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MTBE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) MTBE is among the top 50 chemicals produced (by volume) in the United States. The primary use is as an octane booster in gasoline, in concentrations of up to 11 percent by volume (Garrett et al, 1986).

Specific Substances

    1) Methyl tert-butyl ether
    2) tert-butyl methyl ether
    3) Propane,2-methoxy-2-methyl-
    4) Ether, tert-butyl methyl
    5) MBE
    6) MTBE
    7) (2,-Methyl-2-propyl)methyl ether
    8) 2-Methoxy-2-methylpropane
    9) 2-Methyl-2-methoxypropane
    10) Methyl tertiary butyl ether
    11) CAS 1634-04-4
    1.2.1) MOLECULAR FORMULA
    1) C5-H12-O

Available Forms Sources

    A) SOURCES
    1) MTBE is produced through ether formation (raffinate I + methanol, or isobutylene + methanol) and by the reaction of t-butanol + methanol (Ashford, 1994; Budavari, 1996; Lewis, 1993).
    B) USES
    1) MTBE is used almost exclusively as a blending compound or octane-enhancing agent in gasoline; typical concentrations in gasoline range from 5% to 8% by volume, but there may be as much as 15%. It has also been used as a chromatographic eluent for liquid and thin-layer chromatographic procedures. Since it is an excellent cholesterol-solubilizing agent, it has been used to dissolve cholesterol gallstones via a thistle catheter (ACGIH, 1996; Budavari, 1996; Leuschner et al, 1988; Lewis, 1993).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Nausea, vomiting, vertigo, and sedation were observed in humans during MTBE gallbladder installation for gallstone dissolution. Similar effects including vomiting, incoordination, and sedation were seen in animal oral exposure studies. General anesthesia (CNS and respiratory depression) may also occur. Liver function test abnormalities have been seen in experimental animals following intraductal administration, possibly due to mechanical effects. Mild, transient increases in liver transaminase enzymes have been reported in humans following transhepatic instillation of MTBE into the gallbladder to dissolve gallstones.
    1) Aspiration of gasoline-MTBE mixtures following ingestion may result in chemical pneumonitis.
    B) Workers exposed to MTBE in ambient air have complained of headache, nausea, nasal congestion, and eye irritation. Inhalation of MTBE produces anesthesia, eye irritation, irregular respirations, incoordination, and prostration in experimental animals. In acute gavage studies in experimental animals, death was preceded by marked CNS depression, ataxia, tremors, labored breathing, and loss of righting reflexes.
    C) Although MTBE has been shown to be metabolized to methanol and formic acid in experimental animal models, methanol or formic acid have only been detected in trace quantities in humans treated with MTBE for gallstone dissolution.
    0.2.3) VITAL SIGNS
    A) Respiratory depression may be noted.
    0.2.4) HEENT
    A) Conjunctivitis lasting 72 hours, corneal opacities and chemosis have been seen in rabbits following instillation into unwashed eyes.
    0.2.6) RESPIRATORY
    A) Labored and irregular breathing were associated with anesthetic effects in rats.
    B) Aspiration pneumonitis is possible following ingestion of gasoline-MTBE mixtures.
    0.2.7) NEUROLOGIC
    A) Somnolence was seen after instillation of as little as 8 mL into the biliary ducts in humans; pronounced sedation occurred with instillation of 140 mL. As approximately 30 percent of the dose is retrieved by aspiration during this procedure, this represents absorption of approximately 6 mL and 100 mL, respectively.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting have been seen in patients receiving MTBE instillation into the biliary duct.
    0.2.9) HEPATIC
    A) Elevated serum transaminases and alkaline phosphatase have been observed after administration of MTBE into the biliary ducts.
    0.2.10) GENITOURINARY
    A) Acute renal failure requiring dialysis was noted after MTBE gallbladder infusion. Hemolysis was the suspected cause.
    0.2.14) DERMATOLOGIC
    A) MTBE is not a primary skin irritant. Slight erythema and irritation has been noted in experimental animals when MTBE was applied to abraded skin or under occlusive dressings.
    0.2.19) IMMUNOLOGIC
    A) In a small study, gasoline service station attendants had MTBE IgG and IgM antibodies at levels 3 to 15 times higher than controls.
    0.2.20) REPRODUCTIVE
    A) At present, no human data is available regarding potential reproductive effects in humans.
    B) MTBE has exhibited little if any reproductive effects in 1- and 2-generation experimental animal studies, except at doses also producing maternal toxicity.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were found in available references.

