TOXICOLOGICAL PROFILE FOR
 

METHYL tert-BUTYL ETHER
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

August 1996 
METHYL tert-BUTYL ETHER ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for 

Toxic Substances and Disease Registry. 
METHYL tert-BUTYL ETHER iii 

UPDATE STATEMENT 

Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information 

regarding the update status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology/Toxicology Information Branch
 

1600 Clifton Road NE, E-29
 

Atlanta, Georgia 30333
 


vi 

*Legislative Background 

The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization Act 

(SARA) of 1986 (Public Law 99-499) which amended the Comprehensive Environmental Response, Compensation, and 

Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to prepare toxicological profiles for 

hazardous substances most commonly found at facilities on the CERCLA National Priorities List and that pose the most 

significant potential threat to human health, as determined by ATSDR and the EPA. The availability of the revised 

priority list of 275 hazardous substances was announced in the Federal Register on April 29, 1996 (61 FR 18744). For 

prior versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); October 20, 

1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17, 1990 (55 FR 42067); October 17, 199l (56 FR 

52166); October 28, 1992 (57 FR 48801); and February 28, 1994 (59 FR 9486). Section 104(I)(3) of CERCLA, as 

amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. 
METHYL tert-BUTYL ETHER vii 

CONTRIBUTORS
 

CHEMICAL MANAGER(S)/AUTHOR(S):
 

Moiz Mumtaz, Ph.D.
 

ATSDR, Division of Toxicology, Atlanta, GA
 

Sharon Wilbur, M.A.
 

Research Triangle Institute, Research Triangle Park, NC
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:
 

1.	 Green Border Review. Green Border review assures consistency with ATSDR policy. 

2.	 Health Effects Review. The Health Effects Review Committee examines the health effects chapter 

of each profile for consistency and accuracy in interpreting health effects and classifying end 

points. 

3.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific minimal risk levels (MRLs), reviews the health effects database of each profile, 

and makes recommendations for derivation of MRLs. 

METHYL tert-BUTYL ETHER ix 

PEER REVIEW 

A peer review panel was assembled for MTBE. The panel consisted of the following members: 

1. Dr. C. Clifford Conaway, Research Scientist, 80 Watermelon Hill Rd., Mahopac, New York; 

2. Dr. Arthur Gregory, Private Consultant, 220 West Ash Road, Sterling, Virginia; and 

3. Dr. Norbert Page, Private Consultant, 17601 Stoneridge Court, Gaithersburg, Maryland. 

These experts collectively have knowledge of MTBE’s physical and chemical properties, toxicokinetics, key health end 

points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were 

selected in conformity with the conditions for peer review specified in Section 104(i)(13) of the Comprehensive 

Environmental Response, Compensation, and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers’ 

comments and determined which comments will be included in the profile. A listing of the peer reviewers’ comments not 

incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative 

record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the 

administrative record. 

The citation of the peer review panel should not be understood to imply its approval of the profile’s final content. The 

responsibility for the content of this profile lies with the ATSDR. 









METHYL tert-BUTYL ETHER 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about methyl tert-butyl ether (MTBE) and the effects of 

exposure. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the nation. These sites 

make up the National Priorities List (NPL) and are the sites targeted for long-term federal cleanup activities. MTBE has 

been found in at least 12 of the 1,430 current or former NPL sites. However, it’s unknown how many NPL sites have 

been evaluated for this substance. As more sites are evaluated, the sites with MTBE may increase. This information is 

important because exposure to this substance may harm you and because these sites may be sources of exposure. 

When a substance is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, 

it enters the environment. This release does not always lead to exposure. You are exposed to a substance only when you 

come in contact with it. You may be exposed by breathing, eating, or drinking the substance or by skin contact. 

If you are exposed to MTBE, many factors determine whether you’ll be harmed. These factors include the dose (how 

much), the duration (how long), and how you come in contact with it. You must also consider the other chemicals you’re 

exposed to and your age, sex, diet, family traits, lifestyle, and state of health. 

1.1 WHAT IS MTBE? 

MTBE is the common name for a synthetic chemical called methyl tert-butyl ether. It is a flammable liquid made from 

combinations of chemicals like isobutylene and methanol. It has a distinctive odor that most people find disagreeable. It 

was first introduced as an additive for unleaded gasolines in the 1980s to enhance octane ratings. In city areas where 

there are concerns over pollutants like carbon monoxide, EPA may require the use of MTBE or ethanol 
METHYL tert-BUTYL ETHER 2 

1. PUBLIC HEALTH STATEMENT 

as an oxygenating agent to make the fuel burn more cleanly during the winter months. Fuels containing these additives 

are called reformulated gasolines. Most MTBE is mixed with gasoline, so most people would come in contact with it 

while exposed to automobile fuel vapors or exhausts. MTBE has other special uses as a laboratory chemical and in 

medicine to dissolve gallstones. Its basic physical and chemical properties are summarized in Chapter 3; for more 

information on its production and use, see Chapter 4. 

1.2 WHAT HAPPENS TO MTBE WHEN IT ENTERS THE ENVIRONMENT? 

MTBE will quickly evaporate from open containers. In the open air, it will quickly break down into other chemical 

compounds, with half of it disappearing in about 4 hours. Like most ethers and alcohols, MTBE dissolves readily in 

water. If MTBE is spilled on the ground, rainwater can dissolve it and carry it through the soil into the groundwater. 

Spills or leaks from storage containers can seep into deeper soil layers and pollute groundwater, especially near 

manufacturing sites, pipelines, and shipping facilities. Leakage from underground storage tanks, such as tanks at gasoline 

filling stations, can also add MTBE to groundwater. MTBE is not expected to concentrate in fish or plants found in lakes, 

ponds, and rivers. For more information, please see Chapters 4 and 5. 

1.3 HOW MIGHT I BE EXPOSED TO MTBE? 

Low levels of MTBE can be present in both indoor and outdoor air, and are mostly linked with the use of MTBE as a 

gasoline additive. Because it is not presently considered a major harmful pollutant, it is usually not included in routine 

national monitoring programs for liquids. This makes it difficult to estimate how much you could be exposed to. 

Because MTBE evaporates quickly, large amounts of the vapor could enter closed spaces. Leaks, spills, or open 

containers of MTBE pose a fire and explosion threat in the presence of open flames and electrical sparks, especially in 

closed spaces. Most people are exposed to MTBE from auto exhaust when driving or from gasoline while fueling their 

cars. People can also be exposed to MTBE from groundwater pollution. The chemical is likely to be present in very 

small amounts in the 
METHYL tert-BUTYL ETHER 3 

1. PUBLIC HEALTH STATEMENT 

air in cities or near highways. MTBE is used to treat gallstones, so patients treated with this medical procedure will have 

some exposure. 

1.4 HOW CAN MTBE ENTER AND LEAVE MY BODY? 

MTBE can enter your body rapidly if you breathe air, drink water, or eat food that contains it. 

If your skin comes into contact with MTBE, it can enter your body through the skin, but this 

happens more slowly. Most of the MTBE that you breathe in or take in by mouth can get into 

your blood. Not as much gets into the blood through the skin. No matter how you are 

exposed, a large amount of MTBE is breathed out without being changed into other chemicals. The MTBE that is not 

breathed out is changed into other chemicals such as butyl alcohol, methyl alcohol, formaldehyde, formic acid, and 

carbon dioxide. These chemicals also leave the body quickly in the air that you breathe out or in the urine. MTBE does 

not stay in any organs of your body for a long time. Most of it and its breakdown products leave the body in 1 or 2 days. 

For more information, see Chapter 2. 

1.5 HOW CAN MTBE AFFECT MY HEALTH? 

Some people who were exposed to MTBE while pumping gasoline, driving their cars, or 

working as attendants or mechanics at gas stations complained of headaches, nausea, dizziness, irritation of the nose or 

throat, and feelings of spaciness or confusion. These symptoms were reported when high levels of MTBE were added to 

gasoline in order to lower the amount of carbon monoxide, a known poison, released from cars. MTBE has a very 

unpleasant odor that most people can smell before any harmful effects would occur, but some people might feel irritation 

of the nose or throat before noticing the smell. MTBE caused side effects in some patients who were given MTBE to 

dissolve gallstones. The MTBE is given to these patients through special tubes that are placed into their gallbladders. If 

MTBE leaks from the gallbladder into other areas of the body, the patient can have minor liver damage, a lowering of the 

amount of white blood cells, nausea, vomiting, sleepiness, dizziness, and confusion. These effects are not long lasting. 
METHYL tert-BUTYL ETHER 4 

1. PUBLIC HEALTH STATEMENT 

We know more about how MTBE affects the health of animals than the health of humans. Some rats and mice died after 

they breathed high amounts of MTBE, but these levels were much higher than people are likely to be exposed to. MTBE 

also caused irritation to the noses and throats of animals that breathed MTBE, The most common effect of MTBE in 

animals is on their nervous systems. Breathing MTBE at high levels can cause animals to act as if they are drunk. For 

example, some became less active, staggered, fell down, were unable to get up, and had partially closed eyelids. These 

effects lasted only for about an hour, and then the animals seemed normal again. Some animals that breathed high levels 

of MTBE for several hours a day for several weeks gained less weight than normal, probably because they ate less food 

while they were inactive. When rats breathed high levels of MTBE for several hours every day for two years, some got 

more serious kidney disease than these rats usually get as they grow old. Some of the male rats developed cancer in the 

kidney, but whether this has meaning for people is not known When mice breathed high levels of MTBE for several 

hours every day for a year and a half, some had larger livers than normal, and some mice developed tumors in the liver. 

When rats were given high levels of MTBE by mouth for 2 years, some male rats developed cancer in the testes and 

some female rats developed cancer of the blood (leukemia) and cancer (lymphoma) of some of the tissues that produce 

blood cells. The Department of Health and Human Services (DHHS), the International Agency for Research on Cancer 

(IARC), and the EPA have not classified MTBE for its ability to cause cancer. When pregnant rats, rabbits, or mice 

breathed MTBE, birth defects occurred only in the baby mice. We do not know if this has any relevance for people. 

MTBE did not affect the animals’ ability to reproduce. 

Some rats and mice died after being given very large amounts of MTBE by mouth. The 

amounts were much higher than people are likely to swallow from drinking water containing 

MTBE. The effects on the nervous system in animals that are given MTBE by mouth are the 

same as the effects that occur in animals that breathe MTBE. Some animals that were given 

MTBE by mouth had diarrhea and irritation in their stomachs and intestines. Some animals also had very slight liver 

damage. 

MTBE irritated the skin of animals when it was placed directly on their skin. MTBE also 
METHYL tert-BUTYL ETHER 5 

1. PUBLIC HEALTH STATEMENT 

irritated the eyes of animals when it was placed in their eyes or when air containing MTBE came 

into contact with their eyes. For more information on the health effects of MTBE, please see 

Chapter 2. 

1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN 

EXPOSED TO MTBE? 

There are no specific medical tests to determine whether you have been exposed to MTBE. But MTBE and its 

breakdown product, butyl alcohol, can be measured in exhaled air, in blood, and in urine. Because MTBE and its 

breakdown products leave the body in 1 or 2 days, these measurements can only tell if you have been exposed recently. 

The effects of exposure to MTBE, such as stomach aches, fatigue, and dizziness, are common to many chemicals and 

illnesses. These symptoms are not very useful in determining whether you were exposed to this particular chemical. For 

more information, see Chapters 2 and 6. 

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

 PROTECT HUMAN HEALTH? 

To protect workers, the American Conference of Governmental Industrial Hygienists (ACGIH) recommends that the 

amount in workroom air be limited to 100 parts per million (ppm) in an 8-to 10-hour work shift. At this time, 

governmental agencies such the National Institute for Occupational Safety and Health (NIOSH), Occupational Safety and 

Health Administration (OSHA), and EPA have not established exposure criteria for MTBE. For more information, see 

Chapter 7. 
METHYL tert-BUTYL ETHER 6 

1. PUBLIC HEALTH STATEMENT 

1.8 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department or: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology
 

1600 Clifton Road NE, E-29
 

Atlanta, Georgia 30333
 

(404) 639-6000 

This agency can also provide you with information on the location of occupational and 

environmental health clinics. These clinics specialize in the recognition, evaluation, and 

treatment of illness resulting from exposure to hazardous substances. 
METHYL tert-BUTYL ETHER 7 

2. HEALTH EFFECTS
 

2.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective of the toxicology of methyl tert-butyl 

ether (MTBE). It contains descriptions and evaluations of toxicological studies and epidemiological 

investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic 

data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure-inhalation, 

oral, and dermal; and then by health effect-death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure 

periods-acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. 

The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels 

(LOAELs) reflect the actual doses (levels of exposure) used in the studies. LOAELS 

have been classified into “less serious” or “serious” effects. “Serious” effects are those that evoke failure 

in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress or death). 

“Less serious” effects are those that are not expected to cause significant dysfunction or death, or those 

whose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable 

amount of judgment may be required in establishing whether an end point should be classified as a 

NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in some cases, there will be insufficient 

data to decide whether the effect is indicative of significant dysfunction. However, the Agency has 

established guidelines and policies that are used to classify these end points. ATSDR believes that there is 

sufficient merit in this approach to warrant an attempt at distinguishing between “less serious” and 

“serious” effects. The distinction between “less serious” effects and “serious” effects is considered to be 
METHYL tert-BUTYL ETHER 8 

2. HEALTH EFFECTS 

important because it helps the users of the profiles to identify levels of exposure at which major health 

effects start to appear. LOAELs or NOAELs should also help in determining whether or not the effects 

vary with dose and/or duration, and place into perspective the possible significance of these effects to 

human health. 

The significance of the exposure levels shown in the LSE tables and figures may differ depending on the 

user’s perspective. Public health officials and others concerned with appropriate actions to take at 

hazardous waste sites may want information on levels of exposure associated with more subtle effects in 

humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAELs) have been 

observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may be of 

interest to health professionals and citizens alike. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of MTBE are 

indicated in Tables 2-1 and 2-2, and Figures 2-l and 2-2. 

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been 

made for MTBE. An MRL is defined as an estimate of daily human exposure to a substance that is likely 

to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of 

exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect 

or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are 

based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived 

for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

A User’s Guide has been provided at the end of this profile (see Appendix B). This guide should aid in the 

interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 
METHYL tert-BUTYL ETHER 9 

2. HEALTH EFFECTS 

2.2.1 Inhalation Exposure 

2.2.1.1 Death 

No studies were located regarding death in humans following inhalation exposure to MTBE. 

Information regarding death in animals was located for rats, mice, and rabbits. Acute inhalation 4-hour 

LC50 (lethal concentration, 50% kill) values in rats for 2 grades of MTBE were determined to be 

39,395 ppm for ARCO MTBE (96.2% MTBE) and 33,370 ppm for commercial MTBE (99.1% MTBE) 

(ARCO 1980). An acute LC50 in mice following inhalation of MTBE for 10 minutes was determined to be 

180,000 ppm (Snamprogetti 1980). The LT50 (time at which death occurs in 50% of exposed animals) in 

mice following inhalation exposure to 209,300 ppm MTBE was 5.6 minutes. No deaths occurred in male 

or female Fischer rats exposed to < 8,000 ppm for 6 hours (Bioresearch Labs 1990d; Gill 1989). 

Intermittent inhalation exposure of Sprague-Dawley rats of both sexes to MTBE for 9 days to 

concentrations ranging from 100 to 3,000 ppm did not result in any treatment-related deaths (Biodynamics 

1981). Intermittent exposure of rats for 5 days (Vergnes and Morabit 1989), rats and mice for 13 days 

(Dodd and Kintigh 1989), or mice for 1 or 2 days (Vergnes and Chun 1994; Vergnes and Kintigh 1993) to 

concentrations <8,000 ppm MTBE was not lethal. Similarly, no deaths occurred in pregnant SpragueDawley rats (Conaway et al. 1985), pregnant CD-l mice (Conaway et al. 1985; Tyl and Neeper-Bradley 

1989), or pregnant New Zealand rabbits exposed intermittently to < 8,000 ppm (Tyl 1989) during 

gestation. 

Intermediate-duration exposure of rats (5-10 minutes per day, 5 days per week for 30 days) to 50,000 and 

80,000 ppm MTBE caused no mortality (Snamprogetti 1980). However, in mice similarly exposed, death 

occurred in 1 of 30 mice exposed to 80,000 ppm for 10 minutes per day, 5 days per week for 30 days, but 

no mice died after exposure to 50,000 ppm for 10 minutes per day or to 80,000 ppm for 5 minutes per day. 

No mortality was observed in rats or mice exposed to <8,000 ppm MTBE 6 hours per day, 5 days per week 

for 4 or 5 weeks (Chun and Kintigh 1993). No rats died during intermittent exposure to <8,000 ppm 

MTBE for I3 weeks (Dodd and Kintigh 1989; Greenough et al. 1980) or to <2,500 ppm for 16-28 weeks 

(Biles et al. 1987). 

In a 24-month inhalation study, increased mortality and decreased mean survival time occurred in male 

rats exposed intermittently to 3,000 and 8,000 ppm MTBE (Chun et al. 1992). These groups were 

sacrificed at weeks 97 and 82, respectively. A slight increase in mortality and a significantly decreased 
METHYL tert-BUTYL ETHER 10 

2. HEALTH EFFECTS 

mean survival time also occurred in the male rats exposed to 400 ppm (lowest concentration tested). This 

group was maintained until the scheduled sacrifice. Chronic progressive nephropathy was the main cause 

of death. Although female rats had slightly more deaths from chronic progressive nephropathy, the 

increased mortality was not statistically significant. As discussed for Renal Effects in Section 2.2.1.2, the 

higher incidence and greater severity of chronic progressive nephropathy at lower exposure concentrations 

in male rats compared with female rats may be due to the exacerbation of this syndrome by the 

accumulation of α2u-globulin or another unknown protein unique to male rats. In mice exposed to the 

same concentrations of MTBE for 18 months, increased mortality and decreased mean survival time, due 

to a slightly increased incidence of obstructive uropathy, occurred in males at 8,000 ppm (Burleigh-Flayer 

et al. 1992). No increased mortality occurred in female mice. The LC50 values in rats and mice, the LT50 

value in mice, and the concentrations associated with increased mortality in male mice in the chronicduration 

studies are recorded in Table 2-l and plotted in Figure 2- 1. 

2.2.1.2. Systemic Effects 

Studies regarding the systemic effects in humans and animals after inhalation exposure to MTBE are 

discussed below. The highest NOAEL values and the LOAEL values for each systemic effect from all 

reliable studies for each species and duration category are recorded in Table 2-l and plotted in Figure 2-l. 

Respiratory Effects. Since MTBE has been used as a gasoline additive to increase octane levels and 

more recently to reduce the levels of carbon monoxide emissions; some humans have reported respiratory 

symptoms while adding gasoline to automobile tanks or while driving. Such anecdotal reports have 

prompted studies by the Centers for Disease Control and Prevention (CDC). Preliminary investigations 

were conducted by the state of Alaska, with the assistance of CDC (Belier and Middaugh 1992; Chandler 

and Middaugh 1992). To determine whether symptoms were occurring, whether symptoms occurred in a 

consistent pattern, and whether symptoms could be related to exposure to oxyfuel in Fairbanks and 

Anchorage, Alaska, people believed to travel routinely in motor vehicles (taxi cab drivers and health-care 

workers) were asked if they experienced an increase in health complaints during 1 or 2 months since 

oxyfuel programs were initiated. In the study in Fairbanks (Beller and Middaugh 1992), university 

students were used as controls. No appropriate control group was identified in Anchorage; university 

students did not live in dormitories on a campus as isolated as in Fairbanks, and thus could not serve as a 

control group (Chandler and Middaugh 1992). In the Fairbanks study (Beller and Middaugh 1992), the 

percentage of persons who met the case definition (an increase in headaches or an increase in two or more 

of the following: nausea or vomiting; burning sensation in the nose, mouth, or throat; cough; dizziness; 



















METHYL tert-BUTYL ETHER 30 

2. HEALTH EFFECTS 

spaciness or disorientation; eye irritation) was highest in taxi drivers (4 of 12 or 33%), followed by health – care workers 

(26 of 90 or 29%); the percentage of Fairbanks university students who met the case definition was 15% (15 of 101). The 

proportion of cases in which symptoms while traveling were reported was 3 of 4 taxi drivers, I1 of 26 health-care 

workers, and 3 of 15 students; the proportion of cases in which symptoms while fueling were reported was 1 of 4 taxi 

drivers, 9 of 26 health-care workers, and 3 of 15 students. Of the cases, burning sensation in the nose or throat was 

reported by 0 of 4 (0%) taxi drivers, 2 of 26 (8%) health workers, and 3 of 15 (20%) students, and cough was reported by 

1 of 4 (25%) taxi drivers, 8 of 26 (31%) health-care workers, and 3 of 15 (20%) students. On average, taxi drivers, 

healthcare workers, and students reported spending 69, 7.7, and 0.8 hours/week, respectively, traveling by motor vehicle. 

In the Anchorage study (Chandler and Middaugh 1992), the proportion of persons who met the case definition, as 

defined above, was 12 of 25 (48%) taxi drivers and 36 of 137 (26%) health-care workers. The proportion of cases in 

which symptoms while traveling were reported was 12 of 12 taxi drivers and 27 of 36 health-care worker, and the 

proportion of cases in which symptoms while fueling were reported was 9 of 12 taxi drivers and 19 of 36 health-care 

workers. Of these cases, nose or throat burning was reported by 5 of 12 (42%) taxi drivers and 13 of 36 (36%) healthcare workers, and cough was reported by 4 of 12 (33%) taxi drivers and 13 of 36 (36%) health-care workers. The authors 

of these reports noted that these investigations do not provide definitive evidence that symptoms are due to the oxyfuel 

programs, but since these investigations were initiated with only modest goals and had many limitations, no definitive 

results could be expected. Limitations of these studies include the observations that the university students were 

interviewed shortly before their final examinations took place (when students historically experience more headaches) 

and that some of the students had access to motor vehicles, factors which could bias results against finding an association 

between symptoms and exposure to oxyfuel. In addition, the investigations were not conducted when the temperature 

dropped below 0 oF, when many people reported that health complaints were worse. Furthermore, the results of these 

investigations could have been heavily influenced by widespread media coverage and public opposition to the oxyfuel 

program. Several Anchorage taxi drivers mentioned issues that could bias their symptom 

reporting: that oxyfuels cost more money, that their cabs were running poorly, that they experienced 

decreased gas mileage, and that they lost profits because the airport was charging the taxi drivers more. 

CDC studies were conducted in Fairbanks, Alaska (CDC 1993a; Moolenaar et al. 1994) and in Stamford, 

Connecticut (CDC 1993b; White et al. 1995), during oxygenated fuel programs. In the Fairbanks study, 

people exposed to MTBE in gasoline were monitored during the first 2 weeks of December, 1992 (Phase 

I), when the oxygenated fuel program was in full effect, and during the beginning of February, 1993 

(Phase II), after the oxygenated fuel program had ended on December 22, 1992 (CDC 1993a; Moolenaar et 
METHYL tert-BUTYL ETHER 31 

2. HEALTH EFFECTS 

al. 1994). In Phase I, the subjects consisted of 10 mechanics and workers at service stations and 

automobile dealerships and 8 subjects who spent most of their workdays in motor vehicles (animal control 

officers, meter and telephone technicians, and a garbage collector). The median 8-hour time-weighted 

average (TWA) concentration of MTBE in the workplace air of the service stations and dealership garages 

was 0.1 ppm, with a range of 0.01-0.81 ppm. The frequencies of key respiratory symptoms were 9 of 18 

for burning sensation of nose or throat and 5 of 18 for cough. In Phase II, the subjects consisted of 12 of 

the original 18 participants in Phase I and an additional 16 workers from service stations and garages 

(n=28 workers). The median 8-hour TWA concentration of MTBE in the workplace air was 0.04 ppm, 

with a range of nondetectable to 0.14 ppm. The difference in the median TWAs of MTBE concentrations 

in Phase I and Phase II was statistically significant. The frequency of key respiratory symptoms in the 

Phase II subjects was 0 of 28 for both cough and burning sensations of the nose or throat. As discussed in 

Section 2.3.1.1, the median preshift concentrations of MTBE in blood of occupationally exposed workers 

were 1.15 μg/L (range, 0.1-27.8 μg/L) in Phase I and 0.20 μg/L (range, 0.05 to 4.35 μg/L) in Phase II, 

which were statistically significantly different. Likewise, postshift blood concentrations of MTBE in 

occupationally exposed workers were statistically significantly higher in Phase I (median 1.80 μg/L and 

range 0.2-37.0 μg/L) than in Phase II (median 0.24 μg/L and range 0.05-I .44 μg/L). The authors reported 

that when the Phase I postshift blood concentrations were separated into quartiles, all of the 4 workers 

whose levels were in the top quartile (above 9.6 μg/L) had one or more of the 7 key health complaints 

(headache, eye irritation, burning of the nose of throat, cough, nausea or vomiting, dizziness, and a 

sensation of spaciness or disorientation) on the day the blood samples were obtained, compared with 9 of 

14 of those whose levels were in the lower 3 quartiles. The Stamford, Connecticut study (CDC 1993b; 

White et al. 1995) was conducted from April 5 to 16, 1993, about 5 months after gasoline stations began 

selling gasoline containing 15% MTBE (no Phase II in Stamford study). The study participants were 

divided into 4 groups: Group 1 consisted of 48 male mechanics or gasoline station attendants; Group 2 

consisted of 57 male taxi or limousine drivers; Group 3 consisted of 12 “other” male workers who spent 

most of their time around traffic or motor vehicles (e.g., meter readers); and Group 4 consisted of 59 men 

not occupationally exposed, but who commuted to work in their cars. The frequency of key respiratory 

symptoms was as follows: burning nose or throat in 7 of 48 (14.6%) mechanics (Group 1), in 0 of 57 (0%) 

professional drivers (Group 2), in 4 of 12 (33.3%) “other” workers (Group 3), and in 4 of 59 (6.8%) 

commuters (Group 4); cough in 7 of 48 (14.6%) mechanics, in 3 of 57 (5.3%) professional drivers, in 5 of 

12 (41.7%) “other” workers, and in 9 of 59 (15.3%) in commuters. Approximate median blood levels of 

MTBE were 0.1 μg/L in 14 commuters, 2 μg/L in 2 1 car repairers, 0.1 μg/L in 6 “other” workers, and 

25 μg/L in 3 gas station attendants. The 11 individuals with the highest blood MTBE levels (>2.4 μg/L) 

were significantly more likely to report one or more key symptoms. Both personal breathing zone levels 
METHYL tert-BUTYL ETHER 32 

2. HEALTH EFFECTS 

of MTBE for the mechanics and workroom levels of MTBE were measured. Personal breathing zone 

levels of mechanics ranged from <0.03 to 12.04 ppm, while workroom levels ranged from 0.001 to 

0.429 ppm. In both the Stamford and the Fairbanks studies, the accuracy of the measured workroom levels 

was questionable since the content of the air a worker actually breathed may have been substantially 

different from the air level measured by the monitoring devices. In addition, in the Stamford study, many 

of the windows and doors were open due to the mildness of the weather, leading to an underestimation of 

the exposure levels (CDC 1993b; White et al. 1995). Furthermore, the breathing zone levels, which were 

measured approximately one week earlier, were questioned because exposure to higher levels of MTBE 

probably occurred while the workers were close to the gasoline tank. Other limitations of these studies 

include the participation of only healthy working adults, no control groups, small to modest numbers of 

participants limiting the statistical power, and the possibilities that an unknown contaminant or 

combustion product of MTBE, interaction between MTBE and other gasoline components, or the other 

components alone, may have been responsible for the symptoms. In addition, it is possible that persons 

willing to participate in the study may have been more likely to report symptoms; or that participants and 

investigators may have been biased due to awareness of the purpose of the study, publicity, the cost of 

oxygenated fuel, the odor, or negative personal views. 

A telephone interview survey was conducted in metropolitan Milwaukee, Wisconsin, and in metropolitan 

Chicago, Illinois (the use of reformulated gasoline was required in both of these areas), and in the rest of 

Wisconsin exclusive of metropolitan Milwaukee (where the use of reformulated gasoline was not required) 

(Anderson et al. 1995). In the Milwaukee metropolitan area, 23% of the telephone survey respondents 

reported experiencing unusual symptoms since the reformulated gasoline program started, while in the 

Chicago metropolitan area and in the rest of Wisconsin, only 6% of the respondents reported experiencing 

unusual symptoms. Therefore, the proportion in Chicago was not statistically different from that found in 

Wisconsin. Prevalence of respiratory symptoms associated with MTBE exposure in the questionnaire 

(throat irritation, difficulty breathing, sinus congestion, funny smells) was statistically higher in 

Milwaukee than in either Chicago or Wisconsin; the prevalence was not different between Chicago and 

Wisconsin for any symptom. These results suggest that factors other than reformulated gasoline use 

contributed significantly to the differences in symptom prevalence between Milwaukee and the other two 

areas. Knowledge about reformulated gasoline, including the likely awareness of the potential negative 

effects of reformulated gasoline in Milwaukee and Wisconsin, may have biased the symptom reporting. It 

was noted that following the nationally televised story about the health effects of MTBE on January 19, 

1995, a local Milwaukee television station ran a week-long feature about MTBE, which prompted an 

increasing number of complaints from Milwaukee residents. In the telephone survey, familiarity with 
METHYL tert-BUTYL ETHER 33 

2. HEALTH EFFECTS 

MTBE as a reformulated gasoline additive was reported by 54% of the Milwaukee residents, 23% of 

Chicago residents, and 40% of the Wisconsin residents. The authors concluded that the study was unable 

to attribute the increased prevalence of symptoms in Milwaukee to reformulated gasoline use, but did not 

rule out subtle effects or the possibility that a relatively small number of individuals in Milwaukee may 

have had a greater sensitivity to reformulated gasoline mixtures. 

In May 1993, CDC and New York state health officials investigated whether exposure to MTBE in fuels 

was measurable in occupationally and nonoccupationally exposed people in Albany, where MTBE is used 

in small concentrations (CDC 1993c). Questionnaires regarding MTBE-associated symptoms (headache, 

eye irritation, burning of the nose or throat, cough, nausea, dizziness, and spaciness) were administered. 

Group 1 consisted of 34 automobile repair shop workers and service station attendants exposed to gasoline 

fumes; Group 2 consisted of 48 policemen, toll booth workers, and parking garage attendants exposed to 

automobile exhaust; and Group 3 consisted of 182 office workers and college students who may have been 

exposed to minute amounts of automobile emissions, but who were not occupationally exposed to 

gasoline. Ambient air and worksite levels of MTBE were nondetectable (<5 ppb), but MTBE was 

detectable in the personal air monitoring zone of 2 of 13 auto mechanics and gas station attendants, one at 

a level of 140 ppb. The proportion of subjects who reported burning nose or throat was 2 of 34 (6%) in 

Group I, 2 of 48 (4%) in Group 2, and 24 of 182 (13%) in Group 3. The proportion of subjects who 

reported cough was 5 of 34 (15%) in Group 1, 12 of 48 (25%) in Group 2, and 37 of 182 (20%) in Group 

3. All key symptoms were slightly more prevalent and the presence of 2 or more key symptoms was 

2-3 times more prevalent in Groups 2 and 3 than in Group 1, but the increases were not statistically 

significant. Thus, no increase in health complaints among people with higher gasoline exposures was 

detected. Limitations of the this study included that the study sample may not have accurately represented 

the population in the various exposure categories; that subjects in Group 3 may have been more likely to 

report symptoms; and that the study was conducted in early May, when the people may have been driving 

with their car windows open, when car repair garages typically had their bays open, and when allergies 

related to pollen may have affected the symptom reporting. 

A cross-sectional cohort study investigated self-reported symptoms (headache, nausea, cough, 

lightheadedness, sleepiness while driving, daytime sleepiness, eye irritation) of garage workers in the state 

of New Jersey exposed to high (115 workers in northern New Jersey during the wintertime oxyfuel 

program) and low (122 workers in southern New Jersey 10 weeks after the phase-out date for oxyfuel 

program) MTBE concentration environments; the results of the questionnaire regarding respiratory 

symptoms (cough) over the last 30 days showed no significant difference (12% in the northern workers 
METHYL tert-BUTYL ETHER 34 

2. HEALTH EFFECTS 

and 17% in the southern workers, p=0.23) (Mohr et al. 1994). Results of the pre- and postshift 

questionnaires revealed that all workers felt worse at the end of the workday with regard to symptoms 

associated with MTBE (not otherwise specified), but no difference was found between the groups or in 

reporting rates between groups across the work shift. No difference in 30-day symptom reporting was 

found in subgroups of 13 northern New Jersey workers and 15 southern New Jersey workers who spent an 

average of >5 hours per day pumping gasoline. However, analysis of the pre- and postshift questionnaires 

showed a higher rate of symptom reporting (p=0.03 for MTBE-associated symptoms) for the northern gas 

pumpers than for the southern gas pumpers, but not when the same analysis was repeated with northern 

gas pumpers and age-, sex-, and education-matched southern gas pumpers. Active air sampling done for 

1 hour, which was converted to 8-hour TWAs, yielded high MTBE levels (1.66-6.1 ppm) in northern New 

Jersey garages and nondetectable (<0.28 ppm) to low (0.28-0.83 ppm) MTBE levels in southern New 

Jersey garages. Passive samplers worn by some of the workers indicated high (1.66-6.1 ppm) or very high 

(>6.1 ppm) MTBE levels in northern New Jersey. For the southern New Jersey workers, some of the 

samplers had high levels, but most were low or nondetectable. The authors concluded that no increased 

rate of symptom reporting was found, even though the northern New Jersey workers received higher 

exposures. Nevertheless, even 10 weeks after the phase-out date of oxyfuels in southern New Jersey, some 

workers still received significant exposure, probably due to changing fuel filters and pumps in vehicles 

that still contained the wintertime oxyfuel. 

To address some of the issues identified in the occupational and field studies, an experimental double - blind 

study was conducted in 22 healthy men and 21 healthy women, who were examined for both objective 

and subjective effects (Cain et al. 1994). In this study, half of the subjects were exposed 

sequentially to 1.7 ppm MTBE for 1 hour on 1 day, to uncontaminated air for 1 hour 2 days later, and to 

7.1 ppm of a 17-component mixture of volatile organ compounds (VOCs) for 1 hour 2 days later. The 

other half of the subjects were similarly exposed in the reverse order. The subjects were able to detect the 

odor of MTBE, but expressed little objection to it. Analysis of nasal lavage material for differential cell 

counts of polymorphonuclear neutrophilic leukocytes (PMNs), epithelial cells, monocytes, eosinophils, 

and lymphocytes revealed no statistically significant differences across the three exposure conditions. In 

addition, statistical analysis of the results of questionnaires administered every 10 minutes during the 

various exposure conditions revealed no differences for irritation of the nose or throat, dry or sore throat, 

stuffy or runny nose, sinus congestion, cough, wheezing, chest tightness, or shortness of breath when the 

subjects were exposed to MTBE or when they exposed to air. In a similar study, 19 healthy men and 

18 healthy women were exposed for 1 hour to clean air and 1.39 ppm MTBE in separate sessions at least 

1 week apart (Prah et al. 1994). The order of exposure was randomly selected, but because of the odor of 
METHYL tert-BUTYL ETHER 35 

2. HEALTH EFFECTS 

MTBE, it is likely that subjects were aware of the exposure conditions. Results of questionnaires 

administered prior to exposure, immediately upon entering the exposure chamber, after 30 minutes of 

exposure, and during the last 5 minutes of exposure revealed no differences for irritation of the nose, 

cough, wheezing, chest tightness, shortness of breath, stuffy or runny nose, or irritation of the throat. No 

differences were found for nasal inflammation by the determination of neutrophils, interleukin-8, albumin 

and prostaglandin D2 in nasal lavage material. Female subjects reported that the air quality in the MTBE 

condition was worse than in the clean air condition. The odor threshold was determined to be 

approximately 0.18 ppm. Thus, other than detection of the odor and the reported poor air quality in these 

experimental studies, no reactions to exposure to MTBE were observed or reported under the conditions of 

the studies. Although the exposure concentrations used in these experimental studies were chosen on the 

basis of airborne concentrations of MTBE to which commuters are exposed, the studies could not resolve 

whether multiple exposures, exposure to higher concentrations, and exposure for longer durations, which 

are more relevant for real-life exposure of motorists to MTBE, would have caused cumulative effects. 

In a study conducted to determine whether symptoms associated with MTBE were reported at an increased 

rate among subjects known to be sensitive to chemicals and in situations where exposure to MTBE was 

likely to be greatest, 14 individuals with multiple chemical sensitivities, 5 individuals with chronic fatigue 

syndrome, and 6 normal control individuals were interviewed regarding symptoms in response to 

situations in which gasoline containing MTBE was used (driving a car, gasoline stations) and not used 

(shopping malls, grocery stores, office buildings, parks) (Fiedler et al. 1994). The symptoms of interest 

included cough and burning sensation in the nose. Although multiple chemical sensitivity subjects and 

chronic fatigue syndrome subjects reported more symptoms than normal controls in some situations, no 

significant differences were found among the groups for driving a car or visiting gas stations. The authors 

concluded that the study did not provide clear evidence to support that an unusually high rate of symptoms 

or an increase of symptoms occurred uniquely where MTBE exposure was likely. 

Respiratory effects have been observed in animals following inhalation exposure to MTBE. A 4-hour 

exposure of rats to > 19,621 ppm ARCO MTBE (96.2% MTBE) caused hyperpnea, while a 4-hour 

exposure of rats to >18,892 ppm commercial MTBE (99.1% MTBE) caused tachypnea and nasal 

discharge, with respiration gradually slowing until the rats died (ARCO 1980). In a study to determine the 

RD50 (the concentration that results in 50% decrease in respiratory rate) for respiratory irritancy of MTBE, 

mice were exposed to 83,277,832, 2,774, or 8,321 ppm MTBE for 1 hour (Tepper et al. 1994). A 

threshold irritant response (13%) in respiratory rate occurred at 83 ppm, and a 52% decrease in breathing 

frequency occurred at 8,321 ppm. No pulmonary irritation was observed at < 2,774 ppm, but a mixed 
METHYL tert-BUTYL ETHER 36 

2. HEALTH EFFECTS 

pattern of irritant response, indicating both sensory and pulmonary irritation, occurred at 8,321 ppm. The 

RD50, indicative of sensory irritation, was determined to be 4,604 ppm. 

Intermittent exposure of rats for 9 days to concentrations of 1,000 or 3,000 ppm MTBE resulted in high 

incidence (27 of 40 in both groups) and increased severity of chronic inflammation of the nasal mucosa 

and trachea (Biodynamics 1981). In mated female rabbits exposed to < 8,000 ppm MTBE on 

gestational days 6 through 18, no gross lesions were observed in the respiratory tract of the exposed dams 

when sacrificed on gestational day 29 (Tyl 1989), but histological examination was not performed. 

However, labored breathing was observed in mouse dams exposed to 8,000 ppm, but not 1,000 or 

4,000 ppm, MTBE on gestational days 6-15 (Tyl and Neeper-Bradley 1989). Necropsy revealed color 

changes in the lungs of 1 dam in the control group, 3 dams in the 4,000 ppm group, and 5 dams in the 

8,000 ppm group, but histological examination was not performed. In rats exposed intermittently for 

16-28 weeks to concentrations < 2,500 ppm MTBE, nasal discharge and rales were among the most 

common observations, but control animals were reported to have similar types and incidences of these 

clinical signs (Biles et al. 1987). However, male and female rats exposed intermittently for 13 days or 

13 weeks to < 8,000 ppm had no gross or microscopic lesions in the lungs (Dodd and Kintigh 1989). Rats 

exposed intermittently for 13 weeks to 1,000 ppm MTBE had significant reductions in absolute and 

relative lung weights (Greenough et al. 1980). This appears to be a nonspecific effect; gross necropsy of 

the respiratory tract of males and females exposed to 250-l,000 ppm revealed froth in the airways, 

congestion of the lung tissues, and small grey foci over the lungs, but these changes were not sex- or doserelated. Rats of 

both sexes exposed intermittently for 14-19 weeks to concentrations < 8,000 MTBE 

showed no treatment-related lesions in the gross examination or in the histological evaluation of the upper 

and lower respiratory tract (Neeper-Bradley 1991). In chronic-duration inhalation studies in rats (Chun et 

al. 1992) and mice (Burleigh-Flayer et al. 1992) exposed intermittently to 400, 3,000, or 8,000 ppm 

MTBE, gross and histological examination of lungs, nasopharynx, trachea, and larynx revealed no 

treatment-related lesions. 

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after 

inhalation exposure to MTBE. 

MTBE does not appear to have adverse effects on the cardiovascular system of rats. No treatment-related 

gross or histopathological lesions in the heart were found in rats exposed intermittently for 9 days to 

< 3,000 ppm (Biodynamics 1981) or for 13 weeks to < 1,000 ppm (Greenough et al. 1980) or < 8,000 ppm 

(Dodd and Kintigh 1989). Similarly, histological examination of the aorta revealed no treatment-related 
METHYL tert-BUTYL ETHER 37 

2. HEALTH EFFECTS 

lesions following 13 weeks exposure to < 1,000 ppm MTBE (Greenough et al. 1980). In chronic-duration 

inhalation studies in rats (Chun et al. 1992) and mice (Burleigh-Flayer et al. 1992) exposed intermittently 

to 400, 3,000, or 8,000 ppm MTBE, gross and histological examination of the heart revealed no treatment-related lesions. 

Gastrointestinal Effects. Nausea or vomiting were among the symptoms reported by motorists or 

gas station workers during oxygenated fuel programs in which MTBE had been added to gasoline to 

reduce carbon monoxide emissions. Since these symptoms may be related to the neurological symptoms, 

the gastrointestinal symptoms are also discussed in Section 2.2.1.4. In a preliminary investigation to 

determine whether symptoms were occurring, whether symptoms occurred in a consistent pattern, and 

whether symptoms could be related to exposure to oxyfuel in Fairbanks, Alaska, nausea or vomiting was 

reported by 3 of 4 (75%) taxi drivers, 9 of 26 (35%) health-care workers, and 6 of 15 (40%) students who 

met the case definition (4 of 12 taxi drivers, 26 of 90 health-care workers, and 15 of 101 students) (Beller 

and Middaugh 1992). In the preliminary investigation in Anchorage, Alaska,, nausea or vomiting was 

reported by 5 of 12 (42%) taxi drivers and 9 of 36 (25%) health-care workers who met the case definition 

(12 of 25 taxi drivers and 36 of 137 health-care workers) (Chandler and Middaugh 1992). 

In the more definitive CDC study in Fairbanks, Alaska, the frequency of nausea or vomiting in the Phase I 

subjects, when the oxyfuel program was in full effect, was 6 of 18 in occupationally exposed workers 

(CDC 1993a; Moolenaar et al. 1994). In the Phase II subjects, after the oxyfuel program was terminated, 

the frequency of nausea or vomiting was 1 of 28. In the CDC study in Stamford, Connecticut, when the 

oxyfuel program was in full effect (no Phase II in Stamford), nausea or vomiting was reported by 1 of 48 

(2.1%) mechanics and gas station attendants, 0 of 57 (0%) professional drivers, I of 12 (8.3%) in “other” 

workers, and 0 of 59 (0%) commuters (CDC 1993b; White et al. 1995). 

In the telephone interview survey conducted in metropolitan Milwaukee, Wisconsin and in metropolitan 

Chicago, Illinois (where the use of reformulated gasoline was required in both of these areas) and in the 

rest of Wisconsin exclusive of metropolitan Milwaukee (where the use of reformulated gasoline was not 

required), the prevalence of nausea associated with MTBE exposure was statistically higher in Milwaukee 

than in either Chicago or Wisconsin; prevalence was not different between Chicago and Wisconsin for any 

symptom (Anderson et al. 1995). As discussed under Respiratory Effects in Section 2.2.1.2, these results 

suggest that factors other than reformulated gasoline use, such as knowledge about reformulated gasoline 

and the likely awareness of potential negative effects, significantly contributed to the differences in 

symptom prevalence between Milwaukee and the other two areas. 
METHYL tert-BUTYL ETHER 38 

2. HEALTH EFFECTS 

In a cross-sectional cohort study of self-reported symptoms of garage workers in the state of New Jersey 

exposed to high (115 workers in northern New Jersey during the wintertime oxyfuel program) and low 

(122 workers in southern New Jersey 10 weeks after the phase-out date for oxyfuel program) MTBE 

concentration environments, the results of the questionnaire regarding nausea over the last 30 days 

indicated that southern New Jersey workers experienced nausea (35%) more often than the northern New 

Jersey workers (27%) (p=0.03) (Mohr et al. 1994). 

In the study conducted in Albany, New York, the proportion of subjects who reported nausea was 2 of 34 

(6%) in Group 1 (automobile repair shop workers and service station attendants), 3 of 48 (6%) in Group 2 

(policemen, toll booth workers, and parking garage attendants), and 14 of 182 (8%) in Group 3 (office 

workers and college students) (CDC 1993c). Key symptoms were slightly more prevalent and the 

presence of 2 or more key symptoms was 2-3 times more prevalent in Groups 2 and 3 than in Group 1, but 

the increases were not statistically significant. Thus, no increase in health complaints among people with 

higher gasoline exposures was detected. 

In the study conducted to determine whether symptoms associated with MTBE were reported at an 

increased rate among subjects known to be sensitive to chemicals and in situations where exposure to 

MTBE was likely to be greatest, the symptoms of interest included gastrointestinal upset (Fiedler et al. 

1994). As discussed in the Respiratory Effects category in Section 2.2.1.2, although multiple chemical 

sensitivity subjects and chronic fatigue syndrome subjects reported more symptoms than normal controls 

in some situations, no significant differences were found among the groups for driving a car or visiting gas 

stations. The authors concluded that the study did not provide clear evidence that an unusually high rate 

of symptoms or an increase of symptoms occurred uniquely where MTBE exposure was likely. (See 

Respiratory Effects in Section 2.2.1.2 for a more complete discussion of the human studies regarding 

protocols, limitations, and conclusions.) 

The gastrointestinal tract was not affected in rats exposed to MTBE by inhalation. Intermittent exposure 

of rats for 9 days to 3,000 ppm MTBE caused no gross or histological changes of the stomach, duodenum, 

jejunum, ileum, colon, or rectum (Biodynamics 1981). Likewise, gastrointestinal tract tissue of rats 

exposed intermittently for 13 weeks to 8,000 ppm did not exhibit microscopic lesions (Dodd and Kintigh 

1989). Histological examination of the salivary glands, tongue, esophagus, and gastrointestinal tract 

revealed no treatment-related lesions in rats exposed intermittently for 13 weeks to 1,000 ppm (Greenough 

et al. 1980) or for 14-19 weeks to 8,000 ppm MTBE (Neeper-Bradley 1991). In chronic-duration 

inhalation studies in rats (Chun et al. 1992) and mice (Burleigh-Flayer et al. 1992) exposed intermittently 
METHYL tert-BUTYL ETHER 39 

2. HEALTH EFFECTS 

to 400, 3,000, or 8,000 ppm MTBE, gross and histological examination of the gastrointestinal tract 

revealed no treatment-related lesions. 

Hematological Effects. No studies were located regarding hematological effects in humans after 

inhalation exposure to MTBE. 

Rats exposed intermittently for 9 days to < 3,000 ppm MTBE had mean hematological values that were not 

significantly different from controls (Biodynamics 1981). Male and female rats exposed intermittently for 

13 weeks to 1,000 ppm MTBE exhibited a slight increase in white blood cell counts, while males also 

showed a slight but statistically significant increase in hemoglobin levels (Greenough et al. 1980). Both 

of these increases were considered of no biological or toxicological significance. All other hematological 

parameters were normal. Intermittent exposure of male rats for 13 weeks to 800, 4,000, or 8,000 ppm 

MTBE caused mild decreases (2-4%) in erythrocyte count and mean corpuscular hemoglobin 

concentration (MCHC) and mild increases (2-5%) in mean corpuscular volume (MCV), mean corpuscular 

hemoglobin (MCH), and reticulocytes (Dodd and Kintigh 1989). This exposure also induced a 15% 

decrease in the leukocyte count, primarily in the lymphocyte population, in male rats. At the end of the 

treatment period, female rats of the 8,000 ppm group had increased hematocrit and segmented neutrophil 

count. In chronic-duration inhalation studies in rats (Chun et al. 1992) and mice (Burleigh-Flayer et al. 

1992) exposed intermittently to 400, 3,000, or 8,000 ppm MTBE, no treatment-related changes in 

hematological parameters were found. In addition, histological examination of the bone marrow revealed 

no treatment-related lesions. 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after 

inhalation exposure to MTBE. 

Gross and histological examination of bone and skeletal muscle of rats revealed no treatment-related 

lesions following intermittent exposure to 3,000 ppm MTBE for 9 days (Biodynamics 1981) or to 

1,000 ppm for 13 weeks (Greenough et al. 1980). Similarly, an intermittent exposure for 13 weeks to 

concentrations < 8,000 ppm MTBE produced no microscopic lesions in bones of treated rats (Dodd and 

Kintigh 1989). Intermittent exposure for 2-l 5 weeks to 300 ppm MTBE did not affect muscle succinate 

dehydrogenase or acetylcholinesterase activities in rats (Savolainen et al. 1985). Muscle creatine kinase 

activity decreased at 2 weeks, returned to normal levels at week 10, and then significantly increased at 

I5 weeks in rats exposed to 100 or 300 ppm. These changes in creatine kinase activity were attributed to 

adaptation at the muscle level to MTBE exposure and were not considered adverse. In chronic-duration 
METHYL tert-BUTYL ETHER 40 

2. HEALTH EFFECTS 

inhalation studies in rats (Chun et al.1992) and mice (Burleigh-Flayer et al. 1992) exposed intermittently 

to 400, 3,000, or 8,000 ppm MTBE, gross and histological examination of the gastrocnemius muscle 

revealed no treatment-related lesions. No treatment-related histopathological lesions were found in the 

bone tissue of mice (Burleigh-Flayer et al. 1992); however, fibrous osteodystrophy, which was secondary 

to chronic progressive nephropathy, was observed in male rats at all concentrations and in female rats at 

3,000 and 8,000 ppm (Chun et al. 1992). As discussed for Renal Effects in Section 2.2.1.2, the higher 

incidence and greater severity of chronic progressive nephropathy at lower exposure concentrations in 

male rats compared with female rats may be due to the exacerbation of this syndrome by the accumulation 

of α2u,-globulin or another unknown protein unique to male rats. 

Hepatic Effects. No studies were located regarding hepatic effects in humans after inhalation 

exposure to MTBE. 

Acute-, intermediate-, or chronic-duration inhalation exposure to MTBE did not produce substantial 

hepatic toxicity in rats. Intermittent exposure for 9 days to < 3,000 ppm MTBE had no effect in serum 

glutamic-pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT), serum alkaline 

phosphatase, serum bilirubin, and serum cholesterol (Biodynamics 1981). Relative liver weights were 

significantly increased in both sexes of rats exposed to 3,000 ppm MTBE. In addition, exposure of male 

and female rats to MTBE intermittently for 13 days resulted in increased relative liver weights in both 

sexes at 8,000 ppm (17-24%) and 4,000 ppm (10-l 3%), and increased absolute liver weights in female 

rats at 8,000 ppm (21%) and 4,000 ppm (14%), but not in males (Dodd and Kintigh 1989). No changes in 

liver weight or gross liver lesions were observed in mated rats exposed to 2,500 ppm intermittently 

from day 6-l 5 of gestation (Conaway et al. 1985). At 8,000 ppm MTBE, liver weight of female rabbits 

exposed on gestational days 6-l8 was significantly increased (Tyl 1989). This increase probably resulted 

from induction of metabolizing enzymes. 

