epithelial hyperplasia, and a dose-related trend in the incidence of endometrial adenomas. The observed increases in liver weight appear to be related to the induction of hepatic metabolizing enzymes, similar to those that are induced in the presence of phenobarbital. D4 is not mutagenic or genotoxic in standard in vitro and in vivo tests; therefore, the benign uterine tumors observed likely occur by a non-genotoxic mechanism. Results from mechanistic studies suggest that D4 has very weak estrogenic and antiestrogenic activity, as well as dopamine agonist-like activity. In rats, D4 exposure delays ovulation and hypothesized to prolong exposure of the uterine endometrium to endogenous estrogen. Though this mode of action may play a role in the development of benign uterine tumors in the rat, it is considered unlikely to occur in the human due to the marked differences in cycle regulatory mechanisms. Reproductive effects were observed following D4 exposure in female rats. These effects appear to be related to a delay of the luteinizing hormone (LH) surge, which fails to induce complete ovulation in the rat. However, based on differences in ovulatory control in rats and humans, it appears these effects may be species-specific with no risk or relevance to human health. Results from pharmacokinetic studies indicate that dermal absorption of D4 is limited, due to its high volatility and, if absorbed via dermal, oral or inhalation exposure, the majority of D4 is rapidly cleared from the body, indicating bioaccumulation is unlikely.