tert-butyl methyl ether

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Assessment taken from EU-RAR, acceptable for assessment.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Rapid dissolution of gallstones by methyl tert-butyl ether. Preliminary observation.

Author:

Allen MJ, Borody JJ, Bugliosi TF, May GR, LaRusso NF & Thistle JL

Year:

1985

Bibliographic source:

The New England Journal of Medicine, 312, 217-20.

Reference 2

Reference Type:

publication

Title:

Transhepatic topical dissolution of gallbladder stones with MTBE and EDTA. Results, side effects, and correlation with CT imaging.

Author:

Janowitz P, Schumacher KA, Swobodnik W, Kratzer W, Tudyka J & Wechsler JG

Year:

1993

Bibliographic source:

Digestive Diseases and Sciences, 38, 2121-9.

Reference 3

Reference Type:

publication

Title:

Gallstone dissolution with methyl tert-butyl ether in 120 patients - efficacy and safety.

Author:

Leuschner U, Hellstern A, Schmidt K, Fischer H, Güldütuna S, Hübner K & Leuschner M

Year:

1991

Bibliographic source:

Digestive Diseases and Sciences, 36, 193-9.

Reference 4

Reference Type:

publication

Title:

Gallstone recurrence after direct contact dissolution with methyl tert-butyl ether.

Author:

Pauletzki J, Holl J, Sackmann M, Neubrand M, Klueppelberg U, Sauerbruch T & Paumgartner G

Year:

1995

Bibliographic source:

Digestive Diseases and Sciences, 40, 1775-81.

Reference 5

Reference Type:

publication

Title:

Renal failure during dissolution of gallstones by methyl-tert-butyl ether.

Author:

Ponchon T, Baroud J, Pujol B, Valette PJ & Perrot D

Year:

1988

Bibliographic source:

The Lancet, 2, 176-7.

Reference 6

Reference Type:

publication

Title:

Dissolution of cholesterol gallbladder stones by methyl tert-butyl ether administered by percutaneous transhepatic catheter.

Author:

Thistle JL, May GR, Bender CE, Williams HJ, LeRoy AJ, Nelson PE, Peine CJ, Petersen BT & McCullough JE

Year:

1989

Bibliographic source:

New England Journal of Medicine, 320, 633-9.

Reference 7

Reference Type:

publication

Title:

Human gallbladder morphology after gallstone dissolution with methyl tert-butyl ether.

Author:

van Sonnenberg E, Zakko S, Hofmann AF, D'Agostino HB, Jinich H, Hoyt DB, Miyai K, Ramsby G & Moossa AR

Year:

1991

Bibliographic source:

Gastroenterology, 100, 1718-23.

Reference 8

Reference Type:

publication

Title:

Choledocholithiasis--in vivo stone dissolution using methyl tertiary butyl ether (MTBE).

Author:

Murray WR, LaFerla G & Fullarton GM

Year:

1988

Bibliographic source:

Gut, 29, 143-5.

Reference 9

Reference Type:

publication

Title:

Methyl-tert-butyl-ether for treating bile duct stones: the British experience.

Author:

Neoptolemos JP, Hall C, O'Connor HJ, Murray WR & Carr-Locke DL

Year:

1990

Bibliographic source:

British Journal of Surgery, 77, 32-5.

Reference 10

Reference Type:

publication

Title:

Systemic and local toxicity in the rat of methyl tert-butyl ether: a gallstone dissolution agent.

Author:

Akimoto R, Rieger E, Moossa AR, Hofmann AF & Wahlstrom HE

Year:

1992

Bibliographic source:

Journal of Surgical Research, 53, 572-7.

Materials and methods

Study type:

other: case reports of gallstone dissolution patients

Principles of method if other than guideline:

patients treated with MTBE to dissolve gallstones

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

tert-butyl methyl ether

EC Number:

216-653-1

EC Name:

tert-butyl methyl ether

Cas Number:

1634-04-4

Molecular formula:

C5H12O

IUPAC Name:

