Toxicological
Profile
for
ETHYLBENZENE
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
TP-90-15
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TOXICOLOGICAL PROFILE FOR
ETHYLBENZENE
Prepared by:
Clement International Corporation
Under Contract No. 205-88-0608
Prepared for:
gency for Toxic Substances and Disease Registry
U.S. Public Health Service
December 1990
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DISCLAIMER
The use of company or product name(s) is for idenlification only and does
not imply endorsement by the Agency for Toxic Substances and Disease Registry
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iii
FOREWORD
The Superfund Amendments and Reauthorization Act (SARA) of 1986
(Public Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law directed the Agency for Toxic Substances and Disease
Registry (ATSDR) to prepare toxicological profiles for hazardous
substances which are most commonly found at facilities on the CERCLA
National Priorities List and which pose the most significant potential
threat to human health, as determined by ATSDR and the Environmental
Protection Agency (EPA). The lists of the 250 most significant hazardous
substances were published in the Federal Register on April 17, 1987, on
October 20, 1988, on October 26, 1989, and on October 17, 1990.
Section 104(i)(3) of CERCLA, as amended, directs the Administrator of
ATSDR to prepare a toxicological profile for each substance on the list.
Each profile must include the following content:
(A) An examination, summary, and interpretation of available
toxicological information and epidemiological evaluations on the
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute, subacute,
and chronic health effects,
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects, and
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans.
This toxicological profile is prepared in accordance with guidelines
developed by ATSDR and EPA. The original guidelines were published in the
Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by CERCLA, as amended.
The ATSDR toxicological profile is intended to characterize succinctly
the toxicological and adverse health effects information for the hazardous
substance being described. Each profile identifies and reviews the key
literature (that has been peer-reviewed) that describes a hazardous
substance's toxicological properties. Other pertinent literature is also
presented but described in less detail than the key studies. The profile
is not intended to be an exhaustive document; however, more comprehensive
sources of specialty information are referenced.
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iv
Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the public health statement is
information concerning significant health effects associated with exposure
to the substance. The adequacy of information to determine a substance's
health effects is described. Data needs that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program (NTP) of the Public Health Service, and EPA. The focus
of the profiles is on health and toxicological information; therefore, we
have included this information in the beginning of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested private
sector organizations and groups, and members of the public.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed
by scientists from ATSDR, the Centers for Disease Control, the NTP, and
other federal agencies. It-has also been reviewed by a panel of
nongovernment peer reviewers and is being made available for public
review. Final responsibility for the contents and views expressed in this
toxicological profile resides with ATSDR,
William L. Roper
Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS ETHYLBENZENE? 1
1.2 HOW MIGHT I BE EXPOSED TO ETHYLBENZENE? 2
1.3 HOW CAN ETHYLBENZENE ENTER AND LEAVE MY BODY? 3
1.4 HOW CAN ETHYLBENZENE AFFECT MY HEALTH? 3
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH
EFFECTS? 4
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
EXPOSED TO ETHYLBENZENE? 4
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? 9
1.8 WHERE CAN I GET MORE INFORMATION? 9
2. HEALTH EFFECTS 11
2.1 INTRODUCTION 11
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 11
2.2.1 Inhalation Exposure 12
2.2.1.1 Death 12
2.2.1.2 Systemic Effects 19
2.2.1.3 Immunological Effects 25
2.2.1.4 Neurological Effects 25
2.2.1.5 Developmental Effects 26
2.2.1.6 Reproductive Effects 27
2.2.1.7 Genotoxic Effects 27
2.2.1.8 Cancer 27
2.2.2 Oral Exposure 28
2.2.2.1 Death 28
2.2.2.2 Systemic Effects 28
2.2.2.3 Immunological Effects 31
2.2.2.4 Neurological Effects 31
2.2.2.5 Developmental Effects 32
2.2.2.6 Reproductive Effects 32
2.2.2.7 Genotoxic Effects 32
2.2.2.8 Cancer 32
2.2.3 Dermal Exposure 33
2.2.3.1 Death 33
2.2.3.2 Systemic Effects 33
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2.2.3.3 Immuno1og iea 1 E f f ec ts
2.2.3.4 Neurol op[ca] Effects
2.2.3.5 Developmental EHeet s
2.2.3.6 Reproduct ive Kf 1 c-ct .s
2.2.3.7 Genotoxic Effects
2.2.3.8 Cancer
2.3 TOXICOKINETICS
2.3.1 Absorption
2.3.1.1 Inhalation Exposure
2.3.1.2 Oral Exposure
2.3.1.3 Dermal F.xposurc
2.3.2 Distribution . . . .
2.3.2.1 Inhalation Exposure
2.3.2.2 Oral Exposure
2.3.2.3 Dermal Exposure
2.3.3 Metabolism
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
2.3.4.2 Oral Exposure
2.3.4.3 Dermal Exposure
2.3.4.4 Other Routes of Exposure
2.4 RELEVANCE TO PUBLIC HEALTH . .
2.5 BIOMARKERS OF EXPOSURE AND EFFECT
2.5.1 Biomarkers Used to Identify or Quantify Exposure to
Ethylbenzene
2.5.2 Biomarkers Used to Characterize Effects Caused by
Ethylbenzene
2.6 INTERACTIONS WITH OTHER CHEMICALS
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCKPT 1IILE
2.8 ADEQUACY OF THE DATABASE ...
2.8.1 Existing Information on Health Effects of
Ethylbenzene
2.8.2 Identification of Data Needs
2.8.3 On-Going Studies
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
3.2 PHYSICAL AND CHEMICAL PROPERTIES
4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAI
4.1 PRODUCTION
4.2 IMPORT/EXPORT
4.3 USE
4.4 DISPOSAL
5. POTENTIAL FOR HUMAN EXPOSURE . .
5.1 OVERVIEW
33
33
33
33
33
33
34
34
34
34
34
35
35
36
36
36
39
39
40
41
41
41
46
47
48
49
49
50
50
52
56
57
57
57
61
61
61
61
61
65
ft*
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vii
5.2 RELEASES TO THE ENVIRONMENT 66
5.2.1 Air 66
5.2.2 Water 68
5.2.3 Soil 68
5.3 ENVIRONMENTAL FATE 68
5.3.1 Transport and Partitioning 68
5.3.2 Transformation and Degradation 69
5.3.2.1 Air 69
5.3.2.2 Water 70
5.3.2.3 Soil 71
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 71
5.4.1 Air 71
5.4.2 Water 72
5.4.3 Soil 74
5.4.4 Other Media 74
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 75
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 76
5.7 ADEQUACY OF THE DATABASE 76
5.7.1 Identification of Data Needs 76
5.7.2 On-going Studies 78
6. ANALYTICAL METHODS 81
6.1 BIOLOGICAL MATERIALS 81
6.2 ENVIRONMENTAL SAMPLES 8 5
6.3 ADEQUACY OF THE DATABASE 87
6.3.1 Identification of Data Needs 87
6.3.2 On-Going Studies 88
7. REGULATIONS AND ADVISORIES 89
8. REFERENCES 93
9. GLOSSARY 125
APPENDIX 129
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ix
LIST OF FIGURES
2-1 Levels of Significant Exposure to Ethylbenzene - Inhalation .... 17
2-2 Levels of Significant Exposure to Ethylbenzene - Oral 30
2-3 Metabolic Scheme for Ethylbenzene in Humans 37
2-4 Existing Information on Health Effects of Ethylbenzene 51
5-1 Frequency of Sites with Ethylbenzene Contamination 67
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xi
LIST OF TABLES
1-1 Human Health Effects from Breathing Ethylbenzene 5
1-2 Animal Health Effects from Breathing Ethylbenzene 6
1-3 Human Health Effects from Eating or Drinking Ethylbenzene 7
1-4 Animal Health Effects from Eating or Drinking Ethylbenzene 8
2-1 Levels of Significant Exposure to Ethylbenzene - Inhalation .... 13
2-2 Levels of Significant Exposure to Ethylbenzene - Oral 29
2-3 Genotoxicity of Ethylbenzene In Vitro 45
3-1 Chemical Identity of Ethylbenzene 58
3-2 Physical and Chemical Properties of Ethylbenzene 59
4-1 Ethylbenzene Producers in the United States 62
5-1 Ethylbenzene Concentrations in Ambient Air Samples Collected in
the United States 73
6-1 Analytical Methods for Determining Ethylbenzene in Biological
Materials 82
6-2 Analytical Methods for Determining Ethylbenzene in Environmental
Samples 83
7-1 Regulations and Guidelines Applicable to Ethylbenzene 90
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1
1. PUBLIC HEALTH STATEMENT
This Statement was prepared to give you information about ethylbenzene
and to emphasize the human health effects that may result from exposure to it.
The Environmental Protection Agency (EPA) has identified 1,177 sites on its
National Priorities List (NPL). Ethylbenzene has been found at 227 of these
sites. However, we do not know how many of the 1,177 NPL sites have been
evaluated for ethylbenzene. As EPA evaluates more sites, the number of sites
at which ethylbenzene is found may change. The information is important for
you because ethylbenzene may cause harmful health effects and because these
sites are potential or actual sources of human exposure ethylbenzene.
When a chemical 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 as a chemical emission. This emission, which is also called a
release, does not always lead to exposure. You can be exposed to a chemical
only when you come into contact with the chemical. You may be exposed to it
in the environment by breathing, eating, or drinking substances containing the
chemical or from skin contact with it.
If you are exposed to a hazardous substance such as ethylbenzene,
several factors will determine whether harmful health effects will occur and
what the type and severity of those health effects will be. These factors
include the dose (how much), the duration (how long), the route or pathway by
which you are exposed (breathing, eating, drinking, or skin contact), the
other chemicals to which you are exposed, and your individual characteristics
such as age, sex, nutritional status, family traits, life style, and state of
health.
1.1 WHAT IS ETHYLBENZENE?
Ethylbenzene is a colorless liquid that smells like gasoline. It
evaporates at room temperature and burns easily. Ethylbenzene occurs
naturally in coal tar and petroleum. It is also found in many man-made
products, including paints, inks, and insecticides. Gasoline contains about
2% (by weight) ethylbenzene. It is most commonly found as a vapor in the air.
This is because ethylbenzene moves easily into the air from water and soil.
Once in the air, other chemicals help break down ethylbenzene into chemicals
found in smog. This breakdown happens in about 3 days with the aid of
sunlight. In surface water such as rivers and harbors, ethylbenzene breaks
down by reacting with other compounds naturally present in the water. In
soil, the major way ethylbenzene is broken down is by soil bacteria. It can
also move very quickly into groundwater, since it does not readily bind to
soil. Near hazardous waste sites, the levels of ethylbenzene in the air,
water, and soil could be much higher than in other areas. For more
information on the physical and chemical properties of ethylbenzene, its
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2
1. PUBLIC HEALTH STATEMENT
production, and use, and its fate in the environment, see Chapters 3, 4,
and 5 .
1.2 HOW MIGHT I BE EXPOSED TO ETHYLBENZENE?
There are a variety of ways you may be exposed to this chemical. If you
live in a highly populated area or near many factories or heavily traveled
highways, you may be exposed to ethylbenzene in the air. Releases of
ethylbenzene into these areas occur from burning oil, gas, and coal arid from
discharges of ethylbenzene from some types of factories. The median level of
ethylbenzene in city air is about 0.62 parts of ethylbenzene per billion parts
(ppb) of air. The median level in suburban air is about 0.62 ppb. In
contrast, the median level of ethylbenzene measured in air in country
locations is about 0.01 ppb. Indoor air has a higher medi.nn concentration of
ethylbenzene (about 1 ppb) than outdoor air. This is because ethylbenzene;
builds up after you use household products such as cleaning products or
paints.
Ethylbenzene was found in only 1 out of 10 of the United States rivers
and streams tested in 1982 and 1983. The average level measured was 5.0 ppb.
Ethylbenzene gets into water from factory releases, boat fuel, and poor
disposal of waste. Background levels in soils have not been reported.
Ethylbenzene may get into the soil by gasoline or other fuel spills and poor
disposal of industrial and household wastes.
Some people are exposed to ethylbenzene in the workplace. Gas and oil
workers may come into contact with ethylbenzene either through the skin or by
breathing ethylbenzene vapors. Varnish workers, spray painters and persons
involved in gluing operations may also be exposed to high levels of
ethylbenzene. Exposure may also occur in factories that use ethylbenzene to
produce other chemicals. Families of these workers may be exposed to
ethylbenzene through contact with contaminated clothing.
You may be exposed to ethylbenzene if you live near hazardous waste
sites containing ethylbenzene or areas where ethylbenzene spills have
occurred. Higher than background levels of ethylbenzene were detected in
groundwater near a landfill and near an area where a fuel spill had occurred.
No specific information on human exposure to ethylbenzene near hazardous waste
sites is available.
You may also be exposed to ethylbenzene from the use of many consumer
products. Gasoline is a common source of ethylbenzene exposure. Other
sources of ethylbenzene exposure come from the use of this chemical as a
solvent in pesticides, carpet glues, varnishes and paints, and from the use of
tobacco products. Ethylbenzene does not generally build up in food. However,
some vegetables may contain very small amounts of it. For more information on
human exposure to ethylbenzene, see Chapter 5.
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3
1. PUBLIC HEALTH STATEMENT
1.3 HOW CAN ETHYLBENZENE ENTER AND LEAVE MY BODY?
When you breathe air containing ethylbenzene vapor, it enters your body
rapidly and almost completely through your lungs. Ethylbenzene in food or
water can also rapidly and almost completely enter your body through the
digestive tract. It may enter through your skin when you come into contact
with liquids containing ethylbenzene. Ethylbenzene vapors do not enter
through your skin to any large degree. People living in urban areas or in
areas near hazardous waste sites may be exposed by breathing air or by
drinking water contaminated with ethylbenzene.
Once in your body, ethylbenzene is broken down int". other chemicals.
Most of it leaves in the urine within 2 days. Small amoun s can also leave
through the lungs and in feces. Liquid ethylbenzene also enters through your
skin and is broken down. Ethylbenzene in high levels is broken down slower ir
your body than low levels of ethylbenzene. Similarly, ethylbenzene mixed wit!
other solvents is also broken down more slowly than ethylbenzene alone. This
slower breakdown may increase the time it takes for ethylbenzene to leave youi
body. For more information on how ethylbenzene. enters and leaves the body,
see Chapter 2.
1.4 HOW CAN ETHYLBENZENE AFFECT MY HEALTH?
At certain levels, exposure to ethylbenzene can harm your health.
People exposed to low levels of ethylbenzene in the air for short periods of
time have complained of eye and throat irritation. Persons exposed to higher
levels have shown signs of more severe effects such as decreased movement and
dizziness, No studies have reported death in humans following exposure to
ethylbenzene. However, evidence from animals suggests that it can cause deatl
at very high concentrations. Whether or not long-term exposure to
ethylbenzene affects human health is not known because little information is
available. Short-term exposure of laboratory animals to high concentrations
of ethylbenzene in air may cause liver and kidney damage, nervous system
changes, and blood changes. The link between these health effects and
exposure to ethylbenzene is not clear because of conflicting results and
weaknesses in many of the studies. Also there is no clear evidence that the
ability to get pregnant is affected by breathing air, drinking water
containing ethylbenzene, or coming into direct contact with ethylbenzene
through the skin. Birth defects have occurred in newborn animals whose
mothers were exposed by breathing air contaminated with ethylbenzene. The
seriousness of these effects seems to increase with higher exposure levels.
One long-term study in animals suggests that ethylbenzene may cause tumors.
However, this study had many weaknesses and no conclusions could be drawn
about possible cancer effects in humans. For more information on health
effects associated with exposure to ethylbenzene, see Chapter 2.
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1. PUBLIC HEALTH STATEMENT
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Low levels of ethylbenzene in the air may cause harmful health effects
More serious effects to your health may occur at higher levels. You can smell
ethylbenzene in the air at concentrations as low as 2 parts of ethylbenzene
per million parts of air by volume (ppm).
There are no reliable data on the effects in humans after eating
drinking, or breathing ethylbenzene or following direct exposure to the skin
For this reason, levels of exposure that may affect your health are estimated
from animal studies. Only two reports described the results of eye or skin
exposure to ethylbenzene. In these studies, liquid ethylbenzene caused eye
damage and skin irritation in rabbits. More animal studies are available thit
describe the effects of breathing air or drinking water containing ethyl-
benzene. Tables 1-1 through 1-4 show the relationship between exposure to
ethylbenzene in air, food, or water and known health effects.
A Minimal Risk Level (MRL) is also included in Table 1-1. This MRL was
derived from animal data for long-term exposure, as described in Chapter 2 and
in Table 2-1. The MRL provides a basis for comparison with levels that people
might encounter either in the air, in food, or in drinking water. If a person
is exposed to ethylbenzene at an amount below the MRL, it is not expected that
harmful (noncancer) health effects will occur. Because this level is based
only on information currently available, some uncertainty is always associated
with it. Also, because the method for deriving MRLs does not use any
information about cancer, an MRL does not imply anything about the presence
absence, or level of risk for cancer.
For more information on levels of exposure associated with harmful
health effects see Chapter 2.
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
ETHYLBENZENE?
Ethylbenzene is found in the blood, urine, breath, and some body tissues
of exposed persons. Urine is most commonly tested to determine exposure to
ethylbenzene. The test measures the presence of substances formed following
an exposure to ethylbenzene. These substances are formed by the breakdown of
ethylbenzene. You should have this test done within a few hours after
exposure occurs, because these substances leave the body very quickly.
Although this test can prove your exposure to ethylbenzene, it cannot yet
predict the kind of health effects that might develop from that exposure. For
more information on the different substances formed by ethylbenzene breakdown
and on tests to detect these substances in the body, see Chapters 2 and 6.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing Ethylbenzene*
Short-term Exposure
(less than or equal
to 14 days)
Levels
in Air
(ppm)
Leneth of Exposure
Description of Effects
The health effects of short-
term exposure of humans to
air containing specific
levels of ethylbenzene are
not known.
Long-term Exposure
(greater than 14
days)
Levels
in Air
(pom}
Length of Exposure
DescriDtion of Effects
0.3
Minimal Risk Level (based on
animal studies; see Section
1.5 for discussion).
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing Ethylbenzene
Short-term Exposure
(less than or equal to 14 days)
Levels in Air
(prim)
Leneth of Exposure
Descriotion of Effects*
138
9 days
Birth defects in rats.
750
7 days
Chemical changes in brains of
rabbits.
1,200
4 days
Death in mice.
2,400
4 days
Death in rats.
Long-term Exposure
(greater than 14
days)
levels in Air
(pom)
Leneth of Exposure
Description of Effects*
782
28 days
Increased number of white
blood cells in rats.
~These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking Ethylbenzene*
Short-term Exposure
(less than or equal to 14 days)
Levels
in Food
Leneth of ExDosure
Descriotion of Effects
The health effects of short-
term exposure of humans to
food containing specific
levels of ethylbenzene are
not known.
Levels
in Water
The health effects of short-
term exposure of humans to
water containing specific
levels of ethylbenzene are
not known.
Long-term Exposure
(greater than 14 days)
Levels
in Food
Length of ExDosure
Description of Effects
The health effects of long-
term exposure of humans to
food containing specific
levels of ethylbenzene are
not known.
Levels
in Water
The health effects of long-
term exposure of humans to
water containing specific
levels of ethylbenzene are
not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal Health Effects from Eating or Drinking Ethylbenzene
Short-term Exposure
(less than or equal to 14 clays)
Levels
in Food
(dm)
Length of ExDosure
Description of Effects*
The health effects of short-
term exposure of animals to
food containing specific
levels of ethylbenzene are
not known.
Levels
in Water
(opto)
The health effects of short-
term exposure of animals to
water containing specific
levels of ethylbenzene are
not known.
Long-term Exposure
(greater than 14 days)
Levels
in Food
(x>vn)
Length of ExDosure
Description of Effects*
The health effects of long-
term exposure of animals to
food containing specific
levels of ethylbenzene are
not known.
Levels
in Water
(ppm)
The health effects of
long-term exposure of
animals to water containing
specific levels of ethyl-
benzene are not known.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN
HEALTH?
The federal government has formed regulatory standards and guidelines to
protect you from possible health effects of ethylbenzene in the environment.
EPA's Office of Drinking Water (ODW) recommends 680 ppb (0.68 mg/L) as the
acceptable exposure concentration of ethylbenzene in drinking water for an
average weight adult. This value is for lifetime exposure and is not expected
to increase the chance of experiencing (noncancer) health effects. The same
EPA office (ODW) recommends higher acceptable levels of ethylbenzene in water
for shorter periods (32,000 ppb or 32 mg/L for 1 day, 3,200 ppb or 3.2 mg/L
for 10 days). These levels are stated to be acceptable for small children.
EPA also recommends that if you eat fish and drink water from a body of water,
the water should contain no more than 1.4 mg ethylbenzene/L.
EPA requires that a release of 1,000 pounds or more of ethylbenzene be
reported to the Federal Government National Response Center in Washington,
D.C.
The Occupational Safety and Health Administration (OSHA) set a legal
limit of 100 ppm ethylbenzene in air. This is for exposure at work for
8 hours per day. OSHA also set a limit of 125 ppm for a 15-minute period.
The National Institute for Occupational Safety and Health (NIOSH) also
recommends an exposure limit for ethylbenzene of 100 ppm. This is for
exposure to ethylbenzene in air at work for up to 10 hours per day in a
40-hour work week. NIOSH classifies ethylbenzene exposures of 2,000 ppm in
air as immediately dangerous to life or health.
For more information on regulations and advisories see Chapter 7.
1.8 WHERE CAN I GET MORE INFORMATION?
If you have any more questions or concerns not covered here, please
contact your State Health or Environmental Department or:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
This agency can also give you information on the location of the nearest
occupational and environmental health clinics. Such clinics specialize in
recognizing, evaluating, and treating illnesses that result from exposure to
hazardous substances.
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
ethylbenzene. Its purpose is to present levels of significant exposure for
ethylbenzene based on toxicological studies, epidemiological investigations,
and environmental exposure data. This information is presented to provide
public health officials, physicians, toxicologists, and other interested
individuals and groups with (1) an overall perspective of the toxicology of
ethylbenzene and (2) a depiction of significant exposure levels associated
with various adverse health effects.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons living
or working near hazardous waste sites, the data in this section are organized
first by route of exposure -- inhalation, oral, and dermal -- and then by
health effect -- death, systemic, immunological, neurological, developmental,
reproductive, genotoxic, and carcinogenic effects. These data are discussed
in terms of three exposure periods -- acute, intermediate, and chronic.
Levels of significant exposure for each exposure route and duration (for
which data exist) 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. These distinctions are intended to help
the users of the document identify the levels of exposure at which adverse
health effects start to appear, determine whether or not the intensity of the
effects varies 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 on the tables and figures
may differ depending on the user's perspective. For example, physicians
concerned with the interpretation of clinical findings in exposed persons or
with the identification of persons with the potential to develop such disease
may be interested in levels of exposure associated with "serious" effects.
Public health officials and project managers concerned with response actions
at Superfund 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 (NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels, MRLs) are of interest to
health professionals and citizens alike.
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2. HEALTH EFFECTS
Estimates of exposure posing minimal risk to humans (MRLs) have been
made, where data were believed reliable, for the most sensitive noncancer end
point for each exposure duration. MRLs include adjustments to reflect human
variability and, where appropriate, the uncertainty of extrapolating from
laboratory animal data to humans. Although methods have been established to
derive these levels (Barnes et al. 1987; EPA 1989a), uncertainties are
associated with the techniques.
2.2.1 Inhalation Exposure
Table 2-1 and Figure 2-1 describe the health effects in laboratory
animals associated with various inhalation exposure levels and exposure
durations.
2.2.1.1 Death
No studies were located regarding lethality in humans following
inhalation exposure to ethylbenzene.
The LC50 for rats following inhalation exposure to ethylbenzene is
reported to be 4,000 ppm (Smyth et al. 1962) and 13,367 ppm (Ivanov 1962)
following exposure durations of 4 and 2 hours, respectively. The dose
required to cause 1005E mortality in rats was shown to be 8,000 ppm (Smyth et
al. 1962) and 16,698 ppm (Ivanov 1962) for 4- and 2-hour inhalation exposures
respectively. However, it is important to note that the results of both of
these studies have limited utility because the recorded concentrations were
not analytically verified. Although no studies were located regarding the
effect of nutritional status on mortality, it has been postulated that food
deprivation may decrease ethylbenzene toxicity since the detoxification of
ethylbenzene is increased significantly in fasted rats (Nakajima and Sato
1979).
The lethality of ethylbenzene in animals following inhalation exposure
has been shown to vary among species. This was demonstrated in a study using
rats, mice, and rabbits in which the animals were exposed to 0, 400, 1,200 or
2,400 ppm ethylbenzene 6 hours/day for 4 days (Cragg et al. 1989). Mortality
occurred in mice at half the dose (1,200 ppm) required to cause death in rats
(2,400 ppm). All rabbits in each exposure group survived. No mortality was
observed in a 4-week inhalation study in which rats and mice were exposed to
99, 382, or 782 ppm ethylbenzene, 6 hours/day, 5 days/week, and all rabbits
survived after exposure to 1,610 ppm ethylbenzene in the same study (Cragg et
al. 1989). According to a preliminary report of a 90-day study, no lethality
was observed in rats and mice exposed to 0, 100, 250, 500, 750, or 1,000 ppm
ethylbenzene, 6 hours/day, 5 days/week (NTP 1988c).
The highest NOAEL values for death in each species and duration category
and the reliable LOAEL values for rats and mice following acute exposure are
recorded in Table 2-1 and plotted in Figure 2-1.
-------
TABLE 2 1. Levels of Significant Exposure to Ethylbenzene ~ Inhalation
Figure
Key Species
Exposure
Frequency/ NOAEL
Duration Effect (ppm)
LOAEL (Effect)
Less Serious
(ppm)
Serious
(pptn)
Reference
ACUTE EXPOSURE
Death
1 Rat
2 Mouse
3 Rabbit
Systemic
4 Rat
5 House
6 Mouse
Neurological
7 Rat
8
Rabbit
Rabbit
4 d
6hr/d
4 d
6hr/d
4 d
6hr/d
3 d
6hr/d
1 d
30min/d
1 d
5min/d
3 d
6hr/d
7 d
12hr/d
7d
12hr/d
Resp
Hepatic
Renal
Resp
Resp
400
1610
2000
2000
2000
4060 (502 respiratory
depression)
1432 (501 respiratory
depression)
2400* (100Z mortality) Cragg et al.
1989
1200a (80X mortality) Cragg et al,
1989
Cragg et al.
1989
Toftgard and
Nilsen 1932
Nielson and
Alarie 1982
De Ceaurriz et
al. 1981
2000 (neurotransmission
disturbances)
750* (dopamine
depletion)
750 (dopamine
depletion)
Andersson et al.
1981
Romanelli et al.
1986
Mutti et al.
1988
3:
>
r"
H
3:
tn
T)
O
H
CO
-------
Exposure
Figure Frequency/ NOAEL
Key Species Duration Effect Cppm)
Developmental
10 Rat
11
12
Rat
House
INTERMEDIATE EXPOSURE
Systemic
13 Rat
14
Rat
15
Mouse
9 d
Gd7-15
6hr/d
9 d
Gd7-15
24hr/d
10 d
Gd6-15
12hr/d
138
16 wk
Hepatic
600
5d/wk
Renal
600
6hr/d
h wk
Resp
782
5d/vk
Gastro
782
6hr/d
Hemato
382
Musc/skel
782
Hepatic
782
Renal
782
Dera/Oc
4 wk
Resp
782
5d/wk
Gastro
782
6hr/d
Hemato
782
Husc/skel
782
Hepatic
782
Renal
782
TABLE 2-1 (Continued)
LOAEL (Effect)
Less Serious Serious
(ppcn) (ppm) Reference
138* (skeletal
malformations)
115 (malformations)
782® (increase in
leukocyte count)
Ungvary and
Tatrai 1985
Ungvary and
Tatrai 19 85
Ungvary and
Tatrai 1985
X
m
>
r
Elovaaraetal.
1985 _
^ragg et a.
1989
T]
O
H
V*.
382 (lacrimatior.)
Cragg et al
1989
-------
Figure
Key Species
Exposure
Frequency/
Duration
NOAEL
Effect (ppm)
16
Rabbit
Neurological
17 Rat
18
19
Mouse
Rabbit
Developmental
20 Rat
A wk
Resp
1610
5d/wfc
Gastro
1610
6hr/d
Hemato
1610
Musc/skel
1610
Hepatic
1610
Renal
1610
Other
1610
4 wk
5d/wk
6hr/d
4 wk
5d/wk
6hr/d
4 wk
5d/wk
6hr/d
19d
Gdl-19
7hr/d
782
782
1610
100"
21
Rabbit
Reproductive
22 Rat
23
House
24 d
Gdl-24
7hr/d
4 wk
5d/wk
6hr/d
4 wk
5d/wk
6hr/d
1000
782
782
TABLE 2-1 (Continued)
LOAEL (Effect)
Less Serious
(ppm)
Serious
(ppm)
Reference
Crags et al,
1989
Cragg et aL.
1989
Cragg et al.
1989
1000 (skeletal
anomalies)
Cragg et. al.
1989
Andrew et al.
1981
X
m
>
H
K
W
M
o
H
in
Andrew et al.
1981
Cragg et a 1.
1989
Cragg et al.
1989
-------
TABLE 2-1 (Continued)
Figure
Key Species
Exposure
Frequency/ NOAEL
Duration Effect (ppm)
LOAEL (Effect)
Less Serious
(ppm)
Serious
(ppm)
Reference
24
Rabbit
4 wk
5d/wk
6hr/d
1610
Cragg et al.
1989
'This concentration is presented in Table 1-2.
''Used to derive intermediate inhalation NIL; dose adjusted for intermittent exposure and divided by an uncertainty factor of
100 (10 for extrapolation from animals to humans, and 10 for human variability), resulting in an MRL of 0.3 ppm. This MRL
is presented in Table 1-1.
