Comparative toxicokinetics of low-viscosity mineral oil in Fischer 344 rats, Sprague-Dawley rats, and humans - Implications for an Acceptable Daily Intake (ADI)

Oral repeated-dose studies with low-viscosity mineral oils showed distinct species and strain differences, which are hypothesized to be due to differences in bioavailability, with Fischer 344 rats being more susceptible than Sprague-Dawley rats or dogs.Sensitive analytical methodology was developed for accurate measurement of low levels of mineral hydrocarbons and applied in single-dose toxicokinetics studies in rats and humans. Fischer 344 rats showed a 4-fold higher AUC0-∞ and consistently higher blood and liver concentrations were found than Sprague-Dawley rats. Hepatic mineral hydrocarbon concentration tracked the blood concentration in both strains, indicating that blood concentrations can serve as functional surrogate measure for hepatic concentrations. In human volunteers receiving 1 mg/kg body weight of low-viscosity white oil, all blood concentrations of mineral hydrocarbons were below the detection limit. Comparison with threshold blood concentrations associated with NOAELs in both rat strains, indicate that the margin-of-exposure is at least 37-fold. Using an internal dose metric rather than applied dose reduces the uncertainty around the temporary ADI considerably since it intrinsically accounts for intra- and inter-species differences. The current data support replacement of the temporary ADI of 0.01 mg/kg/day by a (permanent) ADI of at least 1.0 mg/kg/day for low- and medium-viscosity mineral oils.

► Novel approach to assess safety of mineral oils based on internal dose. ► Development of sensitive analytics to quantitate mineral hydrocarbons in tissues. ► Mineral hydrocarbon levels in rats and humans following exposure to mineral white oil. ► Critical blood threshold concentration in rats used to demonstrate safety in humans.