In rats exposed intermittently to 3,000 or 8,000 ppm, but not 400 ppm, MTBE for 4-5 weeks, increased 

absolute and/or relative liver weights occurred in both sexes (Chun and Kintigh 1993). No clinical or 

histological evidence of hepatic toxicity was found. Intermittent exposure of rats for 13 weeks to 

800-8,000 ppm MTBE caused an increase in liver weight that was greater in male rats than females (Dodd 

and Kintigh 1989). No treatment-related histopathological hepatic lesions were found. In some rats, there 

was a decrease in SGOT and SGPT, the toxicological significance of which is unclear. Intermittent 

exposure to 1,000 ppm MTBE for 13 weeks caused no histological lesions in rat liver, but caused a slight 

increase in serum lactic dehydrogenase levels in male rats and a decrease in females (Greenough et al. 
METHYL tert-BUTYL ETHER 41 

2. HEALTH EFFECTS 

1980). In a reproductive study, inhalation exposure of rats for 14-19 weeks to MTBE intermittently 

resulted in increased liver weight in F1 males at >3,000 ppm and in F1 females at 8,000 ppm, but no liver 

lesions were found (Neeper-Bradley 1991). Liver microsomal uridine diphosphate glucuronosyl 

transferase (UDPGT) activity was increased in a dose-related manner in rats exposed to 50, 100, and 

300 ppm MTBE for 2 weeks, but not at other times (Savolainen et al. 1985). The biological significance 

of this finding is not clear. Exposure to these levels for up to 15 weeks did not affect rat liver microsomal 

cytochrome P-450 content or the enzymatic activities of NADP-cytochrome c reductase or 

7-ethoxycoumarin 0-deethylase. Although induction of liver microsomal enzymes may be potentially 

adverse, other studies (Biodynamics 1981; Burleigh-Flayer et al. 1992; Chun and Kintigh 1993; Chun et 

al. 1992; Dodd and Kintigh 1989; Greenough et al. 1980) indicate that mild microscopic hepatic lesions 

and increased liver weight due to enzyme induction occur in animals only at much higher exposure levels. 

In male and female rats exposed intermittently to 400, 3,000, or 8,000 ppm MTBE for 24 months, 

increased absolute and relative liver weights (to both body weight and brain weight) in females were 

concentration-related at 3,000 and 8,000 ppm (Chun et al. 1992). However, gross and histological 

examination of the liver revealed no treatment-related lesions in females or males at any concentration. 

The increase in liver weight was probably due to microsomal enzyme induction, which may be considered 

potentially adverse. 

MTBE was slightly more toxic to the liver in mice than in rats. While a 10-day exposure of mated female 

mice on gestational days 6-15 to 2,500 ppm (Conaway et al. 1985) or 8,000 ppm (Tyl and Neeper-Bradley 

1989) MTBE produced no effect on liver weight, increased relative liver weights occurred in both sexes of 

mice exposed to 8,000 ppm (13-l 8%) and in females exposed to 4,000 ppm (12%) and 2,000 ppm (13%) 

MTBE intermittently for 13 days (Dodd and Kintigh 1989). Absolute liver weights were increased by 

16-20% in female mice at all exposure levels. Intermittent exposure of mice to 400, 3,000, or 8,000 ppm 

for 28 days also resulted in increased absolute and/or relative liver weight at 3,000 and 8,000 ppm in 

female mice and 8,000 ppm in male mice, and increased incidence of centrilobular hepatocellular 

hypertrophy in both sexes at 8,000 ppm (Chun and Kintigh 1993). In addition, in male and female mice 

exposed to 400, 3,000, or 8,000 ppm for 18 months, increased absolute and relative liver weights (to both 

body weight and brain weight) were concentration-related in both sexes at 3,000 and 8,000 ppm (BurleighFlayer et al. 1992). Increased liver weight in mice at 400 ppm was described as minimal. Gross 

examination of the livers revealed an increased incidence of liver masses in male and female mice exposed 

to 8,000 ppm. Histological examination revealed an increased incidence of hepatocellular hypertrophy in 

both sexes at 8,000 ppm and in males at 3,000 ppm. 
METHYL tert-BUTYL ETHER 42 

2. HEALTH EFFECTS 

In a special experiment for cell proliferation evaluations of hepatocytes, male and female mice were 

exposed to these concentrations for 5 or 23 exposures (Chun and Kintigh 1993). Significantly increased 

uptake of 5-bromo-2’-deoxyuridine in the nuclei of hepatocytes of female mice, but not male mice, was 

found at an exposure level of 8,000 ppm, but not <3,000 ppm, for 5 days. No increase in hepatocellular 

proliferation was found when mice were similarly exposed for 23 exposures. These results suggest that 

MTBE initially places an increased metabolic demand on liver cells resulting in a compensatory increase 

in hepatocellular proliferation that eventually leads to hepatocellular hypertrophy with longer exposure. 

Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to 

MTBE. 

Acute intermittent exposure for 9 days to concentrations ranging from 100 to 3,000 ppm MTBE produced 

no renal toxicity in rats-as indicated by the lack of effect on blood urea nitrogen (BUN) level and 

urinalysis and by the absence of gross and histological changes in the kidney and urinary bladder 

(Biodynamics 1981). Exposure of male and female rats to MTBE intermittently for 13 days resulted in 

increased relative kidney weights in males at 8,000 ppm (14%) and 4,000 ppm (8%) and absolute kidney 

weights in females at 8,000 ppm (8%) (Dodd and Kintigh 1989). Inhalation exposure of rats for 13 weeks 

to 1,000 ppm MTBE produced no histological changes of the kidneys and urinary bladder, but male rats 

exposed to 1,000 ppm exhibited significant increases in BUN (Greenough et al. 1980). No lesions were 

observed in the gross or histological examination in kidneys of rats exposed to < 8,000 ppm MTBE for 

14-19 weeks (Neeper-Bradley 1991). In another intermediate-duration study, exposure of rats to 

concentrations < 8,000 ppm MTBE had no effect on BUN, creatinine, or albumin levels, but concentrations 

of >800 ppm produced statistically significant increases in kidney weights that were greater in male than 

female rats (Dodd and Kintigh 1989). No histopathological changes in the kidneys were observed, but 

male rats exposed to 8,000 ppm had large hyaline droplets in the renal proximal tubules, an effect that may 

be specific to male rats. The finding of large hyaline droplets in the renal tubules of male rats suggests, 

but not definitively, the involvement of α2u-globulin accumulation. The accumulation of α2u-globulin 

complex leads to a nephropathy that is specific for male rats. Male, but not female, rats exposed to 

> 800 ppm MTBE for 13 weeks showed a treatment-related increase in area and intensity of α2u -globulin 

positive staining (Swenberg and Dietrich 1991). However, the α2u -globulin positive staining was not 

dose-related, and α2u-globulin positive proteinaceous casts at the junction of the proximal tubules and thin 

limb of Henle were not observed, unlike the classical lesions of other α2u-globulin inducing agents. 
METHYL tert-BUTYL ETHER 43 

2. HEALTH EFFECTS 

The possible involvement of α2u-globulin accumulation in MTBE-induced male rat nephropathy has been 

specifically examined using immunostaining with an antibody to α2u-globulin (Chun and Kintigh 1993). 

In this study, exposure of male and female rats to 400, 3,000, or 8,000 ppm MTBE for 4-5 weeks resulted 

in increased protein accumulation and proliferation of epithelial cells in the proximal convoluted tubules 

of male rats, but not female rats, at 3,000 and 8,000 ppm. However, no evidence of α2u-globulin 

accumulation was found, suggesting that a mechanism other than a α2u-globulin accumulation (perhaps the 

accumulation of another protein unique to male rats) may be responsible for the increased cell 

proliferation in the epithehal cells of the proximal convoluted tubules. The increased proliferation was 

also observed in males rats, but not female rats, after 5 exposures. Increased absolute and relative kidney 

weights were observed in male rats at 8,000 ppm and in female rats at >3,000 ppm after exposure for 

4-5 weeks. Urinalysis and urine chemistry evaluations revealed increased urine volume and decreased 

urinary pH in both sexes at 8,000 ppm, but there was no other indication of renal damage. No renal effects 

were observed in mice similarly exposed in this study. 

The effect of intermittent inhalation exposure to 50-300 ppm MTBE for 2-15 weeks on rat kidney 

microsomal enzymes has been studied (Savolainen et al. 1985). Cytochrome P-450 content was reported 

to be significantly increased only after 15 weeks of exposure to 100-300 ppm MTBE, while UDPGT and 

NADP-cytochrome c reductase activities were significantly increased only after 2 weeks of exposure. The 

enzymatic activity of 2-ethoxycoumarin 0-deethylase was not affected. Although induction of kidney 

microsomal enzymes may be potentially adverse, other studies (Biodynamics 1981; Burleigh-Flayer et al. 

1992; Chun and Kintigh 1993; Chun et al. 1992; Dodd and Kintigh 1989; Greenough et al. 1980) indicate 

that microscopic renal lesions and increased kidney weight due to enzyme induction occur in animals only 

at much higher exposure levels. 

In rats intermittently exposed to 400, 3,000, or 8,000 ppm MTBE for up to 24 months, increased absolute 

kidney weight and kidney weights relative to both body weight and brain weight were concentration- related 

in females at 3,000 and 8,000 ppm (Chun et al. 1992). Gross examination of kidneys revealed 

evidence of chronic progressive nephropathy in male rats at all concentrations and in female rats at 

3,000 and 8,000 ppm. Histological examination revealed increased incidence and severity of chronic 

progressive nephropathy, accompanied by fibrous osteodystrophy, hyperplasia in the parathyroid glands, 

and mineralization in numerous tissues. Chronic progressive nephropathy is an age-related spontaneous 

disorder of rats that is more severe in males than in females. The exacerbation of chronic progressive 

nephropathy by MTBE was concentration-related in males at all exposure concentrations and in females at 

3,000 and 8,000 ppm. No evidence of renal effects was found in the female rats at 400 ppm. The higher 
METHYL tert-BUTYL ETHER 44 

2. HEALTH EFFECTS 

incidence and greater severity of chronic progressive nephropathy at lower exposure concentrations in 

male rats as compared with female rats is consistent with the known greater susceptibility of male rats 

compared with female rats and may be due to the exacerbation of this syndrome by the accumulation of a 

unique protein in male rats (α2u-globulin or other unknown protein) induced by MTBE. Thus, the 

enhancement of chronic progressive nephropathy in male rats is generally not considered for MRL 

derivation. However, since female rats also had enhanced chronic progressive nephropathy, another 

mechanism not associated with α2u-globulin or other protein accumulation also appears to be involved. 

Therefore, the chronic inhalation MRL of 0.7 ppm was calculated based on the NOAEL of 400 ppm for 

kidney effects in female rats as described in the footnote in Table 2-I. The chronic-duration inhalation 

NOAEL for renal effects is also a NOAEL for clinical signs of neurotoxicity (see Section 2.2.1.4). 

In mice similarly exposed to 400, 3,000, or 8,000 ppm for 18 months, increased absolute and relative 

kidney weights (to both body weight and brain weight) were observed in male mice at all exposure 

concentrations and in female mice at 8,000 ppm (Burleigh-Flayer et al. 1992). The increase in kidney 

weight in males, however, was not concentration-related. Furthermore, gross and histological examination 

revealed no treatment-related lesions in the kidneys of mice. A slight increase in the pH of the urine in 

male and female mice at 8,000 ppm and a slight increase in the gamma globulin fraction in male mice at 

8,000 ppm were found upon urinalysis. Male mice exposed to 8,000 ppm were reported to have increased 

mortality and decreased mean survival time due to a slightly increased incidence of obstructive uropathy, 

which may have been due to the increases in pH and gamma globulin fraction. 

Endocrine Effects. No studies were located regarding endocrine effects in humans after inhalation 

exposure to MTBE. 

Acute intermittent exposure of rats to 100-3,000 ppm MTBE for 9 days produced no treatment-related 

lesions in the adrenals, pancreas, and thyroid/parathyroid glands (Biodynamics 1981). No treatment-related 

changes in adrenal weights were found. However, exposure of male and female rats to MTBE 

intermittently for 13 days resulted in increased relative and absolute adrenal weights in both sexes at 

8,000 ppm, but histological examination of the adrenal glands was not performed (Dodd and Kintigh 

1989). In mice exposed to <8,000 ppm MTBE for 28 days, no effects on thyroid weight and no 

histopathological lesions of the thyroid were found (Chun and Kintigh 1993). Special blood chemistry 

evaluation of total T3, total T4, thyroid stimulating hormone (TSH), total bile acid, and estradiol revealed 

that an increase in total T4 and TSH occurred in male mice at 8,000 ppm. However, these increases were 

not considered to be biologically significant due to the absence of histological evidence of thyroid lesions. 
METHYL tert-BUTYL ETHER 45 

2. HEALTH EFFECTS 

Decreases in total T4 were found in female mice in the special hepatic cell proliferation studies (see 

Hepatic Effects above), but net in the main study; therefore, the decrease in T4 was not considered 

exposure-related. Adrenal weights were significantly increased in male rats exposed to 8,000 ppm and in 

female rats exposed to 3,000 and 8,000 ppm for 4-5 weeks, but the adrenal glands were not examined 

histologically (Chun and Kintigh 1993). Although longer exposure (13 weeks) to high concentrations 

ranging from 800 to 8,000 ppm MTBE had no effect on serum aldosterone or adrenocorticotropic hormone 

levels in rats, there was an increase in corticosterone level at 8,000 ppm MTBE (Dodd and Kintigh 1989). 

Exposure to concentrations of 4,000 or 8,000 ppm MTBE produced increases in adrenal weight that were 

greater in male rats than females. No histopathological changes resulted from this treatment in the 

adrenals, pancreas, or pituitary glands. These results are in agreement with other intermediate-duration 

intermittent exposures of rats. In rats exposed to < 1,000 ppm MTBE, no treatment-related lesions were 

found in the pancreas, thyroid, parathyroid, adrenal, or pituitary (Greenough et al. 1980). Similarly, no 

exposure-related gross or microscopic lesions in the pancreas or pituitary were found in parental F0 and F1 

rats following exposure for 10 weeks prior to breeding to < 8,000 ppm for 5 days per week and through day 

19 of gestation (Neeper-Bradley 1991). 

In a 24-month study in which rats were exposed intermittently to 400, 3,000, or 8,000 ppm, decreased 

levels of corticosterone were found at 81 weeks in male rats exposed to 8,000 ppm (Chun et al. 1992). 

This group was terminated at week 82 because of high mortality from chronic progressive nephropathy. 

Hyperplasia of the parathyroid gland, which was secondary to chronic progressive nephropathy, was found 

in male rats at all exposure concentrations and in female rats at 3,000 and 8,000 ppm. No treatment-related 

histopathological lesions were found in the pituitary, adrenal gland, or pancreas. In mice similarly 

exposed to the same concentrations for 18 months, no treatment-related histopathological lesions were 

found in the pituitary, thyroid/parathyroid, or pancreas (Burleigh-Flayer et al. 1992). Adrenal gland 

weights were increased in high dose males, but were not accompanied by histopathological lesions. 

However, corticosterone levels were increased at week 79 in both sexes exposed to 8,000 ppm. The 

toxicological significance of these transient and inconsistent changes in corticosterone levels in rats and 

mice is questionable. 

Dermal Effects. In two experimental studies in which human subjects were exposed to MTBE vapors 

for 1 hour at 1.7 ppm (Cain et al. 1994) or 1.39 ppm (Prah et al. 1994), no evidence was found that 

exposure to MTBE vapors resulted in skin rash or dry skin. Rats and mice have been examined for dermal 

effects after exposure to MTBE vapors in air (Biles et al. 1987; Burleigh-Flayer et al. 1992; Chun et al. 

1992; Dodd and Kintigh 1989; Greenough et al. 1980). Since any dermal effects in these studies in 
METHYL tert-BUTYL ETHER 46 

2. HEALTH EFFECTS 

humans and animals would probably be due to direct contact of the skin with the vapor, these studies are 

discussed more fully in Section 2.2.3.2. 

Ocular Effects. Eye irritation was among the symptoms reported by motorists or gas station workers 

during oxygenated fuel programs in which MTBE had been added to gasoline to reduce carbon monoxide 

emissions. Several survey studies in humans (Anderson et al. 1995; Belier and Middaugh 1992; CDC 

1993a, 1993b, 1993c; Chandler and Middaugh 1992; Mohr et al. 1994; Moolenaar et al. 1994; White et al. 

1995) and experimental studies in humans (Cain et al. 1994; Prah et al. 1994) have investigated whether 

the eye irritation was specifically associated with exposure to MTBE vapor in air. In addition, rats and 

mice have been examined for ocular effects following exposure to MTBE vapors in air (ARCO 1980; Biles 

et al. 1987; Biodynamics 1981; Burleigh-Flayer et al. 1992; Chun et al. 1992; Conaway et al. 1985; Dodd 

and Kintigh 1989; Greenough et al. 1980; Neeper-Bradley 1991; Tyl and Neeper-Bradley 1989). Since 

any ocular effects in these studies in humans and animals would probably be due to direct contact of the 

eyes with the vapor, these studies are discussed in Section 2.2.3.2. 

Body Weight Effects. No studies were located regarding body weight effects in humans after 

inhalation exposure to MTBE. 

A single exposure of rats to < 8,000 ppm for 6 hours had no effect on body weight (Gill 1989). Acute 

exposure of rats intermittently for 9 days to < 3,000 ppm MTBE (Biodynamics 1981) or to < 2,500 ppm for 

10 days during gestational days 6-15 did not affect body weight (Conaway et al. 1985). In contrast, in rats 

exposed intermittently to 800, 4,000, or 8,000 ppm for 5 days, an unspecified weight loss in males and an 

unspecified decrease in body weight gain in females occurred at 8,000 ppm (Vergnes and Morabit 1989). 

Male rats of the 800 and 4,000 ppm groups had marginally depressed body weight gains during the 

exposure regimen. Similarly, a decrease in body weight gain of 65-66% occurred in male rats during the 

first l-3 and 1-14 days of exposure to 4,000 and 8,000 ppm, respectively, and a 36% decrease in body 

weight gain occurred in female rats during the first 1-7 days of exposure to 8,000 ppm in a preliminary 

13-day range-finding study for a 13-week study (Dodd and Kintigh 1989). In the 13-week study, transient 

decreases in body weight or body weight gain occurred during the first few weeks, accompanied by 

reduced food consumption, in the rats exposed to 4,000 or 8,000 ppm, but both body weight and food 

consumption recovered thereafter. Thus, compared with controls, final body weights were only 6% lower 

in male rats and 3% lower in female rats exposed to 8,000 ppm. The initial depressions in body weight 

were, therefore, probably due to the reduced food consumption, which in turn may have been secondary to 

the reduced motor activity of the 4,000 ppm and 8,000 ppm groups (Dodd and Kintigh 1989). In a 
METHYL tert-BUTYL ETHER 47 

2. HEALTH EFFECTS 

4-5-week study in rats, a 2% loss of body weight was observed in male rats exposed to 8,000 ppm during 

the first week, and decreased body weight gain occurred throughout the study in male rats exposed to 

8,000 ppm, with a decreased body weight gain as high as 49% from exposure days 1-12 (Chun and 

Kintigh 1993). Similarly, decreased body weight gain (24%) occurred in female rats exposed to 

8,000 ppm, but only during the first 2 weeks. Exposure of mated rabbits to > 4,000 ppm (Tyl 1989) and 

mated mice to 8,000 ppm (Tyl and Neeper-Bradley 1989) during gestation decreased body weight of the 

dams, and there was a reduction in food consumption. However, exposure of mice for 10 days during 

gestation to < 2,500 ppm MTBE did not affect the dams’ body weight (Conaway et al. 1985). Similarly, 

intermittent exposure of mice to < 8,000 ppm for 1 or 2 days (Vergnes and Kintigh 1993) for 13 days 

(Dodd and Kintigh 1989), or for 28 days (Chun and Kintigh 1993) had no effect on body weight. In 

intermediate-duration studies, no effects on body weight were found in rats exposed to 300-2,500 ppm 

(Biles et al. 1987; Greenough et al. 1980; Savolainen et al. 1985). However, male rats exposed to 

8,000 ppm for 14-19 weeks had a 10.3% reduction in body weight gain (Neeper-Bradley 1991). 

In a 24-month inhalation study in rats intermittently exposed to 400, 3,000, or 8,000 ppm MTBE, both 

male and female rats had decreased absolute body weight and decreased body weight gain at 8,000 ppm 

(Chun et al. 1992). In mice similarly exposed to the same concentrations for 18 months, slightly decreased 

absolute body weight and decreased body weight gain were observed in both sexes at 8,000 ppm 

(Burleigh-Flayer et al. 1992). 

2.2.1.3 Immunological and Lymphoreticular Effects 

Effects on the immune system were measured by monitoring plasma interleukin-6 levels in 22 volunteers 

exposed to auto emissions derived from oxyfuels during a 4-week period in late November and early 

December 1992 at several different locations around Fairbanks, Alaska (Duffy 1994). Blood samples were 

collected at the beginning of work shifts and the end of the workday and analyzed for interleukin-6 by an 

immunochemical assay. No differences in interleukin-6 levels were found between the morning and 

evening blood samples. 

In the experimental double-blind study in humans exposed sequentially to 1.7 ppm MTBE for 1 hour on 

1 day, to uncontaminated air for 1 hour 2 days later, and to 7.1 ppm of a 17-component mixture of VOCs 

for 1 hour 2 days later (or the reverse sequence) (see Respiratory Effects in Section 2.2.1.2), nasal lavage 

material and tear fluid from the eyes were stained for the total numbers of cells and differential counts for 

polymorphonuclear neutrophilic leukocytes, epithelial cells, monocytes, eosinophils, and lymphocytes 
METHYL tert-BUTYL ETHER 48 

2. HEALTH EFFECTS 

(Cain et al. 1994). No notable changes between pre- and postexposure values were observed for exposure 

to MTBE or air. 

Acute intermittent exposure of rats for 9 days to < 3,000 ppm MTBE did not produce gross or histological 

lesions in bone marrow, lymph nodes, or spleen (Biodynamics 1981). Similar results were obtained for 

lymph nodes of rats after exposure for 13 days to < 8,000 ppm MTBE (Dodd and Kintigh 1989). In rats 

and mice exposed to 400, 3,000 or 8,000 ppm for < 28 days, decreased absolute and relative spleen weights 

were found in both sexes of rats and in female mice, but not in male mice, at 8,000 ppm, but spleens were 

not examined histologically (Chun and Kintigh 1993). In some studies in which rats were exposed for 

13 weeks to 1,000 ppm (Greenough et al. 1980) or for 14-19 weeks to 8,000 ppm (Neeper-Bradley 1991), 

MTBE did not cause treatment-related gross or histopathological lesions in the spleen, thymus, or lymph 

nodes (Greenough et al. 1980; Neeper-Bradley 1991); in another study, however, exposure for 13 weeks to 

8,000 ppm of MTBE resulted in a higher incidence of lymphoid hyperplasia in submandibular lymph 

nodes in male rats (Dodd and Kintigh 1989). 

In rats exposed to 400, 3,000, or 8,000 ppm for 24 months, gross and histological examination revealed no 

treatment-related lesions in the spleen, lymph nodes, thymus, or bone marrow (Chun et al. 1992). In mice 

exposed to 400, 3,000, or 8,000 ppm for 18 months, absolute spleen weights were decreased in male and 

female mice at 8,000 ppm, but no treatment-related gross or histopathological lesions accompanied the 

decreased spleen weights (Burleigh-Flayer et al. 1992). Furthermore, no treatment-related lesions were 

found in the lymph nodes, thymus, or bone marrow. 

The highest NOAEL values for acute-, intermediate-, and chronic-duration inhalation exposure to MTBE 

for immunological and lymphoreticular effects in rats and mice and the LOAEL for lymphoid hyperplasia 

in rats after intermediate-duration inhalation exposure to MTBE are recorded in Table 2-l and plotted in 

Figure 2- 1. 

2.2.1.4 Neurological Effects 

Headache, nausea or vomiting, dizziness, and a feeling of spaciness or disorientation were among the 

symptoms reported by motorists or gas station workers during oxygenated fuel programs in which MTBE 

had been added to gasoline to reduce carbon monoxide emissions. In the preliminary investigation to 

determine whether symptoms were occurring, whether symptoms occurred in a consistent pattern, and 

whether symptoms could be related to exposure to oxyfuel in Fairbanks, Alaska, headache was reported by 
METHYL tert-BUTYL ETHER 49 

2. HEALTH EFFECTS 

3 of 4 (75%) taxi drivers, 21 of 26 (81%) health-care workers, and 10 of 15 (67%) students who met the 

case definition (4 of 12 taxi drivers, 26 of 90 health-care workers, and 15 of 101 students) (Beller and 

Middaugh 1992). Nausea or vomiting was reported by 3 of 4 (75%) taxi drivers, 9 of 26 (35%) health-care 

workers, and 6 of 15 (40%) students, and spaciness was reported by 1 of 4 (25%) taxi drivers, 1 of 26 (4%) 

health-care worker, and 2 of 15 ( 13%) students who met the case definition. In the preliminary 

investigation in Anchorage, Alaska, headache was reported by 11 of 12 (92%) taxi drivers and 31 of 36 

(86%) health-care workers who met the case definition (12 of 25 taxi drivers and 36 of 137 health-care 

workers) (Chandler and Middaugh 1992). Nausea or vomiting was reported by 5 of 12 (42%) taxi drivers 

and 9 of 36 (25%) health-care workers, dizziness was reported by 4 of 12 (33%) taxi drivers and 7 of 36 

(19%) health-care workers, and spaciness was reported by 4 of 12 (75%) taxi drivers and 3 of 36 (8%) of 

health-care workers. As discussed in the Respiratory Effects in Section 2.2.1.2, these investigations do not 

provide definitive evidence that these symptoms were due to the oxyfuel programs. 

In the more definitive CDC study in Fairbanks, Alaska, the frequency of headache in the Phase I subjects, 

when the oxyfuel program was in full effect, was 13 of 18 in occupationally exposed workers (CDC 

1993a; Moolenaar et al. 1994). Nausea or vomiting was reported by 6 of 18, dizziness by 8 of 18, and 

spaciness by 6 of 18 workers. In the Phase II subjects, after the oxyfuel program was terminated, the 

frequency of headache was 1 of 28, of nausea or vomiting was 1 of 28, of dizziness was 0 of 18, and of 

spaciness was 0 of 18. In the CDC study in Stamford, Connecticut, when the oxyfuel program was in full 

effect (no Phase II in Stamford), headache was reported by 13 of 48 (27.1%) at least once, 12 of 48 (25%) 

at least twice, and 4 of 48 (8.3%) at least 5 times in mechanics and gas station attendants; by 15 of 57 

(26.3%) at least once, 12 of 57 (21.1%) at least twice, and 5 of 57 (8.8%) at least 5 times in professional 

drivers; by 5 of 12 (41.7%) at least once, 5 of 12 (41.7%) at least twice, and 1 of 12 (8.3%) at least 5 times 

in “other” workers; and by 15 of 59 (25.4%) at least once, 14 of 59 (23.7%) at least twice, and 3 of 59 

(5.1%) at least 5 times in commuters (CDC 1993b; White et al. 1995). Nausea or vomiting was reported 

by 1 of 48 (2.1%) mechanics and gas station attendants, 0 of 57 (0%) professional drivers, 1 of 12 (8.3%) 

“other” workers, and 0 of 59 (0%) commuters. Dizziness was reported by 3 of 48 (6.3%) mechanics and 

gas station attendants, 3 of 57 (5.3%) professional drivers, 2 of 12 (16.7%) “other” workers, and 1 of 59 

(1.7%) commuters. Spaciness was reported by 5 of 48 (10.4%) mechanics and gas station attendants, 1 of 

57 (1.8%) professional drivers, 1 of 12 (8.3%) “other” workers, and 2 of 59 (3.4%) commuters. 

In the cross-sectional cohort study of self-reported symptoms of garage workers in the state of New Jersey 

exposed to high (115 workers in northern New Jersey during the wintertime oxyfuel program) and low 

(122 workers in southern New Jersey 10 weeks after the phase-out date for oxyfuel program) MTBE 
METHYL tert-BUTYL ETHER 50 

2. HEALTH EFFECTS 

concentration environments, the results of the questionnaire regarding headache (36% of northern workers, 

39% of southern workers, p=0.82), lightheadedness (10% of northern workers, 13% of southern workers, 

p=0.4 I), sleepiness while driving (20% of northern workers, 24% of southern workers, p=0.37), daytime 

sleepiness (13% of northern workers, 24% of southern workers, p=0.00l), and nausea (27% of northern 

workers, 35% of southern workers, p=0.03) over the last 30 days showed either no significant differences 

or a greater prevalence in southern workers (Mohr et al. 1994). 

In the study conducted in Albany, New York, the proportion of subjects who reported headache was 7 of 

34 (21%) in Group 1 (automobile repair shop workers and service station attendants), 23 of 48 (47%) in 

Group 2 (police officers, toll booth workers, and parking garage attendants), and 44 of 182 (24%) in 

Group 3 (office workers and college students) (CDC 1993c). The proportion of subjects who reported 

dizziness was 3 of 34 (9%) in Group 1, 6 of 48 (13%) in Group 2, and 5 of 182 (3%) in Group 3. The 

proportion of subjects who reported spaciness was 0 of 34 (0%) in Group 1, 2 of 48 (4%) in Group 2, and 

13 of 182 (7%) in Group 3. Nausea was reported by 2 of 34 (6%) Group 1 subjects, 3 of 48 (6%) Group 2 

subjects, and 14 of 182 (8%) Group 3 subjects. Key symptoms were slightly more prevalent and the 

presence of two or more key symptoms was 2-3 times more prevalent in Groups 2 and 3 than in Group 1, 

but the increases were not statistically significant. Thus, no increase in health complaints among people 

with higher gasoline exposures was detected. 

A telephone interview survey was conducted in metropolitan Milwaukee, Wisconsin, metropolitan 

Chicago, Illinois (use of reformulated gasoline was required in both of these areas), and in the rest of 

Wisconsin exclusive of metropolitan Milwaukee (where the use of reformulated gasoline was not 

required). Prevalence of headache, dizziness, and spaciness associated with MTBE exposure was 

statistically higher in Milwaukee than in either Chicago or Wisconsin; prevalence was not different 

between Chicago and Wisconsin for any symptom (Anderson et al. 1995). As discussed in the Respiratory 

Effects in Section 2.2.1.2, these results suggest that factors other than reformulated gasoline use, such as 

knowledge about reformulated gasoline and the likely awareness of potential negative effects, 

significantly contributed to the differences in symptom prevalence between Milwaukee and the other two 

areas. 

In the study conducted to determine whether symptoms associated with MTBE were reported at an 

increased rate among subjects known to be sensitive to chemicals and in situations where exposure to 

MTBE was likely to be greatest, the symptoms of interest included headache, dizziness, nausea, 

sleepiness, spaciness, and disorientation (Fiedler et al. 1994). Although multiple chemical sensitivity 
METHYL tert-BUTYL ETHER 51 

2. HEALTH EFFECTS 

subjects and chronic fatigue syndrome subjects reported more symptoms than normal controls in some 

situations, no significant differences were found among the groups for driving a car or visiting gas 

stations. The authors concluded that the study did not provide clear evidence to support that an unusually 

high rate of symptoms or an increase of symptoms occurred uniquely where MTBE exposure was likely. 

In the experimental double-blind study in humans exposed sequentially to 1.7 ppm MTBE for 1 hour on 

1 day, to uncontaminated air for 1 hour 2 days later, and to 7.1 ppm of a 17-component mixture of VOCs 

for 1 hour 2 days later (or the reverse sequence), neurobehavioral tests evaluating symbol-digit 

substitution, switching attention, and a profile of mood state (POMS) were administered at 1 hour before 

exposure and during the last 15 minutes of exposure (Cain et al. 1994). In addition, the subjects were 

administered questionnaires regarding subjective symptoms of headache; difficulty remembering things or 

concentrating; feelings of depression; unusual tiredness, fatigue or drowsiness; tension, irritability, or 

nervousness; dizziness or lightheadedness; mental fatigue or “fuzziness;” and pain or numbness in the 

hands or wrists. Results of statistical analysis of variance in the neurobehavioral tests revealed no 

differential effects across the three conditions of exposure to MTBE, air, or VOCs. No differences in 

reporting of symptoms were noted for exposure to MTBE versus exposure to air. In a similar study, 

19 healthy men and 18 healthy women were exposed for 1 hour to clean air and 1.39 ppm MTBE in 

separate sessions separated by at least 1 week (Prah et al. 1994). The order of exposure was randomly 

selected, but because of the odor of MTBE, it is likely that the subjects were aware of the exposure 

conditions. Analysis of the results of the questionnaires administered prior to exposure, immediately upon 

entering the exposure chamber, after 30 minutes of exposure, and during the last 5 minutes of exposure 

revealed no differences for headache, difficulty in memory or concentration, depressed feelings, unusual 

tiredness, fatigue, drowsiness, tension, irritability, nervousness, dizziness, lightheadedness, mental fatigue, 

“fuzziness,” or pain, stiffness, or numbness of the back, shoulders, neck, hands, or wrists. Specific 

neurobehavioral evaluation system tests, which consisted of symbol-digit substitution, switching attention, 

and mood scales, were completed as baseline before entering the chamber and after 45 minutes of 

exposure. No measures approached significance. (See Respiratory Effects in Section 2.2.1.2 for a more 

complete discussion of the human studies regarding protocols, limitations, and conclusions.) 

Acute inhalation exposure of laboratory animals to MTBE results in neurological deficits. Rats exposed to 

19,62 1 ppm ARCO MTBE (96.2% MTBE) exhibited lacrimation within 3 minutes of exposure (ARCO 

1980). After 4 hours of exposure, these animals developed ataxia, loss of righting reflex, hyperpnea, 

incoordination, and prostration. Similar effects were observed when the rats were exposed to 18,892 ppm 

of commercial MTBE (99.1 % MTBE). Similarly, in rats exposed to 400 or 8,000 ppm MTBE for 6 hours, 
METHYL tert-BUTYL ETHER 52 

2. HEALTH EFFECTS 

ataxia occurred within 0.5 hours and drowsiness occurred within 1.5 hours (Bioresearch Labs 1990d). In 

rats exposed intermittently to 4,000 or 8,000 ppm for 5 days, ataxia was noted at 8,000 ppm (Vergnes and 

Morabit 1989). In addition, clinical signs of neurotoxicity were observed in mice exposed intermittently 

for 2 days at 3,000 ppm (hypoactivity and lack of startle response) and at 8,000 ppm (hypoactivity, 

abdominal breathing, ataxia, and prostration) (Vergnes and Chun 1994). 

In rats studied for motor activity and given a functional observation battery of tests after a 6-hour exposure 

to 800, 4,000, or 8,000 ppm, concentration-related increases in incidence and severity of ataxia and duck- walk gait 

occurred in both males and females at 4,000 and 8,000 ppm (Gill 1989). Other effects noted in 

high-dose males included labored respiration pattern, decreased muscle tone, decreased performance on a 

treadmill, and increased hind limb splay. Other effects noted in females included decreased hind limb grip 

strength at > 4,000 ppm and labored respiration and increased latency to rotate on the inclined screen at 

8,000 ppm. These effects were seen at 1 hour after exposure, but not at 6 or 24 hours after exposure, 

indicating the transient nature. The time course of changes in motor activity corresponded with the 

functional observation battery findings, and supported the exposure-related central nervous system 

depression. No neurological effects were observed at 800 ppm for 6 hours. Based on this NOAEL, an 

acute-duration inhalation MRL of 2 ppm was calculated as described in the footnote in Table 2-l. 

In a preliminary 13-day range-finding study for a 13-week study, rats exposed to 4,000 and 8,000 ppm 

MTBE exhibited hypoactivity and ataxia as well as decreased startle and pain reflexes, and decreased 

muscle tone (Dodd and Kintigh 1989). The 2,000 ppm level also resulted in hypoactivity. Concentrations 

of 2,000 or 4,000 ppm did not produce neurobehavioral changes. In the 13-week study, hypoactivity was 

observed at 4,000 ppm and hypoactivity and ataxia were observed at 8,000 ppm daily after the 6 hour/day 

exposure, thus representing effects of acute exposure. Similarly, when rats and mice were exposed to 

MTBE at concentrations of 400, 3,000, and 8,000 ppm 6 hours per day, 5 days per week for < 28 days, 

ataxia, hypoactivity, and lack of startle response were observed at > 3,000 ppm during daily exposures 

(Chun and Kintigh 1993). The rats also showed blepharospasm. Exposure for 9 days to < 3,000 ppm 

showed no treatment-related lesions in rat brains (Biodynamics 1981). While no clinical signs were 

observed in mice exposed to < 8,000 ppm for 1 or 2 days (Vergnes and Kintigh 1993), in a 13-day study in 

mice, hypoactivity and ataxia occurred at 4,000 and 8,000 ppm during exposure, but only ataxia occurred 

following exposure in the 8,000 ppm group (Dodd and Kintigh 1989). Hypoactivity was also observed in 

the 2,000 ppm group during exposures on days 2 and 3, and prostration occurred in 2 of 5 females during 

exposure to 8,000 ppm on day 9. Also, mice exposed to 4,000 and 8,000 ppm MTBE on gestational days 

6-15 exhibited hypoactivity and ataxia (Tyl and Neeper-Bradley 1989). Mice also became prostrate at 
METHYL tert-BUTYL ETHER 53 

2. HEALTH EFFECTS 

8,000 ppm. Similar signs of toxicity were observed in rabbits exposed to < 8,000 ppm MTBE for I3 days 

during gestation (Tyl 1989). 

In a 13-week intermediate-duration study, MTBE induced anesthesia in rats exposed intermittently to 

250-l,000 ppm (Greenough et al. 1980), but the lowest concentration resulting in anesthesia was not 

specified. In these animals, MTBE did not result in histopathologic lesions in the brain or the sciatic 

nerve. In another 13-week study in rats, exposure to < 8,000 ppm did not affect relative brain weights and 

did not produce microscopic changes, but decreased hindlimb grip strength occurred in males exposed to 

4,000 ppm at 1, 2,4, 8, and 13 weeks; decreased motor activity occurred in males exposed to 8,000 ppm at 

week 8; and increased motor activity occurred in females exposed to 800 and 4,000 ppm at week 8 and at 

4,000 ppm at week 13 (Dodd and Kintigh 1989). Exposure of male and female rats for 10 weeks prior to 

mating and through day 19 of gestation to the concentration of 8,000 ppm MTBE resulted in salivation 

and hypoactivity in F0 and F1 parental rats (Neeper-Bradley 1991). F0 and F1 parental groups also showed 

hypoactivity and lack of startle response, as well as blepharospasm, at 3,000 ppm. A concentration of 

400 ppm did not produce any effects. Based on the NOAEL of 400 ppm, an intermediate-duration 

inhalation MRL of 0.7 ppm was calculated as described in the footnote in Table 2- 1. Neither rat brain 

succinate dehydrogenase nor acetylcholinesterase activity was affected by exposure for 15 weeks to 

50-300 ppm MTBE (Savolainen et al. 1985). 

In chronic-duration studies in which rats (Chun et al. 1992) and mice (Burleigh-Flayer et al. 1992) were 

intermittently exposed to 400, 3,000, or 8,000 ppm MTBE, clinical signs of neurotoxicity were observed at 

3,000 and/or 8,000 ppm in males and/or females. These signs consisted of blepharospasm, hypoactivity, 

ataxia, lack of startle reflex, salivation (rats), stereotypy (mice), and prostration (mice). Gross and 

histological examination of the brains, spinal cords, and sciatic nerves, however, revealed no treatment- related lesions 

in either species at any concentration. 

The highest NOAEL values and all LOAEL values for each reliable study for neurological effects in each 

species and duration category are recorded in Table 2-l and plotted in Figure 2- 1. 
METHYL tert-BUTYL ETHER 54 

2. HEALTH EFFECTS 

2.2.1.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after inhalation exposure to MTBE. 

Acute exposure to MTBE did not produce reproductive toxicity in experimental animals. Exposure of rats 

for 9 days to < 3,000 ppm MTBE did not result in gross or histological changes in the reproductive system 

of males or females (Biodynamics 1981). Also, studies on the potential developmental effects of MTBE 

showed no effects on the dams or the fetuses. Exposure of rats or mice for 10 days during gestation to 

< 2,500 ppm MTBE did not adversely affect the mean number of corpora lutea, uterine implantations, 

resorptions, or live fetuses (Conaway et al. 1985). Also, exposure of rabbits for 13 days (Tyl 1989) or 

mice for 10 days (Tyl and Neeper-Bradley 1989) to < 8,000 ppm MTBE during gestation did not cause 

gross lesions in the reproductive tract of the dams. This treatment did not affect the number of ovarian 

corpora lutea, number of total, nonviable, or viable implantations, proportion of pre- or postimplantation 

loss, fetal body weight, or sex ratio. Only gravid uterine weights were decreased in both species of dams 

exposed to 8,000 ppm. Exposure of male mice for 13 days at < 8,000 ppm MTBE neither produced 

microscopic lesions in testes, nor did it cause changes in testicular weight (Dodd and Kintigh 1989). 

A study on the effect of long-term exposure (16-28 weeks) to 250-2,500 ppm MTBE on fertility, 

reproductive systems, performance of male and female rats, and the development of offspring revealed that 

MTBE had no structural effect on the reproductive system or effect on reproductive performance of male 

and female rats (Biles et al. 1987). MTBE did not produce microscopic lesions in the prostate, testes, 

uterus, ovaries, or mammary tissues of rats exposed to < 8,000 ppm for 13 weeks (Dodd and Kintigh 1989; 

Greenough et al. 1980). A reproductive study was carried out in rats exposed to < 8,000 ppm MTBE for 

14-19 weeks including 10 weeks prebreeding period, l-3 weeks breeding period, 3 weeks gestational 

period, and for females, 3 weeks postnatal period (Neeper-Bradley 1991). This treatment had no effect on 

F0 and F1 reproductive parameters including gestational length and mating, fertility, and gestational 

indices. No histological lesions were seen in the vagina, uterus, ovaries, testes, epididymis, seminal 

vesicles, or prostate. 

In chronic-duration studies, in which male and female rats (Chun et al. 1992) and male and female mice 

(Burleigh-Flayer et al. 1992) were intermittently exposed to 400, 3,000, or 8,000 ppm MTBE, gross and 

histological examination of reproductive organs (testes, epididymides, prostate, seminal vesicles, ovaries, 

vagina, uterus, fallopian tubes, mammary glands) revealed no treatment-related lesions. 
METHYL tert-BUTYL ETHER 55 

2. HEALTH EFFECTS 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in 

each species and duration category are recorded in Table 2- 1 and plotted in Figure 2-I. 

2.2.1.6 Developmental Effects 

No studies were located regarding developmental effects in humans after inhalation exposure to MTBE. 

MTBE did not cause adverse developmental effects in rats and rabbits. Exposure of female rats during 

days 6-15 of gestation to < 2,500 ppm MTBE had no effect on percentage of resorption, percentage of live 

fetuses, mean fetal weights, crown-rump distances, incidence of external malformations, or the incidence 

of fetal soft-tissue and fetal skeletal malformations (Conaway et al. 1985). Similarly, exposure of rabbits 

during gestational days 6-18 to < 8,000 ppm did not change the number of total nonviable fetuses (such as 

early or late resorptions or dead fetuses), viable implantations, percentage of pre- or postimplantation loss, 

fetal body weight, or sex ratio (Tyl 1989). This treatment did not increase the incidence of fetal 

malformations. 

MTBE has been found to produce dose-dependent developmental effects in mice. Exposure for 

10 gestational days to 250-2,500 ppm MTBE had no effects on percentage of resorption, percentage of 

live fetuses, mean fetal weights, crown-rump distances, incidence of external malformations, or the 

incidence of fetal soft-tissue malformations (Conaway et al. 1985). In this study, a slight but not 

statistically significant increase in fused sternebrae was observed in the offspring of all exposed groups, 

while no fused sternebrae were present in controls. Thus, while no treatment-related developmental 

effects were found in mice at < 2,500 ppm (Conaway et al. 1985), exposure of mice to a higher 

concentration (8,000 ppm) of MTBE resulted in the following developmental effects: increased number of 

nonviable implantations per litter; increased late resorption; and reduced number of viable implantations, 

sex ratio (% male fetuses), and fetal body weight (Tyl and Neeper-Bradley 1989). Mice exposed to 

8,000 ppm MTBE also exhibited a significant increase in the incidence of cleft palate and a significant 

reduction in the incidence of partial fetal atelectasis. Skeletal malformations included the following 

regions: cervical centra, thoracic centra, caudal centra, skull plates/bones, forepaws, hindpaws, and 

sternebrae. At 4,000 ppm, there was an increased incidence of reduced skeletal ossification, and reduced 

fetal body weight. Maternal toxicity consisted of reduced maternal body weight, reduced maternal weight 

gain, and reduced food consumption at 8,000 ppm and increased incidence of treatment-related clinical 

signs of central nervous system depression at 4,000 and 8,000 ppm. The authors speculated that the cleft 

palate could have resulted from maternal stress, which may be related to elevated endogenous maternal 
METHYL tert-BUTYL ETHER 56 

2. HEALTH EFFECTS 

blood levels of corticosterone (see Endocrine Effects in Section 2.2.1.2), which may produce cleft palate in 

susceptible strains of mice. 

Long-term exposure of male and female rats to 250-2,500 ppm MTBE during premating and gestational 

periods for a total of 16-28 weeks (without exposing the litters) had no effect on the offspring when the 

following parameters were determined: pup viability, mean pup body weight, and renal pelvises (Biles et 

al. 1987). Exposure of rats for 10 weeks prior to mating, 3 weeks during gestation, and 3 weeks during 

postnatal period to 400, 3,000, or 8,000 ppm MTBE had no effects on pups except for reduced body 

weights at 3,000 and 8,000 ppm (Neeper-Bradley 1991). Maternal exposure to MTBE did not affect the 

total number of live and stillborn F1 or F2 litter size or sex ratio. MTBE did not affect F1 or F2 pup live 

birth and survival indices. At 8,000 ppm, pup weights were significantly reduced in F2 pups from 

lactational day 7 to lactational day 28. Significant weight reductions were also observed in F2 pups from 

lactational day 14 to lactational day 28 at 3,000 ppm. Significant weight gain reductions were observed 

during most of the lactational period at 3,000 and 8,000 ppm. 

The highest NOAEL values and all LOAEL values from each reliable study for developmental effects in 

each species and for each duration category are recorded in Table 2-1 and plotted in Figure 2-l. 

2.2.1.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans after inhalation exposure to MTBE. 

Whole body inhalation exposure of male and female Fischer 344 rats to 800, 4,000, and 8,000 ppm MTBE 

vapor for 6 hours per day for 5 days resulted in no concentration-related increase or significant increase in 

the number of chromosomal aberrations at any concentration compared with unexposed controls (Vergnes 

and Morabit 1989). Similarly, no statistically significant increases in the incidence of micronucleated 

polychromatic erythrocytes (Vergnes and Kintigh 1993) or increases in DNA repair in cultured primary 

hepatocytes (Vergnes and Chun 1994) were found in male or female CD-l mice exposed to 400, 3,000, or 

8,000 ppm MTBE for 6 hours per day for 1 or 2 days compared with controls. However, in the Vergnes 

and Chun (1994) study, the MTBE exposed mice were sacrificed 18 hours after the second exposure, 

which may have been too late to detect DNA repair. The positive control mice, which were treated 

intraperitoneally with N-nitrosodemethylamine at 10 mg/kg, were sacrificed 2 hours after the dose and 

showed increased DNA repair. Other genotoxicity studies are discussed in Section 2.5. 
METHYL tert-BUTYL ETHER 57 

2. HEALTH EFFECTS 

2.2.1.8. Cancer 

No studies were located regarding cancer in humans after inhalation exposure to MTBE. 

In a 24-month inhalation study, in which rats were intermittently exposed to 400, 3,000, or 8,000 ppm 

MTBE, increased mortality occurred in males exposed to 3,000 and 8,000 ppm due to chronic progressive 

nephropathy (Chun et al. 1992). These groups were terminated at 97 and 82 weeks, respectively. 

Increased incidences of renal tubular cell adenoma and carcinoma were observed in male rats at 3,000 and 

8,000 ppm. The incidences of renal tubular adenoma and carcinoma (combined) were 1 of 50 in controls, 

0 of 50 at 400 ppm, 8 of 50 at 3,000 ppm, and 3 of 50 at 8,000 ppm. Renal tubular cell carcinomas were 

observed only in the 3,000 ppm group at an incidence of 3 of 50. The increase was statistically significant 

at 3,000 ppm (p=0.015), although not at 8,000 ppm. Since the rats in these groups had increased mortality 

and decreased survival time, it is possible that the number of tumor-bearing rats might have increased if 

they had survived longer. These renal tumors may have resulted from accumulation of α2u-globulin or 

other protein unique to male rats (see Renal Effects in Section 2.2.1.2) in the renal tubular cells. In 

addition, a dose-related increased incidence of interstitial cell adenoma in the testes was observed at 3,000 

and 8,000 ppm. The incidence was 32 of 50 in controls, 33 of 50 at 400 ppm, 41 of 50 at 3,000 ppm, and 

47 of 50 at 8,000 ppm. However, Fischer 344 rats commonly develop testicular tumors, as seen from the 

high incidence in the concurrent control group. Furthermore, the incidences in the mid- and high-dose 

groups were in the range of historic controls, while the incidence in the concurrent control group was 

lower than the incidence in historic controls. 

In an 18-month inhalation study, in which mice were intermittently exposed to 400, 3,000, or 8,000 ppm 

MTBE, an increased incidence of hepatocellular adenoma was observed in female mice at 8,000 ppm 

(10 of 50 compared with 2 of 50 in controls, 1 of 50 at 400 ppm, and 2 of 50 at 3,000 ppm) (BurleighFlayer et al. 1992). Male mice exposed to 8,000 ppm also had increased incidences of hepatocellular 

adenoma and carcinoma. The incidences of the hepatic tumors (adenoma and carcinoma combined) were 

12 of 49 in controls, 12 of 50 at 400 ppm, 12 of 50 at 3,000 ppm and 16 of 49 at 8,000 ppm. The 

incidences of hepatocellular carcinoma alone in male mice were 2 of 49 in controls and 8 of 49 at 

8,000 ppm (p=0.045). The incidence of combined hepatocellular adenoma and carcinoma in high-dose 

males was reported to be within the range seen in historic controls; therefore, the authors suggested that 

the increased incidence of hepatic neoplasms in male mice may not have been due to MTBE exposure. 

However, the increased incidence of hepatocellular carcinoma in the high-dose males was statistically 

significant compared with the concurrent control, suggesting that the increase was due to MTBE exposure. 
METHYL tert-BUTYL ETHER 58 

2. HEALTH EFFECTS 

Furthermore, the increased incidence of hepatocellular adenoma in high-dose females was attributed to 

MTBE exposure. 

The cancer effect levels (CELs) are recorded in Table 2- 1 and plotted in Figure 2-1. 

2.2.2 Oral Exposure 

2.2.2.1 Death 

No studies were located regarding death in humans after oral exposure to MTBE. 

MTBE has a low oral acute toxicity in experimental animals. Its oral LD50 (lethal dose, 50% kill) was 

determined by administering the undiluted MTBE by gavage to rats of both sexes and was found to be 

3,866 mg/kg (ARCO 1980). The low acute toxicity of MTBE has also been documented in the mouse with 

a reported oral LD50 of 4,000 mg/kg (Little et al. 1979). No treatment-related deaths were observed in rats 

given MTBE by gavage in water at 400 mg/kg (Bioresearch Labs 1990a) or in rats given MTBE by gavage 

in oil at < 1,428 mg/kg/day for 14 days (Robinson et al. 1990). No deaths in male or female rats resulted 

from oral gavage doses of 90-l,750 mg/kg/day MTBE for 4 weeks (ITT Research Institute 1992) or 

100-l,200 mg/kg/day for 90 days (Robinson et al. 1990). Similarly, no deaths in male or female mice 

resulted from oral gavage doses of < 1,000 mg/kg/day for 3 weeks (Ward et al. 1994). However, in a 

104-week carcinogenicity study, in which male and female rats were given gavage doses of 250 or 

1,000 mg/kg/day, 4 days per week, a dose-related increased mortality was observed in female rats, 

beginning at 16 weeks from the start of the study (Belpoggi et al. 1995). The LD50 values in rats and mice 

and the intermediate LOAEL value for increased mortality in female rats are recorded in Table 2-2 and 

plotted in Figure 2-2. 

2.2.2.2 Systemic Effects 

No studies were located regarding systemic effects in humans after oral exposure to MTBE. The systemic 

effects observed in animals after oral exposure to MTBE are discussed below. The highest NOAEL values 

and all LOAEL values from each reliable study for systemic effects in each species and duration category 

are recorded in Table 2-2 and plotted in Figure 2-2. 