2-methoxy-2-methylpropane

Results and discussion

Any other information on results incl. tables

Studies of patiens treated with MTBE to dissolve gallstones

Studies of patients treated with MTBE to dissolve gallstones In clinical trials, hundreds of patients have undergone contact dissolution of radiolucent gallbladder or bile duct stones with MTBE by instillation through a transhepatic (Allen et al., 1985; Janowitz et al., 1993; Leuschner et al., 1991; Pauletzki et al., 1995; Ponchon et al., 1988; Thistle et al., 1989; van Sonnenberg et al., 1991) or nasobiliary catheter (Murray et al., 1988; Neoptolemos et al., 1990). Dissolution of cholesterol stones in the gallbladder involves the placement of a percutaneous transhepatic catheter, and instillation and aspiration of MTBE manually four to six times a minute with a glass syringe. The volume of MTBE instilled is adjusted such that it envelops the stones but does not overflow from the gallbladder (volumes of 1-15 ml have been used). The duration of treatment has been up to seven hours per day for one to three days; dissolution of the stones has been monitored with fluoroscopy. The mean treatment time in one large study was 5.1 hours (Leuschner et al., 1991). Dissolution of stones in the bile duct with MTBE by a nasobiliary catheter inserted following endoscopic retrograde cholagiopancreatography has proved less successful because of the variable prevalence of cholesterol stones in this condition, and difficulties in effecting optimum contact between MTBE and the gallstones (Neoptolemos et al., 1990). In most cases, after MTBE instillation, the bile was aspirated manually in 1-15 treatment cycles lasting altogether from 1.5 to 42 hours. The total volume of MTBE instilled was 30-480 ml (Neoptolemos et al., 1990). During dissolution treatment of stones in the gallbladder there is the possibility of MTBE overflow to the cystic duct and further down to the duodenum, or leakage alongside the catheter into the liver and contact with a vascular structure, whereas treatment of bile duct stones likely results in some spill-over into the intrahepatic canaliculi and duodenum; in all cases systemic absorption of MTBE is expected.

Mild complications during dissolution treatment (nausea, drowsiness, vomiting, local burning sensation) are frequent, and transient elevation of liver transaminases, fever and leukocytosis have occurred among 5-24% of the patients (Janowitz et al., 1993; Leuschner et al., 1991; Neoptolemos et al., 1990). It was proposed that since the abnormal laboratory findings have mostly peaked after the removal of the catheter they might be caused by transient leakage of bile (Thistle et al., 1989). Treatment of bile duct stones with MTBE by the nasobiliary catheter caused elevation of liver enzymes in every fourth patient but no fever or leukocytosis was reported. Therefore, it cannot be excluded that high local concentrations of MTBE in the biliary tract also had an adverse effect on hepatocytes. In rats, intrahepatic injection of MTBE (0.2 ml/kg) caused necrosis at the site of injection (Akimoto et al., 1992). MTBE may have a transient, reversible irritating and inflammatory effect on the gallbladder wall, and in the duodenum (Janowitz et al., 1993; Leuschner et al., 1991; van Sonnenberg et al., 1991).

On several occasions, the presumed overflow of MTBE during instillation to the gallbladder (i.e. not all substance was recovered during aspiration) was found to lead to reversible sedation and an odour of MTBE on the breath of the patient. Among 27 patients who were not reported to exhibit adverse symptoms (Leuschner et al., 1991), blood was sampled after the treatment (mean duration 5.1 hours). The mean blood MTBE concentration was about 450 μmol/l (0.04 mg/ml) with a two times higher maximum level, and the mean blood TBA was about 540 μmol/l, showing that marked body burdens can develop during treatment. Another group of patients was found to have losses of 4-18 ml from the balance of MTBE instilled vs. aspirated, and two patients became reversibly somnolent and had the odour of MTBE on the breath (Ponchon et al., 1988). Three hours from the start of treatment, a third patient became confused after 6 ml of MTBE could not be retrieved during 30 minutes. When the patient had recovered, the treatment continued and at 5 hours, when 15 ml of MTBE were not retrieved in 45 minutes, the patient went into coma with an odour of MTBE on the breath. Coma reversed after 4 hours but acute renal failure with anuria developed, probably due to haemolysis. Haemoglobinuria was detected before anuria set in, and reduced serum haptoglobin as well as increased serum lactate dehydrogenase and unconjugated bilirubin were found (Ponchon et al., 1988). After dialysis treatments over 18 days, the patient’s renal function recovered completely.

An elderly female patient showed persistent overflow of 5 to 7 ml MTBE per hour during seven hours of treatment, and developed gradually increasing sedation, nausea and slight emesis (Thistle et al., 1989). Since the emesis contained occult blood, gastroduodenoscopy was performed, revealing superficial ulcerative duodenitis. In addition, serum haptoglobin concentration was decreased, plasma free haemoglobin level was increased, and free haemoglobin was detected in the urine, clearly indicating intravascular haemolysis. The previous data allow a crude calculation of the body burden of MTBE associated with adverse symptoms and haemolysis. Assuming an hourly overflow of 6 ml MTBE into the duodenum, the dose for a 60 kg person was about 74 mg/kg per hour. The total dose over 7 hours would have been approximately 31 g (about 520 mg/kg). Assuming that the elimination half-time for MTBE is 5 hours, the body burden of unchanged MTBE at the end of treatment peaked at about 340 mg/kg. It is however reasonable to presume that even TBA remaining in the body after MTBE metabolism has an impact which is possibly additive to that of MTBE.