Cardio ¦ cardiovascular; d m day; Derm/Oc " dermal/ocular; Gastro - gastrointestinal; Gd " gestation day; Hecnato =
hematological; hr «* hour; LC^q ™ lethal concentration, 501 kill; LOAEL » lowest dose at which an adverse effect was noted;
min " minute; Musc/skel ~ Musculoskeletal; NOAEL ~ highest dose at which no effect was noted; Resp = respiratory; wk = week
-------
ACUTE
(<14 Days)
^ jf / /
(PP"i)
t-1
H t-1
2C -J
m
m
c->
H
t/">
081 # LOAEL for serious effects (animals)
Mouse (J LOAEL for less serious effects (animals)
Rabbit O NOAEL (animals)
The number next to each point corresponds to entries in Table 2-1.
FIGURE 2-1. Levels of Significant Exposure to Ethylbenzene - Inhalation
-------
INTERMEDIATE
(15-364 Days)
/
(PPm)
100,000 r-
H
01
Key
r Rat
m Mouse
h Rabbit
•
9
O
LOAtl for senous effects (animals) i
LOAEL tor less senous effects (animals) .
NOAEL (arwmate) 1
Minimal nsk level tor
effects other than cancer
r
The nurrt>*f new to each point corresponds to entries in Tab to 2-1.
FIGURE 2-1 (Continued)
-------
19
2. HEALTH EFFECTS
2.2.1.2 Systemic Effects
Data are limited on the systemic effects of inhaled ethylbenzene in
humans. Most of the information available is from case reports in which
quantitative data on exposure concentrations and durations were not reported.
In addition, most of these studies lack important study details or have
confounding factors (e.g., concurrent exposures to other toxic substances).
In general, the systemic effects observed in humans were pulmonary and ocular
irritation, and possible hematological alterations (Angerer and Wulf 1985;
Thienes and Haley 1972; Yant et al. 1930).
Several studies were located on the systemic effects of ethylbenzene in
animals following inhalation exposure. The principal target organs appear to
be the lungs, liver, and kidney, with transient toxic effects on the
hematological system. However, no definitive conclusions can be drawn because
of the limitations of many of the studies.
Respiratory Effects. Throat irritation and chest constriction were
reported in the human volunteers acutely exposed to levels of ethylbenzene in
the air as low as 2,000 ppm (Yant et al, 1930). Symptoms became more extreme
following exposure to higher doses. No other significant respiratory changes
were reported. The utility of these results is limited because the exposure
durations necessary for these effects to occur were not clearly described and
the ethylbenzene used for testing reportedly contained small amounts of
impurities (e.g., benzol and diethylbenzene). In addition, the methods used
to calculate the actual vapor concentration of ethylbenzene were not well
described thus making it difficult to determine the accuracy of the methods.
In case studies involving a male patient and a female patient, no respiratory
effects were observed when the patients were exposed to 55.3 ppm ethylbenzene
for 15 minutes in an inhalation chamber (Moscato et al. 1987).
Microscopic examination of tissues from rats and mice exposed to
1,200-2,400 ppm ethylbenzene via inhalation for 4 days showed pulmonary
congestion in animals that had died. However, no information on the cause of
death was provided, and therefore it is not known if these effects are
treatment related (Biodynamics 1986). The concentration of ethylbenzene
required to decrease the respiratory rate in mice by 50% (RD50) has been
determined (De Ceaurriz et al. 1981; Nielsen and Alarie 1982). These values
were reported to be 1,432 ppm in male Swiss OF: mice (De Ceaurriz et al. 1981)
and 4,060 ppm in Swiss Webster mice exposed to ethylbenzene (Nielsen and
Alarie 1982). No adverse pulmonary effects were reported when mice (Cragg et
al. 1989) and rats (Cragg et al. 1989; Toftgard and Nilsen 1982) were exposed
to concentrations of ethylbenzene at 782 or 2,000 ppm. Rabbits exposed to
concentrations as high as 1,610 ppm for 4 weeks also showed no adverse effects
(Cragg et al. 1989). Possible explanations for the inconsistent results
-------
20
2. HEALTH KFFKCTS
include lower doses administered t;o mice and rat s (Cragg ct al. ] 989) and
possible differences in susceptibility to ethyl benzene among species.
In a series of studies in which rats, monkeys, rabbits, and guinea pigs
were exposed for 6-7 months to concentrations of ethyI benzene as high as
2,200 ppm, no toxic effects were reported in any ol the laboratory animals
(Wolf et al. 1956). These parameters (i.e., toxic eiulpoints), however, were
not well defined and may account for conflicts in results with those reported
by De Ceaurriz et al . (1981), and Nielsen and Marie (1982). The utility of
this study is further limited by a general lack of study details (e.g., no
exposure or control data were provided).
In the preliminary report of a 90-day inhalation study, it was noted
that both male and female rats exposed to 100, 2 50, 500, 7 b 0, or 1,000 ppm
ethylbenzene developed lung lesions and hyperplastic bronchi a 1/mediastinal
lymph nodes. These effects were not seen in the exposed mice in the same
study (NTP 1988c). It was the opinion of the NTP Pathology Working Croup that
"the pulmonary lesions and lymph node hyperplasia were more typical of an
infectious agent than a response to the test: compound." However, "no
infectious agent was identified in histologic sections, and serology performec
on control groups (which had no lesions) was negative." In order to confirm
these observations, the Pathology Working (.'roup recommends that "a portion of
the. 90 day study be repeated (NTP 1989b)."
The highest NOAEL values and all reliable I.OAKL values for respiratory
effects in each species and duration category are recorded in Table 2-1 and
plotted in Figure 2-1.
Cardiovascular Effects. No studies were located regarding
cardiovascular effects in humans following inhalation exposure to ethyl-
benzene .
A series of experiments using rats, monkeys, rabbits, and guinea pigs
exposed for 6-7 months to ethylbenzene concentrations ranging from 400 to
2,200 ppm reported no changes in the gross appearance of the heart or abnormal
histopathological changes in cardiac tissue (Wolf et al. 1956). This study,
however, is of little value because of a lack of study details (e.g., no
cardiovascular data were presented), small number of study animals (e.g., one
to two rabbits and monkeys), and poor definition of the parameters monitored.
No additional animal studies regarding cardiovascular effects were located.
Gastrointestinal Effects. No studies were located regarding
gastrointestinal effects in humans following inhalation exposure to ethyl-
benzene .
In animals, a series of experiments using rats and mice exposed to
ethylbenzene concentrations as high as 782 ppm and rabbits exposed to
-------
21
2 . HEALTH EFFECTS
ethylbenzene concentrations as high as 1,610 ppm for 4 weeks reported no
changes in the gross appearance or abnormal histopathological changes in the
intestines (Cragg et al. 1989) . No additional studies that investigated
gastrointestinal effects in animals were located.
The highest NOAEL values for gastrointestinal effects in each species
exposed for an intermediate duration are recorded in Table 2-1 and plotted in
Figure 2 -1.
Hematological Effects. Two studies involving long-term monitoring of
workers occupationally exposed to ethylbenzene showed conflicting results with
respect to effects on the hematopoietic system (Angerer and Wulf 1985;
Bardodej and Cirek 1988). In one human study involving workers chronically
exposed to organic solvents containing ethylbenzene, the average number of
lymphocytes and hemoglobin levels decreased in exposed individuals compared
with controls (Angerer and Wulf 1985). The average level of ethylbenzene in
the blood of these workers at which correlations were seen between exposure
and hematological effects was 61.4 g/L. Concomitant exposure to lead in
these workers could be a confounding factor. The use of the median lead
level, rather than the mean and variance of this measurement, could result in
a lower estimate of the impact of concomitant exposure to lead. No adverse
hematological effects were seen in a long-term study (20 years) on workers
occupationally exposed to unspecified concentrations of ethylbenzene (Bardodej
and Cirek 1988). Given the overall lack of a substantial amount of
quantitative exposure data and concurrent exposure to other hazardous
chemicals such as xylene isomers, n-butanol, and C-9 aromatic hydrocarbons in
the study of Angerer and Wulf (1985), these results are inadequate for
evaluating hematological effects of ethylbenzene following inhalation exposure
in humans.
Experiments with rats demonstrated a statistically significant increase
in platelet counts in male rats and a statistically significant increase in
the mean total leukocyte count in female rats exposed to 782 ppm ethylbenzene
for 4 weeks (Cragg et al. 1989). Hematological parameters did not change for
mice or rabbits exposed to the same or higher concentrations.
The effects of ethylbenzene on bone marrow counts and total blood counts
were investigated in a series of experiments using rats, mice, rabbits, guinea
pigs, and monkeys exposed for 6-7 months to concentrations ranging from 400 to
2,200 ppm (Wolf et al. 1956). No effects were reported in any of the animals
tested, but a number of limitations (e.g., small number of test animals) and
poorly defined parameters (e.g., specific toxic endpoints that were
investigated) may explain these conflicting results. In a preliminary report
of a 90-day inhalation study in rats and mice, no adverse hematological
effects were noted following exposure to ethylbenzene vapor concentrations of
up to 1,000 ppm (NTP 1988c). Based on the available data, no definitive
-------
7. HKAi.I!! KM'K':'!'.
conclusion can be drawn regarding the etf.-.-t ot t t hv1 l>ei:::ene cm hematological
parameters.
The highest NOAEL values and a reliable I.OAKl. value lor lu-matological
effects in each species lor i nt e-rniedi at e dui at ho. at .• i -..rded in Table 2-1
and plotted in Figure. 2-1.
Musculoskeletal Effects. N'<» t mi i were- located r ega rd i ng
musculoskeletal effects in humans following inhalat '<»«• exposure to ethyl-
benzene. Histopathologic^ examinat ion of botl.- t j .«;/.ue J r.»m mice, rats, and
rabbits exposed to concentrat ions of e i 1,y i benr.eim up t.. ,,pm in mice and
rats and 1,610 ppm in rabbits for 4 « S •• r.-v.-,, I .-<1 no bone tissue
abnormalities in any of the animals examineel ll ' • ] '#H'J) • tUven the
limited inhalation data on musculoskeletal elhrts Jol lowing ethylbenzene
exposure, no conclusions can be drawn.
The highest NOAEL values for muscu 1 oske 1 et a 1 effect:; in each species
exposed for an intermediate duration are recendcd in Table - 1 and plotted in
Figure 2-1.
Hepatic Effects. In a 20-year study ol workers on npationally exposed
to an undetermined concentration of e t by 1 l>en:-.e-ne , no rases of liver lesions or
significant differences in liver function tests between exposed and nonexposed
workers were reported (Bardodej and f.irek l'(KH).
The results from several studies have sugjested that hepatic effects may-
result from inhalation exposure to ethylbenzene in laboratory animals. No
j.t-i„0 (inclusions can be drawn because limitations are present in many of
U liuiu -*.»»» _ .
definitive conclusions can be drawn because limitations are present ]
the studies. Effects include biochemical changes, hi st opatholopical
alterations, and an increase oi liver weight relative- to body weipht These
changes may be an adaptive response, but potential toxicity cannot be ruled
out. Studies with rats, mice, and rabbits showed dillerenres in effects
across species (Cragg et al. 1989; klovaara et a!. 148'); NTP J 9ggc; Toftgard
' l » v.,1 V , t
.11 , and rabbits showed di 1 1 erences
. ;ragg et al. 1 b
and Nilsen 1982).
Hepatic congestion was observed upon mi e >nseop i c examinations of li
tissue from mice exposed to 1,200 ppm or 2,400 ppm for /, days and from ra^
exposed to 2,400 ppm for 4 days
-------
23
2. HEALTH EFFECTS
ethylbenzene. In general, enzyme induction enhances the metabolism of
ethylbenzene and may be considered an adaptive phenomenon rather than a
hepatotoxic effect. Increased liver-to-body-weight ratios were observed in
rats (Biodynamics 1986; Cragg et al. 1989; Toftgard and Nilsen 1982) and mice
(Gragg et al. 1989) exposed to ethylbenzene, but as with intracellular and
biochemical changes, the significance of the increased liver weight with
regards to possible health effects is unclear. No hepatic effects were
observed in rabbits (Cragg et al. 1989).
Increased liver weights in rats, guinea pigs, and rhesus monkeys and
histopathological changes in the liver of rats exposed to ethylbenzene for up
to 6 months were reported in another inhalation study (Wolf et al. 1956). No
hepatic effects were reported in rabbits (Wolf et al. 1956). The utility of
this study, however, is limited given the lack of study details and
statistical analysis of the histopathology results. Increased relative liver
weights were also noted in a preliminary report of a 90-day inhalation study
in which rats and mice were exposed to 250 ppm and 750 ppm ethylbenzene,
respectively (NTP 1988c). However, no corresponding organ dysfunction or
histopathological change accompanied this observation.
The highest NOAEL values for hepatic effects in each species and
duration category are recorded in Table 2-1 and plotted in Figure 2-1.
Renal Effects. No studies were located regarding renal effects in
humans following inhalation exposure to ethylbenzene.
Renal effects, manifested as histopathological changes, enzymatic
changes, or increased kidney-to-body-weight ratios, has been observed in a
number of species following inhalation exposure to ethylbenzene (Biodynamics
1986; Elovaara et al. 1985; Toftgard and Nilsen 1982; Wolf et al. 1956). The
significance of these changes with regard to possible health effects is not
known, but these studies suggest variations across species, indicating that
rats and mice may be more susceptible to ethylbenzene-induced renal effects
than rabbits, guinea pigs, and monkeys. However, this is difficult to
determine given weaknesses present (e.g., poor study details, lack of
statistical analysis, small number of animals used) in many of these studies.
Enzymatic changes in the kidney (e.g., increased concentration of
7-ethoxycoumarin, O-deethylase, UDPG transferase, NADPH-cytochrome c
reductase) were reported in rats following a 3-day exposure to 2,000 ppm
ethylbenzene (Toftgard and Nilsen 1982). Increased kidney-to-body-weight
ratios were reported following a 4-day exposure to 2,400 ppm, and renal
congestion was reported in mice and rats following a 4-day exposure to 1,200
and 2,400 ppm ethylbenzene, respectively (Biodynamics 1986). These effects
were not unusual in animals that died and were not exsanguinated. Therefore,
this effect may be a secondary effect and may not be treatment related.
-------
24
2. HEALTH EFFECTS
Longer exposure durations produced renal effects at lower ethylbenzene
exposure concentrations. Dose related increases in 7-ethoxycoumarin
O-deethylase and UDPG-transferase were reported in rats following a 16-week
exposure to ethylbenzene at concentrations ranging from 50 to 600 ppm
(Elovaara et al. 1985). In the same study, significant increases in the
kidney-to-body-weight ratio was observed at weeks 2 and 9 in animals exposed
to 600 ppm when compared with control animals. No renal changes were reported
in rats or mice exposed to ethylbenzene concentrations as high as 7 82 ppm for
4 weeks or in rabbits exposed to ethylbenzene concentrations as high as
1,610 ppm for the same duration (Cragg et al. 1989).
In a preliminary report of a 90-day inhalation study, it was noted that
rats and mice exhibited increased relative kidney weights at ethylbenzene
concentrations of 500 ppm and 1,000 ppm, respectively (NTP 1988c).
Regeneration of renal tubules in the kidneys of male rats was also seen in all
exposure groups, including controls. It was noted that the degree of
regeneration was somewhat greater in the 1,000 ppm group compared to the
controls; this difference was not statistically significant. Swelling of the
tubular epithelium in the kidney was observed in rats exposed to 680 ppm
ethylbenzene for up to 7 months (Wolf et al. 1956). No toxic effects were
reported in rabbits, guinea pigs or monkeys. The usefulness of this study,
however, is limited given the lack of study details and statistical analysis
of the histopathology data.
The highest NOAEL values for renal effects in each species and duration
category are recorded in Table 2-1 and plotted in Figure 2-1.
Dermal/Ocular Effects. Ethylbenzene concentrations of 1,000 ppm have
been shown to cause momentary ocular irritation, a burning sensation, and
profuse lacrimation in humans (Thienes and Haley 1972; Yant et al. 1930).
These effects became more severe in humans exposed to 2,000 ppm ethylbenzene
and intolerable at concentrations of 5,000 ppm or higher (Yant et al. 1930).
The strength of these results, however, is diminished by a number of
limitations (e.g., unclear exposure durations, impurities in ethylbenzene, and
limited information on methodology for analysis of the concentrations used).
Similar ocular effects to those in humans were seen in animals exposed
to ethylbenzene vapors. Eye irritation accompanied by lacrimation was
observed in guinea pigs 8 minutes following exposure to 1,000 ppm ethylbenzene
and 1 minute following exposure to 2,000-10,000 ppm ethylbenzene (Yant et al.
1930) and in rats exposed to concentrations as low as 382 ppm ethylbenzene
(Biodynamics 1986; Cragg et al. 1989).
One reliable L0AEL value for dermal/ocular effects in rats exposed for
4 weeks is recorded in Table 2-1 and plotted in Figure 2-1,
-------
25
2. HEALTH EFFECTS
2.2.1.3 Immunological Effects
No studies were found regarding immunological effects in humans or
animals following inhalation exposure to ethylbenzene.
2.2.1.4 Neurological Effects
Symptoms of dizziness accompanied by vertigo have been observed in
humans acutely exposed to air concentrations of ethylbenzene ranging from
2,000-5,000 ppm (Yant et al. 1930). Complete recovery occurs if exposure is
not prolonged. As reported earlier, this study had a number of weaknesses
(e.g., unclear exposure durations, impurities in ethylbenzene, and limited
information on the methodology for analysis of vapor concentrations). No
studies were found regarding neurological effects in humans following
intermediate or chronic exposure durations.
The primary effects in animals following acute exposure to high air
concentrations of ethylbenzene are neurological effects. Central nervous
system depression and ataxia were observed in guinea pigs exposed to 2,000 ppm
ethylbenzene (Yant et al. 1930). Moderate activation in motor behavior was
observed in rats following a 4-hour inhalation exposure to levels of
ethylbenzene ranging from 400 to 1500 ppm. Narcotic effects were observed in
rats at ethylbenzene concentrations as low as 2,180 ppm (Molnar et al. 1986).
This study is limited by a lack of methodological detail and appropriate
statistical analysis. No behavioral changes and no histopathological
alterations were reported in rats or mice exposed to concentrations of up to
782 ppm for 6 hours/day, 5 days/week, for 4 weeks (Cragg et al. 1989).
Similarly, no behavioral changes or histopathological alterations were
observed in rabbits exposed to concentrations up to 1,610 ppm ethylbenzene for
4 weeks (Cragg et al. 1989). Changes in dopamine and other biochemical
alterations were observed in rats (Andersson et al. 1981) and rabbits (Mutti
et al. 1988; Romanelli et al. 1986) exposed for 3-7 days to ethylbenzene
concentrations as low as 750 ppm. Differences in results in the studies using
rats (Andersson et al. 1981; Cragg et al. 1989; Molnar et al. 1986) and
rabbits (Cragg et al. 1989; Mutti et al. 1988; Romanelli et al. 1986) exposed
to ethylbenzene are probably due to parameters monitored, duration of
exposure, analytical technique, and species studied. No studies were found
regarding neurological effects in animals following chronic expo'sure
durations.
The highest NOAEL values and all reliable LOAEL values for neurological
effects in each species and duration category are recorded in Table 2-1 and
plotted in Figure 2-1.
-------
26
2. HEALTH EFFECTS
2.2.1.5 Developmental Effects
No studies were located regarding developmental effects in human.s
following inhalation exposure to ethylbenzene.
The developmental effects of inhalation exposure to ethylbenzene have
been studied in rats, mice, and rabbits (Andrew et al. 1981; Ungvary and
Tatrai 1985). In rats, exposure to ethylbenzene for 24 hr/day for 9 days at
doses ranging from 138 to 552 ppm during gestation resulted in fetal
resorption and retardation of skeletal development in surviving fetuses
(Ungvary and Tatrai 1985). Increased incidence of extra ribs and anomalies of
the uropoietic apparatus were observed at the 552-ppm dose level. No effects
were observed after exposure to 138 ppm for 6 hours/day for 9 days (Ungvary
and Tatrai 1985). Maternal toxicity was reported to be moderate and dose-
dependent, but no data were presented.
A statistically significant increase in the incidence of fetuses with
supernumerary ribs was observed in rats exposed to 1000 ppm ethylbenzene for 7
hours daily, 5 days a week during days 1-19 of gestation. Similar results
were obtained in rats exposed to 1000 ppm ethylbenzene for 7 hours daily, 5
days a week for 3 weeks prior to mating, followed by exposure to the same
regimen during days 1-19 of gestation (Andrew et al. 1981). Maternal toxicity
was also reported at this level. No supernumerary ribs were observed in the
100 ppm dose group. Based on this NOAEL value, an intermediate inhalation MRL
of 0.3 ppm was calculated, as described in the footnote in Table 2-1. This
value is also presented in Table 1-1.
Mice exposed to 115 ppm ethylbenzene during gestation demonstrated an
increased incidence of anomalies of the uropoietic apparatus (Ungvary and
Tatrai 1985). The nature of the renal malformation was not characterized and
no maternal toxicity was reported. Reduction in the weight of female fetuses
was reported in rabbits exposed to 115 ppm during gestation (Ungvary and
Tatrai 1985) but not following longer exposure to higher doses (up to
1,000 ppm) (Andrew et al. 1981). These conflicting results in rabbits might
be attributable to differences in study design, methodology used, and the end
points investigated. These studies suggest that ethylbenzene may produce
fetotoxicity and maternal toxicity at exposure levels as low as 138 ppm in
rats and 115 ppm in mice and rabbits.
The highest NOAEL values and all reliable LOAEL values for developmental
effects in each species and duration category are recorded in Table 2-1 and
plotted in Figure 2-1.
-------
27
2. HEALTH EFFECTS
2.2.1.6 Reproductive Effects
No studies were located regarding reproductive effects in humans
following inhalation exposure to ethylbenzene.
No reproduction studies over one or more generation of animals were
located for inhalation exposure to ethylbenzene. No testicular
histopathological abnormalities were reported in rats and mice exposed to
concentrations as high as 782 ppm and rabbits exposed to ethylbenzene
concentrations as high as 1,610 ppm for 4 weeks (Cragg et al. 1989). Pre-
gestational exposure of female rats to 100 or 1,000 ppm ethylbenzene for
3 weeks resulted in no conclusive evidence of reproductive effects, but the
possibility of these effects occurring was not ruled out (Andrew et al. 1981).
Inhalation exposure of male rhesus monkeys and rabbits to 600 ppm ethyl-
benzene for 6 months produced degeneration of germinal epithelium in the
testes of one monkey and one rabbit (Wolf et al. 1956). Because there was
only one male per exposure group and because insufficient details on the study
protocol were provided, the usefulness of this study is limited. Based on
this limited evidence, no conclusions can be drawn concerning the possible
reproductive consequence of this effect in animals.
The highest NOAEL values for reproductive effects in each species for
intermediate duration are recorded in Table 2-1 and plotted in Figure 2-1.
2.2.1.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans or animals
following inhalation exposure to ethylbenzene.
2.2.1.8 Cancer
No association has been found between the occurrence of cancer in humans
and occupational exposure to ethylbenzene. Only one study was located that
monitored the condition of workers chronically exposed to ethylbenzene
(Bardodej and Cirek 1988). No cases of malignancy in workers monitored for
10 years were reported. However, no conclusions can be drawn from this study
because no quantitative exposure information was provided and the length of
time for which the workers were monitored for tumors was only 10 years, which
is insufficient for detecting long latency tumors in humans. No other studies
were found regarding cancer effects in humans exposed to ethylbenzene by
inhalation.
No studies were located regarding carcinogenic effects in animals
following inhalation exposure to ethylbenzene. A carcinogenicity bioassay was
begun in 1988 by the NTP (see Section 2.8.3. Ongoing Studies).
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28
2. HEALTH EFFECTS
2.2.2 Oral Exposure
Table 2-2 and Figure 2-2 describe the healch effects observed in animals
associated with oral exposure to ethylbenzene at acute exposure durations.
2.2.2.1 Death
No studies were located regarding death in humans following oral
exposure to ethylbenzene. However, lethality has been observed in laboratory
animals following ingestion of ethylbenzene. The oral LD50 for gavage
administration of ethylbenzene to rats was reported to be approximately
4,728 mg ethylbenzene/kg (Smyth et al. 1962). No short-term studies using
ethylbenzene administered in food or drinking water were located.
In another oral study with rats exposed to ethylbenzene, the LD50 was
reported to be approximately 3,500 mg/kg (Wolf et al. 1956). The usefulness
of this data, however, was questionable since the methodology by which this
value was derived was not reported.
An oral LDtr, value for rats is recorded in Table 2-2 and plotted in
Figure 2-2.
2.2.2.2 Systemic Effects
Respiratory Effects. No studies were located regarding respiratory
effects in humans following oral exposure to ethylbenzene. The only animal
study available presented no data on adverse respiratory effects in female
rats orally exposed to 13.6 to 680 mg ethylbenzene/kg by gavage for 6 months
(Wolf et al. 1956). The only parameters monitored were gross necropsy and
histopathological effects. The utility of this study is limited because of
poor protocol description and because the data on respiratory effects were not
presented.
Cardiovascular Effects. No studies were located regarding
cardiovascular effects in humans following oral exposure to ethylbenzene. In
a single study in animals, female rats were exposed to 13.6-680 mg
ethylbenzene/kg body weight via gavage for 6 months (Wolf et al. 1956). The
only parameter monitored was histopathology of the cardiac tissue. However,
these data were not presented in the study. Therefore, no conclusions can be
drawn.
Gastrointestinal Effects. No studies were located regarding
gastrointestinal effects in humans or animals following oral exposure to
ethylbenzene,
Hematological Effects. No studies were located regarding hematological
effects in humans following oral exposure to ethylbenzene. The only animal
-------
T»mg 2-2. Levels of Significant Exposure to Ethyl benzene - Oral
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key Species Route Duration Effect (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference
ACUTE EXPOSURE
Death
1 Rat (G) 1 d
lx/d
4728 (LD50) Smyth et al.
1962
d ¦ day; (G) " gavage; LD^q - lethal dose, 50Z kill; LOAEL "¦ lowest dose at which an adverse effect was noted; NOAEL =
highest dose at which no effect was noted.
-------
ACUTE
(<14 Days)
(mg/kg/day)
10,000 ,--
llr
sc
m
>
r~
H
m
n
H
1,000
Key
' ¦ LD50
The number next to each point corresponds to entries in Table 2-2.
FIGURE 2-2. Levels of Significant Exposure to Ethylbenzene - Oral
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31
2. HEALTH EFFECTS
study available reported no adverse hematological effects in female rats
orally exposed to 13.6 to 680 mg ethylbenzene/kg body weight by gavage for
6 months (Wolf et al. 1956). The only parameter monitored, however, was bone
marrow counts and total cell counts, thus other hematological effects might
have occurred but might not have been detected. Other weaknesses of this
study include a poor description of study protocol and general lack of study
details (e.g., hematological data).
Musculoskeletal Effects. No studies were located regarding
musculoskeletal effect in humans and animals following oral exposure to ethyl-
benzene.
Hepatic Effects. No studies were located regarding hepatic effects in
humans following oral exposure to ethylbenzene. In the only animal study
located, female rats were administered 13.6 to 680 mg ethylbenzene/kg by
gavage for 6 months (Wolf et al. 1956). The authors reported
histopathological changes characterized by cloudy swelling of parenchymal
cells of the liver in rats administered 408 mg/kg/day. No other hepatic
changes were reported. No conclusions could be drawn from these results
because of serious weaknesses in the methodology and reporting of the data
(e.g., no data on number of animal with hepatic effects). Furthermore, no
statistical analysis was performed.
Renal Effects. No studies were located regarding renal effects in
humans following oral exposure to ethylbenzene. The only animal study that
investigated renal effects following ethylbenzene exposure involved female
rats administered 13.6 to 680 mg ethylbenzene/kg body weight by gavage for
6 months (Wolf et al. 1956). Histopathological changes characterized as
cloudy swelling of the tubular epithelium in the kidney were observed at the
408-mg/kg/day dose level. No other renal changes were reported. As in
hepatic effects, no conclusions could be drawn from these results because of
serious weaknesses in the methodology and reporting of the data (e.g., no data
on the number of animals with renal effects). Furthermore, no statistical
analyses were performed.
Dermal/Ocular Effects. No studies were located regarding dermal/ocular
effects in humans or animals following oral exposure to ethylbenzene.
2.2.2.3 Immunological Effects
No studies were located regarding immunological effects in humans or
animals following oral exposure to ethylbenzene.
2.2.2.4 Neurological Effects
No studies were located regarding neurological effects in humans
following oral exposure to ethylbenzene.
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32
2. HEALTH EFFECTS
In an animal study that monitored behavioral changes, female rats were
administered ethylbenzene by gavage for 6 months at. concentrations ranging
from 13.6 to 680 mg ethylbenzene/kg body weight (Wolf et a] 1936). No data
on ethylbenzene-related behavioral changes were presented. No other
parameters were investigated. The utility of this study is limited because
the monitored behavioral changes were not reported, and the study protocol was
poorly described. Given these weaknesses, no conclusions on neurological
effects resulting from oral exposure to ethylbenzene can be drawn. No
additional studies in animals were located regarding neurological effects
following oral exposure to ethylbenzene.
2.2.2.5 Developmental Effects
No studies were located regarding developmental effects in humans and
animals following oral exposure to ethylbenzene.
2.2.2.6 Reproductive Effects
No studies were located regarding reproductive effects in humans
following oral exposure to ethylbenzene.
The only available reproduction study with animals indicates that acute
oral exposure to 500 or 1,000 mg/kg ethylbenzene decreases peripheral hormone
levels and may block or delay the estrus cycle in female rats during the
diestrus stage (Ungvary 1986). Decreased levels of hormones, including
luteinizing hormone, progesterone, and 17 ^-estradiol, were accompanied by
uterine changes, which consisted of increased stromal tissue with dense
collagen bundles and reduced lumen. No dose response was noted. The study
limitations include lack of rationale for dose selection, use of only two
doses, small number of test animals, and no statistical analysis of the data
2.2.2.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans or animals
following oral exposure to ethylbenzene.
2.2.2.8 Cancer
No studies were located regarding carcinogenic effects in human
following oral exposure to ethylbenzene.