METHYL tert-BUTYL ETHER 69 

2. HEALTH EFFECTS 

Respiratory Effects. High oral doses (> 4,080 mg/kg) of MTBE caused labored respiration in rats 

(ARCO 1980). This treatment, however, did not produce grossly observable changes in the major organ 

systems at 1,900 mg/kg, and at higher doses (> 2,450 mg/kg) the few gross signs were attributed to the 

irritating nature of MTBE. In rats given daily oral doses of 357, 714, 1,071, or 1,428 mg/kg/day for 

14 days, absolute and relative lung weight was decreased at all doses in female rats but only at 

714 mg/kg/day in male rats (Robinson et al. 1990). Histological examination of the lungs, however, 

revealed no treatment-related lesions at any dose: No gross lesions were found in the lungs, larynx, nasal 

turbinates, or trachea, and no histopathological lesions were found in the lungs or trachea (other 

respiratory tissues were not examined microscopically) of rats given < 1,750 mg/kg/day for 4 weeks 

(ITT Research Institute 1992). Similarly, while absolute and relative lung weights were significantly 

increased in males gavaged with 1,200 mg/kg/day MTBE for 90 days, no significant changes in lung 

weights were found in female rats, and no treatment-related histopathological lesions were found in the 

lungs of either sex at any dose (100-l,200 mg/kg/day) (Robinson et al. 1990). In a 104-week study, in 

which male and female rats were given gavage doses of 250 or 1,000 mg/kg/day, 4 days per week, 

histological examination of the nasal cavity, pharynx, larynx, diaphragm, trachea, lung, and mainstream 

bronchi revealed no treatment-related lesions (Belpoggi et al. 1995). 

Cardiovascular Effects. Based on histological examination of the heart and aorta of rats, oral 

exposure to MTBE appears to be without effects on the cardiovascular system. Daily oral administration 

of < 1,428 mg/kg/day MTBE for 14 days had no significant effects on heart weights and did not produce 

histopathological lesions in the heart (Robinson et al. 1990). Histological examination of the heart and 

aorta of rats given < 1,750 mg/kg/day for 4 weeks revealed no treatment-related lesions (ITT Research 

Institute 1992). While heart weights were significantly increased in female rats given a daily oral dose of 

900 mg/kg/day MTBE for 90 days, no accompanying pathological lesions were found in the heart of either 

sex at doses < 1,200 mg/kg/day (Robinson et al. 1990). In a 104-week study, in which male and female 

rats were given gavage doses of 250 or 1,000 mg/kg/day, 4 days per week, histological examination of the 

heart revealed no treatment-related lesions (Belpoggi et al. 1995). 

Gastrointestinal Effects. MTBE appears to be irritating to the gastrointestinal tract of rats as 

evidenced by diarrhea and histological lesions. Rats treated with daily oral doses > 357 mg/kg/day MTBE 

had diarrhea by the third day of dosing, which continued throughout the 14-day treatment period 

(Robinson et al. 1990). Similarly, when MTBE was orally administered daily to rats for 90 days at 

> 100 mg/kg/day, it produced diarrhea immediately after dosing throughout the exposure period (Robinson 

et al. 1990). Daily oral administration for 4 weeks of 1,750 mg/kg/day MTBE to rats produced no gross 
METHYL tert-BUTYL ETHER 70 

2. HEALTH EFFECTS 

pathological changes in the duodenum, jejunum, ilium, cecum, colon, rectum, salivary glands, stomach, or 

tongue (ITT Research Institute 1992). Histopathological changes, however, were seen as submucosal 

edema, subacute inflammation, epithelial hyperplasia, and ulceration in the stomach of male and female 

rats given 1,750 mg/kg/day MTBE. In a 104-week study, in which male and female rats were given 

gavage doses of 250 or 1,000 mg/kg/day, 4 days per week, histological examination of the oral cavity, 

salivary glands, tongue, esophagus, stomach (fore and glandular), and intestines (4 levels) revealed no 

treatment-related lesions (Belpoggi et al. 1995). 

Hematological Effects. In some male rats treated with daily oral doses of MTBE for 14 days, 

elevated red blood cell, hemoglobin, hematocrit, and lymphocyte values were seen at doses 

> 714 mg/kg/day, but monocyte values were significantly reduced at > 357 mg/kg/day (Robinson et al. 

1990). Male rats given an oral dose of 440 mg/kg/day MTBE for 4 weeks had significantly increased 

mean red blood cell counts, while female rats given 90 and 1,750 mg/kg/day had significantly increased 

MCH (ITT Research Institute 1992). The toxicological significance of these changes is not certain since 

they are not dose-related and no other hematological effects were noted. No pathology was seen in the 

femur, sternum, or bone marrow. In a 90-day oral administration study, male rats had increased 

monocytes and decreased MCV at 1,200 mg/kg/day (Robinson et al. 1990). Female rats given 

1,200 mglkglday MTBE showed elevated levels of erythrocytes, hemoglobin, and hematocrit, while 

leukocyte counts were significantly reduced. This hemoconcentration might have resulted from the 

clinical dehydration condition associated with diarrhea observed in these animals instead of being a direct 

effect of MTBE. 

Musculoskeletal Effects. Daily oral administration of < 1,750 mg/kg MTBE to rats for 4 weeks did 

not produce gross pathology in the femur, sternum (bone marrow) or bone marrow smear, or skeletal 

muscle, nor histopathological changes in skeletal muscle or in the sternum (femur and bone marrow 

smears were not examined microscopically) (ITT Research Institute 1992). In a 104-week study, in which 

male and female rats were given gavage doses of 250 or 1,000 mg/kg/day, 4 days per week, histological 

examination of the cranium (5 levels) revealed no treatment-related lesions (Belpoggi et al. 1995). 

Hepatic Effects. Relative, but not absolute, liver weights were increased in rats given a daily large 

oral dose (1,428 mg/kg/day) of MTBE for 14 days (Robinson et al. 1990). Although this treatment did not 

produce histopathological lesions in the liver, it significantly increased SGOT and lactic dehydrogenase 

levels in male rats at 1,071 mg/kg/day and significantly decreased BUN levels in female rats at 

1,428 mg/kg/day. In the 90-day study, relative liver weights were significantly increased in female rats at 
METHYL tert-BUTYL ETHER 71 

2. HEALTH EFFECTS 

900 mg/kg/day and in male rats at 900 and 1,200 mg/kg/day (Robinson et al. 1990). BUN levels were 

significantly decreased in both males and females at > 100 mg/kg/day. Serum lactic dehydrogenase was 

significantly elevated in females only at 300 mg/kg/day, and SGOT was significantly elevated in males at 

300 and 1,200 mg/kg/day. However, no treatment-related histopathological lesions were found in the liver 

in either the 14-day study or the 90-day study. Liver weight was increased in rats following daily oral 

doses of 1,750 mg/kg/day for 4 weeks of MTBE in rats (ITT Research Institute 1992). No treatment- related 

gross or microscopic lesions were seen in the liver. In a 104-week study, in which male and female 

rats were given gavage doses of 250 or 1,000 mg/kg/day, 4 days per week, histological examination of the 

liver revealed no treatment-related lesions (Belpoggi et al. 1995). Based on the LOAEL of 100 mg/kg/day 

for decreased BUN levels in male and female rats in the 90-day study (Robinson et al. 1990), an 

intermediate-duration oral MRL of 0.3 mg/kg/day was calculated as described in the footnote to Table 2-2. 

Renal Effects. Large daily oral doses of MTBE for 14 days increased relative but not absolute kidney 

weight in rats at 1,428 mg/kg/day (Robinson et al. 1990). Serum creatinine was significantly elevated in 

male rats, while being reduced in females treated with MTBE. The toxicological significance of this 

change is not clear. Daily oral treatment with 1,428 mg/kg/day of MTBE for 14 days also resulted in a 

renal tubular disorder characterized by increased hyaline droplets in male rats (Robinson et al. 1990). 

Similar results were obtained following an oral dose of 440 mg/kg/day of MTBE for 4 weeks (ITT 

Research Institute 1992). Severe tubular changes, which consisted of mild increases in cytoplasmic 

hyaline droplets in proximal tubular cells and small numbers of intratubular granular casts at the junction 

of the outer and inner stripe of the outer medulla, were seen in male rats, but not female rats, following 

gavage doses of 1,200 mg/kg/day MTBE, but not < 900 mg/kg/day (Robinson et al. 1990). However, in a 

104-week study, in which male and female rats were given gavage doses of 250 or 1,000 mg/kg/day, 

4 days per week, histological examination of the kidneys and urinary bladder revealed no treatment-related 

lesions (Belpoggi et al. 1995). 

Endocrine Effects. Daily oral administration of MTBE for 14 days neither affected adrenal gland 

weights nor did it produce histopathological lesions in the adrenals (Robinson et al. 1990). On the other 

hand, female rats given 1,200 mg/kg/day MTBE for 90 days showed significantly elevated relative adrenal 

gland weight, but no histopathological lesions were observed in males or females at < 1,200 mg/kg/day 

(Robinson et al. 1990). In a 4-week study, a dose of 1,750 mg/kg/day in rats resulted in a significant 

increase in relative adrenal weight in males, but no gross or histopathological lesions were found in the 

adrenal gland, pancreas, parathyroids, pituitary, or thyroid (ITT Research Institute 1992). Similarly, in a 

104-week study, in which male and female rats were given gavage doses of 250 or 1,000 mg/kg/day, 
METHYL tert-BUTYL ETHER 72 

2. HEALTH EFFECTS 

4 days per week, histological examination of the pituitary gland, Zymbal gland, thyroid, parathyroid, 

pancreas, and adrenal glands revealed no treatment-related lesions (Belpoggi et al. 1995). 

Dermal Effects. No gross or histopathological lesions were found on the skin of rats dosed orally with 

1,750 mg/kg/day MTBE for 4 weeks (ITT Research Institute 1992). Similarly, in a 104-week study, in 

which male and female rats were given gavage doses of 250 or 1,000 mg/kg/day, 4 days per week, 

histological examination of the skin and subcutaneous tissues revealed no treatment-related lesions 

(Belpoggi et al. 1995). 

Ocular Effects. No gross lesions were found in the eyes, exorbital lachrymal glands, or Harderian 

glands, and no histopathological lesions were found in the eyes (glands not examined microscopically) in 

rats dosed orally with < 1,750 mg/kg/day MTBE for 4 weeks (ITT Research Institute 1992). 

Body Weight Effects. High daily oral doses of MTBE for 14 days caused significant decreases in 

body weight of female rats and in weight gain of males (Robinson et al. 1990); however, the percentage 

decrease can not be determined from the data. These results may be related to the significant decrease in 

food intake in treated rats, secondary to the hypoactivity induced by MTBE (see Section 2.2.2.4). In 

contrast, daily oral doses of up to 1,750 mg/kg/day for 4 weeks (ITT Research Institute 1992) or 

1,200 mg/kg/day for 90 days (Robinson et al. 1990) did not cause any body weight change in treated rats. 

In addition, no changes in body weight were found in mice given < 1,000 mg/kg/day MTBE by gavage 

5 days per week for 3 weeks (Ward et al. 1994). Similarly, in a 104-week study, in which male and female 

rats were given gavage doses of 250 or 1,000 mg/kglday, 4 days per week, no treatment-related differences 

between treated and control rats were found for water and food consumption or body weight changes 

(Belpoggi et al. 1995). 

Other Systemic Effects. Elevated cholesterol levels were consistent findings in rats dosed orally 

with 714 mg/kg/day (females) or 1,428 mg/kg/day (males) for 14 days (Robinson et al. 1990), 

1,750 mg/kglday for 4 weeks (ITT Research Institute 1992), and 100 mg/kg/day (females) or 

900 mg/kg/day (males) for 90 days (Robinson et al. 1990). 
METHYL tert-BUTYL ETHER 73 

2. HEALTH EFFECTS 

2.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological or lymphoreticular effects in humans after oral exposure 

to MTBE. 

Oral administration of 1,428 mg/kg/day MTBE for 14 days significantly reduced absolute spleen weight 

and absolute and relative thymus weights in female rats but not males (Robinson et al. 1990). This 

treatment did not produce histopathological lesions in the spleen or thymus. Similar results were obtained 

following 90 days treatment with an oral daily dose of 100 to 1,200 mg/kg MTBE (Robinson et al. 1990). 

Also, rats given < 1,750 mg/kg/day MTBE orally for 4 weeks had no pathology in the bone marrow, 

mesenteric lymph nodes, mandibular lymph nodes, spleen, or thymus (ITT Research Institute 1992). This 

treatment did not produce microscopic histopathological changes in all tissues examined (i.e., mesenteric 

lymph nodes, spleen, or thymus). However, in a 104-week study, in which male and female rats were 

given gavage doses of 250 or 1,000 mg/kg/day, 4 days per week, an increased incidence of dysplastic 

proliferation of lymphoreticular tissues (hyperplastic lymphoid tissues, at various body sites, consisting of 

atypical lymphoid cells, usually lymphoimmunoblasts) was observed in females at both doses (Belpoggi et 

al. 1995). The increase was greater at the low dose than at the high dose. Since dose-related increased 

incidences of lymphomas and leukemia were observed in the female rats (see Section 2.2.2.8), more of the 

dysplastic proliferation lesions might have developed into the lymphomas and leukemias in the high dose 

female, suggesting that the dysplastic proliferation represents a preneoplastic lesion. No histopathological 

lesions were found in the spleen or thymus. The highest NOAEL values and the LOAEL value for 

lymphoreticular effects in rats in each study in each duration category are recorded in Table 2-2 and 

plotted in Figure 2-2. 

2.2.2.4 Neurological Effects 

No studies were located regarding neurological effects in humans after oral exposure to MTBE. 

The immediate acute effect of orally administered MTBE is on the central nervous system. Acute oral 

doses caused marked central nervous system depression, ataxia, tremors, labored breathing, and loss of 

righting reflex in rats at doses > 4,080 mg/kg, loss of righting reflex and ataxia at 3,160 mg/kg, ataxia at 

2,450 mg/kg and slight to marked central nervous system depression at 1,900 mg/kg (ARCO 1980). Onset 

of neurological signs was rapid, but they disappeared or were markedly reduced within 24 hours. Another 

study in rats reported drowsiness, which subsided within 24 hours after a single oral dose of 400 mg/kg 
METHYL tert-BUTYL ETHER 74 

2. HEALTH EFFECTS 

(Bioresearch Labs 1990b). A NOAEL of 40 mg/kg for neurological effects for acute oral exposure was 

identified in the Bioresearch Labs (1990b) study. Based on this NOAEL value, an acute oral MRL of 

0.4 mg/kg/day was calculated as described in the footnote to Table 2-2. Large daily oral doses of 

1,428 mg/kg/day MTBE for l-14 days in rats also resulted in profound anesthesia soon after treatment, 

with subsequent recovery of motor and sensory functions within 2 hours of dosing (Robinson et al. 1990). 

Male rats given 1,428 mg/kg/day for 14 days had significantly reduced brain weights, while female rats 

given the same dose had significantly increased relative brain weights. However, no histopathological 

lesions were found in the brain. Anesthesia was also produced in rats immediately after dosing with 

1,200 mg/kg/day MTBE every day in a 90-day oral administration study, followed by recovery in 

approximately 2 hours (Robinson et al. 1990). This treatment did not significantly affect brain weight nor 

did it produce histopathological lesions in the brain. Daily oral administration of 90, 440, and 

1,750 mg/kg/day MTBE for 4 weeks caused salivation in treated rats (ITT Research Institute 1992). In 

addition, hypoactivity and/or ataxia were observed in rats given the two highest doses. Because all signs 

of neurotoxicity in the 90-day study by Robinson et al. (1990) and in the 4-week study by ITT Research 

Institute (1992) occurred shortly after dosing, they are considered signs of acute toxicity. No 

histopathological lesions were seen in the brain, spinal cord, or sciatic nerve at the termination of the 

4-week study (ITT Research Institute 1992). In a 104-week study, in which male and female rats were 

given gavage doses of 250 or 1,000 mg/kg/day, 4 days per week, no clinical signs of behavioral changes 

and no histopathological brain lesions were observed (Belpoggi et al. 1995). The NOAEL value and all 

LOAEL values for neurological effect in rats for the acute-duration category are recorded in Table 2-2 and 

plotted in Figure 2-2. Although no histopathological effects in the brains were observed in intermediate- and chronicduration studies, the doses have been associated with clinical signs of neurological effects; 

therefore, these doses are not presented as NOAEL values for neurological effects in the intermediate- and 

chronic-duration categories. 

2.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after oral exposure to MTBE. 

Daily oral administration of 357 to 1,428 mg/kg/day MTBE in rats for 14 days did not affect testicular or 

ovarian weights, nor did it produce histopathological lesions in the testes or ovaries (Robinson et al. 

1990). Treatment of male and female mice with < 1,000 mg/kg/day MTBE by gavage for 3 weeks resulted 

in no effects on the frequency of germ cells in the testes or ovaries (Ward et al. 1994). Daily oral dosing 

of 90 to 1,750 mg/kg/day MTBE for 4 weeks in rats produced no gross pathology in the epididymides, 
METHYL tert-BUTYL ETHER 75 

2. HEALTH EFFECTS 

mammary gland, prostate, seminal vesicles, testes, uterus, vagina, or ovaries (ITT Research Institute 

1992). Histological examination revealed no treatment-related lesions in these organs (vagina not 

examined microscopically). Also, a 90-day treatment with daily oral doses of 100-1,200 mg/kg/day 

MTBE in rats had no significant effect on absolute testicular or ovarian weights (Robinson et al. 1990). 

This treatment did not produce histopathological lesions in the testes or ovaries. In a 104-week study, in 

which male and female rats were given gavage doses of 250 or 1,000 mg/kg/day, 4 days per week, 

histological examination of the prostate, uterus, and gonads revealed no nonneoplastic treatment-related 

lesions; however, a significantly increased incidence of testicular Leydig cell tumors was found in the 

high-dose males (see Section 2.2.2.8) (Belpoggi et al. 1995). 

2.2.2.6 Developmental Effects 

No studies were located regarding developmental effects in humans or animals after oral exposure to 

MTBE. 

2.2.2.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans after oral exposure to MTBE. 

MTBE did not cause chromosomal aberrations in the bone marrow of Sprague-Dawley rats that were 

gavaged with 0.04, 0.13, or 0.4 ml/kg/day (30, 96, or 296 mg/kg/day) once or for 5 days (ARCO 1980). 

Similarly, no significant induction of chromosome aberrations in spleen lymphocytes and no evidence of a 

dose-related increase in hypoxanthine-guanine phosphoribosyl transferase (hprt) mutant frequency in 

spleen lymphocytes were found in mice treated with < 1,000 mg/kg/day MTBE by gavage for 3 weeks 

(Ward et al. 1994). Other genotoxicity studies are discussed in Section 2.5. 

2.2.2.8 Cancer 

No studies were located regarding cancer in humans after oral exposure to MTBE. 

In a 104-week carcinogenicity study, in which male and female rats were given MTBE in oil by gavage at 

250 or 1,000 mg/kg/day, 4 days per week, a dose-related increased incidence of lymphomas and leukemia 

was observed in female rats (2 of 60 in controls, 6 of 60 at 250 mg/kg/day, 12 of 60 at 1,000 mg/kg/day) 

(Belpoggi et al. 1995). When expressed as the incidence in the female rats alive at 56 weeks of age, when 
METHYL tert-BUTYL ETHER 76 

2. HEALTH EFFECTS 

the first leukemia was observed, these incidences were 2 of 58 (3.4%) in controls, 6 of 51 (11.8%) at 

250 mg/kg/day, and 12 of 47 (25.5%) at 1,000 mg/kg/day. The increased incidence was statistically 

significant (p<0.0l) at both dose levels compared with controls. As noted in Section 2.2.2.4, there was 

also an increased incidence in dysplastic proliferation of lymphoreticular tissues in female rats, which was 

greater in the low-dose group than in the high-dose group, suggesting that the dysplastic proliferation was 

preneoplastic. An increase in uterine sarcomas was found in the females only at the low dose (1 of 60 in 

controls, 5 of 60 at 250 mg/kg/day, and 0 of 60 at 1,000 mg/kg/day). In male rats, there was a statistically 

significant (p<0.05) increased incidence of testicular Leydig cell tumors at the high dose (2 of 60 in 

controls, 2 of 60 at 250 mg/kg/day, and 11 of 60 at 1,000 mg/kg/day). When expressed as the incidence in 

male rats alive at 96 weeks of age, when the first Leydig cell tumor was observed, the incidence was 2 of 

26 (7.7%) in controls, 2 of 25 (8.0%) at 250 mg/kg/day, and 11 of 32 (34.4%) at 1,000 mg/kg/day. 

2.2.3 Dermal Exposure 

2.2.3.1 Death 

No studies were located regarding death in humans following dermal exposure to MTBE. 

No deaths occurred in rats exposed to MTBE dermally at < 400 mg/kg for 6 hours (Bioresearch Labs 

1990b) or in rabbits exposed to MTBE dermally at 10,000 mg/kg for 24 hours (ARCO 1980). 

2.2.3.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, hematological, musculoskeletal, hepatic, 

renal, endocrine, or body weight effects in humans or animals after dermal exposure to MTBE. Studies on 

dermal and ocular effects in humans and gastrointestinal, dermal, and ocular effects in animals after 

dermal exposure to MTBE are discussed below. The highest NOAEL values and all LOAEL values from 

each reliable study in each species and duration category are recorded in Table 2-3. 

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after 

dermal exposure to MTBE. 




METHYL tert-BUTYL ETHER 81 

2. HEALTH EFFECTS 

In a pharmacokinetic study, in which MTBE was applied dermally to the dorsal flank of rats via an 

occluded chamber, the rats developed slight diarrhea at a dermal dose of 40 mg/kg (Bioresearch Labs 

1990b). Since the dermally applied MTBE was protected by occlusion, it is unlikely that oral uptake via 

grooming contributed to the absorbed dose. 

Dermal Effects. Because inhalation exposure to chemicals may result in dermal effects due to direct 

contact of the vapor on the skin, relevant inhalation studies for dermal effects are presented briefly in 

Section 2.2.1.2, but are more fully discussed here. In a double-blind study, human volunteers were 

exposed sequentially to 1.7 ppm MTBE for 1 hour on 1 day, to uncontaminated air for 1 hour 2 days later, 

and to 7.1 ppm of a 17-component mixture of VOCs for 1 hour 2 days later (or the reverse sequence) (see 

Respiratory Effects in Section 2.2. I .2) (Cain et al. 1994). Statistical analysis of the results of 

questionnaires administered every 10 minutes during the various exposure conditions revealed no 

differences in reporting of skin rash or dry skin. In a similar study, 19 healthy men and 18 healthy women 

were exposed for 1 hour to clean air and 1.39 ppm MTBE in separate sessions separated by at least 1 week 

(Prah et al. 1994). The order of exposure was randomly selected, but because of the odor of MTBE, it is 

likely that the subjects were aware of the exposure conditions. Analysis of the results of the 

questionnaires administered prior to exposure, immediately upon entering the exposure chamber, after 

30 minutes of exposure, and during the last 5 minutes of exposure revealed no differences for skin rash or 

dry skin. 

Application of 0.5 mL or 10,000 mg/kg ARCO MTBE (96.2% MTBE) or commercial MTBE (99.1% 

MTBE) to the intact or abraded skin of rabbits resulted in slight to severe erythema, blanching, epidermal 

thickening, acanthosis, or focal necrosis (ARCO 1980). In a dermal sensitization test in guinea pigs (see 

Section 2.2.3.4), local irritation and increased erythema developed at the site after the initial intradermal 

injection of 0.5 mL of a 1% MTBE solution (ARCO 1980). 

It appears that direct application of liquid MTBE is required to produce these effects since exposure of the 

skin to MTBE vapors in air during inhalation studies did not result in dermal effects. Histological 

examination of skin of rats exposed to airborne MTBE at concentrations < 8,000 ppm for 13 weeks 

revealed no treatment-related lesions (Dodd and Kintigh 1989; Greenough et al. 1980). Alopecia was 

commonly observed in rats exposed to < 2,500 ppm for 16-28 weeks, but it was not considered to be 

related to MTBE-exposure because the incidence was similar in the exposed and control groups (Biles et 

al. 1987). In chronic-duration studies, in which rats (Chun et al. 1992) and mice (Burleigh-Flayer et al. 
METHYL tert-BUTYL ETHER 82 

2. HEALTH EFFECTS 

1992) were exposed intermittently by inhalation to 400, 3,000, or 8,000 ppm MTBE, histological 

examination of the skin revealed no treatment-related lesions. 

Ocular Effects. Because inhalation exposure to chemicals may result in ocular effects due to direct 

contact of the vapor to the eyes, relevant inhalation studies for ocular effects are briefly presented in 

Section 2.2.1.2, but are more fully discussed here. Eye irritation was among the symptoms reported by 

motorists or gas station workers during oxygenated fuel programs in which MTBE had been added to 

gasoline to reduce carbon monoxide emissions. In the preliminary investigation to determine whether 

symptoms were occurring, whether symptoms occurred in a consistent pattern, and whether symptoms 

could be related to exposure to oxyfuel in Fairbanks, Alaska, eye irritation was reported by 1 of 4 (25%) 

taxi drivers, 9 of 26 (35%) health-care workers, and 3 of 15 (20%) students who met the case definition 

(4 of 12 taxi drivers, 26 of 90 health-care workers, and 15 of 101 students) (Beller and Middaugh 1992). 

In the preliminary investigation in Anchorage, Alaska, eye irritation was reported by 8 of 12 (67%) taxi 

drivers and 13 of 36 (36%) health-care workers who met the case definition (12 of 25 taxi drivers and 

36 of 137 health-care workers) (Chandler and Middaugh 1992). 

In the more definitive CDC study in Fairbanks, Alaska, the frequency of eye irritation in the Phase I 

subjects, when the oxyfuel program was in full effect, was 12 of 18 for occupationally exposed workers 

(CDC 1993a; Moolenaar et al. 1994). In the Phase II subjects, after the oxyfuel program was terminated, 

the frequency of eye irritation was 2 of 28. In the CDC study in Stamford, Connecticut, when the oxyfuel 

program was in full effect (no Phase II in Stamford), the eye irritation was reported by 10 of 48 (20.8%) 

mechanics and gas station attendants, 4 of 57 (7%) professional drivers, 2 of 12 (16.7%) “other” workers, 

and 11 of 59 (18.6%) commuters (CDC 1993b; White et al. 1995). 

In the study conducted in Albany, New York, although eye irritation was considered a key symptom and 

was included in the questionnaire, the percentage of subjects who reported eye irritation was not reported 

(CDC 1993c). However, it was noted that key symptoms were slightly more prevalent and the presence of 

2 or more key symptoms was 2-3 times more prevalent in Group 2 (48 police officers, toll booth worker, 

and parking garage attendants) and Group 3 (182 office workers and college students) than in Group 1 

(34 automobile repair shop workers and service station attendants), but the increases were not statistically 

significant. Thus, no increase in health complaints among people with higher gasoline exposures was 

detected. 
METHYL tert-BUTYL ETHER 83 

2. HEALTH EFFECTS 

In the cross-sectional cohort study of self-reported symptoms of garage workers in the state of New Jersey 

exposed to high (115 workers in northern New Jersey during the wintertime oxyfuel program) and low 

(122 workers in southern New Jersey 10 weeks after the phase-out date for oxyfuel program) MTBE 

concentration environments, the results of the questionnaire regarding eye irritation over the last 30 days 

showed no significant difference (22% in the northern workers and 27% in the southern workers, p=0.39) 

(Mohr et al. 1994). 

In the telephone interview survey conducted in metropolitan Milwaukee, Wisconsin, metropolitan 

Chicago, Illinois (use of reformulated gasoline was required in both of these areas), and in the rest of 

Wisconsin exclusive of metropolitan Milwaukee (where the use of reformulated gasoline was not 

required), prevalence of eye irritation associated with MTBE exposure was statistically higher in 

Milwaukee than in either Chicago or Wisconsin; prevalence was not different between Chicago and 

Wisconsin for any symptom (Anderson et al. 1995). As discussed in the Respiratory Effects in Section 

2.2.1.2, these results suggest that factors other than reformulated gasoline use, such as knowledge about 

reformulated gasoline and the likely awareness of potential negative effects, significantly contributed to 

the differences in symptom prevalence between Milwaukee and the other two areas. 

In the double-blind study in humans exposed sequentially to 1.7 ppm MTBE for 1 hour on 1 day, to 

uncontaminated air for 1 hour 2 days later, and to 7.1 ppm of a 17-component mixture of VOCs for 1 hour 

2 days later (or the reverse sequence), subjects were examined for ocular effects (eye redness, tear-film 

break-up time, epithelial damage to the eye, and staining of tear fluid for total number of cells and 

differential numbers of polymorphonuclear neutrophilic leukocytes, epithelial cells, monocytes, 

eosinophils, and lymphocytes) (Cain et al. 1994). The subjects were also administered questionnaires 

regarding subjective symptoms of eye irritation (dry, itching, or irritated eyes; tired or strained eyes; 

burning eyes). Statistical analysis revealed no increase in eye irritation due to MTBE exposure for the 

objective and subjective tests. In a similar study, 19 healthy men and 18 healthy women were exposed for 

1 hour to clean air and 1.39 ppm MTBE in separate sessions separated by at least 1 week (Prah et al. 

1994). The order of exposure was randomly selected, but because of the odor of MTBE, it is likely that 

the subjects were aware of the exposure conditions. Analysis of the results of the questionnaires 

administered prior to exposure, immediately upon entering the exposure chamber, after 30 minutes of 

exposure, and during the last 5 minutes of exposure revealed no differences for irritation of the eyes, tired 

or strained eyes, or burning eyes. In addition to the subjective reporting of ocular effects, tear film 

breakup time (the time from a blink to the appearance of discontinuities of the projected pattern) was 

determined pre- and postexposure using a keratoscope that projects a white-light pattern on concentric 
METHYL tert-BUTYL ETHER 84 

2. HEALTH EFFECTS 

rings onto the cornea. Hyperemia was determined using color slides of the temporal and nasal conjunctiva 

obtained pre- and postexposure. For increased ocular inflammation, the levels of mRNA coding for 

inflammatory mediators present in the conjunctival epithelial cells and the number of inflammatory cells 

present on the conjunctiva were assessed. No measures approached significance. (See Respiratory Effects 

in Section 2.2.1.2 for a more complete discussion of the human studies regarding protocols, limitations, 

and conclusions.) 

Direct instillation of ARCO MTBE (96.2% MTBE) or commercial MTBE (99.1% MTBE) into the eyes of 

rabbits resulted in ocular irritation regardless of whether the eyes were washed after exposure or not 

(ARCO 1980). ARCO MTBE, however, was more irritating than the commercial MTBE. ARCO MTBE 

induced cornea1 opacities, chemosis, and conjunctival redness, while commercial MTBE caused slight 

conjunctival redness and some discharge, but no cornea1 opacities. In a similar study, delayed and 

reversible congestion of the conjunctivae, palpebral thickening, and hypersecretion were observed in the 

eyes of rabbits (Snamprogetti 1980). Direct exposure of the eyes to MTBE vapors during inhalation 

exposure has also resulted in ocular effects in animals. A 4-hour exposure to commercial MTBE vapors at 

concentrations > 18,892 ppm resulted in ocular discharge in rats, while rats exposed to ARCO MTBE 

displayed varying degrees and rapidity of onset of eye irritation (ARCO 1980). Inhalation exposure for 

9 days to concentrations > 100 ppm MTBE caused higher incidences of lacrimation and conjunctival 

swelling in exposed rats than in controls (Biodynamics 1981). Gross and histological examination of the 

eyes, however, revealed no lesions. Pregnant mice exposed to 250-2500 ppm MTBE on gestational days 

6-15 had a slight increase in the incidence of lacrimation during exposure (Conaway et al. 1985). In 

another inhalation developmental study in mice, lacrimation was observed in 1 of 30 mouse dams at 

4,000 ppm and 30 of 30 dams at 8,000 ppm (Tyl and Neeper-Bradley 1989). Periocular encrustations were 

also observed at 8,000 ppm. No ocular effects, as determined histologically or by ophthalmoscopy, were 

found in rats treated for 13 days (Dodd and Kintigh 1989) or for 13 weeks with < 8,000 ppm MTBE (Dodd 

and Kintigh 1989; Greenough et al. 1980). At longer exposure durations, (16-28 weeks), lacrimation was 

among the most common effects observed in adult rats exposed to < 2,500 ppm (Biles et al. 1987). This 

sign may not have been the result of this particular exposure, since it was seen at similar incidences in 

controls. Parental F1 rats exposed to 8,000 ppm MTBE for 10 weeks before breeding and throughout the 

19-day gestational period exhibited ocular discharges and periorbital encrustation (Neeper-Bradley 1991). 

Blepharospasm was observed in parental F0 male and female rats at 3,000 and 8,000 ppm, but this is 

probably a neurological effect due to inhalation of MTBE. 
METHYL tert-BUTYL ETHER 85 

2. HEALTH EFFECTS 

In chronic-duration studies, in which rats (Chun et al. 1992) and mice (Burleigh-Flayer et al. 1992) were 

exposed intermittently by inhalation to 400, 3,000, or 8,000 ppm MTBE, no treatment-related lesions were 

observed in eyes. Blepharospasm was observed in both sexes of both species at 3,000 and/or 8,000 ppm, 

but, as noted above, this is probably a neurological effect due to inhalation of MTBE. Increased 

incidences of swollen periocular tissue were also observed in male rats exposed to 3,000 and 8,000 ppm 

(Chun et al. 1992). 

2.2.3.3 Immunological and Lymphoreticular Effects 

In the experimental double-blind study in humans exposed sequentially to 1.7 ppm MTBE for 1 hour on 

1 day, to uncontaminated air for 1 hour 2 days later, and to 7.1 ppm of a 17-component mixture of VOCs 

for 1 hour 2 days later (or the reverse sequence) (see Respiratory Effects in Section 2.2.1.2), tear fluid from 

the eyes was stained for the total numbers of cells and differential counts for polymorphonuclear 

neutrophilic leukocytes, epithelial cell, monocytes, eosinophils, and lymphocytes (Cain et al. 1994). No 

notable changes between pre- and postexposure values were observed for exposure to MTBE or air. 

In a dermal sensitization test, guinea pigs received an initial intradermal injection of 0.5 mL of a 1% 

MTBE solution, followed by intradermal injection of 0.1 mL every other day for 3 weeks for a total of 

10 injections (ARCO 1980). Two weeks after the tenth injection, a challenge dose of 0.05 mL was 

injected. The injection sites were evaluated at 24 and 48 hours after treatment and scored for erythema, 

edema, and color. MTBE produced no significant increase in response to the challenge compared with the 

initial sensitizing or inducing injection. The NOAELs for immunological effects in the eyes of humans 

and for dermal sensitization in guinea pigs are recorded in Table 2-3. 

2.2.3.4 Neurological Effects 

No studies were located regarding neurological effects in humans after dermal exposure to MTBE. 

The only information regarding neurological effects in animals after dermal exposure to MTBE is that 

rabbits cried out and were hyperactive for 3-5 minutes after 6,800 or 10,200 mg/kg MTBE was applied 

dermally to the occluded skin (IBT Labs 1969). It should be noted that the results of studies from IBT are 

often suspected as being unreliable. 
METHYL tert-BUTYL ETHER 86 

2. HEALTH EFFECTS 

2.2.3.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans or animals after dermal exposure to 

MTBE. 

2.2.3.6 Developmental Effects 

No studies were located regarding developmental effects in humans or animals after dermal exposure to 

MTBE. 

2.2.3.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans or animals after dermal exposure to MTBE. 

Genotoxicity studies are discussed in Section 2.5. 

2.2.3.8 Cancer 

No studies were located regarding cancer in humans or animals after dermal exposure to MTBE. 

2.3 TOXICOKINETICS 

Information is available regarding blood levels of MTBE and tert-butanol in motorists, gas stations 

workers, and experimental subjects after inhalation exposure. The data indicate that MTBE is rapidly 

absorbed by the lungs during exposure, that MTBE is metabolized to tert-butanol, the levels of which also 

increase in blood after exposure to MTBE, and that levels of MTBE in blood decline rapidly after 

exposure ceases. Limited information regarding distribution, metabolism, and excretion of MTBE by 

humans was available for patients who received MTBE via intracystic infusion for the dissolution of 

gallstones. In these patients, MTBE and the metabolite, tert-butanol, were detected in blood, abdominal 

wall fat, and breast milk. Methanol was also found in the urine. Excretion of MTBE in the urine of these 

patients was nearly complete by 12-18 hours after treatment, but tert-butanol levels in urine declined very 

little during this time. 

Information regarding absorption, distribution, metabolism, and excretion of MTBE in animals after 

inhalation, oral, or dermal exposure was available only for rats. Information regarding the rate and extent 
METHYL tert-BUTYL ETHER 87 

2. HEALTH EFFECTS 

of absorption of MTBE after inhalation exposure was limited to data on the peak plasma concentration and 

time to peak plasma concentrations of MTBE. These data indicated that absorption by the lungs is 

relatively rapid and extensive. Absorption by the gastrointestinal tract was also rapid, with peak plasma 

concentrations achieved within 15 minutes of dosing. Absorption factors were calculated to be 58% for 

male rats and 81% for female rats for gastrointestinal absorption, compared with 23-39% for male rats and 

9.6-16% for female rats for dermal absorption. A greater percentage of a high dermal dose was absorbed 

than of a low dermal dose. 

MTBE showed little tendency to accumulate in tissues. One inhalation study in rats, however, indicated 

that MTBE and its metabolite tert-butanol were distributed to the brain at concentrations similar to blood 

concentrations, which may account for the central nervous system toxicity of MTBE. 

Metabolic pathways appear to be similar regardless of route of exposure. Unchanged MTBE was the 

major component in expired air. tert-Butanol was expired to a lesser extent, and very little carbon dioxide 

was formed as a result of MTBE metabolism. Urinary metabolites include 2-methyl-1, 2-propanediol, 

α-hydroxyisobutyric acid, formaldehyde, methanol, and formic acid. A metabolic pathway was proposed 

whereby demethyiation results in equimolar amounts of tert-butanol and formaldehyde, and tert-butanol is 

oxidized to 2-methyl-1, 2-propanediol, which is in turn oxidized to α-hydroxyiscbutyric acid. According 

to the pathway, formaldehyde can then be reduced to methanol or oxidized to formic acid. A small 

amount of carbon dioxide may arise from further metabolism of formic acid. 

After inhalation and oral dosing with radiolabeled MTBE, the major routes of excretion were via the lungs 

and kidneys. Urinary excretion of radioactivity predominated at low doses, while respiratory excretion 

predominated at high doses. This shift in relative percentages of radioactivity excreted by these routes 

may be due to shifts in metabolic pathways as metabolizing enzymes become saturated at high doses. No 

such dose-dependent shift was observed after dermal exposure, presumably because dermal absorption of 

the higher dose was not great enough to result in enzyme saturation. Very little radioactivity was excreted 

in the feces after exposure to MTBE by any route. Excretion by lungs was more rapid than by the kidneys 

after inhalation, oral, and dermal exposure, with excretion by lungs nearly complete in 6 hours and 

excretion by the kidneys nearly complete by 36 hours. Complete excretion after dermal exposure took 

somewhat longer. 
METHYL tert-BUTYL ETHER 88 

2. HEALTH EFFECTS 

2.3.1 Absorption 

2.3.1.1 Inhalation Exposure 

As MTBE is a volatile, lipophilic molecular of small molecular size, it is expected to be rapidly and 

extensively absorbed from the respiratory tract. Information on blood levels of MTBE and its metabolite, 

tert-butanol, in motorists, gas station attendants and mechanics, and in experimentally exposed humans 

after inhalation of MTBE indicates that MTBE is well absorbed from the lungs. During the oxygenated 

fuel program in Fairbanks, Alaska, in which MTBE (15% by volume) was added to gasoline to reduce 

emissions of carbon monoxide, the median preshift blood concentration of MTBE in occupationally 

exposed workers (mechanics, gas station attendants, and people who spent most of their workdays in 

motor vehicles) was 1.15 μg/L (range, 0.1-27.8 μg/L) (CDC 1993a; Moolenaar et al. 1994). The median 

postshift level was 1.80 μg/L (range 0.2-37.0 μg/L). The median 8-hour TWA concentrations of MTBE in 

the workplace air of service stations and garages were 0.10 ppm with a range of 0.01-0.81 ppm during the 

program. A strong correlation was found between the air levels of MTBE and the difference in preshift 

and postshift MTBE blood levels during the program (r = 0.9; p = 0.0001). When blood levels were again 

monitored a few months after the oxygenated fuel program had ended, the preshift blood level was 

0.20 μg/L (range 0.05-4.35 μg/L) and the postshift level was 0.24 μg/L (range 0.05-l .44 μg/L). The 

median workplace air level of MTBE was 0.04 ppm, with a range from nondetectable to 0.14 ppm. Blood 

levels of MTBE in nonoccupationally exposed motorists were 0. 18 μg/L before they left their homes and 

0.83 μg/L upon arrival at the workplace after their morning commute during the oxygenated fuel program. 

After the program had ended, the pre- and post-commute MTBE blood levels were 0.09 μg/L and 

0.10 μg/L, respectively. 

In May 1993, CDC and New York state health officials investigated whether exposure to MTBE in fuels 

was measurable in occupationally and nonoccupationally exposed people in Albany, where MTBE is used 

in small concentrations (CDC 1993c). Group 1 consisted of 34 automobile repair shop workers and 

service station attendants exposed to gasoline fumes; Group 2 consisted of 48 police officers, toll booth 

workers, and parking garage attendants exposed to automobile exhaust; and Group 3 consisted of 

182 office workers and college students. In both smokers and nonsmokers, subjects in Group 1 had higher 

levels of MTBE (mean, 0.46 μg/L; range, 0.09-l .5 μg/L for smokers; mean, 0.38 μg/L, range, 

nondetectable to 0.58 μg/L for nonsmokers) and tert-butanol (mean, 5.47 μg/L, range, 1.12-13.77 μg/L for 

smokers; mean, 3.58 μg/L; range, 1.08 to 5.34 μg/L for nonsmokers) in their blood when compared to 

subjects in Groups 2 and 3. In Group 2, MTBE blood levels averaged 0.08 μg/L for smokers and 
METHYL tert-BUTYL ETHER 89 

2. HEALTH EFFECTS 

0.05 μg/L for nonsmokers and ranged from nondetectable to 0.11 μg/L for smokers and nondetectable to 

0.15 μg/L for nonsmokers; tert-butanol blood levels averaged 1.17 μg/L for smokers and 1.16 μg/L for 

nonsmokers and ranged from 1.14 to 1.53 μg/L for smokers and 0.69 to 2.24 μg/L for nonsmokers. In 

Group 3, no MTBE was detectable in the blood of smokers or nonsmokers, but tert-butanol blood levels 

averaged 1.36 μg/L in smokers and 1.10 μg/L for nonsmokers and ranged from 1.03 to 1.69 μg/L for 

smokers and 0.23 to 3.05 μg/L for nonsmokers. 

In a similar study conducted in Stamford, Connecticut, during an oxygenated fuel program, the 

approximate median blood levels of MTBE were 0.1 μg/L in commuters, 2 μg/L in car repairers, 0.1 μg/L 

in “other” workers (such as meter readers), and 15 μg/L in gas station attendants (CDC 1993b; White et al. 

1995). Thus, the blood levels were about an order of magnitude higher in mechanics and two orders of 

magnitude higher in gas station attendants than in commuters and “other” workers. Blood levels of 

tert-butanol were higher than blood levels of MTBE, but showed the same relative differences among the 

groups. Workroom air levels and personal breathing zone levels of MTBE, which were considered to 

underestimate the exposure levels of mechanics and gas station workers, ranged from <0.03 to 12.04 ppm 

for breathing zones and from 0.001 to 0.429 ppm for workroom air. 

In a group of 2 healthy men and 2 healthy women experimentally exposed to 1.7 ppm MTBE for 1 hour, 

mean blood levels of MTBE rose steeply from a level of 0.83 μg/L preexposure to 17.14 μg/L at the end of 

the 1-hour exposure, followed by a decline to an average level of 9.74 μg/L at 40 minutes postexposure 

and 6.32 μg/L at 60 minutes postexposure (Cain et al. 1994). tert-Butanol was also monitored but the 

levels were highly variable. The mean blood level of tert-butanol was 2.79 μg/L preexposure and 

increased during exposure, but remained in the vicinity of 10-15 μg/L from 30 minutes during exposure to 

90 minutes postexposure, indicating continued metabolism of MTBE to tert-butanol. In a similar study in 

1 healthy man and 1 healthy woman experimentally exposed to 1.39 ppm MTBE for 1 hour, the blood 

level of MTBE rose rapidly to 8.2 μg/L and 14.7 μg/L in the man and woman, respectively (Prah et al. 

1994). The blood level of tert-butanol rose gradually to a plateau of 7-l 0 μg/L. 

Studies in rats indicate that MTBE is also readily absorbed by the pulmonary tract in animals, as it is in 

humans. Data regarding the excretion of radioactivity in expired air, urine, and feces in Fischer 344 rats 

exposed nose-only to 400 and 8,000 ppm 14C-MTBE for 6 hours provides information on the rate and 

extent of absorption (Bioresearch Labs 1990d). Samples were collected at various times for up to 48 hours 

after exposure. Excretion of radioactivity in feces was minor, with only 0.74-0.76% recovered after 

exposure to 400 ppm and 0.75-1.06% recovered after exposure to 8,000 ppm. The relative percentages of 
METHYL tert-BUTYL ETHER 90 

2. HEALTH EFFECTS 

radioactivity recovered in the urine and expired air were dose-dependent. At 400 ppm, 64.7 and 65.4% of 

the total radioactivity was recovered in the urine 48 hours after termination of exposure of males and 

females, respectively, while 21.2 and 21.9% of radioactivity was recovered in the expired air of males and 

females, respectively. At 8,000 ppm, radioactivity recovery in urine accounted for 41.6% in males and 

35% in females, while radioactivity recovery in expired air accounted for 53.6% in males and 59% in 

females. The values indicate that at least 85.9-87.3% of the low dose and at least 94-95.2% of the high 

dose were absorbed via the pulmonary tract in 48 hours. Similar percentages of radioactivity in expired air 

and urine were obtained in rats exposed nose-only to 400 ppm unlabeled MTBE for 6 hours per day for 

14 days and then to 400 ppm 14C-MTBE for 6 hours on day 15. 

Data on the peak plasma concentrations and time to peak plasma concentrations in rats provide some 

information on the rate of pulmonary absorption of MTBE. In rats exposed nose-only to MTBE for 

6 hours, plasma concentrations of MTBE and its metabolite tert-butanol peaked at 4-6.5 hours during 

exposure (Bioresearch Labs 1990c). Plasma tert-butanol increased more gradually than plasma MTBE 

concentrations. At an exposure concentration of 400 ppm, plasma MTBE concentrations peaked at 

4-6 hours (about 15 μg/mL), while plasma tert-butanol concentrations peaked at 6-6.5 hours (about 

39 μg /mL). At a concentration of 8,000 ppm MTBE, plasma MTBE levels peaked at 4-6 hours (about 

560 μg /mL), while plasma tert-butanol levels peaked at 6-6.5 hours (536 μg /mL for males and 245 μg /mL 

for females). 

Blood MTBE levels were generally related to inhaled dose in rats exposed to 50, 100, or 300 ppm, 6 hours 

per day, 5 days per week for 2-l5 weeks (Savolainen et al. 1985). At the 2 lower exposure concentrations, 

peak blood MTBE levels of 11 and 24 nmol/g, respectively (about 1.3 μg /mL and 2.9 μg /mL, respectively) 

were reached at 6 weeks. At the highest exposure concentration, the peak blood level of 72 nmol/g (about 

8.6 μg /mL) was reached at 15 weeks. Thus, MTBE blood levels continue to rise for a substantial amount 

of time during prolonged exposure, indicating a relatively long time for steady state to be reached. 

2.3.1.2 Oral Exposure 

No studies were located regarding absorption of MTBE in humans after oral exposure. However, as 

MTBE is a volatile, lipophilic molecular of small molecular size, it is expected to be rapidly and 

extensively absorbed from the gastrointestinal tract of humans after oral exposure, as confirmed in studies 

in animals. 
METHYL tert-BUTYL ETHER 91 

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A peak blood concentration of 5.9 μg /mL MTBE was reached in 0.9 hours in rats given a single oral dose 

of 0.379 mg/kg MTBE (Li et al. 1991). In rats given a single oral dose of 40 or 400 mg/kg of MTBE in 

water, MTBE and tert-butanol were detected in plasma of both treatment groups (Bioresearch Labs 

1990a). The maximum plasma concentrations of MTBE in both males and females at both doses were 

achieved within 15 minutes, suggesting rapid absorption. The oral bioavailability of MTBE was 

determined to be 58% in males and 81% in females. In rats given 40 or 400 mg/kg of 14C-MTBE, a total 

of 80.2-86.3% of the dose of radioactivity was recovered in urine, feces, and volatile radioactive 

components in the expired air in 48 hours (Bioresearch Labs 1990b). Most of the radioactivity was 

recovered in the expired air and the urine. Recovery in expired air was 48.5% (males) and 54.4% 

(females) after a dose 40 mg/kg, and 65.3% (males) and 68.7% (females) after a dose of 400 mg/kg. 

Recovery in urine was 36.2% (males) and 39% (females) after a dose of 40 mg/kg and 16% (males), and 

10.8% (females) after a dose of 400 mg/kg. Recovery of radioactivity in feces was only about 1% or lower 

in the dosed groups, and recovery in the tissues/carcass was < 2% at 48 hours after dosing. These data 

indicate that as much as 80% of an oral dose of MTBE was absorbed from the gastrointestinal tract of rats 

within 48 hours. 

In rats given a single oral or intravenous dose of 40 mg/kg MTBE, blood samples were collected for up to 

240 minutes after dosing (Exxon 1988). Maximum blood levels of MTBE in the orally treated rats 

occurred within 2.5 to 10 minutes. From a comparison of the mean areas under the curves (AUC) for 

blood clearance for the intravenous dose group and the oral dose group, an oral bioavailability of 37.4% 

was obtained. However, the total elimination of MTBE in expired air was 50-55% of the administered 

dose by 3 hours after dosing, indicating that at least 50-55% of MTBE was absorbed from the 

gastrointestinal tract. Furthermore, the MTBE in this study was not radiolabeled, precluding the 

measurement of any radiolabeled metabolites that may have been formed from radiolabeled MTBE. 

Analysis of total radioactivity would have provided a more accurate estimate of the extent of MTBE 

absorption by the gastrointestinal tract. In addition, the body weights of the rats used in these experiments 

varied widely, which could effect the individual values of blood levels obtained. 

2.3.1.3 Dermal Exposure 

No studies were located regarding absorption of MTBE in humans after dermal exposure, but it is 

probably less well absorbed by the skin than by the pulmonary or gastrointestinal tract. 
METHYL tert-BUTYL ETHER 92 

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In rats, MTBE is absorbed to a lesser extent by the skin than by the gastrointestinal tract. In rats 

administered 400 mg/kg MTBE to the shaved skin via a dermal chamber to prevent evaporation and crossexposure by inhalation or ingestion due to grooming, MTBE and tert-butanol were detected in plasma 

within 10 minutes (Bioresearch Labs 1990a). However, measurable MTBE and tert-butanol in plasma 

were barely detectable this soon in rats similarly treated with 40 mg/kg. The peak plasma concentration of 

MTBE was achieved in 2-6.5 hours after the low dose and 2-4 hours after the high dose. The 

bioavailability of the dermal dose of MTBE compared with the oral dose (see Section 2.3.1.2) was 

23-39% in male rats and 9.5-16% in female rats. In a mass balance study in male and female rats 

similarly treated with 40 or 400 mg/kg 14C-MTBE, analysis of radiolabeled carbon dioxide, MTBE, and 

metabolites in urine, feces, and expired air, tissues/carcass, and chamber washings yielded 69.4-76.9% 

recovery of the dose in 48 hours (Bioresearch Labs 1990b). Most of the radioactivity was excreted in the 

expired air and urine. Recovery in expired air was 6.05% (males) and 9.67% (females) after a dose of 

40 mg/kg and 19.6% (males) and 23.2% (females) after a dose of 400 mg/kg. Recovery in urine was 

6.49% (males) and 6.12% (females) after a dose of 40 mg/kg and 12.4% (males) and 10.7% (females) after 

a dose of 400 mg/kg. Recovery of radioactivity in feces was only about 0.2% or lower in the dosed 

groups, and recovery in the tissues/carcass and application site was < 1 % at 48 hours after dosing. 

Recovery of radioactivity from the dermal chambers was 56.9% (males) and 59.8% (females) after the low 

dose and 38.2% (males) and 34.6% (females) after the high dose, representing unabsorbed MTBE. Thus, 

the dermal absorption of MTBE was higher for the high-dose group than the low-dose group. In a similar 

mass balance study in rats, recovery of radioactivity in the various components was measured for up to 

168 hours after dosing and in selected tissues at 7 days post-dosing (Bioresearch Labs 1991). Total 

recovery of radioactivity was 88.8% for the 40 mg/kg dose and 99.9% for the 400 mg/kg dose. At 

168 hours after dosing, 76.8% of the low-dose and 69.5% of the high dose were recovered in the chamber 

washes, indicating that dermal absorption was <50% in both dose groups. In the low-dose group, 6.29, 

7.58, and 0.25% of the dose was recovered in the urine, expired air, and feces, respectively, at 168 hours. 