Laboratory Monitoring

    A) Monitor respiratory function in exposed individuals, and arterial blood gases or pulse oximetry if aspiration pneumonitis is present. Pulmonary function tests may be indicated in patients with respiratory signs or symptoms. If pulmonary aspiration is suspected, a chest x-ray is indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) DECONTAMINATION - Ipecac-induced emesis is NOT recommended following ingestion of pure MTBE due to the risk of aspiration pneumonitis. Activated charcoal is of questionable benefit.
    B) TREATMENT - Is primarily supportive with respiratory support as needed.
    C) RESPIRATORY SUPPORT - Patients should be monitored carefully for respiratory depression and apnea. Respiratory support should be available at all times.
    D) COUGHING - If the patient is already coughing upon arrival at the medical facility, pulmonary aspiration has probably already occurred. Monitor arterial blood gases or pulse oximetry in cases of aspiration pneumonitis to assure adequate ventilation and oxygenation.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) Inhalation exposure to an airborne concentration of 1000 ppm MTBE produced light anesthesia in experimental animals.
    B) Ingestion of 6 mL produced somnolence, while 100 mL produced sedation.

Clinical Effects

Summary Of Exposure

    A) Nausea, vomiting, vertigo, and sedation were observed in humans during MTBE gallbladder installation for gallstone dissolution. Similar effects including vomiting, incoordination, and sedation were seen in animal oral exposure studies. General anesthesia (CNS and respiratory depression) may also occur. Liver function test abnormalities have been seen in experimental animals following intraductal administration, possibly due to mechanical effects. Mild, transient increases in liver transaminase enzymes have been reported in humans following transhepatic instillation of MTBE into the gallbladder to dissolve gallstones.
    1) Aspiration of gasoline-MTBE mixtures following ingestion may result in chemical pneumonitis.
    B) Workers exposed to MTBE in ambient air have complained of headache, nausea, nasal congestion, and eye irritation. Inhalation of MTBE produces anesthesia, eye irritation, irregular respirations, incoordination, and prostration in experimental animals. In acute gavage studies in experimental animals, death was preceded by marked CNS depression, ataxia, tremors, labored breathing, and loss of righting reflexes.
    C) Although MTBE has been shown to be metabolized to methanol and formic acid in experimental animal models, methanol or formic acid have only been detected in trace quantities in humans treated with MTBE for gallstone dissolution.

Vital Signs

    3.3.1) SUMMARY
    A) Respiratory depression may be noted.
    3.3.2) RESPIRATIONS
    A) RESPIRATORY DEPRESSION - may be noted.

Heent

    3.4.1) SUMMARY
    A) Conjunctivitis lasting 72 hours, corneal opacities and chemosis have been seen in rabbits following instillation into unwashed eyes.
    3.4.3) EYES
    A) LACK OF EFFECT - Eye measurements showed no effect of MTBE exposure when 10 healthy male volunteers were exposed to MTBE vapors for 2 hours at 3 different levels (5, 25 and 55 ppm) while performing light physical work (Nihlen et al, 1998).
    B) MTBE produced corneal opacities and chemosis when applied to unwashed eyes of rabbits in 3 instances. Conjunctival redness persisted for 72 hours in 2 other rabbits (Neal et al, 1987).
    3.4.5) NOSE
    A) LACK OF EFFECT - In 10 healthy male volunteers exposed to 5, 25, and 50 ppm of MTBE vapor during 2 hours of light exercise, no to only minimal effects on the nasal mucosa and nasal airflow were found (Nihlen et al, 1998).
    B) Chronic inflammation of the nasal mucosa was observed in rats exposed to airborne concentrations of 1000 and 3000 ppm 6 hours per day, 5 days per week, for 9 exposures (Neal et al, 1987).
    3.4.6) THROAT
    A) Chronic inflammation of the tracheal mucosa was observed in rats exposed to airborne concentrations of 1000 ppm and 3000 ppm 6 hours per day, 5 days per week, for 9 exposures (Neal et al, 1987).
    B) Patients absorbing sufficient MTBE have developed a disagreeable ether odor on the breath (DiPadova et al, 1986; Teplick et al, 1987; Ponchon et al, 1988).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) VASODILATATION
    1) A feeling of heat or warmth has been described in patients receiving MTBE via biliary duct perfusion (Carrick et al, 1987).