The carcinogenicity of ethylbenzene by the oral route has been evaluated
in a chronic study in rats (Maltoni et al. 1985). A statistically significant
increase in total malignant tumors was reported in females and in combined
male and female groups exposed to 500 mg ethylbenzene/kg/day via gavage for
104 weeks and observed until after week 141. Evaluation of these results is
difficult because no data on specific tumor type were presented. Other
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33
2. HEALTH EFFECTS
limitations of this study include the fact that only one dose was tested, and
no information on survival was provided.
2.2.3 Dermal Exposure
2.2.3.1 Death
No studies were located regarding lethal effects in humans following
dermal exposure to ethylbenzene.
The dermal LD50 in rabbits exposed to liquid ethylbenzene was calculated
to be 15,415 mg ethylbenzene/kg body weight (Smyth et al. 1962). However, it
is difficult to apply precise quantities of volatile compounds to the skin.
No additional studies were located regarding death in animals following dermal
exposure to ethylbenzene.
2.2.3.2 Systemic Effects
No studies were located regarding respiratory, cardiovascular,
gastrointestinal, hematological, musculoskeletal, hepatic, or renal effects in
humans or animals after dermal exposure to ethylbenzene.
Dermal/Ocular Effects. No studies were located regarding systemic
effects in humans following dermal exposure to ethylbenzene.
Liquid ethylbenzene applied directly to the skin of an unspecified
number of rabbits caused irritation characterized by reddening, exfoliation,
and blistering (Wolf et al. 1956). Similarly, liquid ethylbenzene applied
directly to the eyes of rabbits for an unspecified duration caused slight
irritation of conjunctival membranes (Wolf et al. 1956) and slight corneal
injury (Smyth et al. 1962; Wolf et al. 1956).
No studies were located regarding the following health effects in humans
and animals after dermal exposure to ethylbenzene.
2.2.3.3
Immunological Effects
2.2.3.4
Neurological Effects
2.2.3.5
Developmental Effects
2.2.3.6
Reproductive Effects
2.2.3.7
Genotoxic Effects
2.2.3.8
Cancer
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34
2. HEALTH EFFECTS
2.3 TOXICOKINETICS
2.3.1 Absorption
2.3.1.1 Inhalation Exposure
Inhalation studies in humans demonstrate that ethylbenzene is rapidly
and efficiently absorbed via this route. Human volunteers exposed for 8 hours
to ethylbenzene at concentrations of 23 to 85 ppm were shown to retain 64% of
the inspired vapor, with only trace amounts detected in expirt-d air (Bardodej
and Bardodejova 1970). Another inhalation study that involved humans exposed
to similar levels of ethylbenzene demonstrated mean retention rates of 49%t
suggesting possible variability of absorption rates among individuals (Gromiec
and Piotrowski 1984).
Inhalation studies in animals exposed to ethylbenzene showed similar
results to those found in humans. , Harlan-Wistar rats rapidly absorbed
radiolabeled ethylbenzene during respiration, with a retention rate of 44%
(Chin et al. 1980b). This absorption value may have been slightly
overestimated, however, because possible contributions from dermal exposure
were not addressed. These studies did not correlate measured toxic effects
with kinetic observations. No studies describing factors affecting absorption
of ethylbenzene following inhalation exposure were available.
2.3.1.2 Oral Exposure
No studies were located regarding the absorption of ethylbenzene in
humans following oral exposure. Studies in animals, however, indicate that
ethylbenzene is quickly and effectively absorbed by this route. Recovery of
ethylbenzene metabolites in the urine of rabbits administered a single dose of
593 mg ethylbenzene/kg was between 72% and 92% of the administered dose
24 hours following exposure (El Masry et al. 1956). Similarly, 84% of the
radioactivity from a single oral dose of 30 mg ethylbenzene/kg administered to
rats was recovered within 48 hours (Climie et al. 1983).
2.3.1.3 Dermal Exposure
Studies in humans dermally exposed to liquid ethylbenzene demonstrate
rapid absorption through the skin, but absorption of ethylbenzene vapors
through the skin appears to be minimal. Absorption rates of 24-33 mg/cm2/hr
and 0.11-0.23 mg/cm2/hr have been measured for male subjects exposed to liquid
ethylbenzene and ethylbenzene from aqueous solutions, respectively (Gromiec
and Piotrowski 1984). The average amount of ethylbenzene absorbed after the
volunteers immersed one hand for up to 2 hours in an aqueous solution of 112
or 156 mg/L solution was 39.2 and 70.7 mg ethylbenzene, respectively. These
results indicate that skin absorption could be a major route of uptake of
liquid ethylbenzene or ethylbenzene in water. In contrast, ethylbenzene
metabolite levels in urine following dermal exposure of human volunteers to
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35
2. HEALTH EFFECTS
ethylbenzene vapors did not differ from values taken prior to exposure,
indicating minimal, if any, dermal absorption of ethylbenzene vapors (Gromiec
and Piotrowski 1984).
The limited animal data on dermal absorption of liquid ethylbenzene are
inconclusive. An unspecified number of rabbits dermally exposed to liquid
ethylbenzene demonstrated no apparent absorption through the skin (Wolf et al.
1956). However, this study is of limited value because absorption was
measured only by overt signs of acute toxicity (e.g., gross appearance,
behavior, and changes in body weight). The penetration rates of liquid
ethylbenzene have been examined in excised rat skin (Tsuruta 1982). The
penetration rate of ethylbenzene following 3-, 4-, and 5-hour exposure
durations in rat skin were calculated to be 0.002, 0.003, and 0.004 mg/cm2/hr,
which is substantially lower than the rate of dermal absorption determined for
humans. This might be attributed to differences between in vitro and in vivo
testing and/or differences in rat versus human skin.
2.3.2 Distribution
2.3.2.1 Inhalation Exposure
In humans exposed for 2 hours to a mixture of industrial xylene
containing 40.4% ethylbenzene, the estimated solvent retention in adipose
tissue was 5% of the total uptake (Engstrom and Bjurstrom 1978). Since there
was no indication of differences in turnover rates of chemicals within the
mixture, it is likely that the retention of ethylbenzene in adipose tissue was
approximately 2% of the total uptake. No studies were located concerning the
distribution of ethylbenzene in humans following exposure to ethylbenzene
alone.
In rats, the concentrations of ethylbenzene in perirenal adipose tissue
were reported to increase, although not linearly, with increasing
concentrations of ethylbenzene (Engstrom et al. 1985) and in a mixture of
solvent vapors containing ethylbenzene (Elovaara et al. 1982). The less-than-
linear increase of ethylbenzene in adipose tissue with increasing dose was
partially attributed to the induction of drug-metabolizing enzymes occurring
with increasing exposure concentrations, altered blood flow to adipose tissue,
changes in lung excretion, and changes in the distribution of ethylbenzene in
different tissues. Ethylbenzene was shown to be efficiently distributed
throughout the body in rats following inhalation exposure to radiolabeled
ethylbenzene (Chin et al. 1980b). The highest amounts of radioactivity in
tissues 42 hours after exposure to 230 ppm ethylbenzene for 6 hours were found
in the carcass, liver, and gastrointestinal tract, with lower amounts detected
in the adipose tissue.
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36
2. HEALTH EFFECTS
2.3.2.2 Oral Exposure
No studies were located regarding distribution of ethylbenzene in humans
following oral exposure. Data on the distribution of radiolabeled
ethylbenzene hydroperoxide 1, 3, and 8 days after oral administration to rats
were provided by Climie et al. (1983). Tissue residues were highest in the
intestine, liver, kidney, and fat (0.53, 0.20, 0.21, and 0.27 Mg/g tissue,
respectively) 1 day after exposure and decreased to trace amounts (less than
0.05 Mg/g tissue) in all tissues monitored (carcass, skin, muscle, and blood)
8 days after exposure. However, differences in the physical and chemical
properties of ethylbenzene and ethylbenzene hydroperoxide may affect
distribution. No distribution data on radiolabeled ethylbenzene were
provided.
2.3.2.3 Dermal Exposure
No studies were located regarding distribution in humans or animals
following dermal exposure to ethylbenzene.
2.3.3 Metabolism
The metabolism of ethylbenzene has been studied in humans and other
mammalian species. The data demonstrate that ethylbenzene rapidly undergoes a
complex series of biotransformations from which numerous metabolites have been
isolated. The major urinary metabolites have been traced to hepatic
metabolism (Kiese and Lenk 1974; Sullivan et al. 1976), and evidence suggests
that the adrenal cortex may be a major site of extra-hepatic ethylbenzene
metabolism (Greiner et al. 1976). Figure 2-3 summarizes the proposed
metabolic pathway for ethylbenzene in humans (Engstrom et al. 1984).
Comparisons of in vitro data with data from intact animals indicate that liver
microsomal enzymes may participate in ethylbenzene hydroxylation (McMahon and
Sullivan 1966; McMahon et al. 1969). No significant differences in metabolism
between oral and inhalation routes were reported in humans or animals. The
metabolism of ethylbenzene has been found to vary with species, sex, and
nutritional status. These differences are described below.
In humans exposed via inhalation, the major metabolites of ethylbenzene
are mandelic acid (approximately 70%) and phenylglyoxylic acid (approximately
25%) (Bardodej and Bardejova 1970; Engstrom et al. 1984). /Based on data from
human, animal, and in vitro studies, the metabolic pathways for ethylbenzene
in humans was proposed (Engstrom et al. 1984). This pathway is shown in
Figure 2-3. / Evidence indicates that the initial step in this metabolic
pathway is oxidation of the side chain of ethylbenzene to produce
1-phenylethanol. Microsomal preparations from rat liver have shown that the
oxidation of ethylbenzene proceeds/with the incorporation of atmospheric
oxygen, as opposed to oxygen from water molecules (McMahon et al. 1969).
1-Phenylethano1 is conjugated to glucuronide, which then is both excreted and
converted to subsequent metabolites. Hydrogenation of 1-phenylethanol yields
-------
OH
OH
C — COOH
Mandelicacid
1 - Phenyl-1,2-ethanediol
CJ-Hydroxyacelophanona
^CH,
Hydro«yacatophanon*
OH
Phenylglyoxylic acid
xr ^
p-Hydroxyaoetophenon*
MAWLY
QUUCURONIDES
OH
"CM,
OH
QLUCUAONIDES
SULFATES
MANLY
OLUCUROMOES
CH.CH,
URINE
GLUCURONIC ES
SULFATES
OH
Source: Engstrometal. 1984.
FIGURE 2-3. Metabolic Scheme for Ethylbenzene in Humans
-------
38
2. HEALTH EFFECTS
acetophenone, which is both excreted in the urine as a minor metabolite and
further transformed. Continued oxidation of the side chain leads to the
sequential formation of w-hydroxyacetophenone, 1-phenyl-1,2-ethanediol,
mandelic acid, and phenylglyoxylic acid. Minor pathways (e.g., ring
oxidation) include glucuronide and sulfate conjugation with intermediates to
form glucuronides and sulfates that are excreted in the urine. Analysis of
urine from humans exposed via the inhalation route to ethylbenzene showed that
approximately 70% and 25% of the retained dose of ethylbenzene is excreted as
mandelic acid and phenylglyoxylic acid, respectively (Bardodej and Bardodejova
1970; Engstrom et al. 1984). Additional metabolites detected in human urine
include 1-phenylethanol (4%), E'hydroxyacetophenone (2.6%), m-hydroxyace to-
phenone (1.6%), and trace amounts of 1-phenyl-l,2-ethanediol, acetophenone,
w-hydroxyacetophenone, and 4-ethylphenol. Following dermal exposure of
humans, however, excretion of mandelic acid was shown to be only 3.5% of the
absorbed dose (Dutkiewicz and Tyras 1967), which may indicate differences in
the metabolic fate between inhalation and dermal exposure routes. However,
the small percentage of absorbed dose accounted for limits the interpretation.
No animal data were located which could confirm these metabolic differences
following dermal exposure. Generally, ethylbenzene metabolites and
intermediates are thought to be only slightly toxic (Bardodej and Bardodejova
1970).
Qualitative and quantitative differences in the biotransformation of
ethylbenzene in animals as compared to humans have been reported^(Bakke and
Scheline 1970; El Masry et al. 1956; Engstrom 1984; Engstrom et al. 1985;
Climie et al. 1983; Smith et al. 1954a, 1954b; Sollenberg 1985). /The major
metabolites of ethylbenzene differ from species to species, and different
percentages of the metabolites are seen in different species. The principal
metabolic pathway in rats is believed to begin with oxidation of the side
chain as in humans (Climie et al. 1983; Engstrom 1984; Engstrom et al. 1985;
Smith et al. 1954a). In rats exposed by inhalation to ethylbenzene, the major
metabolites were identified as hippuric and benzoic acids (approximately 38%),
1-phenylethanol (approximately 25%), and mandelic acid (approximately
15%-23%), with phenylglyoxylic acid making up only 10% of the metabolites
(Climie et al. 1983; Engstrom 1984; Engstrom et al. 1985). Both in vivo
studies using rats and in vitro studies using liver microsomes showed that
2-hydroxyethylbenzene and 4-hydrooxyethylbenzene were also produced from
ethylbenzene, perhaps by isomerization of corresponding arene oxides (Bakke
and Scheline 1970; Kaubisch et al. 1972). The level of ethylbenzene exposure
was shown to affect the metabolic pattern. -This was thought to be due either
to selective enzymatic induction in the biotransformation of ethylbenzene or
to delayed excretion of certain metabolites with increasing doses.
Further clarification of ethylbenzene metabolic pathways was provided by
Sullivan et al. (1976). Using intraperitoneally dosed rats, the authors
demonstrated that the conversion of 1-phenylethanol to mandelic acid initially
involves dehydrogenation to acetophenone. Acetophenone was considered to be
the precursor of mandelic acid, benzoylformic acid, and benzoic acid.
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39
2. HEALTH EFFECTS
Rabbits given an oral dose of ethylbenzene showed the major metabolic
pathway to be hydroxylation of the a-carbon to 1-phenylethanol, which is
oxidized further to a number of intermediates and metabolites (El Masry et al.
1956; Smith et al. 1954a). Many of these intermediates are subsequently
conjugated to glucuronides and sulfates and excreted. In rabbits, the most
important metabolite is hippuric acid, which is probably formed by oxidative
decarboxylation of phenylglyoxylic acid (Bardodej and Bardodejova 1970).
Oxidation of the methyl group of ethylbenzene was also shown to occur, as
evidenced by the presence of phenaceturic acid in the urine. A slight
increase in the excretion of thioether suggests that glutathione conjugation
may also play a minor role.
The nutritional status of animals was demonstrated to have a marked
effect on ethylbenzene metabolism in rats (Nakajima and Sato 1979). The in
vitro metabolic activity of liver microsomal enzymes on ethylbenzene was shown
to be significantly enhanced in fasted rats despite a marked loss of liver
weight. No significant increases in the microsomal protein and cytochrome
P-450 contents were detected in fasted rats compared with fed rats. In
addition, the metabolic rate in fasted males was significantly higher than in
fasted females, but the difference in rates decreased following food
deprivation for 3 days. These results suggest possible sex differences in the
rate of ethylbenzene metabolism. However, it is not known if such differences
exist in the normally fed rats.
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
Excretion of ethylbenzene has been studied in humans and in a number of
animal species. Ethylbenzene has been shown to be rapidly metabolized and
then eliminated from the body, primarily as urinary metabolites. The major
metabolic products have been previously described in Section 2.3.3.
Elimination of ethylbenzene has been studied in human volunteers exposed
by inhalation (Bardodej and Bardodejova 1970; Dutkiewicz and Tyras 1967;
Engstrom and Bjurstrom 1978; Gromiec and Piotrowski 1984; Yamasaki 1984). The
elimination of the ethylbenzene metabolite, mandelic acid, was reported to be
rapid, with the acid detected in the first urine sample following the
initiation of an 8-hour inhalation exposure to 0, 4, 8, 18, 35, and 46 ppm
ethylbenzene (Gromiec and Piotrowski 1984). Elimination of mandelic acid was
reported to be biphasic, with half-lives of 3.1 hours for the rapid phase and
25 hours for the slow phase (Gromeic and Piotrowski 1984). During the 8-hour
exposure, 23% of the retained ethylbenzene was eliminated in the urine, and
14 hours following termination of exposure an additional 44% of the retained
ethylbenzene was eliminated. The highest excretion rate of urinary
metabolites in huunans exposed to ethylbenzene by inhalation occurred
6-10 hours after the beginning of exposure (Gromeic and Piotrowski 1984;
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40
2. HEALTH EFFECTS
Yamasaki 1984). The metabolic efficiency was reported to be independent of
the exposure dose.
In animals, elimination of ethylbenzene metabolites following inhalation
exposure is rapid and occurs primarily via urinary metabolites (Chin et al.
1980a, 1980b; Engstrom 1984; Engstrom et al. 1985) and to a much lesser degree
via the feces and expired carbon dioxide (Chin et al. 1980b). Rats exposed to
230 ppm radiolabeled ethylbenzene for 6 hours via inhalation excreted
virtually all of the radioactivity within 24 hours after the onset of exposure
(Chin et al. 1980a, 1980b). Ninety-one percent of the radioactivity was
recovered, primarily in the form of urinary metabolites. In a similar
inhalation experiment using rats exposed to 300 or 600 ppm, urinary excretion
was reported to be 83% of the absorbed dose within 48 hours after the onset of
exposure, with 13% eliminated during the first 6 hours of exposure (Engstrom
1984) .
Quantitative differences in the percentages of metabolites excreted in
the urine between species were also reported by Chin et al. (1980a). in this
report, urinary metabolites in dogs and rats exposed to ethylbenzene by
inhalation were studied. Although similarities in the types of metabolites
recovered following inhalation exposure were reported, quantitative
differences, albeit minor ones, were noted in the ratio of metabolites present
in the urine. These results were attributed to differences in metabolism
between dogs and rats.
2.3.4.2 Oral Exposure
No studies were located regarding the excretion of ethylbenzene
metabolites in humans following oral exposure to ethylbenzene.
Elimination of ethylbenzene and its metabolites in animals has been
shown to be similar to that following inhalation exposure. Female rats
administered a single oral dose of 30 mg radiolabeled ethylbenzene/kg body
weight showed very rapid elimination, mostly in the urine (Climie et al.
1983). Eighty-two percent of the radioactivity was detected in the urine,
while 1.5% was detected in the feces. The major metabolites were mandelic
acid (23%) and hippuric acid (34%), with 1-phenylethyl glucuronide detected as
a minor metabolite. Relatively minor metabolites (e.g., Ł-ethylphenol,
2-phenylethanol, 1-phenylethanol) were shown to be excreted in the urine of
rats exposed to a single oral dose of 100 mg/kg (Bakke and Scheline 1970). No
data on the major metabolites were provided in this study.
In a similar study in which male rats were given single oral doses of
350 mg ethylbenzene/kg body weight, the excretion of mandelic acid and
phenylglyoxylic acid was detected in the first urine sample after exposures.
Peak concentration was reached within 15-19 hours, and ethylbenzene was
virtually eliminated 48 hours following the onset of exposure (Sollenberg
1985).
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41
2. HEALTH EFFECTS
As in inhalation experiments, quantitative and qualitative differences
between species were shown to exist in the percentages of metabolites excreted
in the urine. Rabbits orally exposed to ethylbenzene excreted large amounts
of glucuronide conjugates in the urine (El Masry et al. 1956; Smith et al.
1954a, 1954b) instead of mandelic acid and hippuric acid, which are the major
metabolites in rats (see above). Glucuronide conjugates accounted for 32% of
the administered dose, with mandelic acid making up only 2% of the
administered dose (El Masry et al. 1956). These results were confirmed in a
study by Smith et al. (1954a, 1954b), who detected 32% of a single oral dose
of ethylbenzene (433 mg/kg) administered to rabbits as glucuronide conjugates
excreted in the urine.
2.3.4.3 Dermal Exposure
In humans, the pattern of excretion of ethylbenzene metabolite following
dermal exposure has been shown to differ significantly from the pattern in
which humans have been exposed by inhalation. Excretion of mandelic acid in
humans dermally exposed to ethylbenzene was only 4.6% of the absorbed
ethylbenzene (Dutkiewicz and Tyras 1967). Interpretation is difficult due to
the small percentage of absorbed dose accounted for. No ethylbenzene was
reported to be excreted in exhaled air. No further details on the excretion
patterns were provided.
No studies were located regarding the excretion of ethylbenzene
metabolites in animals following dermal exposure.
2.3.4.4 Other Routes of Exposure
Rats intraperitoneally exposed to a single dose of 100 mg ethyl-
benzene/kg excreted low levels of mandelic acid in the urine (Sullivan et al.
1976). No quantitative values were provided. A similar study in which
rabbits were intraperitoneally injected with a single dose of 250 mg ethyl-
benzene/kg body weight was conducted by Kiese and Lenk (1974). This study
showed that between 1% and 10% of the dose was excreted as 1-phenylethanol in
the urine and less than 1% was excreted in the urine as w-hydroxyacetophenol,
E-hydroxyacetophenol, and m-hydroxyacetophenol,
2.4 RELEVANCE TO PUBLIC HEALTH
Evidence from the reviewed literature has shown that ethylbenzene is
toxic to both humans and laboratory animals. Clinical observations in humans
and observations in animals indicate that the primary symptoms resulting from
acute exposure to ethylbenzene are manifested as neurological and respiratory
depression and eye and throat irritation. Several studies suggest that target
organs of ethylbenzene toxicity, identified in animals but not in humans, may
be the liver, kidney, and hematopoietic system. These results, however, are
inconclusive (particularly regarding dose-response data) given the weaknesses
present in many of these studies.
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2. HEALTH EFFECTS
Ethylbenzene is widely distributed in the environment. The exposure
route of most concern to the general public would be low-level inhalation
exposure over long periods of time. This is due to the direct release of
ethylbenzene into the air by the burning of fossil fuels or industrial
processes and partitioning into the air from other media (e.g., soil, surface
water) . This partitioning of ethylbenzene into the air would play an
important role in exposure to populations living near hazardous Waste sites
In addition to inhalation exposure, ingestion of ethylbenzene may also be a
cause of concern because trace amounts have been found in many open water
supplies. This concern would be greater for those populations living near
hazardous waste sites or gasoline spill sites in which water supplies have
been contaminated
Death. No deaths have been reported in humans following ethylbenzene
exposure, but death has occurred in laboratory animals following acute
exposure to high levels of ethylbenzene administered via the inhalation, oral
and dermal routes. The concentrations o.f ethylbenzene necessary to cause
death in animals have been shown to be relatively high (1,200-13,367 ppm,
inhalation exposure; 4,728 mg/kg/day, oral exposure; 15,415 mg ethylbenzene/kg
body weight, dermal exposure). Given this information, death in humans
resulting from chronic low-level exposure to ethylbenzene is unlikely.
Systemic Effects. Moderate upper respiratory irritation accompanied by
chest constriction has been reported in humans exposed by inhalation to
ethylbenzene (Yant et al. 1930). Animal studies support these findings and
show more severe effects with increased doses (De Ceaurriz et al. 1981;
Nielsen and Alarie 1982). The NTP study (1988c) indicates that lung
inflammation may result from ethylbenzene exposure, but infection could not be
ruled out as a causal factor. The available data on adverse respiratory
effects associated with ethylbenzene exposure in animals, coupled with the
limited data available on humans, suggest that severe respiratory effects in
humans could result following inhalation exposure to high doses of
ethylbenzene.
Studies using several species of laboratory animals exposed to
ethylbenzene indicate that of the species tested only rats are susceptible to
ethylbenzene-induced hematological effects following inhalation exposure
(i.e., increased platelet counts and total leukocyte counts) (Cragg et
al. 1989). Because of these observed interspecies differences following
inhalation exposure and a lack of data following oral and dermal exposures it
is unknown whether hematological effects might occur in humans following
exposure to ethylbenzene.
No hepatotoxic effects in humans have been reported in the available
literature. Inhalation studies in animals suggest that biochemical changes
and histopathological alterations in the liver may be related to dose and
duration of exposure to ethylbenzene (Cragg et al. 1989; Elovaara et al. 1985-
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43
2. HEALTH EFFECTS
Toftgard and Nilsen 1982). These biochemical changes are accompanied by
hepatic hypertrophy, with increased microsomal enzyme activity. These results
are supported by an intraperitoneal study in rats that demonstrated marked
increases in liver enzyme activity (Pyykko et al. 1987). Similar hepatic
alterations in mice and rats exposed orally and by inhalation suggest that
these effects might occur in humans, but no definitive conclusions can be
drawn given the weaknesses of some of the studies, as outlined earlier {Cragg
et al. 1989; Elovaara et al. 1985; Toftgard and Nilsen 1982; Wolf et
al. 1956). Despite these weaknesses, the data suggest that humans exposed to
ethylbenzene in high concentrations, particularly individuals with compromised
liver function, may be at increased risk for ethylbenzene- induced hepatic
effects
Renal effects, manifested as enzyme changes, increases in organ weight,
and tubular swelling, have been observed in rats and mice (Biodynamics Inc.
1986; Wolf et al. 1956). These studies suggest that renal effects may occur
in humans exposed to high doses of ethylbenzene. However, significant
weaknesses of many of these studies prevent any conclusions regarding
relevance to public health from being drawn.
Neurological Effects. The principal effect in humans acutely exposed
via inhalation to high concentrations of ethylbenzene has been central nervous
system toxicity (dizziness, vertigo) (Yant et al. 1930). Complete recovery
has been shown to occur following acute exposure. Neurochemical alterations
were observed in animal studies in which dopamine depletion in the brain
following exposure to high concentrations of ethylbenzene was reported. It
was suggested that changes in the dopamine levels and turnover might disturb
catecholamine neurotransmission in the brain leading to altered brain function
(Andersson et al. 1981; Mutti et al. 1988). However, data are available that
show dopamine turnover to be increased, but brain tissue levels remaining
constant in all but one of the regions of the brain examined (Andersson et
al. 1981). Given the available human and supporting animal data, there is
considerable likelihood that human populations acutely exposed to high
concentrations of ethylbenzene are at risk for developing neurological
effects. The effects of long-term exposure of humans to ethylbenzene are
unknown.
Developmental Effects. No reports of developmental toxicity following
exposure to ethylbenzene in humans were located. The available information
from animal studies indicates that inhalation exposure of pregnant rats to
ethylbenzene can produce fetotoxic effects at doses that also induce maternal
toxicity (i.e., increased liver, kidney, and spleen weights) (Andrew et al.
1981). No developmental effects were seen in rabbits exposed to similar
levels of ethylbenzene (Andrew et al. 1981). Because of observed interspecies
differences, the relevance of these findings with regard to developmental
effects in humans cannot be ascertained.
-------
¦) . HKM.Til KFFKCTS
Reproductive Effects. No studies on the reproduct ive et(ects in humans
™ rn prhvlberat'W were found. Oval administration of
following «¦»•<«•« „i u„. |„ l.malo r.« (Ungvary
ethylbenzene resu weaknesses (e.p,. . smalt ii'imlK i' ' Concentrations of
100 mg/L in mous ymp .(J r0 t.00 mg/E. No dose-response was reported.
ethylbenzene used ranged from 10 ^ % mc P01), lnc„J. ln
Ethylbenzene induced a margin . ^ ^ ^ ^ 6
which was^lso toxic to the cells (Norppa and V.lnio 1983). The relevance of
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TABI.K 2-3. Genotozicity of Ethylbenzene In Vitro
Results
With Without
End Point Species (Test System) Activation Activation Reference
Frokaryotic organisms:
Gene mutation
Rn1nwm«)lla typhi murium (plate-incorporation assay;
strains TA98, TA100, TA1535, TA1537, TA1538)
S. tvphirouriuia (plate-incorporation assay; strains
TA97, TA98, TA100, TA1535)
Dean et al. 1985"; Florin et
al. 1980b; Nestmann et
al. 1980C
NTP 1986d
Dean et al. 1985®
Eukaryotic organisms;
Gene mutation
Saccharoroyces cerevisiae JD1 gene conversion assay
S. cerevisiae D7, XV185-14C
KD
Dean et al. 1985
Nestmann and Lee 1983
Mammalian cells:
Gene mutation
Chromosome damage
Chromosomal aberration/
sister-chromatid
exchange
Sister-chromatid exchange
Mouse lymphoma cells
Rat liver (RL4) epithelial type cells/chromosome
assay
Chinese hamster ovary cells
Human lymphocytes
ND
ND
Concentrations of ethylbenzene tested
Concentrations of ethylbeniene tested
^Concentrations of ethylbenzene tested
^Concentrations of ethylbenzene tested
•Weakly positive.
McGregor et al. 1988
Dean et al. 1985
NTP 1986
Norppa and Vainio 1983
0, 0.2, 2, 20, 500, 2,000 /4g/plate {>991 pure).
0, 3, 31, 318, or 3,184 /ig/plate (0, 0.03, 0.3, 3, or 30 /unole/plate) .
Up to 0.4 mg/plate, a concentration causing lethality.
0, 10, 33, 110, 333, 666, or 1,000 /ig/plate.
3C
>
r
H
tc
ro
n
Ci
H
w
Ln
negative; ND = no data; + = positive.
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46
2. HEALTH KFFKCTS
these findings with regard to genotoxic effects of" ethylbenzene in humans is
iot known.
The only in vivo study located which invest igated the Reno toxic effects
of ethylbenzene reported no dose - dependent increase in the frequency of
micronucleated polychromatic erythrocytes (Mohtashamipur et. al. 1985) This
study is limited by inadequate sampling time. In addition, the type of
clastogenic effect occurring cannot be defined.
In summary, genotoxicity studies on ethylbonzenc have provided negative
results in a variety of in vitro assays using numerous prokaryotic organisms
S. cerevisiae. and Chinese hamster ovary eel is and rat liver epithelial cells
and in an in vivo assay using mouse bone marrow cells. it has, however
caused a mutagenic effect in mouse lymphoma cells and has been shown to induce
a marginal yet significant increase in SCK in human lymphocytes, Although the
majority of the data suggest that ethylbenzene is not mutagenic in most
systems, the two studies that did show positive results suggest that
ethylbenzene may cause an increase potential for genotoxicity in humans
Cancer. No association between increased cancer incidence in humans and
exposure to ethylbenzene has been reported in current literature. The only
chronic bioassay located in the literature showed a significant increase in
tumors in rats orally exposed to ethylbenzene (MaLtoni et al. 1985) These
results however are inconclusive, given the weaknesses of the study (e g
only one dose was tested and no survival data were provided). Therefore 'the
relevance of ethylbenzene induced carcinogenicity to public health cannot be
ascertained.