In the high-dose group these recoveries were 15.9, 18.9, and 0.39%, respectively. Therefore, about 14.5 

and 35.7% of the low and high dose, respectively, were absorbed dermally. The greater percentage of the 

dose absorbed after the high dose in this study (Bioresearch Labs 1991) is consistent with that in the other 

mass balance study (Bioresearch Labs 1990b). 
METHYL tert-BUTYL ETHER 93 

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2.3.2 Distribution 

As MTBE is a small molecular weight, volatile, lipophilic compound, it is expected to readily cross 

biological membranes during it transport via the blood. Although no studies were located regarding 

distribution of MTBE in humans after inhalation, oral, or dermal exposure, there is no reason to expect 

that the tissues to which MTBE distributes would differ from those of animals (fatty tissue, brain, liver 

kidney). Furthermore, MTBE has been detected in fatty tissue and breast milk of patients who received 

MTBE via intracystic infusion for dissolution of gallstones (see Section 2.3.2.4). 

2.3.2.1 Inhalation Exposure 

No studies were located regarding distribution of MTBE in humans after inhalation exposure. 

The levels of MTBE and tert-butanol in samples of blood, cerebral hemispheres, and perirenal fat were 

monitored in Wistar rats sacrificed at 2, 6, 10, or 15 weeks of exposure to 50, 100, or 300 ppm MTBE, 

6 hours per day, 5 days per week (Savolainen et al. 1985). Blood MTBE levels were generally related to 

exposure concentration. At the 2 lower exposure concentrations, peak blood MTBE levels of 11 and 

24 nmol/g, respectively (about 1.3 μg /mL and 2.9 μg /mL, respectively) were reached at 6 weeks. At the 

highest exposure concentration, the peak blood level of 72 nmol/g (about 8.6 μg /mL) were reached at 

15 weeks. Blood tert-butanol levels peaked at 6 weeks for all concentrations tested (38, 82, and 

151 nmol/g or 3.3, 7.2, and 13 μg /mL, respectively) and then decreased sharply at week 10 (11, 34, and 

89 nmol/g or 0.97, 3.0, or 7.8 μg /mL, respectively). Brain MTBE and tert-butanol levels followed a 

similar course as blood levels. At the 300 ppm exposure concentration, brain and blood MTBE levels 

were approximately similar. MTBE levels were considerably higher in perirenal fat than in blood and 

brain tissues at all exposure concentrations. At 2 weeks, the perirenal fat concentration of MTBE was 184, 

245, and 642 nmol/g at 50, 100, and 300 ppm, respectively. The perirenal concentration of MTBE 

declined to 81-92 nmol/g at 6-15 weeks in the 50 ppm exposed group but remained relatively unchanged 

at the higher exposure concentrations. No trace levels of tert-butanol were found in perirenal fat at any 

exposure concentration and any duration. 

The tissue retention of MTBE after acute- and intermediate-duration inhalation exposure has been studied 

in Fischer 344 rats. Rats exposed nose-only to 14C-MTBE at 400 or 8,000 ppm for 6 hours or to 400 ppm 

unlabeled MTBE for 6 hours per day for 14 days, and then to 400 ppm 14C-MTBE on day 15 were 

sacrificed at 48 hours post-exposure (Bioresearch Labs 1990d). Blood, liver, kidney, lungs, heart, brain, 
METHYL tert-BUTYL ETHER 94 

2. HEALTH EFFECTS 

gonads, bone (femur), fat (perirenal), muscle (leg adductor) and skin were removed for analysis of 

radioactivity. For the single 6-hour exposure, the percentages of total radioactivity recovered from 

tissues/carcass were as follows: 13.4% (male) and 11.9% (female) after exposure to 400 ppm; 4.07% 

(male) and 5.02% (female) after exposure to 8,000 ppm. The higher percentage of radioactivity in the 

tissues after the low dose compared with the high dose may be due to shifts in metabolic and elimination 

pathways as enzyme systems become saturated at high doses (see Section 2.3.3). In the repeated exposure 

study, the percentages of total radioactivity recovered from tissues/carcass were 10.9% (males) and 10.4% 

(females), which were essentially the same as in the single exposure study at 400 ppm. In both 

experiments, except for the skin, mean radioactivity recoveries in tissues were very low (<1% of the total), 

indicating that MTBE or its metabolites do not accumulate in tissues after acute exposure. The relatively 

high radioactivity in the skin of the rats may have been due to contamination. 

2.3.2.2 Oral Exposure 

No studies were located regarding distribution of MTBE in humans after oral exposure. 

In rats given a single oral dose of 40 mg/kg MTBE, the level of MTBE in perirenal fat was determined to 

be 53.75 μg /g at 30 minutes, 35.51 μg /g at 60 minutes, 25.87 μg /g at 90 minutes, 38.67 μg /g at 

120 minutes, 7.86 μg /g at 240 minutes, and 3.43 μg /g at 300 minutes after dosing (Exxon 1988). Thus, the 

highest levels were found in the first samples at 30 minutes. A time-related decrease in the MTBE fat 

levels occurred thereafter; however, the plateau of MTBE levels in fat at 90 and 120 minutes was 

unexplainable. However, the body weights of the rats used in these experiments varied widely, which 

could effect the individual values of fat levels obtained. Blood clearance curves were fitted to a 

2-compartment model with instantaneous distribution and first-order elimination. The volume of 

distribution for the central compartment was calculated to be 521 mL. 

2.3.2.3 Dermal Exposure 

No studies were located regarding distribution of MTBE in humans after dermal exposure. 

Studies in animals did not follow the course of MTBE distribution during exposure, but tissues levels of 

radioactivity were measured at > 2 days after exposure to 14C-MTBE ceased. These studies generally 

indicate that MTBE does not tend to accumulate in tissues of the rat body. In rats to which 40 or 

400 mg/kg 14C-MTBE was applied to the shaved skin via a dermal chamber for 6 hours, the percentages of 
METHYL tert-BUTYL ETHER 95 

2. HEALTH EFFECTS 

radioactivity in tissues, carcass, and site of application at 48 hours after exposure were 0.28% (males) and 

0.67% (females) at the high dose, and 0.67% (males) and 1.02% (females) at the low dose (Bioresearch 

Labs 1990b). In rats similarly treated, radioactivity in selected tissues was measured at 7 days post-dosing 

(Bioresearch Labs 1991). Except for detectable radioactivity at the application site in both dose groups 

(0.0 1-0.12% of the dose), no radioactivity was detected in tissues (liver, kidneys, lungs, heart, brain, 

gonads, femur, perirenal fat, muscle, and skin) or carcass at 7 days post-dosing. 

2.3.2.4 Other Routes of Exposure 

Limited information regarding distribution of MTBE was available for humans who received MTBE via 

intracystic infusion for dissolution of gallstones. Among a group of 113 patients who received MTBE 

(1-15 mL instilled 3-6 times per minute and reaspirated) by this route, fatty tissue from the abdominal 

wall was collected from 9 patients at the end of treatment (Leuschner et al. 199 I ). Breast milk was 

sampled from one patient after treatment. The mean MTBE concentration in fatty tissue was 0.135 mg/g 

after a mean treatment time of 9.6 hours. MTBE and tert-butanol were present in breast milk in 

concentrations only slightly less than in blood. 

In Charles River CD (Sprague-Dawley) rats that received a single intraperitoneal dose of 232 mg/kg 

14C-MTBE (radiolabeled on the methyl and central carbon of the tert-butyl group), the total accumulation 

of radioactivity in tissues averaged 3.39, 1.94, and 1.14% of the administered dose at 15 minutes, 6 hours, 

and 24 hours after dosing, respectively (Biodynamics 1984). At 15 minutes, radioactivity was found 

primarily in mesenteric fat (325 ppm in males, 138.5 ppm in females), liver (93.7 ppm in males, 68.7 ppm 

in females), and kidney (49.8 ppm in males, 19.4 ppm in females). High levels of radioactivity were no 

longer found in mesenteric fat at 6 and 24 hours, but levels in liver were 65.5 ppm at 6 hours and 37.7 ppm 

at 24 hours. Levels in the kidney were 40 ppm at 6 hours and 28.5 ppm at 24 hours. Qualitative data 

indicated that formic acid and methanol were present in the liver and kidney, but quantification of the 

metabolites was not possible. In Fischer 344 rats given a single intravenous dose of 40 mg/kg 14C-MTBE, 

the percentages of the radioactive dose in tissues/carcass were 1.69% in males and 1.13% in females at 

48 hours (Bioresearch Labs 1990b). When samples were collected 7 days after treatment, <1% of the dose 

was recovered in the liver, kidneys, fat, skin, and remaining carcass. 
METHYL tert-BUTYL ETHER 96 

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2.3.3 Metabolism 

No studies were located regarding the metabolism of MTBE in humans after oral or dermal exposure. In a 

group of 4 nonsmoking, healthy subjects (2 men and 2 women) experimentally exposed to 1.7 ppm MTBE 

for 1 hour, the mean blood concentration of tert-butanol was 2.79 μg /L preexposure, which was 3 times 

higher than the preexposure mean MTBE blood level (Cain et al. 1994). However, postexposure blood 

levels of tert-butanol exceeded those measured before exposure to MTBE, indicating metabolism of 

MTBE to tert-butanol. Mean blood levels of tert-butanol, although highly variable, remained in the 

vicinity of l0-15 μg /L from 30 minutes during exposure to 90 minutes postexposure, indicating continued 

metabolism of MTBE to tert-butanol. In a similar study in one healthy man and one healthy woman 

experimentally exposed to 1.39 ppm MTBE for 1 hour, the blood level of tert-butanol rose gradually to a 

plateau of 7-10 μg /L, where it remained for up to 7 hours postexposure, again indicating continued 

metabolism of MTBE to tert-butanol (Prah et al. 1994). In 27 patients who received MTBE via intracystic 

infusion for dissolution of gallstones, blood and urine samples were collected before treatment, 

immediately after treatment, and up to 18 hours after treatment for the determination of blood and urine 

levels of MTBE, methanol, tert-butanol, formic acid and formaldehyde (Leuschner et al. 1991). Mean 

blood levels of tert-butanol were 0.04 mg/mL immediately after and 5 hours after treatment and fell only 

to 0.025 mg/mL at 12-18 hours. Mean urinary levels of MTBE were about 0.018 mg/mL at 5 hours after 

treatment and <0.005 mg/mL at 12-l 8 hours. Mean urinary levels of tert-butanol were higher than those 

of MTBE, with about 0.036 mg/mL at 5 hours and 0.03 mg/mL at 12-l 8 hours after treatment. Methanol 

was found in only 3 patients, while no formaldehyde or formic acid were found. tert-Butanol was also 

detected in the abdominal wall fat of 9 patients and breast milk of 1 patient. 

MTBE is also metabolized to tert-butanol in rats. The metabolism of 14C-MTBE has been studied in 

Fischer 344 rats exposed by the inhalation (Bioresearch Labs 1990d), oral (Bioresearch Labs 1990b), 

dermal (Bioresearch Labs 1990b, 1991), and intravenous (Bioresearch Labs 1990b, 1991) routes. 

Respiratory and urinary metabolites were generally similar following exposure of Fischer 344 rats by all 

routes, indicating that metabolic pathways are not route dependent. After exposure by all routes, most of 

the exhaled radioactivity was due to unchanged MTBE and tert-butanol, with MTBE predominating. Only 

a small amount of 14C-carbon dioxide was detected. MTBE and tert-butanol were generally not found in 

the urine, but four urinary metabolites were isolated, with two identified as α-hydroxyisobutyric acid and 

2-methyl-1,2-propanediol. The two other metabolites remained unidentified. After inhalation and oral 

exposure, there was a larger fraction of exhaled tert-butanol in low-dose rats than in high-dose rats, 
METHYL tert-BUTYL ETHER 97 

2. HEALTH EFFECTS 

probably due to less extensive metabolism at the high dose as metabolizing enzyme systems become 

saturated. The proportion of α-hydroxyisobutyric acid increased relative to 2-methyl-1,2-propanediol with 

increasing sampling time, suggesting that the diol is an intermediate to the formation of the acid. The 

results are consistent with a metabolic pathway whereby MTBE is biotransformed by demethylation to 

tert-butanol followed by further oxidation to 2-methyl-1,2-propanediol and then to α-hydroxyisobutyric 

acid. No differences in biotransformation were observed with respect to gender or duration of exposure. 

In inhalation experiments, rats were exposed to 14C-MTBE at 400 or 8,000 ppm for 6 hours or to 400 ppm 

unlabeled MTBE for 6 hours per day for 14 days then to 400 ppm 14C-MTBE on day 15 (Bioresearch Labs 

1990d). tert-Butanol accounted for 25 and 30% of the recovered radioactivity in expired air at 3 hours 

after the single and repeated low exposure concentration, respectively. Exposure to the higher 

concentration for 6 hours resulted in a lower fraction recovered (7-10%) due to tert-butanol. At 3-6 hours 

after exposure, tert-butanol represented 72-80% of the radioactivity at the low dose in the single and 

repeated exposure experiments and 43-54% at the high dose. 

In rats treated by gavage with 14C-MTBE at 40 or 400 mg/kg, and in rats to which 40 or 400 mg/kg 

14C-MTBE was applied to the shaved skin via a dermal chamber for 6 hours, only 0.01-0.2% of the dose 

was recovered as 14C-carbon dioxide in expired air (Bioresearch Labs 1990b). After oral dosing, MTBE 

predominated in expired air during the first 3 hours, with the ratio of tert-butanol to MTBE increasing 

during the next 3 hours. Elimination of tert-butanol by the lungs represented 3.1% of the low dose and 

1.4% of the high dose. Similarly, another study also found that, in Fischer 344 rats given a single oral 

dose of 40 mg/kg, pulmonary elimination of tert-butanol for 5 hours after exposure represented 2% of the 

administered MTBE dose (Exxon 1988). After dermal exposure, a greater percentage of the dose was 

recovered in the expired air (6.05% in males, 9.67% in females at 40 mg/kg and 19.6% in males, 23.2% in 

females at 400 mg/kg) than in the urine (6.12-6.49% at 40 mg/kg and 10.7-l 2.4% at 400 mg/kg) 

(Bioresearch Labs 1990b). MTBE predominated in expired air. Only 0.63% to 0.93% of the dermal dose 

was eliminated in expired air as tert-butanol at the low dose, and 1.0% to 1.3% of the dose as tert-butanol 

at the high dose. The reason that the percentage of tert-butanol in expired air was not greater after the low 

dermal dose than after the high dose is probably that MTBE is less well absorbed after dermal exposure 

than after oral or inhalation exposure. Thus, the amount absorbed after the high dermal dose was probably 

not great enough to saturate metabolizing enzymes. When samples were collected for up to 168 hours 

after dermal dosing, 11.6% of the dose was exhaled as MTBE and 0.39% as tert-butanol in rats given 
METHYL tert-BUTYL ETHER 98 

2. HEALTH EFFECTS 

400 mg/kg (Bioresearch Labs 1991). Expired air levels of MTBE and tert-butanol were below detection 

limits in rats given 40 mg/kg dermally. 

Results of dosing Fischer 344 rats with 14C-MTBE intravenously were similar to those obtained by the 

inhalation, oral, and dermal routes (Bioresearch Labs 1990b). In Charles River CD (Sprague-Dawley) rats 

injected with a single intraperitoneal dose of 232 mg/kg 14C-MTBE, blood, tissue, expired air, urine, and 

feces were sampled at various times up to 48 hours (Biodynamics 1984). At 6 hours, about 92% of the 

radioactive dose was eliminated in expired air, 99.1% of which was unchanged MTBE. An average of 

7.38% of the administered dose was expired as radiolabeled carbon dioxide. Although not specified, 

apparently no tert-butanol was found in expired air. Urinary radioactivity accounted for an average of 

2.95% of the administered dose. Analysis of the urine revealed that radiolabeled formic acid accounted for 

96.6% of the urinary radioactivity. The remaining radioactivity in the urine was assumed to be 

radiolabeled methanol and formaldehyde. Methanol and formic acid were also detected in plasma, kidney, 

and liver. No tert-butanol was found in the urine. The reason for differences in metabolites found by 

Biodynamics (1984) compared with those found by Bioresearch Labs (1990b, 1990d, 1991) is not clear, 

except that these studies used different strains of rats and different analytical methods for identification of 

the metabolites. 

Some aspects of the in vitro metabolism of MTBE have been studied using microsomes prepared from 

Sprague-Dawley rats (Brady et al. 1990). Incubation of MTBE with microsomes prepared from 

phenobarbital-pretreated rats resulted in equimolar amounts of tert-butanol and formaldehyde. In 

comparing the metabolism of MTBE using microsomes from phenobarbital- and acetone-pretreated rats 

and untreated rats, a 4-fold increase in Vmax value with acetone-induced microsomes and a 5.5-fold 

increase in the Vmax value with phenobarbital-induced microsomes was found compared with the control 

max value. These results indicated that cytochrome P-4502B1, which is inducible by phenobarbital, and 

cytochrome P-4502E1, which is inducible by acetone, play a role in the demethylation of MTBE. 

Inclusion in the incubation of monoclonal antibody against cytochrome P-4502E1, the major acetoneinducible 

isoenzyme, resulted in a 35% inhibition of the demethylation of MTBE, indicating that 

cytochrome P-4502El only partially contributes to the demethylation. Microsomes prepared from rats 

pretreated with MTBE yielded a 47-fold induction of liver microsomal pentoxyresorufin O-dealkylase, 

with no change in N-nitrosodimethylamine demethylase activity. These results are consistent with an 

elevation of cytochrome P-4502B 1 activity with no change in cytochrome P-4502El activity, which was 

confirmed by immunoblot analysis. 
METHYL tert-BUTYL ETHER 99 

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The metabolism of MTBE to formaldehyde was studied using liver microsomes from control and 

phenobarbital-pretreated rats (strain not specified) (Snyder 1979). Phenobarbital-pretreatment 

approximately doubled in formation of formaldehyde from MTBE. The author postulated that 

formaldehyde and tert-butanol are the first metabolites of MTBE formed as a result of o-demethylation 

reaction by the hepatic mixed function oxidases. Further metabolism of formaldehyde would yield 

methanol and/or formic acid with the probable enzymes and cofactors being alcohol dehydrogenase and 

NADH for the formation of methanol and aldehyde dehydrogenase and NAD for the formation of formic 

acid. 

To account for the results in the in vivo and in vitro studies in rats discussed above, a proposed metabolic 

scheme for MTBE is presented in Figure 2-3. 

2.3.4 Excretion 

2.3.4.1 Inhalation Exposure 

In a group of 2 healthy men and 2 healthy women experimentally exposed to 1.7 ppm MTBE for 1 hour, 

the mean blood level of MTBE rose steeply from a level of 0.83 μg /L preexposure to 17.14 μg /L at the end 

of the 1-hour exposure, followed by a decline to an average level of 9.74 μg /L at 40 minutes postexposure 

and 6.32 μg /L at 60 minutes postexposure (Cain et al. 1994). At 90 minutes postexposure, the average 

blood level of MTBE was 7.42 μg /L, indicating that the rapid elimination phase lasted about 60 minutes, 

but that levels did not drop to preexposure levels within the 60-90 minute postexposure period. Blood 

levels were not measured beyond the 90-minute postexposure period. In a similar study in one healthy 

man and one healthy woman experimentally exposed to 1.39 ppm MTBE for 1 hour, the blood level of 

MTBE rose rapidly to 8.2 μg /L and 14.7 μg /L in the man and woman, respectively (Prah et al. 1994). 

Immediately after exposure, the blood levels of MTBE started to decline rapidly with clearance half-times 

of 36 and 37 minutes, respectively. At the end of the 7-hour sampling period, 0.2 and 0.6 μg/L MTBE 

were detected in the blood of the man and woman, respectively. The blood level of tert-butanol rose 

gradually to a plateau of 7-10 μg /L, where it remained for up to 7 hours postexposure. 

The excretion of radioactivity in expired air, urine, and feces was studied in Fischer 344 rats exposed noseonly 

to 400 and 8,000 ppm 14C-MTBE for 6 hours (Bioresearch Labs 1990d). Samples were collected at 

various times for up to 48 hours after exposure. Excretion of radioactivity in feces was minor, with only 

0.74-0.76% recovered after exposure to 400 ppm and 0.75-l.06% recovered after exposure to 8,000 ppm. 

METHYL tert-BUTYL ETHER 101 

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The relative percentages of radioactivity recovered in the urine and expired air were dose-dependent. At 

400 ppm, 64.7 and 65.4% of the total radioactivity was recovered in the urine 48 hours after termination of 

exposure of males and females, respectively, while 21.2 and 21.9% of radioactivity was recovered in the 

expired air of males and females, respectively. At 8,000 ppm, radioactivity recovery in urine accounted 

for 41.6% in males and 35% in females, while radioactivity recovery in expired air accounted for 53.6% in 

males and 59% in females. The shift in excretion route from urine to expired air with increase in dose was 

probably due to shifts in metabolic pathways as metabolizing enzymes become saturated at high doses. 

The rate of excretion of radioactivity via the lungs was rapid, with a total of 82% of the recovered 

radioactivity in expired air excreted by 3 hours and 91-92% excreted by 6 hours. Urinary excretion was 

slower than excretion in expired air, but was faster after exposure to 400 ppm than after exposure to 

8,000 ppm. At the low exposure concentration, the percentages of recovered radioactivity excreted in the 

urine were 27-30% by 6 hours, 65% by 12 hours, 81-85% at 24 hours, and 94-96% by 36 hours. At the 

high exposure concentration, the percentages were 8-10% by 6 hours, 38-47% by 12 hours, 82-88% by 

24 hours, and 95-98% by 36 hours. Similar percentages and rates of excretion of radioactivity in expired 

air and urine were obtained in rats exposed nose-only to 400 ppm unlabeled MTBE for 6 hours per day for 

14 days and then to 400 ppm 14C-MTBE for 6 hours on day 15. 

2.3.4.2 Oral Exposure 

No studies were located regarding the excretion of MTBE or its metabolites in humans after oral exposure. 

The excretion of radioactivity in expired air, urine, and feces was studied in Fischer 344 rats given single 

gavage doses of 40 or 400 mg/kg 14C-MTBE (Bioresearch Labs 1990b). Samples were collected at 

various times up to 48 hours after dosing. As after inhalation exposure, the major routes of excretion are 

expired air and urine, with dose-dependent shifts in the relative percentages excreted by these routes, and 

some significant gender differences. After the 40 mg/kg dose, total recovery of radioactivity in expired air 

was 45.8% in males and 54.4% in females. After the 400 mg/kg dose, this recovery was 65.3 and 68.7% in 

males and females, respectively. The total recovery of radioactivity in urine was 36.2 and 29% of the dose 

in males and females, respectively, at the low dose and 16 and 10.8% in males and females, respectively, 

at the high dose. As with inhalation exposure, the shift in excretion route from urine to expired air with 

increase in dose was probably due to shifts in metabolic pathways as metabolizing enzymes become 

saturated at high doses. Feces contained only 0.87-l. 19% of the radioactivity after the low dose and 

0.26-0.28% after the high dose. Excretion of radioactivity was rapid, with complete elimination in 

expired air and urine occurring within 6 and 36 hours, respectively. Excretion in expired air was 92-93% 
METHYL tert-BUTYL ETHER 102 

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complete at 3 hours and 98% complete at 6 hours after the low dose. After the high dose, excretion in 

expired air at 3 hours accounted for less radioactivity (85-86%) than after the low dose. At 6 hours after 

dosing with 400 mg/kg, however, excretion in expired air was 98% complete. At 6 hours after either dose, 

very little radioactivity was recovered in urine (5-7%), but urinary excretion of radioactivity at 12 hours 

was 41-46% complete at 40 mg/kg and 41-50% complete at 400 mg/kg. Recovery of urinary 

radioactively continued to increase to almost complete excretion by 36 hours. 

In another study in Fischer 344 rats treated with a single oral dose of 40 mg/kg, mean blood concentrations 

of MTBE were 5.37 μg /mL at 1 minute, 15.01 μg /mL at 2.5 minutes, 15.83 μg /mL at 5 minutes, 

14.22 μg /mL at 7.5 minutes, 12.68 μg /mL at 10 minutes, 9.81 μg /mL at 20 minutes, 5.56 μg /mL at 

40 minutes, 3.83 μg /mL at 60 minutes, 2.25 μg /mL at 90 minutes, 1.46 μg /mL at 120 minutes, 0.70 μg /mL 

at 180 minutes, and 0.26 μg /mL at 240 minutes, with a half-life of blood clearance of 56.7 minutes (Exxon 

1988). Thus, after the initial absorptive phase, blood MTBE levels declined sharply from 10 minutes to 

about 40 minutes, followed thereafter by a slower decline. The time course of elimination of MTBE in 

expired air revealed a rapid elimination of unmetabolized MTBE, with >30 and 40% of the administered 

dosed expired by 45 and 90 minutes, respectively, and <10% expired between 120 and 300 minutes. Total 

expiration of MTBE by 3 hours after dosing represented 50-55% of the administered dose. In contrast to 

MTBE, the elimination of tert-butanol in expired air remained fairly constant over the time period, with a 

maximum amount of expired tert-butanol over 5 hours post dosing of 2% of the administered MTBE dose. 

2.3.4.3 Dermal Exposure 

No studies were located regarding excretion of MTBE or its metabolites in humans after dermal exposure 

to MTBE. 

The excretion of radioactivity in expired air, urine, and feces was studied in Fischer 344 rats administered 

40 or 400 mg/kg MTBE to the shaved skin via a dermal chamber for 6 hours (Bioresearch Labs 1990b). 

Samples were collected at various times up to 48 hours after exposure. As after inhalation and oral 

exposure, the major routes of excretion are expired air and urine with some significant gender differences. 

However, in contrast with the observed shifts after inhalation and oral dosing, no dose-dependent shifts in 

the relative percentages excreted by lungs and kidneys were found for the dermal route. Since MTBE is 

less well absorbed after dermal exposure than after oral or inhalation exposure, the amount absorbed after 

the high dermal dose was probably not great enough to saturate metabolizing enzymes, thus accounting for 

lack of shift. A greater percentage of the dose was recovered in the expired air (6.05% in males, 9.67% in 
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females) at 40 mg/kg and (19.6% in males, 23.2% in females) at 400 mg/kg than in the urine. Recovery of 

radioactivity in urine was 6.49 and 6.12% in males and females, respectively, at 40 mg/kg and 12.4 and 

10.7% in males and females, respectively, at 400 mg/kg. Only 0.13-0.14% of the dose was recovered 

from the feces after the low dose and 0.11-0.19% after the high dose. At 3 hours after dosing with 

40 mg/kg, 48-49% of the recovered radioactivity in expired air was excreted. At 6 hours, excretion of 

radioactivity in expired air was 58-60% complete. At 3 hours after dosing with 400 mg/kg, excretion of 

radioactivity in expired air was 70% complete, and at 6 hours after dosing, recovery was 78-80% 

complete. At 6 hours after dosing with either dose, excretion of radioactivity in urine was only l-5% 

complete. After dosing with 40 mg/kg, urinary excretion was 14% (males) and 26% (females) complete at 

12 hours, 55-56% complete at 24 hours, and 75-77% complete at 36 hours. After dosing with 400 mg/kg, 

urinary excretion was 16-17% (both sexes) complete at 12 hours, 72% (males) and 61% (females) 

complete at 24 hours, and 87% (males) and 80% (females) complete at 36 hours. 

2.3.4.4 Other Routes of Exposure 

Limited information regarding excretion of MTBE and its metabolites was provided in a study of 

27 patients who received MTBE via intracystic infusion for dissolution of gallstones (Leuschner et al. 

1991). Urine samples were collected before treatment, immediately after treatment, and up to 18 hours 

after treatment for the determination of levels of MTBE, methanol, tert-butanol, formic acid, and 

formaldehyde. Mean urinary levels of MTBE were about 0.018 mg/mL at 5 hours after treatment and 

< 0.005 mg/mL at 12-l8 hours. Mean urinary levels of tert-butanol were higher than levels of MTBE, with 

about 0.036 mg/mL at 5 hours and 0.03 mg/mL at 12-18 hours after treatment. Methanol was found in 

only 3 patients, while no formaldehyde or formic acid were found. 

The excretion of radioactive MTBE after intraperitoneal (Biodynamics 1984) and intravenous 

(Bioresearch Labs 1990b, 1991; Exxon 1988) dosing with 14C-MTBE has been studied in rats. In general, 

results are similar to those obtained after inhalation and oral dosing of rats (Bioresearch Labs 1990b, 

1990d; Exxon 1988). Since intraperitoneal and intravenous routes of exposure are not environmentally 

relevant, and since information is available for the inhalation, oral, and dermal routes, details of the results 

of studies by the other routes are not provided. 

The only toxicokinetic information for MTBE in mice involves pulmonary excretion after intraperitoneal 

dosing (Yoshikawa et al. 1994). The mice were injected with 50, 100, or 500 mg/kg. The pulmonary 

eliminations were very similar for each dose. MTBE concentrations in air increased rapidly and reached 
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maximum concentrations within 35-45 minutes after dosing. The peak air concentrations of MTBE were 

approximately 8 ppm at the dose of 50 mg/kg, 30 ppm at the dose of 100 mg/kg, and 200 ppm at the dose 

of 500 mg/kg. Thereafter, the MTBE concentrations decreased exponentially, with an initial rapid 

decrease (α-phase; 40-200 minutes) followed by a slow decrease (β phase; 200-360 minutes) for the 

100 and 500 mg/kg doses. No β phase was observed for the 50 mg/kg dose because the measurement of 

MTBE could not be continued after 2 10 minutes. The mean pulmonary elimination rate constants of the 

α phase were 0.0166 per minute for the 50 mg/kg dose, 0.0159 per minute for the 100 mg/kg dose, and 

0.0148 per minute for the 500 mg/kg dose. The mean pulmonary elimination constants for the β phase 

were 0.0086 per minute at the 100 mg/kg dose and 0.0089 per minute at the 500 mg/kg dose. Thus, the 

half-time for the α phase was approximately 45 minutes, and the half-time for the β phase was 

approximately 80 minutes. The amount of MTBE exhaled was dose-dependent: the mice exhaled 23.2% 

of the 50 mg/kg dose, 37.6% of the 100 mg/kg dose, and 69.0% of the 500 mg/kg dose, reflecting the low 

solubility of MTBE in blood. Greater than 90% of the amount excreted in air was eliminated within 

3 hours. 

2.3.5 Physiologically Based Pharmacokinetic (PBPK) Model 

A physiologically based pharmacokinetic (PBPK) model for MTBE and tert-butanol in male Fischer 344 

rats is being developed (Borghoff et al. 1996). The model is based on chemical-specific parameters of 

solubility of MTBE and tert-butanol in blood and selected tissues and metabolic rate constants using vial 

equilibration and gas uptake techniques performed by Borghoff et al. (1996) and the pharmacokinetic data 

for male Fischer 344 obtained in the studies by Bioresearch Labs (1990a, I990b, 1990c, 1990d) and for 

humans in the study by Cain et al. (1994). The model described MTBE metabolism as occurring via two 

saturable pathways and predicted gas uptake data up to 2,000 ppm initial concentrations. The model was 

also able to predict MTBE blood concentrations in rats exposed by inhalation to 400 or 8,000 ppm for 

6 hours, in rats injected intravenously with 40 mg/kg, and in rats treated orally at 40 or 400 mg/kg in the 

Bioresearch Labs (1990a, 1990b, 1990c, 1990d) studies. Since the pharmacokinetics of tert-butanol 

appeared to be more complex than those of MTBE, Borghoff et al. (1996) indicated that additional 

experimental data on the distribution and elimination of tert-butanol are needed to refine the model. 
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2.4 MECHANISMS OF ACTION 

As MTBE is a volatile, lipophilic molecule of small molecular size (see Chapter 3) it is rapidly and 

extensively absorbed from the respiratory and gastrointestinal tracts (Bioresearch Labs 1990a, 1990b, 

1990c, 1990d). Dermal absorption is less extensive (Bioresearch Labs 1990a, 1990b). Absorption is 

probably by passive diffusion. Much of the absorbed MTBE is rapidly excreted as unchanged MTBE in 

the expired air. The remainder is demethylated to tert-butanol and formaldehyde via cytochromes 

P-4502El and P-4502B1 activities (Brady et al. 1990). Formaldehyde may be further reduced to methanol 

and oxidized to formic acid (Snyder 1979), which may be further metabolized to carbon dioxide. 

tert-Butanol is further metabolized to 2-methyl-1,2-propanediol and α-hydroxyisobutyric acid, which are 

excreted in the urine (Bioresearch Labs 1990b). Unchanged MTBE and tert-butanol are the main 

respiratory excretion products. MTBE and its metabolites show little tendency to accumulate in tissues 

(Bioresearch Labs 1990b). An inhalation study in rats indicated that MTBE and its metabolite tert-butanol 

were distributed to the brain at concentrations similar to blood concentrations (Savolainen et al. 1985). In 

addition, the perirenal fat concentration of MTBE was higher than the blood concentration of MTBE, but 

no levels of tert-butanol were found in perirenal fat. 

Neurological Effects. The presence of MTBE and/or tert-butanol in the brain may account for the central 

nervous system toxicity of MTBE. Numerous studies have shown that exposure to MTBE results in 

profound central nervous system depression in animals (ARCO 1980; Bioresearch Labs 1990d; BurleighFlayer et al. 1992; Chun and Kintigh 1993; Chun et al. 1992; Dodd and Kintigh 1989; Gill 1989; 

Greenough et al. 1980; ITT Research Institute 1992; Neeper-Bradley 1991; Robinson et al. 1990; Tyl 

1989). The central nervous system depression has been characterized by ataxia, hypoactivity, drowsiness, 

anesthesia, prostration, lack of startle response, and lack of righting reflex. The exact mechanism by 

which MTBE and tert-butanol exert their central nervous system depression is not known, but may involve 

changes in membrane fluidity. 

Hepatic Effects. MTBE is minimally toxic to the liver of animals, resulting in increased liver weights 

(Biodynamics 1981; Burleigh-Flayer et al. 1992; Chun et al. 1992; Dodd and Kintigh 1989; ITT Research 

Institute 1992; Neeper-Bradley 1991; Robinson et al. 1990; Tyl 1989). This increase in liver weight may 

be due to induction of microsomal enzymes. Intraperitoneal injection of rats with MTBE resulted in a 

47-fold induction of pentoxyresorufin O-dealkylase activity, an activity associated with cytochrome 

P-4502B1 (Brady et al. 1990). Cytochrome P-4502B1 is also involved in the demethylation of MTBE; 

thus, MTBE appears to induce its own metabolism. Mice exposed to MTBE by inhalation had an 
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increased incidence of hepatocellular hypertrophy (which could be related to enzyme induction) after 

exposure for intermediate (Chun and Kintigh 1993) and chronic (Burleigh-Flayer et al. 1992) durations 

and hepatocellular adenoma after exposure for chronic durations (Burleigh-Flayer et al. 1992), but no liver 

lesions were found in rats similarly exposed chronically (Chun et al. 1992). Mice are particularly 

susceptible to chemically induced hepatic tumors. The results of cell proliferation evaluations of 

hepatocytes from male and female mice exposed for 5 or 23 exposures revealed statistically significant 

increased uptake of 5-bromo-2’-deoxyuridine in the nuclei of hepatocytes after 5 exposures, but not after 

23 exposures (Chun and Kintigh 1993). The authors proposed that MTBE initially places an increased 

metabolic demand on liver cells resulting in a compensatory increase in hepatocellular proliferation that 

eventually leads to hepatocellular hypertrophy. As noted in Section 2.5 for Genotoxic Effects, the 

available data indicate that MTBE has little or no genotoxic activity. The mechanism by which MTBE 

induces liver tumors in mice is a topic of ongoing studies, which indicate that the mechanism may involve 

the modulation of hormones, specifically estrogen, but that MTBE did not show tumor-promoting activity 

(see Section 2.10.3). 

Suggestive clinical evidence of hepatocellular necrosis (increased SGPT or SGOT, serum lactic 

dehydrogenase) was found in rats given MTBE orally for 14 or 90 days (Robinson et al. 1990), but 

histological evidence of hepatocellular necrosis was not found in any study (Burleigh-Flayer et al. 1992; 

Chun and Kintigh 1993; Chun et al. 1992; Greenough et al. 1980; ITT Research Institute 1992; NeeperBradley 1991; Robinson et al. 1990). 

Renal Effects. MTBE produces renal effects in male rats that are consistent with the α2u-globulin 

syndrome, including large hyaline droplets in proximal tubular cells (Dodd and Kintigh 1989; Robinson et 

al. 1990); intratubular granular casts at the junction of the outer and inner stripe of the outer medulla 

(Robinson et al. 1990); increases in α2u-globulin accumulation in kidney tissues (Swenberg and Dietrich 

1991); increased incidence and severity and earlier onset of chronic progressive nephropathy, 

accompanied by fibrous osteodystrophy, hyperplasia in the parathyroid glands, and mineralization in 

numerous tissues; and an increased incidence of renal tubular adenoma and carcinoma (Chun et al. 1992). 

However, the evidence that the renal effects observed in male rats exposed to MTBE are associated with 

α2u-globulin accumulation has been questioned, since the increase in α2u-globulin accumulation was not 

dose-related, and α2u-globulin positive proteinaceous casts at the junction of the proximal tubules and thin 

limb of Henle were not observed, unlike the classical lesions of other α2u-globulin inducing agents 

(Swenberg and Dietrich 1991). Furthermore, a study specifically designed to determine whether MTBE 

induces α2u-globulin accumulation in male rats found no evidence, based on immunostaining with an 
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antibody to α2u-globulin (Chun and Kintigh 1993). However, an increased accumulation of protein in 

male renal proximal convoluted tubule epithelium associated with increased epithelial cell proliferation 

was found as determined by Mallory’s Heidenhain technique. Chun and Kintigh (1993) suggested that a 

mechanism other than α2u-globulin accumulation (perhaps the accumulation of another unknown protein 

unique to male rats) may be involved. It is possible that the hypothetical protein is also unique to male 

rats and acts in the same way as α2u-globulin. Since the female rats did not have increased epithehal cell 

proliferation in the renal tubules, the female rat kidney tissues were not examined for protein 

accumulation. 

α2u-Globulin is a low molecular weight protein synthesized in large quantities in the male rat liver, 

secreted into the blood under the influence of testosterone (Alden 1986), and filtered through the 

glomerulus. Renal tubule cells reabsorb α2u-globulin and sequester it into lysosomes, where it is 

catabolized into amino -acids and peptides. In the normal rat kidney, the rate of catabolism of α2u-globulin 

is relatively slow compared with that of other proteins (Swenberg et al. 1989). Chemicals that bind to 

α2u-globulin yield a complex that is more resistant to the proteolytic enzymes in the lysosomes, which 

leads to the accumulation of the complex in the tubule cells. Accumulation of the chemical α2u-globulin 

complex causes lysosomal overload and necrosis of the tubule cells, with subsequent proliferative 

regeneration. If exposure to the chemical is chronic, accumulation, necrosis, and subsequent cellular 

proliferation continues, and can lead to a carcinogenic response. α2u-Globulin nephropathy is a condition 

specific to male rats; that is, it has not been found in female rats or males and females of any other species, 

including humans. 

The increased incidence, increased severity, and earlier onset of chronic progressive nephropathy observed 

in male rats exposed by inhalation to MTBE may involve the accumulation of α2u-globulin or a similarly 

acting unknown other protein unique to male rats. Although chronic progressive nephropathy is an agerelated 

phenomenon common in rats, chemicals that induce α2u-globulin (or by extension, the unknown 

protein) accumulation may exacerbate chronic progressive nephropathy in male rats. However, chronic 

progressive nephropathy was also enhanced in female rats (which do not produce α2u-globulin in the 

liver), but at higher doses of MTBE, with lesser severity, and at later onset than in males (Chun et al. 

1992). Thus, an additional unknown mechanism may also be involved in the enhancement of chronic 

progressive nephropathy by MTBE. 

Lymphoreticulur Effects. Although most studies in animals exposed to MTBE indicate that the 

lymphoreticular system is not a target of MTBE toxicity, a 13-week inhalation study indicated a higher 
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incidence of lymphoid hyperplasia in the submandibular lymph nodes in male rats (Dodd and Kintigh 

1989), and a chronic oral study indicated an increased incidence of dysplastic proliferation of 

lymphoreticular tissues and of leukemia and lymphoma in female rats (Belpoggi et al. 1995). Since the 

increased incidence of leukemia and lymphoma was dose-related, but the increased incidence of dysplastic 

proliferation of the lymphoreticular tissues was higher at the low dose than at the high dose, more of the 

dysplastic proliferation lesions might have developed into the lymphomas and leukemias in the high dose 

female, suggesting that the dysplastic proliferation represents a preneoplastic lesion (Belpoggi et al. 1995). 

Although the mechanism by which MTBE produced lymphoreticular effects and leukemia is not known, 

the authors discussed the possibility that formaldehyde, a known metabolite of MTBE (see Section 2.3.3), 

is involved, since formaldehyde increased the incidence of lymphomas and leukemias in male and female 

rats in other studies from their laboratories. 

Reproductive Effects. Although reproductive studies in animals indicate that MTBE exposure does not 

affect reproductive performance or result in nonneoplastic histopathological lesions in reproductive 

organs, a dose-related increased incidence of interstitial cell adenoma in the testes was observed in 

Fischer 344 male rats in a chronic inhalation study (Chun et al. 1992). Fischer 344 rats commonly develop 

testicular tumors, and the incidences in MTBE-exposed groups were in the range of historic controls, 

while the incidence in the concurrent control group was lower than the incidence in historic controls. 

However, in a chronic oral study of Sprague-Dawley rats, an increased incidence of Leydig interstitial cell 

tumors of the testes was found (Belpoggi et al. 1995). As noted in Section 2.5 for Genotoxic Effects, the 

available data indicate that MTBE has little or no genotoxic activity. The mechanism by which MTBE 

induces testicular tumors in rats is not known, but ongoing or future studies investigating the relationship 

between endocrine modulation and the mechanism of MTBE-induced toxicity may provide some insight 

(see Section 2.10.3). 

Developmental Effects. MTBE exposure of pregnant rats and rabbits did not result in developmental 

effects in the offspring (Conaway et al. 1985; Tyl 1989). MTBE did produce developmental effects in 

mice, including increased incidence of fused sternebrae, increased number of nonviable implantations per 

litter, increased late resorptions, reductions in the number of viable implantations, reduced fetal body 

weight, significantly increased incidences of cleft palate, skeletal defects, and reduced skeletal 

ossification, and a significantly reduced incidence of partial fetal atelectasis (Tyl and Neeper-Bradley 

1989). The mechanism by which MTBE resulted in most of these development effects is not known, but 

the increased incidence of cleft palate was considered to be related to maternal stress with possible 

associated increased endogenous levels of corticosterone. 
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2.5 RELEVANCE TO PUBLIC HEALTH 

Until recently (1980), commercial production of MTBE was relatively low; however, MTBE is currently 

used extensively as a gasoline additive to increase octane levels and to reduce the levels of carbon 

monoxide emissions. This widespread use has increased the possibility of general population exposure. 

In addition to inhalation risks while fueling motor vehicles, MTBE is emitted to the ambient air, primarily 

from pre-combustion volatilization. These atmospheric pathways are of most concern for the general 

population; however, more localized risks can arise if MTBE becomes a groundwater or soil contaminant 

from major production sites, large tank batteries, transfer terminals, active or abandoned waste sites, 

leaking underground storage tanks, or from gasoline spills. Thus, while inhalation exposure is the major 

route of concern, exposure from contaminated drinking water or dermal contact with contaminated soil can 

also occur. MTBE is also used to dissolve gallstones by injecting it into the bile duct or gallbladder, but 

side effects of this procedure are of concern only for individuals undergoing this therapy. 

MTBE is a volatile, lipophilic molecule of small molecular size, which is rapidly and extensively absorbed 

from the respiratory and gastrointestinal tracts. Dermal absorption is less extensive. Absorption is 

probably by passive diffusion. Much of the absorbed MTBE is rapidly excreted as unchanged MTBE in 

the expired air. The remainder is metabolized to tert-butanol, formaldehyde, methanol, formic acid, 

carbon dioxide, 2-methyl-l,2-propanediol, and α-hydroxyisobutyric acid. Unchanged MTBE and 

tert-butanol are the main respiratory excretion products. MTBE and its metabolites distribute to tissues, 

but show little tendency to accumulate. MTBE and its metabolite tert-butanol may distribute to the brain 

at concentrations similar to blood concentrations. The presence of MTBE and tert -butanol in the brain 

may account for the transient central nervous system depression, which appears to be the most sensitive 

effect of acute exposure. 

Information regarding health effects of MTBE exposure in humans was located in studies of motorists, gas 

station attendants, and mechanics, in experimental studies in subjects exposed by inhalation to MTBE for 

one hour, and in clinical studies of patients receiving MTBE therapy for the dissolution of gallstones. In 

some situations, motorists and workers have reported symptoms of coughing, burning sensations in the 

nose and throat, headache, nausea or vomiting, dizziness, and feelings of spaciness and disorientation that 

may been associated with MTBE exposure. In some studies, it was determined that the subjective 

reporting of these symptoms declined when the oxyfuel programs were terminated. Other studies failed to 

detect symptoms associated with MTBE exposure. Whether the symptoms reported for MTBE in gasoline 

are directly due to MTBE, to mixtures of the components in the oxygenated gasoline, or to atmospheric 
METHYL tert-BUTYL ETHER 110 

2. HEALTH EFFECTS 

degradation products of MTBE (e.g., formaldehyde, tert -butanol, or tert-butyl formate), to all of these 

factors, or not even MTBE-related are current topics of debate and research. In addition, such factors as 

cloud cover, the condition of individual automobiles, dose-time factors, and the role of weather and 

sunlight in modulating the amounts of the atmospheric degradation products of MTBE may partly explain 

why some individuals experience these effects and other don’t and why some individuals experience 

effects on some days, but not on other days. 

In patients receiving MTBE for gallstone dissolution, effects include typical signs of transient central 

nervous system depression, gastrointestinal irritation, evidence of necrosis in the liver and gallbladder, 

transient cardiovascular effects such as hyper- or hypotension and palpitations, and transient leukocytosis. 

These side effects have occurred from overflow of MTBE from the gallbladder lumen or extravasation into 

the systemic circulation. In most cases, the patients who experienced these side effects recovered with no 

residual effects. 

The central nervous system effects are characteristic of ether anesthesia and ethyl alcohol intoxication and 

include lacrimation, ataxia, loss of righting reflex, hyperpnea, labored breathing, incoordination, 

prostration, drowsiness, hypoactivity, decreased startle and pain reflexes, decreased muscle tone, 

anesthesia, blepharospasm, and stereotypy. These effects have been observed in animals exposed for 

acute-, intermediate-, and chronic-durations by the inhalation and/or oral routes, and probably can also 

occur after dermal exposure. Other effects noted in animals include increased liver and kidney weights, 

induction of liver and kidney microsomal enzymes, respiratory irritation after inhalation exposure, 

gastrointestinal irritation and decreased BUN levels after oral exposure, dermal irritation after dermal 

exposure, and ocular irritation after direct contact of the liquid or vapor with the eyes. Histological 

hepatic effects have been observed only in mice and consisted of increased incidences of hepatocellular 

hypertrophy and hepatocellular adenoma after chronic-duration inhalation exposure. Renal effects have 

been observed in rats, and are suggestive of accumulation a α2u -globulin or another protein unique to male 

rats, which has no relevance to human health, and exacerbation of chronic progressive nephropathy in 

male and female rats, which may have relevance to human health. In addition, male rats developed renal 

tubule cell carcinoma and adenoma, the development of which may be related to α2u -globulin or other 

unique protein accumulation in the proximal renal tubule cells. However, the evidence that the kidney 

tumor development in male rats is related to α2u -globulin or another protein accumulation is limited, 

making the relevance to human health uncertain. In a chronic oral study, female rats were reported to 

develop dysplastic proliferation of lymphoreticular tissues (possibly preneoplastic) and lymphoma and 

leukemia, while male rats were reported to develop testicular Leydig cell tumors. 
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MTBE has been well studied for reproductive effects in animals exposed by the inhalation routes for acute, 

intermediate, and chronic durations. The results indicate that MTBE is not a reproductive toxicant in 

animals. MTBE has also been studied for developmental effects in rats, rabbits, and mice. No 

developmental effects were found in rabbits and the only effect in rats was decreased body weight of F1 

and F2 pups. MTBE did produce developmental effects in mice, including increased incidence of fused 

sternebrae, increased number of nonviable implantations per litter, increased late resorptions, and 

reductions in the number of viable implantations. In addition, reduced fetal body weight, significantly 

increased incidences of cleft palate, skeletal defects, and reduced skeletal ossification, and a significantly 

reduced incidence of partial fetal atelectasis were observed in mouse fetuses. Whether the offspring of 

humans exposed to MTBE would develop developmental effects is not known. The available data on the 

genotoxic potential of MTBE indicate that it may be weakly genotoxic. 

Based on toxicity and toxicokinetic data from studies in animals, potentially susceptible humans 

populations may be people who ingest barbiturates or alcoholic beverages, which induce microsomal 

enzymes; human embryos and fetuses because of the developmental effects observed in mice; and elderly 

people or people with pre-existing nephropathy, because of the exacerbation of chronic progressive 

nephropathy in female rats. In addition, some people may become more chronically sensitive to MTBE as 

a result of prolonged low level exposure. 

Minimal Risk Levels for MTBE 

Inhalation MRLs 

z An MRL of 2 ppm has been derived for acute-duration inhalation exposure (14 days or less) to 

MTBE. 

The MRL for acute-duration inhalation exposure is based on a NOAEL of 800 ppm for 6 hours for 

neurological effects in rats in a study by Gill (1989). In this study, groups of 22 male and 22 female 

Fischer 344 rats were exposed to 0, 800, 4,000, or 8,000 ppm MTBE for 6 hours. Groups of 14 male and 

14 female rats were studied for motor activity, and the remaining groups of 8 male and 8 female rats were 

given a functional observation battery of tests at 1, 6, and 24 hours after exposure. Concentration-related 

increases in ataxia and duck-walk gait occurred in both males and females at 4,000 and 8,000 ppm (Gill 

1989). Other effects noted in high-dose males included labored respiration pattern, decreased muscle tone, 

decreased performance on a treadmill, and increased hind limb splay. Other effects noted in females 
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included decreased hind limb grip strength at > 4,000 ppm and labored respiration and increased latency to 

rotate on the inclined screen at 8,000 ppm. These effects were seen at 1 hour after exposure, but not at 6 or 

24 hours after exposure, indicating the transient nature. The time course of changes in motor activity 

corresponded with the functional observation battery findings, and supported the exposure-related central 

nervous system depression. No neurological effects were observed at the NOAEL of 800 ppm for 6 hours. 

The NOAEL of 800 ppm is supported by another study, which found only increased motor activity in 

female rats, but no other neurological effects in rats at 800 ppm, 6 hours per day, 5 days per week for 

13 weeks (Dodd and Kintigh 1989). In this study, hypoactivity at 4,000 ppm and hypoactivity and ataxia 

at 8,000 ppm were observed daily after the 6-hour per day exposure, thus representing effects of acute 

exposure. A number of acute-duration inhalation studies in rats, mice, and rabbits have described similar 

clinical signs of neurotoxicity at MTBE concentrations > 2,000 ppm (ARCO 1980; Biodynamics 1981; 

Bioresearch Labs 1990d; Chun and Kintigh 1993; Dodd and Kintigh 1989; Tyl 1989; Tyl and NeeperBradley 1989). 

z An MRL of 0.7 ppm has been derived for intermediate-duration inhalation exposure (15-364 days)

 to MTBE. 