Respiratory

    3.6.1) SUMMARY
    A) Labored and irregular breathing were associated with anesthetic effects in rats.
    B) Aspiration pneumonitis is possible following ingestion of gasoline-MTBE mixtures.
    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) Aspiration pneumonitis is possible following ingestion of gasoline-MTBE mixtures.
    B) COUGH
    1) Reports of cough and shortness of breath among the general population have been reported in cities that introduced MTBE into their gasoline. Several studies have shown minimal to no significant basis for these complaints (IPCS, 1998).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY DEPRESSION
    a) RATS - Labored and irregular breathing patterns have been seen in rats receiving lethal oral or inhalation exposures (Neal et al, 1987).

Neurologic

    3.7.1) SUMMARY
    A) Somnolence was seen after instillation of as little as 8 mL into the biliary ducts in humans; pronounced sedation occurred with instillation of 140 mL. As approximately 30 percent of the dose is retrieved by aspiration during this procedure, this represents absorption of approximately 6 mL and 100 mL, respectively.
    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) Pronounced sedation has been observed in patients receiving large amounts of MTBE (140 to 150 mL) via the biliary duct (vanSonnenberg et al, 1986; (Teplick et al, 1987). Mild somnolence has been seen with smaller amounts (8 to 22 mL) given intraductally (DiPadova et al, 1986). Coma lasting 4 hours was reported in one patient who received 10 mL every 15 minutes for 5 hours; 21 mL could not be retrieved (Ponchon et al, 1988).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) RATS - given oral MTBE developed ataxia, tremors, labored breathing, and loss of the righting reflex (Neal et al, 1987). CNS depression was seen occasionally when rats were exposed to 3000 ppm (API, 1984). Light anesthesia has been noted in rats exposed to 1000 ppm by inhalation (Conaway et al, 1985). Acute 6 hour inhalation studies in rats revealed no effect at 800 ppm and progressive but rapidly reversible CNS depression at 4000 and 8000 ppm (Daughtrey et al, 1997).
    b) Chronic experimental animal exposure studies at these same concentrations resulted in no persistent neurotoxic effects after 13 weeks of exposure, 6 hours/day, 5 days/week (Daughtrey et al, 1997; Lington et al, 1997).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting have been seen in patients receiving MTBE instillation into the biliary duct.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Nausea and a burning sensation have been noted in patients receiving MTBE instillation into the biliary duct (Allen et al, 1985a; DiPadova et al, 1986; Leuschner et al, 1988).
    B) DUODENITIS
    1) Duodenitis has been seen in patients receiving intraductal MTBE administration (DiPadova et al, 1986).

