2-methylpropan-2-ol

Endpoint summary

Description of key information

Absorption by the oral route of exposure is estimated at 100% of the applied dose and absorption by the dermal route of exposure is estimated at 11% of the applied dose.   Tertiary butyl alcohol has the ability to induce its own metabolism and pulmonary retention is approximately 60% of the inhaled dose. The major metabolites of tertiary butyl alcohol in both humans and rats following oral exposure are 2-methyl-1,2-propanediol and 2-hydroxyisobutyrate.  The T1/2 for elimination in rats varied between 3.8 and 5 hours with elimination becoming saturated at higher dose levels.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

11

Absorption rate - inhalation (%):

60

Additional information

There are a number of studies describing the toxicokinetics and metabolism of tertiary butyl alcohol in both rats and humans which show strong similarities between these species.

General

Two publications are included as supporting studies which involved the development of a PBPK model for TBA and a parent compound ETBE (Salazar et al., 2015 & Borghoff et al., 2016). The PBPK models developed in these publications were based on i.v., inhalation and oral exposure to rat studies included in the registration dossier and helped provide justifications and a commentary on the carcinogenic and non-carcinogenic effects observed when dosing with TBA and ETBE.

From the initial publication (Salazar et al, 2015), the results based on the developed rat PBPK model demonstrated that non carcinogenic kidney effects (i.e. weight changes, urothelial hyperplasia, and chronic progressive nephropathy) showed consistent dose response relationships across varying routes of exposure and across both TBA and ETBE exposure in studies using TBA blood concentrations and metabolic rate as dose metrics. The relative liver weights were also consistent across studies on the basis of TBA metabolism which was proportional to TBA liver concentrations. It was found however that observed kidney and liver tumours were not consistent across dose metrics. This information assisted in supporting a hypothesis that although TBA itself mediates the non carcinogenic kidney and liver effects as a result of ETBE administration (as a key metabolite), other factors besides internal dosimetry are required in order to explain the induction of liver and kidney tumours.

The second reported publication (Borghoff et al., 2016) assists in understanding the contribution of ETBE and TBA kinetics under varying exposure scenarios to kidney and liver tumor responses using a developed PBPK model.  

Metabolism of ETBE and TBA was described as a single, saturatable pathway in the liver. The shift from linear to non-linear kinetics at exposure concentrations less than those associated with liver tumours in rats (5000 ppm ETBE) suggested that the mode of action for the development of liver tumors operates under nonlinear kinetics following chronic exposure with ETBE which is not considered relevant for assessing human risk.

This model also predicts similar kidney TBA AUC values following TBA or ETBE exposure. As such, the different kidney tumour responses noted between TBA and a parent compound ETBE are most likely influenced by other differences (aside from kidney AUCs and chemical binding to α2u-globulin). However, because male rat specific renal tumors induced by TBA operate through modes of action (i.e. α2u-globulin nephropathy and chronic progressive nephropathy) not relevant in humans the lesions associated with these conditions should not be used as a basis for risk assessments for either substance.

Absorption

Oral

Since tertiary butyl alcohol is a small, hydrophilic, molecule, oral absorption is predicted to be extensive. The results of one limited study in mice supports this prediction (Faulkner et al (1989)). On this basis, a default basis of 100 % will be taken forward to risk characterization.

Dermal

Absorption via the dermal route has been investigated in a standard guideline toxicokinetic study (Huntingdon Life Sciences, 1998). In this study, 4 male Sprague Dawley rats per group were exposed to tertiary butyl alcohol under a semi-occlusive dressing for 6 hours. Following application, each rat was placed in a metabolism cage in order to collect urine, feces and volatile materials. After 6 hours, the application site was washed to remove any unabsorbed dose. At time of termination, a blood sample was taken from the tail vein. Radioactive volatile material trapped in the meta-bowl apparatus, represented 4.4–8.4 % and 0.5-0.6 % of the dose at 1 and 6 hours respectively. The nature of the radioactivity in one of the traps at 1 hour was tertiary butyl alcohol and may potentially be the result of evaporation from the application site rather than being expired by the rats. However, as this was not determined, this radioactivity was included in the absorption calculations. Overall the dermal absorption of tertiary butyl alcohol was measured to be between 6-11 %. On this basis, an absorption value of 11 % (obtained at 72 hour post exposure) will be taken forward to risk characterization.

Inhalation

No experimental data are available informing on the extent of absorption via the inhalation route. A value of 60 % absorption was used in a PBPK model to model the pharmacokinetics of tertiary butyl alcohol (Leavens and Borghoff, 2009). This value takes into account the volatile nature of tertiary butyl alcohol, which can limit the extent of absorption. This value was used in the model, along with literature values for other parameters and other modifiers (e.g. to take account of the induction tertiary butyl alcohol metabolism). The model compared well with the blood, liver and kidney concentrations of tertiary butyl alcohol following single and repeated inhalation exposure (8 day) of tertiary butyl alcohol (250-1750 ppm per 6 hour/day) to female rats (the model for male rats is complicated due to the binding of tertiary butyl alcohol in the kidneys). On this basis, a value of 60 % will be taken forward to risk characterization.