The MRL for intermediate-duration inhalation exposure is based on a NOAEL of 400 ppm for clinical 

signs of neurotoxicity in a reproductive study in male and female rats (Neeper-Bradley 1991). In this 

study, groups of 25 male and 25 female rats were exposed to 0, 400, 3,000, or 8,000 ppm MTBE for 

6 hours per day, 5-7 days per week. Exposure for 10 weeks prior to mating and through day 19 of 

gestation to the concentration of 8,000 ppm MTBE resulted in salivation and hypoactivity in F0 and F1 

parental rats. F0 and F1 parental groups also showed hypoactivity and lack of startle response, as well as 

blepharospasm, at 3,000 ppm. In a 28-day study, rats and mice had similar effects at exposure levels of 

> 3,000 ppm, but not at 400 ppm (Chun and Kintigh 1993). In a 13-week study, rats were exposed to 0, 

800, 4,000, or 8,000 ppm MTBE 6 hours per day, 5 days per week (Dodd and Kintigh 1989). At 

4,000 ppm, the rats were hypoactive, had elevated body temperature, and decreased hind limb grip 

strength. At 8,000 ppm, both ataxia and hypoactivity were observed. Some hyperactivity occurred in 

female rats at 800 ppm, but no signs were observed in males at 800 ppm. 
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z An MRL of 0.7 ppm has been derived for chronic-duration inhalation exposure (365 days or more)

 to MTBE. 

The MRL for chronic-duration inhalation exposure to MTBE is based on a NOAEL of 400 ppm for chronic 

progressive nephropathy in female rats in a study by Chun et al. (1992). In this study, groups of 50 male 

and 50 female Fischer 344 rats were exposed to 0, 400, 3,000, or 8,000 ppm MTBE 6 hours per day, 5 days 

per week for up to 24 months. Male rats exposed to > 400 ppm had increased mortality and decreased 

mean survival time due to chronic progressive nephropathy. End points monitored were clinical signs, 

body weight, organ weight, hematological parameters, corticosterone evaluation, and comprehensive gross 

and histological examination. Increased absolute and relative liver and kidney weights were observed in 

females at > 3,000 ppm. No gross or histopathological lesions were found in the liver of either sex, but 

concentration-related increased incidence and severity of chronic progressive nephropathy, accompanied 

by osteodystrophy, hyperplasia of the parathyroids, and mineralization in numerous tissues was found in 

males at all exposure levels and in females at > 3,000 ppm. No evidence of renal effects was found in the 

female rats at 400 ppm. The higher incidence and greater severity of chronic progressive nephropathy at 

lower exposure concentrations in male rats compared with female rats may be due to the exacerbation of 

this syndrome by the accumulation of α2u -globulin or another unknown protein unique to male rats. 

Because the enhancement of chronic progressive nephropathy, which led to increased mortality and 

decreased survival time in males, may be associated with the accumulation of α2u -globulin or other protein 

unique to male rats, these end points in male rats are not considered for MRL derivation. However, since 

female rats also had enhanced chronic progressive nephropathy not associated with accumulation of a 

male rat specific protein, the chronic inhalation MRL of 0.7 ppm was calculated based on the NOAEL of 

400 ppm for renal effects in female rats. The chronic-duration inhalation NOAEL for renal effects is also a 

NOAEL for clinical signs of neurotoxicity in rats in this study. The NOAEL of 400 ppm for chronicduration 

inhalation exposure to MTBE is supported by a similar study in male and female mice similarly 

exposed to the same concentrations for 18 months (Burleigh-Flayer et al. 1992). In this study, absolute 

and relative liver weights were increased at > 3,000 ppm, and absolute and relative kidney weights were 

increased at 8,000 ppm. Comprehensive histological examination of organs and tissues revealed an 

increased incidence of hepatocellular hypertrophy and hepatocellular adenoma in female mice at 

8,000 ppm. The NOAEL for liver effects in this study was 400 ppm, which was also a NOAEL for 

neurotoxicity in mice in this study. 
METHYL tert-BUTYL ETHER 114 

2. HEALTH EFFECTS 

Oral MRLs 

z An MRL of 0.4 mg/kg/day has been derived for acute-duration oral exposure (14 days or less) to

 MTBE. 

The acute-duration oral MRL is based on a NOAEL of 40 mg/kg for neurological effects in a 

pharmacokinetic study in rats (Bioresearch Labs 1990b). In this study, groups of 6 male and 6 female 

Fischer 344 rats were treated by gavage with MTBE in water at doses of 0, 40, and 400 mg/kg. The rats 

given 400 mg/kg showed signs of drowsiness. Although this study was designed as a pharmacokinetic 

study rather than a toxicity study, the observation of drowsiness is consistent with observations of central 

nervous system depression in animals exposed to MTBE by the inhalation and oral routes, and the study 

provides the highest NOAEL below which there is no LOAEL. In other acute-duration oral studies, rats 

had mild central nervous system depression at 1,900 mg/kg and ataxia at 2,450 mg/kg (ARCO 1980), 

salivation at 90 mg/kg and hypoactivity and/or ataxia at 440 mg/kg (ITT Research Institute 1992), and 

profound but transient anesthesia at 1,200 mg/kg or 1,428 mg/kg/day for 14 days (Robinson et al. 1990). 

z An MRL of 0.3 mg/kg/day has been derived for intermediate-duration oral exposure (15-364 days)

 to MTBE. 

The intermediate-duration oral MRL of 0.3 mg/kg/day is based on a minimal LOAEL of 100 mg/kg/day 

for hepatic effects in rats exposed by gavage to MTBE for 90 days (Robinson et al. 1990). In this study, 

significantly decreased BUN levels were observed in both male and female rats exposed to the lowest dose 

tested. Significantly decreased BUN levels were also observed in female rats given 1,428 mg/kg/day 

orally for 14 days (Robinson et al. 1990). In the 90-day study, relative liver weights were significantly 

increased in female rats at 900 mg/kg/day and in male rats at 900 and 1,200 mg/kg/day. Serum lactic 

dehydrogenase was significantly elevated in females only at 300 mg/kg/day, and SGOT was significantly 

elevated in males at 300 and 1,200 mg/kg/day. However, no treatment-related histopathological lesions 

were found in the liver in either the 14-day study or the 90-day study. 

An MRL was not derived for chronic-duration oral exposure to MTBE because in the only chronic oral 

study (Belpoggi et al. 1995), increased mortality occurred in female rats at the lowest dose tested 

(250 mg/kg/day). Furthermore, the dose of 250 mg/kg/day was associated with dysplastic proliferation of 

lymphoreticular tissues and an increased incidence of lymphoma and leukemia in female rats. 
METHYL tert-BUTYL ETHER 115 

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Death. No information was located regarding death in humans exposed to MTBE by any route. The 

data in animals indicate that very high inhalation concentrations, oral doses, or derrnal doses are required 

to cause death after acute exposure. Acute inhalation LC50 values range from 33,700 ppm for 4 hours in 

rats (ARCO 1980) to 180,000 ppm for 10 minutes in mice (Snamprogetti 1980). Acute oral LD50 values 

were 3,866 mg/kg in rats (ARCO 1980) and 4,000 mg/kg in mice (Little et al. 1979). No deaths occurred 

in rats exposed to < 8,000 ppm for 6 hours (Bioresearch Labs 1990d; Gill 1989). Repeated inhalation and 

oral dosing of rats, mice, and rabbits even with high doses generally has resulted in no deaths in acute- or 

intermediate-duration studies. The following inhalation concentrations did not result in death: 

> 8,000 ppm for 6 hours per day for 1 or 2 days (Vergnes and Chun 1994; Vergnes and Morabit 1989) or 

for 5 days per week for < 13 weeks (Biodynamics 1981; Chun and Kintigh 1993; Dodd and Kintigh 1989; 

Greenough et al. 1980); <2,500 ppm for 16-28 weeks (Biles et al. 1987); and 80,000 for 5-10 minutes per 

day, 5 days per week for 30 days (Snamprogetti 1980). Oral doses > 1,750 mg/kg/day for < 4 weeks 

(Bioresearch Labs 1990a; ITT Research Institute 1992; Robinson et al. 1990; Ward et al. 1994) and 

> 1,200 mg/kg/day for 90 days (Robinson et al. 1990) also did not result in death. Similarly, no deaths 

occurred in rats, mice, or rabbits exposed to 8,000 ppm during gestation (Conaway et al. 1985; Tyl 1989; 

Tyl and Neeper-Bradley 1989). In addition, no deaths occurred after dermal exposure of rats at 

< 400 mg/kg for 6 hours (Bioresearch Labs 1990b) or rabbits at 10,000 mg/kg for 24 hours (ARCO 1980). 

However, chronic inhalation exposure resulted in increased mortality due to enhanced chronic progressive 

nephropathy in male rats at > 400 ppm (Chun et al. 1992) and to obstructive uropathy in male mice at 

8,000 ppm (Burleigh-Flayer et al. 1992). Mortality was not increased at 400 or 3,000 ppm in male mice or 

at any concentration in female rats or mice. In a chronic oral study, female rats, but not male rats, had a 

dose-related increase in mortality at > 250 mg/kg/day beginning at 16 weeks from the start of the study 

(Belpoggi et al. 1995). 

Lower doses produced death in animals after exposure routes that are not environmentally relevant (e.g., 

intravenous, intrahepatic), but humans have been treated with MTBE via intracystic infusion for the 

dissolution of gallstones. Significant numbers of rats died after a dose of only 148 mg/kg was 

administered intravenously or intrahepatically, but no rats died after the same dose was administered 

intraperitoneally (Akimoto et al. 1992). In other intraperitoneal studies, 2 of 5 rats died after dosing with 

3,705 mg/kg (Brady et al. 1990), but intraperitoneal LD50 values of 1,249 mg/kg in rats and 1,010 mg/kg 

in mice were determined (Snamprogetti 1980). The intravenous LD50 in rats was 415 mg/kg. 

Subcutaneous LD50 values were much higher (4,946 mg/kg for rats and 2,646 mg/kg for mice). Two of 

6 rabbits that received 1,782 mg/kg through the bile duct died (Adam et al. 1990). 
METHYL tert-BUTYL ETHER 116 

2. HEALTH EFFECTS 

Based on the information in animals, it is unlikely that levels of MTBE in occupational settings, the 

ambient environment, and at hazardous waste sites would be high enough to cause death of humans. 

Exposure to MTBE at high levels would be expected only in the case of accidental spills. 

Systemic Effects 

Respiratory Effects. Coughing and a burning sensation of the nose or throat were frequently reported 

symptoms in motorists, gas station attendants, and mechanics during oxygenated fuel programs in which 

MTBE was added to gasoline for reducing carbon monoxide emissions (CDC 1993a, 1993b; Moolenaar et 

al. 1994; White et al. 1995). In addition, a preliminary survey of symptoms in petroleum refinery 

employees working with gasoline containing MTBE indicated high self-reporting of respiratory 

symptoms, such as nose irritation, cough, and shortness of breath (Mehlman 1995). However, these and 

other studies (Anderson et al. 1995; Beller and Middaugh 1992; Chandler and Middaugh 1992) in humans 

suggest that knowledge about oxygenated fuel programs, including the likely awareness of the potential 

negative effects of MTBE and the higher cost of oxygenated fuels, may have biased the subjective 

symptom reporting. In addition, other surveys of humans (CDC 1993c; Fiedler et al. 1994; Mohr et al. 

1994) and experimental studies in humans (Cain et al. 1994; Prah et al. 1994) found no increase in health 

complaints among people with high oxygenated fuel or MTBE exposure. No information was located 

regarding respiratory effects in humans after exposure to MTBE by the oral or dermal routes. In animals, 

changes in lung weight (either decreases or increases) have been observed after intermediate-duration 

inhalation exposure (Greenough et al. 1980) or after oral dosing for 14 or 90 days (Robinson et al. 1990). 

However, treatment-related gross or histopathological lung or respiratory tract lesions generally have not 

been observed in rats, mice, or rabbits exposed by inhalation or orally for any duration (ARCO 1980; 

Belpoggi et al. 1995; Burleigh-Flayer et al. 1992; Chun et al. 1992; Dodd and Kintigh 1989; ITT Research 

Institute 1992; Neeper-Bradley 1991 ; Robinson et al. 1990; Tyl 1989). However, a high incidence of 

increased severity of chronic inflammation of the nasal mucosa and trachea was observed in rats exposed 

to 1,000 or 3,000 ppm for 9 days (Biodynamics 1981), indicative of irritation at the portal of entry and 

exit, as much unchanged MTBE and the metabolite tert-butanol are eliminated in the expired air. An RD50 

(50% decrease in respiratory rate) of 4,604 ppm, indicative of sensory irritation, was found in mice 

exposed by inhalation for 1 hour (Tepper et al. 1994). Four-hour inhalation exposures of rats to very high 

concentrations of MTBE (> 18,892 ppm) resulted in such effects as hyperpnea, tachypnea, nasal discharge, 

and respiratory failure (ARCO 1980); labored breathing was observed in mouse dams exposed to 

8,000 ppm MTBE during gestation (Tyl and Neeper-Bradley 1989); and labored respiration was observed 
METHYL tert-BUTYL ETHER 117 

2. HEALTH EFFECTS 

in rats given high oral doses ( > 4,080 mg/kg) (ARCO 1980). These effects may be related to the central 

nervous system effects of MTBE (see Neurological Effects, below). 

Respiratory effects have also been found in animals after exposure routes that are not environmentally 

relevant (e.g., intravenous, intrahepatic, intraperitoneal), but humans have been treated with MTBE 

intracystically for the dissolution of gallstones. While a number of clinical studies of patients receiving 

MTBE therapy have recorded side effects, no studies were located that reported respiratory effects. A 

number of studies have been conducted in animals to determine possible side effects of MTBE therapy for 

gallstone dissolution. Pulmonary hemorrhage was observed in rats given 148 mg/kg MTBE 

intrahepatically, intraperitoneally, or intravenously, with intravenous dosing producing the greatest 

damage (Akimoto et al. 1992). Intravenous injection of rats, rabbits, and cats with >7.4 mglkg resulted in 

increased respiratory rates which paralleled decreases in blood pressure and bradycardia, and 

intraperitoneal injection of rats with 185 mg/kg/day for 15 days resulted in pneumonia (Snamprogetti 

1980). Transient dyspnea occurred in rabbits injected with 740.5 mg/kg MTBE through a catheter to the 

cystic duct (Tritapepe et al. 1989), and lung congestion with pneumonia occurred in pigs infused with 

4,255 mg/kg MTBE through a catheter to the gallbladder (McGahan et al. 1988). However, no 

histopathological lung lesions were found in dogs injected with 635 mg/kg MTBE through a catheter to 

the gallbladder (Allen et al. 1985a). 

Based on the subjective reports of symptoms of coughing and respiratory irritation in motorists, gas 

station attendants, and mechanics during oxygenated fuel programs, levels of MTBE in occupational 

settings, the ambient environment, and at hazardous waste sites might be high enough to cause respiratory 

tract irritation and breathing difficulties in humans. Based on animal studies, effects on the lungs might 

conceivably occur in patients receiving MTBE for gallstone dissolution if leakage from the gallbladder 

occurred, but none of clinical studies located documented respiratory effects. 

Cardiovascular Effects. No information was located regarding cardiovascular effects in humans after 

exposure to MTBE by the inhalation, oral, or dermal routes or in animals exposed by the dermal route. 

However, inhalation studies in which rats and/or mice were exposed to MTBE for acute, intermediate, and 

chronic durations (Biodynamics 1981; Burleigh-Flayer et al. 1992; Chun et al. 1992; Dodd and Kintigh 

1989; Greenough et al. 1980) or orally for intermediate or chronic durations (Belpoggi et al. 1995; ITT 

Research Institute 1992; Robinson et al. 1990) indicated that MTBE produced no treatment-related 

histopathological lesions in the heart or aorta. 
METHYL tert-BUTYL ETHER 118 

2. HEALTH EFFECTS 

Although no studies were located regarding cardiovascular effects in humans exposed to MTBE by 

environmentally relevant routes, humans have been treated with MTBE intracysticafly for the dissolution 

of gallstones. A number of clinical studies of patients receiving MTBE therapy have recorded side effects, 

among which are transient hypertension in 1 of 10 patients (Murray et al. 1988) and hypotension in 2 of 

29, palpitations in 1 of 29, and angina in 1 of 29 patients (Neoptolemos et al. 1990) given MTBE via 

nasobiliary catheter. Vasovagal reactions were found in 4 of 24 patients given MTBE via the 

percutaneous transhepatic route to the gallbladder (Eidsvoll et al. 1993). A number of studies have been 

conducted in animals to determine possible side effects of MTBE therapy for gallstone dissolution. 

Effects noted in animals after administration of MTBE by other routes include decreased blood pressure in 

rabbits and decreased blood pressure, heart rate changes, and electrocardiographic variations in cats given 

7.4 mg/kg intravenously and decreased blood pressure and bradycardia in rats given 7.4 mg/kg 

intravenously or 370 mg/kg intraperitoneally (Snamprogetti 1980). 

Levels of MTBE in occupational settings, the ambient environment, and at hazardous waste sites are 

probably not high enough to cause cardiovascular effects in humans. Based on animal studies and clinical 

studies in humans, effects on the cardiovascular system might occur in patients receiving MTBE for 

gallstone dissolution. 

Gastrointestinal Effects. Nausea or vomiting, which may be related to neurological symptoms, were 

reported symptoms in motorists, gas station attendants, and mechanics during oxygenated fuel programs in 

which MTBE was added to gasoline for reducing carbon monoxide emissions (CDC 1993a, 1993b; 

Moolenaar et al. 1994; White et al. 1995). In addition, a preliminary survey of symptoms in petroleum 

refinery employees working with gasoline containing MTBE indicated high self-reporting of nausea 

(Mehlman 1995). However, these and other studies (Anderson et al. 1995; Beller and Middaugh 1992; 

Chandler and Middaugh 1992) in humans suggest that knowledge about oxygenated fuel programs, 

including the likely awareness of the potential negative effects of MTBE and the higher cost of 

oxygenated fuels, may have biased the subjective symptom reporting. In addition, other humans surveys 

(CDC 1993c; Fiedler et al. 1994; Mohr et al. 1994) and experimental studies in humans (Cain et al. 1994; 

Prah et al. 1994) found no increase in health complaints among people with high oxygenated fuel or 

MTBE exposure. No information was located regarding gastrointestinal effects in humans exposed to 

MTBE by the oral or dermal routes. The gastrointestinal tract was not affected in rats exposed to MTBE 

by inhalation for any duration or in mice exposed chronically, as determined by histological examination 

(Biodynamics 1981; Burleigh-Flayer et al. 1992; Chun et al. 1992; Dodd and Kintigh 1989; Greenough et 

al. 1980; Neeper-Bradley 1991). However, MTBE appears to be irritating to the gastrointestinal tract of 
METHYL tert-BUTYL ETHER 119 

2. HEALTH EFFECTS 

rats exposed orally as evidenced by diarrhea and histological lesions. Effects included diarrhea in rats 

treated with > 357 mg/kg/day MTBE for 14 days or > 100 mg/kg/day for 90 days (Robinson et al. 1990), 

and submucosal edema, subacute inflammation, epithelial hyperplasia, and ulceration in the stomach of 

male and female rats given 1,750 mg/kg/day MTBE (ITT Research Institute 1992). As with irritation of 

the respiratory tract observed in animals after inhalation exposure, these gastrointestinal effects represent 

irritation at the portal of entry. However, in a study in which MTBE was applied dermally to the dorsal 

flank of rats via an occluded chamber, the rats developed slight diarrhea at a dermal dose of 40 mg/kg 

(Bioresearch Labs 1990b). Since the MTBE was applied under occlusion, it is unlikely that oral exposure 

via grooming contributed to the exposure. 

A number of clinical studies of patients receiving MTBE therapy for gallstone dissolution have recorded 

gastrointestinal side effects, indicative of irritation. These include vomiting, nausea, anorexia, emesis, 

duodenitis, retching, upper abdominal burning sensation during infusion, gas, and duodenal ulcer in 

patients receiving MTBE via percutaneous intracystic infusion, gallbladder catheter, or nasobiliary 

catheter (Allen et al. 1985b; Bonardi et al. 1986; Brandon et al. 1988; DiPadova et al. 1986; Eidsvoll et al. 

1993; Hellstem et al. 1990; Ho11 et al. 1991; Janowitz et al. 1993; Kaye et al. 1990; Leuschner et al. 1988, 

1991; McNulty et al. 1991; Murray et al. 1988; Neoptolemos et al. 1990; Saraya et al. 1990; Thistle et al. 

1989; Tobio-Calo et al. 1992; Uchida et al. 1994). The irritation occurs due to leakage from the 

gallbladder into the gastrointestinal tract. A number of studies have been conducted in animals to 

determine possible side effects of MTBE therapy for gallstone dissolution. Effects noted in animals after 

administration of MTBE by other routes include light diarrhea in rats injected intravenously (Bioresearch 

Labs 1990b), necrosis of the duodenum in rabbits infused intraductally (Adam et al. 1990) and vomiting 

and/or duodenitis in rabbits (Tritapepe et al. 1989) and pigs (McGahan et al. 1988; Vergunst et al. 1994) 

treated intraductally and dogs infused via gallbladder catheter (Allen et al. 1985a). 

In a study in which jejunal segments were cannulated in rats, filled with 2-3 mL of MTBE, and perfused 

with α-aminoisobutyric acid (an actively absorbed nonmetabolizable amino acid) and polyethylene glycol 

4000 (a nonabsorbable reference marker), or with mannitol (a passively absorbed hexone) and 

polyethylene glycol, MTBE caused reduction in active transport, increased passive permeability, and loss 

of mucusol weight (Zakko et al. 1995). 

Levels of MTBE inhaled by motorists, in occupational settings, the ambient environment, and at 

hazardous waste sites are probably not high enough to cause gastrointestinal effects unrelated to 
METHYL tert-BUTYL ETHER 120 

2. HEALTH EFFECTS 

neurological symptoms in humans. Based on clinical studies in humans, effects on the gastrointestinal 

tract are likely in patients receiving MTBE for gallstone dissolution. 

Hematological Effects. No information was located regarding hematological effects in humans after 

exposure to MTBE by the inhalation, oral, or dermal routes or in animals after exposure by the dermal 

route. Some changes in hematological parameters have been found in animals after inhalation (Dodd and 

Kintigh 1989; Greenough et al. 1980) and oral exposure (ITT Research Institute 1992; Robinson et al. 

1990) to MTBE, but it is difficult to discern a typical pattern. In one oral study, female rats had changes 

indicative of hemoconcentration (elevated levels of erythrocytes, hemoglobin, and hematocrit, while 

leukocyte counts were reduced (Robinson et al. 1990). This hemoconcentration may have been due to a 

clinical dehydration condition associated with diarrhea observed in these animals instead of being a direct 

effect of MTBE. No treatment-related hematological effects were found in mice or rats in chronic-duration 

inhalation studies (Burleigh-Flayer et al. 1992; Chun et al. 1992). 

Although no studies were located regarding hematological effects in humans exposed to MTBE by 

environmentally relevant routes, humans have been treated with MTBE intracystically for the dissolution 

of gallstones. A number of clinical studies of patients receiving MTBE therapy have recorded 

hematological findings. These include a transient leukocytosis (Allen et al. 1985b; Hellstern et al. 1990; 

Ho11 et al. 1991; Janowitz et al. 1993; Leuschner et al. 1991, 1994; Neubrand et al. 1994; Thistle et al. 

1989) and decreased hemoglobin levels (Kaye et al. 1990). The transient leukocytosis has been attributed 

to a slight leakage of bile after removal of the catheter (Thistle et al. 1989). In two studies of 75 patients 

(Thistle et al. 1989) and 8 patients (Ponchon et al. 1988), hemolysis and/or hematuria occurred in 1 patient 

in each study. In both cases, excessive overflow of MTBE from the gallbladder occurred leading to 

systemic absorption or direct contact of MTBE with the vascular structure. Most clinical studies in which 

hematological parameters were monitored did not find changes except in a few patients, and some found 

none at all (DiPadova et al. 1986; Eidsvoll et al. 1993; McNulty et al. 1991; Uchida et al. 1994). A 

number of studies have been conducted in animals to determine possible side effects of MTBE therapy for 

gallstone dissolution, but only three studies were located that monitored hematological parameters. In 

these studies, dogs (Allen et al. 1985a; Peine et al. 1990) or pigs (Vergunst et al. 1994) received MTBE via 

gallbladder catheter, and no hematological effects were found. 

Hematological effects do not seem to be a concern for humans exposed to MTBE in occupational settings, 

the ambient environment, and at hazardous waste sites. Based on clinical studies in humans, 
METHYL tert-BUTYL ETHER 121 

2. HEALTH EFFECTS 

hematological effects might occur in patients receiving MTBE for gallstone dissolution if accidental 

overflow of MTBE or bile leakage occurs during the procedure. 

Musculoskeletal Effects. No information was located regarding musculoskeletal effects in humans after 

any route of exposure or in animals after dermal exposure. MTBE does not appear to have effects on 

skeletal muscle or bone of animals except for fibrous osteodystrophy, which was secondary to MTBE- induced 

exacerbation of chronic progressive nephropathy, in rats exposed chronically by inhalation (Chun 

et al. 1992). Gross and histological examination of bone and skeletal muscle of rats exposed to MTBE via 

inhalation for acute (Biodynamics 1981) and intermediate durations (Dodd and Kintigh 1989; Greenough 

et al. 1980), in mice exposed via inhalation for chronic durations (Burleigh-Flayer et al. l992), and in rats 

exposed orally for 4 weeks (ITT Research Institute 1992) or 104 weeks (Belpoggi et al. 1995) revealed no 

treatment-related lesions. MTBE had no effect on muscle succinate dehydrogenase or acetylcholinesterase 

activities in rats exposed by inhalation (Savolainen et al. 1985). Muscle creatinine kinase activity 

decreased at 2 weeks, returned to normal levels at week 10, and then significantly increased at 15 weeks. 

Since muscle creatinine kinase is associated with contractile activity, the changing activity due to MTBE 

exposure may represent an adaptation of the muscle cell. 

The available information indicates that musculoskeletal effects are not a concern for humans exposed to 

MTBE in occupational settings, the ambient environment, and at hazardous waste sites. Clinical studies of 

patients receiving MTBE for gallstone dissolution have not described any effects on muscles or bone. 

Hepatic Effects. No information was located regarding hepatic effects in humans after exposure to MTBE 

by the inhalation, oral, or dermal routes or in animals after dermal exposure. MTBE appears to be mildly 

toxic to the liver of animals exposed by the inhalation or oral routes, producing little or no clinical or 

histological evidence of hepatotoxicity in most studies. However, increased absolute and/or relative liver 

weight has been observed in rats exposed to 3,000 ppm for 9 days (Biodynamics 1981), in rats exposed to 

> 4,000 ppm and in mice exposed to > 2,000 ppm for 13 days (Dodd and Kintigh 1989), in rabbits exposed 

to 8,000 ppm during gestation (Tyl 1989), in rats exposed to 800-8,000 ppm for intermediate durations 

(Dodd and Kintigh 1989; Neeper-Bradley 1991), in rats and mice exposed to > 3,000 ppm for intermediate 

(Chun and Kintigh 1993) and chronic durations (Burleigh-Flayer et al. 1992; Chun et al. 1992), and in rats 

dosed orally with 900-l,750 mg/kg/day for 14 days to 13 weeks (ITT Research Institute 1992; Robinson 

et al. 1990). Since the increased liver weight may be due to induction of hepatic microsomal enzymes or 

to increased hepatocellular proliferation (Chun and Kintigh 1993), and because the incidence of 

hepatocellular hypertrophy was significantly increased in mice at > 3,000 ppm for intermediate (Chun and 
METHYL tert-BUTYL ETHER 122 

2. HEALTH EFFECTS 

Kintigh 1993) and chronic (Burleigh-Flayer et al. 1992) durations, the increased liver weight is considered 

to be potentially adverse. Exposure of rats to relatively low inhalation concentrations (50-300 ppm) 

resulted in transient dose-related increases in liver microsomal UDPGT at 2 weeks, but had no effects on 

rat liver cytochrome P-450 content or the activities of other microsomal enzymes (Savolainen et al. 1985). 

In addition, intraperitoneal pretreatment of rats with 741 mg/kg MTBE resulted in a 47-fold induction of 

liver microsomal pentoxyresorufin O-dealkylase, an activity associated with cytochrome P-4502B1 (Brady 

et al. 1990). Much higher inhalation exposure levels and oral doses were required to result in increased 

liver weight and hepatocellular hypertrophy. 

Some clinical evidence of hepatocellular necrosis was found in rats exposed orally to MTBE, although 

other than the hepatocellular hypertrophy found in mice exposed chronically by inhalation, no 

histopathological lesions were found in the liver in any studies. Nevertheless significantly increased 

levels of SGOT and lactic dehydrogenase were found in rats treated orally for 14 days or 13 weeks 

(Robinson et al. 1990). In addition, decreased levels of BUN were observed in male and female rats 

treated orally with > 100 mg/kg/day for 13 weeks. 

Although no studies were located regarding hepatic effects in humans exposed to MTBE by 

environmentally relevant routes, humans have been treated with MTBE intracystically for the dissolution 

of gallstones. A number of clinical studies of patients receiving MTBE therapy have recorded side effects 

in liver, bile duct, and gallbladder, due perhaps to leakage or overflow of MTBE. For example, clinical 

studies reported transient or slight elevations of serum transaminases, indicative of hepatocellular 

necrosis, hematobilia, or increases in serum bilirubin (Allen et al. 1985b, Bonardi et al. 1986; Holl et al. 

1991; Janowitz et al. 1993; Kaye et al. 1990; Leuschner et al. 1991, 1994; Neubrandt et al. 1994; Thistle et 

al. 1989; Uchida et al. 1994). Other effects reported in patients exposed to MTBE by these procedures 

include cholangitis in patients with elevated serum transaminase levels (Kaye et al. 1990), cholecystitis 

and pericholecystitis (Schumacher et al. 1990), persistent dilatation of the common bile duct (Tritapepe et 

al. 1989), and transient, reversible edema and inflammation of the gallbladder mucosa (Eidsvoll et al. 

1993; Uchida et al. 1994; vansonnenberg et al. 1991). A number of studies have been conducted in 

animals to determine possible side effects of MTBE therapy for gallstone dissolution. These treatments of 

animals have also resulted in increases in serum levels of liver enzymes, such as serum alkaline 

phosphatase in dogs (Allen et al. 1985a) and increased serum alkaline phosphatase, SGOT, and SGPT in 

rabbits (Tritapepe et al. 1989). Lobular necrosis of hepatocytes and mild portal inflammation in the liver 

was found in pigs given MTBE via the percutaneous transhepatic route to the gallbladder (Chen et al. 

1995). Effects on the gallbladder after administration of MTBE via catheter to the gallbladder or the liver 
METHYL tert-BUTYL ETHER 123 

2. HEALTH EFFECTS 

include necrosis of the gallbladder and bile ducts, fibrosis of the gallbladder, hyperplastic cholecystitis, 

inflammation and focal ulceration of the gallbladder mucosa, and edema in rabbits and pigs (Adam et al. 

1990; Chen et al. 1995; Dai et al. 1989; Esch et al. 1992; Griffith et al. 1990; McGahan et al. 1988; 

Vergunst et al. 1994). That these effects were not due to the surgical procedure was demonstrated using 

sham-treated saline controls or solvent controls. 

Levels of MTBE in occupational settings, the ambient environment, and at hazardous waste sites are 

probably not high enough to cause serious hepatic effects in humans. Based on clinical studies in humans 

and experimental studies in animals, effects on the liver, gallbladder, and bile duct are, however, likely in 

patients receiving MTBE for gallstone dissolution. 

Renal Effects. No information was located regarding renal effects in humans after exposure to MTBE by 

the inhalation, oral, or dermal routes or in animals exposed by the dermal route. The kidney is a target for 

male rats exposed to MTBE by the inhalation and oral routes. In male rats, MTBE exposure resulted in the 

accumulation of hyaline droplets containing α2u -globulin or possibly another unknown protein unique to 

male rats in the renal tubule cells, which may have lead to renal tubule cell carcinoma and exacerbation of 

chronic progressive nephropathy (see Section 2.4). The accumulation of α2u -globulin in hyaline droplets 

in renal tubules is suggested by studies in male rats exposed by inhalation to MTBE for 13 weeks (Dodd 

and Kintigh 1989; Swenberg and Dietrich 1991) or orally for 14-90 days (ITT Research Institute 1992; 

Robinson et al. 1990). The evidence that the renal effects observed in male rats exposed to MTBE are 

associated with α2u -globulin accumulation has been questioned, however. In a 90-day inhalation study, 

the increase in α2u -globulin accumulation in male rats was not dose-related, and α2u -globulin positive 

proteinaceous casts at the junction of the proximal tubules and thin limb of Henle were not observed 

(Swenberg and Dietrich 1991). This is unlike the classical lesions of other α2u -globulin inducing agents. 

Furthermore, a study specifically designed to determine whether MTBE induces α2u -globulin 

accumulation in male rats found no evidence, based on immunostaining with an antibody to α2u -globulin 

(Chun and Kintigh 1993). However, an increased accumulation of protein in male renal proximal 

convoluted tubule epithelium associated with increased epithelial cell proliferation was found as 

determined by Mallory’s Heidenhain technique. Chun and Kintigh (1993) suggested that a mechanism 

other than α2u -globulin accumulation (perhaps the accumulation of another unknown protein unique to 

male rats) may be involved. It is possible that the hypothetical other protein unique to male rats acts in the 

same the way as α2u -globulin. In rats given > 100 mg/kg/day MTBE orally for 90 days, severe tubular 

changes were observed (Robinson et al. 1990). These changes consisted of increases in hyaline droplets in 
METHYL tert-BUTYL ETHER 124 

2. HEALTH EFFECTS 

proximal tubular cells and small numbers of intratubular granular casts at the junction of the outer and 

inner stripe of the outer medulla. 

The accumulation of α2u -globulin (or by extension, the hypothetical other protein unique to male rats) can 

lead to the exacerbation of chronic progressive nephropathy, which is commonly seen in aging rats. 

Increased incidence and severity of chronic progressive nephropathy, accompanied by fibrous 

osteodystrophy, hyperplasia in the parathyroid glands, and mineralization in numerous tissues was 

observed in both male and female rats exposed to MTBE by inhalation for up to 24 months, but the 

nephropathy occurred at greater incidence and severity, at earlier onset, and at a lower exposure 

concentration in males than in females (Chun et al. 1992). The production of α2u -globulin (or the other 

protein) associated with renal tubule nephropathy has not been demonstrated in female rats or in males or 

females of any other species, including humans. However, because female rats also had enhanced chronic 

progressive nephropathy, the possibility of the relevance to renal toxicity in humans exposed to MTBE is 

strengthened. 

In addition to the other renal effects noted above, MTBE inhalation and oral exposure of animals has been 

associated with increased kidney weight, generally in the absence of clinical (increased BUN, creatinine, 

or albumin levels) or histological evidence of kidney or urinary bladder lesions (Biodynamics 1981; 

Burleigh-Flayer et al. 1992; Chun and Kintigh 1993; Chun et al. 1992; Dodd and Kintigh 1989; 

Greenough et al. 1980; Neeper-Bradley 1991). However, increased levels of BUN were reported in male 

rats exposed to 1,000 ppm for 13 weeks (Greenough et al. 1980), and urinalysis revealed a slight increase 

in the pH of the urine in male and female mice at 8,000 ppm and a slight increase in the gamma globulin 

fraction in male mice at 8,000 ppm in an 18-month inhalation study (Burleigh-Flayer et al. 1992). The 

increases in pH and gamma globulin fraction may have caused the obstructive uropathy in male mice, 

since a urethra plug composed largely of proteinaceous material is characteristic of the urethral 

obstruction. 

In rats exposed to relatively low concentrations of MTBE (50-300 ppm) the cytochrome P-450 content of 

kidney microsomes was significantly increased only after 15 weeks of exposure, while UDPGT and 

NADP-cytochrome c reductase activities were significantly increased only after 2 weeks of exposure 

(Savolainen et al. 1985). Although induction of kidney microsomal enzymes may be potentially adverse, 

other studies (Biodynamics 1981; Burleigh-Flayer et al. 1992; Chun and Kintigh 1993; Chun et al. 1992; 

Dodd and Kintigh 1989; Greenough et al. 1980; Robinson et al. 1990) indicate that microscopic renal 
METHYL tert-BUTYL ETHER 125 

2. HEALTH EFFECTS 

lesions and increased kidney weight due to enzyme induction occur in animals only at much higher 

exposure levels and longer exposure durations. 

Although no studies were located regarding renal effects in humans exposed to MTBE by environmentally 

relevant routes, humans have been treated with MTBE intracystically for the dissolution of gallstones. A 

number of clinical studies of patients receiving MTBE therapy have recorded side effects. In two such 

studies, urinalysis in 1 patient suggested that MTBE did not cause abnormal renal function (Allen et al. 

1985b) and no renal failure was found in 12 patients (Uchida et al. 1994). Renal failure and anuria, 

however, were reported in a patient who experienced severe complications due to extravasation of MTBE 

from the gallbladder lumen (Ponchon et al. 1988). In one study conducted in rabbits to determine possible 

side effects of MTBE therapy for gallstone dissolution, histological examination revealed no renal damage 

(Dai et al. 1989). 

Since humans commonly experience age-related nephropathy, the possibility that prolonged exposure to 

MTBE occupationally, in the ambient environment, or at hazardous waste sites could enhance this process 

can not be ruled out. Severe renal complications due to acute exposure during MTBE therapy for gallstone 

dissolution appear to be rare. 

Endocrine Effects. No information was located regarding endocrine effects in humans exposed to MTBE 

by the inhalation, oral, or dermal routes or in animals exposed by the dermal route. Inhalation and oral 

studies in rats and/or mice have demonstrated that MTBE exposure generally produces no treatment-related 

histopathological lesions in the adrenals, pancreas, thyroid/parathyroid, or pituitary regardless of 

exposure concentration or dose and duration of exposure (Belpoggi et al. 1995; Biodynamics 1981; 

Burleigh-Flayer et al. 1992; Chun and Kintigh 1993; Dodd and Kintigh 1989; Greenough et al. 1980; ITT 

Research Institute 1992; Neeper-Bradley 1991; Robinson et al. 1990). However, in rats exposed 

chronically to MTBE by inhalation, hyperplasia of the parathyroid gland, which was secondary to chronic 

progressive nephropathy, was found at > 400 ppm in males and at > 3,000 ppm in females (Chun et al. 

1992). While most studies found no effects on adrenal weight, other studies reported conflicting effects 

on adrenal weight. An increase in adrenal weight was found in male and female rats at 8,000 ppm for 

13 days (Dodd and Kintigh 1989), in male rats at 8,000 ppm and female rats at > 3,000 ppm in a 4-5 week 

study (Chun and Kintigh 1993); an increase in adrenal weight that was greater in male rats than in female 

rats exposed to > 4,000 ppm for 13 weeks was reported in another study (Dodd and Kintigh 1989), while 

an increase in adrenal weight in only female rats given 900 mg/kg/day MTBE orally for 90 days was 

reported in yet another study (Robinson et al. 1990). Results of studies measuring hormone levels are also 
METHYL tert-BUTYL ETHER 126 

2. HEALTH EFFECTS 

contradictory. While an increase in corticosterone levels was reported in rats exposed to 8,000 ppm for 

13 weeks (Dodd and Kintigh 1989), a decrease in corticosterone levels was found at 81 weeks in male rats 

exposed chronically to 8,000 ppm (Chun et al. 1992). Furthermore, mice of both sexes exposed to 

8,000 ppm for 18 months were reported to have increased corticosterone levels at 79 weeks, and male mice 

exposed to 8,000 ppm had increased adrenal gland weight (Burleigh-Flayer et al. 1992). In mice exposed 

to MTBE for 28 days, no effects on thyroid weight and no histopathological lesions of the thyroid were 

found (Chun and Kintigh 1993). Special blood chemistry evaluation of total T3, total T4, TSH, total bile 

acid, and estradiol revealed that an increase in total T4 and TSH occurred in male mice at 8,000 ppm, 

while decreases in total T4 were found in female mice in the hepatic cell proliferation studies, but not in 

the main experiment. However, these changes were not considered to be biologically significant or 

exposure related due to the absence of histological evidence of thyroid lesions and the lack of consistent 

results in the various experiments. 

Although no studies were located regarding endocrine effects in humans exposed to MTBE by 

environmentally relevant routes, humans have been treated with MTBE intracystically for the dissolution 

of gallstones. A number of clinical studies of patients receiving MTBE therapy have investigated effects 

on the pancreas. In one study of 75 patient administered MTBE via percutaneous intracystic infusion, 

follow-up examination 6-42 months after therapy revealed that none had pancreatitis (Thistle et al. 1989). 

Furthermore, pancreatic function tests administered to 8 patients 1 year after intraductal administration of 

MTBE revealed no pancreatic abnormalities (Tritapepe et al. 1989). Several studies conducted in animals 

to determine possible side effects of MTBE therapy for gallstone dissolution have examined the pancreas 

histologically. No treatment-related histological lesions were found in the pancreas of rabbits (Adam et al. 

1990; Dai et al. 1989), dogs (Allen et al. 1985a) or pigs (McGahan et al. 1988; Vergunst et al. 1994). 

The weight of evidence suggests that endocrine effects are not of concern for humans exposed to MTBE 

under any exposure scenario. 

Dermal Effects. The only information located regarding dermal effects in humans exposed to MTBE is 

that subjects exposed experimentally to 1.7 ppm (Cain et al. 1994) or 1.39 ppm (Prah et al. 1994) MTBE 

for 1 hour reported no greater frequency of skin rash or dry skin than when exposed to uncontaminated air. 

MTBE is irritating to the skin of rabbits and guinea pigs. Application of MTBE to the intact or abraded 

skin of rabbits resulted in slight to severe erythema, blanching, epidermal thickening, acanthosis, or focal 

necrosis (ARCO 1980). Guinea pigs developed local irritation at the site of intradermal injection of 

MTBE. Rats and mice have been examined for dermal effects after exposure to MTBE vapors in air. Any 
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2. HEALTH EFFECTS 

dermal effects in these studies would probably be due to direct contact of the skin with the vapor. 

However, since histological examination of skin of rats or mice exposed to MTBE vapors revealed no 

treatment-related lesions (Burleigh-Flayer et al. 1992; Chun et al. 1992; Dodd and Kintigh 1989; 

Greenough et al. 1980), it appears that direct application of liquid MTBE is required to produce dermal 

effects. Furthermore, no gross or histopathological lesions were found on the skin of rats dosed orally 

with 1,750 mg/kg/day MTBE for 4 weeks (ITT Research Institute 1992) or with 1,000 mg/kg/day MTBE 

for 104 weeks (Belpoggi et al. 1995). 

Dermal irritation resulting from direct skin contact with the undiluted ether is likely in humans. However, 

the presence of MTBE in air would not be expected to cause skin irritation. MTBE in water would 

probably be too dilute to cause skin irritation. The ability of MTBE in soil to cause skin irritation would 

depend on the concentration. 

Ocular Effects. Eye irritation was among the symptoms reported by motorists or gas station workers 

during oxygenated fuel programs in which MTBE had been added to gasoline to reduce carbon monoxide 

emissions (CDC 1993a, 1993b; Moolenaar et al. 1994; White et al. 1995). However, these and other 

studies (Anderson et al. 1995; Beller and Middaugh 1992; Chandler and Middaugh 1992) in humans 

suggest that knowledge about oxygenated fuel programs, including the likely awareness of the potential 

negative effects of MTBE and the higher cost of oxygenated fuels, may have biased the subjective 

symptom reporting. In addition, other humans surveys (CDC 1993c; Fiedler et al. 1994; Mohr et al. 1994) 

found no increase in health complaints among people with high oxygenated fuel exposure. Furthermore, 

an experimental study in humans exposed to 1.7 ppm MTBE for 1 hour found no statistically significant 

differences for eye redness; tear-film break-up time; epithelial damage to the eye; and total number of cells 

and differential numbers of polymorphonuclear neutrophilic leukocytes, epithelial cells, monocytes, 

eosinophils, and lymphocytes in tear fluid than when the subjects were exposed to uncontaminated air 

(Cain et al. 1994). The subjects also reported no greater frequency of subjective symptoms of eye 

irritation (dry, itching, or irritated eyes; tired or strained eyes; burning eyes) than when they were exposed 

to air alone. Similar results were found in a experimental study in which humans were exposed to 

1.39 ppm MTBE for 1 hour (Prah et al. 1994). No information was located regarding ocular effects in 

humans after exposure to MTBE by the oral or dermal routes. MTBE is irritating to the eyes of animals. 

Direct instillation of MTBE into the eyes of rabbits resulted in ocular irritation (ARCO 1980; 

Snamprogetti 1980), regardless of whether the eyes were washed after exposure or not (ARCO 1980). 

Such effects as cornea1 opacities, chemosis, conjunctival redness, delayed and reversible congestion of the 

conjunctivae, palpebral thickening, and hypersecretion were observed. Direct exposure of the eyes to 
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2. HEALTH EFFECTS 

MTBE vapors during inhalation exposure has also resulted in ocular effects in animals, such as ocular 

discharge, eye irritation (ARCO 1980; Neeper-Bradley 1991), lacrimation (Biodynamics 1981; Conaway 

et al. 1985; Tyl and Neeper-Bradley 1989), conjunctival swelling (Biodynamics 198 I), periocular 

encrustations (Tyl and Neeper-Bradley 1989), and swollen periocular tissue (Chun et al. 1992). Gross, 

histological, and ophthalmoscopic examination of the eyes of rats and mice exposed by inhalation, 

however, revealed no lesions (Biodynamics 1981; Burleigh-Flayer et al. 1992; Chun et al. 1992; Dodd and 

Kintigh 1989; Greenough et al. 1980). No gross lesions were found in the eyes, exorbital lachrymal 

glands, or Harderian glands, and no histopathological lesions were found in the eyes in rats dosed orally 

(ITT Research Institute 1992). 

Direct contact of the eyes with liquid MTBE or MTBE vapor in air, such as could occur in occupational 

settings, is likely to be irritating to the eyes of humans. Eye irritation has also been reported by motorists 

and gas station workers during oxygenated fuel programs when MTBE was added to gasoline to reduce 

carbon monoxide emissions. Concentrations in ambient air would probably not be high enough to cause 

eye irritation. The possibility that concentrations at hazardous waste sites, especially around storage 

containers, would be high enough to cause eye irritation cannot be ruled out. 

Body Weight Effects. No information was located regarding body weight effects in humans after exposure 

to MTBE by any route or in animals after dermal exposure. Decreased body weight gains have been 

observed in some studies in which rats, mice, or rabbits were exposed to MTBE by the inhalation 

(Burleigh-Flayer et al. 1992; Chun and Kintigh 1993; Chun et al. 1992; Dodd and Kintigh 1989; NeeperBradley 1991; Tyl 1989; Tyl and Neeper-Bradley 1989) and oral (Robinson et al. 1990) routes. In some 

cases, the decreases were accompanied by decreases in food consumption, which could be secondary to the 

hypoactivity induced by MTBE. Decreased body weight does not seem to be of concern to humans 

exposed to MTBE. 

Other Systemic Effects. The only information regarding other systemic effects of inhalation, oral, or 

dermal exposure of humans or animals is that elevated cholesterol levels were consistent findings in rats 

dosed orally with MTBE for 14-90 days (ITT Research Institute 1992; Robinson et al. 1990). The 

relevance of this effect to public health with respect to MTBE exposure is not known. 
METHYL tert-BUTYL ETHER 129 

2. HEALTH EFFECTS 

Immunological and Lymphoreticular Effects. No differences in interleukin-6 levels were found 

between the morning and evening blood samples collected from volunteers exposed to auto emissions 

derived from oxygenated fuels (Duffy 1994). In addition, the total number of cells and differential counts 

for polymorphonuclear neutrophilic leukocytes, epithelial cells, monocytes, eosinophils, and lymphocytes 

in nasal lavage material and tear fluid from the eyes did not differ significantly in human subjects exposed 

experimentally to 1.7 ppm MTBE for I hour than when they were exposed to uncontaminated air (Cain et 

al. 1994). No information was located regarding immunological or lymphoreticular effects in humans 

exposed to MTBE by the oral or dermal routes. No studies were located that conducted immunological 

tests in animals exposed to MTBE by inhalation or orally. However, no evidence that MTBE was a dermal 

sensitizer was found in guinea pigs (ARCO 1980). 

Most studies in animals exposed by the inhalation and oral routes indicate that the lymphoreticular system 

is not a target of MTBE toxicity regardless of the exposure concentration or oral dose or the duration of 

exposure. In most studies, histological examinations of bone marrow, lymph nodes, spleen (Biodynamics 

1981 ; Burleigh-Flayer et al. 1992; Chun et al. 1992; Dodd and Kintigh 1989; Greenough et al. 1980; 

Neeper-Bradley 1991 ), and thymus (Robinson et al. 1990; ITT Research Institute 1992) revealed no 

treatment-related lesions. However, exposure for 13 weeks to 8,000 ppm of MTBE was reported to result 

in a higher incidence of lymphoid hyperplasia in submandibular lymph nodes in male rats (Dodd and 

Kintigh 1989). In addition, in a chronic oral study, female rats, but not male rats, developed dysplastic 

proliferation of lymphoreticular tissues (possibly preneoplastic) at 250 mg/kg/day (Belpoggi et al. 1995). 

Some studies have reported decreases in spleen or thymus weight, in the absence of histopathological 

lesions. Absolute and relative spleen weights were decreased in rats and mice exposed to 8,000 ppm for 

about 28 days, but the spleens were not examined histologically (Chun and Kintigh 1993). Absolute 

spleen weights were decreased in male and female mice exposed to 8,000 ppm for 18 months (BurleighFlayer et al. 1992). Similarly, oral administration of MTBE for 14 days significantly reduced absolute 

spleen weight and absolute and relative thymus weights in female rats but not males (Robinson et al. 

1990). These effects on spleen and thymus weights were not found in other studies, and in the absence of 

other evidence of toxicity to the spleen or thymus, the toxicological significance is unclear. In a study. in 

which MTBE was infused into the gallbladders of pigs through a catheter, histological examination of the 

spleens revealed no lesions (McGahan et al. 1988). 

The weight of evidence suggests that effects of MTBE on the immunological or lymphoreticular system 

are not a concern for humans. Clinical studies of patients receiving MTBE for gallstone dissolution have 

not described any effects on the immunological or lymphoreticular system. 
METHYL tert-BUTYL ETHER 130 

2. HEALTH EFFECTS 

Neurological Effects. Headache was the symptom most frequently reported by motorists or gas 

station workers during oxygenated fuel programs in which MTBE had been added to gasoline to reduce 

carbon monoxide emission (CDC 1993a, 1993b; Moolenaar et al. 1994; White et al. 1995). Nausea or 

vomiting, dizziness, and a feeling of spaciness or disorientation were also reported. In addition, a 

preliminary survey of symptoms in petroleum refinery employees working with gasoline containing 

MTBE indicated high self-reporting of these symptoms (Mehlman 1995). However, these and other 

studies (Anderson et al. 1995; Beller and Middaugh 1992; Chandler and Middaugh 1992) in humans 

suggest that knowledge about oxygenated fuel programs, including the likely awareness of the potential 

negative effects of MTBE and the higher cost of oxygenated fuels, may have biased the subjective 

symptom reporting. In addition, other humans surveys (CDC 1993c; Fiedler et al. 1994; Mohr et al. 1994) 

found no increase in health complaints among people with high oxygenated fuel exposure. Furthermore, 

experimental studies in humans exposed to 1.7 ppm (Cain et al. 1994) or 1.39 ppm (Prah et al. 1994) 

MTBE or air for 1 hour found no statistically significant differences in neurobehavioral tests evaluating 

symbol-digit substitution, switching attention, and POMS or subjectively reported frequency of headache, 

difficulty remembering things or concentrating, feelings of depression, unusual tiredness, fatigue or 

drowsiness, tension, irritability, or nervousness, dizziness or lightheadedness, mental fatigue or 

“fuzziness,” and pain or numbness in the hands or wrists. No information was located regarding 

neurological effects in humans exposed to MTBE by the oral or dermal routes. 

Only one study described neurological effects in animals exposed dermally (IBT Labs 1969), but its 

reliability is questionable. MTBE exposure of animals by the inhalation and oral routes has produced 

signs of central nervous system depression. These signs usually occur immediately after high inhalation 

concentrations or high oral doses, are transient in nature, and resemble effects of ether anesthesia or ethyl 

alcohol intoxication. Signs include lacrimation, ataxia, loss of righting reflex, hyperpnea, labored 

breathing, incoordination, prostration, drowsiness, hypoactivity, decreased startle and pain reflexes, 

decreased muscle tone, anesthesia, blepharospasm, and stereotypy (ARCO 1980; Bioresearch Labs 1990b; 

Burleigh-Flayer et al. 1992; Chun and Kintigh 1993; Chun et al. 1992; Dodd and Kintigh 1989; 

Greenough et al. 1980; ITT Research Institute 1992; Neeper-Bradley 1991 Robinson et al. 1990; Tyl 1989; 

Tyl and Neeper-Bradley 1989). In a study in which a functional observation battery of tests was given to 

rats exposed to up to 8,000 ppm for 6 hours, effects were similar to those described above, and included 

ataxia, duck-walk gait, labored respiration, decreased muscle tone, decreased performance on a treadmill, 

increased hind limb splay, decreased hind limb grip strength, and increased latency to rotate on an inclined 

screen (Gill 1989). All of the these effects were seen only at 1 hour after exposure, not at 6 or 24 hours, 

confirming the transient nature of the central nervous system depression. In none of the studies conducted 
METHYL tert-BUTYL ETHER 131 

2. HEALTH EFFECTS 

in animals were histopathological lesions found in the brain. Furthermore, neither brain succinate 

dehydrogenase nor acetylcholinesterase activity was affected by exposure for 15 weeks to 50-300 ppm 

MTBE (Savolainen et al. 1985). MTBE and its metabolite tert-butanol were found to be distributed to the 

brain of rats at concentrations similar to blood concentrations (Savolainen et al. 1985). 