Hepatic

    3.9.1) SUMMARY
    A) Elevated serum transaminases and alkaline phosphatase have been observed after administration of MTBE into the biliary ducts.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Transient elevation (2 to 3-fold) of serum aminotransferases has been reported following the use of MTBE to dissolve gallstones (Allen et al, 1985a; LaFerla et al, 1987). It is unknown whether these transient changes are a result of MTBE or the surgical procedure.
    B) INJURY OF LIVER
    1) CASE REPORTS - Two cases of patients having abnormal dilation of the common bile duct one year following administration of intraductal MTBE for gallstone dissolution have been reported (Tritapepe et al, 1989).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC ENZYMES INCREASED
    a) In dogs receiving MTBE via gallbladder catheter, a 2 to 4-fold increase in serum alkaline phosphatase was noted (Allen et al, 1985b). Elevated serum transaminases and alkaline phosphatase were also seen in rabbits receiving MTBE by this route (DiPadova et al, 1986). It is unclear whether this is a toxic MTBE or simply a mechanical phenomenon.
    2) HEPATOMEGALY
    a) In multiple studies, high doses of MTBE have produced hepatomegaly with chronic administration (Bird et al, 1997; Lington et al, 1997).

Genitourinary

    3.10.1) SUMMARY
    A) Acute renal failure requiring dialysis was noted after MTBE gallbladder infusion. Hemolysis was the suspected cause.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) CASE REPORT - Anuria and complete renal failure were noted in a patient treated with continuous MTBE gallbladder infusion. It was estimated that 21 mL of MTBE was retained. Hemolysis was suspected, and the patient required dialysis for 18 days (Ponchon et al, 1988).
    2) Savolainen (1988) commented that methanol and formic acid are metabolites of MTBE. Serum or urine of this patient was not tested for the presence of methanol or formic acid. If present, these agents might have played a role in the development of the patient's renal failure.
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL INJURY
    a) Chronic MTBE exposure by several routes produces vacuolation of renal cells and chronic nephropathy in male rats and, at very high doses, female rats (Bird et al, 1997; Prescott-Mathews et al, 1997). This phenomenon is believed to be specific to rats and is dependent on the production of alpha-2U-globulin by this species (Prescott-Mathews et al, 1997).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) CASE REPORT - Hemolysis and renal failure were attributed to intrahepatic and intravascular extravasation of MTBE during a gallbladder dissolution procedure in one patient (Ponchon et al, 1988).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEMOLYSIS
    a) Rapid infusion of MTBE in experimental animals has produced hemolysis (Allen et al, 1985a).

Dermatologic

    3.14.1) SUMMARY
    A) MTBE is not a primary skin irritant. Slight erythema and irritation has been noted in experimental animals when MTBE was applied to abraded skin or under occlusive dressings.
    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) Direct contact with MTBE may irritate or burn the skin (CHRIS , 1990).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RASH
    a) RABBITS - MTBE was not a primary dermal irritant when applied to rabbit skin, but did produce erythema and blanching in 2 of 6 rabbits when applied to abraded skin (Neal et al, 1987).
    2) IRRITATION
    a) GUINEA PIGS - Slight irritation was noted in guinea pigs when MTBE was applied for 24 hours under an impervious cover (Neal et al, 1987).

Musculoskeletal

    3.15.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CREATINE PHOSPHOKINASE INCREASED
    a) RATS - Following inhalation of 50 to 200 ppm, 6 hours/day, 5 days/week, rats had an initial decrease followed by an increase in muscle creatine kinase levels (Savolainen et al, 1985).

Immunologic

    3.19.1) SUMMARY
    A) In a small study, gasoline service station attendants had MTBE IgG and IgM antibodies at levels 3 to 15 times higher than controls.
    3.19.2) CLINICAL EFFECTS
    A) INCREASED IMMUNOGLOBULIN
    1) SERUM ANTIBODIES - In a study of 24 gasoline service station attendants compared to 12 unexposed controls, 7 of the 12 potentially exposed workers had serum IgG and IgM antibodies to MTBE at levels 3 to 15 times higher than those detected in only 1 of the 12 control subjects (Vojdeni et al, 1997).