In the 1989 Integrated Risk Information System (IRIS 1989) database EPA
has classified ethylbenzene as a Group D agent (Not Classifiable as to
Carcinogenicity). This classification applies to those chemical agents for
which there is inadequate evidence of carcinogenicity in animals. No potency
factor (qx*) or other quantitative estimate of carcinogenicity has been
developed by EPA for ethylbenzene.
2.5 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)
A biomarker of exposure is a xenobiotic substance or its metabolite(s)
or the product of an interaction between a xenobiotic agent and some target'
molecule or cell that is measured within a compartment of an organism (NAS/NRC
1989). The preferred biomarkers of exposure are generally the substance
itself or substance-specific metabolites in readily obtainable body fluid or
excreta. However, several factors can confound the use and interpretation of
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2. HEALTH EFFECTS
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 (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 biologic 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 ethylbenzene are discussed in Section 2.5.1.
Biomarkers of effect are defined as any measurable biochemical,
physiological, 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 often not substance specific.
They also may not be directly adverse, but can indicate potential health
impairment (e.g., DNA adducts). Biomarkers of effects caused by ethylbenzene
are discussed in Section 2.5.2.
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. It can be an intrinsic genetic or other characteristic
or a preexisting disease that results in an increase in absorbed dose,
biologically effective dose, or target tissue response. If biomarkers of
susceptibility exist, they are discussed in Section 2.7, "POPULATIONS THAT ARE
UNUSUALLY SUSCEPTIBLE."
2.5.1 Biomarkers Used to Identify or Quantify Exposure to Ethylbenzene
Information on ethylbenzene concentrations in human tissue or fluids is
available. Exposure to ethylbenzene can be determined by the detection of
mandelic acid and phenylglyoxylic acid in urine or by direct detection of
ethylbenzene in whole human blood. The only available study that associated
levels of ethylbenzene in human tissue and fluids with health effects was
conducted by Angerer and Wulf (1985). In this study, specimens of whole blood
from 35 workers chronically exposed to organic solvents containing
ethylbenzene were analyzed. The mean ethylbenzene concentrations detected
from personal air monitoring was 4.0 ppm, and the corresponding mean
concentration of ethylbenzene in the blood samples was 61.4 jig/L. Significant
correlations between the concentrations of ethylbenzene In aLr and blood and
leukocyte counts, were reported. However, blood lead levels could have been a
confounding factor.
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48
2. HEALTH EFFECTS
The 1982 National Human Adipose Tissue Survey conducted by EPA measured
ethylbenzene in 96% of the 46 composite samples analyzed for volatile organic
ompounds (Stanley 1986). A wet tissue concentration range of not detected
(detection limit=2 ng/g) to 280 ng/g was reported, but an average
concentration was not provided.
Numerous studies indicate that environmental exposures to ethylbenzene
can result in detectable levels in human tissues (Antoine et al. 1986; Cramer
et al. 1988; Pellizzari et al. 1982; Wolff 1976; Wolff et al. 1977) and in
expired air (Conkle et al. 1975; Engstrom and Bjurstrom 1978; Wallace et
al. 1984). Analysis of blood specimens from a test population of 250 patients
(Antoine et al. 1986) and composite samples obtained from blood donations of
laboratory personnel with potentially low-level exposure (Cramer et al. 1988)
indicated ethylbenzene concentrations in the blood to range from below
detection limits to 59 ppb. Similarly, ethylbenzene was detected in 8 of 12
milk samples from lactating women living in various urban areas of the United
States with high probability of emissions of pollutants (Pellizzari et
al. 1982). Subcutaneous fat samples taken from individuals exposed to an
average of 1-3 ppm ethylbenzene in the workplace contained ethylbenzene levels
as high as 0.7 ppm (Wolff 1976; Wolff et al. 1977).
Studies examining the correlation of ethylbenzene concentrations in
ambient air with concentrations measured in expired or alveolar air have also
been conducted (Conkle et al. 1975; Engstrom and Bjurstrom 1978; Wallace et
al. 1984). Ethylbenzene concentrations in breath samples were reported to
correlate well with ethylbenzene concentrations in indoor samples taken with
personal air monitors (Wallace et al. 1984). A correlation was also found
between ethylbenzene uptake and ethylbenzene concentrations in alveolar air
during, but not after, inhalation exposure in human volunteers (Engstrom and
Bjurstrom 1978). Rates of ethylbenzene expiration measured in volunteers with
no known previous exposure to ethylbenzene ranged from 0.78 pg/hr to
14.0 fJg/hr, with higher rates detected in smokers than in nonsmokers (Conkle
et al. 1975).
2.5.2 Biomarkers Used to Characterize Effects Caused by Ethylbenzene
No specific biomarkers of effect for ethylbenzene were identified. Most
of the information on humans is from case reports in which the effects are
general and non-specific, such as eye and throat irritation and chest
constriction (Yant et al. 1930).
There is one study that indicates that the average number of lymphocytes
and hemoglobin levels are decreased following exposure to ethylbenzene
(Angerer and Wulf 1985), but these data were not substantiated in a long-term
study on occupationally exposed workers (Bardodej and Cirek 1988). Given the
nonspecificity of these end points and the presence of blood lead levels that
could confound the results (Angerer and Wulf 1985), it would be difficult to
correlate changes in these parameters with exposure to ethylbenzene.
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2. HEALTH EFFECTS
2.6 INTERACTIONS WITH OTHER CHEMICALS
Interaction of ethylbenzene with carbon monoxide, phenobarbital, and
m-xylene have been described in numerous studies. Carbon monoxide has been
shown to inhibit the in vitro hydroxylation of ethylbenzene when the ratio of
carbon monoxide to atmospheric oxygen is 2 to 1 (Maylin et al. 1973).
Similarly, simultaneous exposure of rats to ethylbenzene and xylenes has
produced inhibitory effects on ethylbenzene metabolism as evidenced by a
decreased excretion rate of urinary ethylbenzene metabolites (Angerer and
Lehnert 1979; Elovaara et al. 1984; Engstrom et al. 1984). Similar metabolic
inhibitory effects were seen in female rats intraperitoneally pretreated with
ethanol before inhalation exposure to ethylbenzene as evidenced by
significantly increased ethylbenzene blood levels compared with animals
pretreated with physiological saline (Romer et al. 1986). The authors
suggested that increased central nervous system disturbances (e.g.,
depression) may be expected following concurrent exposure to ethylbenzene and
ethanol. Conversely, pretreatment with phenobarbital has been shown to
increase the rate of ethylbenzene oxidation both in vitro (Maylin et al. 1973;
McMahon and Sullivan 1966) and in vivo in rats (McMahon and Sullivan 1966).
Though no further studies were located that demonstrate specific
interactions of ethylbenzene with other chemicals, a number of substances are
known to influence the metabolism of many xenobiotics. For instance, the
metabolism of ethylbenzene can be markedly altered by inhibitors (e.g.,
SKF 525A) and inducers (e.g., phenobarbital, described above) of drug-
metabolizing enzymes (Gillette et al. 1974) and by the availability of
detoxification agents (e.g., glucuronic acid or sulfates) that bind ethyl-
benzene metabolites and subsequently are excreted from the body.
Mono-oxygenases (MOs) are a class of enzymes involved in the detoxification of
xenobiotics, including ethylbenzene. Substances that induce MO enzymes may
decrease the toxicity of ethylbenzene by increasing the rate of production of
its less toxic metabolites. Conversely, MO enzyme inhibitors would be
expected to have the opposite effect. Compounds that affect glucuronic acid
availability could also affect the excretion rate of ethylbenzene metabolites.
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
Even though ethylbenzene is not known to bioaccumulate, human and animal
studies suggest that several factors can contribute to an increased
probability of adverse health effects following ethylbenzene exposure
(Mackinson et al. 1978). Exposure of individuals with impaired pulmonary
function to ethylbenzene in air has been shown to exacerbate symptoms because
of ethylbenzene's irritant properties. Because ethylbenzene is detoxified
primarily in the liver and excreted by the kidney, individuals with liver or
kidney disease might be more susceptible to ethylbenzene toxicity, as would
persons taking medications or other drugs (e.g., alcohol) that are known
hepatotoxins. Persons with dermatitis or other skin diseases may be at
greater risk, since ethylbenzene is a defatting agent and may aggravate these
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2. HEALTH EFFECTS
symptoms. Because of immature enzyme detoxification systems, young children
ind fetuses are at increased risk since they are less able to detoxify and
xcrete xenobiotics such as ethylbenzene (Calabrese 19/8). Although no
specific developmental toxicity data are available from human studies,
inhalation experiments with animals suggest that ethylbenzene may cause
fetotoxicity as well as maternal toxicity (Andrew et al. 1981; Ungvary and
Tatrai 1985). Therefore, adverse health effects might occur in pregnant women
exposed to ethylbenzene.
In summary, groups that might be more susceptible to the toxic effects
of ethylbenzene are individuals with diseases of the respiratory system,
liver, kidney, or skin, young children, fetuses, pregnant, women, and
individuals taking certain medications such as hepatotoxic medications or
drugs.
2.8 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA 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 ethylbenzene 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 ethylbenzene.
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 or eliminate
the uncertainties of human health assessment. In the future, the identified
data needs will be evaluated and prioritized, and a substance - specific
research agenda will be proposed.
2.8.1 Existing Information on Health Effects of Ethylbenzene
The existing data on health effects of inhalation, oral, and dermal
exposure of humans and animals to ethylbenzene are summarized in Figure 2-4.
The purpose of this figure is to illustrate the existing information
concerning the health effects of ethylbenzene. Each dot in the figure
indicates that one or more studies provide information associated with that
particular effect. The dot does not imply anything about the quality of the
study or studies. Gaps in this figure should not be interpreted as "data
needs" information.
Figure 2-4 graphically describes the existing health effects information
on ethylbenzene by route and duration of exposure. Little information
concerning humans exposed via inhalation to ethylbenzene is available. Most
of the information concerning health effects in humans is reported in
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51
2. HEALTH EFFECTS
SYSTEMIC
Ł
Inhalation
Oral
Dermal
Inhalation
Oral
Dermal
HUMAN
SYSTEMIC
&
ANIMAL
Existing Studies
FIGURE 2-4. Existing Information on Health Effects of
Ethylbenzene
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52
2. HEALTH EFFECTS
occupational studies, which are difficult to interpret given the limitations
of the studies (e.g., concurrent exposure to other hazardous substances,
^quantified exposure concentrations, and exposure probably occurring by a
combination of routes). No data were available concerning human health
effects following oral or dermal exposures to ethylbenzene.
In animals, the lethality of ethylbenzene is documented for all routes
of exposure. Systemic health effects following inhalation exposure to ethyl-
benzene for acute and intermediate durations as well as neurologic,
developmental, and reproductive effects are also described. Limited data on
the health effects resulting from oral or dermal exposure to ethylbenzene were
located. No chronic systemic, immunologic, or genotoxic studies were located
for the oral, inhalation, or dermal routes of exposure.
2.8.2 Identification of Data Needs
In general, data on the toxic effects of ethylbenzene in humans and
animals are limited. In many areas for which studies have been conducted, the
lack of reliable data precludes any definitive conclusions from being drawn
and the development of corresponding MRLs.
Acute-Duration Exposure. Inhalation exposure of humans to ethylbenzene
results in irritation of the eyes and lungs. In addition, neurological
effects such as dizziness have been reported in humans following acute
exposure to this chemical. Similarly, respiratory and neurological effects
have been observed in animals exposed to ethylbenzene via inhalation.
However, only one dose level was used in many of the studies; therefore,
information on dose-response relationships was not available. Furthermore,
data for acute oral exposure to ethylbenzene are lacking. No acute studies
were suitable for deriving inhalation or oral MRLs for ethylbenzene. Well-
conducted acute-duration studies via inhalation and the oral route, using a
number of exposure concentrations and well-defined protocols would be useful
in establishing this dose-response relationship and elucidating any thresholds
that may exist for acute adverse health effects. The potential for brief
human exposure to high concentrations of ethylbenzene exists in accidental
exposure in the workplace, hazardous waste sites, and gasoline spill sites.
Intermediate-Duration Exposure. No intermediate-duration studies were
located for humans. Repeated inhalation exposures of animals to ethylbenzene
have been evaluated. Respiratory, hepatic, renal, and neurological effects
have been characterized in animals. No intermediate-duration studies were
suitable for deriving oral MRLs for ethylbenzene. Following completion of
peer review, the NTP 90-day inhalation study may provide definitive
information on systemic toxicity following inhalation exposure. Additional
histopathology data resulting from repeated oral exposure would be
particularly useful, sine¦> the potential exists for humans to be exposed to
ethylbenzene in the drink lg water. These data would help confirm that the
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2. HEALTH EFFECTS
liver and kidney are target organs following intermediate exposure to ethyl-
benzene. There are data suggesting that the lung may be a target, but these
data need to be confirmed. Presently, one study exists that may suggest the
occurrence of histopathological changes in the liver and kidney following
repeated oral exposure to ethylbenzene (Wolf et al. 1956). However, these
results are marked by limitations in the methodology, the end points
monitored, and the reporting of data; therefore, no definitive conclusions can
be drawn. Data on intermediate dermal exposure in animals and humans are
lacking. Such information would also be useful in determining human health
effects, since the potential exists, both in the occupational setting and at
hazardous waste sites, for such exposure to occur.
Chronic-Duration Exposure and Cancer. No adverse health effects were
seen in a long-term (20 years) study of 200 workers occupationally exposed to
ethylbenzene. No chronic inhalation, oral, or dermal studies in animals were
located in the literature. Studies that evaluate the effects of long-term
exposures and provide quantitative exposure data would be useful as the
potential exists for human populations to be exposed to ethylbenzene from
contamination at hazardous waste sites, particularly from oral and inhalation
exposures. Such information may be provided by the ongoing NTP inhalation
s tudy.
The carcinogenicity of ethylbenzene was investigated in two studies,
namely, an epidemiological study of humans occupationally exposed by
inhalation and an oral study using rats. The results of both studies were
inconclusive given the marked limitations present in both studies (e.g.,
possible concurrent exposure to other chemicals in the human study; only one
dose group used and no survival data in the animal study). No carcinogenicity
studies following dermal exposure were located in the literature. Additional
data on carcinogenicity following chronic inhalation exposure to ethylbenzene
are being obtained in an ongoing bioassay conducted by the NTP.
Genotoxicity. Available human data indicate that ethylbenzene may be
genotoxic. A weak induction of SCEs in human lymphocytes following
ethylbenzene exposure was seen. Data are available regarding the genotoxic
potential of ethylbenzene from in vitro assays in bacteria, yeast, and
mammalian cell cultures. Although the results generally indicate that ethyl-
benzene is not genotoxic, marginal genotoxic effects have been reported in
some tests. Independent confirmation or refutation of these studies, as well
as further genotoxicity studies, especially in mammalian systems, would help
provide clarification of these conflicting results. In particular, chromosome
aberrations in occupationally exposed persons would provide useful
information.
Reproductive Toxicity. No studies on reproductive effects in humans and
few studies using animals were located. The results from limited animal
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2. HEALTH EFFECTS
studies suggest that adverse reproductive effects may occur in animals
following oral exposure to ethylbenzene. No reduced fertility was reported in
ats exposed to ethylbenzene by inhalation, but the possibility of this
occurring was not ruled out. Additional reproduction studies, particularly
for the inhalation and oral routes of exposure and involving multigenerational
or continuous breeding studies, would help clarify the potential for ethyl-
benzene to cause adverse reproductive effects in humans.
Developmental Toxicity. No human data on developmental toxicity of
ethylbenzene are available. A developmental MRL for intermediate inhalation
exposure was determined based on data from a rat study. No studies were
located that considered subtle developmental effects (e.g., behavioral or
learning disability). These studies would be helpful in evaluating potential
developmental effects in humans exposed to ethylbenzene via inhalation or
ingestion.
Immunotoxicity. No data are available regarding the imniunotoxicity of
ethylbenzene in humans or animals. There are some data to suggest that
hematological effects may be seen, but these data are inconsistent.
Inhalation and oral exposure studies would be most useful in confirming the
potential of ethylbenzene to affect blood cells, since these routes are the
major ways by which persons are exposed to ethylbenzene. Dermal sensitization
tests may also provide useful data on the likelihood of an allergic response
occurring, since the potential for skin contact by humans occurs in the
workplace and in soil and water at hazardous waste sites.
Neurotoxicity. Acute inhalation studies in humans and animals exposed
to ethylbenzene indicate that ethylbenzene causes neurological effects. Some
data are available on possible mechanisms of action through dopamine
depletion. No ethylbenzene-related behavioral changes were reported in one
study, but other neurological parameters were not monitored. Studies have
been conducted that investigated biochemical changes in the brains of animals
following inhalation exposure, and some studies were located regarding
histopathological changes following ethylbenzene exposure. Well-conducted
acute, intermediate, and chronic studies including functional observation
batteries, motor activity and neurological evaluation across all exposure
routes would be useful for confirming these data.
Epidemiological and Human Dosimetry Studies. The few available
epidemiological studies on the health effects of ethylbenzene were primarily
limited to occupational studies in which quantitative estimates of exposure
were lacking and other limitations (e.g., multiple exposure routes, concurrent
exposure to other hazardous chemicals) were present. Studies using volunteers
exposed to low concentrations of ethylbenzene have provided useful information
on effects of acute inhalation exposure on the central nervous system. No
studies were available in which humans were exposed orally or dermally to
ethylbenzene. Further ep demiological studies conducted in the vicinity of
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2. HEALTH EFFECTS
hazardous waste sites containing ethylbenzene or in occupational settings
where ethylbenzene is used would provide useful information on the health
effects in humans. Data on lung function and neurological effects from these
studies would be particularly valuable as these are likely to be targets of
ethylbenzene toxicity.
Biomarkers of Exposure and Effect. Sensitive methods are available for
determining ethylbenzene and ethylbenzene metabolites in biological tissues
and fluids. However, limited data are available associating levels of
ethylbenzene in human tissues and fluids with adverse health effects.
Hematopoietic changes were shown to correlate with ethylbenzene concentrations
in the blood. Additional animal or epidemiological studies evaluating the
association between levels in tissue or fluids and adverse health effects
would be useful to devise more sensitive and more specific early biomarkers of
effect.
Absorption, Distribution, Metabolism, and Excretion. Quantitative and
qualitative evidence indicates that ethylbenzene is rapidly and efficiently
absorbed by humans following inhalation and dermal exposures. Animal data
support these findings and indicate that absorption rates are high following
oral exposures as well.
Only one study is available that outlines the distribution of ethyl-
benzene in humans following inhalation exposure. This study indicates rapid
distribution to adipose tissues throughout the body. Numerous oral and
inhalation studies in animals support these results. Ethylbenzene is
accumulated primarily in the intestine, liver, kidney, and fat, which provides
some basis for ethylbenzene-induced effects observed in the liver and kidney.
No data on distribution of ethylbenzene following dermal exposure were
located. Such information would be useful because absorption of liquid
ethylbenzene via this route is rapid in humans and because the potential
exists in humans for dermal exposure.
The metabolism of ethylbenzene in humans and animals has been
characterized. Although some differences in the metabolic pattern according
to route of exposure, sex, nutritional status, and species have been
documented, pharmacokinetic data show no significant differences in metabolism
between oral and inhalation routes in either humans or animals. Further
studies that correlate these differences in metabolism with differences in
health effects would be useful. Data on metabolism following dermal exposure
are sparse, because it is difficult to accurately measure absorption of
volatile compounds. Additional data on metabolism following dermal exposure
would be useful as these exposures could occur both from contaminated soil or
groundwater.
Ethylbenzene has been shown to be rapidly eliminated from the body
following inhalation exposure (primarily in the urine) in both humans and
-------
56
2. HEALTH EFFECTS
animals. These studies are sufficient to characterize the elimination of
ethylbenzene following inhalation exposure. A small number of studies in
nimals exposed orally and humans exposed dermally support these findings.
Further studies on elimination of ethylbenzene via these exposure routes would
be useful, especially because differences in the excretion patterns have been
observed with different routes of exposure.
Comparative Toxicokinetics. Quantitative and qualitative variations in
the absorption, distribution, metabolism, and excretion of ethylbenzene were
observed depending on exposure routes, sex, nutritional status, and species
as previously outlined. Further studies that focus on these differences and
their implications for human health would be useful. Additionally, in vi
studies using human tissue and physiologically based pharmacokinetic modeling
would contribute significantly to the understanding of the kinetics of ethyl-
benzene, since they would provide information on half-lives and saturation
problems associated with ethylbenzene.
2.8.3 On-Going Studies
The Health Effects Research Laboratory (HERL) in Cincinnati, Ohio, is
scheduled to conduct an acute inhalation study with rats and mice that will
measure pulmonary functions, metabolism, immunotoxicity, and biochemical
changes for EPA's Office of Research and Development (NTP 1988a). As of now
no date has been set to begin testing. A carcinogenicity bioassay was begun
in 1988 by IIT Research Institute for the National Toxicology Program (NTP
1990). The segment of this study investigating subchronic toxicity has been
completed and is under internal review.
No other on-going studies regarding health effects of ethylbenzene
exposure were identified in the available literature.
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57
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
The synonyms and identification numbers for ethylbenzene are listed in
Table 3-1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Important physical and chemical properties of ethylbenzene are listed in
Table 3-2.
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58
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Ethylbenzene
Value Reference
Chemical name
Ethylbenzene
Windholz 1983
Synonyms
Aethylbenzol (German); EB;
HSDB
1988
ethyl benzene; ethylbenzeneen
(Dutch); ethylbenzol;
etilbenzene (Italian);
etylobenzen (Polish);
phenylethane
Trade names
No data
Chemical formula
C8Hio
Windholz 1983
Chemical structure
,ch,ch3
(of
Identification numbers:
CAS Registry
100-41-4
HSDB
1988
NIOSH RTECS
NIOSH/DA0700000
HSDB
1988
EPA Hazardous Waste
F003; Ethylbenzene
HSDB
1988
OHM/TADS
7216709
HSDB
1988
DOT/UN/NA/IMCO
UN 1175; Ethylbenzene
HSDB
1988
Shipping
IMCO 3.2, Ethylbenzene
HSDB
84
HSDB
1988
NCI
NCI-C56393
HSDB
1988
STCC
49 091 63; Ethylbenzene
HSDB
1988
CAS - Chemical Abstracts Service; NIOSH - National Institute for Occupational
Safety and Health; RTECS - Registry of Toxic Effects of Chemical Substances-
EPA - Environmental Protection Agency; OHM/TADS - Oil and Hazardous Materi-'
als/Technical Assistance Data System; DOT/UN/NA/IMCO - Department of Trans-
portation/United Nations/North America/International Maritime Dangerous Goods
Code; HSDB - Hazardous Substances Databank; NCI - National Cancer Institute-
and STCC - Standard Transport Commodity Code.
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59
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of Ethylbenzene
Property
Values
References
Molecular weight
Color
Physical state
Melting point
Boiling point
Density at 20°C/4°C
at 25°C/25°C
Odor
Odor threshold:
Water
Air
Solubility:
Water at 06C
at 15°C
at 20°C
at 25°C
at 25°C
at 25°C
at 25°C
Organic solvents
Partition coefficients:
Kow
Log octanol/water
Koc
Vapor pressure at 20'C
at 25°C
at 25.9°C
at 30°C
at 74.1°C
106.16
Colorless
Liquid
-95°C
136.25°C
0.8670
0.866
Sweet, gasoline - like
0.029 ppm
0.140 mg/L
2-2.6 mg/m3
2.3 ppm
197 ppm
140 mg/L
152 mg/L
160 ppm
161.2 ppm
177 ppm
208 mg/L
Miscible with usual or-
ganic solvents
Soluble in alcohol and
ether
2.2xl03
3.13
3.15
165®
240b
254°
7 mmHg
1.27 kPa (9.53 mmHg)
10 mmHg
12 mmHg
100 mmHg
Windholz 1983
Windholz 1983
Windholz 1983
Weast 1988
Windholz 1988
Weast 1988
Windholz 1983
CHRIS 1985
Amoore and Hautala 1983
Rosen et al. 1963;
Verschueren 1983
Verschueren 1983
Amoore and Hautala 1983
Polak and Lu 1973
Verschueren 1983
Verschueren 1983
Amoore and Hautala 1983
Sutton and Calder 1975
Polak and Lu 1973
Bohon and Claussen 1951
Windholz 1983
Weast 1988
Mabey et al. 1982
Yalkowsky and Valvani
1976
Hansch and Leo 1979
Chiou et al. 1983
Hodson and Williams 1988
Vowles and Mantoura 1987
Verschueen 1983
Mackay and Shiu 1981
OHM/TADS 1988; Sax and
Lewis 1989
Verschueren 1983
OHM/TADS 1988
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60
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2 (Continued)
Property
Values
References
Henry's law constant:
at 20°C
at 20°C
at 25°C
at 25 °C
Autoignition temperature
Flash point
Flammability limits
Conversion factors
6. 6xlO~3 atm*m3/mol
8 . 7xl0~3 atm«m3/mol
8.43xl0~3 atm'm3 g^mol"1
0.80 kPa-m3/mol
(7.9xlO~3 atm»m3/mol)
810°F (432°C)
64°F (18°C) closed cup
59°F (15°C) closed cup
80°F (26.7°C) open cup
1. 0%-6.7%
1 mg/m3 - 0.2 3 ppm
1 ppm - 4.35 mg/m3
Mabey et al. 1982
Lyman et al. 1982
Mackay et al. 1979
Mackay and Shiu 1981
Sax and Lewis 1989
Windholz 1983
CHRIS 1985
CHRIS 1985
CHRIS 1985
Verschueren 1983
Converted from observed K^, by relationship K„ = 1.724 Kom (Lyman et al.1982).
bMeasured with HPLC using a cyanopropyl column.
Calculated from the measured Kd and measured soil organic carbon contents of
4.02 by: Koc - Kd/0.0402.
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61
4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL
4.1 PRODUCTION
Ethylbenzene is primarily produced by the alkylation of benzene with
ethylene (EPA 1987c; Ransley 1984; Sandmeyer 1981). Other methods of
manufacturing ethylbenzene include preparation from acetophenone,
dehydrogenation of naphthenes, catalytic cyclization and aromatization,
separation from mixed xylenes, reaction of ethylmagnesium bromide and
chlorobenzene, extraction from coal oil, and recovery from benzene-toluene -
xylene (B-T-X) processing (HSDB 1988; Ransley 1984; Sandmeyer 1981; Windholz
1983). Commercial grades of ethylbenzene may also contain small amounts of m-
and jD-xylene, cumene, and toluene (HSDB 1988).
In 1986, U.S. production of ethylbenzene was reported to be
approximately 9 billion pounds (USITC 1987). The annual capacity of U.S.
manufacturers of ethylbenzene has been estimated at 1.0764xl010 pounds (SRI
1990) .
The producers of ethylbenzene and the locations and annual capacities of
their facilities, as estimated by SRI (1990), are presented in Table 4-1.
4. 2 IMPORT/EXPORT
In 1981, 2.09xl010 grams of ethylbenzene were imported to the United
States. In 1978, 1.53xl010 grams were imported (HSDB 1988). U.S. exports of
7.49xl010, 4.84xl010, 8.59xl010 g have been reported for 1985, 1983, and 1978,
respectively (Bureau of the Census 1985; HSDB 1988)
4.3 USE
Ethylbenzene is used primarily in the production of styrene (ACGIH 1986;
Ransley 1984; Vershueren 1983; Windholz 1983). Other uses of ethylbenzene
include use as a solvent, as a constituent of asphalt and of naphtha, and in
fuels (ACGIH 1986; Vershueren 1983; Windholz 1983). It is also used in the
manufacture of acetophenone, cellulose acetate, diethylbenzene, ethyl
anthraquinone, ethylbenzene sulfonic acids, propylene oxide, and
a-methylbenzyl alcohol (HSDB 1988; Verschueren 1983).
4.4 DISPOSAL
Methods for disposal of ethylbenzene include rotary kiln incineration,
liquid injection incineration, and fluidized bed incineration (Bonner et al.
1981; HSDB 1988). Also, ethylbenzene can be concentrated via biological
treatment, chemical precipitation, air and steam stripping, solvent
extraction, or activated carbon treatment (HSDB 1988).
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62
4. PRODUCTION, IMPORT, USE AND DISPOSAL
TABLE 4-1. Ethylbenzene Producers in the United States
Company
Location
Annual Capacity
(millions of pounds)
Amoco Corporation:
Amoco Chemical Company,
subsidiary
ARCO Chemical Company:
Lyondell Petrochemical
Company, subsidiary
Chevron Corporation:
Chevron Chemical Company,
subsidiary
Aromatics and Derivatives
Division
Cos-Mar, Inc.
Dow Chemical U.S.A.
Hoechst Celanese Corp.:
Engineering Plastics Group
Koch Industries, Inc.:
Koch Refining Company,
subsidiary
Rexene Products Co.
Sterling Chemicals, Inc.
Texas City, TX
Channelview, TX
St. James, LA
Carville, LA
Freeport, TX
Bayport, TX
Corpus Christi, TX
Odessa, TX
Texas City, TX
908
1,770
679
2,600
1,750
"1,035
100
362
1,560
"All production is tolled for Huntsman Chemical.
Source: SRI International estimates as of January 1, 1990
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63
4. PRODUCTION, IMPORT, USE AND DISPOSAL
Criteria regarding the disposal of ethylbenzene are currently subject to
significant revision (HSDB 1988). Spent ethylbenzene solvents and still
bottoms from the recovery of these solvents are designated hazardous wastes
and, as such, are subject to handling and recordkeeping requirements (EPA
1981).