A number of clinical studies of patients receiving MTBE therapy for gallstone dissolution have recorded 

neurological effects that are typical of transient central nervous system depression and have been 

described as drowsiness, mild sedation, somnolence, confusion, coma, vertigo, and dizziness (Allen et al. 

1985b; Bonardi et al. 1986; Brandon et al. 1988; DiPadova et al. 1986; Eidsvoll et al. 1993; Kaye et al. 

1990; McNulty et al. 1991; Murray et al. 1988; Neoptolemos et al. 1990; Ponchon et al. 1988; Saraya et al. 

1990; Thistle et al. 1989; Tobio-Calo et al. 1992; vanSonnenberg et al. 1986). A vasovagal reaction was 

found in 4 of 24 patients in the study by Eidsvoll et al. (1993). These conditions usually occurred in 

patients as a result of MTBE overflow from the gallbladder into the systemic circulation. A number of 

studies have been conducted in animals by intravenous and intraperitoneal injection, or by infusion into 

the gallbladder to determine possible side effects of MTBE therapy for gallstone dissolution. Effects 

noted in animals after administration of MTBE by other routes (Allen et al. 1985a; Dai et al. 1989; 

McGahan et al. 1988; Snamprogetti 1980; Tritapepe et al. 1989) are similar to those noted for inhalation 

and oral exposure. 

The subjective reports of headache, dizziness, nausea, and disorientation by motorists and gas station 

workers indicate that inhalation of MTBE added to gasoline for the reduction of carbon monoxide 

emissions may have neurological effects of concern to humans exposed to MTBE under any scenario. 

Reproductive Effects. No information was located regarding reproductive effects in humans exposed 

to MTBE by any route or in animals exposed dermally. MTBE appears to have no reproductive effects in 

animals exposed by inhalation and oral routes. MTBE had no structural effect on the reproductive system 

or reproductive performance of male and female rats exposed by inhalation in 2-generation (Biles et al. 

1987) and 3-generation studies (Neeper-Bradley 1991). In studies on the potential developmental effects 

of MTBE, inhalation exposure of rat dams (Conaway et al. 1985) rabbit dams (Tyl 1989) or mouse dams 

(Tyl and Neeper-Bradley 1989) during gestation did not adversely affect the mean number of corpora 

lutea, uterine implantations, resorptions, or live fetuses, percentage of pre- or postimplantation loss, or sex 

ratio. However, gravid uterine weights were decreased in mouse dams exposed to 8,000 ppm (Tyl and 

Neeper-Bradley 1989). In toxicity studies conducted in rats or mice exposed to MTBE by inhalation for 

all duration categories (Biodynamics 1981; Burleigh-Flayer et al. 1992; Chun et al. 1992; Dodd and 
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2. HEALTH EFFECTS 

Kintigh 1989; Greenough et al. 1980) or orally for all duration categories (Belpoggi et al. 1995;
 

ITT Research Institute 1992; Robinson et al. 1990), gross and histological examination of male and female
 

reproductive organs and tissues revealed no treatment-related nonneoplastic lesions. However, rats
 

exposed chronically to MTBE by the oral route developed testicular Leydig cell tumors (Belpoggi et al.
 

1995). Although no information was located for humans, the animal data strongly suggest that MTBE
 

would pose no reproductive risk for humans.
 

Developmental Effects. No information was located regarding developmental effects in humans
 

exposed to MTBE by any route or in animals exposed orally or dermally. In inhalation developmental
 

studies, exposure of pregnant animals to MTBE did not result in adverse structural developmental effects
 

in the offspring of rats or mice at < 2,500 ppm (Conaway et al. 1985) or rabbits at < 8,000 ppm (Tyl 1989).
 

However, inhalation exposure of mouse dams to 8,000 ppm MTBE during gestation resulted in
 

developmental effects in the offspring, increased number of nonviable implantations per litter, increased
 

late resorptions, reductions in the number of viable implantations, sex ratio changes, significantly
 

increased incidences of cleft palate and skeletal defects, significantly reduced incidence of partial fetal
 

atelectasis, increased incidence of reduced skeletal ossification, and reduced fetal body weight (Tyl and
 

Neeper-Bradley 1989). Signs of toxicity (decreased maternal weight, decreased food consumption,
 

increased incidence of signs of central nervous system depression) were observed in maternal mice at the
 

same exposure levels that resulted in developmental effects in the offspring. The increased incidence of
 

cleft palate was considered to be related to maternal stress with possible associated increased endogenous
 

levels of corticosterone. Long-term exposure of male and female rats during premating and gestational
 

periods of 16-28 weeks, without exposing the litters, had no effects on pup viability, mean pup body
 

weight, and renal pelvises (Biles et al. 1987). The only effect on rat pups in the 3-generation study was a
 

decreased weight gain of developing pups (Neeper-Bradley 1991).
 

Although no information on developmental effects in humans was located, the developmental findings in 

mice and rats indicate that the possibility that MTBE exposure could result in developmental effects 

cannot be ruled out. 

Genotoxic Effects. Information regarding genotoxic effects of MTBE indicates that it has little if any 

genotoxic activity. As seen from Table 2-4, MTBE was negative in the sex-linked recessive lethal assay in 

Drosophila melanogaster (Semau 1989) for chromosomal aberrations in Fischer 344 rats exposed via 

inhalation (Vergnes and Morabit 1989), and Sprague-Dawley rats (ARCO 1980), and CD-1 mice (Ward et 

al. 1994) exposed orally, for hprt mutant frequency in lymphocytes of CD-1 mice exposed orally (Ward et 

METHYL tert-BUTYL ETHER 134 

2. HEALTH EFFECTS 

al. 1994), and for micronuclei formation in erythrocytes (Vergnes and Kintigh 1993) and increases in 

DNA repair in cultured primary hepatocytes (Vergnes and Chun 1994) of CD-1 mice exposed via 

inhalation. In vitro assays were also generally negative. As seen from Table 2-5, MTBE was negative for 

reverse mutation in Salmonella typhimurium strains TAl535, TA 1537, TA 1538, TA98, and TAl00 

(ARCO 1980; Cinelli et al. 1992) and in Saccharomyces cerevisiae D4 (ARCO 1980) both in the presence 

and in the absence of metabolic activation. In addition, negative results were obtained for unscheduled 

DNA synthesis in primary rat hepatocytes and for gene mutation in Chinese hamster V79 fibroblasts 

(Cinelli et al. 1992). However, MTBE was positive for forward mutations in mouse lymphoma L5178Y 

tk+

/tk- cells in the presence, but not in the absence, of metabolic activation (ARCO 1980). That the 

positive result was not due to the metabolite, tert-butanol, was demonstrated by McGregor et al. (1988), 

who found that tert-butanol was negative for forward mutations in the L5178Y tk+

/tk- mouse lymphoma 

cell assay with and without metabolic activation. MTBE produced equivocal results for sister chromatid 

exchange in Chinese hamster ovary cells in the presence of metabolic activation (ARCO 1980). However, 

no increase in chromosomal aberrations in Chinese hamster ovary cells was found with or without 

metabolic activation. In addition, MTBE was predicted to be non-genotoxic in an analysis by a structureactivity 

relational expert system using results generated by the National Toxicology Program (NTP) for rodent carcinogenicity, 

Salmonella mutagenicity test results, the induction of sister chromatid exchanges 

and chromosomal aberrations, and structural alerts for genotoxicity (Rosenkranz and Klopman 1991). The 

weight of evidence indicates that MTBE has little or no genotoxic activity. 

Cancer. No information was located regarding cancer in humans exposed to MTBE by any route or in 

animals exposed dermally. Chronic inhalation exposure of rats to 400, 3,000, or 8,000 ppm MTBE, 

resulted in increased incidences of renal tubular adenoma and carcinoma in male rats at 3,000 and 

8,000 ppm (Chun et al. 1992). These tumors may have resulted from accumulation of α2u -globulin or 

some other unknown protein unique to male rats in the renal tubular cells (see Section 2.4). In addition, 

male Fischer 344 rats exposed to the two higher concentrations had increased incidences of interstitial cell 

testicular adenoma when compared with concurrent controls, but not when compared with historic 

controls. Furthermore, the incidence in the concurrent control group was low compared with the historic 

controls, suggesting that the higher incidence of testicular adenoma in the MTBE-exposed rats was not 

exposure related. Male Fischer 344 rats have a high spontaneous rate of testicular tumors. However, 

chronic oral exposure of male Sprague-Dawley rats to 250 or 1,000 mg/kg/day resulted in testicular 

Leydig cell tumors (Belpoggi et al. 1995). Chronic inhalation exposure of mice exposed to 400, 3,000, or 

8,000 ppm MTBE resulted in an increased incidence of hepatocellular adenoma in female mice and 

increased incidence of hepatocellular adenoma and carcinoma in male mice at 8,000 ppm (Burleigh-Flayer 

METHYL tert-BUTYL ETHER 136 

2. HEALTH EFFECTS 

et al. 1992). Chronic oral exposure of female rats at 250 or 1,000 mg/kg/day resulted in lymphoma and 

leukemia (Belpoggi et al. 1995). Since the available carcinogenicity studies indicate the MTBE can 

produce tumors in multiple species of animals, multiple strains of rats, and at multiple sites, the relevance 

of the carcinogenic effects of MTBE to humans is of concern. However, the NTP, EPA, and International 

Agency for Research on Cancer (IARC) have not yet classified MTBE as to its carcinogenicity potential 

for humans. Formaldehyde, a metabolite of MTBE (see Section 2.3.3), is a substance which may 

reasonably be anticipated to be a carcinogen (NTP 1994). There is sufficient evidence that formaldehyde 

induces squamous cell carcinomas in the nasal cavity of male and female rats exposed by inhalation and 

limited evidence that formaldehyde induces nasal or nasopharyngeal cancer in humans exposed by 

inhalation. However, nasal cavity tumors were not observed in rats (Chun et al. 1992) or mice (BurleighFlayer et al. 1992) exposed by inhalation to MTBE at concentrations as high as 8,000 ppm. Therefore, the 

possibility that metabolism of MTBE to formaldehyde might lead to the development of nasal cancer 

seems to be unfounded.and not to pose a concern for humans exposed to MTBE. However, the mechanism 

by which MTBE induced lymphoma and leukemia in female rats may involve formaldehyde, which has 

resulted in the lymphoma and leukemia in male and female rats in other studies conducted by Belpoggi 

and co-workers (Belpoggi et al. 1995). The main metabolite of MTBE, tert-butanol, was studied for 

carcinogenicity in rats and mice exposed via drinking water for 2 years (Cirvello et al. 1995). Increased 

incidences of renal tubule adenoma and carcinoma in male rats, increased incidences of transitional 

epithelial hyperplasia of the kidney in male and female rats, increased incidences of follicular cell 

adenoma of the thyroid in female mice, and increased incidences of follicular cell hyperplasia of the 

thyroid and inflammation and hyperplasia of the urinary bladder in male and female mice were observed. 

In addition, there was a slight increase in follicular cell adenoma and carcinoma (combined) of the thyroid 

in male mice, which may be related to exposure to tert-butanol. Since increased incidences of renal 

tubular adenoma and carcinoma in male rats were observed in the inhalation study of MTBE by Chun et al. 

(1992), it is possible that the metabolite, tert-butanol, was responsible for or contributed to the renal 

tumors seen in the rats in the inhalation study of MTBE. 

2.6 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic 
METHYL tert-BUTYL ETHER 137 

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substance or its metabolite(s), or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NRC 1989). The preferred 

biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily 

obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of 

biomarkers of exposure. The body burden of a substance may be the result of exposures from more than 

one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high 

urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on 

the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and 

route of exposure), the substance and all of its metabolites may have left the body by the time samples can 

be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly 

found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). 

Biomarkers of exposure to MTBE are discussed in Section 2.6.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly adverse, 

but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by MTBE 

are discussed in Section 2.6.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 2.8, Populations That Are Unusually Susceptible. 

2.6.1 Biomarkers Used to Identify or Quantify Exposure to MTBE 

As discussed in Section 2.3, much of absorbed MTBE is excreted unchanged in the expired air. In 

addition, lower levels of its metabolite tert-butanol are found in expired air. MTBE and tert-butanol can 

be measured in the blood. A strong correlation was found between the workroom air levels of MTBE in 

service station and dealership garages and the difference in blood concentrations of MTBE between 
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preshift and postshift measurements (r = 0.9, p = 0.0001) in Fairbanks, Alaska, during the oxygenated fuel 

program in which MTBE (about 15% by volume) was added to gasoline to reduce emission levels of 

carbon monoxide (CDC 1993a; Moolenaar et al. 1994). The median 8-hour TWA concentration of MTBE 

in the workplace air was 0.10 ppm, with a range of 0.01-0.81 ppm. The median preshift blood 

concentration of MTBE was 1.15 μg/L, with a range of 0.1-27.8 μg/L, while the postshift blood 

concentration of MTBE was 1.80 μg/L, with a range of 0.2-37.0 μg/L. In a similar study conducted in 

Stamford, Connecticut, personal breathing zone levels of MTBE were strongly correlated with blood 

levels of both MTBE and tert-butanol, although the breathing zone levels varied widely among the 

different garage locations, as well as within garages (CDC 1993b; White et al. 1995). For mechanics, 

TWA concentrations of personal breathing zones levels ranged from <0.03 ppm-12.04 ppm. The median 

blood concentrations of MTBE were approximately 2 μg/L for car repairers and 15 μg/L for gas station 

attendants. Median blood concentrations of tert-butanol were about 15 μg/L for car repairers and 75 μg/L for gas station 

attendants. The estimated correlation coefficients were 0.80 between air MTBE and blood 

MTBE (p = 0.0001) and 0.7 between air MTBE and blood tert-butanol (p = 0.0001). 

MTBE and tert-butanol blood levels were also generally related to exposure concentrations in rats 

(Savolainen et al. 1985). Urinary metabolites found in rats exposed by the inhalation, oral, and dermal 

routes were identified as 2-methyl-1,2-propanediol and α-hydroxyisobutyric acid (Bioresearch Labs 

1990b, 1990d, 1991), but no studies were located that identified these metabolites in the urine of humans. 

In addition, another study in which rats were injected with 14C-MTBE intraperitoneally, analysis of the 

urine revealed that radiolabeled formic acid accounted for 96.6% of the urinary radioactivity 

(Biodynamics 1984). The remaining radioactivity in the urine was assumed to be radiolabeled methanol 

and formaldehyde. 

In a study of 27 humans treated with MTBE via percutaneous intracystic infusion for the dissolution of 

gallstones, mean blood levels of tert-butanol were 0.04 mg/mL immediately after and 5 hours after 

treatment and fell only to 0.025 mg/mL at 12-l 8 hours (Leuschner et al. 1991). Mean urinary levels of 

MTBE were about 0.018 mg/mL at 5 hours after treatment and <0.005 mg/mL at 12-18 hours. Mean 

urinary levels of tert-butanol were higher than those of MTBE, with about 0.036 mg/mL at 5 hours and 

0.03 mg/mL at 12-18 hours after treatment. Methanol was found in only 3 patients, while no 

formaldehyde or formic acid were found. tert-Butanol was also detected in the abdominal wall fat of 

9 patients and breast milk of 1 patient. 
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In rats exposed to 14C-MTBE by inhalation for 6 hours or to unlabeled MTBE for 6 hours per day for 

14 days and to 14C-MTBE for 6 hours on day 15 (Bioresearch Labs 1990d), the rate of excretion of 

radioactivity via the lungs was rapid, with a total of 82% of the recovered radioactivity in expired air 

excreted by 3 hours and 91-92% excreted by 6 hours (Bioresearch Labs 1990d). Similar rates of excretion 

of radioactivity were found in rats exposed to unlabeled MTBE for 6 hours per day for 14 days and to 

14C-MTBE for 6 hours on day 15. Urinary excretion of radioactivity was 96-98% complete by 36 hours 

after exposure. Similar rates of excretion of radioactivity were found in rats exposed by the oral route 

(Bioresearch Labs 1990b). Excretion was considerably slower in rats exposed dermally to MTBE. Halflives 

for MTBE and tert-butanol for plasma clearance in rats exposed by the inhalation and oral routes 

were generally <1 or 2 hours (Bioresearch Labs 1990a, 1990c). 

Thus, the presence of MTBE in blood, expired air, or urine of humans would probably be sufficient as a 

biomarker of exposure. Of the various possible metabolites (tert-butanol, methanol, formaldehyde, and 

formic acid) that might be monitored in humans, tert-butanol appears to be the best metabolite for use as a 

biomarker of exposure because blood levels of tert-butanol rise after exposure to MTBE, but any of the 

metabolites may either be present naturally (formic acid) or arise from the metabolism of other xenobiotic 

chemicals. 

Based on limited information in humans and clearance data in rats, monitoring of expired air, blood, or 

urine for MTBE or tert-butanol in humans could be used for determining very recent exposure to MTBE, 

but after exposure ceases for a few days, MTBE and its metabolites would be cleared. 

No known effects or combination of effects resulting from MTBE exposure are specific for MTBE (see 

Section 2.6.2); therefore, no known effect or combination of effects can be used as a biomarker to identify 

or quantify exposure to MTBE specifically. 

2.6.2 Biomarkers Used to Characterize Effects Caused by MTBE 

MTBE exposure can lead to central nervous system depression characterized by ataxia, hypoactivity, 

drowsiness, anesthesia, duck-walk gait, decreased muscle tone, prostration, lack of startle response, and 

lack of righting reflex (ARCO 1980; Bioresearch Labs 1990d; Burleigh-Flayer et al. 1992; Chun et al. 

1992; Dodd and Kintigh 1989; Gill 1989; Greenough et al. 1980; ITT Research Institute 1992; NeeperBradley 199 I ; Robinson et al. 1990; Tyl 1989). MTBE exposure can induce hepatic microsomal enzymes 

(Brady et al. 1990; Savolainen et al. 1985), or lead to elevated levels of SGPT, SGOT, or serum lactic 
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dehydrogenase (Robinson et al. 1990), and may increase (Greenough et al. 1980) or decrease (Robinson et 

al. 1990) BUN levels. However, many ethers, alcohols, and other chemicals can lead to these effects or 

combination of effects; therefore, no known effect or combination of effects can be used as a biomarker to 

identify or quantify exposure to MTBE specifically. 

For more information on biomarkers for renal and hepatic effects of chemicals see ATSDR/CDC 

Subcommittee Report on Biological Indicators of Organ Damage (1990) and for information on 

biomarkers for neurological effects see OTA (1990). 

2.7 INTERACTIONS WITH OTHER CHEMICALS 

No studies were located regarding interactions between MTBE and other chemicals agents. However, 

pretreatment of rats with phenobarbital or acetone enhanced the metabolism MTBE to tert-butanol and 

formaldehyde in liver microsomes, by inducing cytochromes P-4502B1 and P-4502E1, respectively 

(Brady et al. 1990; Snyder 1979). Thus, acetone and phenobarbital, as well as other inducers of these 

enzymes, would be expected to enhance the metabolism of MTBE. Whether this enhanced metabolism of 

MTBE would lead to greater or lesser toxicity is not clear, because the toxicity of MTBE relative to the 

toxicities of its metabolites is not known. Pretreatment of rats with MTBE resulted in a 47-fold induction 

of liver microsomal pentoxyresorufin O-dealkylase, an activity associated with cytochrome P-4502B1 

(Brady et al. 1990). Thus, MTBE itself is an inducer of cytochrome P-4502B1, which can lead to the 

enhanced metabolism and toxicity of a number of chemicals. Since MTBE is a component of gasoline in 

oxygenated fuels, it is possible that MTBE may interact with other components of gasoline, such as 

benzene and branched chain alkanes. 

2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to MTBE than will most persons 

exposed to the same level of MTBE in the environment. Reasons include genetic make-up, developmental 

stage, age, health and nutritional status (including dietary habits that may increase susceptibility, such as 

inconsistent diets or nutritional deficiencies), and substance exposure history (including smoking). These 

parameters result in decreased function of the detoxification and excretory processes (mainly hepatic, 

renal, and respiratory) or the pre-existing compromised function of target organs (including effects or 

clearance rates and any resulting end-product metabolites). For these reasons we expect the elderly with 

declining organ function and the youngest of the population with immature and developing organs will 
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generally be more vulnerable to toxic substances than healthy adults. Populations who are at greater risk 

due to their unusually high exposure are discussed in Section 5.6, Populations With Potentially High 

Exposure. 

No specific human populations that are unusually susceptible to the toxic effects of MTBE have been 

identified. As discussed in Section 2.2.1.2, in a study conducted to determine whether symptoms 

associated with MTBE were reported at an increased rate among subjects with known multiple chemical 

sensitivities or chronic fatigue syndrome compared to normal control individuals, no significant 

differences were found among the groups for driving a car or visiting gas stations (Fiedler et al. 1994). 

The authors concluded that the study did not provide clear evidence to support that an unusually high rate 

of symptoms or an increase of symptoms occurred uniquely where MTBE exposure was likely. 

Studies in rats (Brady et al. 1990; Snyder 1979) suggest that people who are exposed to inducers of 

cytochromes P-4502Bl and P-4502El may be more susceptible. For example, people who take 

phenobarbital, an inducer of cytochrome P-4502B1, or people who are exposed to acetone or drink 

alcoholic beverages, may be more susceptible. Both acetone and ethanol are inducers of cytochrome 

P-4502E1. 

Pharmacokinetic studies in rats indicated some differences between males and females in absorption and 

elimination kinetics (Bioresearch Labs 1990a, 1990b, 1990c, 1990d, 1991). In general these studies 

indicated that female rats absorbed more MTBE than did males after inhalation, oral, or dermal exposure, 

and eliminated it more quickly. Whether or not these relations would operate in humans is not known. 

MTBE was fetotoxic in mice, resulting in skeletal anomalies, reduced fetal weights, increased resorption, 

and increased incidences of cleft palate (Conaway et al. 1985; Tyl and Neeper-Bradley 1989) and 

minimally toxic to developing rats, resulting in reduced F1 and F2 pup weight (Neeper-Bradley 1991). 

MTBE exposure of rabbit dams, however, did not result in developmental effects in the offspring (Tyl 

1989). Thus, human embryos and fetuses may be susceptible. 

MTBE appears to be minimally toxic to the liver, except in mice (Burleigh-Flayer et al. 1992). Mice 

developed hepatocellular hypertrophy and hepatocellular adenoma and carcinoma at high exposure levels 

for chronic durations, but mice have a high spontaneous rate of liver tumor development. Whether MTBE 

would exacerbate preexisting liver disease in humans is not known. 
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As discussed in Sections 2.4 and 2.5, MTBE exposure of male rats results in renal effects that may be 

associated with the accumulation α2u-globulin or other protein unique to male rats (Chun and Kintigh 

1993; Dodd and Kintigh 1989; Robinson et al. 1990; Swenberg and Dietrich 1991); chronic progressive 

nephropathy, accompanied by fibrous osteodystrophy, hyperplasia in the parathyroid glands, and 

mineralization in numerous tissues; and an increased incidence of renal tubular adenoma and carcinoma 

(Chun et al. 1992). The increased incidence of renal tubular adenoma and carcinoma may have resulted 

from α2u-globulin or other protein accumulation. Accumulation of α2u-globulin (or by extension, a 

hypothetical protein unique to male rats) is specific for male rats, and has no relevance to human health. 

When α2u-globulin accumulation is accompanied by chronic progressive nephropathy in male rats, the 

chronic progressive nephropathy is believed to be exacerbated by α2u-globulin accumulation. However, 

female rats, which do not produce a α2u-globulin, also had increased incidence and severity of chronic 

progressive nephropathy, but at higher doses and later onset than males. The fact that female rats also 

showed an enhancement of chronic progressive nephropathy indicates that an additional factor other than 

accumulation of α2u-globulin or another protein unique to male rats may be involved. Since humans often 

develop age-related nephropathy, elderly people or people with pre-existing nephropathy may be more 

susceptible to the nephrotoxicity of MTBE. 

It is also possible that some persons are or can become more chronically sensitive to MTBE as a result of 

prolonged low-level exposure, but no studies were located that specifically addressed this possibility. 

2.9 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to MTBE. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to MTBE. When specific 

exposures have occurred, poison control centers and medical toxicologists should be consulted for medical 

advice. 

2.9.1 Reducing Peak Absorption Following Exposure 

Human exposure to MTBE may occur by inhalation, ingestion or by dermal contact. Vapors are likely to 

be irritating to the eyes and upper respiratory tract and once absorbed can cause central nervous system 

and respiratory depression. Unprotected skin exposure can cause defatting and subsequent dermatitis. 
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Exposed individuals should be moved to fresh air and administered 100% humidified supplemental 

oxygen. If skin contact occurred, the skin should be thoroughly irrigated with water. 

Following ingestion, the potential risk of aspiration leading to airway and pulmonary damage usually 

outweighs the potential benefit of administering syrup of ipecac to induce emesis. Aspiration of MTBE is 

another complication that must be avoided. If patients present with cough following acute ingestion, the 

possibility of prior aspiration must be considered and evaluated with careful respiratory exam, arterial 

blood gases and radiography (HSDB 1995). Once in the care of a health professional, gastric lavage can 

be useful if administered within 1 hour of the exposure to reduce the amount of absorbed solvent. 

Following ocular contamination, the eyes should be irrigated with copious amounts of room temperature 

water or saline, for at least 15 minutes. If irritation, lacrimation, or especially pain, swelling, and 

photophobia persist after 15 minutes of irrigation, then ophthalmologic consultation should be sought to 

evaluate potential ocular damage. 

2.9.2 Reducing Body Burden 

The body does not retain significant amounts of MTBE. Exhaled concentrations of the vapor represent an 

important means of elimination. There is no currently recognized treatment to enhance detoxification, and 

orthodox treatment for ingestion is entirely supportive. 

2.9.3 Interfering with the Mechanism of Action for Toxic Effects 

Clinical effects caused by acute MTBE exposure include central nervous system depression and mild liver 

function abnormalities (Burg 1992). Other effects include malaise, dizziness, fatigue, headache, and 

lightheadedness, all of which may disappear soon after the exposure ceases. The mechanism of action for 

the central nervous system effects has not been clearly established, but may be related to solvent effects on 

cellular membranes. Just as for other VOCs, this is often referred to as an “anesthetic effect.” The usually 

short duration of such symptoms and the absence of known chronic effects make pharmacological therapy 

difficult to justify. 

In addition to causing acute central nervous system effects similar to solvent exposure, beverage ethanol 

may compete or enhance the metabolic activation of solvents and can increase the severity of health 
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2. HEALTH EFFECTS 

effects, particularly liver toxicity. Alcoholic beverages should be avoided following exposure to MTBE 

and other solvents. 

2.10 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate 

information on the health effects of MTBE is available. Where adequate information is not available, 

ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation 

of a program of research designed to determine the health effects (and techniques for developing methods 

to determine such health effects) of MTBE. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

2.10.1 Existing information on Health Effects of MTBE 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

MTBE are summarized in Figure 2-4. The purpose of this figure is to illustrate the existing information 

concerning the health effects of MTBE. Each dot in the figure indicates that one or more studies provide 

information associated with that particular effect. The dot does not necessarily imply anything about the 

quality of the study or studies, nor should missing information in this figure be interpreted as a “data 

need.” A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs 

Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct 

comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any 

substance-specific information missing from the scientific literature. 

As seen from Figure 2-4, no studies were located regarding health effects in humans after oral or dermal 

exposure to MTBE. Information on toxic effects of MTBE in humans was available from subjective 

reports of symptoms (headache, eye irritation, nose and throat irritation, nausea or vomiting, dizziness, 

confusion, spaciness) in motorists and gas station workers during oxygenated programs in which MTBE 

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2. HEALTH EFFECTS 

was added to gasoline for reduction of carbon monoxide emissions. In addition information on toxic 

effects in humans were available from clinical studies of patients receiving MTBE via percutaneous 

intracystic infusion or infusion into the gallbladder via catheter for the dissolution of gallstones. While 

this does not represent an environmentally relevant route, the side effects of this therapeutic treatment are 

generally consistent with health effects observed in animals exposed to MTBE by the inhalation and oral 

routes. These side effects include typical signs of transient central nervous system sedation, 

gastrointestinal irritation, evidence of necrosis in the liver and gallbladder, transient cardiovascular effects, 

such as hyper- or hypotension and palpitations, and transient leukocytosis. These side effects have 

occurred from overflow of MTBE from the gallbladder lumen or extravasation into the systemic 

circulation. In most cases, the patients who experienced these side effects recovered with no residual 

effects. 

Figure 2-4 shows that MTBE has been well studied for health effects by the inhalation route in animals. 

Since MTBE is a volatile liquid used as an additive to gasoline, inhalation exposure is the major route of 

concern. Data on death, systemic effects, lymphoreticular, neurological, reproductive, developmental, and 

genotoxic effects, and cancer are available in animals for the inhalation route. For the oral route of 

exposure, data on lethal levels, systemic effects, lymphoreticular, neurological, genotoxic, and 

reproductive effects and cancer are available. No developmental studies conducted by the oral route in 

animals were located. The dermal route of exposure is the least well studied. No lethality data were 

located for the dermal route. Data for acute-duration dermal exposure concerns irritation of the skin and 

eyes from direct application of the liquid to the skin or eyes, respectively, or irritation to the eyes from 

exposure to vapor during inhalation experiments. All of the intermediate- and chronic-duration data 

concerns irritation to the eyes from vapor contact during inhalation exposure. In a study performed by 

IBT Labs, dermally applied MTBE was reported to cause neurological effects, but results of studies from 

IBT are often suspected as being unreliable. 

2.10.2 Identification of Data Needs 

Acute-Duration Exposure. No studies were located regarding systemic effects in humans after oral 

or dermal exposure to MTBE for acute durations. People exposed to MTBE while operating or fueling 

motor vehicles or people occupationally exposed (such as mechanics, service station workers) have 

reported subjective symptoms of headache; nausea or vomiting, irritation of eyes, nose, and throat; 

dizziness; and disorientation (Beller and Middaugh 1992; CDC 1993a, 1993b; Chandler and Middaugh 

1992; Moolenaar et al. 1994; White et al. 1995). However, two experimental studies in humans exposed 
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2. HEALTH EFFECTS 

to < 1.7 ppm for 1 hour did not find any of these effects (Cain et al. 1994; Prah et al. 1994). In animals, 

information on acute-duration inhalation exposure includes LC50 values for rats (ARCO 1980) and mice 

(Snamprogetti 1980). Information on systemic effects includes clinical signs of respiratory irritation in 

rats exposed acutely (ARCO 1980); a 5-day intermittent exposure study that found increased 

hepatocellular proliferation in mice and increased renal tubule cell epithelial proliferation in rats (Chun 

and Kintigh 1993); a 9-day intermittent exposure study in rats that examined respiratory, cardiovascular, 

gastrointestinal, musculoskeletal, hepatic, renal, endocrine, and body weight effects in rats and identified 

the nasal mucosa and trachea and the liver (increased liver weight) as targets (Biodynamics 1981); a 

developmental study that found no effects on the liver or body weight of rat or mouse dams (Conaway et 

al. 1985); a developmental study in mouse dams that reported labored breathing and reduced maternal 

weight gain (Tyl and Neeper-Bradley 1989); a developmental study in rabbit dams that found increased 

liver weight and reduced maternal weight gain (Tyl 1989); a 13-day intermittent exposure study in rats and 

mice that found no effects on lungs but decreased body weight gains of rats (Dodd and Kintigh 1989), an 

intermediate-duration study that found decreased body weight gain in rats during the first 2 weeks (Chun 

and Kintigh 1993). Some of these studies also provided information on the immunological/ 

lymphoreticular system, on neurological effects, on reproductive toxicity, and developmental toxicity (see 

separate data needs). An acute inhalation neurotoxicity study (Gill 1989) provided the NOAEL used for 

the MRL of 2 ppm for acute-duration inhalation exposure to MTBE. Information on acute-duration oral 

exposure includes LD50 values for rats (ARCO 1980) and mice (Little et al. 1979). Information on 

systemic effects includes a report of labored respiration in rats given a single high oral dose (ARCO 

1980); a single dose study in rats that reported diarrhea; and a 14-day gavage study in rats that provided 

information on all systemic end points and found gastrointestinal, hematological, hepatic, renal, body 

weight, and other (elevated cholesterol) effects (Robinson et al. 1990). Acute-duration oral studies also 

provided information on the immunological/lymphoreticular, neurological, and reproductive systems (see 

separate data needs). An acute oral study that described neurological effects in rats provided the NOAEL 

used for the MRL of 0.4 mg/kg/day for acute-duration oral exposure to MTBE (Bioresearch Labs 1990b). 

Acute-duration dermal studies reported diarrhea in rats (Bioresearch Labs 1990b) and dermal irritation in 

rabbits and guinea pigs (ARCO 1980). Data on ocular irritation was also available for direct application of 

liquid MTBE into the eyes (ARCO 1980; Snamprogetti 1980) and exposure of the eyes to MTBE vapors in 

inhalation studies (ARCO 1980; Biodynamics 1981; Conaway et al. 1985; Dodd and Kintigh 1989; Tyl 

and Neeper-Bradley 1989). Thus, information on acute-duration inhalation and oral exposure was 

sufficient to identify the central nervous system as the most sensitive target system from which to derive 

acute MRLs. Because absorption of MTBE by the dermal route is substantially lower than absorption by 

the inhalation and oral routes, the concern for systemic effects of dermal exposure to MTBE is probably 
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less important than the concern for systemic effects of inhalation or oral exposure to persons who might be 

exposed to MTBE for acute-duration periods around hazardous waste sites. However, dermal or ocular 

exposure would be of concern for irritation at the site of contact. 

Intermediate-Duration Exposure. No studies were located regarding systemic effects in humans 

after oral or dermal exposure to MTBE for intermediate durations. People exposed to MTBE while 

operating or fueling motor vehicles or people occupationally exposed (such as mechanics, service station 

workers) have reported subjective symptoms of headache; nausea or vomiting; irritation of eyes, nose, and 

throat; dizziness; and disorientation (Beller and Middaugh 1992; CDC 1993a, 1993b; Chandler and 

Middaugh 1992; Moolenaar et al. 1994; White et al. 1995). Several intermediate-duration inhalation 

studies in animals were located that provided information on respiratory, cardiovascular, gastrointestinal, 

hematological, musculoskeletal, hepatic, renal, endocrine, and body weight effects in rats (Biles et al. 

1987; Chun and Kintigh 1993; Dodd and Kintigh 1989; Greenough et al. 1980; Neeper-Bradley 1991; 

Savolainen et al. 1985; Swenberg and Dietrich 1991) and hepatic effects in mice (Chun and Kintigh 1993). 

In addition to central nervous system toxicity (see Neurotoxicity, below), the kidney (Chun and Kintigh 

1993; Dodd and Kintigh 1989; Greenough et al. 1980; Swenberg and Dietrich 1991) and liver (NeeperBradley 1991) have been identified as target organs. In addition, effects have been observed on 

hematological and endocrine end points (Dodd and Kintigh 1989). These studies also provided 

information on immunological or lymphoreticular, neurological, reproductive, and developmental effects 

(see separate data needs). An intermediate-duration inhalation study that described neurological effects in 

rats provided the NOAEL used for the MRL of 0.7 ppm for intermediate-duration inhalation exposure to 

MTBE (Neeper-Bradley 1991). Two oral studies in rats (ITT Research Institute 1992; Robinson et al. 

1990) were located that provided information on all aforementioned systemic end points. Target organs 

and systems identified consisted of the gastrointestinal tract, the liver, the kidneys, other (serum 

cholesterol) (ITT Research Institute 1992; Robinson et al. 1990), and hematological (Robinson et al. 

1990). These studies also provided information on immunological/lymphoreticular, neurological, and 

reproductive effects (see separate data needs). An MRL of 0.3 mg/kg/day for intermediate-duration oral 

exposure to MTBE was derived based on a LOAEL for hepatic effects in rats (Robinson et al. 1990). 

Intermediate-duration dermal studies were not located. The available information concerns dermal and 

ocular effects of direct contact of the skin or eyes with MTBE vapors during inhalation studies. Because 

absorption of MTBE by the dermal route is substantially lower than absorption by the inhalation and oral 

routes, the concern for systemic effects of dermal exposure to MTBE is probably less important than the 

concern for systemic effects of inhalation or oral exposure to persons who might be exposed to MTBE for 
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2. HEALTH EFFECTS 

intermediate-duration periods around hazardous waste sites. However, information on dermal or ocular 

exposure is needed regarding irritation at the site of contact. 

Chronic-Duration Exposure and Cancer. No studies were located regarding systemic effects or 

cancer in humans after inhalation, oral, or dermal exposure to MTBE. Two chronic-duration inhalation 

studies, one in rats (Chun et al. 1992) and one in mice (Burleigh-Flayer et al. 1992), were located. The 

study in rats monitored clinical signs, mortality, body weight, organ weights, hematology, corticosterone 

levels, and performed comprehensive gross and histological examination. The study in mice monitored all 

of the above, and also monitored water consumption and performed urinalysis. Mortality was increased in 

male rats and male mice. The cause of death of male rats was chronic progressive nephropathy. The cause 

of death for male mice was obstructive uropathy. In rats, the kidney was the major target with secondary 

involvement of the bone and parathyroid. In addition, liver weights were increased and body weights 

decreased. In mice, the liver was the major target (increased weight and hepatocellular hypertrophy). 

Mice also had increased kidney weights and decreased body weight gains. Based on the NOAEL for 

chronic progressive nephropathy in female rats, a chronic-duration inhalation MRL of 0.7 ppm was 

derived for MTBE. One study was located regarding effects in rats after oral exposure to MTBE for 

chronic duration (Belpoggi et al. 1995). The chronic oral study monitored mortality, clinical signs, food 

and water consumption, and body weight changes, and performed comprehensive histological 

examination. No effects on food or water consumption or body weight, and no nonneoplastic tissue 

lesions were found. However, increased mortality and dysplastic proliferation of lymphoreticular tissues 

(possibly preneoplastic) were observed in the female rats at the lowest dose tested (250 mg/kg/day). 

Comprehensive studies by the oral route in rats at lower doses and in mice are needed to provide further 

information on target organs of chronic-oral exposure and define thresholds that could be used to 

determine a chronic oral MRL. No chronic dermal studies were located. The available information 

concerns dermal and ocular effects of direct contact of the skin or eyes with MTBE vapors during 

inhalation studies. Because absorption of MTBE by the dermal route is substantially lower than 

absorption by the inhalation and oral routes, the concern for systemic effects of dermal exposure to MTBE 

is probably less important than the concern for systemic effects of inhalation or oral exposure to persons 

who might be exposed to MTBE for chronic-duration periods around hazardous waste sites. However, 

information on dermal or ocular exposure is needed for irritation at the site of contact. 

In the chronic-duration inhalation studies in rats (Chun et al. 1992) and mice (Burleigh-Flayer et al. 1992), 

MTBE was studied for potential carcinogenicity. In male rats exposed to the 2 highest concentrations, 

there was a concentration-related increased incidence of renal tubule cell adenoma and carcinoma (Chun et 
METHYL tert-BUTYL ETHER 150 

2. HEALTH EFFECTS 

al. 1992). The development of these tumors may have been related to the accumulation of α2u-globulin in 

male rat renal tubule cells, which has no relevance to human health. However, the evidence that the renal 

effects observed in male rats exposed to MTBE are related to α2u-globulin accumulation has been 

questioned. The accumulation of α2u-globulin was not dose related, and α2u-globulin positive 

proteinaceous casts at the junction of the proximal tubules and thin limb of Henle were not observed, 

unlike the classical lesions of other α2u-globulin inducing agents (Swenberg and Dietrich 1991). 

Furthermore, another study found no evidence of α2u-globulin accumulation in male rats, but did find an 

accumulation of protein in the renal proximal convoluted tubule associated with epithelial cell 

proliferation in male rats (Chun and Kintigh 1993). Since no epithelial cell proliferation was found in the 

renal tubules of the female rats, the authors did not look for protein accumulation in the female rat. The 

existence of another unknown protein unique to male rats that accumulates in the renal proximal 

convoluted tubule in male rats exposed to MTBE was proposed. Thus, further studies on the mechanism 

by which MTBE leads to nephropathy and renal tumors in male rats are needed to provide information on 

whether these effects have any relevance to humans. In female mice exposed to the highest concentration 

of MTBE, there was an increased incidence of hepatoceilular adenoma (Burleigh-Flayer et al. 1992). Mice 

are especially susceptible to chemical-induced hepatic tumors. In the chronic oral study in rats (Belpoggi 

et al. 1995), female rats developed lymphoma and leukemia at both doses (250 and 1,000 mg/kg/day) and 

male rats developed testicular Leydig cell tumors at the high dose. If a chronic oral study in mice were 

conducted, comprehensive histological examination of organs and tissues would reveal whether MTBE is 

carcinogenic in mice by the oral route. 

Genotoxicity. Information regarding genotoxic effects of MTBE is limited. No studies were located 

regarding genotoxic effects in humans exposed to MTBE by any route of exposure. MTBE was negative 

in the sex-linked recessive lethal assay in D. melanogaster (Sernau 1989), for chromosomal aberrations in 

Fischer 344 rats exposed via inhalation (Vergnes and Morabit 1989) and Sprague-Dawley rats (ARCO 

1980) and CD-1 mice (Ward et al. 1994) exposed orally, for hprt mutant frequency in lymphocytes of 

CD-1 mice exposed orally (Ward et al. 1994), and for micronuclei formation in erythrocytes (Vergnes and 

Kintigh 1993) and increases in DNA repair in cultured primary hepatocytes (Vergnes and Chun 1994) of 

CD-1 mice exposed via inhalation. In vitro assays were negative in S. typhimurium (ARCO 1980; Cinelli 

et al. 1992) and S. cerevisiae for reverse mutations, negative for unscheduled DNA synthesis in primary 

rat hepatocytes and for gene mutations in Chinese hamster V79 fibroblasts (Cinelli et al. 1992), negative 

for chromosomal aberrations in Chinese hamster ovary cells (ARCO 1980), positive for forward mutations 

in mouse lymphoma cells with metabolic activation (ARCO 1980), and equivocal for sister chromatid 

exchange in Chinese hamster ovary cells with activation (ARCO 1980). A structure-activity analysis 
METHYL tert-BUTYL ETHER 151 

2. HEALTH EFFECTS 

predicted that MTBE would not be genotoxic (Rosenkranz and Klopman 1991). While the available data 

indicate that MTBE has little if any genotoxic activity, an extensive battery of in vivo or in vitro studies 

are needed to provide confirmation. 

Reproductive Toxicity. No studies were located regarding reproductive effects in humans after 

inhalation, oral, or dermal exposure to MTBE or in animals after dermal exposure. MTBE has been tested 

in two inhalation reproduction studies in rats (Biles et al. 1987; Neeper-Bradley 1991) with negative 

results. MTBE has also been tested for developmental effects by inhalation in rat dams (Conaway et al. 

1985), rabbit dams (Tyl 1989), and mouse dams (Tyl and Neeper-Bradley 1989) during gestation without 

evidence of reproductive effects in the dams. In toxicity studies conducted in rats or mice exposed to 

MTBE by inhalation for all duration categories (Biodynamics 1981; Burleigh-Flayer et al. 1992; Chun et 

al. 1992; Dodd and Kintigh 1989; Greenough et al. 1980) or orally for all duration categories (Belpoggi et 

al. 1995; ITT Research Institute 1992; Robinson et al. 1990), gross and histological examination of male 

and female reproductive organs and tissues revealed no treatment-related nonneoplastic lesions. However, 

in the chronic oral study, male rats developed testicular Leydig cell tumors (Belpoggi et al. 1995). 

Although no information was located for humans, the animal data strongly suggest that MTBE would pose 

no reproductive risk for humans. 

Developmental Toxicity. No studies were located regarding developmental effects in humans after 

inhalation, oral, or dermal exposure to MTBE or in animals exposed orally or dermally. In inhalation 

developmental studies, MTBE did not cause structural developmental effects in the offspring of rat 

(Conaway et al. 1985) and rabbit (Tyl 1989) dams exposed during gestation. However, MTBE was a 

developmental toxicant in the offspring of mouse dams exposed by inhalation (Conaway et al. 1985; Tyl 

and Neeper-Bradley 1989). No developmental effects, other than decreased weight gain of developing 

pups, were observed in the multigeneration reproductive inhalation studies in rats (Biles et al. 1987; 

Neeper-Bradley 1991). Although no developmental studies were conducted by the oral route, 

pharmacokinetic data are similar for the inhalation and oral routes, suggesting no need for oral studies 

other than to determine dose-responses. 

Immunotoxicity. No indication was found that MTBE exposure increased interleukin-6 levels in 

volunteers exposed to auto emissions derived from oxygenated fuels (Duffy 1994) or increased 

polymorphonuclear neutrophilic leukocytes in nasal lavage material or tear liquid from eyes of humans 

exposed by inhalation to 1.7 ppm MTBE for 1 hour (Cain et al. 1994). No studies were located regarding 

immunological or lymphoreticular effects in humans after oral or dermal exposure. No studies were 
METHYL tert-BUTYL ETHER 152 

2. HEALTH EFFECTS 

located that conducted immunological tests in animals exposed to MTBE by the inhalation or oral routes. 

No evidence that MTBE was a dermal sensitizer was found in guinea pigs (ARCO 1980). Most studies in 

animals exposed by the inhalation and oral routes indicate that the lymphoreticular system is not a target 

of MTBE toxicity regardless of the exposure concentration or oral dose or the duration of exposure 

(Biodynamics 1981 ; Burleigh-Flayer et al. 1992; Chun et al. 1992; Dodd and Kintigh 1989; Greenough et 

al. 1980; ITT Research Institute 1992; Neeper-Bradley 1991; Robinson et al. 1990). However, MTBE was 

reported to result in a higher incidence of lymphoid hyperplasia in submandibular lymph nodes in male 

rats exposed by inhalation (Dodd and Kintigh 1989) and dysplastic proliferation of lymphoreticular tissue 

(possibly preneoplastic) in female rats exposed orally (Belpoggi et al. 1995). Some studies have reported 

decreases in spleen or thymus weight, in the absence of histopathological lesions (Burleigh-Flayer et al. 

1992; Chun and Kintigh 1993; Robinson et al. 1990). A battery of immune tests in animals exposed by 

inhalation are needed to determine or rule out whether MTBE has immunological effects. Since inhalation 

is the most likely route of exposure, and since pharmacokinetic data suggest similar kinetic and metabolic 

behavior regardless of route, testing by the oral route seems unwarranted. 

Neurotoxicity. No studies were located regarding neurological effects in humans after oral or dermal 

exposure to MTBE. People exposed to MTBE while operating or fueling motor vehicles or people 

occupationally exposed (such as mechanics, service station workers) have reported subjective symptoms 

of headache, nausea or vomiting, dizziness, and disorientation (Beller and Middaugh 1992; CDC 1993a, 

1993b; Chandler and Middaugh 19921; Moolenaar et al. 1994; White et al. 1995). The central nervous 

system is without question the most sensitive target of acute exposure to MTBE. MTBE exposure of 

animals by the inhalation and oral routes has produced signs of central nervous system depression. These 

signs usually occur immediately after inhalation concentrations or oral doses, are transient in nature, and 

resemble effects of ether anesthesia or ethyl alcohol intoxication (ARCO 1980; Bioresearch Labs 1990b; 

Burleigh-Flayer et al. 1992; Chun and Kintigh 1993; Chun et al. 1992; Dodd and Kintigh 1989; 

Greenough et al. 1980; ITT Research Institute 1992; Neeper-Bradley 1991; Robinson et al. 1990; Tyl 

1989; Tyl and Neeper-Bradley 1989). MTBE has been tested in a functional observation battery of tests in . 

rats exposed by inhalation (Gill 1989) with evidence of transient central nervous depression. Additional 

testing by the oral route appears to be unwarranted, since there is no reason to believe that the effects are 

route specific. MTBE and tert-butanol were found to be distributed to the brain of rats at concentrations 

similar to blood concentrations (Savolainen et al. 1985), which probably accounts for the sensitivity of 

this end point. The acute- and intermediate-duration inhalation MRLs of 2 and 0.7 ppm, respectively, are 

based on NOAELs for neurological effects. Likewise, the acute-duration oral MRL of 0.4 mg/kg/day is 

based on a NOAEL for neurological effects. 
METHYL tert-BUTYL ETHER 153 

2. HEALTH EFFECTS 

Epidemiological and Human Dosimetry Studies. No studies were located regarding health effects 

in humans exposed to MTBE by oral or dermal routes. Survey studies in motorists and workers at gas 

stations, automobile dealerships, and people whose occupations require extensive use of motor vehicles 

have been conducted in Anchorage and Fairbanks, Alaska, and Stamford, Connecticut, during oxygenated 

fuel programs, in which MTBE (15% by volume) was added to gasoline for the reduction of carbon 

monoxide emissions (Beller and Middaugh 1992; CDC 1993a, 1993b; Chandler and Middaugh 1992; 

Moolenaar et al. 1994; White et al. 1995). A preliminary survey of petroleum refinery employees working 

with gasoline containing MTBE (Mehlman 1995) provided no detail other than the percentages of workers 

with self-reported symptoms. In the CDC studies, blood levels of MTBE were analyzed in some of the 

mechanic and gas station workers and were to correlate with workroom or personal breathing zone levels, 

but exposure levels were considered to be underestimated because the content of the air a worker actually 

breathed may have been substantially different from the air level measured by the monitoring devices, 

many of the windows a.nd doors were open due to the mildness of the weather, or higher exposure levels of 

MTBE probably occurred while the workers were close to the gasoline tank (CDC 1993a; CDC 1993b). In 

addition, these and other studies (Anderson et al. 1995) in humans suggest that knowledge about 

oxygenated fuel programs, including the likely awareness of the potential negative effects of MTBE and 

the higher cost of oxygenated fuels, may have biased the subjective symptom reporting. Furthermore, 

other human surveys (CDC 1993c; Fiedler et al. 1994; Mohr et al. 1994) found no increase in health 

complaints among people with high oxygenated fuel exposure. Experimental studies, in which volunteers 

were exposed to 1.7 ppm (Cain et al. 1994) or 1.39 ppm (Prah et al. 1994) MTBE for 1 hour, found no 

indication of adverse effects. However, whether multiple exposures, higher exposure levels, or exposures 

of longer duration, which are more relevant for real-life exposure of motorists to MTBE, could cause 

cumulative effects could not be resolved. Thus, the relationship between the experimental studies and the 

field studies is not clear. Information on toxic effects of MTBE in humans was available from clinical 

studies of patients receiving MTBE via percutaneous intracystic infusion or infusion into the gallbladder 

via catheter for the dissolution of gallstones. While this does not represent an environmentally relevant 

route, the side effects of this therapeutic treatment (central nervous system sedation, liver effects, 

leukocytosis) are generally consistent with health effects observed in animals exposed to MTBE by the 

inhalation and oral routes. However, doses associated with effects for this treatment route are not 

predictive of environmental exposure levels. Experimental studies of volunteers exposed to more realistic 

exposure levels for longer durations are needed to establish the threshold for irritation and mild central 

nervous system effects. Since MTBE is widely used as a gasoline additive, more studies of workers 

involved in the gasoline industry and of people who work at or live near gasoline filling stations are 

needed to provide more reliable information on atmospheric levels that produce effects, especially signs of 
METHYL tert-BUTYL ETHER 154 

2. HEALTH EFFECTS 

irritation and central nervous system depression, and to eliminate biases in the subjective symptom 

reporting. People who live in areas where the air, groundwater, or soil is contaminated from major 

production sites, large tank batteries, transfer terminals, active or abandoned waste sites, and gasoline 

leaks should also be studied for adverse health effects. More data are needed regarding the possibility that 

some persons are or can become more chronically sensitive to MTBE, that a combustion product of MTBE 

may be playing a role in causing symptoms, and that such factors as cloud cover that may contribute to 

reported adverse effects of exposed humans. 