Distribution

In a study to characterize the pharmacokinetic profile of tertiary butyl alcohol in rats and conducted by a method equivalent or similar to EPA OPPTS Guideline 870.7485, the test substance was administered to groups of male and female rats through an intravenous cannula and blood levels of tertiary butyl alcohol were monitored for 24-hours (Poet et al., 1997). The kinetics are best described by a two-compartment model. Tertiary butyl alcohol underwent a rapid distribution phase (approximately 3 minutes) and a slower elimination phase (~ 3.8 hours at lower doses; 4.3 hours in females and 5.0 hours in males at higher doses). Both the volume of the central compartment and the volume of distribution at steady state suggest significant tissue distribution. Based on a decreased rate of clearance, a disproportional increase in area under the curve, and an increase in the T½ at higher doses, the elimination of tertiary butyl alcohol appears to saturate at higher doses.

Metabolism

A metabolism study conducted in a manner similar to OECD Guideline 417 (Bernauer, et al., 1998) administered C13-labeled tertiary butyl alcohol via the oral route to rats and humans, and metabolites in the urine were identified. The major metabolites in the rat urine were identified as 2-methyl-1,2-propanediol, 2-hydroxyisobutyrate, and the presumed tertiary butyl alcohol sulfate. In the urine from the human individual, 2-methyl-1,2-propanediol and 2-hydroxyisobutyrate were the major metabolites identified. Cytochrome P-450 enzymes were postulated to contribute to the oxidative metabolism of tertiary butyl alcohol to 2-methyl-1,2-propanediol. A number of studies were conducted in humans to evaluate the kinetics of methyl tertiary butyl ether and its metabolism to tertiary butyl alcohol.

In a study to expand the existing physiologically based pharmacokinetic (PBPK) models for tertiary butyl alcohol to include a mechanism for chemical binding to the male rat-specific protein alpha 2u-globulin, tertiary butyl alcohol was administered to groups of male and female F344 rats via whole-body inhalation 6 hours/day for 1 or 8 days (Leavens and Borghoff, 2009). Blood, liver and kidney concentrations of tertiary butyl alcohol were determined at 2, 4, 6 and 8 hours following exposure. Tissue concentrations of tertiary butyl alcohol for both sexes were lower following 8 days of repeated inhalation exposure compared with a single day of exposure supporting the hypothesis that tertiary butyl alcohol has the ability to induce its own metabolism. In addition, the tertiary butyl alcohol blood, liver and kidney concentrations differed between genders following repeated but not single inhalation exposures to tertiary butyl alcohol. Based on comparisons of the model predictions with tertiary butyl alcohol concentrations in the tissues of both male and female rats following inhalation exposure to tertiary butyl alcohol, the PBPK model for tertiary butyl alcohol inhalation exposure included loss in the nasal cavity and upper airways (accounted for due to the high blood to air partition coefficient for tertiary butyl alcohol) with a pulmonary retention of approximately 60%.

In addition to available studies conducted with tertiary butyl alcohol, a number of pharmacokinetics studies have been conducted with methyl tertiary butyl ether that support the justification for an analogue approach for a read across in considering the evaluation of tertiary butyl alcohol hazard and risk. In a study conducted by Miller et al. (1997), the absorption, distribution, metabolism and elimination of methyl tertiary butyl ether was investigated in male and female Fischer 344 rats by the inhalation, oral, dermal and intravenous routes of exposure. The Miller et al. (1997) study, as well as in vivo studies conducted by a number of other investigators, demonstrated that methyl tertiary butyl ether is metabolized to form tertiary butyl alcohol (Amberg et al., 1999; Bernauer et al., 1998; Borghoff et al., 2010; Dekant et al., 2001; Savolainen et al., 1985; Nihlén et al., 1998; Nihlén et al., 1999; Leavens and Borghoff, 2009; Prah et al., 2004). Tertiary butyl alcohol is then subsequently biotransformed to 2-methyl-1,2-propanediol and 2-hydroxyisobutyrate which are excreted in the urine where both of these metabolites were identified. In addition, low concentrations of tertiary butyl alcohol glucuronide, free tertiary butyl alcohol and possibly tertiary butyl alcohol sulfate were identified in urine following exposure to methyl tertiary butyl ether by all routes of exposure. Tertiary butyl alcohol was measured in blood of rats exposed to methyl tertiary butyl ether via drinking water for 12 months (Bermudez et al., 2010). In this regard, tertiary butyl alcohol blood level was used as a biomarker of exposure to methyl tertiary butyl ether. The concentration of tertiary butyl alcohol in blood increased with methyl tertiary butyl ether drinking water concentrations.