Reproductive

    3.20.1) SUMMARY
    A) At present, no human data is available regarding potential reproductive effects in humans.
    B) MTBE has exhibited little if any reproductive effects in 1- and 2-generation experimental animal studies, except at doses also producing maternal toxicity.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) LACK OF EFFECT
    a) At present, no human data is available regrading potential reproductive effects in humans.
    B) ANIMAL STUDIES
    1) A teratology evaluation in CD-1 mice and Sprague-Dawley rats with inhalation of MTBE at up to 2500 ppm during organogenesis failed to reveal any significant findings. A non-dose-related increase in resorptions attributable to specific animals and a slight increase in fused sternebrae in the high concentration group were believed to be due to maternal toxicity (Conaway et al, 1985; IPCS, 1998).
    2) In a single generation rat study, both sexes were exposed to airborne concentrations up to 3400 ppm, 6 hours per day, 5 days per week from 12 weeks prior to mating through the end of gestation (females). No significant effects were found on either reproductive function or reproductive tract histopathology. A non-dose related dilation of the renal pelvis was noted in both adult high dose animals and their offspring (Biles et al, 1987).
    3) Inhalation exposure at 1000, 4000, and 8000 ppm in pregnant mice (days 6 to 15) and rabbits (days 6 to 18) produced maternal illness at 4000 and 8000 ppm in both species. In spite of this, no effect on reproduction was seen in rabbits. Mice had increased post implantation loss, altered sex ratios, and reduced fetal weight at 4000 ppm, and increased numbers of cleft palate at 8000 ppm (Bevan et al, 1997a).
    4) A two generation inhalation study in rats also produced maternal illness at 3000 and 8000 ppm. No treatment-related changes in reproductive parameters occurred. Increased but delayed changes in offspring mortality and weight were noted at 3000 and 8000 ppm, but no adverse effects were noted at 400 ppm (Bevan et al, 1997b).
    5) t-Butanol, the primary metabolite of MTBE in rats, produced dose-dependent developmental delays in the offspring when given in the liquid diet of pregnant rats at 0.75 or 1.0 percent w/v (Daniel & Evans, 1982). Microcephaly was produced when t-butanol was given to neonatal rats during the rapid brain growth spurt (corresponding to the third trimester of human pregnancy) (Grant & Samson, 1982).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) MTBE and its metabolite t-butanol were present in breast milk in a concentration slightly less than in the blood in an adult female treated over 4 hours with MTBE four weeks after a caesarean section (Leuschner et al, 1991). Concentrations were not detected beyond 72 hours after the end of the 4-hour MTBE treatment. It is not known if these substances were harmful to the infant.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS1634-04-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Methyl tert-butyl ether
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were found in available references.
    3.21.3) HUMAN STUDIES
    A) CARCINOGENICITY RISK
    1) At the time of this review, no human data regarding the potential carcinogenic activity of MTBE were found.
    2) MTBE metabolizes into t-butyl alcohol and formaldehyde. Formaldehyde shows strong evidence of human carcinogenicity (Bingham et al, 2001).
    3.21.4) ANIMAL STUDIES
    A) CARCINOGENICITY RISK
    1) MTBE in oil was administered by gavage, 4 days per week for 104 weeks at 250 and 1000 mg/kg in a lifetime study in rats. An increase in Leydig interstitial cell tumors in males and a dose-related increase in leukemia and lymphoma in females was reported (Belpoggi et al, 1995).
    2) These results have been questioned because neither leukemias nor lymphomas were individually increased in treated females and because Leydig cell tumors are common in rats and do not predict the response to drugs or chemicals in humans (Mennear, 1997). As it is generally not mutagenic, MTBE-induced neoplasms occur through non-genetic mechanisms requiring chronic exposure to toxic doses unlikely to be voluntarily tolerated by humans because of the intense odor and taste at air or water concentrations predicted to result in cellular proliferation (Mennear, 1997).
    3) Using in vitro murine cell systems, various authors have argued for (MacKerer et al, 1996) or against (Casanova & Heck, 1997) an important role for the formaldehyde metabolite in the carcinogenicity of MTBE.
    B) CARCINOMA
    1) MTBE by inhalation at airborne concentrations of 400, 3000, and 8000 ppm for 18 months in mice and 24 months in rats (6 hours/day, 5 days/week) produced an increased incidence of hepatocellular adenomas in female mice only and an increase in renal tubular cell tumors in male rats. The latter occur in association with nephropathy, which is believed to be unique to the rat. An increased incidence of Leydig cell tumors was found relative to controls, but this appears to be due to an unusually low incidence in the control group relative to historical controls (Bird et al, 1997).
    2) MTBE was found to affect cell growth and induce cell transformation in cultured rodent fibroblasts (Iavicoli et al, 2002).
    3) The ACGIH considers MTBE to be an animal carcinogen (Group A3) (ACGIH, 1996a).
    C) LACK OF EFFECT
    1) Inhaled MTBE at an airborne concentration of 8000 ppm did not exhibit promotional activity for diethylnitrosamine induced hepatic foci in female mice (Moser et al, 1996).