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65
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Ethylbenzene is an aromatic hydrocarbon naturally present in crude
petroleum. It is widely distributed in the environment because of human
activities such as the use of fuels and solvents (which account for the bulk
of emissions) and through chemical manufacturing. Because of its volatile
nature, partitioning into the atmosphere from various environmental media is
an important environmental fate process. Exposure to this chemical is thus
most likely to occur by inhalation. However, it is present in trace amounts
in some water supplies. Thus, ingestion may be important in some cases.
Physical, chemical, and biological processes can remove ethylbenzene
from the medium of concern and reduce human exposures. In the atmosphere,
ethylbenzene is removed by partitioning into rainwater or by chemical
transformations caused by the sun's energy (photooxidation), which
structurally alter the molecule. Photolytic transformations may also take
place in surface water in the presence of naturally occurring humic materials
(sensitized photolysis). Biologically induced transformations take place
largely in soil and surface water in the presence of oxygen. Although
chemical transformations can result in reduced exposures to ethylbenzene, the
by-product may be of concern. For example, ethylbenzene has been implicated
in the atmospheric formation of peroxyacetylnitrate, a toxic component of
smog.
The kinetics of partitioning and/or transformation processes are site
specific and depend upon many external factors. For example, the extent of
biodegradation observed in an environmental medium depends upon the type and
population of microbes present, the concentration of ethylbenzene, the
presence of other compounds that may act as a substrate, and the presence or
absence of oxygen. Biodegradation in soil will also compete with migration
processes such as volatilization and infiltration to groundwater. Because
ethylbenzene migration is not significantly retarded through adsorption onto
soil, rapid transport to an anaerobic environment before biotransformation in
soil is possible and may allow ethylbenzene to persist in an aquifer.
Although information is limited on dietary exposures, ethylbenzene does
not significantly bioaccumulate in the food chain, and exposure through this
route is not likely to be of concern.
Exposure of the general population to ethylbenzene Is possible through
contact with gasoline, automobile emissions, solvents, pesticides, printing
ink, varnishes, coatings, and paints. Cigarette smoke has been identified as
a source of exposure to this chemical. Ethylbenzene is widely present at low
concentrations in rural, urban, and suburban atmospheres.
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66
5. POTENTIAL FOR HUMAN EXPOSURE
Occupational exposures are expected within the petroleum industry;
within industries using solvents, paints, and coatings; and during the
mufacture and handling of ethylbenzene and styrene (which is manufactured
from ethylbenzene). High exposure to the general population would be expected
around refineries and manufacturing facilities and from residential wells
downgradient of uncontrolled landfills, waste sites, and leaking underground
storage tanks.
5.2 RELEASES TO THE ENVIRONMENT
Ethylbenzene has been measured in all environmental media, although it
is most widely distributed in the atmosphere. To date, it: has been identified
at 227 of the 1,177 NPL sites (VIEW Database 1989). The frequency of these
sites within the United States can be seen in Piguie 5-1.
5.2.1 Air
The majority of ethylbenzene releases to the environment occur into the
atmosphere. Because of its frequent use, and production in manufacturing
operations, ethylbenzene is an important industrial chemical. Its release can
occur during manufacturing and handling. In 1978, emissions of ethylbenzene
in the United States from catalytic reformate production alone were estimated
at over 2 million pounds (Fishbein 1985). According to the TRI database (TRI
1989), air emissions of ethylbenzene from manufacturing facilities were
estimated to be about 47 billion pounds in 1988. Fuels and solvents, however,
are considered to account for the bulk of emissions (Fishbein 1985). Gasoline
contains approximately 2% (by weight) ethylbenzene, which is added as an anti-
knocking agent (Mayrsohn et al. 1978 as cited in NAS 1980). Ethylbenzene has
been measured from tail pipe emissions of gasoline-powered vehicles at a
weighted average rate of 12 mg/km (considering both catalyst and noncatalyst
equipped cars) (Hampton et al. 1983). Emissions from gasoline-powered
vehicles were found to be somewhat higher than from diesel trucks (Hampton et
al. 1983). Similarly, ethylbenzene has been measured in jet fuel emissions
(Katzman and Libby 1975) and has been reported in waste incinerator stack
emissions (Junk et al. 1980).
Levels of ethylbenzene monitored in ambient air show much variation
(Jonsson et al. 1985). Generally, air concentrations are much lower in rural
areas than in urban areas, where vehicle emissions are thought to be a major
contributor of ethylbenzene to ambient air. Ethylbenzene concentrations in
the same rural areas range from none detected in a rural area to 23.1 ppb on
busy urban streets (Jonsson et al. 1985).
Ethylbenzene releases to the air can occur with the use of consumer
products such as pesticides, solvents, carpet glue, and varnishes (NAS 1980;
Wallace et al. 1987b). Ethylbenzene (in addition to other aromatic
hydrocarbons, such as benene, styrene, and xylenes) has also been measured in
cigarette smoke (Wallace t al, 1986, 1987c).
-------
FIGURE 5-1. FREQUENCY OF SITES WITH ETHYLBENZENE CONTAMINATION
-------
68
5. POTENTIAL FOR HUMAN EXPOSURE
5.2.2 Water
Releases to water occur as a result of industrial discharges (Snider and
Manning 1982), the use of gasoline fuel for boating (Gschwend et al 1982)
fuel spillage (Tester and Harker 1981), leaking underground storage tanks
(Cotruvo 1985), landfill leachate (Barker 1987), and the inappropriate
disposal of waste (Eiceman et al. 1986). Ocean releases occur as a result of
offshore oil production, hydrocarbon venting, oil field brines, an
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69
5. POTENTIAL FOR HUMAN EXPOSURE
Sorption and retardation by soil organic carbon will occur to a small
extent, but sorption is not significant enough to prevent migration in most
soils typically encountered in the environment. In fact, solvent spills of
chemicals such as ethylbenzene may enhance the mobility of other organic
chemicals, which do strongly adsorb to soil (Rao et al. 1985).
Once in the atmosphere, ethylbenzene will be transported until it is
removed by physical or chemical processes. Physical removal processes, which
involve partitioning into clouds or rainwater, are relevant to ethylbenzene,
which has been measured in Los Angeles rainwater (Kawamura and Kaplan 1983).
The concentrations of several dissolved organic chemicals in rainwater and in
the atmosphere during rainfall events were measured by Ligocki et al. (1985).
The authors found that the concentration of ethylbenzene in rainwater was
approximately equal to the inverse of the dimensionless Henry's law constant
at atmospheric temperatures. This indicates that ethylbenzene is removed from
the atmosphere through precipitation to some extent, but it can re-enter the
atmospheric environment upon evaporation.
In comparison to chemicals such as PCBs, DDT, and other chlorinated
pesticides, which are of great concern with respect to bioaccumulation,
ethylbenzene does not significantly bioaccumulate in aquatic food species. A
bioconcentration factor (BCF) in fish of 37.5 based on a log Kow of 3.15 has
been estimated (EPA 1980). A 3% weighted average lipid content in fish and
shellfish was assumed by EPA in the calculation. The calculated BCF is a
theoretical value based on known constants, and is a conservative estimate of
the bioconcentration of this chemical in fish. In a shellfish study, the
ethylbenzene concentration in clam tissue was five times higher than that
measured in water after an 8-day continuous-flow exposure to the water-soluble
fraction of Cook Inlet crude oil (Nunes and Benville 1979).
Ethylbenzene also partitions into human adipose tissue (see
Section 5.5).
5.3.2 Transformation and Degradation
5.3.2.1 Air
Ethylbenzene undergoes atmospheric transformations through the reaction
with photolytically generated hydroxyl radicals (Atkinson et al. 1978; Ohta
and Ohyama 1985; Ravishankara et al. 1978), N03 radicals (Atkinson et al.
1987), and atomic oxygen (Grovenstein and Mosher 1970; Herron and Huie 1973).
Gas phase reactions with ozone and structurally similar molecules such as
toluene have been observed (Atkinson and Carter 1984). Reactions with
hydroxyl radicals appear to be of most importance, and a chemical lifetime of
3J5 daylight hours for ethylbenzene has been estimated (Atkinson et al. 1978).
Oxidation by-products from the reaction with hydroxyl radicals and nitrogen
oxides include ethylphenols, benzaldehyde, acetophenone, and jm- and Ł-
nitroethylbenzene (Hoshino et al. 1978).
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70
5. POTENTIAL FOR HUMAN EXPOSURE
Experiments conducted with various hydrocarbons on the formation of
photochemical aerosols or the haze associated with smog revealed that
aromatics such as ethylbenzene produced only low yields of aerosol when
compared with more reactive compounds such as alkenes (O'Brien et al. 1975).
Similarly, ethylbenzene has been implicated in the formation of
peroxyacetylnitrate (PAN), a toxic component of smog. The formation of PAN is
related to the photoreactivity of the reacting hydrocarbon. The
photoreactivity of ethylbenzene is intermediate relative to other atmospheric
hydrocarbons, and it is less reactive than gasoline, toluene, and alkenes such
as propene (Yanagihara et al. 1977).
5.3.2.2 Water
In surface water, transformations of ethylbenzene may occur through
photooxidation and biodegradation.
Although ethylbenzene does not directly absorb light wavelengths that
reach the troposphere, it is capable of undergoing photooxidation in water
thrnncrh an indirect reaction with other light-absorbing molecules, a process
environment similar degradation xs expectea to occur m tne presence or
ubiquitous, naturally occurring humic material sensitizers.
Biodegradation in aerobic surface water will compete with sensitized
. j nrocesses such as volatilization. Volatilization and
photolysis and transport y i_ v i,
biodegradation of ethylbenzene in seawater have been observed by Gschwend et
,1 (1982) and Wakeham et al. (1983). Migration from surface rnter to
' K Iovj amounts of oxygen or to aquifers with lower microbial
poDulItions^however, will limit the rate of transformation. No significant
Hi
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71
5. POTENTIAL FOR HUMAN EXPOSURE
5.3.2.3 Soil
Biodegradation of ethylbenzene by aerobic soil microbes has been
reported by various researchers. The common soil microorganism Pseudomonas
putida is able to utilize ethylbenzene as a sole source of carbon and energy
(Gibson et al. 1973). In some instances, co-oxidation or co-metabolism was
observed; i.e., ethylbenzene was degraded by Nocardia sp. in the presence of
other compounds that are more readily metabolized by the microorganism
(Jamison et al. 1970; Van der Linden and Thijsse 1965). Anaerobic degradation
of ethylbenzene in soil has not been reported, but based on observations from
studies conducted under anaerobic conditions in other media as discussed above
(Bouwer and McCarty 1983, 1984; Wilson et al. 1986), transformation would be
much slower than that observed under aerobic conditions.
Biotic transformations by aerobic soil microbes involve oxidation of the
ethyl side chain to form phenylacetic acid (Van Der Linden and Thijsse 1965)
and 1-phenylethanol (Bestetti and Galli 1984 as cited in ECETOC 1986); ring
hydroxylation to form 2,3-dihydroxy-l-ethylbenzene (Gibson et al. 1973),
2-hydroxyphenlacetic acid, 4-hydroxyphenylacetic acid, 2,5- and
3,4-dihydroxyphenylacetic acid (Van der Linden and Thijsse 1965); and ultimate
ring cleavage to form straight chain carboxylic acids such as fumaric and
acetoacetic acids (Van der Linden and Thijsse 1965).
No information was found on the rate at which such degradation occurs in
the environment. The kinetics of biodegradation are site specific, however,
and depend upon factors such as the type and population of microbes present,
the concentration of ethylbenzene, the presence of other compounds that may
act as a substrate, and the amount of oxygen present. Biodegradation in soil
will also compete with migration processes such as volatilization and
infiltration to groundwater. Migration to anaerobic environments where
biodegradation is limited may be faster than the rate of biotransformation in
soil under certain site conditions.
5.A LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
Because ethylbenzene is a constituent of automotive emissions, it is
widely present in urban and rural atmospheres. An update of the 1980 national
ambient volatile organic compounds data base prepared for USEPA summarized
concentrations of ethylbenzene by site type (Shah and Heyerdahl 1988). Median
values are reported because they are less biased by a few high or low
concentrations and thus may better represent the database than would average
values. Median concentrations for 6 remote and 122 rural locations are
reported as 0.156 and 0.013 ppb, respectively. Higher median concentrations
were reported for 886 suburban (0.62 ppb) and 1,532 urban (0,62 ppb)
locations. The median indoor concentration from 95 locations was 1 ppb, while
personal air monitoring of 1,650 individuals reports a median concentration of
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72
5. POTENTIAL FOR HUMAN EXPOSURE
1.3 ppb. The daily median concentration of ethylbenzene considering all site
types (including source dominated and workplace) was 0.60 ppb. Table 5-1
lists some monitoring results reported for ethylbenzene in various cities
Of particular interest is that personal air monitoring reports higher
concentrations of ethylbenzene than those observed in outdoor air. This was
also observed during the Total Exposure Assessment Methodology (TEAM) Study
conducted by EPA between 1979 and 1985 in an effort to measure exposures to 20
volatile organic compounds in personal air, outdoor air, and drinking water
The major cause for the higher personal air concentrations was felt to be the
presence of ethylbenzene sources in the home.
In the TEAM study, tobacco smoke was concluded to be a main source of
exposure to volatile aromatic compounds such as ethylbenzene (Wallace et al
1987a,c). Based on the results of a stepwise regression carried out on data
collected during the fall in New Jersey from 352 participants, overnight
geometric mean ethylbenzene exposures of persons living in homes with smokers
were approximately 1.5 times the geometric mean exposures of persons living in
homes without smokers. The amount of ethylbenzene measured in mainstream
smoke of a single cigarette containing 16 mg of tar and nicotine was 8 up
(Wallace et al. 1987c).
Ethylbenzene concentrations at four locations along U.S. Highway 70 near
Raleigh, NC, during the month of May were reported to range from 10 to 16 ppb
(corrected to include upwind concentrations) (Zweidinger et al. 1988)
The analytical methods available for monitoring ethylbenzene in air are
detailed in Chapter 6.
5.4.2 Water
The median ethylbenzene concentration in ambient surface waters in the
United States in 1980-1982 was less than 5.0 Hg/h according to EPA's STORET
water quality data base (Staples et al. 1985). The chemical was detected in
10% of the 1,101 samples collected during that period. Ethylbenzene was
detected in 7.4% of the 1,368 industrial effluent samples collected during
1980-1983 at a median concentration of less than 3.0 pg/L. The median
ethylbenzene concentration in sediment was 5.0 /ig/kg; the compound was
detected in 11% of 350 samples.
Ethylbenzene was measured in seawater at an average concentration of
0.011 Mg/L and a concentration range of 0.0018-0.022 /ig/L over a 15-month
observation period at Vineyard Sound, MA (Gschwend et al. 1982). Ethylbenzene
has been reported in surface waters of the Gulf of Mexico at a concentration
range of 0.0004-0.0045 /ig/L (Sauer et al. 1978).
Ethylbenzene was measured in 4% of the municipal runoff samples
collected in 15 cities of the United States as part of EPA's Nationwide Urban
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73
5. POTENTIAL FOR HUMAN EXPOSURE
TABLE 5-1. Ethy Lbenzeme Cone act rat ions in Ambient Air Samples Collected in the United States
Location Concentration Comments Reference
Newark, NJ
0.3 3 ppb (mean)
July 6-August 16, 1981;
Harkov
et
al
1983
11-38
Elizabeth, NJ
0.26 ppb (mean)
July 6-August 16, 1981;
Harkov
et
al
1983
n*37
Camden, NJ
0.17 ppb (mean)
July 6-August 16, 1981;
Harkov
et
al
1983
n"35
St. Louis, MI
0.6±0.5 ppb
(niaaivtS .D.)
Kay 29-Jvme 9, I960;
Singh
et
al.
1985
2.1 ppb"
n-100
Denver, CO
2.213.1 ppb
(mean±S.D.)
June 15-28, 1980; n-100
Singh
et
al.
1985
18.5 ppb*
Riverside, CA
1.3±0.8 ppb
(mean±S.D.)
July 1-13, 1980; n4-100
Singh
et
al.
1985
4 .0 ppb*
Staten Island, BY
1,7±2,5 ppb
(mean±S.D.)
March 26-ApriL 5, 1981;
Singh
et
al.
1985
17.2 ppb*
n-100
Pittsburgh, FA
0.8±1.6 ppb
(meanrS.D.)
April 7-17, 1981; n-100
Singh
et
al.
1985
10.5 ppb'
Chicago, IL
Q. 811.2 ppb
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74
5. POTENTIAL FOR HUMAN EXPOSURE
Runoff Program (Co!. 19»>. Vol public
drinkingZwater°supplies. The 1982 Ground Water Supply Survey conducted by EPA
dnnKing w ^ , 3 of 466 raiv
-------
75
5. POTENTIAL FOR HUMAN EXPOSURE
of 0.01 mg ethylbenzene/kg body weight was measured in the tissue of
bottomfish from Commencement Bay in Tacoraa, WA (Nicola et al. 1987).
The analytical methods available for monitoring ethylbenzene in various
environmental media are detailed in Chapter 6.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
Occupational exposure to ethylbenzene in the petroleum industry has been
reported in a study that measured ethylbenzene concentrations in air for 49-56
workers during the summer of 1984 (Rappaport et al. 1987). The average air
concentrations of ethylbenzene measured over the full work shift for gasoline
service station attendants, transport drivers, and outdoor refinery personnel
were comparable at 0.063, 0.079, and 0.079 mg/m3, respectively (14.5, 18.2,
and 18.2 ppb, respectively). The authors noted that exposures of service
station attendants were significantly lower when vapor recovery systems were
present.
Personal air monitoring of 35 varnish workers (spraymen) has revealed an
average ethylbenzene concentrations of 4.0 ppm, while the average
concentration in blood was 61.4 ng/1 (Angerer and Wulf 1985).
The indoor air of screen printing plants was found to contain median
time-weighted average concentrations of ethylbenzene ranging from <0.03
(6.9 ppb) to 1.30 mg/m3 (299 ppb) and maximum time-weighted average
concentrations ranging from 0.11 (25.3 ppb) to 3.21 mg/m3 (739 ppb) (Verhoeff
et al. 1988).
Spray-painting and gluing operations can also result in exposure to
ethylbenzene; personal air monitoring of workers measured average exposures of
approximately 0.5 ppm (Whitehead et al. 1984). Most of the operations
measured during the study were performed in ventilation hoods.
A recent survey conducted by the Styrene and Ethylbenzene Association
(SEBA) of U.S. manufacturers of ethylbenzene indicated that typical workplace
exposure levels of ethylbenzene in styrene and/or ethylbenzene processing
plants were in the range of 0.1 to 1.0 ppm for an 8-hour Time-Weighted-Average
(TWA) (Helmes 1990). The analytical methods used for the survey were not
specified.
The highest exposures to the general public most likely occur through
the use of self-service gasoline pumps. In addition, ethylbenzene is
ubiquitous in urban and rural atmosphere because of vehicular and industrial
emissions (Shah and Heyerdahl 1988). Tobacco smoke also provides a general
source of exposure to ethylbenzene (Wallace et al. 1987c). No information was
found regarding human exposure to ethylbenzene in the vicinity of hazardous
waste sites.
-------
76
5. POTENTIAL FOR HUMAN EXPOSURE
The 1982 National Human Adipose Tissue Survey conducted by EPA measured
ethylbenzene in 96% of the 46 composite samples analyzed for volatile organic
compounds (Stanley 1986). A wet tissue concentration range of not detected
(detection limit=2 ng/g) to 280 ng/g was reported, but an average
concentration was not provided.
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
Populations living or working near petroleum refineries or chemical
manufacturing plants may receive higher inhalation exposures than those
experienced by the general population. Residents in the vicinity of gasoline
stations and highways may also receive a higher than average inhalation
exposure. Residential wells downgradient of leaking underground storage
tanks, landfills, and hazardous waste sites contaminated with petroleum
solvents may contain high levels of ethylbenzene and other solvents.
5.7 ADEQUACY OF THE DATABASE
Section 104(i)5 of CERCLA 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 ethylbenzene is available. Where adequate information is not
available, ATSDR, in conjunction with 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
ethylbenzene.
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 or eliminate
the uncertainties of human health assessment. In the future, the identified
data needs will be evaluated and prioritized, and a substance-specific
research agenda will be proposed.
5.7.1 Identification of Data Needs
Physical and Chemical Properties. The physical and chemical properties
of ethylbenzene are well characterized and allow prediction of the transport
and transformation of the compound in the environment. Experimental data
confirm the predictive value of the known chemical and physical properties.
No additional studies are needed at the present time.
Production, Use, Release, and Disposal. Ethylbenzene has numerous uses,
and production of the chemical is, and probably will remain, high. Releases
occur from a variety of common sources including automobile exhaust and fumes
from paints, varnishes, and solvents. Therefore, the potential for human
exposure to ethylbenzene is considerable. The medium most likely to be
-------
77
5. POTENTIAL FOR HUMAN EXPOSURE
contaminated is air, although ethylbenzene has also been detected in trace
amounts in water supplies. Criteria regarding disposal practices are
currently subject to significant revision. Some ethylbenzene-containing
wastes are designated as hazardous and are subject to EPA handling and
recordkeeping requirements. Information regarding disposal practices would be
useful in determining potential sources and levels of exposure to
ethylbenzene.
According to the Emergency Planning and Community Right to Know Act of
1986 (EPCRTKA), (§313). (Pub. L. 99-499, Title III, §313), industries are
required to submit release information to the EPA. The Toxic Release
Inventory (TRI), which contains release information for 1987, became available
in May of 1989. This database will be updated yearly a-d should provide a
more reliable estimate of industrial production and emissio
Environmental Fate. Ethylbenzene Is primarily partitioned to, and
transported in, air. The partioning and transport processes in air, water,
and soil are well characterized. Transformation and degradation processes
have also been well studied. However, there are no kinetic data for
biodegradation in soil, because the kinetics are site specific. Information
on the kinetics of degradation, especially in the vicinity of hazardous waste
sites, might indicate the risk of exposure to individuals living or working
near areas where ethylbenzene might persist in the soil.
Bioavailability from Environmental Media. Ethylbenzene is absorbed
following inhalation, oral, and dermal exposure. Information is available on
its absorption from air and water, but very little is known about its
absorption from soil and food. Based on the low affinity of ethylbenzene for
soil and the small estimated bioaccumulation factor, soil and food would not
be expected to be significant sources of ethylbenzene exposure. However,
under certain soil conditions, the chemical may persist longer. More
information on the conditions under which high concentrations of ethylbenzene
may persist in the soil long enough to become bioavailable through contact
with soil or contaminated plant material might be useful in fully evaluating
the risk posed by this compound at hazardous waste sites.
Food Chain Bioaccumulation. The available data Indicate that
ethylbenzene does riot significantly bioaccumulate in food chains leading to
human exposure. No additional bioaccumulation data are needed at the present
time.
Exposure Levels in Environmental Media. An extensive amount of
atmospheric monitoring data exists and much of it is current. Ethylbenzene
has also been detected in water, soil, and foodstuffs. Most of these data
have been collected within the last 10 years. Ethylbenzene concentrations in
groundwater resulting from contamination from underground storage tanks and
hazardous waste sites that have not been investigated as part of the Superfund
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78
5. POTENTIAL FOR HUMAN EXPOSURE
program are not well characterized. This information would be useful in
estimating exposure, through consumption of contaminated drinking water, of
populations living in the vicinity of these sites. Data are also lacking on
the human intake of ethylbenzene from various contaminated environmental
media. More information on human intake from contaminated water and
foodstuffs would be useful in assessing the risk associated with these
possible sources for populations living near hazardous waste sites.
Exposure Levels in Humans. Ethylbenzene and its metabolites have been
detected in human blood, urine, and adipose tissue. Most of the monitoring
data have come from occupational studies of specific worker populations
exposed by inhalation. However, inhalation exposure to ethylbenzene is the
most likely route of exposure for members of the general population as well.
More information of general population exposure to ethylbenzene might be
useful. Very little information is available on the dietary intake of this
chemical. Exposures from this route are likely to be low, except for the
consumption of contaminated drinking water by populations living in the
vicinity of hazardous waste sites. More information on the dietary intake of
ethylbenzene would be useful, given the possible importance of this exposure
route for these populations.
Exposure Registries. No exposure registries for ethylbenzene were
located. This compound is not currently one of the compounds for which a
subregistry has been established in the National Exposure Registry. The
compound 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 the exposure to this
compound.
5.7.2 On-going Studies
Remedial investigations and feasibility studies conducted at the 227 NPL
sites known to be contaminated with ethylbenzene are scheduled to be added to
the available database on exposure levels in environmental media, exposure
levels in humans, and exposure registries.
A biodegradation study being conducted by EPA's Environmental Research
Laboratory in Ada, Oklahoma, is scheduled to be completed in October 1989. No
other on-going studies pertaining to the environmental fate of ethylbenzene
were identified in the available literature.
As part of the Third National Health and Nutrition Evaluation Survey
(NHANES III), the Environmental Health Laboratory Sciences Division of the
Center for Environmental Health anc^ Injury Control, Centers for Disease
Control, will be analyzing human blood samples for ethylbenzene and other
volatile organic compounds. Tfrese data will give an indication of the
-------
79
5. POTENTIAL FOR HUMAN EXPOSURE
frequency of occurrence and background levels of these compounds in the
general population.
-------
81
6. ANALYTICAL METHODS
The purpose of this chapter is to describe the analytical methods that
are available for detecting and/or measuring and monitoring ethylbenzene in
environmental media and in biological samples. The intent is not to provide
an exhaustive list of analytical methods that could be used to detect and
quantify ethylbenzene. Rather, the intention is to identify well-established
methods that are used as the standard methods of analysis by various federal
agencies. Many of the analytical methods used to detect ethylbenzene in
environmental samples are the methods approved by federal agencies such as EPA
and NIOSH. Other methods presented in this chapter are those that are
approved by a trade association such as the Association of Official Analytical
Chemists (AOAC) and the American Public Health Association (APHA). A third
category of analytical methods emphasizes research and development activities,
where efforts are underway to refine previously used methods, to obtain lower
detection limits, and to increase accuracy and precision.
The analytical methods used to quantify ethylbenzene in biological and
environmental samples are summarized below. Table 6-1 lists the applicable
analytical methods for determining ethylbenzene in biological fluids and
tissues, and Table 6-2 lists the methods used for determining ethylbenzene in
environmental samples. Both tables present detection limits and estimates of
method accuracy.
6.1 BIOLOGICAL MATERIALS
Trace amounts of ethylbenzene in biological fluids can be detected by a
number of analytical methods. These include gas chromatography coupled with
mass spectrometry (GC/MS), gas chromatography using a flame ionization
detector (GC/FID), high performance liquid chromatography (HPLC), and
isotachophoresis (ITP).
Identification and quantitation of ethylbenzene in samples of whole
blood taken from humans following occupational exposure to several volatile
organic compounds was discussed by Antoine et al. (1986). Gas purging-and-
trapping on Tenax GC adsorbent was used to remove volatile organic components
from blood for introduction into the GC/MS system. The authors demonstrated
that the inherent volatility of the organic compounds causes excessive foaming
during purging, resulting in low yields of eluting components. The use of an
antifoaming agent, such as emulsion B, greatly reduced the foam and increased
the accuracy and detection limits of the technique for ethylbenzene.
Ethylbenzene can be detected in whole human blood using a dynamic
headspace purge and GC/MS (Cramer et al. 1988). Organic compounds are
thermally desorbed from an adsorbent trap and onto the gas chromatography
column in a GC/MS system where limited mass-scanning data are collected for
qualitative and quantitative identification. Limited mass-scanning involves
-------
TABLE 6-1. Analytical Methods for Determining Etfaylbensene in Biological Materials
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit
Accuracy
Reference
Blood
Purge-and-trap blood sample on Tenax TA
absorbent
GM/MS
34xl0~3
H g/L
30Z RSD
Cramer et al. 1988
Add antifoam emulsion B to blood sample;
purge-and-trap at 40*-50'C on Tenax GC/
silica gel trap
GC/MS
1.0 /ig/L
<51 correla-
tion coeffi-
cient
Antoine et al. 1986
Add sodium chloride to blood sample and
vaporize sample
GC/FID
10 /ig/L
9X RSD
Radzikowska-Kintzi
and Jakubowski 1981
Urine
Add urine specimen to MeOH; centrifuge
and inject supernatant into HPLC column
Add sample to MeOH and centrifuge; inject
supernatant in HPLC column
Extract filtered urine sample with di-
ethyl ether; evaporate to dryness and
dissolve residue with distilled Mater
HPLC
HPLC
HPLC and HP
PGA
8.5xl03
H g/L
MA lOxlO3
f g/L
MA 5xl0"3
^g/sample
MA, PGA
1.5xl03
M g/L
(HPLC)
MA
6.lxlO3
ms/l
(ITP)
PGA
3.OxlO3
Mg/L
(IIP)
PGA 1011 re-
covery
MA 102.61 re-
covery
100Z-101.6Z
recovery
MA 0.982
correlation
coefficient
PBA 0.979
correlation
coefficient
Ogata and Taguchi
1987
Ogata and Taguchi
1988
Sollenberg et al.
1985
>
Z
>
f
H
w
o
>
t-'
OS
M
i-3
SC
o
o
Fat tissue Add saline; freeze; thaw to 0*C prior to GC/FID
analysis; add CS2; inject into GC GC/MS
No data
No data
Wolff et al. 1977
GC/MS - gas chromatography/mass spectrometry; GC/FID = gas chromatography/flame ionization detector; HPLC = high performance liquid
chromatography; IIP - isotachophoresis; MA ~ mandelic acid; PGA = phenylglyoxylic acid; RSD = relative standard deviation; ppm = parts per
million; and ppt = parts per trillion.