PBPK models have been developed for both rats and in humans to describe the metabolism of methyl tertiary butyl ether to tertiary butyl alcohol (Borghoff et al., 2010; Prah et al., 2004). Most recently a PBPK model for methyl tertiary butyl ether and tertiary butyl alcohol in rats was verified with data sets collected in tissues following methyl tertiary butyl ether inhalation exposure and oral (gavage and drinking water) administration (Borghoff et al., 2010). The model was found to predict tissue concentrations of both methyl tertiary butyl ether and tertiary butyl alcohol following different exposure scenarios up to 91 days of exposure and showed that similar kinetic profiles for blood tertiary butyl alcohol are similated following inhalation or drinking water MTBE exposure.

Studies conducted with tertiary butyl alcohol and those conducted with methyl tertiary butyl ether demonstrate that tertiary butyl alcohol is absorbed undergoes oxidative metabolism to 2-methyl-1,2-propanediol with further oxidation to 2-hydroxyisobutyrate and excretion in the urine. Based on all available in vivo data, as well as physical properties that include high water solubility and low octanol/water partition coefficient, tertiary butyl alcohol is expected to have a low potential to bioaccumulate.

Excretion

Tertiary butyl alcohol and/or its metabolites have been shown to be excreted via the urine following oral administration. No information on whether tertiary butyl alcohol is excreted via the feces or in expired air is available.

In the study by Poet et al (1997), a two compartment model best described the pharmacokinetics of tertiary butyl alcohol. Elimination half-lives (t1/2) of 3.8 hours for doses < 300 mg/kg and 5 hours for doses of 300 mg/kg were derived. The results suggest that elimination of tertiary butyl alcohol is saturated at higher doses (≥ 300 mg/kg).

Additional references:

Amberg A, Rosner E, Dekant W. 1999. Biotransformation and kinetics of excretion of methyl-tert-butyl ether in rats and humans. Toxicol Sci. 51(1): 1-8.

Bernauer U, Amberg A, Scheutzow D, Dekant W. 1998. Biotransformation of 12C- and 2-13C-labeled methyl tert-butyl ether, ethyl tert-butyl ether, and tert-butyl alcohol in rats: identification of metabolites in urine by 13C nuclear magnetic resonance and gas chromatography/mass spectrometry. Chem Res Toxicol. 11(6): 651-658.

Borgfoff SJ, Ring C, Banton MI, Leavens TL. 2016. Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether and tertiary-butyl alcohol in rats: Contribution of binding to α2U-globulin in male rats and high-exposure nonlinear kinetics to toxicity and cancer outcomes. J. Appl. Toxicol. 2017; 37: 621–640

Borghoff SJ, Parkinson H, Leavens TL. 2010. Physiologically based pharmacokinetic rat model for methyl tertiary-butyl ether; comparison of selected dose metrics following various MTBE exposure scenarios used for toxicity and carcinogenicity evaluation. Toxicology. 275(1-3): 79-91.

Dekant W, Bernauer U, Rosner E, Amberg A. 2001. Biotransformation of MTBE, ETBE, and TAME after inhalation or ingestion in rats and humans. Res Rep Health Eff Inst (102): 29-71; discussion 95-109.

Leavens TL, Borghoff SJ. 2009. Physiologically based pharmacokinetic model of methyl tertiary butyl ether and tertiary butyl alcohol dosimetry in male rats based on binding to alpha2u-globulin. Toxicol Sci. 109(2): 321-335.

Nihlen A, Sumner SC, Lof A, Johanson G. 1999. 13C(2)-Labeled methyl tert-butyl ether: toxicokinetics and characterization of urinary metabolites in humans. Chem Res Toxicol. 12(9): 822-830.

Nihlen A, Lof A, Johanson G. 1998. Experimental exposure to methyl tertiary-butyl ether. I. Toxicokinetics in humans. Toxicol Appl Pharmacol. 148(2): 274-280.

Prah J, Ashley D, Blount B, Case M, Leavens T, Pleil J, Cardinali F. 2004. Dermal, oral, and inhalation pharmacokinetics of methyl tertiary butyl ether (MTBE) in human volunteers. Toxicol Sci. 77(2): 195-205.

Salazar KD, Brinkerhoff CJ, Lee JS, Chiu WA. 2015. Development and application of a rat PBPK model to elucidate kidney and liver effects induced by ETBE and tert-butanol. Toxicol. Appl. Pharmacol. 288(3): 439–452.

Savolainen H, Pfaffli P, Elovaara E. 1985. Biochemical effects of methyl tertiary-butyl ether in extended vapour exposure of rats. Arch Toxicol. 57(4): 285-288