Genotoxicity

    A) At present, no human data is available regarding potential genotoxic effects of MTBE.
    B) Limited genetic studies in rats have shown that MTBE may damage DNA and cause unscheduled DNA synthesis.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor respiratory function in exposed individuals, and arterial blood gases or pulse oximetry if aspiration pneumonitis is present. Pulmonary function tests may be indicated in patients with respiratory signs or symptoms. If pulmonary aspiration is suspected, a chest x-ray is indicated.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) LIVER FUNCTION TESTS - may be indicated following substantial MTBE exposure.
    2) MTBE concentrations cannot be readily obtained, but have been used for monitoring exposure. The longer half-life of the tertiary butanol metabolite may make it a more useful measure of overall exposure or remote exposures (Johanson et al, 1995) Nihlen et al, 1998a).
    a) A study done in Fairbanks, Alaska compared post-shift blood concentrations of MTBE in workers heavily exposed to motor vehicle exhaust or gasoline fumes during and after a program in which MTBE was used as a gasoline additive. In 18 workers, the median post-shift MTBE blood level was 1.8 micrograms/L during the program (range: 0.2 to 37.0 micrograms/L). After cessation of the MTBE program, the median post-shift blood level in 28 workers was 0.24 micrograms/L (range: 0.05 to 1.44 micrograms/L) (Moolenaar et al, 1994).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor respiratory function in exposed individuals.
    2) PULMONARY FUNCTION TESTS
    a) Pulmonary function tests may be indicated in patients with respiratory symptoms following gasoline-MTBE exposures.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) If pulmonary aspiration is suspected (history of coughing/choking, dyspnea, hypoxemia), obtain baseline chest x-ray and vital signs. Patient should be admitted and observed if symptomatic and/or chest roentgenogram is suggestive of aspiration.
    2) If the baseline chest x-ray and vital signs are normal, and aspiration is still suspected by history, the patient should be observed for 6 hours (obtaining hourly vital signs when possible) and a repeat chest x-ray considered in 6 hours (sooner if the patient becomes symptomatic).
    3) If serial vital signs indicate tachypnea, hyperpnea, fever, or other signs/symptoms of aspiration pneumonitis develop, or the repeat chest x-ray is positive, the patient should be admitted to the hospital.
    4) Asymptomatic patients with a negative chest x-ray require no further hospital observation after 6 hours.