-------
TART.H 6-2. Analytical Methods for Determining Ethylbenzene in Environmental Sanqples
Sample
Detection
Sample Matrix Sample Preparation Analytical Method Limit Accuracy Reference
Mater
Collect river water on glass fiber con-
taining activated charcoal; extract with
carbon disulphide
Purge-and-trap water sample on Tenex GC
adsorbent
Purge-and-trap drinking water sample on
adsorbent
GC/FID and GC/MS
GC/FID and GC/MS
GC/FID-EICD
1.0 (ig/L
0.07 >ig/L
<0.1 ng/L
0.61 RSD
No data
74X recovery
Colenutt and
Thornburn 1980
EPA 1986b (Methods
8010 and 824 0)
Otson and Williams
1982
Air
Extract drinking water sample with hexane GC/FID
and analyse
Purge-and-trap water sample on adsorbent GC/MS
Introduce water sample into head space GC/FID
analyzing system; inject volatile
organics in GC colunn
Collect sample through adsorbent; GC/FID
thermally desorb volatile organics into
GC colum
Collect air sample in Teflon tubing and GC/FID
thermally desorb volatile organic
compounds
Trap air sample on either Tenax or
Carbopak C adsorbent; extract with
organic solvent and analyse
Draw air sample through copper tubing by
means of a diaphragm and analyze
Absorb air sample on Tenax GC; thermally
desorb trapped organics into GC column
Trap air sample through a charcoal
absorbent tube; desorb with carbon
disulfide and inject into GC column
Collect sample in pressurized stainless
steel cannister
GC/MS
GC/PID
GC/FID and GC/MS
GC/FID
GC/FID-ECD and GC/MS
2 (ig/L
0.1 /Jg/L
(Jg/L
range
5 #ig/L
No data
8 ppb
<1 ppb
3.1-4.5
ppb
4.3xl03
ppb
<1 ppb
No data
88X recovery
<101 RSD
100X recovery
94X-99Z re-
covery
No data
No data
No data
No data
No data
Otson and Williams
1981
Otson and Chan 1987
Drozd et al. 1978
Voznakova et al.
1978
Cucco 1987
Possanzini et al.
1982
Hester and Meyer
1979
Bertsch et al. 1974
NIOSH 1984 Method
1501
Pleil et al. 1988
>
!~
t-1
«!
w
O
>
t-1
X
M
H
se
o
o
co
00
-------
TAHT.K 6-2 (Continued)
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit
Accuracy
Reference
Draw air sample through a fitted-glass
bubbler containing isooctane; analyse
extract at 266 ran
UV
25*103
ppb
691 recovery
Yamamoto and Cook
1968
Fly ash
Add water to fly ash sample and extract
(Soxhlet); add benzene to extract and
shake; concentrate organic phase
GC/MS
Ho data
No data
Karasek et al. 1987
Fish
Extract fish muscle with dichloromethane;
cleanup on florisil column
GC/FID
5 HS/S
98X-102I re-
covery
Murray and Loclthart
1981
Freeze fish sample; homogenize in a slush
ice bath; add MeOH and sonicate slurry;
purge-and-trap on adsorbent
GC/MS equipped with
fused-silica capillary
column
5.lxlO"3
fig/r
5. ax RSD
Dreisch and Munson
1983
Fish and
sediment
Add sediments or ground fish sample to
water solution containing acrolein and
acrylonitrile; freeze sample and extract
in vacuum
GC/MS
25xl0-3
Sediments,
971 recovery;
fish, no data
Hiatt 1981
GC/MS * gas chromatography/mass spectrometry; GC/FID « gas chromatography/flame ionization detector; GC/ECD ¦ gas chromatography/electron
capture detector; GC/PID * gas chromatography/photoionization detector; GC/EICD = gas chromatography/electrolytic conductivity detector; UV ^
- ultraviolet spectrophotometry; RSD « relative standard deviation; ppro = parts per million; and ppb » parts per billion. ^
X
O
o
C/3
-------
85
6. ANALYTICAL METHODS
scanning for a smaller number of ions than does full-scan GS/MS, thereby
achieving better sensitivity of target volatile organic compounds at low
levels. Furthermore, some analytes (e.g., ethylbenzene) can be detected by
limited mass - scanning but not by full-scanning GC/MS because of the inherent
differences in sensitivity between the two methods. The absolute recoveries
of the late-eluting volatile organic compounds can be increased by employing a
capillary GC/MS as an alternative to the packed column approach and using a
less vigorously heated purge analyzing system (Cramer et al. 1988).
In addition to direct measurement of ethylbenzene in blood,
concentrations of ethylbenzene metabolites can also be determined in the
urine. A simple, sensitive, and specific automated HPLC method for direct
quantification of mandelic acid (MA) and phenylglyoxylic acid (PGA), which are
the major urinary metabolites of ethylbenzene in humans, was developed by
Ogata and Taguchi (1987, 1988). A possible disadvantage of the automated HPLC
method is that at low concentrations (less than 1 mg/L) in urine these acids
may not be distinguishable from other similar compounds (Ogata and Taguchi
1987).
A new HPLC method for the simultaneous determination of MA and PGA in
the urine of rats was developed by Sollenberg et al. (1985). An
isotachophoresis (ITP) technique may also be employed to quantify and detect
MA and PGA in rat urine (Sollenberg et al. 1985). The authors indicated that
there are essentially no significant difference between results obtained by
the two methods. However, the HPLC method is more sensitive for these
analytes, and the ITP method is more rapid.
6.2 ENVIRONMENTAL SAMPLES
Gas chromatography (GC) is the most widely used analytical technique for
quantifying concentrations of ethylbenzene in air, water, soil, and fish.
Various detection devices used for GC include gas chromatograph (GC) equipped
with a flame ionization detector (FID), mass spectrometer (MS),
photoionization detector (PID), electron capture detector (ECD), or
electrolytic conductivity detector (EICD). Because of the complexity of the
samples matrix and the usually low concentrations of volatile organic
components in environmental media, sample preconcentration is generally
required prior to GC analysis. Methods suitable for determining trace amounts
of ethylbenzene in aqueous and other environmental media can be divided into
three basic approaches that differ in the pretreatment of the sample and the
detection limit. These include gas purging-and-trapping technique, headspace
gas analysis, and extraction with organic solvent.
Gas purging-and-trapping is the most widely used method for the
isolation, concentration, and quantification of volatile organic compounds in
environmental samples (Bertsch et al. 1974, 1975; Clark et al. 1982; EPA
1986b). The purge-and-trap technique offers advantages over other techniques
in that it allows facile isolation and concentration of target compounds,
-------
86
6. ANALYTICAL METHODS
thereby improving overall limits of detection and recovery of sample,
detection limits of less than 1 jig of ethylbenzene per liter of sample have
een achieved (Brass 1982; EPA 1986b [Method 8010 and 8240]; Otson and
Williams 1982; Otson and Chan 1987; Voznakova et al. 1978). A serious
drawback of this technique, particularly for quantitative analysis, is
interference by impurities found in the stripping gas (EPA 1986b).
A headspace gas analyzer and GC has been employed by Drozd et al. (1978)
and Otson and Williams (1982) for the analysis and quantification of ethyl-
benzene in environmental samples. This method is simple and does not require
any sample preparation (Drozd et al. 1978; Otson and Williams 1982).
Extraction with organic solvents (liquid-liquid extraction) provides a
simple, rapid screening method for semi-quantitative determination of ethyl-
benzene in aqueous samples containing limited number of volatile organic
compounds but is less effective for aqueous samples containing large numbers
of volatile organic compounds. Furthermore, interference from the organic
gj^traction solvent (hexane) makes it more difficult to completely identify all
components (Karasek et al. 1987; Otson and Williams 1981).
A GC/MS and gas-purging-and-trapping technique has been recommended by
EPA (1986b, Method 8240) for determining ethylbenzene in water. Following GC
separation, compounds are ionized. Upon ionization, fragmentation occurs,
producing combinations of ions that are differentiated by their mass-to-charge
(m/z) ratio (Bertsch et al. 1975; Bertsch et al. 1974; Brass 1982; Shinohara
et al. 1981). Indications show that mass fragmentography offers a systematic,
accurate, and highly selective method for quantitation of organic compounds at
nanogram levels (Shinohara et al. 1981).
GC/PID is the method employed by NIOSH (1984, Method 1501) for
determining ethylbenzene levels in air. An automated GC/PID has been
developed to identify gas-phase hydrocarbons (including ethylbenzene) for
complex mixtures, such as vehicle exhaust gas (Hester and Meyer 1979). The
GC/PID measures sub ppb concentrations without using trapping or freezing-
concentration of samples before analysis (Hester and Meyer 1979). These
preconcentration steps are usually necessary because of the limited
sensitivity of FID technique commonly used for analysis of air samples. A
modified capillary GC/PID in tandem with an FID to obtain a more sensitive
method for detecting trace levels of ethylbenzene in the air was constructed
by Nutmagul et al. (1983).
A procedure to identify and quantify ethylbenzene in fish samples by
GC/MS using a fused-silica capillary column (FSCC) and vacuum extraction was
developed (Hiatt 1981, 1983; Dreisch and Munson 1983). An advantage of the
vacuum extraction technique is that the system does not require elevated
temperatures or addition ~>f reagents that could produce unwanted degradation
products (Hiatt 1981). Ihe FSCC provides a more attractive approach than a
packed column for chromat' graphic analysis of volatile organic compounds
-------
87
6. ANALYTICAL METHODS
because FSCC can be heated to a higher temperature (350°C) than that
recommended for packed column, thereby improving resolution and detection
limits (at nanogram per gram level) of eluting compounds. A physical
limitation for compounds that can be detected, however, is that the vapor
pressure of the compounds must be greater than 0.78 torr (~50°C) in the sample
chamber (Hiatt 1983).
6.3 ADEQUACY OF THE DATABASE
Section 104(i)5 of CERCLA 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 ethylbenzene is available. Where adequate information is not
available, ATSDR, in conjunction with 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
ethylbenzene.
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 or eliminate
the uncertainties of human health assessment. 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 Biomarkejrs of Exposure and Effect. Existing
methods have the sensitivity necessary to detect and measure low to trace
levels of ethylbenzene and its metabolites in biological fluids that might be
present in the general population, as well as concentrations of ethylbenzene
that might be associated with specific health effects. Information on levels
of ethylbenzene in tissues is limited and the existing methods are not as
sensitive as those used for environmental samples. Improvements in the
sensitivity of the methods for measuring concentrations of ethylbenzene in
tissues would be helpful.
Sensitive methods exist for measuring low to trace levels of
ethylbenzene and its metabolites in blood and urine. These analytical methods
are reliable and precise. Improvements in the sensitivity of the methods for
measuring concentrations of ethylbenzene in tissues, and improvements in the
selectivity of HPLC analysis of metabolites in urine would allow better
assessment of the correlation between levels in these media and observed
health effects.
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88
6. ANALYTICAL METHODS
Methods for Determining Parent Compounds and Degradation Products in
Environmental Media. Sensitive methods for measuring background levels of
,:hylbenzene in air and water, the media of most concern for exposure of the
general population and those populations located near hazardous waste sites
are available. Reliable methods also exist for measuring levels of
ethylbenzene in fish, sediments, and fly ash. Although several good
analytical methods are available for detecting ethylbenzene in environmental
media, further improvements in the accuracy and selectivity of these
techniques would be useful for evaluating the potential for human exposure and
health effects that might result from ethylbenzene contamination.
6.3.2 On-Going Studies
No on-going studies concerning methods for measuring and determining
ethylbenzene in environmental samples were reported.
The Environmental Health Laboratory Sciences Division of the Center for
Environmental Health and Injury Control, Centers for Disease Control, is
developing methods for the analysis of ethylbenzene and other volatile organic
compounds in blood. These methods use purge and trap methodology and magnetic
sector mass spectrometry which gives detection limits in the low parts per
trillion range.
-------
89
7. REGULATIONS AND ADVISORIES
Ethylbenzene is on the list of chemicals appearing in "Toxic Chemicals
Subject to Section 313 of the Emergency Planning and Community Right-to-Know
Act of 1986" (EPA 1987b).
The national and state regulations and guidelines pertaining to ethyl-
benzene in air, water, and other media are summarized in Table 7-1. No
international regulations or guidelines applicable to ethylbenzene were found.
-------
90
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to Etbylbenzene
Agency
Regulations:
a. Air:
OSHA
Description
Value
National
PEL TWA
STEL
100 ppm
125 ppm
References
OSHA 1989 (29 CFR
1910)
b. Water:
EPA ODW
EPA OSW
EPA OWRS
MCL (proposed) 0.7 mg/L
Groundwater monitoring list (Appendix NA
IX)
General permits under the NPDES NA
Effluent guidelines and standards: NA
General provisions
General pretreatment regulations for NA
existing and new sources of pollu-
tion
EPA 1989b
EPA 1987a (40
CFR 264,
Appendix IX)
EPA 1983 (40 CFR
122)
EPA 1979 (40 CFR
401.15)
EPA 1986a (40
CFR 403)
c. Other:
EPA
EPA OERR
EPA OSW
Guidelines:
a. Air:
ACGIB
NIOSH
b. Water:
EPA ODW
Chemical information rules require manu-
facturers to report production,
use, and exposure-related informa-
tion on ethylbenzene
Health and safety data reporting rules
require manufacturers, processors,
etc., to submit lists of unpub-
lished health and safety studies
for ethylbenzene
Reportable quantity (RQ):
Ethylbenzene
Spent nonhalogenated solvents and
still bottoms from the recov-
ery of these solvents
Hazardous waste:
Spent nonhalogenated solvents snd
still bottoms from the recovery
of these solvents
TLV TWA
STEL
REL TWA
IDLH
Health advisories:
1-Day (10-kg child)
10-Day (10-kg child)
Longer-term:
70-kg Adult
10-kg Child
NA
NA
1,000 lb
1,000 lb
NA
100 ppm (o435
mg/m3)
125 ppm (»545
mg/m3)
100 ppm (435
mg/m3)
2,000 ppm
32 mg/L
3.2 mg/L
3.4 mg/L
0.97 mg/L
(=1 mg/L)
EPA 1982 (40 CFR
712.30)
EPA 1987d (40
CFR 716.105)
EPA 1985b (40 CFR
302.4)
EPA 1981a (40
CFR 261.31)
ACGIH 1986
ACGIH 1986
NIOSH 1985
NIOSH 1985
EPA 1987c; IRIS
1989
-------
91
7. REGULATIONS AND ADVISORIES
TABLE 7-1 (Continued)
Agency
Description
Value
References
EPA OWRS
Lifetime 0.68 mg/L
MCLG (proposed) 0.7 mg/L
Ambient water quality criteria for
the protection of human health:
Ingestion of water and aquatic or- 1.4 mg/L
ganisms
Ingestion of aquatic organisms only 3.28 mg/L
EPA 1989b
EPA 1980
Other:
ACGIH
EPA
BE I:
Mandelic acid in urine end of shift
Ethylbenzene in end-exhaled air prior
to shift and end of workweek
Carcinogenic classification
RfD (oral)
2 g/L or below;
1.5 g/g of cre-
atinine
2 ppm
Group Da
0.1 mg/kg/day
ACGIH 1986
IRIS 1989
IRIS 1989
State
Regulations and
Guidelines :
a. Air:
Connecticut
North Dakota
Nevada
New York
South Carolina
Virginia
Acceptable ambient air concentration
8,700 fig/m3 <8-hr)
A.35 mg/m3 (8-hr)
5.A5 mg/m3 (1-hr)
10.357 mg/m3 (8-hr)
1,450 lig/m3 (1-yr)
4,350 fig/m3 (24-hr)
7,250 /ig/m3 (24-hr)
NATICH 1988
Massachusetts
118 Mg/m3 (24-hr)
118 tig/m3 (annual
averages)
MDEQE 1989
b.
Water:
Arizona
California
Illinois
Kansas
Minnesota
New Mexico
Vermont
Wisconsin
Massachusetts
Drinking water
FSTRAC 1988
Drinking water
Groundwater standard
680 /ig/L
680 (ig/L
1 Mg/L
680 Mg/L
680 /jg/L
750 jjg/L
1,400 it g/L
1,400 its/L
700 MS/L
486 pg/L
MDEQE 1989
MDEQE 1989 (310
CMR 6.00)
Rhode Island
Drinking water
680 ng/L
RIDH 1989
'Group D: Not classifiable as to human carcinogenicity.
OSHA - Occupational Safety and Health Administration; PEL ~ Permissible Exposure Limit; TWA " Time-Weighted
Average; STEL - Short-Term Exposure Limit; EPA - Environmental Protection Agency; ODW - Office of Drinking
Water; MCL ¦ Maximum Contaminant Level; OSW " Office of Solid Waste; NA ¦ not applicable; OWRS ¦ Office of
Water Regulations and Standards; NPDES - National Pollutant Discharge Elimination System; OERR - Office of
Emergency and Remedial Response; ACGIH - American Conference of Governmental Industrial Hygienists; TLV
¦ Threshold Limit Valuejl* National Institute for Occupational Safety and Health; REL " Recommended Exposure
Limit; IDLH - Immediately Dangerous to Life or Health; MCLG ¦ Maximum Contaminant Level Goal; BEI
¦ Biological Exposure Index; and RfD " Reference Dose.
-------
93
8. REFERENCES
Abdul AS, Gibson TL, Rai DN. 1987. Statistical correlations for predicting
the partition coefficient for nonpolar organic contaminants between aquifer
organic carbon and water. Haz Waste Haz Hat 4:211-222.
*ACGIH. 1986. Documentation of the threshold limit values and biological
exposure indices. Cincinnati, OH: American Conference of Governmental
Industrial Hygienists, 244.
Alarie Y. 1981. Bioassay for evaluating the potency of airborne sensory
irritants and predicting acceptable levels of exposure in man. Food Gosmet
Toxicol 19:623-626.
Alarie Y, Wakisaka I, Oka S. 1973. Sensory irritation by sulfur dioxide and
chlorobenzylidene malononitrile. Environ Physiol Biochem 3:53-64.
Aldyreva MV. 1983. Styrene and ethylbenzene. Encyclopedia of Occupational
Health and Safety. Vol. 2, 2113-2115.
Al-Gailany KAS, Houston JB, Bridges JW. 1977. The role of substrate
lipophilicity in determining type 1 microsomal P450 binding characteristics.
Biochem Pharmacol 27:783-788.
Almgren M, Grieser F, Powell JR, et al. 1979. A correlation between the
solubility of aromatic hydrocarbons in water and micellar solution, with their
normal boiling points. J Chem Eng Data 24:285-287.
Altshuller AP, Bellar TA. 1963. Gas chromatographic analysis of hydrocarbons
in the Los Angeles atmosphere. J Air Pollut Control Assoc 13:81-87.
Altshuller AP, Lonneman WA, Sutterfield FD, et al. 1971. Hydrocarbon
composition of the atmosphere of the Los Angeles basin - 1967. Environ Sci
Techno1 5:1009-1016.
*Amoore JE, Hautala E. 1983. Odor as an aid to chemical safety: Odor
thresholds compared with threshold limit values and volatilities for 214
industrial chemicals in air and water dilution. J Appl Toxicol 3:272-290.
*Cited in text
-------
94
8. REFERENCES
Andersen P. 1953. Inhibitory reflexes elicited from the trigeminal and
olfactory nerves in rabbits. Acta Physiol Scand 30:137-148.
*Andersson K, Fuxe K, Nilsen OG, et al. 1981. Production of discrete changes
in dopamine and noradrenaline levels and turnover in various parts of the rat
brain following exposure to xylene, ortho-, meta-, and para-xylene, and
ethylbenzene. Toxicol Appi Pharmacol 60:535-548.
^Andrew FD, Buschbom RL, Cannon WC, et al. 1981. Teratologic assessment of
ethylbenzene and 2-ethoxyethanol. Richland, WA: Battelle Pacific Northwest
Laboratory. PB83-208074., 108.
*Angerer J, Lehnert G. 1979. Occupational chronic exposure to organic
solvents: VIII. Phenolic compounds-metabolites of alkylbenzenes in man
Simultaneous exposure to ethylbenzene and xylenes. Int. Arch Occup Environ
Health 43:145-150.
*Angerer J, Wulf H. 1985. Occupational chronic exposure to organic solvents
XI. Alkylbenzene exposure of varnish workers: Effects on hematopoietic
system. Int Arch Occup Environ Health 56:307-321.
Anonymous. 1969. Analytical guides. Ethylbenzene. Vapor phase
chromatography method. Am Ind Hyg Assoc J 30:535-536.
*Antoine SR, DeLeon IR, 0'Dell-Smith RM. 1986. Environmentally significant
volatile organic pollutants in human blood. Bull Environ Contam Toxicol
36:364-371.
Aquatic Life Advisory Committee of the Ohio River Valley Water Sanitation
Committee. 1960. Aquatic life water quality criteria: Third progress
report. J Water Pollut Control Fed 32:65-82.
*Atkinson R, Carter WPL. 1984. Kinetics and mechanisms of the gas-phase
reactions of ozone with organic compounds under atmospheric conditions. Chen-
Rev 84:437-470.
*Atkinson R, Darnall KR, Pitts JN Jr. 1978. Rate constraints for reaction of
OH radicals and ozone with cresols at 300ql K. J Phys Chem 82:2759-2761 As
cited in NAS 1980.
Atkinson R, Carter WPL, Aschmann SM, et al. 1985. Atmospheric fates of
organic chemicals: Prediction of ozone and hydroxyl radical reaction rates
and mechanisms. Riverside, CA: Statewide Air Pollut Res Ctr.
EPA-600/3-85/063 (NTIS PB85 241-529)., 86.
-------
95
8. REFERENCES
*Atkinson R, Aschmann SM, Winer AM. 1987. Kinetics of the reactions of N03
radicals with a series of aromatic compounds. Environ Sci Technol
21:1123-1126.
*Bakke OM, Scheline RR. 1970. Hydroxylation of aromatic hydrocarbons in the
rat. Toxicol Appl Pharmacol 16:691-700.
Banerjee S. 198 5. Calculation of water solubility of organic compounds with
UNIFAC-derived parameters. Environ Sci Technol 19:369-370.
Banerjee S, Howard PH. 1988. Improved estimation of solubility and
partitioning through correction of UNIFAC-derived activity coefficients.
Environ Sci Technol 22:839-841.
Bardodej Z, Bardodejova E. 1961. [Value and application of exposure tests.
X. Exposure test for ethylbenzene], Ceskoslovenska Hygiena 6:537-545.
(Czechoslovakian).
^Bardodej Z, Bardodejova E. 1970. Biotransformation of ethylbenzene,
styrene, and alpha-methy1styrene in man. Am Ind Hyg Assoc J 31:206-209.
^Bardodej Z, Cirek A, 1988. Long-term study on workers occupationally
exposed to ethylbenzene. J Hyg Epidemiolo Microbiol Immunol 32:1-5.
•^Barker JF. 1987. Volatile aromatic and chlorinated organic contaminants in
groundwater at six Ontario landfills. Water Pollut Res J Can 22:33-48.
Barker JF, Tessmann JS, Plotz PE, et al. 1986. The organic geochemistry of a
sanitary landfill plume. J Contam Hydrol 1:171-189.
^Barnes D, Bellin J, DeRosa C, et al. 1987. Reference dose (RfD):
Description and use in health risk assessments. Appendix A: Integrated risk
information system supportive documentation. Washington, DC: US
Environmental Protection Agency, Office of Health and Environmental
Assessment. EPA/600/8-86-032a.
Battelle Labs. 1981. Teratologic assessment of ethylbenzene and
2-ethoxyethanol. US EPA/OTS Public Files. FYI-OTS-0581-0105 .
Bayer CW, Black MS. 1987. Capillary chromatographic analysis of volatile
organic compounds in the indoor environment. J Chromatogr Sci 25:60-64.
Beall JR, Ulsamer AG. 1981. Toxicity of volatile organic compounds present
indoors. Bull N Y Acad Med 57:978-996.
-------
96
8. REFERENCES
Bedding ND, Mclntyre AE, Perry R, et al. 1982. Organic contaminants in the
aquatic environment: I. Sources and Occurrence. Sci Total Environ
25:143-167.
Berglund RL, Whipple GM. 1987. Predictive modeling of organic emissions.
Chem Eng Prog 83:46-54.
*Bertsch W, Chang RC, Zlatkis A. 1974. The determination of organic
volatiles in air pollution studies: Characterization of profiles. J
Chromatogr Sci 12:175-182.
*Bertsch W, Anderson E, Holzer G. 1975. Trace analysis of organic volatiles
in water by gas chromatography-mass spectrometry with glass capillary columns.
J Chromatogr 112:701-718.
*Bestetti G, GaHi E. 1984. Plasmid-coded degradation of ethylbenzene and
1-phenylethanol in Pseudomonas fluorescens. FEMS Microbiology Letters
21:165-168. As cited in ECETOC 1986.
*Bio/dynamics Inc. 1986. A four day inhalation study of ethylbenzene in the
rat, mouse, and rabbit. Submitted to the US EPA/OTS Public Files. Document
#86870000432.
Bocek K. 1976. Relationships among activity coefficients, partition
coefficients and solubilities. Experientia Suppl 23:231-240.
*Bohon RL, Claussen WF. 1951. The solubility of aromatic hydrocarbons in
water. J Am Chem Soc 73:1571-1578.
Bond DL, Thodos G. 1960. Vapor pressures of alkyl aromatic hydrocarbons. J
Chem Eng Data 5:289-292.
*Bonner TA, Cornett CL, Desai BO, et al. 1981. Engineering handbook for
hazardous waste incineration. Report to US Environmental Protection Agency,
Office of Solid Waste, Washington, DC, by Monsanto Research Corp., Dayton, OH.
EPA/SW-899. NTIS PB81-248163
Bos R, Guicherit R, Hoogeveen A. 1977. Distribution of some hydrocarbons in
ambient air near Delft and the influence on the formation of secondary air
pollutants. Sci Total Environ 7:269-281.
Bos R, Goudena EJG, Guicherit R, et al. 1978. Atmospheric precursors and
oxidants concentrations in the Netherlands. In: Guicherit R, ed.
Photochemical smog/formation in the Netherlands. 20-59.
-------
97
8. REFERENCES
*Bouwer EJ, McCarty PL. 1983. Transformations of halogenated organic
compounds under dinitrification conditions. Appl Environ Microbiol
45:1295-1299.
*Bouwer EJ, McCarty PL. 1984. Modeling of trace organics biotransformation
in the subsurface. Groundwater 22:433-440.
*Brass HJ. 1982. Procedures for analyzing organic contaminants in drinking
water. Am Water Works Assoc J 74:107-112.
Brodzinsky R, Singh HB. 1983. Volatile organic chemicals in the atmosphere:
An assessment of available data. Menlo Park, CA: Atmospheric Science Center,
SRI International. Contract 68-02-3452., 198.
Brooke DN, Dobbs AJ, Williams N. 1986. Octanol:water partition coefficients
(P): Measurement, estimation, and interpretation, particularly for chemicals
with P>105. Ecotox Environ Safety 11:251-260.
Brown RL, Wasik SP. 1974. A method of measuring the solubilities of
hydrocarbons in aqueous solutions. J Res Natl Bur Stand Sec A 78:453-460.
*Bureau of the Census. 1985. U.S. Exports, schedule E., 2-69. As cited in
HSDB 1988.
Burkhard LP, Kuehl DW. 1986. N-octanol/water partition coefficients by
reverse phase liquid chromatography/mass spectrometry for eight
tetrachlorinated planar molecules. Chemosphere 15:163-167.
Buswell JA, Jurtshuk P. 1969. Microbial oxidation of hydrocarbons measured
by oxygraphy (using a Clark oxygen electrode). Arch Mikrobiol 64:215-222.
*Calabrese EJ. 1978. Pollutants and high-risk groups. The biological basis
of increased human susceptibility to environmental and occupational
pollutants. New York, NY: John Wiley and Sons, 186-193.
Campbell JR, Luthy RG. 1985. Prediction of aromatic solute partition
coefficients using the UNIFAC group contribution model. Environ Sci Tech
19:980-985.
Canady WT, Robinson DA, Colby HD. 1974. A partition model for hepatic
cytochrome P-450-hydrocarbon complex formation. Biochem Pharmacol
23:3075-3078.
Chao J, Lin CT, Chung TH. 1983. Vapor pressure of coal chemicals. J Phys
Chem Ref Data 12:1033-1063.
CHEMFATE. 1989. Syracuse Research Corporation, Syracuse, NY. January 1989.
-------
98
8. REFERENCES
Chin BH, Sullivan LJ, Kozbelt SJ, et al. 1978. Excretion and urinary
metabolic profiles of ethylbenzene, ethylcyclohexane, and methylethylbenzene
n rats and dogs [Abstract]. Toxicol Appl Pharmacol 45:240.
*Chin BH, McKelvey JA, Calisti LJ, et al. 1980a. A comparison of in vivo and
in vitro (tissue explant) techniques: Metabolic profile of ethylbenzene in
the rat and the dog. Bull Environ Contain Toxicol 25:241-245.
*Chin BJ, McKelvey JA, Tyler TR, et al. 1980b. Absorption, distribution, and
excretion of ethylbenzene, ethylcyclohexane, and methylethylbenzene isomers in
rats. Bull Env Contam Toxicol 24:477-483.
Chin YP, Weber WJ Jr, Voice TC. 1986. Determination of partition
coefficients and aqueous solubilities by reverse phase chromatography-II.
Evaluation of partitioning and solubility models. Water Res 20:1443-1450.
Chiou CT. 1985. Partition coefficients of organic compounds in lipid-water
systems and correlations with fish bioconcentration factors. Environ Sci
Techno1 19:57-62.
*Chiou CT, Porter PE, Schmedding DW. 1983. Partitioning equilibria of
nonionic organic compounds between soil organic matter and water. Environ Sci
Technol 17:227-231.
*CHRIS. 1985. Chemical hazards response information system. US Department
of Transportation, US Coast Guard, Washington, DC.
*Clark Al, Mclntyre AE, Lester JN, et al. 1982. Evaluation of a Tenax GC
sampling procedure for collection and analysis of vehicle-related aromatic and
halogenated hydrocarbons in ambient air. J Chromatogr 252:147-157.
Clark Al, Mclntyre AE, Lester JN, et al. 1984. Ambient air measurements of
aromatic and halogenated hydrocarbons at urban, rural and motorway locations.
Sci Total Environ 39:265-279.
Clark Al, Mclntyre AE, Perry R, et al. 1984. Monitoring and assessment of
ambient atmospheric concentrations of aromatic and halogenated hydrocarbons at
urban, rural, and motorway locations. Environ Pollut Series B 7:141-158.
