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Absorption and distribution

The available data indicate that MTBE is efficiently absorbed following oral and inhalation routes of administration with both MTBE and tert-butyl alcohol (TBA; major metabolite of MTBE) being present in systemic circulation (European Commission, 2002.; McGregor, 2006; Borghoff et al., 2010). Apart from specific binding to male rat kidney protein, the extensive tissue distribution of MTBE appears to be determined by solubility. Based on the blood/air partition coefficient (17.7-20) and the olive oil/air partition coefficient (120-140) measuredin vitro(cited in McGregor, 2006) and its good water solubility it can be stated that MTBE is moderately soluble in blood and 7-10 times more soluble in fat tissue.

The human data on toxicokinetics show a respiratory uptake of MTBE of 42-49% and a respiratory net uptake of 32-42%. The key study showed an oral absorption of over 80% for MTBE in humans.

 

Metabolism

MTBE is metabolised to formaldehyde and tert-butyl alcohol (TBA). Formaldehyde is believed to be metabolised extremely rapidly to formate (which is largely incorporated in the one-carbon pool) and to CO2 (the metabolism of formaldehyde is much quicker than it is formed from MTBE), and TBA is further metabolised to 2-hydroxyisobutyrate, 2-methyl-1,2-propanediol, TBA conjugates and acetone.

The metabolic pathways for MTBE are identical after ingestion and inhalation exposure.

 Metabolic Saturation and Doses Tested in Toxicity Studies

It is important to consider whether dose-dependent toxicity responses in animals are associated with high-dose/exposure concentrations that elicit non-linear toxicokinetic behavior. There have been a number of comprehensive reviews that have emphasized some rodent responses are restricted to high-test doses and may be questionable to the relevance of human health hazard and risk. Thus, high-dose specific saturation of metabolic processes, including toxicokinetics, may result in transition to novel modes of action unique to those high dose levels that are not related to modes of action that operate at lower animal doses and substantially lower real-world human exposures (Foran et al., 1997; Slikker et al., 2004a,b; Barton et al., 2006; Carmichael et al., 2006; Doe et al., 2006). 

 

To identify the dose at which metabolism of MTBE changes from linear to non-linear kinetics, a physiologically based pharmacokinetic (PBPK) model for MTBE was used (Leavens and Borghoff, 2009; Borghoff et al., 2010).  This PBPK model has been verified to predict MTBE and TBA tissue levels in rats following various routes of administration and concentrations of MTBE. This model predicted the amount of MTBE metabolised, along with the percent of the dose exhaled and metabolised, under inhalation exposure conditions or following oral gavage administration (see Table below). Selected predicted parameter values (see below) when plotted vs. MTBE dose/exposure concentration demonstrate that with increased exposure or dose MTBE metabolism changes from linear to non-linear kinetics. (See Figure in attachment).

PBPK Model Simulations and Predicted Parameter Values1

MTBE Exposure Concentration (ppm) or Dose (mg/kg)

MTBE metabolised (micromoles)

% MTBE Exhaled

% MTBE metabolised

Single exposure; 6 h, 24 h simulation

100

17.8

75.1

23.7

400

58.4

80.2

19.5

1000

126.0

83.1

16.8

3000

268.0

88.0

11.9

8000

410.0

93.1

6.8

 

 

 

 

Repeated exposure; 6 h/day, 5 days/week, 91 days simulation

100

 

74.9

23.9

400

 

80.1

19.5

1000

 

83.0

16.9

3000

 

87.9

12.1

8000

 

92.9

7.1

Single oral dose; 24 h simulation

100

39.9

77.6

21.8

250

84.3

81.3

18.5

500

141.0

84.4

15.5

1000

219.0

87.9

12.0

1500

273.0

90.0

10.0

Repeated dosing; 2 days dose, 2 days no dosing for 91 days simulation

100

 

77.6

21.8

250

 

81.3

18.5

500

 

84.4

15.5

1000

 

87.9

12.0

1500

 

90.0

10.0

1PBPK model assumptions: All modeling simulations were based on a previously published model and model parameters (Leavens and Borghoff, 2009), all modeling simulations assumed using male Fischer 344 rats with absorption rate constant based on administration of MTBE in oil. The starting body weight was 0.161 kg for male rats with inhalation scheduled for 6 hours/day, 5 consecutive days per week for 91 days for the repeated exposure (Bird et al., 1997). For oral administration, the repeated dosing regimen was based on the Belpoggi et al. (1995) in which animals were administered MTBE for 2 days, then 2 days off treatment. The simulation was carried out for 91 days to simulate repeated administration. Parameters such as amount of MTBE metabolized, percent of MTBE exhaled and metabolized were predicted following exposure concentrations and scenarios described in the table.

PBPK model predictions of the amount of MTBE metabolised following inhalation and oral gavage administration

In the series of rodentin vivoinhalation toxicity studies reported in McKee et al.(1997), the highest exposure concentration used was 8000 ppm, a concentration where saturation of metabolism was observed in the rat by Miller et al.(1997; 8000 ppm by inhalation after 6 hours and 400 mg/kg bwt by the oral route, based on a greater than proportional rise in MTBE plasma AUC and a less than proportional rise in TBA plasma AUC with increasing doses). Similarly, very high dose levels of up to 1750 mg/kg bw were used in studies employing oral (gavage) and intraperitoneal routes of administration.

Based upon the PB-PK modeling and simulation, the transition from linear to non-linear pharmacokinetics was predicted to occur between 1000-2000 ppm following inhalation exposure and between 400-600 mg/kg bwt following oral administration in the rat. It is now widely recognized that care should be taken in selecting exposure levels in toxicology studies such that these doses do not exceed saturation of absorption, metabolism or excretion as adverse effects observed at dose levels above metabolic saturation are not considered relevant for assessing human safety.

