Inhalation Toxicology of Octamethylcyclotetrasiloxane (D₄) Following a 3-Month Nose-Only Exposure in Fischer 344 Rats

Abstract

Octamethylcyclotetrasiloxane (D4) is a low-molecular-weight cyclic siloxane used primarily in the synthesis of silicone polymers. The objective of the present study was to evaluate the subchronic toxicity of D4 following a 3-month nose-only inhalation exposure. Male and female Fischer 344 rats (20/sex/group) were exposed 6 h/day, 5 days/week for 3 months to vapor concentrations of 0, 35, 122, 488, and 898 ppm D4. Also, an additional 10 per sex in the control and high-exposure groups were allowed a 4-week recovery period to observe reversibility, persistence, or delayed occurrence of any potential adverse effects. Body weights and food consumption were monitored at least twice weekly over the course of exposures. Approximately 18 hours preceding euthanasia, animals were transferred into metabolism cages for urine collection, and were fasted. At necropsy, rats were anesthetized with pentobarbital and euthanized by exsanguination. Blood was collected for hematological and clinical biochemical analyses. Selected organ weights were measured and a complete set of tissues was taken for histopathological examination. A concentration-dependent increase in absolute and relative liver weight (488 to 898 ppm) and a significant decrease in ovarian weight (898 ppm) were observed in female rats. Exposure to D4 via nose-only inhalation (35 to 898 ppm) produced minor alterations in hematological and serum chemistry parameters that were considered either incidental and of little toxicological significance (hematology) or suggestive of metabolic adaptation/alteration (serum chemistry) in response to exposure-related hepatomegaly. There were no histopathological findings noted in the liver. Histopathological evidence indicated the primary target organs following D4 inhalation exposure to be components of the female reproductive tract. Reversible histopathological changes were observed in the ovary (hypoactivity) and vagina (mucification) of female rats in the high-dose group only (898 ppm). Although an increase in the incidence and severity of both macrophage accumulation, interstitial inflammation, and eosinophil infiltration was observed in the lungs of male and female rats exposed to D4, the toxicological significance is uncertain as other inhalation studies at similar concentrations failed to show these effects. In summary, nose-only inhalation of a high concentration of D4 resulted in reversible histopathological changes in the female rat reproductive tract. Lower concentrations did not elicit these same effects.

A survey of cyclic and linear siloxanes in indoor dust and their implications for human exposures in twelve countries

“…Several studies have reported toxicity, especially reproductive and endocrine effects, of siloxanes in laboratory animals (Burns-Naas et al, 1998;Burn-Naas et al, 2002;McKim et al, 2001;He et al, 2003;Meeks et al, 2007;Quinn et al, 2007a,b;Siddiqui et al, 2007). A risk assessment conducted in Canada indicated that D5 met the criteria for persistence (Environment Canada, 2011).…”

Octamethylcyclotetrasiloxane (D4)

“…Liver weight increase was reversible in males, but not in females. The NOAEL was ≥700 ppm (>8.49 mg/L, measured) on the basis that the liver weight changes were adaptive and not toxicological in nature (Burns-Naas and Meeks, 2002). A study of similar design but using lower concentrations was also conducted.…”

Safety Assessment of Cyclomethicone, Cyclotetrasiloxane, Cyclopentasiloxane, Cyclohexasiloxane, and Cycloheptasiloxane

“…However, lower exposure concentrations (35 ppm, 122 ppm, and 488 ppm) did not elicit these same effects. 120…”

“…A separate group of rats (6 males and 6 females), cannulated via jugular vein, was used to determine radioactivity and parent D 6 concentration in the blood at 15 minutes and at 1,6,12,18,24,48,72,96,120,144, and 168 hours postdosing. Wholebody autoradiography (WBA) was used for qualitative in vivo assessment of tissue distribution of radioactivity in male and female rats after single oral administration of D 6 (in corn oil).…”