Biomarkers of Exposure and Effect. 

Exposure. The amount of MTBE in blood or expired air appears to be the most useful biomarker of 

exposure because much of the absorbed MTBE is excreted unchanged in the expired air (Bioresearch Labs 

1990b, 1990d). In addition, expired air or blood levels of its metabolite tert-butanol can be useful 

indicators of MTBE exposure. Recently, investigations of motorists and workers in Alaska and 

Connecticut showed that ambient or personal breathing zone levels of MTBE were strongly correlated 

with human blood levels of MTBE (CDC 1993a, 1993b; Moolenaar et al. 1994; White et al. 1995). MTBE 

and tert-butanol, as well as the metabolite methanol, were measured in the blood of rats, and MTBE blood 

levels were generally related to exposure concentration (Savolainen et al. 1985). Based on limited 

information in humans and based on clearance data in rats, monitoring of expired air, blood, or urine for 

MTBE or tert-butanol in humans could be used for determining very recent exposure to MTBE. However, 

after exposure ceases for a few days, MTBE and its metabolites would be cleared. The development of an 

alternative biomarker does not seem necessary or possible, because MTBE and its metabolites are cleared 

rapidly and no evidence of interactions with biological macromolecules was located. 

Effect. MTBE exposure can lead to central nervous system depression characterized by ataxia, 

hypoactivity, drowsiness, anesthesia, duck-walk gait, decreased muscle tone, prostration, lack of startle 

response, and lack of righting reflex (ARCO 1980; Bioresearch Labs 1990d; Burleigh-Flayer et al. 1992; 

Chun and Kintigh 1993; Chun et al. 1992; Dodd and Kintigh 1989; Gill 1989; Greenough et al. 1980; ITT 

Research Institute 1992; Neeper-Bradley 1991; Robinson et al. 1990; Tyl 1989). Exposure can induce 

hepatic microsomal enzymes (Brady et al. 1990; Savolainen et al. I985), or lead to elevated levels of 

SGPT, SGOT, or serum lactic dehydrogenase (Robinson et al. 1990), and may increase (Greenough et al. 

1980) or decrease BUN (Robinson et al. 1990) levels. However, many ethers, alcohols, and other 

chemicals can lead to these effects or combination of effects; therefore, no known effect or combination of 

effects can be used as a biomarker to identify or quantify exposure to MTBE specifically. The central 
METHYL tert-BUTYL ETHER 155

 2. HEALTH EFFECTS 

nervous system depression appears to be the most sensitive and immediate effect of MTBE exposure, and 

may be due to solvent effects on neuronal membranes. The development of a biomarker to detect the 

effect on cell membranes would not be practical given the transient and short-lived nature of the anesthetic 

effect. 

Absorption, Distribution, Metabolism, and Excretion. The absorption, distribution, metabolism, 

and excretion of MTBE has been well studied in rats after inhalation, oral, dermal, and intravenous 

exposure (Biodynamics 1984; Bioresearch Labs 1990a, 1990b, 1990c, 1990d, 1991; Brady et al. 1990; 

Snyder 1979). These studies provided information on rates and extent of absorption, retention in tissues, 

metabolism, and rates and extent of excretion of relatively low and high doses of MTBE. Based on shifts 

in elimination pathways following exposure to high compared to low doses, saturation of metabolizing 

enzymes appears to occur, but does not appear to influence the overall elimination of MTBE from the 

body. Information on respiratory and urinary metabolites and results of in vitro studies with rat liver 

microsomes have provided sufficient information to propose a plausible metabolic pathway. Metabolism 

does not appear to be route specific. The studies in rats provided some pharmacokinetic parameters, and a 

preliminary physiologically based pharmacokinetic model has recently been developed by Borghoff et al. 

(1996). Further refinement of the model in rats is needed for extrapolating pharmacokinetic, toxicity, and 

dose-response data to humans. 

Comparative Toxicokinetics. Comprehensive information on toxicokinetics of MTBE is available 

only for rats (see data need for Absorption, Distribution, Metabolism, and Excretion). The only 

toxicokinetic information for MTBE in mice involves pulmonary excretion after intraperitoneal dosing 

(Yoshikawa et al. 1994). Information on side effects in patients receiving MTBE therapeutically for the 

dissolution of gallstones indicates that central nervous system depression is also the most sensitive end 

point in humans (Allen et al. 1985b; Bonardi et al. 1986; Brandon et al. 1988; DiPadova et al. 1986; Kaye 

et al. 1990; McNulty et al. 1991; Murray et al. 1988; Neoptolemos et al. 1990; Ponchon et al. 1988; Saraya 

et al. 1990; Thistle et al. 1989; Tobio-Calo et al. 1992; vansonnenberg et al. 1986). Studies in motorists 

and workers occupationally exposed to MTBE (CDC 1993a, 1993b; Moolenaar et al. 1994; White et al. 

1995), and an experimental inhalation study in humans (Cain et al. 1994) indicated that MTBE is well 

absorbed from lungs and metabolized to tert-butanol. Limited information regarding distribution, 

metabolism, and excretion of MTBE was available for humans who received MTBE via percutaneous 

intracystic infusion for dissolution of gallstones (Leuschner et al. 1991). The limited data in humans 

suggest some similarities in metabolism between rats and humans, that is, tert-butanol as a common 

metabolite. However, finding the rat urinary metabolites, 2-methyl-1,2-propanediol and 
METHYL tert-BUTYL ETHER 156 

2. HEALTH EFFECTS 

α-hydroxyisobutyric acid in the urine of patients who receive MTBE therapy would provide a better basis 

for considering the rat a good model to predict the behavior of MTBE in the human body. The data on 

distribution and excretion are too limited to be compared. Toxicokinetic studies in other species are 

needed to determine if the disposition of MTBE is similar across species. As discussed in Absorption, 

Distribution, Metabolism, and Excretion above, the studies in rats provided some pharmacokinetic 

parameters, and a preliminary physiologically based pharmacokinetic model has recently been developed 

by Borghoff et al. (1996). Further refinement of the model in rats is needed for extrapolating 

pharmacokinetic, toxicity, and dose-response data to humans. 

Methods for Reducing Toxic Effects. MTBE is rapidly absorbed, distributed, metabolized, and 

excreted. The most immediate systemic effect is central nervous system depression, which is transient. 

Because MTBE is absorbed rapidly by passive diffusion, gastric lavage can be useful only if performed 

within one hour of exposure to reduce the amount absorbed in the case of ingestion. Reducing absorption 

after inhalation exposure is not feasible. Thorough washing of the skin with water could reduce dermal 

absorption. MTBE and its metabolites are not retained in the body for any substantial period of time, so 

there is little need to reduce body burden. The mechanism of action of the central nervous system effects 

has not been clearly established, but is probably related to solvent effects on cell membranes. The short 

duration of the central nervous system symptoms and the absence of known chronic effects make 

pharmacological therapy difficult to justify. 

MTBE is rapidly absorbed, distributed, metabolized, and excreted. The most immediate effect is central 

nervous system depression, which is transient. Because MTBE is absorbed rapidly by passive diffusion, 

gastric lavage can be useful only if performed within one hour of exposure to reduce the amount absorbed 

in the case of ingestion. Reducing absorption after inhalation exposure is impractical. Thorough washing 

of the skin would reduce dermal absorption. MTBE and its metabolites are not retained in the body for 

any substantial period of time, obviating the need to reduce body burden. The mechanism of action of the 

central nervous system effects has not been clearly established, but is probably related to solvent effects 

on cell membranes. The short duration of the central nervous system symptoms and the absence of known 

chronic effects make pharmacological therapy difficult to justify. 
METHYL tert-BUTYL ETHER 157 

2. HEALTH EFFECTS 

2.10.3 Ongoing Studies 

ATSDR is funding a study on the genotoxicity of MTBE entitled “Genotoxic Effects of a Widely Used 

Gasoline Additive” to be performed by Dr. Norman Kado of the University of California at Davis, who 

will test MTBE in a modified Ames assay using a microsuspension procedure for volatile compounds, in a 

micronucleus assay in pregnant mice and their fetuses, and in an assay for induction of mutations at the 

lacZ gene in kidneys of transgenic mice. Information regarding ongoing research on the genotoxicity of 

MTBE was also found in an abstract. 

As reported in an abstract, Choi et al. (1993) injected MTBE into the liver parenchyme, the peritoneum, 

the tail vein, the portal vein, or the inferior vena cava of rats. In the portal vein and inferior vena cava 

groups, 90% of the rats died. Necropsy revealed localized areas of congestion, hemorrhage, and interstitial 

edema in the lung and degenerative changes and necrosis in the liver. In the other groups, all rats survived 

and showed only mild lung changes upon necropsy after sacrifice. 

In an abstract of a report presented at the International Congress of Toxicology - VII, July 2-6, 1995, 

Johanson et al. (1995) reported that in 10 healthy male volunteers exposed to MTBE by inhalation at 5, 25, 

or 50 ppm for 2 hours during light physical exercise, low uptake (32-41% of inhaled amount), high postexposure 

exhalation (18-34% of uptake), low blood clearance, and low recovery of tert-butanol in urine 

were found. The half-life of tert-butanol was 8-10 hour in blood and urine. The pharmacokinetic data are 

being used to develop a physiologically based pharmacokinetic (PBPK) model for MTBE. The subjects 

reported minimal or no subjective symptoms (discomfort, irritation, central nervous system effects), and 

eye and nose acoustic rhinometry revealed minimal or no effects. 

In another abstract and poster presentation at a meeting of the International Society for Environmental 

Epidemiology in Durham, North Carolina, by these authors, Nihlen et al. (1994) reported that the 

preliminary analysis postexposure decay curve of MTBE in blood of the 10 healthy male volunteers 

exposed to MTBE by inhalation at 5, 25, or 50 ppm for 2 hours during light physical exercise indicated 

three half-times in the blood of about 1 minute, 0.6 hour, and 7 hours. The preliminary half-time of 

tert-butanol in urine was about 4 hours. These values were reported in the abstract. In the poster, 

however, it appeared that the 3 half-times of MTBE in the blood were about 7 minutes, 47 minutes, and 

6.2-7.2 hours. Two half-times of MTBE in the urine were 16-22 minutes and 3-3.1 hours. The half-time 

of tert-butanol in the urine was 10.7 hours for the 25 ppm exposure and 5.4 hours for the 50 ppm 

exposure. 
METHYL tert-BUTYL ETHER 158 

2. HEALTH EFFECTS 

As reported by Medlin (1995), Thomas Goldsworthy and other researchers of CIIT are investigating the 

mechanism by which a number of compounds in unleaded gasoline, including MTBE, cause liver tumors 

in mice. For MTBE, the hypothesis being tested is that MTBE causes liver tumors in mice through 

modulation of hormones, specifically estrogen. Abstracts of these studies have been presented at the 35th 

Annual Meeting of the Society of Toxicology in March, 1996. Borghoff et al. (1996) measured partition 

coefficients of MTBE in blood, liver, kidney, fat, and muscle of male and female Fischer rats for use in the 

development of a physiologically based pharmacokinetic model. Moser et al. (1996), of CIIT, found that 

MTBE exposure of female B6C3F1 mice at 7,988 ppm for 4 months resulted in decreased relative uterine, 

ovary, and pituitary weights, increased relative liver weight and hepatic microsomal P-P50 

pentoxyresorufin O-dealkylase activity, but did not affect DNA synthesis in nonfocal hepatocytes. 

Furthermore, MTBE did not exhibit tumor-promoting activity in the mice that received an initiating dose 

of N-nitrosodiethylamine. The authors stated that MTBE produced endocrine modulation suggestive of 

estrogen antagonism, but did not show tumor-promoting activity. This is unlike the hormonal-modulated 

mechanism of hepatic tumor promotion of unleaded gasoline (Goldsworthy et al. 1996). 

Other abstracts presented at the 35th Annual Meeting of the Society of Toxicology in March 1996, present 

ongoing studies of MTBE. In male Sprague-Dawley rats gavaged with MTBE in corn oil at 

1,000 mg/kg/day for 1 month, serum testosterone was decreased within hours after the first treatment, but 

not at the time of sacrifice (de Peyster et al. 1996). Total liver cytochrome P-450 was elevated after 

1 month, but liver and androgen-dependent organ weights were unchanged. The authors stated that an 

immediate, transient decrease in serum testosterone is consistent with a direct effect on the hypothalamic-pituitarygonadal axis, and that long-term changes in steroid metabolism might occur if P-450 induction is 

sustained. 

Scholl et al. (1996) reported that pretreatment of male Fischer rats with phenobarbital or clofibrate, but not 

beta-naphthoflavone, prolonged the duration of ataxia and narcosis induced by an intraperitoneal dose of 

MTBE. Phenobarbital and clofibrate also induced hepatic microsomal enzymes that metabolize MTBE to 

tert-butanol, suggesting that the metabolic status is a major determinant of sensitivity to the central 

nervous system effects of MTBE. 
METHYL tert-BUTYL ETHER 159 

3. CHEMICAL AND PHYSICAL INFORMATION 

3.1 CHEMICAL IDENTITY 

Methyl tert-butyl ether (MTBE) is a volatile organic compound (VOC) often added to gasoline to reduce 

air pollution. MTBE and other components, commonly known as “oxygenates,” are added to gasoline to 

increase the octane number and reduce carbon monoxide emissions. Information regarding the chemical 

identity of MTBE is located in Table 3- 1. 

3.2 PHYSICAL AND CHEMICAL PROPERTIES 

MTBE is a relatively volatile chemical and is moderately soluble in water. It is very soluble in some 

organic solvents such as alcohol and ether. Oil refiners blend MTBE into gasoline to meet requirements 

for oxygenated fuels. Gasoline containing MTBE has become recognizable by its pungent odor. MTBE is 

flammable, and is a moderate fire risk (Sax and Lewis 1987). Information regarding the physical and 

chemical properties of MTBE is located in Table 3-2. 



METHYL tert-BUTYL ETHER 163 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

During the 1970s EPA moved to phase out leaded gasolines and to reduce the levels of air pollution from 

pre- or post-combustion vehicular emissions. This conversion to unleaded fuels tended to reduce the 

octane ratings. Additives such as benzene or toluene could increase octane levels, but these aromatic 

volatile organic compounds could lead to serious air pollution problems due to their known toxic 

properties. Various highly oxygenated blending agents, including several ethers and alcohols, can boost 

the octane of unleaded gasoline and, since they are less toxic, can mitigate many of the air pollution 

concerns. MTBE is one such product used in Reformulated Gasoline (RFG). Some states started requiring 

the seasonal use of RFGs in the 197Os, and this became a requirement for many parts of the country under 

provisions of the 1990 Clean Air Act. This requirement led to a rapid expansion in the production and use 

of MTBE starting in the late 1980s. 

4.1 PRODUCTION 

Typical production processes use feedstocks like isobutylene, often in combination with methanol, in 

adiabatic fixed reactors. The isobutylene and methanol react in the presence of ion-exchange resin 

catalysts at medium pressures and temperatures. Highly volatile by-products are removed through 

distillation, and methanol is reclaimed using water washing or molecular sieves. In a variant of this basic 

technology called reaction distillation, the catalysis and distillation steps take place simultaneously 

(Shanely 1990). There are numerous variants in these manufacturing processes, the details of which are 

protected under patents or license agreements (Lorenzetti 1994; Rhodes 1991). 

Until the late 1980s isobutylene and other feedstocks could be readily obtained from existing refinery 

operations. With minor investments, these refineries could add MTBE production with yields in the range 

of 8,000-20,000 barrels per day. As demand for MTBE increased, large specialized production facilities 

were built. These larger specialized plants account for the vast majority of domestic production 

(Lorenzetti 1994). These plants are often close to other refineries, pipelines, or navigation shipping 

terminals. For instance, about 70% of the entire salable production capacity for MTBE is concentrated 

along the Houston Ship Channel near Beaumont, Texas (Anonymous 1992b). As MTBE production 

capacity begins to outreach the supplies of such feedstocks as isobutylene, various processes are being 

added to the conventional plant design to tap other petrochemical feedstocks. These processes include 

dehydrogenation of isobutane, dehydration of isobutanol, ethenolysis of branched alkenes, and catalytic 
METHYL tert-BUTYL ETHER 164 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

isomerization of butenes or butane. A drawback to some new technologies is the production of large 

quantities of methyl isobutyl ether (MIBE), a low-octane MTBE isomer (Nicolaides et al. 1993). 

Nearly all the MTBE produced in the United States is used as octane boosters and oxygenating agents in 

reformulated gasoline, and these uses are the only ones for which reliable production figures are readily 

available. Starting in the late 1980s MTBE production increased rapidly. The 1990 Clean Air Act created 

a guaranteed market of some 400,000 barrels per day for all types of reformulated fuel oxygenated 

additives. Since other ingredients such as ethanol and other ethenes are alternative reformulation 

additives, MTBE is expected to command a market share of at least 250,000 barrels (about 64.8 million 

pounds or 29.4 million kg) per day (Lorenzetti 1994). Estimated production capacity in the United States 

during 1995 was 240,100 barrels (about 62.2 million pounds or 28.2 million kg) per day (CMR 1995). 

Since some companies operate plants that make large contributions to the total annual U.S. production of 

MTBE, production estimate statistics may exclude figures from certain companies. In fact, such private 

providers of production information as SRI International (SRI 1995) no longer provide any MTBE 

production quantities for facilities or companies. Annual MTBE production estimates for 1991 were 

9.57 billion pounds (4.34 billion kg), and estimates for 1992 were at 10.86 billion pounds (4.92 billion kg) 

(HSDB 1995; Reisch 1993). The U.S. International Trade Commission (USITC) solicits production 

estimates for a number of synthetic organic chemicals from companies suggested by government and 

industry representatives. MTBE has been included in this survey since 1993. The annual production 

estimates are subject to a series of revisions, so that it often takes at least a year for final figures to become 

stabilized. The most recent set of stable production statistics are for 1993, when the annual production 

was estimated to be 5.547 billion kg (12.229 billion pounds) (USITC 1995). Available statistics, 

therefore, show a dramatic increase in MTBE production from the 1980s to the early 1990s and a slower, 

but steady, increase in production during the 1990s). 

Table 4-l lists the facilities in each state that manufacture or process MTBE, the intended use, and the 

range of maximum amounts of MTBE that are stored on site. The amounts stored at these facilities ranges 

from amounts under the Toxics Release Inventory (TRI) reporting requirements to amounts at or above 

1 million pounds (453,597 kg) per year (TRI93 1995). Four states (California, Louisiana, Michigan, and 

Texas) account for over 50% of the total number of reporting facilities in TRI93. The data from the Toxics 

Release Inventory listed in Table 4-1 should be used with caution, however, since only certain types of 

facilities were required to report (EPA 1995a). This is not an exhaustive list. 

METHYL tert-BUTYL ETHER 166 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

4.2 IMPORT/EXPORT 

The USITC and the U.S. Department of Commerce only started to document import information for MTBE 

in 1993 and export information in 1994. Therefore, only limited quantitative estimates on annual import 

and export levels for MTBE are available for years prior to 1994. For 1994, the level of MTBE imports is 

1.753 billion kg (3.865 billion pounds); the level of exports for 1994 is estimated as 0.405 billion kg 

(0.893 billion pounds) (NTDB 1995). For imports, the 1993 figure is 0.919 billion kg (2.026 billion 

pounds) (NTDB 1995). In earlier published U.S. production figures, the statistics would often combine 

MTBE used domestically with MTBE exports (Reisch 1993). While there has been substantial 

construction of new MTBE production facilities worldwide (Anonymous 1992b; Otto 1993) large U.S. 

production facilities are reported to export a substantial percentage of their output (Lorenzetti 1994). One 

reason that MTBE has only recently attracted interest for purposes of official import and export statistics 

(as opposed to overall, production estimates) is that the vast majority of MTBE output is first blended into 

reformulated gasolines. Foreign producers will generally seek markets for products like finished gasoline, 

so that most MTBE would be imported not as a bulk product but as an ingredient in gasolines 

(Anonymous 1992b; HSDB 1995; Lorenzetti 1994). 

4.3 USE 

Nearly all the MTBE produced in the United States is produced for use in reformulated gasolines. MTBE 

can be thermally decomposed into methanol and isobutene and in the past has been used to produce 

isobutene (HSDB 1995). MTBE is used in small quantities as a laboratory reagent to extract semi-volatile 

organic compounds from such sample types as leachates or solid wastes (EPA 1984a). MTBE is also a 

pharmaceutical agent, which can be used as an alternative to surgery in dissolving gallstones when 

injected intraductally (Angle 1991; Bergman et al. 1994; Eidson et al. 1993; Gilbert and Calabrese 1992). 

4.4 DISPOSAL 

Since most MTBE is used as a component in reformulated gasoline, provisions for its disposal are 

generally subsidiary to regulations for disposing of gasolines or similar volatile or such semi-volatile 

organic compounds as benzene or toluene. MTBE is likely to be encountered in waste sites or NPL sites 

where blended gasoline has been disposed of, or at NPL sites around pipelines, large tank batteries, or 

refineries and other facilities involved in the manufacture of reformulated fuels. Once dissolved in water, 

MTBE can readily leach into groundwater supplies. MTBE from past disposal in dumps and waste sites or 
METHYL tert-BUTYL ETHER 167 

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

from spills, leakage from underground storage tanks, or other releases to the environment is being 

increasingly recognized as a pollutant to groundwater supplies (Schorr 1994; USGS 1995). Chapter 7 

contains an overview of regulations and guidelines regarding disposal practices for MTBE. No 

information was located on the quantities of MTBE disposed of by each disposal method, or on trends in 

disposal amounts or practices. 

METHYL tert-BUTYL ETHER 169 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.1 OVERVIEW 

MTBE is generated solely through manufacturing processes and is released to the environment by human 

activities. Until the 1970s when a shift to unleaded gasolines attracted interest in relatively non-polluting 

high octane additives, MTBE production was extremely limited. As recently as 1980, commercial output 

in the United States was only 19,000 barrels (around 5 million pounds or 2.2 million kg) per day; it has 

since climbed to around 250,000 barrels (about 64.8 million pounds or 29.4 million kg) per day 

(Lorenzetti 1994). When production was low, the risks for human exposure were minimal outside certain 

occupational settings. Exposures to MTBE at high levels would usually be expected only in the case of 

accidents or spills, especially in enclosed spaces. But the current widespread use of MTBE in 

reformulated gasoline significantly increases the possibility of the general public being exposed to MTBE 

at low levels. Opportunities for exposure will closely parallel those for other organic hydrocarbon 

gasoline additives such as benzene or toluene. In addition to inhalation risks while fueling motor vehicles 

and direct exposures from vehicle emissions, MTBE will be emitted to the ambient air, primarily from precombustion 

volatilization. This can then lead to low-level background exposure potentials over a large 

geographical area. 

While these atmospheric pathways are of most concern for the general population, more localized risks can 

arise when MTBE becomes a groundwater contaminant. Groundwater contamination risks exist around 

major production sites, pipelines, large tank batteries, transfer terminals, and active or abandoned waste 

disposal sites; in addition, gasoline leaks from up to 20% of the nation’s 1.4 million underground storage 

tanks (USTs) can lead to exposures to MTBE through contaminated groundwater. Groundwater sampling 

programs are beginning to document numerous cases of MTBE contamination, especially in shallow 

groundwater aquifers; contamination is often related to spills or releases from USTs (Schorr 1994; USGS 

1995). 

According to much of the existing literature, MTBE poses no severe human health threats at the exposure 

levels anticipated for the general population. However, MTBE does produce an extremely offensive odor. 

When included in a liquid mixture, its odor detection threshold is in the neighborhood of 680 μg/L, which 

is much lower than the 4,700 μg/L threshold for other common volatile organic compounds (VOCs) like 

benzene (Angle 1991; Gilbert and Calabrese 1992). In many cases, the smell of MTBE in well water has 
METHYL tert-BUTYL ETHER 170 

5. POTENTIAL FOR HUMAN EXPOSURE 

been an early indicator of groundwater contamination from even more dangerous VOCs released from 

leaking USTs (Angle 1991). 

MTBE has been identified in at least 12 of the 1,430 current or former EPA National Priorities List (NPL) 

hazardous waste sites (HazDat 1996). However, the number of sites evaluated for MTBE is not known. 

The frequency of these sites can been seen in Figure 5-1. 

5.2 RELEASES TO THE ENVIRONMENT 

Environmental releases of MTBE may occur at industrial sites involved in the manufacture of MTBE or in 

the blending of MTBE with gasoline; during the storage, distribution and transfer of MTBE-blended 

gasoline, and from spills or leaks or fugitive emissions at automobile service stations (EPA 1994c). The 

major source for quantitative estimates of releases to environmental media for MTBE is the Toxics 

Release Inventory (TRI). 

Releases of MTBE are required to be reported under SARA Section 313; consequently data are available 

for this compound starting with the 1993 survey period in the TRI (EPA 1995a). According to the TRI, a 

total of 3,163,305 pounds (1,434,865 kg) was released to some environmental media in 1993 (TRI93 

1995). This total figure includes 9,405 pounds (4,266 kg) released through the Underground Injection 

Control program. In addition, an estimated 92,030 pounds (41,744 kg) were released by manufacturing 

and processing facilities to publicly owned treatment works (POTWs), and an estimated 859,424 pounds 

(389,832 kg) were transferred off-site (TRI93 1995). 

MTBE has been identified in at least 12 of the 1,430 NPL current or former NPL hazardous waste sites 

(HazDat 1996). According to HazDat (1996) MTBE has been detected only in groundwater. MTBE has 

been found in groundwater samples at all 12 NPL sites with MTBE contamination (HazDat 1996). 

5.2.1 Air 

Although MTBE was listed as a hazardous air pollutant under the 1990 Clean Air Act Amendments, it is 

also an EPA-approved alternative for use in reformulated gasoline (EPA 1994c). While its notoriety as a 

gasoline additive has led to some regional case studies (LaGrone 1991), information on MTBE is not 

available allowing comprehensive estimates of releases to the air. Since MTBE is a VOC, it has been 

included under emissions inventories for some industrial facilities (LaGrone 1991). 

METHYL tert-BUTYL ETHER 172 

5. POTENTIAL FOR HUMAN EXPOSURE 

Major markets for MTBE were very limited until MTBE and ethanol became the two favored ingredients 

for use in reformulated gasolines in the late 1980s. It is therefore reasonable to assume an increasing trend 

in releases of MTBE to the atmosphere in the 1990s. However, the limited availability of data makes it 

difficult to make any quantitative assessment of trends in releases to the air. 

Most releases would be from the MTBE included in reformulated gasoline. The most common types of 

releases would involve refueling operations at fuel terminals or service stations and emissions from 

automobile exhaust or background levels in the ambient air encountered during commuting (Lioy et al. 

1994). Since these emissions are not from stationary sources, broad-based monitoring and record-keeping 

is minimal, precluding precise estimates of these releases. 

Many types of human exposure will involve transient events related to adding fuel to automobiles or 

igniting reformulated fuels in a car engine under “cold” start-up conditions. With the switch to unleaded 

fuels, manufacturers have encountered challenges in maintaining adequate levels of what is called the 

Front End Octane Number (FEON). When first starting an engine, especially if the weather conditions are 

extremely cold, the initial combustion reactions focus on those components of the fuel that can boil below 

100 °C. In reformulated gasolines, such components will include MTBE, other VOC additives, and the 

most volatile components of the gasoline itself (Piel 1988). This can increase the levels of transient 

exposure and is a major reason that cars burning reformulated fuels give off objectionable odors until the 

engines have warmed up. This phenomenon, which could clearly be exacerbated under extremely cold 

climate conditions, is a factor in the ongoing controversy over MTBE exposure in states with extremely 

cold winters (Illman 1993; Pie1 1988). 

According to the TRI, releases of 3,095,069 pounds (1,403,914 kg) of MTBE to the atmosphere from 

34 manufacturing or processing facilities in 1993 accounted for about 97.8% of the total environmental 

releases (TRI93 1995). These releases are summarized in Table 5-1. The data from the TRI listed in 

Table 5-1 should be used with caution, however, since only certain types of facilities are required to report 

(EPA 1995a). This is not a comprehensive list. 

MTBE has not been identified in air samples collected at any of the 12 NPL hazardous waste sites where it 

was detected in some environmental media (HazDat 1996). 


METHYL tert-BUTYL ETHER 175 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.2.2 Water 

MTBE is not a priority pollutant under the Clean Water Act and has not been a target analyte in ordinary 

surface water quality monitoring and assessment programs or the focus of much attention in discharge 

permitting. Therefore, very limited data are available on releases of MTBE to surface waters. Most 

releases to surface water would likely result from leaks or spills. Since MTBE has a fairly high degree of 

solubility in water (42,000 mg/L as used in Mackay et al. 1993), rain scouring could also transfer MTBE 

from the atmosphere to surface waters (USGS 1995). Wet weather runoff will often wind up being divert 

into storm drains or waste water treatment facilities in urban areas or industrial facilities, where the MTBE 

may then be introduced to receiving waters. Given its high vapor pressure of 245 mm Hg and Henry’s 

Law Constant of around 5.87x 10-4atm-m3

/mole (see Chapter 3, Table 3-2), however, MTBE would be 

expected to volatilize rapidly from surface water or soil surfaces (EPA 1994c). 

According to the TRI, releases of 58,509 pounds (26,539 kg) of MTBE to surface water from 

22 manufacturing or processing facilities in 1993 accounted for about 1.8% of the total environmental 

releases (TRI93 1995). An additional 92,030 pounds (41,744 kg) of MTBE were introduced as influents 

to POTWs (TRI93 1995). While much of this input to municipal waste water treatment works would be 

expected to volatilize to the air, perhaps up to 10% might be released to surface water in treated effluents 

(van Luin and Teurlinckx 1987). These releases are summarized in Table 5-l. The data from the TRI 

listed in Table 5-l should be used with caution, however, since only certain types of facilities are required 

to report (EPA 1995a). This is not a comprehensive list. 

While no comprehensive quantitative estimates of MTBE releases to groundwater seem possible, the 

chemical has been reported in groundwater at all 12 NPL sites where MTBE contamination is documented 

in the HazDat database (HazDat 1996). Another source of groundwater contamination is from leaking 

USTs. There are around 1.4 million small underground storage facilities regulated under the EPA 

Underground Storage Tank (UST) program. Up to 20% of these facilities may either be leaking now or 

can be expected to start leaking in the near future (Mihelcic 1990). Since the UST program requirements 

for upgrading storage tank construction only began to take effect by the late 1980s some leaking tanks 

would have contained reformulated fuels containing MTBE. Since the focus of remediation efforts under 

the UST program is on such known carcinogens as benzene, detection of MTBE contamination often takes 

place qualitatively due to its offensive odor (Angle 1991). The odor threshold of MTBE is in the range of 

0.32-0.47 mg/m3

 (1.15-l.70 ppm) in air (EPA 1994a), which corresponds to a level that would volatilize 
METHYL tert-BUTYL ETHER 176 

5. POTENTIAL FOR HUMAN EXPOSURE 

from a concentration of around 680 ppb (μg/L) in water (Angle 1991); MTBE levels in either media are 

much lower than for other common VOCs such as benzene. 

5.2.3 Soil 

No quantitative estimates of releases to soils or sediments could be identified. Releases around production 

facilities, pipelines, or transfer terminals are possible from spills. The organic carbon partitioning 

coefficient (Koc) for MTBE is around 11.2, a low value indicating little tendency to sorb to soil particles 

and suggesting a considerable mobility, with the leaching of the chemical into groundwater considered 

likely (EPA 1994c; Swann et al. 1983) (see Table 3-2). In estuaries and harbors, aquatic sediments may 

become sinks, at least on a seasonal basis, for MTBE introduced from a combination of spills, runoff, or 

automobile emissions (Bianchi et al. 1991). 

According to the TRI, releases of 320 pounds (145 kg) of MTBE to the land from 10 manufacturing or 

processing facilities in 1993 accounted for less than 1% of the total environmental releases (TRI93 1995). 

These releases are summarized in Table 5-l. The TRI data listed in Table 5-l should be used with caution, 

however, since only certain types of facilities are required to report (EPA 1995a). This is not a 

comprehensive list. 

The limited availability of data makes it difficult to assess releases of MTBE to soils or sediments. MTBE 

has not been identified in soil or sediment samples collected at any of the 12 NPL hazardous waste sites 

where it was detected in some environmental media (HazDat 1996). 

5.3 ENVIRONMENTAL FATE 

5.3.1 Transport and Partitioning 

Based on equilibrium fugacity models, the high vapor pressure of MTBE leads to partitioning to the 

atmosphere (Mackay et al. 1993) for MTBE releases to surface waters or soil surfaces. In model systems, 

half-lives (first-order kinetics) in moving water are estimated in the neighborhood of 4.1 hours (HSDB 

1995, noting estimates based on a method presented in Lyman et al. 1982). Under dynamic systems where 

there might be substantial ongoing loadings to air, soils, sediment, or water, the partitioning to the air 

compartment is slightly less pronounced (Mackay et al. 1993). When introduced into subsurface soils or 

to groundwater, MTBE may be fairly persistent since volatilization to the atmosphere is reduced or 
METHYL tert-BUTYL ETHER 177 

5. POTENTIAL FOR HUMAN EXPOSURE 

eliminated. Especially where MTBE is introduced as part of a gasoline mixture from leaking USTs, its 

relatively high water solubility combined with little tendency to sorb to soil particles can be expected to 

encourage migration to local groundwater supplies (EPA 1994c). 

Based on analogy with other ethers, the potential for bioconcentration appears to be very minor, and 

standard references will often not even attempt to estimate bioconcentration factors (BCFs) for such 

chemicals (Mackay et al. 1993). The only case in the literature presenting an empirical estimate on a BCF 

for MTBE is a Japanese study using the Japanese carp. Using a flow-through water system with exposures 

carried out over a 4-week period, the highest measured BCF for whole tissue was 1.5 (Fujiwara et al. 

1984). Following the end of exposure, tissue levels rapidly declined. A BCF of 3 was estimated from 

octanoYwater partition coefficients for the fathead minnow (ASTER 1995; Veith and Kosian 1983). Based 

on these results, the bioconcentration potential for MTBE can be rated as quite insignificant. 

5.3.2 Transformation and Degradation 

MTBE is expected to be undergo destruction once released into the atmosphere from reactions with 

hydroxyl radicals. Photolytic decay processes do not seem to play a role in its degradation since MTBE 

does not absorb light in range above 210 nm (EPA 1994c). If introduced into surface soils, MTBE would 

rapidly re-volatilize to the atmosphere. When introduced into subsurface soil layers, which would be 

common in seepage from leaking USTs, MTBE may be fairly persistent since it shows very limited 

tendency for either abiotic or biotic degradation processes. When released to surface waters, MTBE would 

also tend to re-volatilize rapidly to the air. While MTBE has a reasonably high water solubility (up to 

42,000 mg/L as used in Mackay et al. 1993), it shows little tendency to degrade from hydrolysis and has 

little tendency to sorb to suspended particulates, soils, or sediments. In groundwater, MTBE can be fairly 

persistent since it shows limited susceptibility to either anaerobic or aerobic biodegradation (EPA 1994c). 

5.3.2.1 Air 

MTBE is not expected to persist in the atmosphere because of its fairly rapid reactions with hydroxyl 

radicals. Based on available laboratory studies, a total atmospheric lifetime for MTBE of approximately 

4 days has been estimated (Cox and Goldstone 1982; Smith et al. 1991; Wallington et al. 1988). In other 

studies, atmospheric half-lives of approximately 3 days are reported in polluted urban air and around 

6.1 days in non-polluted rural air (EPA 1994c). 
METHYL tert-BUTYL ETHER 178 

5. POTENTIAL FOR HUMAN EXPOSURE 

There are two main decomposition pathways depending on whether the methyl group or the tert-butyl 

group is attacked. The pathway involving OH radical decomposition on the methyl group results in such 

final products as acetone and tert-butyl formate. While acetone would be relatively resistant to further OH 

radical degradation, there is very little research on the reactivity of the tert-butyl formate degradation 

products, with available research suggesting atmospheric residence times of up to 15 days (Cox and 

Goldstone 1982). This would make the tert-butyl formate much more persistent in the atmosphere than 

the original MTBE. There is very limited information available on the toxicology and human health 

impacts of tert-butyl formate. The pathway involving decomposition of the tert-butyl group can become 

extremely complex, with the final products being dependent on the levels of other free radicals and such 

pollutants as NOx. The initial decomposition is not sensitive to photolysis since MTBE does not absorb 

radiation in the spectrum above 200-210 nm (EPA 1994c; Schuchmann and von Sonntag 1973); however, 

OH radical decomposition is critical to the initial reactions. Photolysis reactions can play a much greater 

role in the subsequent breakdown of the rert-butyl group. Under conditions typical of polluted urban air 

(Japar et al. 1990), decomposition products can include 2-methoxyl-2-methyl propanol, acetone, 

acetaldehyde, and peroxyacetyl nitrate (PAN). Other laboratory studies also indicate that the 

decomposition products include formaldehyde (Tuazon et al. 1991), and methyl acetate (Smith et al. 1991; 

Tuazon et al. 1991). The decomposition products actually formed are often highly dependent on the 

presence of other types of air pollutants. Studies in highly polluted urban airsheds such as Mexico City 

have documented statistically significant increases in the ambient levels of formaldehyde following efforts 

to encourage greater use of reformulated gasolines such as MTBE (Bravo et al. 1991). Alternative 

oxygenated fuel additives such as ethanol, however, also produce aldehydes as combustion products 

(Shanley 1990). 

Several of the decomposition products stemming from the tert-butyl group breakdown pathway are 

products that can be produced from non-oxygenated unleaded gasolines or from reformulated products 

using such alternative oxygenating agents as ethanol. This can make it hard to relate laboratory studies or 

modeling predictions to actual monitoring observations. For instance, analyses of time series data in both 

Mexico City, Mexico, and Denver, Colorado, have been interpreted as confirmation for the position that 

the use of MTBE in gasolines can contribute, especially when used with other reformulated gasoline 

agents, to increases in the levels of such air pollutants as formaldehyde (Humberto et al. 1991; Illman 

1993). 
METHYL tert-BUTYL ETHER 179 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.3.2.2 Water 

In surface waters, MTBE shows little tendency to degrade due to hydrolysis or other abiotic processes. It 

is also resistant to biodegradation (EPA 1994c). Due to its high volatility, will usually be removed from 

surface waters very rapidly. 

In groundwater, the persistence of MTBE would be accentuated since volatilization to the air is reduced or 

eliminated and this ether is apparently refractory to most types of bacterial biodegradation (Yeh and 

Novak 1991). Since large plants devoted almost exclusively to the manufacture of MTBE are a relatively 

recent phenomenon, most spills around older refineries, pipelines, and transhipment terminals would result 

in a complex mixture of different organic hydrocarbons in groundwater pollution incidents. 

Contamination at larger facilities involving reformulated fuels would involve mixtures, and contamination 

to groundwater from leaking USTs will almost invariably involve blended hydrocarbon mixtures. 

The behavior of a plume of MTBE mixed with gasoline and other organic hydrocarbons such as the BTEX 

series (benzene, toluene, ethylbenzene, and xylene) in contact with water in an aquifer can become very 

complicated. A key factor is the percentage of MTBE in the original fuel mixture. Since 1979, EPA has 

allowed progressively higher percentages of MTBE in reformulated gasolines, the percentage has risen 

from 7% in 1979 to 11% in 1981, and then to 15% in 1988 (Lorenzetti 1994). Below levels of about 5%, 

the pollution chemistry of a reformulated gasoline plume mixing with fresh groundwater will be driven 

mostly by the effects from the BTEX components. At higher MTBE levels, however, studies based on 

theoretical considerations and modeling exercises suggest that MTBE may increase the partitioning of the 

BTEX toxics into groundwater (Mihelcic 1990; Poulsen et al. 1992). These impacts will be minor when 

the levels of MTBE in a reformulated gasoline mixture are less than 10% (by volume), with BTEX 

solubilities in water increasing by 10% or less. At higher MTBE mixture ratios, however, increases in the 

MTBE mixture percentage can increase the BTEX water solubilities to a higher degree. For instance, a 

reformulated gasoline mixture containing 0.1% MTBE by volume could increase BTEX water solubilities 

by only around 1%; a 10% MTBE mixture could result in a 100% increase in BTEX water solubilities 

(Mihelcic 1990). The MTBE co-solvent can also change the sorption/desorption characteristics of other 

hydrocarbons, thus increasing their mobility. 
METHYL tert-BUTYL ETHER 180 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.3.2.3 Sediment and Soil 

There is very limited information available on degradation processes in soils or sediments. On analogy 

with water media, there would be limited tendency for destruction from hydrolysis or other abiotic 

processes. Results from field or laboratory microcosm studies suggest considerable persistence in deeper 

soil layers or in sediments since this ether appears to be highly refractory to microbial decomposition 

(Jensen and Arvin 1990; Yeh and Novak 1991). For instance, microcosm studies using several soil types 

and bacterial flora showed no significant biodegradation in experiments carried out over a 250-day period, 

with most losses due to sorption to organic matter or volatilization (Yeh and Novak 1991). Soils in these 

microcosm studies were taken from agricultural sites showing moderate acidity (pH 5-6) and a wide range 

in organic matter content. 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to MTBE depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. In reviewing data on 

MTBE levels monitored in the environment, it should also be noted that the amount of chemical identified 

analytically is not necessarily equivalent to the amount that is bioavailable. 

5.4.1 Air 

No information could be identified summarizing levels of MTBE in the ambient air based on a national 

monitoring database. One regional ambient study from the Houston Regional Monitoring Network 

(LaGrone 1991) included MTBE in a suite of VOC target analytes to be monitored. This part of Texas 

contains the Houston Ship Channel and includes some of the nations’s largest MTBE manufacturing 

facilities, many in close proximity to residential neighborhoods. Data collections on every sixth day were 

obtained over a period from September 8, 1987, through September 18, 1988, following the EPA National 

Sampling Day protocols. Monitoring results for the Harris and Chambers county area showed total yearly 

MTBE emissions of 285 tons, with a mean ambient air concentration for MTBE less than the detection 

limit of 0.2 ppb (0.0007 mg/m3

). This study used good quality control features and concluded that 

occupational and residential exposure potentials in this area with a heavy concentration of MTBE 

production and processing facilities were likely to be lower than in urban areas in other parts of the United 

States. The EPA has estimated that annual mean MTBE concentrations in ambient air in the United States 

during the late 1980s were less than 0.2 ppb (EPA 1994c). 
METHYL tert-BUTYL ETHER 181 

5. POTENTIAL FOR HUMAN EXPOSURE 

No information was identified on typical levels for indoor residential air spaces. There are a number of 

studies where data were collected around auto service or filling stations that would bear on exposures in 

special locations for the general population as well as for occupational groups that work at these 

automobile service facilities. Levels from several urban locations suggested that MTBE levels around 

such auto service facilities would be less than 1 ppm (Hartle 1993). These special microenvironments can 

help assess a broad range of exposure risks, but often involve short-term exposures or large variations in 

potential dosages that complicate the interpretation of the data; such data do not provide a basis for 

estimating typical ambient air levels (Huber 1994). 

5.4.2 Water 

Until recently, MTBE has not ordinarily been included as a parameter in most surface water or 

groundwater monitoring programs. Especially for surface waters, very limited information could be 

identified in the literature for the United States on ambient levels. Studies in England’s Southampton 

Harbor, with conditions that may find parallels in other countries in temperate climates where there is 

extensive use of reformulated gasoline (Bianchi et al. 1991), found MTBE could accumulate in sediments 

in the pollutant sink environment of the harbor area. The sediment was then a major source of MTBE reintroduction to 

the surface waters. For an 18-month period of record, ambient water concentrations of 

MTBE were observed with a range of 15-81 ng/L (ppt). 

In groundwater, studies of NPL and UST program remediation sites can provide highly site specific 

indications of MTBE levels in groundwater. UST sites showing MTBE groundwater contamination may 

potentially involve a larger total population since older gasoline stations are ubiquitous. Apparently, 

detections of MTBE triggered by reports of offensive odors in groundwater are becoming ever more 

common. A value of 680 μg/L (ppb) is a common odor threshold for MTBE dissolved in water (Angle 

1991). Since the odor thresholds of much more dangerous chemicals like benzene are considerably higher 

(4,700 μg/L [ppb] for benzene), odor detections of MTBE are viewed as a type of early warning indicator 

of potentially more serious groundwater problems (Angle 1991). 

In addition to these highly site-specific sources of information related to groundwater, some states have 

assembled significant amounts of water-well data that include testing for MTBE. Since the mid-l980s, 

New Jersey has conducted some screening analysis for public drinking water supplies that included MTBE 

tests as well as analyses from public and private wells as part of spill investigations or testing related to 

leaking USTs (Schorr 1994). From 1989 to 1983, at least 30 wells serving 6 different community drinking 
METHYL tert-BUTYL ETHER 182 

5. POTENTIAL FOR HUMAN EXPOSURE 

water systems, and at least 150 private wells had documented detectable amounts of MTBE. In cases 

involving a petroleum product spill or leakage, MTBE levels tended to be very high, in one case as high as 

40,000 ppb. In all cases where MTBE levels of 100 ppb or higher were detected, there were also 

detections of such gasoline constituents as benzene, toluene, xylene, or other hydrocarbons. The highest 

incidence of MTBE detections involved non-public wells, where 10% of the wells sampled showed MTBE 

levels of 70 ppb or higher. Extrapolating the available samples to all private wells and public wellheads in 

New Jersey led to the estimate that 0.5-1 % of the state’s drinking water wells might show MTBE levels 

greater than 70 ppb (Schorr 1994). 

The United States Geological Survey (USGS 1995) has also summarized VOC data on MTBE derived 

from a series of studies in its National Water-Quality Assessment (NAWQA) Program. Many of the 

NAWQA studies include a groundwater component. At present, the NAWQA data are available from 

211 shallow wells in 8 urban areas and 524 shallow wells in 20 agricultural areas. MTBE was detected in 

27% of the urban wells, but in only 1.3% of the rural wells. Only 3% of the urban wells showed MTBE 

concentrations that exceeded 20 ppb. One well showed a level of around 23,000 ppb. Certain parts of the 

country with longer histories in the use of reformulated gasolines showed a higher incidence of MTBE 

detections. For instance, 79% of the test wells in the Denver, Colorado, area showed detectable traces of 

MTBE, and 37% of wells in New England showed detectable levels (detection limit, 0.2 ppb). While the 

shallow wells targeted for analysis in the NAWQA studies would seldom be part of the aquifers used in 

public drinking water systems, the USGS suggests that urban areas with a long history of reformulated 

gasoline usage may face increased risks of groundwater contamination from MTBE (USGS 1995). 

5.4.3 Sediment and Soil 

No quantitative information from the United States documenting levels of MTBE in soils or sediments was 

found. The documented instances of MTBE contamination of shallow groundwater supplies demonstrate 

the likelihood of MTBE contamination of soils, especially when related to leaks from USTs that contained 

reformulated gasoline. However, since programs to remediate soil or groundwater contamination from 

underground tanks have generally focussed on clean-up standards for gasoline products in general or 

specific toxicants such as benzene, the EPA and state UST programs do not usually yield much monitoring 

evidence on MTBE. 

Studies in England’s Southampton Harbor, with conditions that may find parallels in other countries in 

temperate climates where there is extensive use of reformulated gasoline (Bianchi et al. 1991), found 
METHYL tert-BUTYL ETHER 183 

5. POTENTIAL FOR HUMAN EXPOSURE 

MTBE could accumulate in sediments in the pollutant sink environment of the harbor area. The sediment 

was then a major source of MTBE re-introduction to the surface waters. For an 18-month period of record, 

concentrations from sediment interstitial water samples were reported with a range of 14-20,645 ng/kg 

(ppt) (Bianchi et al. 1991). 

5.4.4 Other Environmental Media 

Analogies with the behavior of other highly volatile solvents and ethers, results from a QSAR analysis 

based on fathead minnow data (ASTER 1995), and results of a confirmatory laboratory BCF for a fish 

(Fujiwara et al. 1984; HSDB 1995), do not suggest any tendencies for bioconcentration, biomagnification, 

or bioaccumulation of MTBE that would present human health threats. 

Where chemicals have a tendency to bioconcentrate, biomagnify, or bioaccumulate, they may show up in 

fish consumption advisories issued by the states. Examination of EPA’s Fish Consumption Advisory 

Database (EPA 1995b) showed that no advisories had been issued for MTBE through September 1994. 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

MTBE can be emitted to any or all environmental media (air, surface water, groundwater, and soil) 

depending on the source of the release, formulation mixture, and prevailing environmental conditions. 

Little information was identified that would allow estimation of current levels of daily intake or exposure 

to MTBE. General population exposure to MTBE may occur through three routes: inhalation, dermal 

contact, and ingestion of contaminated groundwater. The major route of exposure to MTBE for the 

general population is through inhalation of contaminated ambient air, particularly during regular visits to 

gasoline refueling stations or after major spills or accidents at manufacturing, distribution, or storage 

facilities. During normal manufacturing, distribution, and storage operations, however, very low levels of 

MTBE are generally detected in ambient air. A regional survey for a 2-county area along the Houston 

Ship Channel, where a large number of MTBE production facilities are located, reported average ambient 

air concentration levels at less that 0.2 ppb (LaGrone 1991). 

A second route of exposure is by dermal contact with MTBE-containing gasolines during regular visits to 

refueling stations or when tilling lawn mowers, chain-saws, or other gasoline-powered equipment. The 

oral route of exposure may include consumption of drinking water contaminated with MTBE. Leaking 
METHYL tert-BUTYL ETHER 184 

5. POTENTIAL FOR HUMAN EXPOSURE 

USTs or spills at manufacturing, distribution, or storage sites can all be sources of contamination to local 

groundwater supplies. 

A study of two types of microenvironments with the potential for MTBE general population exposure 

provides useful estimates of air concentrations experienced by many urban commuters (Lioy et al. 1994). 

Air samples from commuter-car interior areas showed a geometric mean for MTBE of 21 μg/m3 

(0.006 ppm) with a range from 4 μg/m3 (0.001 ppm) to 580 μg/m3 (0.16 ppm). Air sampling of gasoline 

refueling station microenvironments involved both the air at the refueling pumps (measured over the hood 

of the car) and pre- and postsampling of the interior cabins. The refueling station air samples ranged in 

concentrations from 0.01 to 14 ppm (40-49,000 μg/m3

) and clearly offered higher short-term exposure 

levels than the interior cabin air. Elevated levels of MTBE have been detected in human blood samples by 

the Centers for Disease Control and Prevention (CDC) in residents of Alaska exposed to MTBE; many of 

these individuals reported various symptoms related to wintertime use of MTBE-enhanced fuels (CDC 

1993a; Illman 1993). Based on those observed effects, the EPA granted Fairbanks a waiver on the 

required use of MTBE in oxygenated fuels. However, since low-level exposures to MTBE have not been 

considered particularly harmful, this ether is not normally included in ambient air sampling studies. 