 

By way of example, all of the recently revised OECD Test Guideline for in vivo genotoxicity assays (TG474, 475, 488, and 489; http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788) state that chemicals exhibiting metabolic saturation are exceptions to typical dose selection based on toxicity and should be evaluated on a case by case basis. The general approach for dose selection based on TK data is clearly spelled out in the OECD TG443 test guideline for extended one generation reproductive toxicity study, the principle of which is equally applicable to genetic toxicology studies: If TK data are available which indicate dose-dependent saturation of TK processes, care should be taken to avoid high dose levels which clearly exhibit saturation, provided of course, that human exposures are expected to be well below the point of saturation. In such cases, the highest dose level should be at, or just slightly above the inflection point for transition to nonlinear TK behaviour.”

  A number of studies have evaluated the toxicity and pharmacokinetics of MTBE in human volunteers (reviewed by McGregor 2006). These studies included single exposures via inhalation at concentrations up to 75 ppm and also oral administration at a high dose of 0.15 mg/kg. In human 4-hour inhalation exposure conducted up to 75 ppm, metabolism was not saturated.

Elimination

In most experimental conditions the major part of MTBE in the body was excreted as urinary metabolites, and less than a half was exhaled unchanged, however, if the uptake rate was high the opposite was true. The main metabolite of MTBE in human urine is 2-hydroxyisobutyric acid. The elimination half-time for MTBE in blood was about 0.5 hour in the rat and about ten times longer in humans.

The kinetics of excretion of MTBE were identical after ingestion and inhalation exposure.

After exposure to MTBE, TBA is found in the blood circulation for a longer period and at higher concentrations than MTBE. TBA is highly water-soluble and distributed in total body water. Apart from lower levels found in fat, soft tissues are expected to show approximately the same concentrations as the blood. The elimination half-time for TBA in blood was about 3 hours in the rat and about 10 hours in humans. The biotransformation capacity for TBA (by unidentified microsomal enzymes) appears to be markedly lower than that for MTBE in the rat, which explains its relatively low rate of elimination. The elimination half-times for the different urinary MTBE metabolites varied between 2.9 and 5 hours in rats and between 7.8 and 17 hours in humans. These data support the conclusion that neither MTBE nor its metabolites will not accumulate in the human body significantly.

 

Information used for DNEL derivation

The oral, inhalation and dermal absorption percentages used for DNEL derivation (in case of route-to-route extrapolation) are 100%, 40% and 0.2%, respectively.

References:

Borghoff SJ, Parkinson H and 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, 79-91.

 

Carmichael NG, Barton HA, Boobis AR, Cooper RL, Dellarco VL, Doerrer NG, Fenner-Crisp PA, Doe JE, Lamb JC 4th, Pastoor TP (2006). Agricultural chemical safety assessment: A multi-sector approach to the modernization of human safety requirements. Crit. Rev. Toxicol.36:1–7.

 

Doe JE, Boobis AR, Blacker A, Dellarco VL, Doerrer NG, Franklin C, Goodman JI, Kronenberg JM, Lewis R, McConnell, EE, Mercier T, Moretto A, Nolan C, Padilla S, Phang W., Solecki R, Tilbury L, van Ravenzwaay B, Wolf DC (2006). A tiered approach to systemic toxicity testing for agricultural chemical safety assessment.Crit. Rev. Toxicol.36:37–68.

 

Foran, JA. and ILSI risk Science Working Group on Dose Selection (1997).Principles for the Selection of Doses in Chronic Rodent Bioassays. ILSI Risk Science Working Group on Dose Selection. Environ. Health Perspect. 105(1):18-20.

Leavens, TL, Borghoff, SJ. (2009). Physiologically based pharmacokinetic mode of methyl tertiary butyl ether and tertiary butyl alcohol dosimetry in male rats based on binding to α2u-globulin. Toxicol Sci109: 321-335.

 

McGregor, D. (2006). Methyl tertiary-butyl ether: studies for potential human health hazards.Crit. Rev. Toxicol.36:319-358.

 

Miller MJ, Ferdinandi ES, Klan M, Andrews LS, Douglas JF, Kneiss JJ. (1997). Pharmacokinetics and disposition of methyl t-butyl ether in Fischer-344 rats. J Appl. Toxicol. 17(S1):S3-S12.

Barton HA, Pastoor TP, Baetcke K, Chambers JE, Diliberto J, Doerrer NG, Driver JH, Hastings CE, Iyengar S, Krieger R, Stahl B, Timchalk C (2006). The acquisition and application of absorption, distribution, metabolism, and excretion (ADME) data in agricultural chemical safety assessments.Crit. Rev. Toxicol.36:9-35.

Slikker W, Jr., Andersen ME, Bogdanffy MS, Bus JS, Cohen, SD, Conolly RB, David RM, Doerrer NG, Dorman DC, Gaylor DW, Hattis D, Rogers JM, Sletzer, WR, Swenberg JA, Wallace K. (2004a). Dose-dependent transitions in mechanisms of toxicity.Toxicol. Appl. Pharmacol. 201:203–225.

 

Slikker W, Jr., Andersen ME, Bogdanffy MS, Bus JS, Cohen, SD, Conolly RB, David RM, Doerrer NG, Dorman DC, Gaylor DW, Hattis D, Rogers JM, Sletzer, WR, Swenberg JA, Wallace K. (2004b). Dose-dependent transitions in mechanisms of toxicity: Case studies.Toxicol. Appl. Pharmacol.201:226–294.