Derivation of a Human Equivalent Concentration for n-Butanol Using A Physiologically Based Pharmacokinetic Model for n-Butyl Acetate and Metabolites n-Butanol and n-Butyric Acid

Abstract

The metabolic series approach for risk assessment uses a dosimetry-based analysis to develop toxicity information for a group of metabolically linked compounds using pharmacokinetic (PK) data for each compound and toxicity data for the parent compound. The metabolic series approach for n-butyl acetate and its subsequent metabolites, n-butanol and n-butyric acid (the butyl series), was first demonstrated using a provisional physiologically based pharmacokinetic (PBPK) model for the butyl series. The objective of this work was to complete development of the PBPK model for the butyl series. Rats were administered test compounds by iv bolus dose, iv infusion, or by inhalation in a recirculating closed chamber. Hepatic, vascular, and extravascular metabolic constants for metabolism were estimated by fitting the model to the blood time course data from these experiments. The respiratory bioavailability of n-butyl acetate (100% of alveolar ventilation) and n-butanol (50% of alveolar ventilation) was estimated from closed chamber inhalation studies and measured ventilation rates. The resulting butyl series PBPK model successfully reproduces the blood time course of these compounds following iv administration and inhalation exposure to n-butyl acetate and n-butanol in rats and arterial blood n-butanol kinetics following inhalation exposure to n-butanol in humans. These validated inhalation route models can be used to support species and dose-route extrapolations required for risk assessment of butyl series family of compounds. Human equivalent concentrations of 169 ppm and 1066 ppm n-butanol corresponding to the rat n-butyl acetate NOAELs of 500 and 3000 ppm were derived using the models.

Physiologically based pharmacokinetic modeling of ethyl acetate and ethanol in rodents and humans

“…The model structure and equations are as reported by Teeguarden et al (Teeguarden et al, 2005) for the butyl series with two significant revisions: 1) the model was reduced to two submodels, one each for ethyl acetate and ethanol (Fig. 2); the structure of the human ethanol submodel was revised in accordance with the recently published model by Dumas-Campagna et al (DumasCampagna et al, 2014).…”

“…This method can facilitate efficient toxicity testing and the development of acceptable exposure levels, and has been used to assess the butyl series (n-butyl acetate, n-butanol, nbutyraldehyde, and n-butyric acid) (Teeguarden et al, 2005). Dosimetry-based analyses can be used to develop toxicity information using pharmacokinetic data for each related compound and toxicity data for the parent compound, because this data necessarily includes exposure to the downstream metabolites (Barton et al, 2000).…”

“…Because of this utility, such models are being used increasingly to develop human exposure limits and provide context to interpretation of laboratory studies on chemical toxicity. The family approach is one such application (Barton et al, 2000;Teeguarden et al, 2005).…”

Scientific Opinion on the evaluation of the substances currently on the list in the annex to Commission Directive 96/3/EC as acceptable previous cargoes for edible fats and oils – Part III of III

“…Hydrolysis half-lives on addition to whole blood from female rats and male human volunteers were 12 min and 4 min, respectively. As anticipated from its rapid hydrolysis, n-butyl acetate has a very short half-life in rats, as does its hydrolysis products, in the order of minutes (Teeguarden et al, 2005, as cited in ECHA online). Acetic acid is oxidised via the citric acid cycle to carbon dioxide and water.…”

Richtwerte für 1-Butanol in der Innenraumluft

“…Zur Simulation der Kinetik von 1-Butylacetat, 1-Butanol, Butanal und Butansäu-re wurde ein pharmakokinetisches Modell entwickelt, das im Rahmen der Bewertung der Toxizität von 1-Butanol durch die US-amerikanische Umweltbehörde zur Extrapolation tierexperimenteller Befunde auf den Menschen herangezogen wurde [2,16].…”