Workers employed in industries that manufacture, formulate, store, or transport MTBE, and workers 

involved in the disposal of MTBE-containing wastes, may be exposed to the highest concentrations of 

MTBE. In occupational settings, inhalation and dermal exposure with subsequent absorption through 

intact skin are the most important routes of exposure. Inhalation of MTBE depends on its volatility, the 

percentage of MTBE in the mixture used, and the physical setting in which it is released. Industrial 

hygiene assessments carried out in the mid-1980s on workspace air concentrations associated with truck 

drivers or truck terminal operators have documented concentrations of MTBE ranging from less than 

1 ppm to 139 ppm (Gilbert and Calabrese 1992). Estimates have also been made for workplace 

concentrations for gasoline truck drivers and gasoline service station attendants, with short-duration 

exposures ranging from 1.4 mg/m3 (0.4 ppm), where trucks with vapor recovery systems are used, to 

< 96 mg/m3

 (26.6 ppm), where vapor recovery systems are not used (Gilbert and Calabrese 1992). In 

research at several urban areas supported by the American Petroleum Institute, occupational exposures for 

service station attendants were well under a level of 1 ppm, even in cities where reformulated fuels 

contained up to 12% MTBE (API 1993; Hartle 1993). The highest of these levels falls well below the 

100 ppm Workplace Environmental Exposure Limit recommended by the American Industrial Hygiene 

Association (see Chapter 7 below). The conversion factor of 1 ppm = 3.61 mg/m3

 (1 ppb = 

0.00361 mg/m3

) can be used for air concentrations of MTBE (Moolenaar et al. 1994). 
METHYL tert-BUTYL ETHER 185 

5. POTENTIAL FOR HUMAN EXPOSURE 

Two studies carried out by the National Institute for Occupational Safety and Health (NIOSH) at the 

request of the National Center for Environmental Health, Centers for Disease Control and Prevention, 

gathered case study measures of levels of MTBE in the air at a variety of workplaces in Stamford, 

Connecticut (NIOSH 1993a), and in Fairbanks, Alaska (NIOSH 1993b). Both studies focused on 

automobile repair centers where workers might be exposed to emissions or combustion by-products. The 

Alaskan study was conducted after January 1993, at which time the use of MTBE as an anti-pollutant 

oxygenating agent had been suspended. MTBE was still in use as an octane booster in high-octane 

(premium) grades of gasoline, but this would have been at levels (1% or less by weight) well below the 

levels associated with the use of MTBE as an anti-pollutant additive. The highest workplace 

concentrations found during the Alaskan studies were less than I ppm. In Stamford, Connecticut, where 

MTBE was being used as an anti-pollutant additive, workplace concentrations at automotive repair centers 

< 12 mg/m3

 (3.3 ppm) were documented. In the Stamford study, blood samples were collected from 

commuters and people in workplace settings where higher MTBE exposures were likely. The blood 

samples were analyzed for MTBE, tert-butanol (the MTBE metabolite), and the gasoline VOC components 

benzene, toluene, and xylene (White et al. 1995). Although the blood levels of MTBE varied widely, 

statistical analysis indicates a tendency for workers in car repair facilities and workers who pump gasoline 

into cars to have considerably elevated blood MTBE levels, compared to average blood levels in 

commuters. The median blood level for MTBE among car repair workers was about 2 μg/L (ppb); for gas 

pumping attendants the median was slightly over 10 μg/L (ppb); while the median level for the commuter 

group was less than 0.3 μg/L (ppb) (White et al. 1995). 

The National Occupation Exposure Survey (NOES) conducted by NIOSH from 1981 to 1983 estimated 

that 5,996 workers (1,783 females, 4,213 males) employed at 614 facilities were potentially exposed to 

MTBE in the United States (NOES 1991). The occupational groups were in industries such as commercial 

testing laboratories, hospitals, medical laboratories, gasoline service stations, airport maintenance 

facilities, and paper mills. The NOES database does not contain information on the frequency, 

concentration, or duration of exposure; the survey provides only estimates of workers potentially exposed 

to chemicals in the workplace (Sieber et al. 1991). 
METHYL tert-BUTYL ETHER 186 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

In addition to individuals occupationally exposed to MTBE during its production, formulation, 

distribution, use, or disposal, people exposed to higher than background concentrations include those 

living near chemical manufacturing or processing sites where accidental releases or spills may occur, 

individuals living in the vicinity of leaking USTs, and individuals living near hazardous waste sites. 

While accidents or spills can pose special exposure threats for workers at petrochemical facilities, 

exposures are ordinarily limited by the closed and highly automated nature of MTBE manufacturing 

processes. The high degree of automation also limits the number of workers at risk (Gilbert and Calabrese 

1992). In the event of major accidents or spills, residential populations close to such facilities could to 

exposed to high concentrations of MTBE in the air. In local areas where leachates from waste disposal 

sites or underground storage facilities might contaminate groundwater used for drinking and bathing 

purposes, there is the potential for lesser MTBE exposures by ingestion of contaminated drinking water, 

and by dermal contact with and inhalation of MTBE during bathing. 

5.7 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate 

information on the health effects of MTBE is available. Where adequate information is not available, 

ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed 

to determine the health effects (and techniques for developing methods to determine such health effects) of 

MTBE. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 
METHYL tert-BUTYL ETHER 187 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.7.1 Identification of Data Needs 

There is limited empirical monitoring data on typical levels of MTBE in all environmental media. Special 

statistically designed national surveys and more routine sampling are needed, especially focusing on such 

obvious exposure pathways as the ambient air or groundwater. In the 1990s the USGS began to include 

MTBE as a target analyte in groundwater sampling under its NAWQA Program (USGS 1995), and some 

states are developing useful databases on groundwater levels related to VOC tests on drinking water wells 

and investigations related to chemical and gasoline spills or leakages from USTs (Schorr 1994). There is 

limited monitoring information for other environmental media. Data are also limited for workplace 

settings; the few studies available provide some rough estimates of air concentrations, and of blood levels 

of people in workplace settings where higher levels of exposure are likely, or of population segments such 

as commuters (Huber 1994; Lioy et al. 1994; White et al. 1995). While the basic physical and chemical 

properties of MTBE are adequately known, the degradation processes in air can become very complicated 

in polluted urban settings. Degradation products such as tert-butyl formate (Cox and Goldstone 1982) 

appear to be more persistent than the original MTBE, and there is little information on the toxicity of this 

degradation product. 

Physical and Chemical Properties. The chemical and physical information available for MTBE is 

generally adequate (EPA 1994c; Mackay et al. 1993). No major data needs have been identified in this 

area. 

Production, Import/Export, Use, Release, and Disposal. Industry trade magazines currently 

give reasonably reliable figures for total domestic production (Lorenzetti 1994). Starting in 1992-l 993, 

the U.S. government began tracking import, export, and production levels of MTBE (NTDB 1995; USITC 

1995), but for earlier time periods, gross production figures are virtually the only available data. Since 

most MTBE is mixed into gasolines, there has been no systematic tracking of disposal of MTBE itself. 

Most releases to the environment involve venting to the atmosphere during the production process (TRI93 

1995) although these releases may pose fewer human health risks than the types of unintentional releases 

resulting from the use of gasoline in workplaces or commuting, or from spills or leaks of gasoline that can 

contaminate groundwater supplies. These types of releases have higher probabilities of human exposures, 

but very limited information is available. 

According to the Emergency Planning and Community Right-to-Know Act of 1986,42 U.S .C. Section 

11023, industries are required to submit chemical release and off-site transfer information to the EPA. The 
METHYL tert-BUTYL ETHER 188 

5. POTENTIAL FOR HUMAN EXPOSURE 

TRI, which contains this information for 1993, became available in 1995 (TRI93 1995). The 1993 TRI 

made provisions for the inclusion of MTBE. This database will be updated yearly and can help provide a 

list of industrial production facilities and emissions. 

Environmental Fate. There has been limited routine monitoring for MTBE for all environmental 

media; most information comes from waste remediation activities, rare regional investigations, or isolated 

case studies (Bianchi and Vamey 1989; Bianchi et al. 1991; Jensen and Arvin 1990; LaGrone 1991; Yeh 

and Novak 1991). Recently, the USGS has placed greater emphasis on including MTBE in the set of 

target analytes for groundwater sampling in its NAWQA Program (USGS 1995), and some states have 

useful databases on groundwater detections of MTBE (Schorr 1994). While such efforts will eventually 

provide a better picture of background conditions for such media as groundwater, there are very limited 

historical data before the early 1990s. Most conclusions on environmental fate, therefore, tend to depend 

heavily on the results of models (MacKay et al. 1993). The degradation processes in air can become very 

complicated in polluted urban settings. Degradation products such as tert-butyl formate (Cox and 

Goldstone 1982) appear to be more persistent than the original MTBE, and there is little information on 

the toxicity of this degradation product. Additional empirical data on fate and transport processes are 

needed, especially around production facilities or from sediments or groundwater supplies where MTBE 

may build up to appreciable concentration levels. 

Bioavailability from Environmental Media. Based on its physical properties and results from 

species tested so far, it is unlikely that MTBE will bioconcentrate to any degree (Fujiwara et al. 1984; 

MacKay et al. 1993). There is no indication that MTBE is a concern in any raw or processed food items. 

MTBE is highly volatile and shows little tendency to sorb to soil particles. Therefore, except in situations 

related to recent spills or other large releases of pure MTBE or reformulated fuels containing MTBE, 

exposure routes involving dermal contact with the chemical or contaminated media such as soils are 

generally of minor concern. The main concerns involve inhalation of fumes in the air or volatilized from 

water or surface soils. The major opportunities for exposure likely involve inhalation of MTBE around 

automobile service or fueling facilities. While there are documented instances of shallow groundwater 

supplies contaminated with MTBE, the chemical’s low odor threshold and extremely offensive smell make 

it unlikely that ingestion of drinking water is of much concern. Additional information on bioavailability 

is not viewed as a significant data need. 
METHYL tert-BUTYL ETHER 189 

5. POTENTIAL FOR HUMAN EXPOSURE 

Food Chain Bioaccumulation. While there is limited information on food chain bioaccumulation of 

MTBE, data for other similar non-chlorinated chemical solvents indicate no potential for bioaccumulation 

(Fujiwara et al. 1984; Gilbert and Calabrese 1992; MacKay et al. 1993). Toxicokinetics, metabolism, and 

excretion data similarly suggest no potential for bioaccumulation (Bioresearch Laboratories 1990a, 1990b, 

1990c, 1990d; Brady et al. 1990; Gilbert and Calabrese 1992). Therefore, information in this area is not 

considered a major data need. 

Exposure Levels in Environmental Media. While limited data preclude the estimation of exposure 

levels in such media as surface waters or surface soils, MTBE’s high volatility and tendency to quickly 

migrate into groundwater suggests that further information for these media is not particularly needed. For 

air, there are a number of special studies around auto service an fueling facilities, but there is still debate 

on how to relate these findings to provide exposure levels for these specialized sites of concern to both the 

general population and.various occupational groups (Huber 1994). Outside the areas around auto service 

or fueling facilities, there is a lack of data on ambient air levels and a lack of up-to-date information on 

exposure opportunities for different occupational groups (NIOSH 1993a, 1993b; White et al. 1995). Data 

on exposures from groundwater sources are also generally lacking (Angle 1991; USGS 1995). 

Additional reliable monitoring data for the levels of MTBE in contaminated media at hazardous waste 

sites are needed so that the information obtained on levels of MTBE in the environment can be used in 

combination with the known body burden of MTBE to assess the potential risk of adverse health effects in 

populations living in the vicinity of hazardous waste sites. MTBE has not been commonly included in 

standard ambient monitoring programs for air, surface water, or groundwater (Angle 1991; LaGrone 

1991). Therefore, the relatively small number of detections at NPL sites (HazDat 1996) does not 

necessarily mean that all NPL sites or candidate waste disposal sites have undergone extensive testing. 

Exposure Levels in Humans. Outside certain occupational settings, the available information is 

inadequate to make reliable estimates of exposure levels in humans (Huber 1994; LaGrone 1991; NIOSH 

1993a, 1993b). The few studies available provide some rough estimates of air concentrations, and of 

blood levels of people in workplace settings where higher levels of exposure are likely, or of population 

segments such as commuters (Huber 1994; Lioy et al. 1994; White et al. 1995). No information could be 

identified documenting levels detected in human adipose tissues, blood, urine, or breast milk. No 

information could be identified dealing with exposure levels in the vicinity of NPL sites. Thus, the 

determination of exposure levels in the general population and in people likely to be exposed at hazardous 

waste sites is needed. 
METHYL tert-BUTYL ETHER 190 

5. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Registries. No exposure registries for MTBE were located. This substance is not currently 

one of the compounds for which a subregistry has been established in the National Exposure Registry. 

The substance will be considered in the future when chemical selection is made for subregistries to be 

established. The information that is amassed in the National Exposure Registry facilitates the 

epidemiological research needed to assess adverse health outcomes that may be related to exposure to this 

substance. 

5.7.2 Ongoing Studies 

As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental 

Health Laboratory Sciences Division of the National Center for Environmental Health, Centers for Disease 

Control and Prevention, will be analyzing human blood samples for MTBE and other volatile organic 

compounds. These data will give an indication of the frequency of occurrence and background levels of 

these compounds in the general population. 

The USGS will continue to collect data on VOCs, including MTBE, as part of the groundwater 

investigations in many of its National Water-Quality Assessment projects (USGS 1995). The USGS also 

cooperates with states and other groups in special studies. A cooperative project involving the USGS and 

the U.S. Virgin Islands Water and Power Authority will implement a groundwater monitoring network on 

the islands of St. Croix and St. Thomas. MTBE will be included among the target analytes (FEDRIP 

1995). 
METHYL tert-BUTYL ETHER 191 

6. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or 

measuring, and/or monitoring MTBE, its metabolites, and other biomarkers of exposure and effect to 

MTBE. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to 

identify well-established methods that are used as the standard methods of analysis. Many of the 

analytical methods used for environmental samples are the methods approved by federal agencies and 

organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other 

methods presented in this chapter are those that are approved by groups such as the Association of Official 

Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, 

analytical methods are included that modify previously used methods to obtain lower detection limits, 

and/or to improve accuracy and precision. 

6.1 BIOLOGICAL SAMPLES 

Few methods are currently available for analysis of MTBE in biological samples. Some methods have 

been developed to measure MTBE in blood and various tissues. The primary method of analysis is gas 

chromatography (GC) with flame ionization detection (FID) or mass spectrometry (MS). Table 6-l is a 

summary of the applicable analytical methods for determining MTBE in biological fluids and tissues. 

Blood can be analyzed by direct injection GC (Li et al. 1991) or by GC/FID analysis of the blood 

headspace (Savolainen et al. 1985; Streete et al. 1992). Detection limits are in the low ppm range (Li et al. 

1991; Savolainen et al. 1985). Otherwise, little performance data are available for these methods. 

Recently purge-and-trap GC/MS methods have been developed (Bonin et al. 1995; Mannino et al. 1995) 

for the measurement of MTBE and its metabolite tert-butanol in blood. Detection limits are in the sub-ppb 

range (Bonin et al. 1995; Mannino et al. 1995). Recovery is excellent for both MTBE and tert-butanol 

(>95%) (Bonin et al. 1995) and reproducibility is very good as well (<10% RSD) (Bonin et al. 1995). 

A screening method for post-mortem body fluids uses headspace combined with GC/MS for identifying 

MTBE. Detection limits are in the low ppb range (Schuberth 1994). MTBE has been determined in urine 

and tissues by GC/FID analysis of urine or by tissue incubation mixture headspace (Streete et al. 1992). 

No performance data were reported. Fat tissue (rat) has been analyzed by GC after homogenization and 

METHYL tert-BUTYL ETHER 193 

6. ANALYTICAL METHODS 

centrifugation (Savolainen et al. 1985). Recovery is very good (>90%) and detection limits are in the low 

ppb range (Savolainen et al. 1985). 

6.2 ENVIRONMENTAL SAMPLES 

Methods exist for determining MTBE in air (ambient, occupational, breathing zone, auto exhaust), water,
 

sediments, foods, and gasoline. Environmental methods are primarily based on GC procedures with
 

detection by FID or MS. Many of the methods approved by federal agencies are robust and sensitive.
 

Table 6-2 summarizes methods that have been used for determination of MTBE in environmental samples.
 

Several methods exist for detecting and measuring MTBE in air. Air samples for MTBE analysis are
 

usually collected in stainless steel canisters (EPA 1984d; Kelley et al. 1993; Lioy et al. 1994; Pate et al.
 

1992). The samples are analyzed by GC with FID (Pate et al. 1992) or MS (Kelley et al. 1993). The limit
 

of detection is in the very low ppb range (Kelly et al. 1993). Other performance data are not available.
 

MTBE may also be determined in air samples by collection on adsorbent tubes followed by desorption and
 

GUMS analysis (EPA 1984c; Lioy et al. 1994). Performance data for this method is not available.
 

GUMS is more specific, and thus more reliable than GUFID in identifying MTBE in samples containing
 

multiple components which have similar GC elution characteristics. A sophisticated optical method based
 

on infrared (IR) spectral data has been developed for remote measurement of MTBE in air (Grant et al.
 

1992).
 

For measuring atmospheric levels of MTBE in the workplace, the air is usually preconcentrated by passing
 

the sample through a trap containing a charcoal adsorbent (NIOSH 1984). The vapors on the charcoal
 

tubes are eluted, then analyzed by GC/FID. This procedure has been modified to measure breathing zone
 

air in the workplace (CDC 1993a; Maninno et al. 1995). A similar method for personal monitoring uses a
 

mixed-bed adsorbent and thermal desorption prior to GC/FID analysis (Coker et al. 1989). Detection
 

limits are in the ppb range (CDC 1993a; Mannino et al. 1995). Little other performance data have been
 

reported. Passive samplers have become available for monitoring occupational or breathing zone air. The
 

adsorbent is desorbed with solvent and analyzed by GC/FID (Harper and Fiore 1995; Mannino et al.
 

1995). Detection limits are in the ppb range (Harper and Fiore 1995; Mannino et al. 1995); analytical
 

recovery is 97% (Harper and Fiore 1995).
 

Methods have been developed for analysis of MTBE in automotive exhaust. The auto exhaust is collected
 

in Tedlar bags and analyzed directly by GC/FID (Hoekman 1993; Schuetzle et al. 1991; Siegel et al. 1992).
 


METHYL tert-BUTYL ETHER 196 

6. ANALYTICAL METHODS 

The sensitivity of the method is sufficient to detect MTBE in the exhaust samples (ppb range); however, 

care must be taken to assure that the chromatographic column has the resolution necessary to detect MTBE 

in the multi-component mixture (Siegel et al. 1992). 

The most frequently used analytical methods for aqueous samples containing MTBE are GC/MS and 

GC/FID (EPA 1984b; Munch and Eichelberger 1992; Wang et al. 1991), although GC/photoionization 

detection (PID) has also been used (Chiang et al. 1992). MTBE is usually isolated from the aqueous 

media by the purge and trap method (EPA 1984b, Munch and Eichelberger 1992). The purged MTBE is 

trapped on an adsorbent, and thermally desorbed onto the GC column. Detection limits are in the low-tosub 

ppb range (Munch and Eichelberger 1992) with excellent recovery >95% (Munch and Eichelberger). 

A headspace method has been developed for determining MTBE in gasoline-contaminated groundwater 

(Chiang et al. 1992; Wang et al. 1991). Detection limits are in the very low ppb range; other performance 

data were not reported. 

Solid wastes, soil, and sediments are most often prepared for analysis using the purge and trap method 

(Bianchi and Vamey 1989; EPA 1994b). GC/MS is recommended as the separation and detection 

technique for these analyses, although GC/FID may be used as well (Bianchi and Vamey 1989). No 

performance data have been reported for these methods. 

Methods exist for detection of MTBE in other environmental media such as gasoline and its fumes. These 

methods include direct analysis by GC/FID (Johansen 1984; Levy and Yancey 1986), GC/IR (Cochrane 

and Hillman 1984) and HPLC/ refractive index (RI) (Pauls 1985). Gasolines are a complex media, and 

dual GC columns or multidimensional GC have been used to improve separation (Johansen 1984; Levy 

and Yancey 1986). Two studies reported quantitative recovery (≈100%) (Cochrane and Hillman 1984; 

Pauls 1985), but other performance data were not reported. A method has been developed capable of 

detecting MTBE at the 0.035% level in gasoline (Gallignani et al. 1994). In this method, gasoline is 

diluted with hexane and analyzed by flow analysis/Fourier transform infrared spectrometry. 
METHYL tert-BUTYL ETHER 197 

6. ANALYTICAL METHODS 

6.3 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate 

information on the health effects of MTBE is available. Where adequate information is not available, 

ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed 

to determine the health effects (and techniques for developing methods to determine such health effects) of 

MTBE. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. Few methods exist for 

measuring MTBE in breath and most tissues other than blood. Sensitive, reliable methods exist for 

determining MTBE in blood (Bonin et al. 1995; Mannino et al. 1995). The data on determination of 

MTBE in urine and tissue samples are very limited, and method performance information is generally not 

available. Methods that could be used to measure low levels in human urine and tissues are needed to 

determine the relationship between exposure and effects observed. Few methods are available for 

determining tert-butanol (the major metabolite of MTBE) in blood, urine, and tissues. However, this 

compound is not unique to MTBE; thus tert-butanol would be a less useful biomarker than MTBE itself. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods for determining MTBE in air (EPA 1984c; Kelley et al. 1993) and water (Munch and 

Eichelberger 1992; Wang et al. 1991) are sensitive enough to measure background levels in the 

environment and levels for which health effects might occur, but additional performance are needed. 

Methods for soil and other solid media are available (Bianchi and Vamey 1989; EPA 1994b). The 

reliability is limited by the background from the complex matrix. There is little information on methods 

for determining MTBE in media such as fish, foods, and plants. Improved methods for these media are 
METHYL tert-BUTYL ETHER 198 

6. ANALYTICAL METHODS 

needed to better assess the extent of MTBE contamination in the environment and the resulting risk of 

exposure. 

6.3.2 Ongoing Studies 

The Environmental Health Laboratory Sciences Division of the National Center for Environmental Health, 

Centers for Disease Control and Prevention, is developing methods for the analysis of MTBE and other 

volatile organic compounds in blood. These methods use purge and trap methodology, high resolution gas 

chromatography, and magnetic sector mass spectrometry which gives detection limits in the low parts per 

trillion (ppt) range. 

The EPA and organizations associated with the fuel industry are currently developing and evaluating 

methods to measure MTBE in human breath. These methods involve collection of a breath sample in a 

stainless steel canister with subsequent analysis by GC/MS. Detected limits are in the low-to-sub ppb 

range. 
METHYL tert-BUTYL ETHER 199 

7. REGULATIONS AND ADVISORIES 

The international, national, and state regulations and guidelines regarding MTBE in air, water, and other 

media are summarized in Table 7-1. 

An acute-duration inhalation MRL of 2 ppm for MTBE was derived. The MRL is based on a NOAEL 

value of 800 ppm for 6 hours for central nervous system sedation in rats in the 6-hour study by Gill 

(1989). 

An intermediate-duration inhalation MRL of 0.7 ppm for MTBE was derived. The MRL is based on a 

NOAEL value of 400 ppm for 6 hours/day, 5 days/week for central nervous system sedation in rats in the 

14-19-week reproduction study by Neeper-Bradley (1991). 

A chronic-duration inhalation MRL of 0.7 ppm for MTBE was derived. The MRL is based on a NOAEL 

value of 400 ppm for 6 hours/day, 5 days/week for increased incidence and severity of chronic progressive 

nephropathy in female rats in the 24-month study by Chun et al. (1992). 

An acute-duration oral MRL of 0.4 mg/kg/day for MTBE was derived. The MRL is based on a NOAEL 

value of 40 mg/kg for drowsiness in rats in the study by Bioresearch Labs (1990b). 

An intermediate-duration oral MRL of 0.3 mg/kg/day for MTBE was derived. The MRL is based on a 

LOAEL value of 100 mg/kg/day for hepatic effects (decreased BUN levels) in rats in the 90-day study by 

Robinson et al. (1990). 

EPA has verified a reference concentration (RfC) of 3 mg/m3

 (0.8 ppm) for MTBE (IRIS 1996). The RfC 

is based on the NOAEL of 400 ppm, 6 hours/day, 5 days/week (equivalent to 259 mg/m3

) in the 24-month 

inhalation study of rats by Chun et al. (1992). The study found increased liver and kidney weights and 

increased severity of spontaneous renal lesions in females, increased prostration in females, and swollen 

periocular tissue in males and females at > 3,000 ppm. 

An oral reference dose (RfD) for MTBE is undergoing review by an EPA Workgroup (IRIS 1996). 

Table 7-1 shows an advisory RfD. 
METHYL tert-BUTYL ETHER 200 

7. REGULATIONS AND ADVISORIES 

The EPA has identified MTBE as a possible human carcinogen, Class C (EPA 1995). Neither the 

International Agency for Research on Cancer (IARC) nor the National Toxicology Program has a cancer 

classification for MTBE. 

MTBE is on the list of chemicals regulated based on “The Emergency Planning and Community Right-toKnow Act of 1986” (EPCRA) (EPA 1988b). Section 313 of Title III of EPCRA requires owners and 

operators of certain facilities that manufacture, import, process, or otherwise use the chemicals on this list 

to report annually their release of those chemicals to any environmental media. 


___________________ 

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METHYL tert-BUTYL ETHER 221 

9. GLOSSARY 

Acute Exposure - Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption Coefficient (Koc) - The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd) - The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Bioconcentration Factor (BCF) - The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Cancer Effect Level (CEL) - The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen - A chemical capable of inducing cancer. 

Ceiling Value - A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure - Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Developmental Toxicity - The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Embryotoxicity and Fetotoxicity - Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurred. The terms, as used here, include malformations and variations, altered growth, and in 

utero death. 

EPA Health Advisory - An estimate of acceptable drinking water levels for a chemical substance based 

on health effects information. A health advisory is not a legally enforceable federal standard, but serves as 

technical guidance to assist federal, state, and local officials. 

Immediately Dangerous to Life or Health (IDLH) - The maximum environmental concentration of a 

contaminant from which one could escape within 30 min without any escape-impairing symptoms or 

irreversible health effects. 

Intermediate Exposure - Exposure to a chemical for a duration of 15-364 days, as specified in the 

Toxicological Profiles. 
METHYL tert-BUTYL ETHER 222 

9. GLOSSARY 

Immunologic Toxicity - The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

In Vitro -Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo -Occurring within the living organism. 

Lethal Concentration(LO) (LCLO) - The lowest concentration of a chemical in air which has been 

reported to have caused death in humans or animals. 

Lethal Concentration (50) (LC5O) - A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLO) - The lowest dose of a chemical introduced by a route other than inhalation that 

is expected to have caused death in humans or animals. 

Lethal Dose(50) (LD5O) - The dose of a chemical which has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50) - A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL) - The lowest dose of chemical in a study, or group 

of studies, that produces statistically or biologically significant increases in frequency or severity of 

adverse effects between the exposed population and its appropriate control. 

Malformations - Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level - An estimate of daily human exposure to a dose of a chemical that is likely to be 

without an appreciable risk of adverse noncancerous effects over a specified duration of exposure. 

Mutagen - A substance that causes mutations. A mutation is a change in the genetic material in a body 

cell. Mutations can lead to birth defects, miscarriages, or cancer. 

Neurotoxicity - The occurrence of adverse effects on the nervous system following exposure to 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL) - The dose of chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow) - The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Permissible Exposure Limit (PEL) - An allowable exposure level in workplace air averaged over an 8­

hour shift. 
METHYL tert-BUTYL ETHER 223 

9. GLOSSARY 

q1* - The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1 * can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and μg/m3 

for air). 

Reference Dose (RfD) - An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human 

studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate 

RfDs and an additional modifying factor, which is based on a professional judgment of the entire database 

on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. 

Reportable Quantity (RQ) - The quantity of a hazardous substance that is considered reportable under 

CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount 

established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are 

measured over a 24-hour period. 

Reproductive Toxicity - The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

Short-Term Exposure Limit (STEL) - The maximum concentration to which workers can be exposed 

for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 

60 min between exposure periods. The daily TLV-TWA may not be exceeded. 

Target Organ Toxicity - This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen - A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV) - A concentration of a substance to which most workers can be exposed 

without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. 

Time-Weighted Average (TWA) - An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose (TD50) - A calculated dose of a chemical, introduced by a route other than inhalation, which 

is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Uncertainty Factor (UF) - A factor used in operationally deriving the RfD from experimental data. UFs 

are intended to account for (1) the variation in sensitivity among the members of the human population, 

(2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating 

from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using 

LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. 

APPENDIX A 

ATSDR MINIMAL RISK LEVEL 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 

99-499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly 

with the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances 

most commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a given 

route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance that is 

likely to be without appreciable risk of adverse noncancer health effects over a specified duration of 

exposure. MRLs are based on noncancer health effects only and are not based on a consideration of cancer 

effects. These substance-specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors to identify contaminants and potential health effects that may be of concern at 

hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or action 

levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level above 

the MRL does not mean that adverse health effects will occur. 
APPENDIX A 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as a hundredfold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, with 

participation from other federal agencies and comments from the public. They are subject to change as 

new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in 

the most recent toxicological profiles supersede previously published levels. For additional information 

regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease 

Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333. 
METHYL tert-BUTYL ETHER A-1 

APPENDIX A
 

MINIMAL RISK LEVEL (MRL) WORKSHEET(S) 

Chemical name: Methyl tert-butyl ether (MTBE) 

CAS number: 1634-04-43 

Date: July 1996 

Profile status: Third Post Public Comment Draft 

Route: [x] Inhalation [ ] Oral 

Duration: [x] Acute [ ]Intermediate [ ] Chronic 

Key to figure: 32 

Species: Rat 

MRL: 2 [ ] mg/kg/day [X] ppm [ ] mg/m3 

Reference: Gill 1989 

Exnerimental design (human study details or strain, number of animals per exposure/control group, sex, 

dose administration details): Groups of 22 male and 22 female Fischer 344 rats were exposed to 0, 800, 

4,000, or 8,000 ppm MTBE for 6 hours. Groups of 14 rats/sex were studied for motor activity, and the 

remaining groups of 8 rats/sex were given a functional observation battery of tests at 1, 6, and 24 hours 

after exposure. 

Effects noted in study and corresponding doses: Concentration-related increases in ataxia and duck-walk 

gait occurred in both males and females at 4,000 and 8,000 ppm. Other effects noted in high-dose males 

included labored respiration pattern, decreased muscle tone, decreased performance on a treadmill, and 

increased hind limb splay. Other effects noted in females included decreased hind limb grip strength at 

24,000 ppm and labored respiration and increased latency to rotate on the inclined screen at 8,000 ppm. 

These effects were seen at 1 hour after exposure, but not at 6 or 24 hours after exposure, indicating the 

transient nature of the effect. Motor activity changes, for which the time course corresponded with the 

functional observation battery findings, supported the exposure-related central nervous system sedation. 

No neurological effects were observed at the NOAEL of 800 ppm for 6 hours. 

Dose endnoint used for MRL derivation: 800 ppm, no central nervous system sedation 

[x] NOAEL [ ]LOAEL 

Uncertainty factors used in MRL derivation: 100 

[ ] 1 [ ] 3 [ ] 10 (for use of a LOAEL)
 

[ ] 1 [ ] 3 [x] 10 (for extrapolation from animals to humans)
 

[ ] 1 [ ] 3 [x] 10 (for human variability)
 

Was a conversion factor used from ppm in food or water to a mg/body weight dose?
 

If so, explain: No
 
METHYL tert-BUTYL ETHER A-2 

APPENDIX A 

If an inhalation study in animals. list conversion factors used in determinine human equivalent dose: The 

NOAEL(HEC) was calculated for a gas:extrarespiratory effect in rats assuming periodicity was attained. 

Because the b:a lambda values are unknown for the experimental species (a) and humans (h), a default 

value of 1 was used for this ratio. Therefore, because the NOAEL in rats and the NOAEL(HEC) are the 

same, an uncertainty factor of 10, rather than 3, for extrapolation from animals to humans was 

recommended by the Interagency MRL Work Group. 

Was a conversion used from intermittent to continuous exposure?
 

If so, explain: The NOAEL of 800 ppm was multiplied by 6 hour/24 hours to yield a NOAELADJ of
 

200 ppm.
 

Other additional studies or pertinent information that lend support to this MRL: 

The NOAEL of 800 ppm is supported by another study, which found only increased motor activity in 

female rats, but no other neurological effects in rats at 800 ppm, 6 hours/day, 5 days/week for 13 weeks 

(Dodd and Kintigh 1989). In this study, hypoactivity at 4,000 ppm and hypoactivity and ataxia at 

8,000 ppm were observed daily after the 6 hour/day exposure, thus representing effects of acute exposure. 

A number of acute-duration inhalation studies in rats, mice, and rabbits have described similar clinical 

signs of neurotoxicity at MTBE concentrations < 2,000 ppm (ARCO 1980; Biodynamics 1981; 

Bioresearch Labs 1990d; Dodd and Kintigh 1989; Tyl and Neeper-Bradley 1989; Tyl 1989). 

Agency Contact (Chemical Manager): Moiz Mumtaz 
METHYL tert-BUTYL ETHER A-3 

APPENDIX A 

MINIMAL RISK LEVEL WORKSHEET 

Chemical name: Methyl tert-butyl ether (MTBE) 

CAS number: 1634-04-4 

Date: July 1996 

Profile status: Third Post Public Comment Draft 

Route: [x] Inhalation [ ] Oral 

Duration: [ ] Acute [x] Intermediate [ ] Chronic 

Key to figure: 60 

Species: Rat 

MRL: 0.7 [ ] mg/kg/day [xl ppm [ ] mg/m3 

Reference: Neeper-Bradley 1991 

Experimental design (human study details or strain, number of animals per exposure/control group, sex, 

dose administration details): Groups of 25 male and 25 female rats were exposed to 0, 400, 3,000, or 

8,000 ppm MTBE for 6 hours/day, 5-7 days/week for 14-19 weeks in a reproductive study. 

Effects noted in study and corresponding doses: Exposure for 10 weeks prior to mating and through day 

19 of gestation to the concentration of 8,000 ppm MTBE resulted in salivation and hypoactivity in F0 and 

F1 parental rats. F0 and Fl parental groups also showed hypoactivity and lack of startle response, as well 

as blepharospasm, at 3,000 ppm. 

Dose endpoint used for MRL derivation: 400 ppm, no central nervous system sedation 

[x] NOAEL [ ]LOAEL 

Uncertainty factors used in MRL derivation: 100 

[ ] 1 [ ] 3 [ ] l0 (for use of a LOAEL)
 

[ ] 1 [ ] 3 [x] 10 (for extrapolation from animals to humans)
 

[ ] 1 [ ] 3 [x] 10 (for human variability)
 

Was a conversion factor used from ppm in food or water to a mg/body weight dose?
 

If so, explain: No
 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: The 

NOAEL(HEC) was calculated for a gas:extrarespiratory effect in rats assuming periodicity was attained. 

Because the b:a lambda values are unknown for the experimental species (a) and humans (h), a default 

value of 1 is used for this ratio. Therefore, because the NOAEL in rats and the NOAEL(HEC) are the same, 

an uncertainty factor of 10, rather than 3, for extrapolation from animals to humans was recommended by 

the Interagency MRL Work Group. 

Was a conversion used from intermittent to continuous exposure?
 

If so, explain: The NOAEL of 400 ppm was multiplied by 6 hour/24 hours/day and by 5 days/7 days/week
 

to yield a NOAELADJ of 71 ppm.
 
METHYL tert-BUTYL ETHER A-4 

APPENDIX A 

Other additional studies or pertinent information that lend support to this MRL: 

In a 13-week study, rats were exposed to 0, 800, 4,000, or 8,000 ppm MTBE 6 hours/day, 5 days/week 

(Dodd and Kintigh 1989). At 4,000 ppm, the rats were hypoactive, had elevated body temperature, and 

decreased hind limb grip strength. At 8,000 ppm, both ataxia and hypoactivity were observed. Some 

hyperactivity occurred in female rats at 800 ppm, but no signs were observed in males at 800 ppm. 

Agency Contact (Chemical Manager): Moiz Mumtaz 
METHYL tert-BUTYL ETHER A-5 

APPENDIX A 

MINIMAL RISK LEVEL WORKSHEET 

Chemical name: Methyl tert-butyl ether (MTBE) 

CAS number: 1634-04-4 

Date: July 1996 

Profile status: Third Post Public Comment Draft 

Route: [x] Inhalation [ ] Oral 

Duration: [ ] Acute [ ]Intermediate [x] Chronic 

Key to figure: 70 

Species: Rat 

MRL: 0.7 [ ] mg/kg/day [x] ppm [ ] mg/m3 

Reference: Chun et al. 1992 

Experimental design (human study details or strain, number of animals per exposure/control group, sex, 

dose administration details): Groups of 50 male and 50 female Fischer 344 rats were exposed to 0, 400, 

3,000, or 8,000 ppm MTBE 6 hours/day, 5 days/week for up to 24 months. Male rats exposed to 

3,000 and 8,000 ppm had increased mortality and decreased mean survival time due to chronic progressive 

nephropathy and these groups were terminated at weeks 97 and 82, respectively. Endpoints monitored 

were clinical signs, body weight, organ weight, hematological parameters, corticosterone evaluation, and 

comprehensive gross and histological examination. 

Effects noted in study and corresponding doses: Male rats exposed to > 400 ppm had increased mortality 

and decreased mean survival time due to chronic progressive nephropathy. Increased absolute and relative 

liver and kidney weights were observed in females at > 3,000 ppm. No gross or histopathological lesions 

were found in the liver of either sex, but concentration-related increased incidence and severity of chronic 

progressive nephropathy, accompanied by osteodystrophy, hyperplasia of the parathyroids, and 

mineralization in numerous tissues were found in males at all exposure levels and in females at 

> 3,000 ppm. No evidence of renal effects was found in the female rats at 400 ppm. 

Dose endpoint used for MRL derivation: 400 ppm, no increased incidence and severity of chronic 

progressive nephropathy. 

[x] NOAEL [ ]LOAEL 

Uncertainty factors used in MRL derivation: 100 

[ ] 1 [ ] 3 [ ] 10 (for use of a LOAEL)
 

[ ] 1 [ ] 3 [x] 10 (for extrapolation from animals to humans)
 

[ ] 1 [ ] 3 [x] 10 (for human variability)
 

Was a conversion factor used from ppm in food or water to a mg/body weight dose?
 

If so, explain: No
 
METHYL tert-BUTYL ETHER A-6 

APPENDIX A 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: The 

NOAEL(HEC) was calculated for a gas:extrarespiratory effect in rats assuming periodicity was attained. 

Because the b:a lambda values are unknown for the experimental species (a) and humans (h), a default 

value of 1 is used for this ratio. Therefore, because the NOAEL in rats and the NOAEL(HEC) are the same, 

an uncertainty factor of 10, rather than 3, for extrapolation from animals to humans was recommended by 

the Interagency MRL Work Group. 

Was a conversion used from intermittent to continuous exposure? 

If so, explain: The NOAEL was multiplied by 6 hour/24 hour/day and 5 days/7 days/week to yield a 

NOAELADJ of 71 ppm 

Other additional studies or pertinent information that lend support to this MRL: 

The higher incidence and greater severity of chronic progressive nephropathy at lower exposure 

concentrations in male rats compared with female rats may be due to the exacerbation of this syndrome by 

the accumulation of α2u-globulin. Because enhancement of chronic progressive nephropathy, which led to 

increased mortality and decreased survival time in males, is associated with α2u-globulin accumulation in 

male rats only, these endpoints in male rats are not considered for MRL derivation. However, since female 

rats also had enhanced chronic progressive nephropathy not associated with α2u-globulin accumulation, 

the chronic inhalation MRL of 2 ppm was calculated based on the NOAEL of 400 ppm for kidney effects 

in female rats. The chronic-duration inhalation NOAEL for renal effects is also a NOAEL for clinical 

signs of neurotoxicity in rats in this study. The NOAEL of 400 ppm for chronic-duration inhalation 

exposure to MTBE is supported by a similar study in male and female mice similarly exposed to same 

concentrations for 18 months (Burleigh-Flayer et al. 1992). In this study, absolute and relative liver 

weights were increased at > 3,000 ppm.and absolute and relative kidney weights were increased at 

8,000 ppm. Comprehensive histological examination of organs and tissues revealed an increased 

incidence of hepatocellular hypertrophy and hepatocellular adenoma in female mice at 8,000 ppm. The 

NOAEL for liver effects in this study was 400 ppm, which was also a NOAEL for neurotoxicity in mice in 

this study. 

Agency Contact (Chemical Manager): Moiz Mumtaz 
METHYL tert-BUTYL ETHER A-7 

APPENDIX A 

MINIMAL RISK LEVEL WORKSHEET 

Chemical name: Methyl tert-butyl ether (MTBE) 

CAS number: 1634-04-4 

Date: July 1996 

Profile status: Third Post Public Comment Draft 

Route: [ ] Inhalation [x] Oral 

Duration: [x] Acute [ ] Intermediate [ ] Chronic 

Key to figure: 8 

Species: Rat 

MRL: 0.4 [x] mg/kg/day [ ] ppm [ ] mg/m3 

Reference: Bioresearch Laboratories. 1990b. Mass balance of radioactivity and metabolism in male and 

female Fischer 344 rats after intravenous, oral and dermal administration of 14C-methyl tertiary-butyl 

ether. Report No. 38843. Senneville, Quebec, Canada. 

Experimental design (human study details or strain, number of animals per exposure/control group, sex, 

dose administration details): Groups of 6 male and 6 female Fischer 344 rats were treated by gavage with 

MTBE in water at doses of 0, 40, and 400 mg/kg in this pharmacokinetic study. 

Effects noted in study and corresponding doses: The rats given 400 mg/kg showed signs of drowsiness. 

Dose endpoint used for MRL derivation: 40 mg/kg, no drowsiness 

[x] NOAEL [ ]LOAEL 

Uncertainty factors used in MRL derivation: 100 

[ ] 1 [ ] 3 [ ] 10 (for use of a LOAEL) 

[ ] 1 [ ] 3 [x] 10 (for extrapolation from animals to humans) 

[ ] 1 [ ] 3 [x] 10 (for human variability)
 

Was a conversion factor used from ppm in food or water to a body weight dose?
 

If so, explain: No
 

If an inhalation study in animals, list conversion factors used in determination human equivalent dose:
 

Was a conversion used from intermittent to continuous exposure? No
 

If so, explain:
 
METHYL tert-BUTYL ETHER A-8 

APPENDIX A 

Other additional studies or pertinent information that lend support to this MRL: 

Although this study was designed as a pharmacokinetic study rather than a toxicity study, the observation 

of drowsiness is consistent with observations of central nervous system sedation in animals exposed to 

MTBE by the inhalation and oral routes, and the study provides the highest NOAEL below which there is 

no LOAEL. In other acute-duration oral,studies, rats had mild central nervous system depression at 

1,900 mg/kg and ataxia at 2,450 mg/kg (ARCO 1990), salivation at 90 mg/kg and hypoactivity and/or 

ataxia at 440 mg/kg (ITT Research Institute 1992), and profound but transient anesthesia at 1,200 mg/kg 

or 1,428 mg/kg/day for 14 days (Robinson et al. 1990). 

Agency Contact (Chemical Manager): Moiz Mumtaz 
METHYL tert-BUTYL ETHER A-9 

APPENDIX A 

MINIMAL RISK LEVEL WORKSHEET 

Chemical name: Methyl tert-butyl ether (MTBE) 

CAS number: 1634-04-4 

Date: July 1996 

Profile status: Third Post Public Comment Draft 

Route: [ ] Inhalation [x] Oral 

Duration: [ ] Acute [x] Intermediate [ ] Chronic 

Key to figure: 15 

Species: Rat 

MRL: 0.3 [x] mg/kg/day [ ] ppm [ ] mg/m3 

Reference: Robinson et al. 1990 

Experimental design (human study details or strain, number of animals per exposure/control group, sex, 

dose administration details): Groups of 10 male and 10 female Sprague-Dawley rats were treated by 

gavage with MTBE in corn oil at doses of 0, 100, 300, 900, and 1,200 mg/kg/day, 7 days/week for 

90 days. 

Effects noted in study and corresponding doses: Relative and absolute lung weights were significantly 

increased in males at 1,200 mg/kg/day. Treated rats in all dose groups had diarrhea throughout the 

exposure period. Heart weight was significantly increased in female rats at 900 mg/kg/day. In females at 

1,200 mg/kg/day, erythrocyte counts, hemoglobin, and hematocrit values were significantly increased, 

while leukocyte counts were significantly decreased. In male rats at 1,200 mg/kg/day, mean corpuscular 

volume values were significantly decreased and monocyte values were significantly elevated. Significant 

increases in relative liver weights were found in females at 900 mg/kg/day and in males at 900 and 

1,200 mg/kg/day. Serum lactic dehydrogenase levels were significantly elevated in females at 

300 mg/kg/day, and serum aspartate aminotransferase levels were significantly elevated in males at 

300 and 1,200 mg/kg/day. Blood urea nitrogen (BUN) levels were significantly decreased in males and 

females at all dose levels, i.e., at > 100 mg/kg/day. No histopathological lesions were found in the liver. 

Relative kidney weights were significantly elevated in female rats at > 300 mg/kg/day, and absolute and 

relative kidney weights were significantly elevated in males rats at >900 mg/kg/day. Significant 

microscopic changes were observed in kidneys from treated male rats. Tubular changes, which were more 

severe in the 1,200 mg/kg/day dose-group males compared with controls, consisted of mild increases in 

cytoplasmic hyaline droplets in proximal tubular cells and small numbers of intratubular granular casts at 

the junction of the outer and inner stripe of the outer medulla. Female rats given 1,200 mg/kg/day had 

significantly elevated adrenal gland weights. Final body weight in both males and females decreased in a 

dose-dependent manner compared with controls, but the decrease in final body weight was significant only 

in females at 1,200 mg/kg/day. Cholesterol was significantly elevated in all treated female rats and in 

900 mg/kg/day males. Profound anesthesia was observed immediately following dosing with 

1,200 mg/kg/day, but the rats recovered in approximately 2 hours. 

Dose endpoint used for MRL derivation: Decreased BUN levels at 100 mg/kg/day 

[ ] NOAEL [x] LOAEL 
METHYL tert-BUTYL ETHER A-10 

APPENDIX A 

Uncertainty factors used in MRL derivation: 300 

[ ] 1 [x] 3 [ ] 10 (for use of a minimal LOAEL)
 

[ ] 1 [ ] 3 [x] 10 (for extrapolation from animals to humans)
 

[ ] 1 [ ] 3 [xl 10 (for human variability)
 

Was a conversion factor used from ppm in food or water to a mg/body weight dose?
 

If so, explain: No
 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: 

Was a conversion used from intermittent to continuous exposure? 

If so, explain: No 

Other additional studies or pertinent information that lend support to this MRL: 

Significantly decreased BUN levels were also observed in female rats given 1,428 mg/kg/day orally for 

14 days (Robinson et al. 1990). In a 4-week study, groups of 10 male and 10 female Sprague-Dawley rats 

given 90, 440, or 1,750 mg/kg/day MTBE by gavage, 5 days/week had increased relative liver weight at 

1,750 mg/kg/day (ITT Research Institute 1992). 

Agenc y Contact (Chemical Manager): Moiz Mumtaz 

METHYL tert-BUTYL ETHER B-1 

APPENDIX B
 

USER’S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public especially people living in the vicinity of a hazardous waste site or chemical 

release. If the Public Health Statement were removed from the rest of the document, it would still 

communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables (2-1, 2-2, and 2-3) and figures (2-l and 2-2) are used to summarize health effects and illustrate 

graphically levels of exposure associated with those effects. These levels cover health effects observed at 

increasing dose concentrations and durations, differences in response by species, minimal risk levels 

(MRLs) to humans for noncancer end points, and EPA’s estimated range associated with an upper- bound 

individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a 

quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and 

figures should always be used in conjunction with the text. All entries in these tables and figures represent 

studies that provide reliable, quantitative estimates of No-Observed-Adverse- Effect Levels (NOAELs), 

Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 2-1 and Figure 2-l are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 

LEGEND 

See LSE Table 2-1 

(1)	 Route of Exposure One of the first considerations when reviewing the toxicity of a substance using 

these tables and figures should be the relevant and appropriate route of exposure. When sufficient 

data exists, three LSE tables and two LSE figures are presented in the document. The three LSE 

tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE 

Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and 

oral (LSE Figure 2-2) routes. Not all substances will have data on each route of exposure and will 

not therefore have all five of the tables and figures. 
METHYL tert-BUTYL ETHER B-2 

APPENDIX B 

(2)	 Exposure Period Three exposure periods - acute (less than 15 days), intermediate (15-364 days), 

and chronic (365 days or more) are presented within each relevant route of exposure. In this 

example, an inhalation study of intermediate exposure duration is reported. For quick reference to 

health effects occurring from a known length of exposure, locate the applicable exposure period 

within the LSE table and figure. 

(3)	 Health Effect The major categories of health effects included in LSE tables and figures are death, 

systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and 

LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are 

further defined in the “System” column of the LSE table (see key number 18). 

(4)	 Key to Figure Each key number in the LSE table links study information to one or more data points 

using the same key number in the corresponding LSE figure. In this example, the study represented 

by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (also see the 2 

“18r” data points in Figure 2-1). 

(5)	 Species The test species, whether animal or human, are identified in this column. Section 2.5, 

“Relevance to Public Health,” covers the relevance of animal data to human toxicity and Section 2.3, 

“Toxicokinetics,” contains any available information on comparative toxicokinetics. Although 

NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses to 

derive an MRL. 

(6)	 Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen 

are provided in this column. This permits comparison of NOAELs and LOAELs from different 

studies. In this case (key number IS), rats were exposed to 1,1,2,2-tetrachloroethane via inhalation 

for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review of the dosing 

regimen refer to the appropriate sections of the text or the original reference paper, i.e., Nitschke et 

al. 1981. 

(7) System This column further defines the systemic effects. These systems include: respiratory, 

cardiovascular, gastrointestinal, hematological, muscuioskeletal, hepatic, renal, and dermal/ocular. 

“Other” refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. 

In the example of key number 18, 1 systemic effect (respiratory) was investigated. 

(8)	 NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no 

harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm 

for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 

0.005 ppm (see footnote “b”). 

(9)	 LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the study 

that caused a harmful health effect. LOAEL,s have been classified into “Less Serious” and “Serious” 

effects. These distinctions help readers identify the levels of exposure at which adverse health 

effects first appear and the gradation of effects with increasing dose. A brief description of the 

specific endpoint used to quantify the adverse effect accompanies the LOAEL. The respiratory 

effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not 

derived from Serious LOAELs. 

(10) Reference The complete reference citation is given in chapter 8 of the profile 
METHYL tert-BUTYL ETHER B-3 

APPENDIX B 

(11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of 

carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious 

effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report 

doses not causing measurable cancer increases. 

(12) Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in 

the footnotes. Footnote “b” indicates the NOAEL of 3 ppm in key number 18 was used to derive an 

MRL of 0.005 ppm. 

LEGEND 

See Figure 2-1 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures heIp the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13) Exposure Period The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the intermediate and chronic exposure periods are illustrated. 

(14) Health Effect These are the categories of health effects for which reliable quantitative data exists. 

The same health effects appear in the LSE table. 

(15) Levels of Exposure concentrations or doses for each health effect in the LSE tables are graphically 

displayed in the LSE figures. Exposure concentration or dose is measured on the log scale “y” axis. 

Inhalation exposure is reported in mg/m3

 or ppm and oral exposure is reported in mg/kg/day. 

(16) NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation 

exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates 

to a NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table. 

The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 

18 in the Table) to the MRL of 0.005 ppm (see footnote “b” in the LSE table). 

(17) CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond 

symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to the 

entry in the LSE table. 

(18) Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the 

upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA’s Human Health Assessment Group’s upper-bound estimates of the slope of the cancer 

dose response curve at low dose levels (ql*). 

(19)	 Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. 


METHYL tert-BUTYL ETHER B-6 

APPENDIX B 

Chapter 2 (Section 2.5) 

Relevance to Public Health 

The Relevance to Public Health section provides a health effects summary based on evaluations of 

existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present 

interpretive, weight-of-evidence discussions for human health end points by addressing the following 

questions. 

1. What effects are known to occur in humans? 

2. What effects observed in animals are likely to be of concern to humans? 

3. What exposure conditions are likely to be of concern to humans, especially around hazardous

 waste sites? 

The section covers end points in the same order they appear within the Discussion of Health Effects by 

Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are 

presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro 

data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in 

this section. If data are located in the scientific literature, a table of genotoxicity information is included. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency 

or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if derived) and 

the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for 

inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These 

MRLs are not meant to support regulatory action; but to acquaint health professionals with exposure levels 

at which adverse health effects are not expected to occur in humans. They should help physicians and 

public health officials determine the safety of a community living near a chemical emission, given the 

concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on 

toxicological studies in animals and on reports of human occupational exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 

2.5, “Relevance to Public Health,” contains basic information known about the substance. Other sections 

such as 2.7, “Interactions with Other Substances,” and 2.8, “Populations that are Unusually Susceptible” 

provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified 

version of the risk assessment methodology the Environmental Protection Agency (EPA) provides (Banes 

and Dourson 1988) to determine reference doses for lifetime exposure (RfDs). 

To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot 
METHYL tert-BUTYL ETHER B-7 

APPENDIX B 

make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all 

potential systemic, neurological, and developmental effects. If this information and reliable quantitative 

data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive species (when 

information from multiple species is available) with the highest NOAEL that does not exceed any adverse 

effect levels. When a NOAEL is not available, a lowest-observed-adverse-effect level (LOAEL) can be 

used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. Additional uncertainty 

factors of 10 must be used both for human variability to protect sensitive subpopulations (people who are 

most susceptible to the health effects caused by the substance) and for interspecies variability 

(extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are 

multiplied together. The product is then divided into the inhalation concentration or oral dosage selected 

from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the 

footnotes of the LSE Tables.