Claus D, Walker N. 1964. The decomposition of toluene by soil bacteria. J
Gen Microbiol 36:107-122.
*Climie IJG, Hutson DH, Stoydin G. 1983. The metabolism of ethylbenzene
hydroperoxide in the rat. Xenobiotica 13:611-618.
*CLPSD. 1989. Contract laboratory program statistical database. US
Environmental Protection agency, July 12, 1989.
-------
99
8. REFERENCES
*Cole RH, Frederick RE, Healy RP, et al. 1984. Preliminary findings of the
priority pollutant monitoring project of the nationwide urban runoff program.
J Water Pollut Control Fed 56:898-908.
*Colenutt BA, Thorburn S. 1980. Gas chromatographic analysis of trace
hydrocarbon pollutants in water samples. Int J Environ Stud 15:25-32.
Confidential. 1987. Industrial hygiene evaluation study with attachments and
cover letter dated 101687 (sanitized). Submitted to US EPA/OTS Public Files.
US EPA/OTS. Document #86-880000078.
*Conkle JP, Camp BJ, Welch BE. 1975. Trace composition of human respiratory
gas. Arch Env Health 30:290-295.
*Cotruvo JA. 1985. Organic micropollutants in drinking water: An overview.
Sci Total Environ 47:7-26.
Cox DP, Goldsmith CD. 1979. Microbial conversion of ethylbenzene to
1-phenethanol and acetophenone by Nocardia tartaricans ATCC 31190. Appl
Environ Microbiol 38:514-520.
*Cragg ST, Clarke EA, Daly IW, et al. 1989. Subchronic inhalation
toxicity of ethylbenzene in mice, rats, and rabbits. Fundam Appl Toxicol
13:399-408.
*Cramer PH, Boggess KE, Hosenfeld JM, et al. 1988. Determination of organic
chemicals in human whole blood: Preliminary method development for volatile
organics. Bull Environ Contam Toxicol 40:612-618.
*Cucco JA. 1987. A method of determining the efficiency of air sampling
traps to collect and release volatile organic compounds. Analytical Letters
20:223-234.
Darnall KR, Lloyd AC, Winer AM, et al. 1976. Reactivity scale for
atmospheric hydrocarbons based on reaction with hydroxyl radicals. Environ
Sci Technol 10:692-696.
*Dean BJ, Brooks TM, Hodson-Walker G, et al. 1985. Genetic toxicology
testing of 41 industrial chemicals. Mutat Res 153:57-77.
De Bortoli M, Knoeppel H, Pecchio E, et al. 1986. Concentrations of selected
organic pollutants in indoor and outdoor air in northern Italy. Environ Int
12:343-350.
-------
100
8. REFERENCES
*De Ceaurriz JC, Micillino JC, Bonnet P, et al. 1981. Sensory irritation
caused by various industrial airborne chemicals. Toxicol Lett (Amst)
:137 -144.
Dmitriev MT, Rastyannikov EG, Etlin SN, et al. 1984. [Chromatographic mass
spectrometric study of toxic substances adsorbed on dust]. Gig Sanit:44-47.
(Russian).
Dowty BJ, Laseter JL, Storer J. 1976. The transplacental migration and
accumulation in blood of volatile organic constituents. Pediatr Res
10:696-701.
*Dreisch FA, Munson TO. 1983. Purge-and-trap analysis using fused silica
capillary column GC/MS. J Chromatogr Sci 21:111-118.
*Drozd J, Novak J, Rijsk JA. 1978. Quantitative and qualitative head-space
gas analysis of parts per billion amounts of hydrocarbons in water: A study
of model systems by capillary-column gas chromatography with splitless sample
injection. J Chromatogr:471-482.
*Dutkiewicz T, Tyras H. 1967. A study of the skin absorption of ethylbenzene
in man. Br J Ind Med 24:330-332.
Dutkiewicz T, Tyras H. 1968. Skin absorption of toluene, styrene, and xylene
by man. Br J Ind Med 25:243.
*ECET0C. 1986. Joint assessment of commodity chemicals. No. 7:
Ethylbenzene. Brussels, Belgium: European Chemical Industry Ecology and
Toxicology Center.
*Ehrhardt M, Petrick G. 1984. On the sensitized photo-oxidation of
alkylbenzenes in seawater. Mar Chem 15:47-58.
*Eiceman GA, McConnon JT, Zaman M, et al. 1986. Hydrocarbons and aromatic
hydrocarbons in groundwater surrounding an earthen waste disposal pit for
produced water in the duncan oil field of New Mexico. Int J Environ Anal Chem
24:143-162.
*Elcombe CR, Bridges JW, Gray TJ, et al. 1975. Studies on the interaction of
safrole with rat hepatic microsomes. Biochem Pharmacol 24:1427-1433.
*E1 Masry AM, Smith JN, Williams RT. 1956. The metabolism of alkylbenzenes:
n-Propylbenzene and n-butylbenzene with further observations on ethylbenzene.
Biochem J 64:50-56.
*Elovaara E, Engstrom K, Vainio H. 1982. Unaltered metabolism of m-xylene in
the presence of ethylbenz-ne. Dev Biochem 23:265-268.
-------
101
8. REFERENCES
*Elovaara E, Engstrora K, Vainio H. 1984. Metabolism and disposition of
simultaneously inhaled m-xylene and ethylbenzene in the rat. Toxicol Appl
Pharmacol 75:466-478.
*Elovaara E, Engstrom K, Nickels J, et al. 1985. Biochemical and
morphological effects of long-term inhalation exposure of rats to
ethylbenzene. Xenobiotica 15:299-308.
*Engstrom KM. 1984. Metabolism of inhaled ethylbenzene in rats. Scand J
Work Environ Health 10:83-88.
Engstrom KM. 1984. Urinalysis of minor metabolites of ethylbenzene and
m-xylene. Scand J Work Environ Health 10:75-82.
*Engstrom J, Bjurstrom R. 1978. Exposure to xylene and ethylbenzene. II.
Concentration in subcutaneous adipose tissue. Scand J Work Environ Health
4:195-203.
^Engstrom K, Riihimaki V, Laine A. 1984. Urinary disposition of ethylbenzene
and m-xylene in man following separate and combined exposure. Int Arch Occup
Environ Health 54:355-363.
*Engstrom K, Elovaara E, Aitio A. 1985. Metabolism of ethylbenzene in the
rat during long-term intermittent inhalation exposure. Xenobiotica
15:281-286.
Enzminger JD, Ahlert RC. 1987. Environmental fate of polynuclear aromatic
hydrocarbons in coal tar. Environ Technol Lett 8:269-278.
•*EPA. 1979. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 401.15.
*EPA. 1980. Ambient water quality criteria for ethylbenzene. Washington,
D.C: US Environmental Protection Agency. EPA-440/5-80-048., 53.
*EPA. 1981. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 261.31.
*EPA. 1982. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 712.30.
*EPA. 1983. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 122 Appendix D.
-------
102
8. REFERENCES
EPA. 1984. Health effects assessment for ethylbenzene. Cincinnati, OH: US
Environmental Protection Agency, Environmental Criteria and Assessement
Office. EPA/540/1-86/008.
*EPA. 1985a. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 302.4.
*EPA. 1985b. Drinking water criteria document for ethylbenzene. Prepared by
the Office Assessment. EPA-600/X-84-163-1.
*EPA. 1986a. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 403.
*EPA. 1986b. Test methods for evaluating solid waste SW-846. US
Environmental Protection Agency.
*EPA. 1986c. Reference values for risk assessment (Final draft).
Cincinnati, Ohio: US Environmental Protection Agency, Office of Solid Waste
ECAO-CIN-477
*EPA. 1987a. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 264 Appendix IX.
*EPA. 1987b. US Environmental Protection Agency. Federal Register.
52:21152-21208.
*EPA. 1987c. Health advisory for ethylbenzene. Washington, DC: US
Environmental Protection Agency, Office of Drinking Water.
*EPA. 1987d. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 716.105.
*EPA. 1989a. Interim Methods for Development of Inhalation Reference Doses.
US Environmental Protection Agency, Office of Health and Environmental
Assessment. Washington, DC. EPA 600/8-88/066F.
*EPA. 1989b. US Environmental Protection Agency. Federal Register
54:22062-22160.
*Ferrario JB, Lawler GC, DeLeon IR, et al. 1985. Volatile organic pollutants
in biota and sediments of Lake Pontchartrain. Bull Environ Contam Toxicol
34:246-255.
*Fishbein L. 1985. An overview of environmental and toxicological aspects of
aromatic hydrocarbons. IV. Ethylbenzene. Sci Total Environ 44:269-287.
-------
103
8. REFERENCES
*Florin I, Rutberg L, Curvall M, et al. 1980. Screening of tobacco smoke
constituents for mutagenicity using the Ames test. Toxicology 18:219-232.
Forrest RG, Worden MH, Perez DR. 1984. A Superfund removal action with
evaluation of safety procedures. Hazardous material spills conference
Proceedings. Prevention, Behavior, Control and Cleanup of Spills and Waste
Sites., April 9-12, Nashville, TN; 17-23.
Forziati AF, Norris WR, Rossini FD. 1949. Vapor pressures and boiling points
of sixty API-NBS hydrocarbons. J Res Natl Bureau Standards 43:555-563.
*FSTRAC. 1988. Summary of state and federal drinking water standards and
guidelines [Database]. Federal- State Toxicology and Regulatory Alliance
Committee. March 1988.
Fujita T, Iwasa J, Hansch C. 1964. A new substituent constant, pi, derived
from partition coefficients. J Amer Chem Soc 86:5175-5180.
Furnas DW, Hine CH. 1958. Neurotoxicity of some selected hydrocarbons. Arch
Ind Health 18:9-15.
Fusillo TV, Hochreiter JJ J, Lord DG. 1985. Distribution of volatile organic
compounds in a New Jersey coastal plain aquifer system. Groundwater
23:354-360.
Gamberale F, Annwall G, Hultengren M. 1978. Exposure to xylene and
ethylbenzene. III. Effects on central nervous function. Scand J Work
Environ Health 4:204-211.
Gerarde HW. 1956. Toxicological studies on hydrocabons. II. A comparative
study of the effect of benzene and certain mono-n-alkylbenzenes on hemopoiesis
and bone marrow metabolism in rats. AMA Arch Ind Health 13:468-474.
Gerarde HW. 1959. Toxicological studies on hydrocarbons. III. The
biochemorphology of the phenylalkanes and phenylalkenes. AMA Arch Ind Health
19:403-418.
*Gerarde HW. 1963. Toxicological studies on hydrocarbons: IX. The
aspiration hazard and toxicity of hydrocarbons and hydrocarbon mixtures. Arch
Env Health 6:329-341.
Gershbein LL. 1975. Liver regeneration as influenced by the structure of
aromatic and heterocyclic compounds. Res Commun Chem Pathol Pharmacol
11:445-466.
-------
104
8. REFERENCES
Gibson DT 1977 Biodegradation of aromatic petroleum hydrocarbons. In:
Wolfe DA, ed. Fate and effects of petroleum hydrocarbons in marine organism
and ecosystems. Vol. 4, New York, NY 36-46.
Gibson DT, Koch JR, Kallio RE. 1968. Oxidative degradation of aromatic
hydrocarbons by microorganisms. I. Enzymatic formation of catechol from
benzene. Biochemistry 7:2653-2662.
*Gibson DT, Geschwendt B, Yeh WK, et al. 1973. Initial reactions in the
oxidation of ethylbenzene by Pseudomonas putida. Biochemistry 12.1520 1528.
Giger W, Schaffner C. 1981. Groundwater pollution by volatile chemicals.
Stud Environ Sci 17 (Qual. Groundwater):517-522.
*Gillette JR, Mitchell JR, Brodie BB. 1974. Biochemical mechanisms of drug
toxicity. Ann Rev Pharmacol 14:271-288.
Gossett RW, Brown DA, Young DR. 1983. Predicting the bioaccumulation of
organic compounds in marine organism using octanol/water partition
coefficients. Mar Pollut Bull 14:387-392.
Grant WM. 1986. Toxicology of the Eye. In: 3rd ed. Springfield, IL:
Charles C. Thomas, 413.
*Greiner JU, Kramer RE, Robinson DA, et al. 1976. Interaction of aromatic
hydrocarbons and drugs with adrenal microsomal cytochrome P-450 lb the gumea
pig, Biochem Pharmacol 25:951-955.
Grigor-eva KV, Klyuzko AS. 1971. Studies of the metabolite of styrene and
ethylbenzene in urine. Hyg Sanit 36:136-137.
Grob K Grob G. 1971- Gas-liquid chromatographic-mass spectrometric
investigation of C6-C20 organic compounds in an urban atmosphere. An
application of ultra trace analysis on capillary columns. J Chromatogr
62:1-13.
*Gromiec JP, Piotrowski JK. 1984. Urinary mandelic-acid as an exposure test
for ethylbenzene. Int Arch Occup Environ Health 55:61-72.
*Grosjean D, Fung K. 1984. Hydrocarbons and carbonyls in Los Angeles air. >
Air Pollut Control Assoc 34:537-543.
*Grovenstein E Jr, Mosher AJ. 1970. Reaction of atomic oxygen with aromatic
hydrocarbons [Letter). J Am.r chem Soc 92:3810-3812.
-------
105
8. REFERENCES
*Gschwend PM, Zafirlou OC, Mantoura RFC, et al. 1982. Volatile organic
compounds at a coastal site, 1. Seasonal variations. Environ Sci Technol
16:31-38.
*Hampton CV, Pierson WR, Schuetzle D, et al. 1983. Hydrocarbon gases emitted
from vehicles on the road. 2. Determination of emission rates from diesel
and spark-ignition vehicles. Environ Sci Technol 17:699-708.
Hannah SA, Austern BM, Eralp AE, et al. 1986. Comparative removal of toxic
pollutants by six wastewater treatment processes. J Water Pollut Control Fed
58:27-34.
*Hansch C, Leo A. 1979. Substituent constants for correlation analysis in
chemistry and biology. New York, NY: John Wiley & Sons, 232. As cited in
HSDB 1988.
Hansch C, Quinlan JE, Lawrence GL. 1968. The linear-free energy relationship
between partition coefficients and the aqueous solubility of organic liquids.
J Org Chem 33:347-350.
Hansch C, Leo A, Nikaitani D. 1972. On the additive-constitutive character
of partition coefficients. J Org Chem 37:3090-3092.
Hardin BD, Bond GP, Sikov MR, et al. 1981. Testing of selected workplace
chemicals for teratogenic potential. Scand J Work Environ Health 7
(Suppl.4):66-75.
Harkonen H, Lindstrom K, Seppalainen AM, et al. 1978. Exposure-response
relationship between styrene exposure and central nervous functions. Scand J
Work Environ Health 4:53-59.
*Harkov R, Kebbekus B, Bozzelli JW, et al. 1983. Measurement of selected
volatile organic compounds at three locations in New Jersey during the summer
season. J Air Pollut Control Assoc 33:1177-1183.
Harkov R, Kebbekus B, Bozzelli JW, et al. 1984. Comparison of selected
volatile organic compounds during the summer and winter at urban sites in New
Jersey. Sci Tot Env 38:259-274.
Harkov R, Kebbekus B, Bozzelli JW. 1987. Volatile organic compounds at urban
sites in New Jersey. In: Lioy, Daisey, eds. Toxic Air Pollut. Chelsea, MI:
Lewis Pub. Inc, 69-90.
Hartwell TD, Crowder JH, Sheldon LS, et al. 1985. Levels of volatile
organics in indoor air. Proc.-APCA Annu. Meet 78th., 1-12.
-------
106
8. REFERENCES
Hawthorne AR, Gammage RB, Dudney CS, et al. 1983. Preliminary results of a
forty-home indoor air pollutants monitoring study. Spec. Conf. Meas Monit
Non-Criter (Toxic) Contam. Air. Pittsburgh, PA: APCA., 514-526.
*Helmes CT. 1990. Written communication (August 14) to Yee-Wan Stevens
Agency for Toxic Substances and Disease Registry, regarding workplace exposure
levels of ethylbenzene. Synthetic Organic Chemical Manufacturers Associati
Inc., Washington, D.C. °n'
*Herron JT, Huie RE. 1973. Rate constants for the reactions of atomic oxygen
(03P) with organic compounds in the gas phase. J Phys Chem Ref Data
2:467-518.
*Hester NE, Meyer RA. 1979. A sensitive technique for measurement of benzene
and alkylbenzenes in air. Environ Sci Technol 13:107-109.
*Hiatt MH. 1981. Analysis of fish and sediment for volatile priority
pollutants. Anal Chem 53:1541-1543.
*Hiatt MH. 1983. Determination of volatile organic compounds in fish samples
by vacuum distillation and fused silica capillary gas chromatography-mass S
spectrometry. Anal Chem 55:506-516.
Higgins IJ, Best DJ, Scott D. 1981. Hydrocarbon oxidation by methylosinus
trichosporium: Metabolic implications of the lack of specificity of methane
monoxygenase. Microb. Growth CI Compd, Proc. Int. Symp 3., 11-20.
*Hodson J, Williams NA. 1988. The estimation of the adsorption coefficient
(KOC) for soils by high performance liquid chromatography. Chemosphere
17:67-77.
Holmberg B, Malmfors T. 1974. The cytotoxicity of some organic solvents
Environ Res 7:183-192.
Holmberg B, Jakobson I, Malmfors T. 1974. The effect of organic solvents
erythrocytes during hypotonic hemolysis. Environ Res 7:193-205. °n
*Hoshino M, Akimoto H, Okuda M. 1978. Photochemical oxidation of benzene
toluene, and ethylbenzene initiated by hydroxyl radicals in the gas phase '
Bull Chem Soc Jpn 51:718-724.
*HSDB. 1988. Hazardous Substances Databank. National Library of Medicine
National Toxicology Information Program, Bethesda, MD. December 9, 1988
-------
107
8. REFERENCES
Hutchinson TC, Hellebust JA, Tam D, et al. 1980. The correlation of the
toxicity to algae of hydrocarbons and halogenated hydrocarbons with their
physical-chemical properties. In: Afghan BK, MacDay D, eds. Hydrocarbon
halo, hydrocarbon aquatic environ. New York, NY: Plenum Press, 577-586.
Huyskens PL, Tack JJ. 1975. Specific interactions of phenols with water. J
Phys Chem 79:1654-1658.
Imamura K, Fuji T. 1979. [Rapid determination of toluene, ethylbenzene, and
xylene isomers at ppb level in ambient air by mass fragmentography]. Bunseki
Kagaku 28:549-554. (Japanese).
Institute of Environmental Medicine. 1985. Analysis of benzene and other
volatile organic compound data obtained in the project on airborne toxic
elements and organic species. Submitted to the US EPA/OTS Public Files.
FYl-AX-1185-0321.
Ioffe BV, Isidorov VA, Zenkevich IG. 1979. Certain regularities in the
composition of volatile organic pollutants in the urban atmosphere. Environ
Sci Technol 13:864-868.
*IRIS. 1989. Integrated Risk Information System [Database], US Environmental
Protection Agency, Washington, DC. March 1, 1989.
*Ivanov SV. 1962. [Toxicology of ethylbenzene.] Tr Voronezh Gos Med Inst
47:80-82. (Russian).
Ivanov SV. 1964. [Materials on toxicity and hygienic rating ethylbenzol
content in the atmosphere of industrial premises]. Gig Tr Prof Zabol 8:9-14.
(Russian).
*Jamison VW, Raymond RL, Hudson JO. 1970. Hydrocarbon cooxidation by
Nocardia corallina strain V-49. Develop Ind Microbiol 12:99-105.
Johnson D, Billick I, Moschandreas D, et al. 1984. Emission rates from
unvented gas appliances. Indoor Air. Volume 4. Chemical characterization
and personal exposure. Proceedings of the Internatinal Conference (3rd) on
Indoor Air Quality and Climate Held in Stockholm on August 20-24, 1984. NTIS
PB85-104-214., 367-374.
Johnstone RAW, Quan PM, Carruthers W. 1962. Composition of cigarette smoke:
Some low-boiling components. Nature 195:1267-1269.
*Jonsson A, Persson KA, Grigoriadis V. 1985. Measurements of some low
molecular-weight oxygenated, aromatic, and chlorinated hydrocarbons in ambient
air and in vehicle emissions. Environ Int 11:383-392.
-------
108
8. REFERENCES
*Junk GA, Ford CS. 1980. A review of organic emissions from selected
combustion processes. Chemosphere 9:187-230.
Juttner F. 1986. Analysis of organic compounds (VOC) in the forest air of
southern Black Forest. Chemosphere 15:985-992.
Kappeler T, Wuhrmann K. 1978. Microbial degradation of the water solubule
fraction of gas oil. I. Water Res 12:327-333.
*Karasek FW, Charbonneua GM, Reuel GJ, et al. 1987. Determination of organic
compounds leached from municipal incinerator fly ash by water at different pH
levels. Anal Chem 59:1027-1031.
*Katzman H, Libby WF. 1975. Hydrocarbon emissions from jet engines operated
at simulated high altitude supersonic flight conditions. Atmos Environ
9:839-842.
*Kaubisch N, Daly JW, Jerina DM. 1972. Arene oxides as intermediate in the
oxidative metabolism of aromatic compounds. Isomerization of
methyl-substituted arene oxides. Biochemistry 11:3080-3088.
*Kawamura K, Kaplan XR. 1983. Organic compounds in the rainwater of Los
Angeles. Environ Sci Tech 17:497-501.
Kelley RD. 1985. Synthetic organic compound sampling survey of public water
supplies. Des Moines, IA: Iowa Department of Water, Air and Waste
Management. NTIS PB85-214427/AS., 38.
*Kiese M, Lenk W. 1974. Hydroxyacetophenones: Urinary metabolites of
ethylbenzene and acetophenone. Xenobiotica 4:337-343.
*Kinlin TE, Muraldihara R, Pittet AO, et al. 1972. Volatile components of
roasted filberts. J Agric Food Chem 20:1021. As cited in EPA 1980.
Kool HJ Van Kreijl CF, Zoeteman BCJ. 1982. Toxicology assessment of organic
compounds in drinking water. Crit Rev Env Control 12:307-357.
Kopfler FC, Melton GG, Mullaney JL, et al. 1977. Human exposure to water
pollutants. Adv Environ Sci Technol 8:419-433.
Krost KJ, Pellizzari ED, Walburn SG, et al. 1982. Collection and analysi
hazardous organic emissions. Anal Chem 54.810-817.
Krotoszynski BK, Bruneau GM, O'Neill HJ. 1979. Measurement of chemical
inhalation exposure in urban population in the presence of endogenous
effluents. J Anal Toxicol 3:225-234.
s of
-------
109
8. REFERENCES
Lambotte-Vandepaer M, Duverger-Van Bogaert M, De Meester C, et al. 1979.
Styrene induced modifications of some rat liver enzymes involved in the
activation and inactivation of xenobiotics. Biochem Pharmacol 28:1653-1660.
LaRegina J, Bozzelli JW, Harkov R, et al. 1986. Volatile organic compounds
at hazardous waste sites and a sanitary landfill. Environ Prog 5:18-27.
Lehmann E, Gmehling J, Weidlich U. 1986. Survey on organic solvents in
various products and methods for estimating workplace exposures. Prog Clin
Biol Res 220:31-41.
*Ligocki MP, Leuenberger C, Pankow JF. 1985. Trace organic compounds in
rain-II. Gas scavenging of neutral orgnaic compounds. Atmos Environ
19:1609-1617.
Litton Bionetics Inc. 1978. Teratology study in rats: Xylene: Final
report. Submitted to the US EPA/OTS Public Files. 878210350.
Lloyd AC, Darnall KR, Winer AM, et al. 1976. Relative rate constants for
reaction of the hydroxyl radical with a series. J Phys Chem 80:789-794.
Logemann W, Giradli P, Gagliardo E, et al. 1964. [Presence of mandelic acid
and hippuric acid in the urine of individuals given (oral) ethylbenzene].
Hoppe-Seylers Z Physiol Chem 337:48-49. (German).
Lonneman WA, Bellar TA, Altshuller AP. 1968. Aromatic hydrocarbons in the
atmosphere of the Los Angeles basin. Environ Sci Technol 2:1017-1020.
*Lovegren NV, Fisher GS, Legendre MG, et al. 1979. Volatile constituents of
dried legumes. J Agric Food Chem 27:851-853.
Lowry LK. 1986. Biological exposure index as a complement to the TLV. J
Occup Med 28:578-582.
*Lyman WJ, Reehl WF, Rosenblatt DH. 1982. Handbook of chemical property
estimation methods. New York, NY: McGraw-Hill Book Company, 15-25.
*Mabey WR, Smith JH, Podoll RT, et al. 1982. Aquatic fate process data for
organic priority pollutants. Report by SRI International, Menlo Park, CA, to
US Environmental Protection Agency, Office of Water Regulations and Standards,
Monitoring and Data Support Division, Washington, DC. EPA 440/4-81-014.
Maclntyre WG, Smith CL, Defur PO, et al. 1981. Hydrocarbon fuel chemistry:
Sediment water interaction. Report to Air Force Engineering and Service
Laboratory, Air Force Engineering and Services Center, Tyndall Air Force Base,
Florida, by Virginia Institute of Marine Science, Gloucester Point, VA.
AFESC/ESL-TR-82-06 (NTIS AD-A117928)., 53.
-------
110
8. REFERENCES
*Mackay D. 1979. Finding fugacity feasible. Environ Sex Techno1
13:1218-1223
, . TTV 1 QQi & critical review of Henry's law constants for
i j ^ch-ReŁ Data
tw cut-Vio-rlAnd RP 1979. Determination of air-water Henry's
ra:Cc:L?;„Strtofiy^ophoMc P.UUC. Environ S=i Technol 13:333-3,7.
r, u A QV.il. UY et al 1980. Relationships between aqueous
coefficients . Che„osphe,e 9:701-711.
tnt7 ,1 1982 Vapor pressure correlations for
™™1 16"6"-649'
*„ackiso„FV,
guidelines for c Public Health Service, Centers for Disease Control,
Nationaflnstitute for Occupational Safety and Health, US Department of Labor,
Occupational Safety and Health Administration.
Maier A, Ruhe R, .^"IJ^et al^l974. Łalth Wjrf q
evaluation/toxicity lvania. Rockville, MD: National Institute for
Health. NT1S Publ. No. PB-232-729/A03 .
nn M,vinnpv RE 1966. Oxidative abilities of benzene-acclimated
Malaney GW, McKmney Kh. , n3-302-309
activated sludge. Water Sewage Works 113.JUi
• n r^rri G et al. 1985. Experimental studies on benzene
*Maltoni C, Conti , Bologna institute of Oncology: Current results and
carcinogenicity at cn® 7-A1S-446
ongoing research. Am J Ind Med 7.415 446,
mtt i 079 Determination of aromatic compounds
Malyarova LK. Nesterova 1972 Dew 16:58-59.
(benzene and its homologues) m the air.
M TA 1982. Teratogenicity of a commercial xylene
Marks TA l*dou* TA «°«^coll^lron Health 9:97-105.
mixture in the mouse. J ioxicoj.
, n « 4-^-1 o-r M 1983 Evaluation of potential employee exposures
while LSing ignition resistant polystyrene. J Cell Plast 19:227-236.
v. mt Anrtprs MW. 1973. Effect of phenobarbital treatment on
*Maylm GA, °°P® ' h t vitro metabolism of ethylbenzene. J Med Chem
the stereochemistry ot tne m
16:606-610.
-------
Ill
8. REFERENCES
*Mayrsohn H, Kuramoto M, Crabtree H, et al. 1978. Hydrocarbon composition of
Los Angeles gasolines. California State Air Resources Board, El Monte, CA.
As cited in NAS 1980.
McAuliffe C. 1963. Solubility in water of C1-C9 hydrocarbons. Nature
200:1092-1093.
McAuliffe C. 1966. Solubility in water of paraffin, cycloparaffin, olefin,
acetylene, cycloolefin and aromatic hydrocarbons. J Phys Chem 70:1267-1275.
^McGregor DB, Brown A, Cattanach P, Edwards I, McBride D, Riach C, Caspary WJ.
1988. Responses of the L5178Y tk+/tk" mouse lymphoma cell forward mutation
assay: III. 72 Coded chemicals. Environ Molecular Mutagenesis 12:85-154.
*McMahon RE, Sullivan HR. 1966. Microsomal hydroxylation of ethylbenzene.
Stereospecificity and the effect. Life Sci 5:921-926.
*McMahon RE, Sullivan HR, Craig JC, et al. 1969. The microsomal oxygenation
of ethylbenzene: Isotopic, stereochemical, and induction studies. Arch
Biochem Biophys 132:575-577.
*MDEQE. 1989. Written communication regarding Massachusetts guidelines for
ethylbenzene. Boston, Mass: Department of Environmental Quality Engineering,
Office of Research and Standards (May 8).
Mill T. 1982. Hydrolysis and oxidation processes in the environment.
Environ Toxicol Chem 1:135-141.
Miller RL, Ettre LS, Johansen NG. 1983. Quantitative analysis of
hydrocarbons by structural group type in gasolines and distillates. II.
Liquid chromatography. J Chromatogr 259:393-412.
Miller RL, Ettre LS, Johansen NG. 1983. Quantitative analysis of
hydrocarbons by structural group type in gasolines and distillates. III.
Combined use of liquid and gas chromatography. J Chromatogr 264:19-32.
Miyake K, Kitaura F, Mizuno N, et al. 1987. Determination of partition
coefficient and acid dissociation constant by high-performance liquid
chromatography on porous polymer gel as a stationary phase. Chem Pharmacol
35:377-388.
Mohtashamipur E, Norpoth K. 1987. Chromosome damaging of alkylated and
halogenated benzenes on bone marrow of mice [Abstract]. Eighteenth Annual
Meeting of the Environmental Mutagen Society, San Francisco, California, USA,
April 8-12, 1987 9:75.
-------
112
8. REFERENCES
*Mohtashamipur E, Norpoth K, Woelke U, et al. 1985. Effects of ethylbenzene,
toluene, and xylene on the induction of micronuclei in bone marrow
polychromatic erythrocytes of mice. Arch Toxicol 58:106-109.