Methods

    A) CHROMATOGRAPHY
    1) Head space gas chromatography can be used to measure MTBE levels with a limit of detection of about 5 parts per billion (Garrett et al, 1986).
    2) GC/MS can be used to measure MTBE levels with a limit of detection of about 100 parts per billion (Garrett et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) SYMPTOMATIC PATIENTS -
    1) If a patient has signs or symptoms consistent with pulmonary aspiration following ingestion, chest x-ray is warranted. If abnormal, hospital admission is indicated.
    B) ASYMPTOMATIC PATIENTS -
    1) Asymptomatic patients ingesting small amounts of gasoline-MTBE mixtures may be observed at home with close observation for development of respiratory signs or symptoms indicative of aspiration.
    6.3.1.2) HOME CRITERIA/ORAL
    A) ACCIDENTAL INGESTIONS -
    1) Patients with accidental ingestion of small quantities of gasoline-MTBE mixtures may safely be handled by home monitoring provided the patient is asymptomatic, there is ready access to a follow-up in a health care facility if needed, and no suspicion of suicidal ideation or child abuse exist.
    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) SYMPTOMATIC PATIENTS -
    1) If a patient has signs or symptoms consistent with pulmonary aspiration, chest x-ray is warranted. If abnormal, hospital admission is indicated.
    B) ASYMPTOMATIC PATIENTS -
    1) Asymptomatic patients with inhalation exposure to gasoline-MTBE mixtures may be observed at home with close observation for development of respiratory signs or symptoms indicative of aspiration.
    6.3.3.2) HOME CRITERIA/INHALATION
    A) ACCIDENTAL INHALATION -
    1) Patients with accidental inhalational exposure to small quantities of gasoline-MTBE fumes may safely be handled by home monitoring provided the patient is asymptomatic, that there is ready access to follow-up in a health care facility if needed, and no suspicion of suicidal ideation or child abuse exist.

Monitoring

    A) Monitor respiratory function in exposed individuals, and arterial blood gases or pulse oximetry if aspiration pneumonitis is present. Pulmonary function tests may be indicated in patients with respiratory signs or symptoms. If pulmonary aspiration is suspected, a chest x-ray is indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) Induction of emesis is NOT recommended for ingestion of pure MTBE due to the potential for pulmonary aspiration and resultant chemical pneumonitis (Tech Info, 1979).
    B) ACTIVATED CHARCOAL -
    1) MTBE is poorly adsorbed to activated charcoal, and its risks therefore outweigh its utility unless co-ingestants are suspected (Garrett et al, 1986).
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS
    1) PURE MTBE - Induction of emesis is NOT recommended for ingestion of pure MTBE due to the potential for pulmonary aspiration and resultant chemical pneumonitis (Tech Info, 1979).
    2) GASOLINE-MTBE - This consumer product is a gasoline-MTBE mixture. Induction of emesis is generally not recommended. Gastric aspiration or lavage may be considered in patients with coma, seizures, or an absent gag reflex after intentional ingestions of gasoline-MTBE or if potentially life-threatening co-ingestants are suspected (Ng et al, 1974).
    B) ACTIVATED CHARCOAL
    1) MTBE is poorly adsorbed to activated charcoal, and its risks therefore outweigh its utility unless co-ingestants are suspected (Garrett et al, 1986); although an in vitro study suggested that activated charcoal in a oral dose greater than 12 grams might be useful to minimize systemic absorption of MTBE spilled into the small intestine during medical use for gallstone dissolution (Ilett et al, 1990).
    6.5.3) TREATMENT
    A) AIRWAY MANAGEMENT
    1) Patients should be monitored carefully for respiratory depression and apnea. Respiratory support should be available at all times.
    B) PULMONARY ASPIRATION
    1) If the patient is already coughing upon arrival at the medical facility, pulmonary aspiration has probably already occurred. Monitor arterial blood gases or pulse oximetry in cases of severe aspiration pneumonitis and assure adequate ventilation and oxygenation. Observe closely for signs and symptoms of worsening respiratory function.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) BURN
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Inhalation exposure to an airborne concentration of 1000 ppm MTBE produced light anesthesia in experimental animals.
    B) Ingestion of 6 mL produced somnolence, while 100 mL produced sedation.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) MTBE has been used investigationally, administered directly into the bile duct or gallbladder, to dissolve cholesterol gallstones. Total amounts of up to 140 milliliters have been administered (Teplick et al, 1987; Carrick et al, 1987; DiPadova et al, 1986).

Minimum Lethal Exposure

    A) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) In a series of controlled human chamber studies, 37 healthy, nonsmoking people (19 females) ranging in age from 18 to 35 were exposed to an airborne concentration of 5 mg/m(3) of MTBE for 1 hour. No headaches, nasal irritation, or eye irritation or inflammation were reported, nor did this exposure affect performance on a battery of neurobehavioral tests (ACGIH, 1996).
    B) The majority of human data relates to the use of MTBE to dissolve cholesterol gallstones in vivo. Side effects are reported in 10 to 100 percent of MTBE treated patients. Typical complaints include: nausea, vertigo, vomiting, and abdominal discomfort; these can be controlled by adjusting or discontinuing the treatment. Overflow of MTBE out of the gallbladder and into the GI tract is associated with sedation, the odor of MTBE on the breath, and burning upper abdominal and back pain (ACGIH, 1996).
    1) Pronounced sedation was observed in a 67-year-old woman who received 140 mL of MTBE by the intraductal route for dissolution of gallstones (Teplick et al, 1987). Heavy sedation was also reported in a 70-year-old woman who received 2 to 5 mL by this route every 30 minutes for 15 hours (vanSonnenberg et al, 1986). In both of these cases, residual instilled MTBE was aspirated prior to the next dose.
    a) In dog studies, 80 to 90 percent of instilled MTBE was recovered by aspiration (Allen et al, 1985b). In human studies, approximately 30 to 36 percent of the total amount given was retrieved by aspiration (DiPadova et al, 1986).
    2) Somnolence was noted in a 67-year-old man who received 11 mL over 6 hours (4 mL was aspirated back and retrieved), in a 82-year-old woman who received 8 mL over 3 hours (2 mL retrieved), and in a 74-year-old woman who received 22 mL (8 mL retrieved) (DiPadova et al, 1986).
    C) Occupational exposure to MTBE has been reported with airborne concentrations as high as 33 ppm TWA (100 mg/m(3)) in refinery workers, but is generally less than 1 ppm (3 mg/m(3)) for an 8-hour TWA (ACGIH, 1996).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) INHALATION EXPOSURE
    a) Blood samples were obtained from 14 commuters and 30 other individuals during the Connecticut 1993 oxy-fuel pollution control program. Service station attendants had median levels of 15 mcg/L (range 7.6 to 28.9), mechanics had median levels of 1.73 mcg/L (0.17 to 36.7), and commuters had median levels of 0.11 mcg/L (not detected to 2.60) of MTBE. Levels correlated well with personal exposure measurements (White et al, 1995).
    b) Similar levels in occupationally exposed individuals were reported from Fairbanks, Alaska with a range of 0.2 to 31.5 mcg/L MTBE and 1.6 to 72.2 mcg/L tertiary butanol (Hutcheon et al, 1996).

Workplace Standards

    A) ACGIH TLV Values for CAS1634-04-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Methyl tert-butyl ether (MTBE)
    a) TLV:
    1) TLV-TWA: 50 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Not Listed
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    c) TLV Basis - Critical Effect(s): URT irr; kidney dam
    d) Molecular Weight: 88.17
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS1634-04-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS1634-04-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Methyl tert-butyl ether (MTBE)
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Methyl tert-butyl ether (MTBE)
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Methyl tert-butyl ether
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Category 3B ; Listed as: tert-Butyl methyl ether
    a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS1634-04-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 1700 mcL/kg
    B) LD50- (ORAL)MOUSE:
    1) 5960 mcL/kg
    C) LD50- (ORAL)RAT:
    1) 4 g/kg (RTECS, 2001)
    2) 2962.8 mg/kg (Neal et al, 1987)

Physicochemical

Physical Characteristics

    A) MTBE is a colorless liquid with an unpleasant, hydrocarbon odor (ACGIH, 1996; Ashford, 1994; Budavari, 1996; Lewis, 1993).

Ph

    1) No information found at the time of this review.

Molecular Weight

    A) 88.15

Other

    A) ODOR THRESHOLD
    1) 0.32-0.47 mg/m(3) (ACGIH, 1996)
    2) Odor Threshold of 97% pure MTBE in gasoline: 0.5 ppm (3% MTBE); 0.28 ppm (11% MTBE); 0.26 ppm (15% MTBE) (ACGIH, 1996)

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