Assessing modes of action, measures of tissue dose and human relevance of rodent toxicity endpoints with octamethylcyclotetrasiloxane (D4)

Abstract

Octamethylcyclotetrasiloxane (D4), a highly lipophilic, volatile compound with low water solubility, is metabolized to lower molecular weight, linear silanols. Toxicity has been documented in several tissues in animals following mixed vapor/aerosol exposures by inhalation at near saturating vapor concentrations or with gavage dosing in vegetable oil vehicles. These results, together with more mechanism-based studies and detailed pharmacokinetic information, were used to assess likely modes of action (MOAs) and the tissue dose measures of D4 and metabolites that would serve as key events leading to these biological responses. This MOA analysis indicates that pulmonary effects arise from direct epithelial contact with mixed vapor/aerosol atmospheres of D4; liver hypertrophy and hepatocyte proliferation arise from adaptive, rodent-specific actions of D4 with nuclear receptor signaling pathways; and, nephropathy results from a combination of chronic progresive nephropathy and silanol metabolites binding with alpha-2u globulin (a male rat specific protein). At this time, the MOAs of other liver effects – pigment accumulation and bile duct hyperplasia (BDH) preferentially observed in Sprague-Dawley (SD) rats- are not known. Hypothalamic actions of D4 delaying the rat mid-cycle gonadotrophin releasing hormone (GnRH) surge that result in reproductive effects and subsequent vaginal/uterine/ovarian tissue responses, including small increases in incidence of benign endometrial adenomas, are associated with prolongation of endogenous estrogen exposures due to delays in ovulation. Human reproduction is not controlled by a mid-cycle GnRH surge. Since the rodent-specific reproductive and the vaginal/uterine/ovarian tissue responses are not relevant for risk assessments in human populations, D4 should neither be classified as a CMR (i.e., carcinogenic, mutagenic, or toxic for reproduction) substance nor be regarded as an endocrine disruptor. Bile duct hyperplasia (BDH) and pigment accumulation in liver seen in SD rats are endpoints that could serve to define a Benchmark Dose (BMD) or No-Observed-Effect-Level (NOEL) for D4 although their human relevance remains uncertain.