*Molnar J, Paksy KA, Naray M. 1986. Changes in the rat's motor behaviour
during 4-hr inhalation exposure to prenarcotic concentrations of benzene and
its derivatives. Acta Physiol Hung 67:349-354.
*Moscato G, Biscaldi G, Cottica D, et al. 1987. Occupational asthma due to
styrene: Two case reports. J Occup Med 29:957-960.
*Murray DAJ, Lockhart WL. 1981. Microextraction and gas chromatographic
analysis of selected petroleum hydrocarbons in water and fish tissue. J
Chromatogr 212:305-311.
Mutti A, Franchini I. 1987. Toxicity of metabolites to dopaminergic systems
and the behavioural effects. Br J Ind Med 44:721-723.
*Mutti A, Falzoi H, Romanelli A, et al. 1988. Brain dopamine as a target for
solvent toxicity: Effects of some monocyclic aromatic hydrocarbons. Toxicol
49:77-82.
*Nakajima T, Sato A. 1979. Enhanced activity of liver drug-metabolizing
enzymes for aromatic and chlorinated hydrocarbons following food deprivation.
Toxicol Appl Pharmacol 50:549-556.
Namkung E, Rittmann BE. 1987. Estimating volatile organic compound emissions
from publicly owned treatment works. J Water Pollut Control Fed 59:670-678.
*NAS. 1980. The alkyl benzenes. Committee on Alkyl Benzene Derivatives,
Board on Toxicology and Environmental Health Hazards, Assembly of Life
Sciences, National Research Council. Washington, DC: National Academy Press.
*NAS/NRC. 1989. Biologic markers in reproductive toxicology. National
Academy of Sciences/National Research Council. Washington, DC: National
Academy Press, 15-35.
*NATICH. 1988. National air toxics information clearinghouse: NATICH data
base report on state, local and EPA air toxics activities. Report to John
Vandenburg, US Environmental Protection Agency, Office of Air Quality Plaaning
and Standards, Emissions Standards Division, Research Triangle Park, NC, by
Radian Corporation, Austin, TX. EPA 450/5-88-007.
*Nestmann ER, Lee EG-H. 1983. Mutagenicity of constituents of pulp and paper
mill effluent in growing cells of Saccharomyces cerevisiae. Mutat Res
119:273-280.
-------
113
8. REFERENCES
*Nestmann ER, Lee EG-H, Matula TI, et al. 1980. Mutagenicity of constituents
identified in pulp and paper mill effluents using the
Salmonella/mammalian-microsome assay. Mutat Res 79:203-212.
Nicholson WJ, Tarr D. 1984. Occupational hazards in production and
processing of styrene polymers - epidemiologic findings. Industrial Hazards
of Plastics and Synthetic Elastomers. New York, NY: Alan R. Liss, Inc.
263-277.
*Nicola RM, Branchflower R, Pierce D. 1987. Chemical contaminants in bottom
fish. J Environ Health 49:342-347.
*Nielsen GD, Alarie Y. 1982. Sensory irritation, pulmonary irritation, and
respiratory stimulation by airborne benzene and alkylbenzenes: Prediction of
safe industrial exposure levels and correlation with their thermodynamic
properties. Toxicol Appl Pharmacol 65:459-477.
Niemi GJ, Veith GD, Regal RR, et al. 1987. Structural features associated
with degradable and persistent chemicals. Environ Toxicol Chem 6:515-527.
*NI0SH. 1984. NIOSH manual of analytical methods. Washington, DC: US
Department of Health, Education, and Welfare, Public Health Service, Center
for Disease Control, National Institute for Occupational Safety and Health.
*NIOSH. 1985. NIOSH Pocket guide to chemical hazards. Washington, DC: US
Department of Health and Human Services, Public Health Service, Centers for
Disease Control, National Institute for Occupational Safety and Health.
*Norppa H, Vainio H. 1983. Induction of sister-chromatid exchanges by
styrene analogues in cultured human lymphocytes. Mutat Res 116:379-387.
Norppa H, Vainio H. 1983. Genetic toxicity of styrene and some of its
derivatives. Scand J Work Environ Health 9:108-114.
*NTP. 1986. Toxicology and carcinogenesis studies of xylenes (mixed) (60%
m-xylene, 14% p-xylene, 9%-xylene, and 17% ethylbenzene) in F334/N rats and
B6C3F1 mice (gavage studies). Research Triangle Park, NC: National
Toxicology Program.
NTP. 1987. Results for mutagenicity in L51784 mouse lymphoma cells. Fiscal
year 1987 annual plan.
*NTP. 1988a. National toxicology program: Review of current DHHS, DOE,
and EPA research related to toxicology. Fiscal year 1988. Research Triangle
Park, NC: US Department of Health and Human Services, Public Health Service.
-------
114
8. REFERENCES
NTP 1988b National toxicology program annual plan for fiscal year 1988.
Research Triangle Park, NC: US Department of Health and Human Services,
ablic Health Service, National Toxicology Program.
.HTP iQRRc Draft Subchronic and chronic toxicity study of ethylbenzene:
So day subchronic stidy report on inhalation exposure of F344/N rats B6C3F1
L-pp Prepared for National Toxicology Program of the National Institute of
Health by IIT Research Institute, Chicago, Illinois. October 27, 1988.
*NTP 1989a Chemical status report. National Toxicology Program. Division
of Toxicology Research and Testing. February 7, 1989.
*NTP 1989b Draft, Chairman's report: Pathology Working Group (PWG)
"ri.,: Subchronic toxicity test on ethylbenzene (C56393) administered by
inhalation in F344 rats and B6C3F1 mice. March 8, 19 .
*NTP. 1990. Chemical status report. National Toxicology Program. Division
of Toxicology Research and Testing. July 3, 1990.
*Nunes P Benville PE Jr. 1979. Uptake and depuration of petroleum
hydrocarbons in the Manila clam, Tapes semidecussata reeve. Bull Environ
Contam Toxicol 21:719-726.
*Nutmaeul W, Cronn DK, Hill HH Jr. 1983. PhotoioniZation-flame-ionization
detection of atmospheric hydrocarbons after capillary gas chromatography.
Anal Chem 55:2160-2164.
40'Brien RJ Holmes JR. Bockian AH. 1975. Formation of photochemical aerosol
horn hydrocarbons chemical reactivity and products. Environ Sci Technol
9:568-576.
^ ^ m Tfl!r.,rhi T 1987. Quantitation of urinary metabolites of toluene,
Qtvrene ethyl- benzene, benzene and phenol by automated
high"performance liquid chromatography. Int Arch Occup Environ Health
59:263-272.
*0eata M Taguchi T. 1988. Simultaneous determination of urinary creatinine
a^f-holltes of toluene, xylene, styrene, ethylbenzene and phenol by
automated high-performance liquid-chromatography. Int Arch Occup Environ
Health 61:131-140.
Ogata M, Fujisawa K, Ogino V, et »1. 1984. Partition coefficients as .
measure of bioconcentration potential of crude oil compounds in fish «„d
shellfish. Bull Environ Contain Toxicol 33.561-567.
-------
115
8. REFERENCES
*OHM/TADS. 1988. Oil and hazardous materials/technical assistance data
system. Chemical Information System, Inc., Baltimore, MD. December 1985.
*Ohta T, Ohyama T. 1985. A set of rate constants for the reactions of OH
radicals with aromatic hydrocarbons. Bull Chem Soc Jpn 58:3029-3030.
Opdyke DLJ. 1975. Monographs on fragrance raw materials. Food Cosmet
Toxicol 13:803-804.
Osborn AG, Scott DW. 1980. Vapor pressures of 17 miscellaneous organic
compounds. J Chem Thermodynamic 12:429-438.
*0SHA. 1989. US Department of Labor, Occupational Safety and Health
Association. Code of Federal Regulations. 29 CFR 1910.
*0tson R, Chan C. 1987. Sample handling and analysis for 51 volatile
organics by an adapted purge and trap GC-MS technique. Int J Environ Anal
Chem 30:275-287.
*0tson R, Williams DT. 1981. Evaluation of a liquid-liquid extraction
technique for water pollutants. J Chromatogr 212:187-198.
*0tson R, Williams DT. 1982. Headspace chromatographic determination of
water pollutants. Anal Chem 54:942-946.
Patterson JW, Kodukala PS. 1981. Biodegradation of hazardous organic
pollutants. Chem Eng Prog 77:48-55.
*Pellizzari ED, Hartwell TD, Harris BSH III, et al. 1982. Purgeable organic
compounds in mother's milk. Bull Environ Contam Toxicol 28:322-328.
Pereira WE, Rostad CE, Taylor HE, et al. 1982. Characterization of organic
contaminants in environmental samples associated with Mount St. Helens 1980
volcanic eruption. Environ Sci Technol 16:387-396.
*Pettersson B, Curvall M, Enzell CR. 1980. Effects of tobacco smoke
compounds on the noradrenaline induced oxidative metabolism in isolated brown
fat cells. Toxicology 18:1-15.
Pilotti A, Ancker K, Arrhenius E, et al. 1975. Effects of tobacco and
tobacco smoke constituents on cell multiplication in vitro. Toxicology
5:49-62.
*Pleil JD, Oliver KD, McClenny WA. 1988. Ambient air analyses using
nonspecific flame ionization and electron capture detection compared to
specific detection by mass spec. J Air Pollut Control Assoc 38:1006-1010.
-------
116
8. REFERENCES
*Polak J Lu BCY. 197 3. Mutual solubilities of hydrocarbons and water at 0
and 25°C. Can J Chem 51:4018-4023.
•Possanzini M Ciccioli P, Brancaleoni E, et al. 1982. Gas chromatographic
detection of hydrocarbons in the atmosphere using specific GC detectors and
mass spectrometry in selected ion monitoring mode. Comm Eur Communities, Eur
Iss Eur 7624 (Phys Chem Behav Atmos Pollut). 76 81.
*Pyykko K, Paavilainen S, Metsa-Ketela T, et al. 1987. The increasing and
decreasing effects of aromatic hydrocarbon solvents on pulmonary and hepatrc
cytochrome P-450 in the rat. Pharmacol Toxicol 60.288-293.
*Radzikowska-Kintzi H, Jakubowski M. 1981. Internal standardization m the
head space analysis of organic solvents in blood. Int Arch Occup Environ
Health 49:115-123.
*Rflnqlev DL 1984. Xylenes and ethylbenzene. In: Grayson M, ed.
Kirk-Othnier encyclopedia of chemical technology. Vol. 24, Ne„ York, NY: John
Wiley & Sons, 709-744.
*R*o PSC Hornsley AG, Kilcreae DF, et al. 1985. Sorption and transport of
hydrophobic organic chemicals in aqueous and mixed systems: Model
development and preliminary evaluation. J Environ Qual 14.376-382
*Rappaport SM, Selvin S, Waters MA. 1987. Ensure to hydrocarbon components
of gasoline in the petroleum industry. Appl Ind Hyg 2:148-154.
*Ravishankara AR, Wagner S, Fischer S, et al. 1978. A kinetics study of the
reactions of hydroxy1 with several aromatic and olefmic compounds. Int J
Chem Kinet 10:783-804.
Rhue RD, Rao PSC, Smith RE. 1988. Vapor-phase adsorption of alkyl benzenes
and water on soils and clays. Chemosphere 17.727-741.
*p-mH 1989 Written communication regarding ethylbenzene levels in private
well water, public drinking water and health-related guidelines. Providence,
RI: Department of Health (June 19).
Ribbons DW, Eaton RW. ^8Jhe chakrabarty AM, ed.
Biodegradation and detoxification of environmental pollutants. CRC Press,
Inc., 59-84.
o-i „ nil Co 1984. Results of industrial hygiene survey at shale
on pr"«s 1th and ""Ched USt °f t<,,liCl^
studies.
-------
117
8. REFERENCES
Roberfroid M, Poncelet F, Lambotte-Vandepaer M, et al. 1978. Acute biotoxic
effect of styrene on rat liver. Correlation with enzyme-mediated
mutagenicity of benzpyrene and acrylonitrile. Scand J Work Environ Health
4:163-168.
*Romanelli A, Falzoi M, Mutti A, et al. 1986. Effects of some monocyclic
aromatic solvents and their metabolites on brain dopamine in rabbits. J Appl
Toxicol 6:431-435.
*Romer KG, Federsel R.J, Freundt KJ. 1986. Rise of inhaled toluene, ethyl
benzene, m-xylene, or mesitylene in rat blood after treatment with ethanol.
Bull Environ Contam Toxicol 37:874-876.
*Rosen AA, Skeel RT, Ettinger MB. 1963. Relationship of river water odor to
specific organic contaminants. J Water Pollut Cont Fed 35:777-782.
Roy WR, Griffin RA. 1985. Mobility of organic solvents in water-saturated
soil materials. Environ Geol Water Sci 7:241-247.
RTECS. 1982. Registry of Toxic Effects of Chemical Substances, Microfiche
Edition. Lewis RJ, Taken RL, (eds.), U.S. Department of Health and Human
Services, Public Health Service, Centers for Disease Control, National
Institute for Occupational Safety and Health, Cincinnati, OH.
Sabljic A. 1984. Prediction of the nature and strength of soil sorption of
organic pollutants by molecular topology. J Agric Food Chem 32:243-246.
Sabljic A. 1987. On the prediction of soil sorption coefficients of organic
pollutants from molecular structure: Application of molecular topology model.
Environ Sci Technol 21:358-366.
*Sandmeyer E. 1981. Aromatic hydrocarbons: Ethylbenzene. In: Clayton GD,
Clayton FE, eds. Patty's industrial hygiene and toxicology. Vol. 2B, 3rd ed.
3303-3307.
Sanemasa I, Araki M, Deguchi T, et al. 1981. Solubilities of benzene and the
alkylbenzenes in water - method for obtaining aqueous solutions saturated with
vapors in equilibrium with organic liquids. Chem Lett 2:225.
Sanemasa I, Araki M, Deguchi T, et al. 1982. Solubility measurements of
benzene and the alkylbenzenes in water by making use of solute vapor. Bull
Chem Soc Jpn 55:1054-1062.
Sato A, Nakajima T. 1979. Partition coefficients of some aromatic
hydrocarbons and ketones in water, blood, and oil. Br J Ind Med 36:231-234.
-------
118
8. REFERENCES
Sauer TC Jr. 1981. Volatile organic compounds in open ocean and coastal
surface waters. Org Geochem 3:91-101.
*Sauer TC Jr, Sackett WM, Jeffrey LM. 1978. Volatile liquid hydrocarbons in
the surface coastal waters of the Gulf of Mexico. Mar Chem 7:1-16.
Sax NI. 1975. Dangerous properties of industrial materials. 4th ed. New
York, NY: Van Nostrand Reinhold, 727.
Sax NI. 1984. Dangerous properties of industrial materials. 6th ed. New
York, NY: Van Nostrand Reinhold, 1323.
*Sax NI, Lewis RJ Sr. 1989. Dangerous properties of industrial materials
Volume II. 7th ed. New York, NY: Van Nostrand Reinhold, 1601.
Schirmer RE, Pahl TR, Phelps DW. 1984. Application of internal standards ln
routine vapor measurements by gas chromatography. Am Ind Hyg Assoc J
45:95-98.
Schwartz FP, Miller J. 1980. Determination of the aqueous solubilities of
organic liquids at 10.0, 20.0 and 30.0°C by elution chromatography. Anal Chem
52:2162-2164.
*Seila RL. 1979. Non-urban hydrocarbon concentrations in ambient air north
of Houston, Texas. Research Triangle Park, NC: US Environmental Protection
Agency. EPA 500/3-79-010., 38.
Selvakumar A, Hsieh HN. 1987. Absorption of organic compounds by microbial
biomass. Int J Environ Stud 30:313-319.
Sgaragli G, Delia Corte L, Rizzotti-Conti M, et al. 1977. Effects of
monocyclic compounds on biomembranes. Biomed Pharmacol 26:2145-2149.
Shackelford WM, Keith LH. 1976. Frequency of organic compounds identified in
water. Athens, GA: US Environmental Protection Agency. EPA 600/4-76-062
*Shah JJ, Heyerdahl EK. 1988. National ambient volatile organic compounds
(VOCs) data base update. Report by Nero and Associates, Inc., Portland OR
to US Environmental Protection Agency, Atmospheric Sciences Research
Laboratory, Research Triangle Park, NC. EPA 600/3-88/010(A).
Shen TT. 1982. Estimation of organic compound emissions from waste lagoons
J Air Pollut Control Assoc 32:79-82.
Shields HC, Weschler CJ. 1987. Analysis of ambient concentrations of organic
vapors with a passive sampler. J Air Pollut Control Fed 37:1039-1045
-------
119
8. REFERENCES
*Shinohara R, Kido A, Eto S, et al. 1981. Identification and determination
of trace organic substances in tap water by computerized gas chromatography-
mass spectrometry and mass fragmentography Water Res 15:535-542.
Singh HG, Salas LJ, Smith AJ, et al. 1981. Measurements of some potentially
hazardous organic chemicals in urban environments. Atmos Environ 15:601-612.
*Singh HB, Salas LJ, Cantrell BK, et al. 1985. Distribution of aromatic
hydrocarbons in the ambient air. Atmos Environ 19:1911-1919.
Smith JH, Harper JC. 1982. Behavior of hydrocarbon fuels in aquatic systems.
Proceed 12th Conf on Environmental Toxicology 3, 4, and 5 Nov 81. OH:
Airforce Aerospace Medical Research Laboratory, 336-353.
*Smith JN, Smithies RH, Williams RT. 1954a. The metabolism of alkylbenzenes.
Stereochemical aspects of the biological hydroxylation of ethylbenzene to
methylphenylcarbinol. Biochem J 56:320-324.
*Smith JN, Smithies RH, Williams RT. 1954b. The metabolism of alkylbenzenes.
(a) Glucuronic acid excretion following the administration of alkylbenzenes.
(b) Elimination of toluene in the expired air of rabbits. Biochem J
56:317-320.
*Smyth H Jr, Carpenter CP, Weil CS, et al. 1962. Range finding toxicity
data: List VI. Am Indus Hyg Assoc J 23:95-107.
*Snider EH, Manning FS. 1982. A survey of pollutant emission levels in
wastewaters and residuals from the petroleum refining industry. Environ Int
7:237-258.
*Sollenberg J, Smallwood AW, Lowry LK. 1985. Determination of mandelic and
phenylglyoxylic acids in rat urine by high- performance liquid chromatography
and by isotachophoresis. J Chromatogr 343:175-178.
*SRI. 1990. 1990 Directory of chemical producers: United States of America.
Menlo Park, CA: SRI International.
*Stanley JS. 1986. Broad scan analysis of the FY82 National Human Adipose
Tissue Survey specimens volume I-executive summary. Report to US
Environmental Protection Agency, Office of Toxic Substances, Design and
Development Branch, Field Studies Branch, National Human Monitoring Program,
Washington, DC.
^Staples CA, Werner AF, Hoogheem TJ. 1985. Assessment of priority pollutant
concentrations in the United States using STORET database. Environ Toxicol
Chem 4:131-142.
-------
120
8. REFERENCES
*Stuermer DH, Ng DJ, Morris CJ. 1982. Organic contaminants in groundwater
near an underground coal gasification site in northeastern Wyoming. Environ
Sci Technol 16:582-587.
*Sullivan HR, Miller WM, McMahon RE. 1976. Reaction pathways of in vivo
stereoselective conversion of ethylbenzene to (-)-mandelic acid. Xenobiotica
6:49-54.
*Sutton C, Calder JA. 1975. Solubility of alkylbenzenes in distilled and
seawater 25.0xC. J Chem Eng Data 20:320-322.
Swedrowska H, Jarnuszkiewicz I, Slebioda K. 1986. Application of gas
chromatography in conjunction with enrichment of samples on active carbon to
determine low concentrations of organic compounds in air. Part I. Aromatic
hydrocarbons. Bull Inst Marit Trop Med Gdynia 37:103-112.
Takeuchi Y, Ono Y, Hisanaga N, et al. 1982. Environmental and health surveys
on car repair workers exposed to organic solvents. Jpn J Ind Health
24:305-313.
Tatrai E, Balogh T, Baca G, et al. 1982. [Embryotoxic effect of
ethylbenzene]. Egeszsegtudomany 26:297-303. (Hungarian).
^Tester DJ, Harker RJ. 1981. Groundwater pollution investigations in the
Great Ouse Basin. Water Pollut Control 80:614-631.
Thelestram M, Curvall M, Enzell CR. 1980. Effect of tobacco smoke compounds
on the plasma membrane of cultured human lung fibroblasts. Toxicology
15:203-217.
*Thienes C, Haley TJ. 1972. Clinical toxicology. 5th ed. Philadelphia, PA:
Lea and Febiger, 126.
Toftgard R, Nilsen OG. 1981. Induction of cytochrome P-450 in rat liver
after inhalation of aromatic organic solvents. Ind Environ Xenobiotics Proc
Int Conf: 307-317.
*Toftgard R, Nilsen OG. 1982. Effects of xylene and xylene isomers on
cytochrome P-450 and in vitro enzymatic activities in rat liver kidney and
lung. Toxicology 23:197-212.
*TRI. 1989. Toxic Chemical Release Inventory (database). U.S. Environmental
Protection Agency, Office of Toxic Substance, Washington, D.C.
Tsani-Bazaca E, Mclntyre AE, Lester J, et al. 1982. Ambient concentrations
and correlations of hydrocarbons and halocarbons in the vicinity of an
airport. Chemosphere 11:11-23.
-------
121
8. REFERENCES
*Tsuruta H. 1982. Percutaneous absorption of organic solvents: 3.
Penetration rates of hydrophobic solvents through excised rat skin. Ind
Health 20:335-346.
*Ungvary G. 1986. Solvent effects on reproduction: Experimental toxicity.
220:169-177.
*Ungvary G, Tatrai E. 1985. On the embryotoxic effects of benzene and its
alkyl derivatives in mice, rats and rabbits. Arch Toxicol (Suppl) 8:425-430.
Uno I, Wakamatsu S, Wadden RA, et al. 1985. Evaluation of hydrogen
reactivity in urban air. Atmos Environ 19:1283-1293.
*USITC. 1987. Synthetic organic chemicals: United States production and
sales, 1986. Washington, DC: US International Trade Commission.
*Van der Linden AC, Thijsse GJE. 1965. The mechanisms of microbial
oxidations of petroleum hydrocarbons. Advanc Enzyrttol 27:469-546.
*Verhoeff AP, Suk J, Van Wijnen JH. 1988. Residential indoor air
contamination by screen printing plants. Int Arch Occup Environ Health
60:201-209.
*Verschueren K. 1983. Handbook of environmental data on organic chemicals.
2nd ed. New York, NY: Van Nostrand Reinhold Co., 628-630.
Veulemans H, Groeseneken D, Masschelein R, et al. 1987. Survey of ethylene
glycol ether exposures in Belgian industries and workshops. Am Indust Hyg
Assoc J 48:671-677.
*VIEW Database. 1989. Agency for Toxic Substances and Disease Registry
(ATSDR), Office of External Affairs, Exposure and Disease Registry Branch,
Atlanta, GA. June 20, 1989. (Map based on VIEW Database, June 12, 1989).
Von Oettingen WF, Neal PA, Donahue DD. 1942. The toxicity and potential
danger of toluene. J Amer Med Assoc 118:579-584.
*Vowles PD, Mantoura RFC. 1987. Sediment-water partition coefficients and
HPLC retention factors of aromatic hydrocarbons. Chemosphere 16:109-116.
*Voznakova Z, Popl M, Berka M. 1978. Recovery of aromatic hydrocarbons from
water. J Chromatogr Sci 16:123-127.
*Wakeham SG, Davis AC, Karas JL. 1983. Mesocosm experiments to determine the
fate and persistence of volatile organic compound in coastal seawater.
Environ Sci Technol 17:611-617.
-------
122
8. REFERENCES
Wallace LA. 1986. Personal exposures, indoor and outdoor air concentrations,
id exhaled breath concentrations of selected volatile organic compounds
measured for 600 residents of New Jersey, North Dakota, North Carolina and
California. Toxicol Environ Chem 12:215-236.
Wallace LA, Pellizzari ED. 1987. Personal air exposures and breath
concentrations of benzene and other volatile hydrocarbons for smokers and
nonsmokers. Toxicol Lett 35:113-116.
^Wallace L, Pellizzari E, Hartwell T, et al. 1984. Analysis of exhaled
breath of 355 urban residents for volatile organic compounds. Indoor Air.
Vol. 4. Chemical Characterization and Personal Exposure. Proceedings of the
International Conference (3rd) on Indoor Air Quality and Climate Held in
Stockholm on August 20-24, 1984. NTIS PB85 104-214., 15-20.
Wallace LA, Pellizzari ED, Hartwell TD, et al. 1985. Personal exposures,
indoor-outdoor relationships, and breath levels of toxic air pollutants
measured for 335 persons in New Jersey. Atmos Environ 19:1651-1661.
~Wallace L, Pellizzari E, Hartwell T, et al. 1986. Concentrations of 20
volatile organic compounds in the air and drinking water of 350 residents of
New Jersey compared with concentrations in their exhaled breath. J Occup Med
28:603-608.
~Wallace LA, Pellizzari ED, Hartwell TD, et al. 1987a. The TEAM study:
Personal exposures to toxic substances in air, drinking water, and breath of
400 residents of New Jersey, North Carolina, and North Dakota. Environ Res
43:290-307.
~Wallace LA, Pellizzari E, Leaderer B, et al. 1987b. Emissions of volatile
organic compounds from building materials and consumer products. Atmos
Environ 21:385-393.
~Wallace L, Pellizzari E, Hartwell TD, et al. 1987c. Exposures to benzene
arid other volatile compounds from active and passive smoking. Arch Environ
Health 42:272-279.
Wasik SP, Miller MM, Tewari YB, et al. 1983. Determination of the vapor
pressure, aqueous solubility, and octanol/water partition coefficient of
hydrophobic substances by coupled generator column/liquid chromatographic
methods. Residue Reviews 85:29-42.
~Weast RC, ed. 1988. CRC Handbook of chemistry and physics. 69th ed. Boca
Raton, FL: CRC Press, Inc., C-269.
-------
123
8. REFERENCES
^Whitehead LW, Ball GL, Fine LJ, et al. 1984. Solvent vapor exposures in
booth spray painting and. spray glueing, and associated operations. Am ind Hyg
Assoc J 45:767-772.
^Wilson BH, Smith GB, Rees JF. 1986. Biotransformations of selected
alkylbenzenes and halogenated aliphatic hydrocarbons in methanagenic aquifer
material: A microcosm study. Environ Sci Technol 20:997-1002.
*Windholz M, ed. 1983. The Merck index. 10th ed. Rahway, NJ: Merck & Co.,
Inc., 546-547.
*Wolf MA, Rowe VK, McCollister DD, et al. 1956. Toxicological studies of
certain alkylated benzenes and benzene: Experiments on laboratory animals.
AMA Arch Ind Health 14:387-398.
*Wolff MS. 1976. Evidence for existence in human tissues of monomers for
plastics and rubber manufacture. Environ Health Perspect 17:183-187.
*Wolff MS, Daum SM, Lorimer WV, et al. 1977. Styrene and related
hydrocarbons in subcutaneous fat from polymerization workers. J Toxicol
Environ Health 2:997-1005.
*Yalkowsky SH, Valvani SC. 1976. Partition coefficients and surface areas of
some alkylbenzenes. J Med Chem 19:727-728.
*Yamamoto RK, Cook W A. 1968. Determination of ethyl benzene and styrene in
air by ultraviolet spectrophotometry. Am Ind Hyg Assoc J:238-241.
*Yamasaki Y. 1984. [The determination of urinary metabolites of ethylbenzene
by high- performance liquid chromatography]. Okayama Igakkai Zasshi
96:531-535. (Japanese).
*Yanagihara S, Shimada I, Shinoyama E, et al. 1977. Photochemical
reactivities of hydrocarbons. Proc Int Clean Air Congr 4th:472-477.
*Yant WP, Schrenk HH, Waite CP, et al. 1930. Acute response of guinea pigs
to vapors of some new commercial organic compounds. II. Ethylbenzene. Pub
Health Rep 45:1241-1250.
Yaws CL. 1975. Toluene, ethylbenzene, and cumene. Chem Eng 82:73-81.
Young P, Parker A. 1984. Vapors, odors, and toxic gases from landfills.
ASTM Spec Tech Publ 851 851:24-41.
Zarth MOF, Smith RG, Schroeder ED, et al. 1984. Removal of toxic organics by
overland flow. Vom Wasser 63:281-197.
-------
124
8. REFERENCES
Zoeteman BCJ, Degreef E, Brinkman FJJ. 1981. Persistency of organic
contaminants in groundwater, lessons from soil pollution incidents in the
etherlands. Sci Total Environ 21:187-202.
«Zweidinger RB, Sigsby JE Jr, Tejada SB, et al. 1988. Detailed hydrocarbon
and aldehyde mobile source emissions from roadway studies. Environ Sci
Technol 22:956-962.
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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
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9. GLOSSARY
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.
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^) (LCloj -- The lowest concentration of a chemical in
air which has been reported to have caused death in humans or animals.
Lethal Concentration^, (LC50) -- 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) (LDn,) -- 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)
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9. GLOSSARY
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-Effeet 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.
q-L* -- The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The qx* can be used to
calculate an estimate of carcinogenic potency, the incremental excess cancer
risk per unit of exposure (usually ng/h for water, mg/kg/day for food, and
/xg/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 lb 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.
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9. GLOSSARY
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.
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APPENDIX
PEER REVIEW
A. peer review panel was assembled for ethylbenzene. The Panel consisted
of the following members: Dr. D.L. Dungworth, Department of Veterinary
Pathology, University of California; Dr. Francis Hall, Department of Earth
Sciences, University of New Hamsphire; Dr. Earle Nestmann, Cantox, Inc.
These experts collectively have knowledge of ethylbenzene1s 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
their approval of the profile's final content. The responsibility of the
content of this profile lies with the Agency for Toxic Substances and Disease
Registry.
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