Author's personal copy Comparative toxicokinetics of low-viscosity mineral oil in Fischer 344 rats, Sprague–Dawley rats, and humans – Implications for an Acceptable Daily Intake (ADI) Peter J. Boogaard a,⇑ , Katy O. Goyak b , Robert W. Biles b , Leo L.P. van Stee c , Matthew S. Miller d , Mary Jo Miller d a Shell Health, Shell International, P.O. Box 162, 2501 AN, The Hague, The Netherlands b ExxonMobil Biomedical Sciences, Inc., Annandale, NJ, USA c TNO Triskelion, Zeist, The Netherlands d Osprey Scientific Consulting, Solomons, MD, USA article info Article history: Received 10 January 2012 Available online 8 March 2012 Keywords: Highly refined base oil Low-viscosity white oil White oil Mineral oil Toxicokinetics ADI Rat Human Strain differences Internal dose metric Steady-state concentration Target dose abstract 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 sus- ceptible 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 AUC 0–1 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. Ó 2012 Elsevier Inc. All rights reserved. 1. Introduction Highly refined base oils, which are commonly known as ‘white oils’, are petroleum substances obtained from crude oil by extensive refining and treatment. They consist of saturated, predominantly branched, alkanes (isoparaffinics), and saturated cyclic alkanes (naphthenics) and are essentially free of polycyclic aromatic hydro- carbons and sulphur. Since these mineral oils are considered non- hazardous from a human health perspective, they are widely used as base oil for food-grade lubricating oils (in some geographical re- gions), in cosmetics, and also in medicine (as laxative). Early 90-day repeated dose feeding studies of white mineral oils in Long Evans rats and Beagle dogs did not reveal any test-item re- lated adverse effects, apart from a mild laxative effect in dogs. These studies essentially confirmed several subchronic feeding studies with highly refined petroleum products from the 1950s and 1960s (Smith et al., 1995). In addition, specific lipid staining with Oil Red O of liver, kidney, spleen, mesenteric lymph nodes, and gastrointes- tinal tract did not indicate any deposition or accumulation of hydro- carbons or lipids. In contrast, in 90-day repeated dose studies with Fischer 344 rats, which were fed 20, 200, 2000, and 20,000 ppm of a range of seven highly refined mineral oils or of a range of five highly refined waxes in the feed, histiocytosis of the mesenteric lymph nodes was found at all but the lowest dose levels (approximately 20–2000 mg/kg/day) with low- and medium-viscosity oils but not with high viscosity oils or waxes (Smith et al., 1996). In addition, he- patic granulomata were found at the highest dose levels (2000 and 20,000 ppm, equivalent to approximately 200 and 2000 mg/kg body weight/day). Adverse effects appeared inversely related to the vis- cosity of the mineral oil and were greater in female than in male rats. In a separate comparative feeding study with Sprague– Dawley-derived (CRL:CD) rats and Fischer 344 rats, fed highly re- fined (i.e. white) low-viscosity mineral oil for at 2000 or 20,000 ppm in the feed, only the Fischer 344 rats showed enlarged hepatic and mesenteric lymph nodes, hepatic microgranulomata as well as mesenteric lymph node histiocytosis at both dose levels. 0273-2300/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yrtph.2012.02.014 ⇑ Corresponding author. Fax: +31 70 3772480. E-mail address: peter.boogaard@shell.com (P.J. Boogaard). Regulatory Toxicology and Pharmacology 63 (2012) 69–77 Contents lists available at SciVerse ScienceDirect Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph