Toxicological
o
Profile
for
TOTAL XYLENES
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
TP-90-30
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TOXICOLOGICAL PROFILE FOR
TOTAL XYLENES
Prepared by:
Clement Associates, Inc.
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
December 1990
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ii
DISCLAIMER
The use of company or product name(s) is for identification only and does
not imply endorsement by the Agency for Toxic Substances and Disease Registry.
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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 XYLENE? 1
1.2 HOW MIGHT I BE EXPOSED TO XYLENE? 2
1.3 HOW CAN XYLENE ENTER AND LEAVE MY BODY? 3
1.4 HOW CAN XYLENE 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 XYLENE? 9
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? 9
1.8 WHERE CAN I GET MORE INFORMATION? 10
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 26
2.2.1.3 Immunological Effects 30
2.2.1.4 Neurological Effects 30
2.2.1.5 Developmental Effects 33
2.2.1.6 Reproductive Effects 34
2.2.1.7 Genotoxic Effects ... 34
2.2.1.8 Cancer 35
2.2.2 Oral Exposure 35
2.2.2.1 Death 35
2.2.2.2 Systemic Effects 52
2.2.2.3 Immunological Effects 55
2.2.2.4 Neurological Effects 55
2.2.2.5 Developmental Effects 56
2.2.2.6 Reproductive Effects 56
2.2.2.7 Genotoxic Effects 56
2.2.2.8 Cancer 57
2.2.3 Dermal Exposure 57
2.2.3.1 Death 57
2.2.3.2 Systemic Effects 57
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vi
2.2.3.3 Immunologic Effects 58
2.2.3.4 Neurological Effects 58
2.2.3.5 Developmental Effects 58
2.2.3.6 Reproductive Effects 59
2.2.3.7 Genotoxic Effects 59
2.2.3.8 Cancer 59
2.3 TOXICOKINETICS 59
2.3.1 Absorption 59
2.3.1.1 Inhalation Exposure 59
2.3.1.2 Oral Exposure 60
2.3.1.3 Dermal Exposure 60
2.3.2 Distribution 61
2.3.2.1 Inhalation Exposure 61
2.3.2.2 Oral Exposure 62
2.3.2.3 Dermal Exposure 62
2.3.3 Metabolism 62
2.3.4 Excretion 66
2.3.4.1 Inhalation Exposure 66
2.3.4.2 Oral Exposure 67
2.3.4.3 Dermal Exposure 67
2.3.4.4 Other Routes of Exposure 68
2.4 RELEVANCE TO PUBLIC HEALTH 68
2.5 BIOMARKERS OF EXPOSURE AND EFFECT 79
2.5.1 Biomarkers Used to Identify or Quantify Exposure to
Xylenes 80
2.5.2 Biomarkers Used to Characterize Effects Caused by
Xylenes 81
2.6 INTERACTIONS WITH OTHER CHEMICALS 81
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 82
2.8 ADEQUACY OF THE DATABASE 83
2.8.1 Existing Information on Health Effects of Xylene .... 83
2.8.2 Identification of Data Needs 86
2.8.3 On-going Studies 90
3. CHEMICAL AND PHYSICAL INFORMATION 91
3.1 CHEMICAL IDENTITY 91
3.2 PHYSICAL AND CHEMICAL PROPERTIES 91
4. PRODUCTION, IMPORT, USE, AND DISPOSAL 105
4.1 PRODUCTION 105
4.2 IMPORT 105
4.3 USE 106
4.4 DISPOSAL 106
5. POTENTIAL FOR HUMAN EXPOSURE 107
5.1 OVERVIEW 107
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vii
5.2 RELEASES TO THE ENVIRONMENT 107
5.2.1 Air 109
5.2.2 Water 109
5.2.3 Soil 110
5.3 ENVIRONMENTAL FATE 110
5.3.1 Transport and Partitioning Ill
5.3.2 Transformation and Degradation 114
5.3.2.1 Air 114
5.3.2.2 Water 114
5.3.2.3 Soil 115
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 116
5.4.1 Air 116
5.4.2 Water 117
5.4.3 Soil 117
5.4.4 Other Media 118
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 118
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 122
5.7 ADEQUACY OF THE DATABASE 122
5.7.1 Identification of Data Needs 122
5.7.2 On-going Studies 126
6. ANALYTICAL METHODS 127
6.1 BIOLOGICAL MATERIALS 127
6.2 ENVIRONMENTAL SAMPLES 132
6.3 ADEQUACY OF THE DATABASE 133
6.3.1 Identification of Data Needs 134
6.3.2 On-going Studies 135
7. REGULATIONS AND ADVISORIES 137
8. REFERENCES 143
9. GLOSSARY 187
APPENDIX 191
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1
2
3
4
5
6
7
8
9
10
11
1
21
23
24
25
45
48
49
50
63
64
84
108
ix
LIST OF FIGURES
Levels of Significant Exposure to Mixed Xylene - Inhalation
Levels of Significant Exposure to m-Xylene - Inhalation . .
Levels of Significant Exposure to o-Xylene - Inhalation . .
Levels of Significant Exposure to ^-Xylene - Inhalation . .
Levels of Significant Exposure to Mixed Xylene - Oral . . .
Levels of Significant Exposure to m-Xylene - Oral
Levels of Significant Exposure to o-Xylene - Oral
Levels of Significant Exposure to j> "Xylene . Oral
Metabolic Scheme for Xylenes - Humans
Metabolic Scheme for Xylenes - Animals
Existing Information on Health Effects of Total Xylenes . .
Frequency of Sites with Total Xylenes Contamination ....
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1
2
3
4
1
2
3
4
5
6
7
8
9
10
11
1
2
3
4
5
6
7
5
6
7
8
13
17
18
19
36
40
42
43
51
76
78
92
93
94
95
96
98
100
xi
LIST OF TABLES
Human Health Effects from Breathing Xylene
Animal Health Effects from Breathing Xylene
Human Health Effects from Eating or Drinking Xylene
Animal Health Effects from Eating or Drinking Xylene
Levels of Significant Exposure to Mixed Xylene - Inhalation . .
Levels of Significant Exposure to m-Xylene - Inhalation . . . .
Levels of Significant Exposure to o-Xylene - Inhalation . . . .
Levels of Significant Exposure to ^-Xylene - Inhalation . . . .
Levels of Significant Exposure to Mixed Xylene - Oral
Levels of Significant Exposure to m-Xylene - Oral
Levels of Significant Exposure to o-Xylene - Oral
Levels of Significant Exposure to ^-Xylene - Oral
Reported Acute Oral LD50 Values for Xylene
Genotoxicity of Xylene In Vitro
Genotoxicity of Xylene In Vivo
Chemical Identity of Mixed Xylene
Chemical Identity of m-Xylene
Chemical Identity of o-Xylene
Chemical Identity of g-Xylene
Physical and Chemical Properties of Mixed Xylene
Physical and Chemical Properties of m-Xylene
Physical and Chemical Properties of o-Xylene
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xi i
3-8 Physical and Chemical Properties of ^-Xylene 102
5-1 Characteristics of Different Environmental Compartments and
Xylene Concentrations on Emission of 100 mol 112
5-2 Percentage Breakdown of NIOSH Occupational Exposure Estimates
from the NOHS and NOES Databases 120
6-1 Analytical Methods for Determining Xylene in Biological
Materials 128
6-2 Analytical Methods for Determining Xylene in Environmental
Samples 130
7-1 Regulations and Guidelines Applicable to Xylenes 138
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1
1. PUBLIC HEALTH STATEMENT
This Statement was prepared to give you information about xylene 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). Xylene has been found at 236 of these sites.
However, we do not know how many of the 1,177 NPL sites have been evaluated
for xylene. As EPA evaluates more sites, the number of sites at which xylene
is found may change. The information is important for you because xylene may
cause harmful health effects and because these sites are potential or actual
sources of human exposure to xylene.
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 xylene, 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 XYLENE?
Xylene is primarily a man-made chemical. Chemical industries produce
xylene from petroleum and to a smaller extent from coal. Xylene also occurs
naturally in petroleum and coal tar, and is formed during forest fires. It is
a colorless liquid with a sweet odor. There are three forms of xylene called
isomers: meta-xylene. ortho-xvlene. and para-xvlene (ig-, o-, and ^-xylene).
Mixed xylene is a mixture of the three forms of xylene and smaller amounts of
other chemicals, primarily ethylbenzene. Mixed xylene usually contains 6%-
15% ethylbenzene, although it may contain higher amounts. The term "total
xylenes," as used in the title of this report, refers to the three forms or
isomers of xylene (meta-. ortho-. and para-xvlene) and also to mixed xylene.
In this report, the term "total xylenes" and xylene will be used
interchangeably.
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2
I. PUBLIC HEALTH STATEMENT
Solvents (liquids that can dissolve solids) and thinners for paints and
varnishes often contain xylene, along with other solvents. Xylene is used as
a solvent in the printing, rubber, and leather industries, and as a cleaning
agent. It is also found in airplane fuel and gasoline, and is used as a
material in the chemical, plastic, and synthetic fiber industries, and as an
ingredient in the coating of fabrics and papers. Isomers of xylene are used
in the manufacture of certain polymers, such as plastics.
Xylene evaporates and burns easily. Xylene does not mix well with
water; however, it does mix with alcohol and with many other chemicals.
Xylene is a liquid, and it can leak into soil, surface water (creeks, streams,
rivers), or groundwater, where it may remain for 6 months or longer before it
is broken down into other chemicals. However, because it evaporates readily,
most xylene goes into the air, where it lasts for several days. During these
several days in the air, the xylene is broken down by sunlight into other
kinds of chemicals. Additional information regarding chemical and physical
properties, use, and environmental fate of xylene can be found in Chapters 3,
4, and 5.
1.2 HOW MIGHT I BE EXPOSED TO XYLENE?
You may become exposed to xylene because of its wide distribution in the
environment. Releases of xylene occur primarily from industrial sources,
automobile exhaust, and from the use of xylene as a solvent. Hazardous waste
disposal sites and spills of xylene into the environment also serve as
possible sources of exposure. Levels of xylene measured in industrial areas
and cities of the United States and Europe range between 0.0007 and 0.09 parts
of xylene per million parts of air (ppm). Xylene is sometimes released into
water and soil as a result of the use, storage, and transport of petroleum
products. Surface water generally contains less than 1 part of xylene per
billion parts of water (ppb), although the level may be higher in industrial
areas. Levels of xylene in public drinking water supplies range from 0 to 750
ppb. Because xylene evaporates rapidly, the presence of xylene in upper
layers of soil is probably not large. Little information exists about the
amount of xylene in food. Levels ranging between 0.05 ppm and 0.12 ppm xylene
have been found in fish.
You may also come in contact with xylene from a variety of consumer
products, including cigarette smoke, gasoline, paint, varnish, shellac, and
rust preventives. Breathing vapors from these types of products can expose
you to xylene. Indoor levels of xylene can be higher than outdoor levels,
especially in buildings with poor ventilation. Skin contact with products
containing xylene, such as solvents, lacquers, paint thinners and removers,
and pesticides may also expose you to xylene.
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1. PUBLIC HEALTH STATEMENT
In addition to painters (or paint industry workers), biomedical
laboratory workers, distillers of xylene, wood processing plant workers,
garage workers, metal workers, and furniture refinishers also may be exposed
to xylene. Exposure to high levels of xylene is most likely to occur in
workers who smoke and routinely come in contact with solvent products.
Additional information on the potential for human exposure can be found in
Chapter 5.
1.3 HOW CAN XYLENE ENTER AND LEAVE MY BODY?
Xylene is most likely to enter your body through breathing xylene
vapors. Less often, xylene enters the body through the skin following direct
contact. Exposure to xylene may also take place by eating or drinking xylene -
contaminated food or water. Xylene is rapidly absorbed by the lungs following
breathing air containing xylene. The amount of xylene retained by the lungs
ranges from 50% to 75% of the amount of xylene to which you are exposed.
Physical exercise increases the amount of xylene absorbed by the lungs.
Absorption of xylene after eating food or drinking water containing it is both
rapid and complete. Absorption of xylene through the skin also occurs rapidly
following direct contact with xylene or exposure to xylene vapors in the air.
At hazardous waste sites, breathing xylene vapors, drinking wellwater
contaminated with xylene, and direct contact of the skin with xylene are
possible ways you can be exposed. Xylene passes into the blood soon after
entering the body.
In humans and laboratory animals, xylene is broken down into other
chemicals in the liver and lungs. This process changes most of the xylene
that is breathed in or swallowed into a different form. Once xylene has been
broken down, the breakdown products rapidly leave the body, mainly in urine
but some unchanged xylene also leaves in breath from the lungs. Small amounts
of broken down xylene have appeared in urine of humans as soon as 2 hours
after breathing air containing xylene. Usually most of the xylene that is
taken in leaves the body within 18 hours after exposure ends. Storage of
xylene in fat or muscle may prolong the time needed for xylene to leave the
body. Additional information on how xylene can enter and leave your body can
be found in Chapter 2.
1.4 HOW CAN XYLENE AFFECT MY HEALTH?
Short-term exposure of humans to high levels of xylene or chemical
mixtures containing xylene causes irritation of the skin, eyes, nose, and
throat; difficulty in breathing; impaired function of the lungs; delayed
response to a visual stimulus; impaired memory; stomach discomfort; and
possible changes in the liver and kidneys. Death can occur in individuals who
are exposed to very high levels of xylene for a short period of time. Both
short- and long-term exposure to high concentrations of xylene can also cause
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1. PUBLIC HEALTH STATEMENT
a number of effects on the nervous system, such as headaches, lack of muscle
coordination, dizziness, confusion, and changes in one's sense of balance.
Results of studies with animals indicate that large amounts of xylene
can cause changes in the liver and adverse effects on the kidney, lung, heart,
and nervous system. Short-term exposure to high concentrations of xylene
causes death in some animals, as well as muscular spasms, incoordination,
hearing loss, changes in behavior, changes in organ weights, and changes in
enzyme activity. Long-term exposure to low concentrations of xylene has not
been well studied in animals.
Information from animal studies is not adequate to determine whether or
not xylene causes cancer in humans. However, exposure of pregnant women to
high levels of xylene may cause adverse effects in the fetus. Studies with
unborn animals indicate that high levels of xylene may cause increased numbers
of deaths, decreased weight, skeletal changes, and delayed skeletal
development. In many instances, the levels of xylenes causing these effects
also caused the mothers to be ill. The higher the level of exposure and the
longer the exposure to xylene, the greater the chance for adverse health
effects. Additional information regarding the health effects of xylene can be
found in Chapter 2.
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Xylene or chemical mixtures containing xylene are deadly to humans if
large enough quantities are swallowed or inhaled. However, the levels which
cause death in humans are not known. Lower levels (100-299 ppm) of inhaled
xylene can cause eye, nose, and throat irritation, delayed response to a
visual stimulus, and poor memory. Direct contact of humans with several drops
of xylene causes skin irritation. The lowest level at which you can detect
the odor (smell) of xylene in air ranges from 0.1 ppm to 2.0 ppm.
In animals, moderate to high levels (1,300-2,000 ppm) of xylene inhaled
for short periods of time may cause decreased breathing rate, hearing loss,
inactivity, unconsciousness, and biochemical changes in the brain. With
longer-term inhalation, adverse health effects in animals generally occur at
lower levels (230-800 ppm). In animals breathing high levels of xylene over
long-term exposures, possible adverse health effects include changes in heart
rate and blood flow, changes in the chemical composition of nerves, and
hearing loss. In animals given high levels (5,000 ppm) of xylene orally over
short-term exposures, a possible adverse health effect is impaired eye
function. In animals exposed by mouth to very high levels (40,000 ppm) of
xylene, death can occur.
Tables 1-1 through 1-4 show the relationship between exposure to xylene
and known health effects.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-L. Human Health Effects from Breathing Xylene*
Short-term Exposure
(less than or equal to 14 days)
Levels in Air
(ODm)
Length of ExDosure
DescriDtion of Effects**
100
1 day
Eye, nose, and throat
irritation.
299
70 minutes
Delayed response to a visual
stimulus and impaired memory
during exercise.
Long-terra Exposure
(greater than 14
days)
Levels in Air
(pom)
Length of Exposure
Description of Effects**
The health effects resulting
from long-term exposure of
humans to air containing
specific levels of xylene
are not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
**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 1-2. Animal Health Effects from Breathing Xylene
Short-term Exposure
(less
than or equal to 14 days)
Levels in Air
fDDm)
Lenpth
of ExDosure
DescriDtion of Effects*
1,300
1
minute
Decreased breathing rate in
mice .
1,450
8
hours
Hearing loss in rats.
1,940
4
5 hours
Inactivity or unconsciousness in
rats.
2,000
3
days
Biochemical changes in brain of
rats.
Long-term Exposure
(greater than 14
days)
Levels in Air
(ppm)
Leneth of ExDOsure
DescriDtion of Effects*
230
4
weeks
Changes in blood vessels of
heart, decreased blood flow in
heart, and increased heart
rate in rats.
300
18
weeks
Changes in fat and protein
composition of nerves in rats.
600
4
weeks
Changes in liver weight in rats.
800
6
weeks
Hearing loss 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 L-3. Human Health Effects from Eating or Drinking Xylene*
Short-term Exposure
(less than or equal to 14 days)
Levels
in
Food
Lenpth of Exposure
Description of Effects
The health effects resulting
from short-term exposure of
humans to food containing
specific levels of xylene
are not known.
Levels
in
Water
The health effects resulting
from short-term exposure of
humans to water containing
specific levels of xylene
are not known.
Long-term Exposure
(greater than 14 days)
Levels
in
Food
Length of Exposure
DescriDtion of Effects
The health effects resulting
from long-term exposure of
humans to food containing
specific levels of xylene
are not known.
Levels
to Warn
The health effects resulting
from long-term exposure of
humans to water containing
specific levels of xylene
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 Xylene
Short-term Exposure
(less than or equal to 14 days)
Levels
in Food
(oom)
Length of Exposure
Description of Effects*
5,000
40,000
1 day
14 days
Impaired eye function in rats.
Death in rats.
Levels
in Water
(ppm)
The health effects resulting
from short-term exposure of
animals to water containing
specific levels of xylene
are not known.
Long-term Exposure
(greater than 14 days)
Levels
in Food
(com)
Leneth of Exposure
Description of Effects
The health effects resulting
from long-term exposure of
animals to food containing
specific levels of xylene
are not known.
Levels
in Water
(pom)
The health effects resulting
from long-term exposure of
animals to water containing
specific levels of xylene 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
More information about the levels of exposure that have resulted in
harmful health effects can be found in Chapter 2.
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
XYLENE?
Medical tests are available to determine if you have been exposed to
xylene at greater than normal background levels. Confirmation of xylene
exposure is determined by measuring xylene's breakdown products that are
eliminated from the body in the urine. These urinary measurements will
specifically determine if you have been exposed to xylene. There is a high
degree of agreement between exposure to xylene and the levels of xylene's
breakdown products in the urine. A urine sample must be provided soon after
exposure ends, because xylene quickly leaves the body. Alcohol and aspirin may
affect the test results. Available tests can only indicate exposure to
xylene; they cannot be used to predict which health effects, if any, will
develop. More information about the detection of xylene can be found in
Chapters 2 and 6.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN
HEALTH?
The U.S. Environmental Protection Agency (EPA) estimates that for an
adult of average weight, exposure to 0.4 milligrams of xylene per liter (mg/L
or ppm) of water each day for a lifetime (70 years) is unlikely to result in
noncancerous adverse health effects. For a long-term but less than lifetime
exposure (about 7 years), 27.3 ppm is estimated to be a level unlikely to
result in noncancerous adverse health effects for an adult. Exposure to 12
ppm of xylene in water for 1 day or to 7.8 ppm of xylene in water for 10 days
or longer is unlikely to present a noncancerous health risk to a small child.
EPA has proposed a recommended maximum level of 0.44 ppm for xylene in
drinking water.
To protect individuals from the potential adverse health effects of
xylene, the federal government regulates xylene in the environment. The
Occupational Safety and Health Administration (OSHA) has set up a legally
enforceable occupational exposure limit of 100 ppm of xylene in air averaged
over an 8-hour workday, and a 15-minute exposure limit of 150 ppm. The
National Institute for Occupational Safety and Health (NIOSH) has recommended
an exposure limit of 100 ppm of xylene averaged over a workday up to 10 hours
long in a 40-hour work week. NIOSH has also recommended that exposure to
xylene not exceed 200 ppm for longer than 15 minutes. NIOSH has classified
xylene exposures of 10,000 ppm as immediately dangerous to life or health.
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1. PUBLIC HEALTH STATEMENT
EPA and the Food and Drug Administration (FDA) specify conditions under
which xylene may be used as a part of herbicides, pesticides, or articles that
are used in contact with food.
EPA reportable quantity regulations require that a spill of 1,000 pounds
or more of xylene or used xylene solvents be reported to the Federal
Government National Response Center.
More information on government regulations can be found in 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 total
xylenes. Its purpose is to present levels of significant exposure for total
xylenes 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 total xylenes,
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, .rid 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" effect. 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
af 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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12
2. HEALTH EFFECTS
Estimates of exposure levels 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 1986), uncertainties are
associated with the techniques.
2.2.1 Inhalation Exposure
Tables 2-1 through 2-4 and Figures 2-1 through 2-4 describe the health
effects in humans and/or animals associated with inhalation exposure to mixed
xylene and xylene isomers.
2.2.1.1 Death
One report was located regarding death in humans following acute
inhalation exposure to xylene (Morley et al. 1970). One of three men died
after breathing paint fumes for several hours that contained an estimated
concentration of 10,000 ppm xylene. Xylene comprised 90% of the solvent in
the paint, with solvent comprising 34% of the paint by weight. Clinical signs
noted in two exposed men who survived included solvent odor of the breath,
cyanosis of the extremities, and neurological impairment (temporary confusion,
amnesia). Both of these men recovered completely. The authors hypothesized
that anoxia did not contribute to the effects observed because diffusion of
oxygen into the area in which the men were working should have been sufficient
to maintain the level of oxygen. No studies were located regarding mortality
in humans after intermediate or chronic inhalation exposure to mixed xylene or
xylene isomers.
Acute inhalation LC50 values have been determined in animals for xylene
and its isomers (Bonnet et al. 1979; Carpenter et al. 1975; Hine and Zuidema
1970) . The 4-hour LCS0 value for mixed xylene in rats ranged between
6,350 ppm (Hine and Zuidema 1970) and 6,700 ppm (Carpenter et al. 1975). The
4-hour LC50 value for jj-xylene in rats was reported to be 4,740 ppm (Harper et
al. 1975). In mice, the 6-hour LC50 values for m-xylene, o-xylene, and
£-xylene were determined to be 5,267 ppm, 4,595 ppm, and 3,907 ppm,
respectively (Bonnet et al. 1979). According to the toxicity classification
system of Hodge and Sterner (1949), these values indicate that mixed xylene
and its isomers are slightly toxic by acute inhalation. Death from inhalation
of xylene is reportedly caused by respiratory failure and/or sudden
ventricular fibrillation (Gosselin et al. 1984).
-------
TAHI.K 2 1. Levels of Significant Exposure to Nixed Xylene * Inhalation
Figure
Key Species
Exposure
Frequency/ HOAEL
Duration Effect (ppm)
LOAEL (Effect)
Less Serious
(ppm)
Serious
(ppm)
Reference
ACUTE EXPOSURE
Death
1 Bat
2 Rat
Systemic
3 Hunan
4 Human
5 Human
6 Rat
7 Mouse
Neurological
8 Human
9 Human
10
11
Human
Rat
1 d
4hr/d
1 d
4hr/d
1 d
30min/d
S d
3d/wk
70min/d
1 d
lx/d
1 d
45min/d
1 d
lmin/d
1 d
30 min/d
S d
3d/wk
70min/d
1 d
70min/d
1 d
4hr/d
Reap
Derm/Oc
Cardio
Derm/Oc
Hemato
Resp
580
6700 (LC50)
6350 (LC50)
396
396
299
460 (eye irritation)
15000
460 1300b (decreased
respiratory rate)
396
299
299* (impairment in
performance tests
while exercising)
1700
Carpenter et al.
1975
Hine and Zuidema
1970
Hastings et al.
1986
Gamberale et al.
1978
Carpenter et al.
1975
Carpenter et al.
1975
Carpenter et al.
1975
Hastings et al.
1986
Gamberale et al.
1978
Gamberale et al.
1978
Pryor et al.
1987
ac
m
>
t-
•-9
nc
•n
T1
m
o
H
in
-------
TABLE 2-1 (Continued)
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key Species Duration Effect (ppm) (ppm) (ppm) Reference
12
13
Rat
Rat
3 d
6hr/d
1 d
8hr/d
2000b (increased dopa-
mine and
catecholamine in
brain)
1450b (hearing loss)
Andersson et al.
1981
Pryor et al.
1987
Developmental.
14 Rat
15
16
Rat
Rat
INTERMEDIATE EXPOSURE
Systemic
17 Rat
18
19
Rat
Rat
6 d
Gd9~14
24hr/d
9 d
24hr/d
Gd7-15
9 d
24hr/d
Gd7-15
230 (increased fetal
anomalies)
58 (skeletal
retardation)
784 (increased
fetal death
and resorption)
53 (skeletal
retardation,
embryolethality)
Hudak and
Ungvary 1978
Ungvary and
Tatrai 1985
Balogh et al.
1982
13 wk
Resp
810
Carpenter et
5d/wk
Cardio
810
1975
6hr/d
Gastro
810
Hemato
810
Musc/skel
810
Hepatic
810
Renal
810
Other
810
4 Nk
Cardio
230b (coronary changes)
Morvai et al
Sd/xk
1987
6hr/d
90 d
Hepatic
320
Kyrklund et i
24hr/d
1987
5C
m
>
r
H
EE
m
Tj
PI
O
H
on
-------
TABLE 2-1 (Continued)
_ LOAEL (Effect)
Exposure
Figure Frequency/ NOAEL Less Serious Serious
Key Species Duration Effect (ppm) (ppn) (ppcn) Reference
20
21
22
Rat
Rat
Dog
Neurological
23 Rat
24
25
26
27
Rat
Rat
Rat
Gerbil
18 Mk
5d/wk
6hr/d
4 wk
5d/wk
6hr/d
13 wk
5d /wk
6hr/d
6 wk
7d/*rk
14hr/d
18 wk
5d/wk
6hr/d
90 d
24hr/d
IB wk
Sd/Mk
6hr/d
3 mo
30d/mo
24hr/d
Hepatic
Hepatic
Reap
Cardio
Gastro
Heaaato
Musc/skeL
Hepatic
Renal
Other
300
600b (increased liver
weight)
810
810
810
810
810
810
810
810
800'* (hearing loss)
300 (CNS effects)
320
160
300b (decreased mem-
brane lipids in
axon membranes)
320 (proteins
increased in
brain)
Elovaara et al.
1980
Toftgard et al.
1981
Carpenter et al,
1975
Pryor et al.
1987
Savolainen et
al. 1979a
Kyrklund et al.
1987
Savolainen and
Seppalainen 1979
Rosengren et al.
1986
X
W
>
t-
H
a:
ti
m
o
Ln
-------
TABLE 2-1 (Continued)
LOAEL (Effect)
Figure
Key Species
Frequency/
Duration
Effect
NOAEL
(ppm)
Less Serious
(ppm)
Serious
(ppm)
Reference
Developmental
28 Rat
166 d
7d/wk
6hr/d
60 (decreased pup
weight)
Bio/dynamics
1983
Reproductive
29 Rat
166 d
7d/wk
6br/d
500
Bio/dynamics
1983
'This concentration is presented in Table 1-1.
bThis concentration is presented in Table 1-2.
Cardio ~ cardiovascular; CHS ™ central nervous system; d = day; Derm/Oc = dermal/ocular; Gastro = gastrointestinal;
Gd ¦ gestation day; Bemato ~ hematological; hr » hour; LC50 » lethal concentration, 501 kill; LOAEL = lowest-observed-
adverse-effect level; min - minute; mo - month; Musc/skel - muscular/skeletal; NOAEL = no-observed-adverse-effect level;
ppm « parts per million; Resp - respiratory; wk = week
X
m
>
t-
H
sc
m
~n
tn
n
H
tn
-------
TABLE 2-2. Levels of Significant Exposure to ¦-Xylene - Inhalation
Figure
Key Species
Exposure
Frequency/ NOAEL
Duration Effect (ppm)
LOAEL (Effect)
Less Serious
(ppm)
Serious
(ppm)
Reference
ACUTE EXPOSURE
Death
1 Mouse
Neurological
2 Rat
3 Rat
Developmenta1
4 Rat
INTERMEDIATE EXPOSURE
Neurological
5 Mouse
1 d
6hr/d
1 d
4.Shr/d
3 d
6hr/d
8 d
Gd7-14
24hr/d
7 wk
5d/wk
4hr/d
2100 (narcosis)
2000 (increased brain
levels of
catecholamine)
345 691 (decreased fetal
weight)
5267 (LC50)
1600 (decreased alpha-
adrenergic bind-
ing in brain)
Bonnet et aL.
1979
Molnar et al.
1986
Andersson et
al. 1981
Ungvary et al.
1980b
DC
m
>
H
tc
m
•n
^1
tn
o
H
in
Rank 1985
d - day; hr » hour; LC50 » lethal concentration, 501 kill; LOAEL » lowest-observed-adverse-effect level; NOAEL = no-
observed-adverse-effect level; ppm " parrper million; wk = week
-------
TABLE 2-3. Levels of Significant Exposure to o-Xylene - Inhalation
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key Species Duration Effect (ppm) (ppm) (ppm) Reference
ACUTE EXPOSURE
Death
1 Mouse
Neurological
2 Rat
1 d
6hr/d
3 d
6hr/d
2000 (increased brain
levels o£
catecholamine)
4595 (LC50)
Bonnet et al.
1979
Andersson et al.
1981
3 Rat
Developmental
4 Rat
1 d
4.5hr/d
B d
Gd7-14
24hr/d
2180 (narcosis)
34.5 345 (decreased fetal
weight)
Molnar et al
1986
Ungvary et al.
1980b
d ™ day; Gd " gestation day; hr = hour; LC50 = lethal concentration, 501 kill; LOAEL = lowest-observed-adverse-effect
level; NOAEL * no-observed-adverse-effect level; ppm = parts per million; Resp = respiratory
ec
m
>
t-
H
EC
m
•n
*TJ
m
o
H
co
-------
TABLE 2-4. Levels of Significant Exposure to j>-Xylene " Inhalation
Figure
Key Species
Exposure
Frequency/
Duration
Effect
NOAEL
(ppm)
LOAEL (Effect)
Less Serious
(ppm)
Serious
(ppm)
Reference
ACUTE EXPOSURE
Death
1 Rat
2 Mouse
Systemic
3 Hunan
Neurological
4 Human
5 Rat
6 Sat
7 Rat
1 d
4hr/d
1 d
6hr/d
5 d
lx/d
5 d
lx/d
1 d
4.5hr/d
3 d
6hr/d
1.5 wt
Sd/Mk
6hr/d
Rasp
Cardio
Other
100
100
100
100* (ENT irritation)
4740 (LC50)
3907 (LC50)
1940b (narcosis)
2000 (increased brain
levels of
catecholamine)
800 (decreased axonal
transport)
Harper et al.
1975
Bonnet et al.
1979
Hake et aL. 1981
Hake et al. 1981
Molnar et al.
1986
Andersson et al.
1981
•x.
>
r
H
a:
m
¦n
¦n
ro
o
1-3
on
Padilla and
Lyerly 1989
-------
TABLE 2-4 (Continued)
Figure
Key Species
Exposure
Frequency/
Duration
LOAEL (Effect)
Effect
NOAEL
(ppm)
Less Serious
(ppm)
Serious
(ppm)
Reference
Developmental
8 Rat
9 Rat
10 d
Gd7-16
6hr/d
48 hr
Gd9-10
24hr/d
1612
691 (decreased fetal
weight)
Rosen et al.
1986
Ungvary et al.
1981
'This concentration is presented in Table 1-1.
'This concentration is presented in Table 1-2. ^
lx « one time; Cardio ™ cardiovascular; d » day; ENT » ear, nose, throat; Gd = gestation day; ppm = parts per million;
hr ~ hour; LC50 « lethal concentration, 50X kill; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed- ^
adverse-effect level; Resp « respiratory; trie = week PI
>
t-
H po
m o
pi
m
o
H
C/}
-------
ACUTE
fe 14 Days)
(ppm) ^
100,000
10.000
1,000
100
10 •-
h' ¦»
O"
J f
, / "
t-1
H
a:
m
m
o
H
C/l
-------
INTERMEDIATE
(15 - 364 Days)
(PPm)
100,000
/ J?
£
/
~
/
/ ¦*
/
/
o*
~
£
/
27g
029r
DC
m
>
r
H ro
ac ro
m
m
n
H
cn
®28r
10 «-
r Rat
d Dog
g Geibtt
Key
9 LOAEL for less serious effects (animals)
O NOAEL (animals)
The number next to each point corresponds lo entries In Table 2-1.
FIGURE 2-1 (Continued)
-------
(PPm)
100,000
ACUTE
(< 14 Days)
¦tr
~
INTERMEDIATE
(15-364 Days)
/v
£
10.000
|1m
1.000
100
®3r
(I 4,
O*
3 5n
10
m Mouse
r Rat
L.C50
Key
O IOAEL lor less serious effects (animals)
O NOAEL (animals)
The number next to each point corresponds to entries in Table 2-2.
FIGURE 2-2. Levels of Significant Exposure torn- Xylene - Inhalation
-------
ACUTE
(< 14 Days)
(ppm)
100.000
10,000
1,000
100
, / /
llm
da®"
/
04,
Key
r Rat
¦ LC50
m Mouse (J LOAEL tor less serious effects (animals)
O NOAEL (animals)
The number next to each point corresponds to entries in Table 2-3.
FIGURE 2-3. Levels of Significant Exposure to o - Xylene - Inhalation
-------
ACUTE
(< 14 Days)
(ppm)
100,000
10,000
1,000
100
12m
y . j
/ / / / / /
(K
A® A» Aa A*
O
O*
Key
r Rat ¦ LCSO
m Mouse 3 LOAEL for lass serious offsets (animals)
O NOAEL (animals)
A LOAEL for lass serious effect (humans)
A NOAEL (humans)
The number next to each point corresponds to enties In Table 2-4.
FIGURE 2-4. Levels of Significant Exposure to p -
Xylene
- Inhalation
-------
26
2. HEALTH EFFECTS
Other acute studies with rats and mice have shown that animal lethality
is determined by length of exposure and concentration. No deaths occurred
after exposure to concentrations ranging from 1,005 ppm m-xylene over a period
of 14 days to 8,982 ppm g-xylene for only 1 hour (Cameron et al. 1938;
Klimisch et al. 1988). No studies were located regarding death in animals
after intermediate or chronic inhalation exposure to mixed xylene or xylene
isomers.
The highest NOAEL values and all reliable LOAEL values for death in each
species and duration category are recorded in Tables 2-1 through 2-4 and
plotted in Figures 2-1 through 2-4.
2.2.1.2 Systemic Effects
Respiratory Effects. Respiratory effects following inhalation exposure
to xylene have been observed in humans and animals. In humans, inhalation
exposure to mixed xylene and jj-xylene-has been associated with dyspnea and
irritation of the nose and throat at a concentration as low as 100 ppm
j>-xylene for an acute exposure period (Goldie 1960; Hake et al. 1981; Klaucke
et al. 1982; Nersesian et al. 1985). However, no increase in reports of nose
and throat irritation and no change in respiratory rate were obtained in a
study of subjects exposed to mixed xylenes at concentrations as high as
398 ppm (Hastings et al. 1986). An autopsy revealed that exposure to
10,000 ppm of xylene produced severe lung congestion with focal intra-alveolar
hemorrhage and pulmonary edema in one worker who died following exposure to
xylene fumes for several hours while painting (Morley et al. 1970). Human
subjects exposed to concentrations ranging from 20 ppm to 150 ppm 2_xylerie f°r
6 weeks had nose and throat irritation, but no pulmonary ventilation effects
(Hake et al. 1981). Chronic occupational exposure of workers to vapors of
mixed xylene has also been associated with labored breathing and impaired
pulmonary function (Hipolito 1980; Roberts et al. 1988).
Adverse respiratory effects noted in rats, mice, and guinea pigs
following acute and intermediate inhalation exposure to xylene are similar to
those observed in humans. They include decreased respiration, labored
breathing, irritation of the respiratory tract, pulmonary edema, pulmonary
hemorrhage, and pulmonary inflammation (Carpenter et al. 1975; De Ceaurriz et
al. 1981; Furnas and Hine 1958). Concentrations of 1,300 ppm mixed xylene
(Carpenter et al. 1975) or 1,467 ppm o-xylene (De Ceaurriz et al. 1981)
produced a 50% decrease in respiratory rate in mice. No histopathological
changes in the lungs were evident in rats, guinea pigs, or monkeys following
intermediate exposure to concentrations ranging between 78 ppm and 810 ppm
mixed xylene or o-xylene (Carpenter et al. 1975; Jenkins et al. 1970). No
-------
27
2. HEALTH EFFECTS
animal studies were located that evaluated the respiratory effects of mixed
xylene or single isomers following chronic inhalation exposure.
The highest NOAEL values and all reliable LOAEL values for respiratory
effects in each species and duration category are recorded in Tables 2-1 and
2-4 and plotted in Figures 2-1 and 2-4.
Cardiovascular Effects. Limited human and animal data are available
regarding the cardiovascular effects of xylene following inhalation exposure.
Chronic occupational exposure to xylene along with other chemical agents
resulted in complaints of increased heart palpitation, severe chest pain, and
an abnormal ECG (Hipolito 1980; Sukhanova et al. 1969). No cardiovascular
effects were noted in humans exposed for an acute or intermediate period to
either 100 or 150 ppm ^-xylene (Hake et al. 1981) or exposed acutely to 299
ppm mixed xylene (Gamberale et al. 1978).
Data regarding cardiovascular effects in animals are limited.
Morphological changes in coronary microvessels (increased vascular tone),
decreased myocardial blood flow, and increased heart weight were noted in rats
exposed to 230 ppm xylene (unspecified composition) for 4 weeks (Morvai et al.
1987). Other effects seen in rats inhaling unspecified high (lethal)
concentrations of xylene of unknown composition included ventricular
repolarization disturbances, atrial fibrillation, arrhythmias, cardiac arrest,
and ECG changes (Morvai et al. 1976). However, histopathological examination
of rats, guinea pigs, or monkeys exposed for an intermediate period (13-18
weeks) to concentrations of mixed xylene or o-xylene ranging between 78 ppm
and 810 ppm revealed no adverse effects upon the heart (Carpenter et al. 1975;
Jenkins et al. 1970). No information was located regarding cardiovascular
effects in animals after chronic exposure to mixed xylene or its isomers.
The highest NOAEL values and all reliable LOAEL values for
cardiovascular effects in each species and duration category are recorded in
Tables 2-1 and 2-4 and plotted in Figures 2-1 and 2-4.
Gastrointestinal Effects. Symptoms of nausea, vomiting, and gastric
discomfort have been noted in case reports of workers exposed by inhalation to
xylene (Goldie 1960; Klaucke et al. 1982; Nersesian et al. 1985). These
symptoms subsided after cessation of the xylene exposure. Samples of air
taken from the sites at which persons experienced these symptoms revealed that
air concentrations of xylene ranged from 1.8 to 18.7 ppb in one case of
gastric disturbance (Nersesian et al. 1985). Other quantitative estimates of
xylene concentrations were not provided. The isomeric composition of xylene
in these case studies also was not reported.
-------
28
2. HEALTH EFFECTS
Limited data were located regarding gastrointestinal effects in animals.
No lesions were observed in the gastrointestinal tract of rats and dogs
exposed to concentrations as high as 810 ppm mixed xylene for an intermediate
period of time (Carpenter et al. 1975). These NOAEL values are recorded in
Table 2-1 and plotted in Figure 2-1. No studies were located regarding
gastrointestinal effects in animals after acute or chronic inhalation exposure
to mixed xylene or the isomers of xylene.
Hematological Effects. Human and animal data provide no indication of
adverse hematological effects following inhalation of xylene.
Previously, chronic occupational exposure to xylene by inhalation was
thought to be associated with a variety of hematological effects. However,
exposure in all cases was to solvent mixtures known or suspected to contain
benzene. Because benzene is an agent strongly suspected of causing leukemia
and other blood dyscrasias in humans, these effects cannot be solely
attributed to xylene (ECETOC 1986). More recent epidemiological studies
suggest a possible relationship between coal-based xylene exposure and
hematological effects (leukemia) (Arp et al. 1983; Wilcosky et al. 1984).
Both of these studies examined workers in the rubber and tire manufacturing
industry and were limited by the small number of subjects, unknown composition
of xylene, exposure to other chemicals, and imprecise historical exposure
estimates.
No adverse hematological effects have been observed in rats or dogs
following acute or intermediate inhalation exposure to concentrations of mixed
xylene as high as 810 ppm for blood chemistry parameters (intermediate
exposure) or 15,000 ppm for erythrocyte fragility (acute exposure) (Carpenter
et al. 1975). The highest NOAEL values for hematological effects are recorded
in Table 2-1 and plotted in Figure 2-1.
Musculoskeletal Effects. No data were available regarding
musculoskeletal effects in humans following inhalation exposure to mixed
xylene or individual isomers. Animal data regarding musculoskeletal effects
following inhalation of xylene provide no indication that xylene produces
musculoskeletal effects. No lesions were observed in the skeletal muscle of
rats and dogs exposed for an intermediate period of time to concentrations as
high as 810 ppm mixed xylene (Carpenter et al. 1975). These NOAEL values are
recorded in Table 2-1 and plotted in Figure 2-1.
Hepatic Effects. Human data regarding hepatic effects following
inhalation of xylene are limited to several case and occupational studies
(Dolara et al. 1982; Kurppa and Husman 1982; Morley et al. 1970). These
studies are inadequate for evaluating the hepatic effects of xylene, because
-------
29
2. HEALTH EFFECTS
their subjects were concurrently exposed to other chemical agents in addition
to xylene.
Animal studies using rats indicate that mixed xylene, m-xylene> 2-
xylene, or jj-xylene generally induce a wide variety of hepatic enzymes, as
well as increase hepatic cytochrome P-450 content in rats (Elovaara 1982;
Elovaara et al. 1980; Patel et al. 1979; Savolainen et al. 1978; Toftgard and
Nilsen 1981, 1982; Toftgard et al. 1981; Ungvary et al. 1980a). Many hepatic
effects appear after intermediate exposure. They include increased hepatic
weight in rats (Tatrai and Ungvary 1980; Toftgard et al. 1981), increased
transient liver-to-body weight ratios in rats (Kyrklund et al. 1987; Toftgard
et al. 1981); decreased hepatic glycogen in rats (Tatrai and Ungvary 1980;
Ungvary et al. 1980b), ultrastructural changes in size hepatic endoplasmic
reticulum in rats (Tatrai and Ungvary 1980); and changes in the distribution
°f hepatocellular nuclei in rats (Tatrai and Ungvary 1980). Conversely, upon
histopathologic examination, no treatment-related effects were noted in rats,
guinea pigs, or monkeys following intermediate exposure to concentrations as
high as 810 ppm mixed xylene or o-xylene (Carpenter et al. 1975; Jenkins et
al. 1970). Increased liver weight and microsomal enzyme activity were
reported in a study in which rats were exposed to o-xylene for one year
(Tatrai et al. 1981). Electron microscopic examination of liver tissue
revealed a proliferation of the endoplasmic reticulum and only very minor
toxic effects on mitochondria as exemplified by increased numbers of perixo-
somes. These authors concluded that the increase in liver weight produced by
chronic exposure to o-xylene is an adaptive rather than a toxic effect.
The highest NOAEL values and a reliable LOAEL value for hepatic effects
in rats exposed for an intermediate period to mixed xylene are recorded in
Table 2-1 and plotted in Figure 2-1.
Renal Effects. Limited data from case reports and occupational studies
suggest that inhalation exposure to solvent mixtures containing xylene may be
associated with renal effects in humans (Askergren 1981, 1982; Askergren et
al. 1981b, 1981c; Franchini et al. 1983; Martinez et al. 1989; Morley et al.
1970). These effects included increased blood urea concentrations, decreased
urinary clearance of endogenous creatinine, increased lysozymuria, increased
urinary levels of £-glucuronidase, and increased urinary excretion of albumin,
erythrocytes, and leukocytes. However, no definitive conclusions can be made
from these renal effects from xylene inhalation exposure because of
confounding exposures to other solvents.
The renal effects of mixed xylene and xylene isomers following
inhalation exposure have been evaluated in acute and intermediate studies with
rats, guinea pigs, dogs, and monkeys (Carpenter et al. 1975; Elovaara 1982;
Jenkins et al. 1970; Toftgard and Nilsen 1982). Effects noted in these
-------
30
2. HEALTH EFFECTS
studies at xylene concentrations of 50-2,000 ppm have included increased renal
enzyme activity, increased renal cytochrome P-450 content, and increased
kidney-to-body weight ratios (o-xylene exposed rats) (Elovaara 1982; Toftgard
and Nilsen 1982). However, histopathologic examination of rats, guinea pigs,
dogs, and monkeys did not reveal any renal lesions after inhalation of 810 ppm
mixed xylene or 78 ppm o-xylene for an intermediate period of time (Carpenter
et al. 1975; Jenkins et al. 1970).
No chronic animal studies were located regarding renal effects following
inhalation exposure to mixed xylene, m-, °-> or ^-xylene.
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. No human or animal data were available regarding
dermal effects following inhalation exposure to mixed xylene or xylene
isomers. However, limited human data indicate that acute inhalation exposure
to mixed xylene and £>-xylene vapors produces mild transient eye irritation
following inhalation at concentrations ranging from 100 ppm £-xylene to 460
ppm mixed xylene (Carpenter et al. 1975; Hake et al. 1981; Nelson et al.
1943). However, exposure to concentrations of mixed xylene as high as 396 ppm
produced no increase in subjective reports of eye irritation or in the number
of eyeblinks in human subjects (Hastings et al. 1986). The highest NOAEL
value and all reliable LOAEL values for dermal/ocular effects are recorded in
Tables 2-1 and 2-4 and plotted in Figures 2-1 and 2-4.
No studies were located regarding dermal/ocular effects in animals
following inhalation exposure to mixed xylene or individual isomers.
2.2.1.3 Immunological Effects
No determination can be made regarding the association between
inhalation of xylene and immunological effects from available human studies,
because workers were concurrently exposed to other chemical agents
(Hoszczynski and Lisiewicz 1983; Smolik et al. 1973; Sukhanova et al. 1969).
No studies were located regarding immunological effects in animals following
inhalation exposure to mixed xylene or xylene isomers.
2.2.1.4 Neurological Effects
The neurological effects of xylene in humans following inhalation expo-
sure have been evaluated in a number of experimental studies, case reports,
and occupational studies. Results of experimental studies with humans
indicate that acute inhalation exposure to mixed xylene or m-xylene causes
impaired short-term memory, impaired reaction time, performance decrements in
-------
31
2. HEALTH EFFECTS
numerical ability, and alterations in equilibrium and body (Gamberal
et al. 1978; Riihimaki and Savolainen 1980; Savolainen and Rl^™k: 1981b'
Savolainen and Linnavuo 1979; Savolainen et al. 1979b, 1984, 1985).
Acute exposure to 299 ppm mixed xylene while performing physical
exercise produced impairment in a variety of tests o cen ra ®
performance. However, exposure to 299 ppm (Gambera e et a . fnrmflnce
(Hastings et al. 1986) mixed xylene at rest had no effect on of
tests. Exercise appears to increase the uptake of xylene. human bodv
m-xylene fluctuating between 64 and 400 ppm produced ^ J",Ban b°dy
balance (Savolainen and Riihimaki 1981b; Savolainen et a . ,
concentrations fluctuating between 135 and 400 ppm pro uce s 6 ot-her
the latency of visual evoked potentials (Seppalainen et a
studies also reported impaired body balance following ^cu!*® ° ""
xylene (Riihimaki and Savolainen 1980; Savolainen et a . ,
Neurological effects following acute or intermediate inhalation exposure
to |)-xylene have not been observed in experimental stu *-®s J"71 1985^
concentrations ranging from 64-150 ppm (Hake et al- • ,S°? B-, nflrsmeter
Differences in such factors as the xylene isomer, the ne^roJ°S^^ £ and '
exposure conditions and concentrations, rapid deve opmen °
total xylene uptake may account for the disagreements m e
Available case reports and occupational studies are t wen
evaluate because exposure conditions in the studies geinerally are not well^
characterized and/or subjects may have been expose ° Hinolito 1980'
in addition to xylene (Arthur and CurnocU ; Gold e 960 H Polito^SO,^
Klaucke et al. 1982; Morley et al. 1970, Nersesian ec a ' ide
1988) . Available case reports and occupatronal ¦^1" Jvlene or
:o!5"rrixSerr„nta"i^;i- rhf—Xt"rs
srt-s jsss -
. leniufdri instances of unconsciousness,
noise. In several case rePor"' ® seizUre have been associated with
amnesia brain hemorrhage, and epileptic containlng xyUne (Arthur and
acute inhalation exposure to solvent m Because other chemicals were
Curnock 1982; Goldie 1960, o studies the effects observed cannot be
present with xylenes in many of these studle ,
conclusively attributed to xylene exposure.
Results of experimental studies *ith £" Zl^iorexposurf^
mixed xylene and its isomers are neurotoxic follo*lnf j"?"J^acute and
Siens of neurotoxicity observed in rats, mice, and gerbils following acute and
inLr„edlaeterinhalatiL exposure
breathing,behavioral'changes, hyperreactivity to stimuli, elevated auditory
-------
32
2. HEALTH EFFECTS
thresholds, hearing loss, changes in brain enzyme activity, and biochemical
changes in the brain (Andersson et al. 1981; Bushnell 1989; Carpenter et al.
1975; De Ceaurriz et al. 1983; Furnas and Hine 1958; Ghosh et al. 1987;
Kyrklund et al. 1987; Molnar et al. 1986; Pryor et al. 1987; Rank 1985;
Rosengren et al. 1986; Savolainen and Seppalainen 1979; Savolainen et al.
1978, 1979b; Wimolwattanapun et al. 1987).
Exposure levels associated with neurological effects in animals are well
defined. Acute concentrations inducing behavioral changes in rats and mice
ranged from 113 ppm for effects of mixed xylene on operant conditioning or
self-stimulation behavior (Ghosh et al. 1987; Wimolwattanapun et al. 1987) to
1,010 ppm for o-xylene-induced immobility in a "behavioral despair swimming
test" (De Ceaurriz et al. 1983). Acute exposure to 1,600 ppm p-xylene
produced hyperactivity (Bushnell 1989) and 1,300 ppm mixed xylene produced
incoordination in rats which did not persist after exposure ended; no overt
signs of toxicity were noted at 580 ppm (Carpenter et al. 1975). Acute
exposure to p-xylene caused decreased axotial transport at concentrations as
low as 800 ppm (Padilla and Lyerly 1989), however no such decrease was
apparent three days after exposure had ceased. At concentrations of
1,600 ppm, however, the decrease in axonal transport oersisted for 13 days
after exposure. All three isomers produced narcosis in rats after 1-4 hours'
exposure to concentrations of approximately 2,000 ppm (Molnar et al. 1986).
Hearing loss occurred in rats exposed to 1,450 ppm mixed xylene for 8 hours,
whereas exposure to 1,700 ppm for 4 hours produced no effects on hearing
(Pryor et al. 1987) indicating that the duration of exposure is important for
the observation of ototoxic effects. Acute inhalation of 2,000 ppm mixed
xylene produced increased dopamine and/or noradrenaline levels in the
hypothalamus of rats; no behavioral changes were assessed (Andersson et al.
1981). Levels of catecholamine in the hypothalamus of rats were increased
following inhalation of 2,000 ppm mixed xylene, m-, o-, or £ xylene (Andersson
et al. 1981).
In intermediate inhalation studies with animals, neurological effects have
been observed following exposure to approximately 300 ppm of xylene. Brain
concentrations of DNA and/or astroglial proteins increased in rats and gerbils
after intermediate exposure to 300-320 ppm xylene (Rosengren et al. 1986;
Savolainen and Seppalainen 1979). In addition, increased levels of brain
enzymes, changes in nerve axon membranes, and behavioral changes occurred in
rats after exposure to 300 ppm of mixed xylene for 18 weeks (Savolainen and
Seppalainen 1979; Savolainen et al. 1979a). Hearing loss was also evident
after exposure for 6 weeks to 800 ppm (Pryor et al. 1987). However, no
significant long-term alterations in fatty acid levels were noted in the
brains of rats after intermediate exposure to 320 ppm mixed xylene (Kyrklund
et al. 1987).
-------
33
2. HEALTH EFFECTS
No animal studies were located regarding neurological effects following
chronic inhalation exposure to mixed xylene or its isomers.
The highest NOAEL values and all reliable LOAEL values for neurological
effects in each species and duration category are recorded in Tables 2-1
through 2-4 and plotted in Figures 2-1 through 2-4.
2.2.1.5 Developmental Effects
Human data are limited for assessing the relationship between inhalation
of xylene and developmental effects, because the available studies involved
concurrent exposure to other chemical agents in addition to xylene in the
workplace (Holmberg and Nurminen 1980; Kucera 1968; Taskinen et al. 1989) and
because of the small number of subjects (Taskinen et al. 1989).
Both mixed xylene and the individual isomers produce fetotoxic effects
in laboratory animals. Effects of mixed xylene observed in rats and mice
included increased incidences of skeletal variations in fetuses, delayed
ossification, fetal resorptions, hemorrhages in fetal organs, and decreased
fetal body weight (Balogh et al. 1982; Bio/dynamics 1983; Hudak and Ungvary
1978; Litton Bionetics 1978a; Mirkova et al. 1983; Ungvary and Tatrai 1985).
The levels at which these effects were observed depended upon the composition
and concentration of mixed xylene, and the choice of strain and test species
used. In addition, animals in a number of studies were exposed 24 hr/day
(Balogh et al. 1982; Hudak and Ungvary 1979; Ungvary and Tatrai 1985), whereas
animals in other studies (Bio/dynamics 1983; Litton Bionetics 1978a; Mirkova
et al. 1983) were exposed 6 hr/day. The study conducted by Litton Bionetics
(Litton Bionetics 1978a) used a formulation of mixed xylene with a
comparatively high percentage (36%) of ethylbenzene. Developmental effects
occurred following maternal exposure to concentrations as low as 12 ppm mixed
xylene in rats (Mirkova et al. 1983), but the health of the test animals may
have been compromised. This is suggested by the relatively low conception
rates and the high incidence of fetal hemorrhages seen in the controls.
Maternal toxicity was observed at 775 ppm in the study by Balogh et al. (1982)
whereas no maternal toxicity occurred in the studies by Bio/dynamics (1983),
Hudak and Ungvary (1978) and Litton Bionetics (1978a). Insufficient evidence
was presented to determine whether maternal toxicity occurred in the studies
by Mirkova et al. (1983) and Ungvary and Tatrai (1985). Many of the studies
(Bio/dynamics 1983; Hudak and Ungvary 1978; Mirkova et al. 1983; Ungvary and
Tatrai 1985) had limitations that made them difficult to assess (e.g., unknown
composition of xylene and insufficient number of doses to form a dose-response
relationship; lack of detail with regard to both methods and data obtained).
An increase In placental weight was seen at 438 and 775 ppm in the study by
Balogh et al. (1982). The biological significance of this effect is unknown.
-------
34
2. HEALTH EFFECTS
Inhalation of m-. . or g-xylene at concentrations similar to those at
which mixed xylenes caused fetal toxicity, produced decreased fetal weight,
skeletal retardation and post - implantation loss in rats following maternal
exposure (Ungvary and Tatrai 1985; Ungvary et al. 1980b, 1981). Both
increases and decreases in placental weight were evident in rats following
inhalation of 345 ppm o-xylene and ^-xylene (Ungvary et al. 1980b). As noted
above, the biological significance of changes in placental weight is unknown.
A NOAEL value of 1,612 ppm E_xylene f°r developmental effects was determined
from one study with rats (Rosen et al. 1986). The large variation in
concentrations of xylene producing developmental effects and those producing
no developmental effects may be influenced by a number of factors (e.g.,
strain and species of animal, purity of xylene, method of exposure, exposure
duration, etc.). For example, Rosen et al. (1986) exposed animals for
6 hr/day whereas animals were exposed 24 hr/day in studies by Ungvary and
Tatrai (1985) and Ungvary et al. (1980b, 1981). No information on maternal
toxicity was available for the studies by Ungvary and Tatrai (1985) or Ungvary
(1981); however, in the studies by Rosen et al. (1986) and Ungvary et al.
(1980b) signs of maternal toxicity in rats following inhalation of the isomers
included decreased weight gain, decreased food consumption, and increased
liver-to-body weight ratios. m-Xylene was the only isomer that resulted in
lasting maternal growth inhibition or maternal mortality (Ungvary et al.
1980b).
The highest NOAEL values and all reliable LOAEL values for developmental
effects in each species and duration category are recorded in Tables 2-1
through 2-4 and plotted in Figures 2-1 through 2-4,
2.2.1.6 Reproductive Effects
No studies were located regarding reproductive effects in humans
following inhalation exposure to mixed xylene or to xylene isomers.
In male and female rats, no adverse reproductive effects were noted
following inhalation exposure of mixed xylene at concentrations as high as
500 ppm during premating, mating, pregnancy, and lactation (Bio/dynamics
1983). This NOAEL value is recorded in Table 2-1 and plotted in Figure 2-1.
2.2.1.7 Genotoxic Effects
Limited human and animal data are available regarding the genotoxic
effects of mixed xylene following inhalation exposure. No inhalation studies
were available on the genotoxicity of m-xylene, o-xylene, or g-xylene.
Results of a study by Pap and Varga (1987) suggests that inhalation exposure
of humans to mixed xylene is not associated with the induction of sister-
chromatid exchanges or chromosomal aberrations. Results of other
investigations were also negative for chromosomal aberrations in humans or
-------
35
2. HEALTH EFFECTS
rats exposed by inhalation to xylene; however, the isomeric composition of the
xylene in these studies was not reported (Haglund et al. 1980; Zhong et al.
1980). The negative findings of these inhalation studies are supported by the
consistently negative results found in other genotoxicity assays in which
bacteria, yeast, insects, mammals, and mammalian cells have been exposed in
or in vivo to mixed xylene or to individual isomers (See Section 2.4).
2.2.1.8 Cancer
Human data regarding cancer are limited to occupational studies. These
studies examined the cancer and leukemia risks among solvent-exposed workers
(Arp et al. 1983, Wilcosky et al. 1984). Both contain limitations (e.g.,
small number of subjects, no exposure concentrations, unknown composition of
xylene) that preclude a definitive conclusion regarding inhalation of xylene
and cancer. No studies were located regarding cancer in animals exposed via
inhalation to mixed xylene or xylene isomers.
2.2.2 Oral Exposure
Tables 2-5 through 2-8 and Figures 2-5 through 2-8 describe the health
effects in humans and/or animals associated with oral exposure to mixed xylene
and xylene isomers. The exposure level and exposure duration associated with
these health effects are also presented.
2.2.2.1 Death
Death in humans following accidental or intentional ingestion of xylene
or mixtures containing xylene was reported (Abu al Ragheb et al. 1986;
Bernardelli and Gennari 1987). In one case, levels of xylene found in blood
and gastric and duodenal contents were 110 mg/L, 8,800 mg/L, and 33,000 mg/L,
respectively, indicating ingestion of a large, but undetermined, quantity of
xylene (Abu Al Ragheb et al. 1986).
Mortality was observed in laboratory animals following the ingestion of
nixed xylene and isomers of xylene. Two females from a group of ten that were
given E-xylene (2,000 gm/kg) orally for ten days died (Condie et al. 1988).
Acute LD50s have been determined for mixed xylene and m-xylene in rats and
mice (Table 2-9). Reported acute oral LD50s in rats for mixed xylene range
from 3,523 mg/kg when administered in corn oil (NTP 1986) to 8,600 mg/kg when
administered as an undiluted sample (Hine and Zuidema 1970). The acute oral
LD50 for mixed xylene in male and female mice was determined to be 5,627 mg/kg
and 5,251 mg/kg, respectively (NTP 1986). An LD50 for m-xylene in rats was
reported as 6,631 mg/kg (Smyth et al. 1962). The wide range of LD50 values in
rats may be due to differences in xylene composition, strain, sex, nutritional
status (fasted or nonfasted), and/or vehicle. According to the toxicity
-------
TABLE 2-5. Levels of Significant Exposure to Mixed Xylene - Oral
Exposure
Figure Frequency/ NOAEL
Key Species Route Duration Effect (mg/kg/day)
LOAEL (Effect)
Less Serious
(mg/kg/day)
Serious
(mg/kg/day)
ACUTE EXPOSURE
Death
1 Rat
2 Rat
3 Rat
4 Rat
5 Mouse
6 Mouse
Systemic
7 Mouse
Developmental
8 Mouse
(G)
(G)
(G)
(G)
(G)
(G)
(G)
INTERMEDIATE EXPOSURE
Death
9 Rat (G)
10
Mouse (G)
1* d
lx/d
1 d
lx/d
1 d
lx/d
1 d
lx/d
1 d
lx/d
14 d
lx/d
(GO) 1 d
10 d
Gd6-15
3x/d
13 wk
5d/«k
lx/d
13 wk
5d/wk
lx/d
Other
1000
2000M
4000F
5100
4000
2000
1000
1030
1000
2000M
2000* (8/10 died)
3523 (LD50 in males)
8600 (LD50)
5950 (4/6 died)
5627M (LD50)
5251F (LD50)
4000 (10/10 died)
2060 (cleft palate)
Reference
NTP 1986
NTP 1986
Hine and Zuidema
1970
Muralidhara and
Krishnakumari 1980
NTP 1986
NTP 1986
Feldt 1986
Marks et al.
1982
NTP 1986
NTP 1986
a:
>
r1
H
EC
m
OT
n
H
CO
LO
o
-------
TABLE 2-5 (Continued)
Figure
Key
Species
Exposure
Frequency/
Route Duration
LOAEL (Effect)
Effect
NOAEL
(nig/kg/day)
Less Serious
(mg/kg/day)
Serious
(mg/kg/day)
Reference
Systemic
11 Rat
(GO)
12
Rat
CG)
13
Mouse
r
H
a:
m
T!
pi
o
CO
-------
TABLE 2~5 (Cootinued)
Figure
Kay Species
Exposure
Frequency/
Route Duration
LOAEL (Effect)
Effect
NOAEL
(mg/kg/day)
Less Serious
(mg/kg/day)
Serious
(mg/kg/day)
Reference
Reproductive
16 Rat
17
Mouse
(G)
(G)
13 wk
5d/wk
lx/d
13 wk
5d/wk
lx/d
1000
2000
NTP 1986
NTP 1986
CHRONIC EXPOSURE
Death
18 Rat
19
Mouse
Systemic
20 Rat
21
Mouse
(G)
(G)
(G)
(G)
103 wk
5d/wk
lx/d
103 wk
Sd/wk
lx/d
103 wk
5d/wk
lx/d
103 wk
5 d/wk
lx/d
Reap
Cardio
Gastro
Musc/skel
Hepatic
Renal
Denn/Oc
Resp
Cardio
Gastro
Musc/skel
Hepatic
Renal
Derm/Oc
Other
1000
500
500
500
500
500
500
500
1000
1000
1000
1000
1000
1000
1000
1000
500 (decreased NTP 1986
survival, males)
NTP 1986
NTP 1986
NTP 1986
n:
n
>
t-
H
re
tn
Tl
pi
o
t-3
Lr,
w
oo
-------
TABLE 2-5 (Continued)
LOAEL (Effect)
Figure
Key Species
Frequency/
Route Duration
KOAEL Less Serious
Effect (mg/kg/day) (mg/kg/day)
Serious
(mg/kg/day)
Reference
Neurological
22 Rat
(G)
103 wk
5d/wk
lx/d
500
NTP 1986
23 House
CG)
103 wk
5d/«&
lx/d
500 1000 (hyperactivity)
NTP 1986
Reproductive
24 Rat
(G)
103 trie
Sd/wfc
lx/d
500
NTP 1986
25 Mouse
CG)
103 wk
5 d/wk
lx/d
1000
NTP 1986
•Converted to an equivalent concentration of 40,000 ppo in food for presentation in table 1-4.
Cardio ¦* cardiovascular; d - day; Derm/Oc = dermal ocular; F = female; Gastro = gastrointestinal; (G) - gavage;
(GO) - Ravage-oil; Gd » gestation day; Banato - hematological; LD50 = lethal dose, SOX kill; LOAEL - lowest-observed-
adverse-effect level; M - male; mg/kg/day « milligrams per kilogram per day; Musc/skel = musculoskeletal; HOAEL - no-
observed-adverse-effect level; Reap = respiratory; wk = week.
rn
>
H
DC
m
T]
•n
pi
>-3
C/l
-------
TABLE 2-6. Levels of Significant Exposure to 0-Xy1ene - 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 Sat (G)
Systemic
2 Rat (GO)
INTERMEDIATE EXPOSURE
Systemic
3 Rat (G)
1 d
lx/d
10 d
lx/d
13 wk
7d/wk
lx/d
Hepatic
Other
Resp
Cardio
Gastro
Hemato
Musc/skel
Hepatic
Renal
Derm/oc
Other
250
1000
BOO
200
800
BOO
800
800
200
800
6631 (LD50)
1000 (increased liver
weight)
2000 (decreased spleen
weight)
800 (decreased
absolute heart
weight in males)
800 (increased
relative kidney
weight in males)
200 (decreased weight
gain and food
consumption in males)
Smyth et aL.
1962
Condie et al.
1988
Hazleton Labs
1988a
X
m
>
r
H
X
m
¦n
n
H
w
o
-------
TABLE 2-6 (Continued)
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key Species Route Duration Effect (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference
Neurological
4 Rat
Reproductive
5 Rat
CG)
13 wk
7d/wk
lx/d
(G) 13 wk
7d/wk
lx/d
200
800
800 (increased brain-
to-body weight
ratio in males)
Hazleton Labs
1986a
Hazleton Labs
1988a
Cardio - cardiological; d " day; Derm/oc " dermal/ocular; Gastro - gastrointestinal; (G) = gavage; (GO) = gavage~oil; Hemato =
hematological; LDS0 ~ lethal dose, S0Z kill; LOAEL - lowest-observed-adverse-effect level; mg/kg/day - milligrams per kilogram per day;
Muac/akel - muscular/skeletal; HQAEL — no-observed-adverse-effect level; Resp - respiratory; wk = week
X
>
r1
H
n
>-9
C/5
-------
TABLE 2-7. Levels of Significant Exposure to o-Xylene - 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
Systemic
1 Rat (GO) 10 d Hepatic 250 1000 (increased liver Condie et al.
lx/d weight) 1986
Other 1000 2000 (decreased spleen
weight)
d ~ day; (00) » gavage-oil; LOAEL ~ lowest-observed-adverse-effect leveL; mg/kg/day = milligrams per kilogram per day;
NOAEL - no-obaerved-adverseeffect level
-------
TABLE 2-8. Levels of Significant Exposure to g-Xylene - 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
(GO)
Systemic
2 Rat
Neurological.
3 Rat
(G)
10 d
lx/d
(GO) 10 d
lx/d
1 d
lx/d
INTERMEDIATE EXPOSURE
Systemic
4 Rat (G)
Hepatic
Other
1000
1000
13 wk
Resp
800
7d/wk
Cardio
800
lx/d
Gastro
800
Hemato
BOO
Husc/skel
800
Hepatic
800
Renal
800
Derm/oc
800
Other
200
2000 (death)
250 (increased liver
weight)
2000 (decreased thymus
weight)
125 250* (impaired visual
function)
Condie et al.
1988
Condie et aL.
1988
Dyer et al. 1968
Hazleton Labs
1988b
DC
>
G
rr
~n
~n
CTJ
o
H
in
4>
800 (salivation)
-------
TABLE 28 (Continued)
Exposure LOAEL (Effect)
Figure Frequency/ HOAEL Less Serious Serious
Key Species Route Duration Effect {mg/kg/day) (mg/kg/day) (mg/kg/day) Reference
Neurological
5 Rat
Reproductive
6 Rat
(G) 13 Mk
7d/Mk
lx/d
(G) 13 Mk
7d/«*
lx/d
BOO
800
Hazleton Labs
1988b
Hazleton Labs
1986b
•Converted to an equivalent concentration of 5,000 ppm in food for presentation in Table 1-4. nj
Cardlo * cardiological; d « day; Denn/oc » dermal/ocular; Gastro = gastrointestinal; (G) = gavage; (GO) = gavage-oil;
Beoato ¦ hematological; LQAEL ~ lowest-observed-adverse-effect level; mg/kg/day = milligrams per kilogram per day;
Musc/skel " muscular/skeletal; HOAEL ¦ no-observed-adverse-effect level; Resp = respiratory; wk = week [5
t-
PI
Tl
m
o
H
m
-------
ACUTE
(< 14 Days)
(mg/kg/day)
100.000
&
&
£
/
10.000
¦ Sm
05m
O6"1
¦ 3r
•«
ISmO*
16m
1.000
2r
%U 02f
0"
07n
^8m
0*n
100
sc
m
>
r
H
re
m
~n
T1
m
n
H
on
¦P-
i_n
10
Key
m Mouse
Rat
¦ LD50
9 LOAEL for serious effects (animals)
O NOAEL (animals)
The number next lo each point corresponds lo entries in Table 2-5.
FIGURE 2-5. Levels of Significant Exposure to Mixed Xylene - Oral
-------
INTERMEDIATE
(15 - 364 Days)
(mg/kg/day)
100,000
/ 4
/ /
/
/
t-
H
a:
m
T1
•n
m
n
H
LO
P-
10
m
Moum
Rat
Key
9 LOAEL lor lass serious alt ecus (animals)
O NOAEL (animals)
Tha number next to each potm corresponds to entries in Table 2-5.
FIGURE 2-5 (Continued)
-------
CHRONIC
(>365 Days)
(mgftgMay)
100,000 i—
$
r&
. i8f O201 O20f O20'
100
10
m Mouse
r Rat
021m Oztm 021m 021rn 021m
Qzor O20r O20' O201
Key
9 LOAEL tor serious effects (animals)
3 LOAEL for less serious effects (animals)
O NOAEL (animals)
The number next lo each point corresponds to entries In Table 2-5.
()23m
023m 022r
025m
024r
sc
m
>
r1
H -o
x -J
m
•n
m
o
H
FIGURE 2-5 (Continued)
-------
ACUTE
(< 14 Days)
(mgfegftlay)
100.000 i-
/
CD
FIGURE 2-6. Levels of Significant Exposure torn- Xylene - Oral
-------
ACUTE
(< 14 Day)
(mgfttftay)
100.000 |—
10 «-
/ /
10.000
1.000 I- ®lr Olr
100
On
Rat
Key
01 LOAEL for less serious affects (animals)
O NOAEL (animate)
sc
t-1
X
PI
Tf
PI
o
H
to
vO
number next to each point corresponds to enMas In Table 2-7.
FIGURE 2-7. Levels of Significant Exposure to o - Xylene - Oral
-------
(mgftflWay) ^
100,000 j-
10,000
1,000
100
10
•ir
O"
ACUTE
(<14 Days)
INTERMEDIATE
(15-364 Days)
/ * /// J
' / / / //
3r
O*
Key
# LOAEL for serious affects (animals)
O LOAEL lor less serious effects (animals)
o NOAEL (animals)
The number next to each point corresponds Id entries in Tabto 2-7.
O O O O* Om O O O* 3* O O*
o
ac
m
>
f
H
n
m
>n
~n
m
n
H
CO
Ln
O
FIGURE 2-8. Levels of Significant Exposure to p - Xylene - Oral
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51
2. HEALTH EFFECTS
TABLE 2-9. Reported Acute Oral LD50 Values for Xylene
Xylene Isomer Species/Strain
Sex
Acute Oral
LD50 Value
Reference
Mixed xylene Rat/Long-Evans Male 8,600 mg/kg
Mixed xylene
m-Xylene
Rat/F344/N
Rat/Carworth-
Wistar
Mixed xylene Mice/B6C3F1
Male
Male
Male
Female
3,523 mg/kg
6,631 mg/kg
5,627 mg/kg
5,251 mg/kg
Hine and
Zuidema 1970
NTP 1986
Smyth et al.
1962
NTP 1986
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52
2. HEALTH EFFECTS
classification system of Hodge and Sterner (1949), these LD50 values indicate
that mixed xylene and m-xylene are slightly toxic by acute oral exposure.
No deaths were observed in rats following intermediate oral
administration of mixed xylene doses as high as 1,000 mg/kg/day (NTP 1986).
Survival was significantly lowered in male rats exposed to mixed xylene at
chronic oral doses of 500 mg/kg/day but not at 250 mg/kg/day (NTP 1986).
Although mortality was dose related in the treated rats, many of the early
deaths were gavage related. No significant increase in mortality was observed
in mice treated chronically with mixed xylene at oral doses up to
1,000 mg/kg/day (NTP 1986).
According to a study by Gerarde (1959), m-xylene may be slightly less
toxic than the other two isomers. A single oral dose of 8,650 mg/kg m-xylene,
o-xylene, or g-xylene produced death in 3/10, 7/10, and 6/10 rats,
respectively.
All reliable NOAEL and LOAEL values for death i each species and
duration category are recorded in Tables 2-5, 2-6, and 2-8 and plotted in
Figures 2-5, 2-6, and 2-8.
2.2.2.2 Systemic Effects
Respiratory Effects. No human studies were located regarding
respiratory effects following oral exposure to mixed xylene or xylene isomers.
Histopathological examination of the lungs and mainstem bronchi of rats and
mice administered mixed xylene at doses as high as 500 mg/kg/day in rats and
1,000 mg/kg/day in mice for up to 2 years revealed no adverse effects (NTP
1986). Gross and histopathological examination of rats administered m-xylene
or £-xylene for 13 weeks at doses as high as 800 mg/kg/day revealed no
treatment-related effects (Hazleton Labs 1988a, 1988b). The highest NOAEL
values for respiratory effects are recorded in Tables 2-5, 2-6 and 2-8 and
plotted in Figures 2-5, 2-6, and 2-8.
Cardiovascular Effects. No studies were located regarding
cardiovascular effects in humans following oral exposure to mixed xylene or
its isomers. No adverse cardiovascular effects were noted following
histopathological examination of the heart in rats and mice exposed to mixed
xylene for 13 or 103 weeks (NTP 1986). No treatment-related effects were
noted upon gross or histopathological examination of the heart in rats
administered m-xylene or ja-xylene at doses as high as 200 mg/kg/day for
13 weeks (Hazleton Labs 1988a, 1988b). However, absolute heart weight was
decreased in male rats administered 800 mg/kg/day m-xylene for 13 weeks. The
highest NOAEL values and all reliable LOAEL values for cardiovascular effects
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53
2. HEALTH EFFECTS
are recorded in Tables 2-5, 2-6, and 2-8 and plotted in Figures 2-5, 2-6, and
2-8.
Gastrointestinal Effects. No superficial erosions, deep ulcerations, or
other lesions were observed after histopathological examination of the gastric
mucosa of a person following ingestion of a "large quantity" of xylene (Abu A1
Ragheb et al. 1986). Histopathological examination of rats administered doses
as high as 1,000 mg/kg/day of mixed xylene and mice administered doses as high
as 2,000 mg/kg/day of mixed xylene for an intermediate or chronic exposure
period revealed no adverse effects on the stomach, small intestine, or colon
(NTP 1986). Administration of doses of m- or g-xylene as high as
800 mg/kg/day for an intermediate period had no significant effect on the
organs of the gastrointestinal system (Hazleton Labs 1988a, 1988b). The
highest NOAEL values for gastrointestinal effects are recorded in Tables 2-5,
2-6, and 2-8 and plotted in Figures 2-5, 2-6, and 2-8.
Hematological Effects. No human studies were located regarding
hematological effects following oral exposure to mixed xylene or xylene
isomers. Acute exposure to o- and m-xylene at 2000 mg/kg/day for ten days
produced a decrease in the spleen weight of male rats (Condie et al. 1988),
however, no hematological effects were observed in rats and mice upon
histopathological examination of the bone marrow of the femur following
intermediate or chronic exposure to doses of mixed xylene as high as 2,000
mS/kg/day (for 13 weeks in mice) and 1,000 mg/kg/day (for 103 weeks in mice)
(NTP 1986). At termination of an intermediate study (13 weeks), no adverse
hematological effects were noted in rats administered gi- or ^-xylene (Hazleton
Labs 1988a, 1988b). Mild polycythemia and leukocytosis in both male and
female rats and an increase in spleen weight in females were observed in rats
exposed to 1,500 mg/kg mixed xylene for 90 days (Condie et al. 1988). The
NOAEL and LOAEL values for hematological effects are recorded in Tables 2-5,
2-6 and 2-8 and plotted in Figures 2-5, 2-6 and 2-8.
Musculoskeletal Effects. No human studies were located regarding
Musculoskeletal effects following oral exposure to mixed xylene or xylene
isomer^. In two animal bioassays, no musculoskeletal effects were observed in
rats and mice upon histopathological examination of the femur, sternebrae, or
vertebrae following intermediate or chronic exposure to doses of mixed xylene
as high as 2,000 mg/kg/day (for 13 weeks in mice) and 1,000 mg/kg/day (for
103 weeks in mice) (NTP 1986). No adverse effects were observed in the
sternum (with marrow), thigh musculature, or femur upon histopathological
examination of rats administered m- or g-xylene at doses as high as
®00 mg/kg/day for 13 weeks (Hazleton Labs 1988a, 1988b). The highest NOAEL
values for musculoskeletal effects are recorded in Tables 2-5, 2-6, and 2-8
and plotted in Figures 2-5, 2-6, and 2-8.
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54
2. HEALTH EFFECTS
Hepatic Effects. No studies were located regarding hepatic effects in
humans following oral exposure to mixed xylene or xylene isomers. However, in
acute and intermediate studies with rats, oral exposure to xylene has been
associated with hepatic enzyme induction and increased hepatic weight (Condie
et al. 1988; Pyykko 1980). In the study by Condie et al. 1988, acute exposure
to p-xylene at 250 mg/kg/day and m- and o-xylene at 1000 rag/kg/day caused
increases in liver weight. Administration of doses as low as 1,060 mg/kg/day
of all three xylene isomers for an acute exposure period also produced
increased liver weight, increased cytochrome P-450 and b5 content and
increased activities of liver enzymes in rats (Pyykko 1980). The different
isomers generally showed different potencies of enzyme induction.
Administration of mixed xylenes to rats for 90 days caused increased liver
weight ratios in males at doses as low as 150 mg/kg/day and in females at
doses as low as 750 mg/kg/day (Condie et al. 1988). No treatment related
histopathological changes were observed in liver tissue samples. Also, no
effects were noted upon histopathological examination of the liver of rats and
mice orally administered mixed xylene for a chronic or intermediate period of
time to doses as high as 2,000 mg/kg/day (for 13 weeks in mice) and
1,000 mg/kg/day (for 103 weeks in mice) (NTP 1986), Administration of doses
as high as 800 mg/kg/day of m- or ^-xylene in rats for 13 weeks produced no
adverse hepatic effects (Hazleton Labs 1988a, 1988b).
The highest NOAEL values and all reliable LOAEL values for hepatic
effects in rats and mice for each duration category are recorded in
Tables 2-5, 2-6, 2-7, and 2-8 and plotted in Figures 2-5, 2-6, 2-7, and 2-8.
Renal Effects. No human studies were located regarding renal effects
following oral exposure to mixed xylene or xylene isomers. No adverse effects
were noted upon histopathological examination of the kidney of rats and mice
following intermediate or chronic exposure to doses of mixed xylene as high as
2,000 mg/kg/day (for 13 weeks in mice) and 1,000 mg/kg/day (for 103 weeks in
mice) (NTP 1986). Increased relative kidney weight in male rats administered
800 mg m-xylene/kg/day for an intermediate period was the only treatment -
related effect noted in rats of both sexes exposed to m- and ^-xylene
(Hazleton Labs 1988a, 1988b). Increased relative kidney weight also was
increased in male rats given mixed xylenes at 750 mg/kg/day and in female rats
at 1500 mg/kg/day (Condie et al. 1988). Gross and histopathology revealed
symptoms consistent with early chronic nephropathy. The NOAEL and LOAEL
values for these studies are recorded in Tables 2-5, 2-6, and 2-8 and plotted
in Figures 2-5, 2-6, and 2-8.
Dermal/Ocular Effects. No human studies were located regarding
dermal/ocular effects following oral exposure to mixed xylene or xylene
isomers. No adverse effects were noted during microscopic examination of the
eyes of rats and mice administered doses as high as 2,000 mg/kg/day in mice
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55
2. HEALTH EFFECTS
and as high as 1,000 mg/kg/day in rats of mixed xylene for an intermediate
(13 weeks) or chronic (103 weeks) period of time (NTP 1986). Upon
histopathologic examination, the skin of rats and mice exposed to mixed xylene
for up to 2 years appeared comparable to that of controls. The eyes and skin
of rats administered doses as high as 800 mg/kg/day of m- or g-xylene for
13 weeks appeared without effect upon histopathological examination (Hazleton
Labs 1988a,b). These NOAEL values are recorded in Tables 2-5, 2-6, and 2-8
and plotted in Figures 2-5, 2-6, and 2-8.
Other Systemic Effects. Salivation was frequently observed in rats
exposed orally to 800 mg m- or g-xylene/kg/day for 13 weeks (Hazleton Labs
1988a, 1988b). Average body weights were slightly decreased in male and
female rats at 800 mg E~xylene/kg/day, but this decrease was not significant.
Food consumption and body weight gain were significantly decreased during
intermediate exposure at a dose as low as 200 mg m-xylene/kg/day in males
(Hazleton Labs 1988a). Decreased relative thymus weights were observed in
rats exposed for 10 days to 2,000 mg/kg ^-xylene (Condie et al. 1988).
The highest NOAEL values and all reliable LOAEL values for other
systemic effects are recorded in Tables 2-5, 2-6 and 2-8 and plotted in
Figures 2-5, 2-6 and 2-8.
2.2.2.3 Immunological Effects
No studies were located regarding immunological effects in humans and
animals after oral exposure to mixed xylene or xylene isomers.
2.2.2.4 Neurological Effects
Information concerning possible neurological effects associated with the
ingestion of xylene is limited. Xylene produced a coma that persisted for
more than 26 hours in a person who accidentally ingested xylene (Recchia et
al. 1985). The composition of the xylene was unknown.
Impairment of visual function, as evidenced by significant decreases in
flash-evoked potentials, was noted in rats treated one time at doses of 250 mg
£-xylene/kg/day and higher (Dyer et al. 1988). Histopathological examination
°f the brain and spinal cord of rats and mice administered doses as high as
1,000 mg/kg/day (rats) or 2,000 mg/kg/day (mice) of mixed xylene for up to
2 years revealed no adverse effects (NTP 1986). However, following gavage of
1.000 mg/kg/day in the chronic bioassay, hyperactivity was noted for
5-30 minutes in weeks 4-103 of study in both male and female mice (NTP 1986).
No adverse effects were noted in the spinal cord of rats administered doses of
or c-xylene as high as 800 mg/kg/day for 13 weeks (Hazleton Labs 1988a,b),
however, the brain-to-body weight ratio was increased in males dosed with
-------
56
2. HEALTH EFFECTS
800 mg/kg/day of m-xylene. Clinical signs included hyperactivity,
convulsions, salivation, and epistaxis.
The highest NOAEL values and all reliable LOAEL values for neurological
effects in rats and mice and for each exposure duration are recorded in
Tables 2-5, 2-6, and 2-8 and plotted in Figures 2-5, 2-6, and 2-8.
2.2.2.5 Developmental Effects
No studies were located regarding developmental or teratogenic effect in
humans following oral exposure to mixed xylene or xylene isomers.
Significantly increased incidences of cleft palate and decreased body
weight were reported following maternal exposure during gestation to doses of
2,060 mg/kg/day mixed xylene in rats (Marks et al. 1982). Mixed xylene was
also toxic to the dams, producing 31.5% mortality at 3,100 mg/kg/day. It is
unclear whether the observation of cleft palate in this study is associated
with a predisposition of mice under stress to give birth to offspring with
this birth defect. In a teratology screening study, 2000 mg/kg/day of
m-xylene produced no evidence of fetal toxicity (Seidenberg 1986). Given the
limited amount of animal data, no conclusion can be made regarding the
relationship between oral exposure of xylene and adverse developmental
effects. The highest NOAEL value and a reliable LOAEL value for developmental
effects are recorded in Table 2-5 and plotted in Figure 2-5.
2.2.2.6 Reproductive Effects
No human studies were located regarding reproductive effects following
oral exposure to mixed xylene or individual isomers. No studies directly
examining reproductive effects of xylene after oral exposure, exist, however,
histological examination of rats and mice administered mixed xylene at doses
as high as 500 mg/kg/day in rats and 1,000 mg/kg/day in mice for up to 2 years
revealed no adverse effects in the prostate/testes (male), ovaries/uterus, or
mammary glands (female) (NTP 1986). The reproductive system organs of rats
administered doses of m- or E"xylene as high as 800 mg/kg/day appeared
comparable to controls after 13 weeks of treatment (Hazleton Labs 1988a,
1988b). The NOAEL values for reproductive effects are recorded in Tables 2-5,
2-6, and 2-8 and plotted in Figures 2-5, 2-6, and 2-8.
2.2.2.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans after oral
exposure to mixed xylene or xylene isomers. No chromosomal aberrations or
change in the incidence of micronuclei were observed in reticulocytes isolated
from mice receiving doses of xylenes as high as 1000 mg/kg in a 24 hour period
(Feldt 1986). Other genotoxicity studies are discussed in Section 2.4.
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57
2. HEALTH EFFECTS
2.2.2.8 Cancer
No data were located regarding the development of cancer in humans
following oral exposure to mixed xylene or xylene isomers.
The carcinogenicity of mixed xylene ..allowing oral exposure has been
evaluated in chronic studies with rats and mice; however, no animal studies
were available on the carcinogenic effects of m-xylene, o-xylene, or ^-xylene
following oral exposure. Results of the chronic oral studies with mixed
xylene have been negative (NTP 1986) or equivocal (Maltoni et al. 1983, 1985).
The interpretation of the results of the NTP bioassay was compromised by the
large number of gavage-related deaths early in the study in the high dose male
rats. The Maltoni studies were weakened because of methodological flaws such
as failure to report site-specific neoplasia, insufficient toxicity data, and
absence of statistical analyses. Therefore, given the limited data, no
definitive conclusion can be made regarding the carcinogenicity of mixed
xylene following oral exposure.
EPA has classified mixed xylene as a Group D agent (not classifiable as
to human carcinogenicity) (IRIS 1989). This classification applies to those
chemical agents for which there is inadequate evidence of carcinogenicity in
animals. No cancer potency factor (ql*) or other quantitative estimate of
carcinogenicity has been developed by EPA for mixed xylene, ©-xylene,
S-xylene, or ^-xylene.
2.2.3 Dermal Exposure
2.2.3.1 Death
No reports of death in humans following dermal exposure to xylene were
located. Limited animal data suggest that mixed xylene and m-xylene can cause
death when applied dermally (Hine and Zuidema 1970; Pound and Withers 1963;
Smyth et al. 1962). The acute dermal LD50 in rabbits has been determined to
be 14.1 mL/kg for nj-xylene and greater than 5.0 mL/kg for mixed xylene (Hine
and Zuidema 1970; Smyth et al. 1962). The studies contain limitations which
compromise their reliability for assessing a dose-response relationship
between dermal exposure to xylene and death.
2-2.3.2 Systemic Effects
No studies were located regarding respiratory, cardiovascular,
gastrointestinal, hematological, musculoskeletal, hepatic or renal effects in
humans and animals after dermal exposure to mixed xylene or xylene isomers.
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58
2. HEALTH EFFECTS
Dermal/Ocular Effects. Acute dermal exposure of human subjects to
m-xylene in hand immersion studies has been associated with transient skin
erythema (irritation), vasodilation of the skin, and dryness and scaling of
the skin (Engstrom et al. 1977; Riihimaki 1979). The concentrations at which
these dermal effects occurred were not well characterized. No human data were
available regarding ocular effects following dermal exposure to mixed xylene
or xylene isomers.
Mild to moderate skin irritation was noted in rabbits and guinea pigs
treated topically with mixed xylene in acute studies (Anderson et al. 1986;
Hine and Zuidema 1970). Localized edema, dryness, and scaling, along with
cellular proliferation of the skin was observed in mice following intermediate
dermal exposure to undiluted xylene (Pound and Withers 1963). No chronic
animal studies evaluating the dermal effects of xylene were located.
No studies were located regarding the ocular effects in humans and
animals after dermal exposure to mixed xylene or xylene isomers.-
2.2.3.3 Immunologic Effects
No studies were located regarding immunologic effects in humans and
animals after dermal exposure to mixed xylene or xylene isomers.
2.2.3.4 Neurological Effects
No studies were located regarding neurological effects in humans and
animals after dermal exposure to mixed xylene or xylene isomers.
2.2.3.5 Developmental Effects
No studies were located regarding developmental effects in humans after
dermal exposure to mixed xylene or its isomers.
Dermal exposure of rats to a 1% solution of xylene (isomeric components
not specified) caused no evidence of fetal toxicity (Rumsey et al. 1969).
This study was limited by the coapplication of the surfactant alkylphenoxy
polyethoxyethanol with xylene. Another study indicated that dermal exposure
of pregnant rats to doses as low as 200 mg xylene/kg/day produced decreases in
enzyme activity (cholinesterase, cytochrome) in fetal and maternal brain
tissue (Mirkova et al. 1979). Pregnant dams exposed to xylene also showed
impaired motor activity in behavioral tests suggesting a neurotoxic effect of
xylene. The doses in this study appear to be unusually high. Other
limitations of this study are the absence of information on the composition of
xylene used and the frequency of application.
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59
2. HEALTH EFFECTS
2.2.3.6 Reproductive Effects
No studies were located regarding reproductive effects in humans and
animals after dermal exposure to mixed xylene or xylene isomers.
2.2.3.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans and
animals after dermal exposure to mixed xylene or xylene isomers.
2.2.3.8 Cancer
No human and no adequate animal data were available for evaluating the
carcinogenicity of mixed xylene or xylene isomers.
2.3 TOXICOKINETICS
2.3.1 Absorption
2-3.1.1 Inhalation Exposure
Evidence for absorption of xylene by humans following inhalation
exposure is provided by the observation that metabolite levels in the urine
increase in proportion to exposure (Ogata et al. 1970; Riihimaki and Pfaffli
1978; Riihimaki et al. 1979b; Sedivec and Flek 1976b; Senczuk and Orlowski
1978; Wallen et al. 1985) and in proportion to increased ventilatory rates
during exercise (Astrand 1982; Astrand et al. 1978; Engstrom and Bjurstrom
1978; Riihimaki et al. 1979b; Riihimaki and Savolainen 1980). Absorption of
the retained isomers appears to be similar, regardless of exposure duration or
dose. There appear to be two phases of absorption; the first is apparently
short, occurring within 15 minutes of initiation of exposure. The second
Phase is longer and represents the establishment of an equilibrium between the
inhaled xylene and blood.
Many authors have measured the retention of xylene following inhalation
exposure. It is this retained xylene that is available for absorption into
the systemic circulation. In experimental studies with human subjects,
detention of the various isomers was similar following inhalation of either
> S"i or E-xylene, and averaged 63.6% (Sedivec and Flek 1979b). Other
authors have estimated that between 49.8% and 72.8% of inhaled xylene is
retained (David et al. 1979; Ogata et al. 1970; Riihimaki and Pfaffli 1978;
Riihimaki and Savolainen 1980; Riihimaki et al. 1979b; Wallen et al. 1985).
Pulmonary retention does not appear to differ on the basis of sex (Senczuk and
°rlowski 1978). Physical exertion, as the result of exercising or working,
and. increased dose can increase the amount of xylene retained and subsequently
absorbed into the body due to enhanced pulmonary ventilation and cardiac
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2. HEALTH EFFECTS
output (Astrand et al. 1978, Riihimaki et al. 1979b). The study by Astrand et
al. (1978) suggests that retention efficiency decreases as exposure duration
increases.
In pregnant mice, approximately 30% of an administered inhalation dose
of 600 ppm E-xylene was absorbed following a 10-minute exposure period
(Ghantous and Danielsson 1986). Absorption was not quantified in the other
animal studies, but effects on microsomal enzyme systems suggested that
absorption occurred following inhalation of xylene (Carlsson 1981; David et
al. 1979; Elovaara 1982; Elovaara et al. 1987; Patel et al. 1978).
2.3.1.2 Oral Exposure
Limited information is available on the absorption of xylene in humans
and animals following ingestion. Excretion of urinary metabolites indicated
that absorption had occurred following oral doses of either 40 or 80 mg/kg/day
of o-xylene or m-xylene in humans (Ogata et al. 1980). However, absorption
was not quantified.
Animal data indicate that xylene is absorbed following oral exposure.
Almost complete absorption (87%-925£) occurred following ingestion of a dose of
1.8 grams m-xylene, or of 1.74 grams o- or ^-xylene (Bray et al. 1949).
Evidence of absorption was indirect and minimally estimated from the amount of
metabolites excreted in different fractions of the urine; no estimate of the
amount of metabolites exhaled was available. The various fractions included
the ether-soluble acid, the ester glucuronide, and the ethereal sulphate. The
results of other studies qualitatively indicate absorption following ingesti n
by animals because metabolites were detected and identified in urine (Bakke
and Scheline 1970; Patel et al. 1978; Pyykko 1980).
2.3.1.3 Dermal Exposure
Results of experimental studies with humans indicate that gi-xylene is
absorbed following dermal exposure; however, the extent of penetration and
absorption of ig-xylene through skin is not nearly as great as that resulting
from inhalation (Engstrom et al. 1977; Riihimaki 1979; Riihimaki and Pfaffli
1978). Absorption of jn-xylene vapor through the skin was approximately
0.1X-2X that of inhalation exposure (Riihimaki and Pfaffli 1978). In addition
to dermal absorption following exposure to m-xylene vapors, m-xylene can be
absorbed through the skin following direct dermal contact with the solvent
(Engstrom et al. 1977; Riihimaki 1979; Riihimaki and Pfaffli 1978). In
humans, the estimated absorption rate following immersion of both hands in
m-xylene for 15 minutes was approximately 2 ng/cm2/®in (Engstrom et al. 1977).
It is generally accepted that absorption of xenobiotics is greater in persons
with diseased or damaged skin than in persons with normal skin (Riihimaki and
Pfaffli 1978).
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61
2. HEALTH EFFECTS
Limited information is available regarding the absorption of xylene
following dermal exposure in animals. Permeability of m-xylene across rat
skin was estimated from blood levels obtained during exposure to m-xylene
vapors by McDougal et al. (1990) and permeability constants were calculated.
The permeability constant for rats was approximately twice that calculated for
humans using data from Riihimaki and Pfaffli (1978). Also, the absorption of
2-xylene was examined in the excised abdominal skin of rats (Tsuruta 1982).
As the time of contact with o-xylene increased, the amount of o-xylene that
penetrated the excised skin also increased. The penetration rate was
estimated to be 0.967 nmol/cm2/min (Tsuruta 1982). However, dermal absorption
studies using excised skin are limited by the lack of an intact blood supply,
cell death and the resultant alterations in membrane permeability, as well as
the lack of nervous system control over blood flow.
2.3.2 Distribution
2.3.2.1 Inhalation Exposure
Xylenes are very soluble in blood and therefore are absorbed easily into
the systemic circulation during exposure (Astrand 1982). The majority (90%)
of an absorbed dose of xylene is predominantly associated with serum proteins
and the remainder is associated with the serum (Riihimaki et al. 1979b).
Following systemic circulation, xylene is distributed primarily to adipose
tissue.
The distribution of xylene in fat following inhalation exposure has been
studied in humans (Astrand 1982; Engstrom and Bjurstrom 1978; Riihimaki et
al. 1979a, 1979b). Estimates of the amount of xylene accumulated in human
adipose tissue range from 5% to 10% of the absorbed dose (Astrand 1982,
Engstrom and Bjurstrom 1978). Exercise may increase the amount of m-xylene
distributed to body fat (Riihimaki et al. 1979a, 1979b). It has been
suggested that following prolonged occupational exposure to xylene,
significant amounts of the solvent could accumulate in adipose tissue (Astrand
1982; Engstrom and Bjurstrom 1978).
Studies in mice (Ghantous and Danielsson 1986) and in rats (Carlsson
1981) indicate that the distribution of ^-xylene and 13-xylene is characterized
by high uptake in lipid-rich tissues, such as brain, blood, and fat. High
uptake also occurs in well-perfused organs, such as the liver and kidney.
According to a chronic animal study, the level of xylene stored in body
fat may decrease as exposure continues due to an increase in metabolic rate
(Savolainen et al. 1979a). Levels of m-xylene in perirenal fat of rats
exposed to 300 ppm technical xylene decreased from 67.6 to 36.6 pg/g tissue as
exposure duration increased from 5 to 18 weeks (Savolainen et al. 1979a).
£-Xylene readily crossed the mouse placenta and was distributed in embryonic
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62
2. HEALTH EFFECTS
and fetal tissues (Ghantous and Danielsson 1986). The level detected in fetal
tissues, which are low in lipids, was only 2% of that detected in the maternal
brain tissue, which contains large amounts of lipids (Ghantous and Danielsson
1986) .
2.3.2.2 Oral Exposure
No studies were located regarding distribution in humans or animals
following oral exposure to mixed xylene, or xylene isomers.
2.3.2.3 Dermal Exposure
No studies were located regarding distribution in humans or animals
following dermal exposure to mixed xylene or individual isomers.
2.3.3 Metabolism
The biotransformation of xylene in humans proceeds primarily by the
oxidation of a side-chain methyl group by microsomal enzymes (mixed function
oxidases) in the liver to yield toluic acids (methylbenzoic acids). These
toluic acids conjugate with glycine to form toluric acids (methylhippuric
acids) that are excreted into the urine (Astrand et al. 1978; Norstrom et al.
1989; Ogata et al. 1970; Riihimaki et al. 1979a, 1979b; Sedivec and Flek
1976b; Senczuk and Orlowski 1978). This metabolic pathway accounts for almost
all of the absorbed dose of xylene, regardless of the isomer, the route of
administration, the administered dose, or the duration of exposure. Results
of both human and animal studies indicate that xylene is a phenobarbital-like
inducer of liver microsomal cytochrome P-450 (David et al. 1979; Toftgard et
al. 1981). Minor metabolic pathways that account for less than 10% of the
absorbed dose include the elimination of unchanged compound in the exhaled
breath and in the urine, and the urinary elimination of methylbenzyl alcohols,
o-toluylglucuronides (o-toluic acid glucuronide), and of xylenols
(dimethylphenols). The metabolism of the various xylene isomers in humans is
presented in Figure 2-9.
The metabolism of xylene in animals is qualitatively similar to that of
humans, though quantitative differences do exist (Bakke and Scheline 1970;
Bray et al. 1949; Ogata et al. 1980; Sugihara and Ogata 1978; van Doorn et al.
1980). The metabolism of the various isomers in animals is presented in
Figure 2-10. The major quantitative difference occurs in the metabolism of
the metabolic intermediate methylbenzoic acid (toluic acid). In rats given
m-, o-, or E-xylene by i.p. injection, 10% to 56.6% of the administered dose
of o-xylene was excreted in the urine as o-toluylglucuronide; whereas
approximately 1% of the administered doses of m-xylene and ^-xylene were
metabolized to the appropriate toluylglucuronide (Ogata et al. 1980; van Doorn
et al. 1980). The amounts of m-methylhippuric acid and E-methylhippuric acid
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63
2. HEALTH EFFECTS
oxidation
unchanged
exhalation
CH3-group
urine
/CH,
c,h4
\
ch2oh
o-isomer
Isomers
free o-toluic acid?
conjugates
(sulphoconjugate +
o-toluylglucuronide)
(trace -1%)
methylbenzylalcohols
(2-,3-,4-lsomers)
urine (traces)
COOH
methylbenzoic
acids (o-,m-,p-
tolulc adds)
CONHCHjCOOH
methylhippuric acids (urine)
(o-,m-,p-toluric acids)
(ortho - 97.1%
meta - 72-99.2%
para - 95.1%)
(ortho - 5.3%
meta - 4-5.8%
para - 3.5%
mixture - 4-5%)
C,H4(CH3)2
unchanged
xylenes
¦urine (ortho-0.0046%
meta - 0.0047%
para - 0.0026%)
aromatic
hydroxytation
* HOC,H3(CH,)j
xylenols
(dlmethylphenols)
urinary excretion as sulphates + etherglucuronides?
urinary excretion of 2,3-,3,4-,2,4-, and 2,5- xylenols
respect, from o-,m- and p- xylene
(ortho-0.86%
meta -1.98%
para - 0.05%)
FIGURE 2-9. Metabolic Scheme For Xylenes - Humans
Source: Astrwtt et al. 1078, Ogata et tl. 1080, RHNmakl et al. 1070a, b, Sedvec and Ftok 1076b, Senczuk and Oriowskl
1078, Tortgard and Gustafsson 1080.
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64
2. HEALTH EFFECTS
p-toiuaidehyde
o,m,p
isomers
o,m,p
oxidation
unchanged
exhalation
C6H4(CH3)2
xylenes
free o-toluic acid?
conjugates
(sulphoconjugate +
toluylglucuronide)
(ortho-10-56.6%
meta -1.3%
para - 0.6%)
CH2OH
CH3-group
methyl benzylaicohols
(2-,3-,4-isomers)
I
urine (traces)
isomers
COOH
methylbenzoic
acids (o-,m-,p-
toluic adds)
XONHCHjCOOH
methylhippuric acids (urine)
(o-,m-,p-toluric acids)
(ortho -15.9-60%
meta - 49-80%
para - 64.2-88%)
aromatic
hydroxylation
~ HOC,H3(CH3)2
xylenola
(dlmethylphenols)
urinary excretion as sulphates + etherglucuronides?
urinary excretion of 2,3-,3,4-,2,4-, and 2,5- xylenols
respect, from o-,m- and p- xylene
(ortho-0.13%
meta - 0.9%
para-0.1%)
FIGURE 2-10. Metabolic Scheme For Xylenes - Animals
Source: BaKKe and ScheHne 1970, Bray et al. 1949, Ogata at at. 1980, Sugihara and Ogata 1979, Toftgard and
Ouatafsaon 1960, van Doom et ai. 1960.
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65
2. HEALTH EFFECTS
excreted in the urine accounted for 49% to 62.6% and 64% to 75% of the
administered dose, respectively (Ogata et al. 1980; Sugihara and Ogata 1978).
In studies with rabbits, 60% of an administered o-xylene dose, 81% of a
ffi-xylene dose, and 88% of a j>"xylene dose were excreted in the urine as
methylhippuric acids (Bray et al. 1949). Minor quantities of methylbenzyl
alcohols and xylenols have also been detected in the urine of experimental
animals administered xylene isomers (Bakke and Scheline 1979; Ogata et al.
1980; van Doom et al. 1980).
A toxic metabolite of E_xylene in animals appears to be £-methylbenz-
aldehyde (j>-tolualdehyde) (Carlone and Fouts 1974; Patel et al. 1978; Smith et
al. 1982). It is formed by the action of alcohol dehydrogenase on
E-methylbenzyl alcohol in lung and liver tissues. The presence of
E-methylbenzaldehyde has not been confirmed in humans. Lung tissue can be
damaged by this intermediate because of its selective inactivation of enzymes
involved in microsomal electron transport (mixed function oxidases, cytochrome
P-450). A reactive intermediate of ^-xylene (probably j)-methylbenzaldehyde)
is capable of binding to lung proteins in rabbits (Smith et al. 1982). This
binding may be associated with the reported destruction of pulmonary
cytochrome P-450. This selective inactivation does not occur in the liver
where £-methylbenzaldehyde is metabolized to £-methylbenzoic acid and
subsequently excreted as E"methylhippuric acid (Patel et al. 1978; Smith et
al. 1982).
The route of exposure (i.e., inhalation, oral, or dermal) does not
influence the metabolism of xylene once it is absorbed. The differences in
xylene metabolism observed between humans and animals may, in part, be
explained by differences in the size of the doses given to humans and animals
in experimental studies (David et al. 1979; Ogata et al. 1980; van Doom et
al. 1980). The formation of glucuronic acid derivatives may be an emergency
mechanism that is activated when the organism can no longer conjugate all
acids with glycine (Ogata et al. 1980; Sedivec and Flek 1976b; van Doom et
al. 1980). Humans dosed with 19 mg/kg xylene excreted only methylhippuric
acids in the urine, whereas rabbits exposed to 600 mg/kg excreted both
®ethylhippuric acids and derivatives of glucuronic acid (Sedivec and Flek
1976b). The second-phase conjugation of the main oxidized intermediate
(methylbenzoic acid with glycine to form methylhippuric acid) may be the rate-
limiting step in humans. It is limited by the amount of available glycine in
normal physiology, 200 /umol/minute (Riihimaki et al. 1979b). If this limit is
aPproached, other elimination pathways may be activated, such as conjugation
with glucuronic acid or aromatic hydroxylation to form xylenols. The capacity
°f the first-phase oxidation reaction, encompassing both side-chain and
aromatic oxidation, is not known. Aromatic oxidation of xylene could possibly
Produce toxic intermediates and phenolic end-metabolites (Riihimaki et al.
1979b); however, this is a minor metabolic pathway.
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2. HEALTH EFFECTS
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
In humans, about 95% of absorbed xylene is biotransformed and excreted
as urinary metabolites, almost exclusively as methylhippuric acids; the
remaining 5% is eliminated unchanged in the exhaled breath (Astrand et al.
1978; Ogata et al. 1980; Riihimaki et al, 1979a, 1979b; Sedivec and Flek
1976b; Senczuk and Orlowski 1978). Less than 0.005% of the absorbed dose of
xylene isomers is eliminated unchanged in the urine, and less than 21 is
eliminated as xylenols (Sedivec and Flek 1976b). The excretion of
methylhippuric acids is rapid and a significant amount is detected in the
urine within 2 hours of exposure. The amount of methylhippuric acid increases
with time and reaches a maximum at the termination of exposure. Differences
in the amount of the metabolites excreted depend on the interpersonal
differences in lung ventilation and retention, not on the isomer of xylene
(Sedivec and Flek 1976b).
There appear to be at least two distinct phases of elimination, a
relatively rapid one and a slower one. These phases of elimination are
consistent with the distribution of xylene into three main tissue
compartments; the rapid and slower elimination phases correspond to
elimination from the muscles and the adipose tissue, respectively, whereas the
elimination of xylene from the parenchymal organs is so rapid that the
available studies could not monitor it (Ogata et al. 1970; Riihimaki et al.
1979a, 1979b). It is also possible that the renal excretion of the most
common xylene metabolite, methylhippuric acid, takes place via the tubular
active secretion mechanism of organic acids. Renal excretion is not a rate-
limiting step in the elimination of absorbed xylene under normal physiological
conditions (Riihimaki et al. 1979b).
Human volunteers acutely exposed by inhalation to 100 or 200 ppm
m-xylene for 7 hours had excreted 54% and 61%, respectively, of the
administered dose by 18 hours after exposure ended (Ogata et al. 1970).
Following intermittent acute exposure of men and women to 23, 69, or 138 ppm
m-xylene, excretion of m-methylhippuric acid peaked 6-8 hours after exposure
began. It decreased rapidly, regardless of exposure level or sex, after
exposure had ended. Almost no xylene or m-methylhippuric was detected 24
hours later (Senczuk and Orlowski 1978).
Exercise increased the amount of xylene absorbed and thus increased the
amount of m-methylhippuric acid and 2,4-xylenol eliminated in the urine of men
exposed to m-xylene (Riihimaki et al. 1979b). The excretion of m-methyl-
hippuric acid appeared to correspond very closely to the estimated xylene
uptake and expired xylene represented about 4%-5% of the absorbed xylene in
all exposure groups (Riihimaki et al. 1979b).
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67
2. HEALTH EFFECTS
Limited information was available on the elimination of the metabolites
of xylene following inhalation exposure of experimental animals. m-Methyl-
hippuric acid was detected in the urine of rats exposed for 6 hours to various
doses of m-xylene (David et al. 1979). The authors did not analyze for other
urinary metabolites.
2.3.4.2 Oral Exposure
Limited information is available on the elimination of the metabolites
of xvlene following ingestion in humans. In male volunteers given oral doses
of 4u mg/kg/day of o-xylene or m-xylene, the molar excretion ratios (total
excretion [mol] in urine during appropriate interval/dose administered
[mol] x 100[%]) for o-methylhippuric acid and m-methylhippuric acid were 33.1
and 53.1, respectively (Ogata et al. 1980). More of the m-xylene is
eliminated as m-methylhippuric acid than is o-xylene. The molar excretion
ratio for o-toluic acid glucuronide (o-toluylglucuronide) was 1.0 in men given
o-xylene as an oral dose of 40 mg/kg/day. The amount of o-methylhippuric acid
(o-toluric acid) and of o-toluic acid'glucuronide excreted in the urine
attained a maximum level in 3-6 hours of exposure, while that of
m-methylhippuric acid attained a maximum in 1-3 hours (Ogata et al. 1980).
These results indicate that the major elimination pathway of o-xylene is the
formation of o-methylhippuric acid in humans. The formation of o-toluic acid
glucuronide is a minor pathway for the elimination of o-toluic acid. It is
expected that at much higher doses, this minor pathway would be used to a
greater degree as the major pathway becomes saturated.
Limited information was available on the elimination of the metabolites
of xylene following ingestion in animals. Rats administered 100 mg/kg doses
IB*, o-, or E-xylene eliminated in the urine 0.1% of a dose of o-xylene as
3,4-xylenol and 0.03% as 2,3-xylenol, 0.9% of a dose of ja-xylene as
2,4-xylenol, and 1% of a dose of ji-xylene as 2,5-xylenol. A trace of
methylbenzyl alcohol was also detected in the urine of rats given o-xylene and
E-xylene (Bakke and Scheline 1970).
2.3.4.3 Dermal Exposure
The elimination of liquid a-xylene absorbed dermally in humans following
a 15 minute exposure was through the exhaled breath and urine (Engstrom et al.
1977; Riihimaki and Pfaffli 1978). Elimination in the exhaled breath followed
a 2-phase elimination curve with a rapid half-life of 1 hour and a longer
half-life of 10 hours. Excretion of js-methylhippuric acid in the urine
following a dermal exposure to g-xylene was delayed and prolonged by
2-4 hours, though elimination of the dermally absorbed a-xylene was similar to
that following inhalation absorption (Riihimaki and Pfaffli 1978). In humans,
the rate of excretion of a-methylhippuric acid was approximately 50 ^mol/hour
at 2 hours following immersion of both hands in ^-xylene for 15 minutes
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68
2. HEALTH EFFECTS
(Riihimaki 1979). It decreased to approximately 1 nmol/L at the 6th post-
exposure hour. These results indicate that although absorption was delayed,
it was gradual and protracted.
2.3.4.4 Other Routes of Exposure
Limited information was available on the elimination of xylene
metabolites in rats following intraperitoneal injection (Ogata et al. 1980;
Sugihara and Ogata 1978; van Doom et al. 1980). The urinary metabolites of
xylene are similar regardless of route of exposure; however, the amounts of
various metabolites differ. Elimination of xylene isomers is related more to
absorption than it is with dose or duration of exposure. In rats, 49% to
62.6% of various doses of m-xylene or 64.2% to 75% of various doses of
^-xylene were excreted in the urine as m-methylhippuric acid or £-methyl-
hippuric acid, respectively (Sugihara and Ogata 1978). Rats that were
administered an intraperitoneal dose of 1,240 mg o-xylene/kg/day excreted o-
toluic acid glucuronide and o-methylhippuric acid in the urine in molar
excretion ratios of 56.6 and 15.9, respectively (Ogata et al. 1980). The
amount of o-toluic acid glucuronide and o-methylhippuric acid excreted reached
a maximum 8-24 hours after dosing. Mercapturic acid derivatives
(sulphoconjugates) were present in the urine of rats following an
intraperitoneal dose of m-, o-, or ^-xylene (van Doom et al. 1980). The
percentages ranged from 0.6% (^-xylene) to 10% (o-xylene).
2.4 RELEVANCE TO PUBLIC HEALTH
The concentrations of mixed xylene and xylene isomers used in animal
studies are much higher than the ambient levels encountered in urban and
industrial areas. However, information about the effects observed at high
concentrations of xylenes is important because potentially high levels may be
present at hazardous waste sites. In addition, subgroups of the population
may be extremely sensitive and effects seen at high levels in animals may be a
predictor of effects seen in these subgroups when they are exposed at much
lower levels.
Both human and animal data suggest that mixed xylene, m-xylene,
o-xylene, and ^-xylene all produce similar effects, although the individual
isomers are not necessarily equal in potency with regard to a given effect.
Human data indicate that both short and long-term xylene exposure result in a
variety of nervous system effects that include headache, mental confusion,
narcosis, alterations in body balance, impaired short-term memory, dizziness,
and tremors. In animals, xylene also produces nervous system effects. The
respiratory system may also be affected. Higher doses of xylene have produced
unconsciousness and death in humans and animals. The liver and kidney may
also be targets of xylene toxicity in humans, although more thorough data are
needed to better assess the relationship.
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69
2. HEALTH EFFECTS
Death. Xylene can be fatal to both humans and animals following
inhalation and oral exposure. Death has been observed in animals following
dermal exposure to xylene, but no cases have been reported in humans. Death
in humans and animals appears to be caused by either respiratory failure or
ventricular fibrillation. The amount of xylene necessary to cause death is
relatively large in both animals and humans, and reports of death in humans
following inhalation of xylene occurred in areas of poor ventilation.
Therefore, it is highly unlikely that inhalation or ingestion of the small
amounts of xylene likely to be present in contaminated water or air would pose
a risk of death.
Systemic Effects. In humans, acute inhalation of xylene produced nose
and throat irritation (Goldie 1960; Hake et al. 1981; Klaucke et al. 1982;
Nersesian et al. 1985). Severe lung congestion with pulmonary hemorrhages and
edema were noted in a worker who died following acute inhalation of paint
fumes containing xylene (Morley et al. 1970). In addition, chronic
occupational exposure to xylene vapors has been associated with labored
breathing and impaired pulmonary function (Hipolito 1980; Roberts et al.
1988).
Animal data provide supporting evidence for the respiratory effects
observed in humans following exposure to xylene. Adverse respiratory effects
noted in rats, mice, and guinea pigs following acute and intermediate
inhalation exposure to xylene included decreased respiratory rate, labored
breathing, irritation of the respiratory tract, pulmonary edema, and pulmonary
inflammation (Carpenter et al. 1975; De Ceaurriz et al. 1981; Furnas and Hine
1958; Smyth and Smyth 1928).
Chronic occupational exposure of workers to xylene by inhalation has
been associated with increased heart palpitation and abnormal ECGs (Hipolito
1980; Sukhanova et al. 1969). However, these particular reports provide no
conclusive evidence that xylene causes cardiovascular effects in humans
because exposure conditions were not well characterized and workers may have
been exposed to other chemical agents in addition to xylene.
Data from animal studies provide limited evidence that humans could be
at increased risk of developing cardiovascular effects following exposure to
xylene. Cardiovascular effects observed in rats following acute and
intermediate inhalation exposure to xylene have included ventricular
repolarization disturbances, atrial fibrillation, arrhythmias, occasional
cardiac arrest, changes in ECG, morphological changes in coronary
^icrovessels, decreased myocardial blood flow, and increased heart weight
(Morvai et al. 1976, 1987). However, histopathologic lesions of the heart
have not been observed in other studies (Carpenter et al. 1975; Hazleton Labs
88a, 1988b; Jenkins et al. 1970; NTP 1986).
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70
2. HEALTH EFFECTS
Symptoms of nausea, vomiting, and gastric discomfort have been noted in
workers following inhalation of xylene. Gastrointestinal effects have not
been reported in animals. However, there are sufficient human data to
conclude that exposure to xylene could produce such effects (e.g., nausea and
vomiting).
Human and animal data provide no indications of adverse hematological
effects following inhalation of xylene. In the past, chronic occupational
exposure to xylene by inhalation was thought to be associated with a variety
of hematological effects. However, exposure in all cases was to solvent
mixtures known or suspected to contain benzene. Because benzene is an agent
strongly suspected of causing leukemia and other blood dyscrasias in humans,
these effects cannot be attributed solely to xylene.
Hematological effects have not been observed in rats, dogs, or guinea
pigs exposed by inhalation to mixed xylene or o-xylene for an intermediate
period (Carpenter et al. 1975; Jenkins et al. 1970). These negative results
from animal studies suggest that humans might not develop hematological
effects from intermediate inhalation of xylene; however, the hematological
effects from chronic inhalation, oral, and dermal exposure are not known.
No data were available regarding the musculoskeletal effects of xylene
in humans following inhalation exposure to mixed xylene, m-, o-, or ^-xylene.
Animal da' regarding musculoskeletal effects following xylene exposure are
limited. microscopic examination of skeletal muscle of rats exposed for an
intermediate period of time to mixed xylenes, m-xylene, or ^-xylene revealed
no treatment-related lesions (Carpenter et al. 1975; Hazleton Labs 1988a,
1988b; NTP 1986). Skeletal anomalies, delayed ossification, and extra ribs
have been observed in the fetuses and offspring of pregnant mice and rats
exposed by inhalation to mixed xylene and o-xylene (Mirkova et al. 1983;
Ungvary et al. 1980b). These latter results suggest that the human fetus
might be at increased risk of such skeletal effects following maternal
exposure to high levels of xylene. The above studies are not definitive,
however, in terms of possible skeletal effects.
Human data regarding the hepatic effects following inhalation of xylene
are limited to several case and occupational studies (Dolara et al. 1982;
Kurppa and Husman 1982; Morley et al. 1970). However, these studies provide
limited evidence for evaluating the hepatic effects of xylene in humans
because these subjects were concurrently exposed to other chemical agents in
addition to xylene.
Available animal studies indicate that mixed xylene and individual
isomers produce a variety of mild hepatic effects, and they provide evidence
that humans might be at increased risk of developing such effects following
xylene exposure. Effects seen in animals have included increased hepatic
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71
2. HEALTH EFFECTS
cytochrome P-450 and b5 content, increased hepatic weight, increased liver to
body weight ratios, decreased hepatic glycogen, ultrastructural changes in
hepatic endoplasmic reticulum, changes in the distribution of hepatocellular
nuclei, congestion of liver cells, and/or degeneration of the liver (Bowers et
al. 1982; Condie et al. 1988; Elovaara 1982; Elovaara et al. 1980; Muralidhara
and Krishnakumari 1980; Patel 1979; Pyykko 1980; Smyth and Smyth 1928; Tatrai
and Ungvary 1980; Tatrai et al. 1981; Toftgard and Nilsen 1981, 1982; Toftgard
et al. 1981; Ungvary et al. 1980a). Many of the observed hepatic effects in
animals following inhalation and oral exposure to xylene are likely due to
increased metabolism of the solvent and are not necessarily adverse effects
(EPA 1985a; Tatrai et al. 1981).
The available human studies that investigate the renal effects following
inhalation of xylene are of limited value because exposure conditions were not
Well characterized and subjects were exposed to other solvents in addition to
xylene. However, they provide suggestive evidence that subjects exposed by
inhalation to solvent mixtures containing xylene may be at an increased risk
of developing renal dysfunction and/or renal damage (Askergren 1982; Franchini
et al. 1983; Morley et al. 1970). Indications of renal effects in humans
exposed to solvent mixtures containing xylene have included increased blood
urea concentrations, decreased urinary clearance of endogenous creatinine,
inereflcoH lvsnzvmuria. increased urinary levels of /8-glucuronidase, and
exposure.
Data from ar mal studies provideadditional evidence that humans could
be at risk of developing renal effects following inhalation exposure to
Xylene. Effects noted in studies with rats, guinea pigs, dogs, and monkeys
have included increased renal enzyme activity, increased renal cytochrome
p-450 content, increased renal microsomal protein, and increased kidney-to-
body weight ratios (Condie et al. 1988; Elovaara 1982; Toftgard and Nilsen
1982). In the study by Condie et al.(1988), tubular dilation and atrophy
consistent with early chronic nephropathy were observed, however in studies
Carpenter et al. (1975) and Jenkins et al. (1970), the biochemical changes
were not associated with any histopathologic lesions of the kidney.
"vuy weignc rauj-wa w(1qoo\ tubular dilation and atrophy
1982). -In the study by J'1however in studies
consistent with early chronic neph P y biochemical changes
Carpenter et al. <»7 > '"VhStooatUogiclesions of the kidney,
were not associated with any histopatnoiog
* j-Viot- wl ene induces renal effects by causing
t +¦ Kaan cinKTAcrftd that xylene
1985a). increased renal permeability caused by "^^™(EPA
effects could result In physiological and poss'tly histological effeo. (EPA
1985a). In humans exposed to solvent mixtures containing
Increased urinary levels of /J-glucuronidase may b%du®"
turnover in the renal tubular epithelium because of a mild toxic effect
(Franchini et al. 1983). The lysozymuria and increase in urinary excretion of
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72
2. HEALTH EFFECTS
albumin may be indicative of potential damage to the renal tubules and renal
glomeruli, respectively (Askergren 1982; Franchini et al. 1983). Increased
urinary excretion of erythrocytes and leukocytes are also indicators of
potential toxic injury to the kidney (Askergren 1982).
Dermal exposure of humans to xylene causes skin irritation, dryness and
scaling of the skin, and vasodilation of the skin (Engstrom et al. 1977;
Riihimaki 1979). Exposure of humans to xylene vapors causes ocular irritation
(Carpenter et al. 1975; Hake et al. 1981; Klaucke et al. 1982; Nelson et
al. 1943).
Animal data provide additional evidence that dermal exposure to xylene
produces dermal and ocular effects. These included skin erythema and edema,
eschar formation in some animals, and epidermal thickening (Hine and Zuidema
1970). No studies were available regarding potential dermal/ocular effects in
animals following exposure to xylene vapor.
Immunological Effects. Very limited human and no animal data are
available to evaluate the immunological effects of xylene. Therefore, the
relevance to public health is not known.
Neurological Effects. Neurological effects in humans following oral or
dermal exposure to xylene have not been studied, although one case was
reported of a man who developed a coma following ingestion of xylene (Recchia
et al. 1985). Results of experimental studies with humans indicate that acute
inhalation exposure to mixed xylene or m-xylene causes impaired short-term
memory, impaired reaction time, performance decrements in numerical ability,
and alterations in equilibrium and body balance (Gamberale et al. 1978;
Riihimaki and Savolainen 1980; Savolainen et al. 1985; Savolainen et al.
1979b; Savolainen and Riihimaki 1981b; Savolainen and Linnavuo 1979;
Savolainen et al. 1984). Available case and occupational studies together
provide suggestive evidence that acute and chronic inhalation exposure to
xylene or solvent mixtures containing xylene may be associated with many
neurological effects and symptoms (Arthur and Curnock 1982; Goldie 1960;
Hipolito 1980; Klaucke et al. 1982; Morley et al. 1970; Nersesian et al. 1985;
Roberts et al. 1988). In several case reports, isolated instances of
unconsciousness, amnesia, brain hemorrhage, and epileptic seizure have been
associated in a limited number of individuals with acute inhalation exposure
to solvent mixtures containing xylene (Arthur and Curnock 1982; Goldie 1960;
Morley et al. 1970).
Results of experimental studies with animals provide further evidence
that mixed xylene and individual isomers are neurotoxicants following
inhalation exposure. Signs of neurotoxicity observed in rats, mice, and
gerbils following acute and intermediate inhalation exposure to the various
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2. HEALTH EFFECTS
xylene isomers have included narcosis, prostration, incoordination, tremors,
muscular spasms, labored breathing, behavioral changes, hyperactivity,
elevated auditory thresholds, hearing loss, changes in brain enzyme activity
and changes in levels of brain proteins (Andersson et al. 1981; Carpenter et
al. 1975; De Ceaurriz et al. 1983; Furnas and Hine 1958; Ghosh et al. 1987;
Kyrklund et al. 1987; Molnar et al. 1986; NTP 1986; Pryor et al. 1987; Rank
1985; Rosengren et al. 1986; Savolainen and Seppalainen 1979; Savolainen et
al. 1978; Savolainen et al. 1979a; Wimolwattanapun et al. 1987). No animal
studies evaluating the neurological effects of xylene following chronic
inhalation exposure were available.
Although a number of mechanisms of action have been proposed, the toxic
mechanism of xylene on the nervous system is not fully understood. Because
xylene is lipid soluble, it can distribute to the central nervous system. A
number of investigators have noted the affinity of xylene for nervous system
tissue, such as myelin and axonal membrane, in humans and animals (Desi et al.
1967; EPA 1985a; Gerarde 1959; Savolainen and Pfaffli 1980).
Neurological effects, including narcosis and anesthesia, are noted after
acute exposure to high concentration of xylene when high blood and brain
levels of the solvent occur (EPA 1985a). It has been suggested that xylene
and other alkylbenzenes act simply by being in the nervous system at
sufficiently high concentrations to inhibit normal function (Desi et al. 1967;
EPA 1985a; Gerarde 1959). A number of experimental studies with humans on CNS
function indicate that the first observable effects of m-xylene are on the
central vestibular system, which controls equilibrium and body balance
(Riihimaki and Savolainen 1980; Savolainen and Linnavuo 1979; Savolainen et
al. 1979b; Savolainen and Riihimaki 1981b; Savolainen et al. 1984; Savolainen
et al. 1985).
Also, xylene may directly affect nerve conductivity by altering the
lipid components of the axonal membrane (EPA 1985a; Savolainen and Seppalainen
1^79) . ^.Altered lipid components in turn could alter sodium permeability and
decrease action potentials, resulting in signs of intoxication (EPA 1985a).
Results of experimental studies with rats suggest that mixed xylene and
, or ^-xylene can cause alterations in dopamine and/or noradrenaline
levels in the brain (Andersson et al. 1981). These changes can produce
disturbances in catecholamine neurotransmission, which in turn can potentially
alter brain function, particularly mental, motor, and neuroendocrine control
(Andersson et al. 1981). Two possible modes of action have been suggested.
Xylene or a metabolite of xylene could act directly on adrenergic receptors in
fche brain, causing increased catecholamines and postsynaptic stimulation. The
s®cond possibility involves alteration of axonal membrane fluidity, which
causes permeability changes and alters neurotransmitter release (Andersson et
al- 1981; EPA 1985a).
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74
2. HEALTH EFFECTS
Some authors have also suggested that metabolic intermediates, such as
arene oxides or methylbenzaldehyde, may be responsible for the toxic effects
of xylene (Savolainen and Pfaffli 1980). Oxidation of xylene to these
intermediates by microsomal enzyme systems may occur within brain cells
(Savolainen and Pfaffli 1980).
Developmental Toxicity. Limited human studies were available regarding
the developmental or teratogenic effects of xylene. However, because of
concurrent exposure with chemical agents in addition to xylene, they cannot be
used to assess the relationship between xylene exposure and developmental
effects in humans. Findings in animal studies suggest that adverse effects
might occur in the unborn and offspring of women exposed to xylene or its
isomers. Results of studies with rats and mice indicate that inhalation
exposure to mixed xylene or xylene isomers may induce increased fetal death,
decreased fetal weight, delayed skeletal development, skeletal anomalies,
enzymatic changes in fetal organs, and maternal toxicity (Hudak and Ungvary
1978; Marks et al. 1982; Mirkova et al. 1983; Ungvary et al. 1980b, 1981).
Oral exposure to mixed xylene has been associated with cleft plate and
decreased fetal weight (Marks et al. 1982). Dermal exposure of rats to xylene
has been associated with biochemical changes in fetal and maternal brain
tissue (Mirkova et al. 1979). However, j>~xylene produced no developmental
effects, with maternal toxicity, in rats (Rosen et al. 1986). These studies
were generally limited but, taken together, suggest fetotoxic effects,
although most of these may have been secondary to maternal toxicity.
The exact mechanism by which mixed xylene or its individual isomers
produce toxic effects in fetuses has not been fully investigated. Based on
results of studies with rats, ^-xylene-induced delayed fetal development may
have been caused by decreased levels of progesterone and estradiol (Ungvary et
al. 1981). The titers of these hormones were apparently lowered due to
xylene's inductive effect on metabolism, which caused increased hormone
catabolism.
Reproductive Toxicity. The relevance to public health regarding xylene
exposure and adverse reproductive effects is not known because of the
limitations of the human and animal data. Occupational exposure of men to
xylenes, in addition to other solvents, was found to increase the potential
for their wives to experience spontaneous abortions, however, this study was
limited by exposure of the men to other solvents and the limited size of the
population studied (Taskinen et al. 1989). No reproductive effects were found
in rats following inhalation of xylene before mating and during gestation and
lactation (Bio/dynamics 1983). Histopathological examination following
intermediate and chronic oral bioassays revealed no adverse effects on the
reproductive organs of rats and mice (Hazleton Labs 1988a, 1988b; NTP 1986).
-------
75
2. HEALTH EFFECTS
No other studies were located regarding reproductive effects in animals
following inhalation or dermal exposure to xylene or its isomers.
Genotoxicity. Mixed xylene, as well as each of the individual xylene
isomers, has been tested for genotoxicity in a variety of in vitro and in vivo
assays. Results of the various assays indicate that mixed xylene and xylene
isomers are nongenotoxic (Tables 2-10 and 2-11). As summarized in Table 2-10,
the results of the various assays indicate that mixed xylene and xylene
isomers are nongenotoxic following in vitro exposure (Bos et al. 1981; Connor
et al. 1985; Florin et al. 1980; Haworth et al. 1983; Litton Bionetics 1978b;
McCarroll et al. 1981a, 1981b; NTP 1986; Shimizu et al. 1985).
The induction of genotoxic effects following in vivo exposure to xylene
has been evaluated in the bone marrow chromosomal aberration test with rats
(Litton Bionetics 1978b), the bone marrow micronucleus test with mice
(Mohtashamipur et al. 1985), and the sperm morphology test with rats
(Washington et al. 1983). The incidence if sister-chromatid exchanges and
chromosomal aberrations in the peripheral lymphocytes of workers exposed
occupationally to xylene also has been evaluated (Haglund et al. 1980; Pap and
Varga 1987). Both human studies involved occupational exposure to other
chemicals in addition to xylene. As summarized in Table 2-11, the results of
these studies indicate that mixed xylene, m-, o-, and ^-xylene are
nongenotoxic following in vivo exposure.
No mutagenic activity was demonstrated for any of the various
metabolites of xylene in bacterial test systems. S. tvphirourium strains TA98,
TA100, TA1535, TAL537, and TA1538, with and without S9 metabolic activation,
have been used to test the mutagenic activity of j>-xylenol (Epler et al. 1979;
Florin et al. 1980; Hejtmankova et al. 1979; Pool and Lin 1982), m-xylenol
(Epler et al. 1979; Florin et al. 1980), and o-methylbenzyl alcohol (Bos et
al. 1981). 2,4-Dimethylphenol has been evaluated in a gene reversion assay
with E. coli strain Sd-4-73 (Szybalski 1958).
Ethylbenzene, a common component of many technical grades of mixed
xylene, also demonstrated no mutagenic effects in the gene reversion assay
with S. cerevisiae (Nestmann and Lee 1983), the Salmonella/microsome assay
with strains TA98, TA100, TA1535, TA1537, and TA1538 (Florin et al. 1980;
Nestmann et al. 1980), or in cytogenic assays with cultured Chinese hamster
ovary cells (NTP 1986). However, in studies with cultured human lymphocytes,
ethylbenzene induced a slight but statistically significant (p<0.01) increase
in the number of the sister-chromatid exchanges (Norppa and Vainio 1983). The
authors of this latter study suggested that ethylbenzene may be a "weak,
ineffective mutagen." Ethylbenzene is the subject of a separate toxicological
Profile, and the reader should refer to that document for a more detailed
review of its genotoxicity potential.
-------
TABLE 2-10. Genotoxicity of Xylene In Vitro
Result
With Without
Endpoint Species/Test System Isomer Purity/Composition Activation Activation Reference
Prokaryotio Systems
Mutation
Salmonella typhimurium TA97, TA98,
TA100, TAlS3S/plate incorporation
assay
Mixed Xylene
60X m-xylene, 91
o-xylene, 14X g-xylene,
171 ethylbenzene
Negative Negative NTP 1986
Mutation
S. typhimurium TA98, TA100, TA1S3S,
TA1537/plate incorporation assay
m-Xylene
o-Xylene
g-Xylene
Not Reported
Purity = 97X
Purity - 991
Negative
Negative
Negative
Negative
Negative
Negative
Haworth et.
al. 1983
Mutation
Mutation
Mutation
Mutation
S. typhimurium TA98, TA1O0,
UTH841*, UTH8*13/plate incorpor-
ation assay
S. typhimurium TA98, TA100, TA1535,
TA1537, TA1538/plate incorporation
assay
S. typhimurium TA98, TA100, TA1535,
TA1537/spot and plate incorporation
assays
S typhimurium TA98, TA100. TA1535,
TA1537, TA1538/suspenslon and plate
incorporation assays
m-Xylan e
o-Xylene
I>-Xylene
m-Xylene
o-Xylene
g-Xylene
m-Xylene
^-Xylene
Mixed Xylene
Not Reported
Purity = 97X
Purity - 99.7X
Not Reported
Not Reported
Not Reported
Purity > 97X
Purity > 97X
52.IX m-xylene, 11. 4X
o-xylene, 0.3X jj-xylene
36.IX ethylbenzene
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative Negative
Connor et
al. 1905
Bos et al.
1981
Negative Florin et
Negative al. 1980
Litton
Bionetics
1978b
X
m
>
r
•X
m
Tl
pi
o
H
-o
o-^
Mutation
S typhimurium TA98, TA100, TA1535,
TA1537, TA1538/plata incorporation
assay
E"Xylene
Purity = 98X
Negative
Negative Shimizu et
al. 1985
Mutation
Escherichia coll WP2uvrA/plate
incorporation assay
g-Xylene
Purity = 98X
Negative Negative Shimizu et
al. 1985
DNA Damage E. coll WP2, WP2uVrA, WP67, CM611,
WP100. W3110polA+, p3*78pola'/DNA
repair microsuspension assay
Not Reported Not Reported
(technical grade)
Negative Negative McCarroll et
al. 1981b
DHA Damage
Bacillus subtills H17, MA5/modified
rec assay
Not Reported Not Reported
(technical grade)
Negative Negative McCarroll et
al. 1981a
-------
TABLE 2-10 (Continued)
Result
With Without
Endpoint Species/Test System Isomer Purity/Composition Activation Activation Reference
Bukarvotlc Systems
Mitotic Gene Sac char ""¦y"' ceravlsiae D4/suspen~
Conversion sion and plate incorporation assays
Mixed Xylene
52.II m-xylene, 11.42
o-xylene, 0.31 g-xylene
36.IX ethylbenzene
Negative Negative
Litton
Bionetics
1978b
ian Systems
Mutation
Sister chro-
matid exchange
and chromo-
somal aberra-
tions
Cultured mouse lymphoma cells Mixed Xylene
(L5178Y, TK+/-)/£orward mutation
assay
Cultured human lymphocytes Not Reported
52.11 m-xylene, 11.41 Negative
o-xylene, 0.3Z ^-xylene,
36.IX ethylbenzene
Negative
Not Reported
Not tested Negative
Litton
Bionetics
1978b
Gerner-Smidt
and Friedrich
1978
fO
Ed
PJ
>
r
H
X
M
•n
m
n
H
C/3
-------
TABLE 2-11. Genotoxicity of Xylene In Vivo
Endpoint
Species/Test System Exposure Route
Isomer
Purity/composition
Result
Reference
Manual^"
Sister Chromatid
Exchange and Chromo-
somal Abborotiona
Human Peripheral
Lymphocytes
Inhalation (Occupa- Not Reported Not Reported
tional exposure)
Negative
Haglund et
al. 1980
Sister Chromatid
Exchange
Chromosomal
Aberrations
Human Peripheral
Lymphocytes
Rat Bone Marrow
Inhalation (Occupa-
tional exposure)
Intraperitoneal
(single exposure)
Mixed Xylene
6-151 ethylbenzene
Mixed Xylene
11.41 o-xylane,
0.3X g-xylene,
36.11 ethylbenzene
52.11 m-xylene,
Negative
Negative
Pap and
Varga 1987
Litton
Bioneti cs
1978b
Chromosomal
Aberrations
Micronuclei
Formation
Sperm-Head
Abnormalities
Rat Bone Marrow
Mouse Bone Marrow
Polychrooatic-Eryth-
rocyte Assay (Micro-
nucleus Test)
Sat Sperm-Head Morph-
ology Assay
Intraperitoneal
(5 exposures)
Intraperitoneal
(two exposures)
Intraperitoneal
Mixed Xylene
0.31 g-xylene,
36.11 ethylbenzene
52.11 m-xylene,
11.41 o-xylene,
m-Xylene
o-Xylene
jj-Xylene
o-Xylene
purity = 981
purity =981
purity = 981
Not Reported
Negative
Negative
Negative
Negative
Negative
Li tton
Bionetics
1978b
Mohtashami-
pur et al.
1985
Washington
et al. 1983
ac
tn
>
t-1
H
3d
w
-n
m
o
H
to
oo
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79
2. HEALTH EFFECTS
In summary, genotoxicity studies on mixed xylene and the individual
isomers of xylene have provided consistently negative results in a variety of
in vitro and in vivo assays and test systems (bacteria, yeast, insects,
cultured mammalian cells, mice, rats, and humans). Based on the genotoxicity
studies conducted to date, there is sufficient evidence to conclude that mixed
xylene, m-xylene, o-xylene, and p-xylene are nonmutagenic, There is also
limited evidence from bacterial test systems that suggest that xylene
metabolites, specifically m-xylenol, £-xylenol, 2,4-dimethylphenol, and
o-methylbenzyl alcohol, are nonmutagenic as well.
Cancer. No data were available regarding the development of cancer in
humans following inhalation, oral, or dermal exposure to mixed xylene or
individual isomers. Animal carcinogenicity data for the xylenes are limited
to oral studies with mixed xylene (Maltoni et al. 1983, 1985; NTP 1986) and
dermal studies in which the isomeric composition of the xylene was not
specified, exposures were less than lifetime, and involved multiple chemicals
(Berenblum 1941; Pound 1970; Pound and Withers 1963). No animal
carcinogenicity data for the xylenes were available for inhalation exposure.
Because of the limited data, no conclusions can be drawn regarding the
relationship between xylene exposure and cancer in humans.
EPA has classified mixed xylene as a Group D agent (not classifiable as
to human carcinogenicity) (IRIS 1989). This classification applies to those
chemical agents for which there is inadequate evidence of carcinogenicity in
animals. No cancer potency factor (ql*) or other quantitative estimate of
carcinogenicity has been developed by EPA for mixed xylene, s-xylene,
a-xylene, orj)-xylene.
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
biomarkers of exposure. The body burden of a substance may be the results 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
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80
2. HEALTH EFFECTS
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 maybe 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 xylene are discussed in Section 2.5.1.
Biomarkers of effect are defined as any measurable biochemical,
physiologic, or other alteration within an organism that, depending on
magnitude, can be recognized as an established or potential health impairment
or disease (NAS/NRC 1989). This definition encompasses biochemical or
cellular signals of tissue dysfunction (e.g. increased liver enzyme activity
or pathologic changes in female genital epithelial cells), as well as
physiologic signs of dysfunction such as increased blood pressure or decreased
lung capacity. Note that these markers are 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 xylene 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 Xylenes
Xylene levels in the blood and levels of its metabolite, methylhippuric
acid, in the urine are the primary markers used to detect exposure to xylenes.
Xylene is very soluble in the blood and is readily absorbed into the
circulation during exposure (Astrand 1982). Measurement of blood levels of
xylene is limited by the rapid metabolism of xylene. Xylene is metabolized
almost exclusively to methylhippuric acid in humans. Detection of
methylhippuric acid in the urine is the most widely used indicator of xylene
exposure (ACGIH 1986). Within 2 hours of an inhalation exposure,
methylhippuric acid may be detected in the urine (Sedivec and Flek 1976b).
The excretion of methylhippuric acid is complete within a day or two of
exposure to xylenes, limiting the utility of this biomarker to the detection
of only very recent exposures. With chronic exposure to xylene, the
metabolism is enhanced, further limiting the time following exposure that
xylene levels may be measured in the blood (Savolainen et al. 1979a). For
additional information on the kinetics of xylene absorption, distribution,
metabolism, or excretion, see Section 2.3.
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81
2. HEALTH EFFECTS
Xylenes cause a number of physiological effects such as hepatic enzyme
induction and a wide spectrum of nervous system effects ranging from cognitive
dysfunction and anesthetic-like symptoms to hyperactivity and convulsions.
However, none of these effects is specific for xylene exposure.
2.5.2 Biomarkers Used to Characterize Effects Caused by Xylenes
The following changes are potential biomarkers of effect for xylenes;
however, none of the changes are unique to xylene exposure. Xylenes have been
observed to enhance the activity of a variety of microsomal enzymes and
increase hepatic cytochrome P-450 content (Elovaara 1982; Elovaara et al.
1980; Patel et al. 1979; Savolainen et al. 1978; Tatrai et al. 1981; Toftgard
and Nilsen 1981, 1982; Toftgard et al. 1981), Increases in liver-to-body
weight ratios and proliferation of endoplasmic reticulum are also
characteristic responses to xylene exposure (Condie et al. 1988; Kyrklund et
al. 1987; Tatrai et al. 1981; Toftgard et al. 1981). Scores consistent with
memory impairment and decreased reaction time have been observed using
standard intelligence tests and measures of reaction time (Gamberale et al.
1978; Riihimaki and Savolainen 1980; Savolainen and Riihimaki 1981b;
Savolainen et al. 1979b; 1984, 1985). Decreases in flash-evoked potentials
have been observed as a result of xylene exposure (Dyer et al. 1988). Also,
decreased axonal transport has been observed following xylene exposure
(Padilla and Lyerly 1989). Increased hypothalamic catecholamine levels have
been observed following xylene exposure (Andersson et al. 1981). Further
study may indicate that one or a combination of the above effects may be a
more specific biomarker of the effects of xylenes.
2.6 INTERACTIONS WITH OTHER CHEMICALS
The interaction of xylene with alcohol, drugs (aspirin, phenobarbital),
and various solvents (1,1,1-trichloroethane, benzene, ethylbenzene) has been
evaluated in experimental studies with humans and animals.
The effects from combined exposure to xylene and ethanol have been
studied most extensively because of the high potential for workers to consume
alcoholic beverages and to be exposed to xylene occupationally by inhalation.
Results of studies with humans and animals indicate that metabolic interaction
between xylene and ethanol occurs. Ethanol appears to inhibit the metabolism
°f xylene and delay microsomal oxidation (Elovaara et al. 1980; Riihimaki et
al- 1982a, 1982b; Romer et al. 1986; Savolainen 1980; Savolainen et al. 1978,
l979b, 1980).
Possibly because of competition for the enzymes involved in conjugation
with glycine during the concurrent metabolism of a-xylene and aspirin by human
v°Xunteers, saturation of the conjugation pathway occurred that led to
decreases in the metabolism of both aspirin and ©-xylene (Campbell et al.
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82
2. HEALTH EFFECTS
1988). Administration of aspirin to pregnant rats which were being exposed to
xylene caused a potentiation of maternal and fetal toxic effects above that
observed in the presence of either xylene or aspirin alone (Ungvary 1985).
This was postulated to be due to the delayed metabolism of aspirin by xylene.
Exposure to xylene combined with benzene or ethylbenzene may produce
mutual inhibition of the metabolism of both solvents (Engstrom et al. 1984;
Gut 1981; Nakajima and Sato 1979). Ethylbenzene is found in mixed xylene.
Co-exposure to m-xylene and methyl ethyl ketone also produced inhibition of
the metabolism of m-xylene (Liira et al. 1988). In contrast, ethyl acetate
exposure in combination with exposure to m-xylene caused a reduction in the
blood of xylene levels (Freundt et al. 1989).
Inhalation of m-xylene following pretreatment with phenobarbital was
associated with both increased pulmonary retention of m-xylene and increased
urinary excretion of m-methylbenzoic acid (David et al. 1979). Surprisingly,
inhalation of m-xylene and 1,1,1-trichloroethane has been associated with
slight improvements in certain psychophysiological parameters, including
reaction time and equilibrium in humans as compared with pre-exposure
measurements (Savolainen et al. 1982a, 1982b) and impairment in others such as
visual evoked potentials and equilibrium (Savolainen et al. 1982a; Seppalainen
et al. 1983). Also, a protective effect of xylene on n-hexane-induced
testicular atrophy was observed when rats were exposed to n-hexane and xylene
simultaneously (Nylen et al. 1989).
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
Available data indicate that subsets of the human population may be
unusually susceptible to the toxic effects of xylene. Pregnant women,
fetuses, and very young children may be at greater risk of adverse health
effects from xylene exposure than the population in general (Barlow and
Sullivan 1982; Holmberg and Nurminen 1980; Hudak and Ungvary 1978; Kucera
1968; Marks et al. 1982; Mirkova et al. 1982; Mirkova et al. 1983; Ungvary et
al. 1980b, 1981). Although no human studies were located indicating maternal
or fetal toxicity following total xylenes exposure, animal studies suggest
there may be a relationship between exposure to the agents and developmental
effects (Hudak and Ungvary 1978; Marks et al. 1982; Ungvary et al. 1980b,
1981). The ability of fetuses and very young children to metabolize certain
xenobiotics, including possibly xylene, is reduced because of their immature
enzyme detoxification systems (Calabrese 1978). This reduced ability to
biotransform and excrete these compounds efficiently may increase or decrease
their toxic effect, depending on whether the parent compound or one or more
metabolites is the actual toxic form. The biotransformation of xylene varies
with the exposure concentration.
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2. HEALTH EFFECTS
People with subclinical and clinical epilepsy are at increased risk of
seizures if exposed to xylene due to its excitatory CNS effects (Arthur and
Curnock 1982; Goldie 1960; Riihimaki and Hanninen 1987). It has also been
demonstrated in human studies (Goldie 1960; Riihimaki et al. 1982a; Savolainen
1980; Savolainen et al. 1978; Savolainen et al. 1980) and animal studies
(Elovaara et al. 1980; Savolainen et al. 1979b) that alcohol consumption
potentiates xylene toxicity. Some people appear particularly susceptible to
the interaction and may develop dizziness, nausea, and dermal flush (Riihimaki
et al. 1982b; Savolainen et al. 1980).
People with clinical or subclinical renal, hepatic, and cardiac disease
may be more susceptible to the effects of xylene. Evidence from occupational
and case studies indicate that exposure to xylene might cause renal impairment
and some hepatic effects, as well as cardiac manifestations, including
tachycardia and ECG abnormalities (Goldie 1960; Hipolito 1980; Morley et
al. 1970; NIOSH 1975; Sikora and Gala 1957; Sukhanova et al. 1969; von
Burg 1982). However, exposure to xylene in these studies was confounded with
exposure to other chemical agents.
Limited human data suggest that people with respiratory diseases, such
as asthma, could potentially be at risk to the adverse effects of xylene
following inhalation exposure (Hipolito 1980; Morley et al. 1970; Muller and
Greff 1980).
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 xylene 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 xylene.
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 Xylene
The existing data on health effects of inhalation, oral, and dermal
exposure of humans and animals to xylene are summarized in Figure 2-11. The
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84
2. HEALTH EFFECTS
Inhalation
Oral
Dermal
Inhalation
Oral
Dermal
SYSTEMIC
HUMAN
SYSTEMIC
ANIMAL
Existing Studies
Figure 2-11. Existing Information on Health Effects
of Total Xylenes
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85
2. HEALTH EFFECTS
purpose of this figure is to illustrate the existing information concerning
the health effects of xylene. 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 2-11 graphically depicts the existing health effects information
for total xylenes for a specific route and duration of exposure.
Persons may be exposed to xylene at hazardous waste sites by inhalation
of contaminated air, drinking contaminated water, or dermal contact with
contaminated water or subsurface soils and sediments. Volatilization of
xylenes from surface water and soil occurs rapidly; therefore, inhalation is
the most likely source of exposure to xylenes at these sites. The health
effects of xylenes by inhalation exposure have been studied to the greatest
extent. There is little information available regarding health effects in
humans following oral or dermal exposure to xylene. As noted above, ingestion
°f xylene may be of concern because of the potential for xylene to contaminate
sources of drinking water (groundwater). Dermal exposure to xylene is of
concern not only because of potential workplace exposures, but also because
members of the general public are potentially exposed to xylene contained in
paints, glues, and other household products. As noted above, dermal exposure
to soils and water contaminated with xylene at waste sites could also occur.
Human fatalities following both inhalation and ingestion of xylene have
been reported in the literature. Acute exposure to xylene has resulted in the
development of both systemic effects, such as hepatic and cardiovascular
effects, and neurologic effects following inhalation or oral exposure. Data
regarding the systemic health effects of intermediate human exposure to xylene
were not reported in the literature. Also, no human carcinogenicity data were
reported in the literature. Very little information is available on the
chronic systemic, immunologic, developmental, reproductive, and genotoxic
health effects of xylene exposure in humans. Interpretation of the large
number of human studies examining the health effects of inhaled xylene vapor
is difficult due to study design limitations, e.g., inadequate
characterization of exposure, and concurrent exposure to other solvents, such
as toluene and benzene.
Studies conducted on experimental animals have been fairly extensive
(Figure 2-11), and have focused on the adverse health effects following
inhalation and oral exposure to xylene. Data are comprehensive on
neurological and systemic effects. There are several developmental studies in
animals, although most have limitations. Limited information exists on the
carcinogenicity of xylene. A large number of studies on the genotoxicity of
xylene are available, with the majority reporting negative results.
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2. HEALTH EFFECTS
2.8.2 Identification of Data Needs
Acute-Duration Exposure. There are acute exposure data in humans and/or
animals that indicate that the central nervous system and possibly the
developing fetus are the major targets of acute xylene toxicity by the
inhalation and oral routes. No information is available on the nervous system
effects of dermal exposure to xylenes. Death has been observed to occur as a
result of exposure by inhalation, oral, and dermal exposure, and lethal and
nonlethal levels of total xylenes have been determined. Acute studies have
demonstrated that xylene is irritating to the skin and eyes. Inhalation of
xylenes has also been shown to cause irritation of the respiratory tract and
dyspnea. Data on NOAELs and LOAELs from acute studies were not sufficient for
deriving either inhalation or oral MRLs for xylene. Additional information on
the effects observed after acute dermal exposure would be helpful due to the
likelihood that acute duration skin contact with xylenes could occur in the
home, workplace, and possibly at hazardous waste sites. Pharmacokinetic data
and toxicity data indicate that xylenes are absorbed through the skin,
although the relative absorption by this route is difficult to ascertain due
to the rapid evaporation of xylenes from the skin. Because short-term
inhalation or oral exposure is likely in the home, workplace, and at hazardous
waste sites, additional acute-duration inhalation and oral studies also would
be helpful in determining the threshold levels at which toxicity occurs.
Intermediate-Duration Exposure. Intermediate-duration inhalation and
oral studies have identified the central nervous system, liver, kidneys, and
possibly the developing fetus as the primary targets of intermediate- duration
xylene exposure. No studies were available that examined the effects
associated with intermediate-duration dermal exposure to xylenes.
Pharmacokinetic data indicate that absorption of xylenes occurs through the
skin; however, it is difficult to determine whether similar end points would
be expected after repeated dermal exposure to xylenes. Human skin may be
repeatedly exposed to xylenes as a result of occupational and home use.
Repeated exposure of the skin to contaminated media at hazardous waste sites
may also occur. Therefore, a well-designed and well-conducted intermediate-
duration dermal study would be helpful in estimating the human health hazard
associated with this type of exposure. No inhalation or oral studies were
sufficient to determine intermediate-duration MRLs. Additional inhalation and
oral studies examining the threshold levels associated with adverse health
effects would be helpful since there are populations surrounding hazardous
waste sites that might be repeatedly exposed to xylene.
Chronic-Duration Exposure and Cancer. Few epidemiological or animal
studies were available regarding the health effects associated with chronic
exposure to xylenes. The central nervous system and the liver appear to be
the primary targets of chronic xylene exposure; however, no study had
-------
87
2. HEALTH EFFECTS
sufficient information on threshold levels associated with these health
effects to allow calculation of a chronic MRL. No information is available on
the health effects of chronic dermal exposure to xylenes. Since the
inhalation and oral routes are potential means of exposure for individuals
living near hazardous waste sites, more information on the health effects
associated with chronic low-level exposure by these routes would be helpful.
No epidemiological studies were available regarding the development of
cancer in humans following inhalation, oral, or dermal exposure to mixed
xylene or xylene isomers. Several oral carcinogenicity bioassays involving
lifetime exposure have been conducted with mixed xylene in rats and mice;
however, all of these bioassays contained limitations that preclude a
definitive conclusion regarding the carcinogenicity of xylene. Several dermal
studies are available in which xylene (unspecified isomeric content) was
evaluated for its ability to enhance tumor induction by tumor-initiating and
tumor-promoting agents; however, these studies are less than lifetime and have
often involved exposures to more than one chemical agent. No animal cancer
bioassays involving inhalation exposure to mixed xylene or isomers of xylene
have been conducted. Because the issue of the potential carcinogenicity of
Xylenej has not been resolved, additional bioassays are desirable. Chronic
inhalation and oral bioassays to low levels would be helpful because chronic
exposure by these routes may be encountered in the workplace, home, or in the
vicinity of hazardous waste sites.
Genotoxicity. Limited data is available regarding the genotoxicity of
inhalation of xylenes in humans. No data is available regarding the potential
genotoxicity of xylenes in humans following oral or dermal exposure. Animal
studies examining the genotoxicity of inhalation or oral exposure to xylenes
have been uniformly negative. Also, a variety of in vitro assays have
Negative results. Because of the large number of negative studies that exist,
additional in vivo or in vitro assays of the genotoxicity potential of xylenes
are not required at this time.
Reproductive Toxicity. One epidemiological study suggested that
Paternal exposure to xylenes in the workplace may increase the likelihood of
Portions; however this study was limited by the size of the sample population
(Taskinen et al. 1989). Only one animal inhalation study has been conducted
to test the potential reproductive toxicity of mixed xylene (Bio/dynamics
1983). No reproduction studies have been conducted on either mixed xylene or
the individual xylene isomers in animals following exposure via oral or dermal
routes. Histopathological examination of reproductive organs of rats and mice
following intermediate and chronic oral bioassays revealed no adverse effects;
however, given the high potential for human exposure to xylene and its isomers
and their ability to cross the placenta, additional studies in animals and
-------
88
2. HEALTH EFFECTS
epidemiological studies in humans would be useful to assess more fully the
reproductive toxicity of xylene and its isomers.
Developmental Toxicity. Congenital defects of the central nervous
system in children whose mothers were exposed occupationally to mixed xylene
vapors were reported in two case studies (Holmberg and Nurminen 1980; Kucera
1968). However, the studies have many limitations, and no conclusion can be
made. Animal inhalation, oral, and dermal studies have provided some
information on the developmental effects of xylene and its isomers; however
the quality of many of these studies precludes drawing definitive conclusions.
Additional animal studies examining the relationship between developmental
effects and xylene exposure would provide useful information because of the
developmental effects evident in inhalation and oral studies and the ability
of xylene to cross the placenta. More information is needed on the mechanism
of xylene-induced developmental toxicity.
Immunotoxicity. Several occupational studies have been conducted to
evaluate the immunological effects of xylene; however, workers in these
studies were exposed to other chemical agents in addition to xylene. No
animal studies involving xposure by any route have been conducted examining
the immunotoxicity of mixed xylene or the xylene isomers. Inhalation exposure
studies in animals employing only xylene or its isomers may remove
uncertainties about the immunotoxicity potential of xylene. Dermal
sensitization tests may also provide useful information on whether an allergic
response to xylene is likely, since the potential for skin contact by humans
occurs in occupational settings and in soil and water at hazardous waste
sites.
Neurotoxicity. Human and animal studies regarding neurologic effects
have been conducted following oral and inhalation exposures to xylene. Data
from such studies indicate that xylene adversely affects the nervous system.
The majority of studies in humans and animals concentrated on the
neurobehavioral effects of xylene. Further studies attempting to elucidate
the mechanism of action of xylenes on the nervous system would be helpful in
understanding the neurotoxic effects produced by xylenes. Additional well-
conducted studies in animals on the histopathologic changes of the central
nervous system following intermediate or chronic exposure also may provide
useful information on permanent structural alterations induced by xylene.
Epidemiological and Human Dosimetry Studies. Limited epidemiological
studies and no human dosimetry studies on any of the xylenes have been
conducted. Much of the available information on the effects of xylene in
humans comes from case reports and occupational studies in which subjects were
exposed to other chemical agents in addition to xylene. Many of the case
reports and occupational studies were also limited in that exposure conditions
-------
89
2. HEALTH EFFECTS
(concentration, duration) were not reported and/or well characterized. Well-
designed and well-controlled epidemiological studies of people living near
waste sites or industries using xylene, or occupational studies in which
xylene exposure conditions are better characterized, would be useful.
Epidemiological studies examining the nervous system, developmental, and renal
effects associated with xylene exposure would be particularly useful since
reports of human exposure and animal studies have suggested that persons
living in the vicinity of hazardous waste sites may be at risk for developing
these types of effects.
Biomarkers of Exposure and Effect, Methods are available for
determining xylene and its metabolite, methylhippuric acid, in biological
tissues and fluids. These biomarkers of exposure are specific for xylene
exposure and are sufficient for determining recent exposure to xylenes but are
incapable of distinguishing short-term from chronic exposures. A number of
Physiological effects occur as a result of xylene exposure, but none of these
effects is specific for xylenes, and, therefore, their occurrence would have
very little usefulness in determining exposure to xylenes. Further study of
the effects associated with xylene exposure may reveal additional biomarkers
that are specific to xylene exposure.
No specific biomarkers of effects have been identified for xylenes.
Xylenes have been demonstrated to cause a number of adverse health effects
including central nervous system disturbances. A number of neurological and
cognitive function tests exist and have been used to identify central nervous
system changes produced by xylenes. However, until the mechanism for nervous
system disruption is identified, it is unlikely that a specific test could
predict xylene-specific intoxication. Assessment of hepatic enzyme induction
is difficult without obtaining liver tissue. Demonstration of enhanced
metabolism of substances by the microsomal enzyme system could be interpreted
as microsomal induction; however, a large number of substances other than
xylenes also induce enhanced enzyme activity. Renal impairment also has been
associated with xylene exposure. Increased excretion of albumin, leukocytes,
and erythrocytes demonstrates kidney damage of the type ascribed to xylene
exposure, but these effects are not specific for xylenes. However, limited
data are available associating levels of xylene in human tissues and fluids
with adverse health effects. Available human studies have focused on the
blood concentrations of jm-xylene associated with central nervous system
effects. Additional animal studies evaluating the association between xylene
(or xylene metabolite) levels in other human tissues or fluids and adverse
health effects would be useful.
Absorption, Distribution, Metabolism, and Excretion. The absorption,
metabolism, and excretion of xylenes following inhalation exposure in humans
and animals have been well characterized. The distribution of xylenes has
-------
90
2. HEALTH EFFECTS
been well characterized in animals and identified to a small extent in humans.
The database for oral and dermal absorption, distribution, and excretion of
xylene isomers in humans and/or animals consists primarily of qualitative
information from experimental and occupational studies. A few quantitative
studies exist that examined the toxicokinetics following oral or dermal
exposure. Differences in the rate of metabolism of xylenes after short-term
or chronic exposure have been identified. Additional information on the
dermal absorption, distribution, metabolism, and excretion would be helpful
for predicting the fate of xylene in persons exposed by this route.
Comparative Toxicokinetics. The target organs and adverse health
effects of xylenes are similar across species. Toxicokinetic studies have
been performed in humans, rats, mice, rabbits, and monkeys. There is
reasonable correlation between the end points examined in these studies. The
metabolism of m- and ^-xylenes is similar in rats and humans. However, a
difference between the metabolism of o-xylene in rats and in humans exists.
Whereas o-xylene is almost exclusively metabolized to o-methylhippuric acid in
humans, 10%-56% of o-xylene is also conjugated by glucuronide and glutathione
in rats. Additional studies would be helpful for determining whether other
differences exist in the metabolism of xylenes among species. Study of the
health effects of the glucuronide and glutathione metabolites of o-xylene may
answer this question.
2.8.3 On-going Studies
On-going studies regarding the health effects of xylene were reported in
the Federal Research in Progress File (FEDRIP) database and in the Directory
of On-Going Research in Cancer Epidemiology (Parkin and Wahrendorf 1987).
P. Moszczynski (Provincial Immunology Lab, Poland) is continuing to examine
the hematological and immunological functions of workers occupationally
exposed to benzene, toluene, and xylene. To date, no effects have been
recorded. J.M. Russo of NIOSH is conducting neurobehavioral tests on several
chemicals including xylene. The results will be used to assess neurological
effects from acute and chronic exposures in high-risk occupations.
On-going studies on mixed xylene and individual xylene isomers are also
being conducted by the Health Effects Research Laboratory in Cincinnati for
EPA's Office of Research and Development (NTP 1988). Testing was to be
started in 1988 on the subchronic, systemic/organ, neurologic/behavioral, and
pulmonary toxicity of mixed xylene. Testing was in progress in 1988 on the
neurologic/behavioral toxicity and systemic/organ toxicity of m-xylene, the
systemic/organ toxicity of o-xylene, and the biochemical/cellular/tissue
effects, neurologic/behavioral toxicity, and pulmonary toxicity of ^-xylene
(NTP 1988).
-------
91
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
The synonyms and identification numbers for mixed, m-, o-, and g-xylene
are listed in Tables 3-1 through 3-4.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Important physical and chemical properties of mixed, m-, o-, and
E.-xylene are presented in Tables 3-5 through 3-8.
-------
92
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Mixed Xylene
Value Reference
Chemical name
Xylene
Windholz 1983
Synonyms
Dimethylbenzene; xylol;
Windholz 1983;
benzene, dimethyl-;
HSDB
1988
Ksylen (Polish);
Xiloli (Italian);
Xylenen (Dutch);
Xylole (German);
methyl toluene
Sax and Lewis
1989
Trade names
Violet 3
Sax and Lewis
1989
Chemical formula
^8^10
HSDB
1988
Chemical structure®
Identification numbers:
CAS Registry
1330-20-7
HSDB
1988
NIOSH RTECS
ZE 2100000
HSDB
1988
EPA Hazardous waste
U239
HSDB
1988
OHM/TADS
No data
DOT/UN/NA/IMCO Shipping
UN 1307; Xylene (xylol)
HSDB
1988
IMCO 3.2
IMCO 3.3
HSDB
4500
HSDB
1988
NCI
C55232
HSDB
1988
STCC
49 093 50; Xylene
HSDB
1988
aMixture of g-xylene, o-xylene, g-xylene, and ethylbenzene. See Tables 3-2,
3-3, and 3-4 for chemical structures of in-, q-, and ^-xylene.
HSDB - Hazardous Substances Data Bank; 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 Materials/Technical Assistance
Data System; D0T/UN/NA/1MC0 - Department of Transportation/United
Nations/North America/International Maritime Dangerous Goods Code; NCI -
National Cancer Institute; STCC - Standard Transport Commodity Code.
-------
93
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Chemical Identity of m-Xylene
Value
Reference
Chemical name
Synonyms
Trade names
Chemical formula
Chemical structure
Identification numbers:
ni-Xylene
1,3-Dimethylbenzene;
1,3-xylene; benzene,
1,3-dimethyl; m-di-
methylbenzene, m-xylol;
in-methyl toluene;
meta-xvlene
No data
CeHio
o
Windholz 1983
HSDB 1988
ECETOC 1986
HSDB 1988
ECETOC 1986
CAS Registry
108-38-3
HSDB
1988
NIOSH RTECS
ZE 2275000
HSDB
1988
EPA Hazardous Waste
U239; Xylene
HSDB
1988
F003; Xylene
OHM/TADS
7216953
HSDB
1988
DOT/UN/NA/IMCO Shipping
UN 1307; a-Xylene; m-Xylol
HSDB
1988
IMCO 3.2 Xylenes
IMCO 3.3 Xylenes
HSDB
135
HSDB
1988
NCI
No data
STCC
49 093 50; Xylenes
HSDB
1988
HSDB - Hazardous Substances Data Bank; 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 Materials/Technical Assistance
Data System; DOT/UN/NA/IMCO - Department of Transportation/United
Nations/North America/International Maritime Dangerous Goods Code; NCI -
National Cancer Institute; STCC - Standard Transport Commodity Code.
-------
94
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-3. Chemical Identity of o-Xylene
Value Reference
Chemical name
2,-Xylene
Windholz 1983
Synonyms
1,2-DimethyIbenzene;
HSDB
1988
1,2-xylene; benzene,
1,2-dimethyl-; o-di-
methylbenzene; o-methyl-
toluene; o-xylol;
ortho-xvlene
ECETOC 1986
Trade names
No data
Chemical formula
CsH10
HSDB
1988
Chemical structure
ECETOC 1986
ch3
i
>\/CH3
p
Identification numbers:
CAS Registry
95-47-6
HSDB
1988
NIOSH RTECS
ZE 2450000
HSDB
1988
EPA Hazardous Waste
TJ239; Xylene
HSDB
1988
F003; Xylene
OHM/TADS
7216952
HSDB
1988
DOT/UN/NA/IMCO Shipping
UN 1307; Xylene; Xylol
HSDB
1988
IMCO 3.2 Xylenes
IMCO 3.3 Xylenes
HSDB
134
HSDB
1988
NCI
No data
HSDB
1988
STCC
49 093 50; Xylene
HSDB
1988
HSDB - Hazardous Substances Data Bank; 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 Materials/Technical Assistance
Data System; DOT/UN/NA/IMCO - Department of Transportation/United
Nations/North America/International Maritime Dangerous Goods Code; NCI -
National Cancer Institute; STCC - Standard Transport Commodity Code.
-------
95
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-4. Chemical Identity of j)"XyIene
Value
Reference
Chemical name
Synonyms
Trade names
Chemical formula
Chemical structure
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO Shipping
HSDB
NCI
STCC
^-Xylene
1,4-Dimethylbenzene;
1,4-xylene; jj-di*
methylbenzene;
p-methyltoluene;
£-xylol; para-xylene
Scintillar
o
106-42-3
ZE 2625000
U239; Xylene
F003; Xylene
7216951
UN 1307; ^.-Xylene; a-Xylol
IMCO 3.2 Xylenes
IMCQ 3.3 Xylenes
136
No data
49 093 51; Xylene
(Efi3L&-xylene)
Windholz 1983
HSDB 1988; ECETOC
1986
HSDB 1988
HSDB 1988
ECETOC 1986
HSDB 1988
HSDB 1988
HSDB 1988
HSDB 1988
HSDB 1988
HSDB 1988
HSDB 1988
HSDB - Hazardous Substances Data Bank; CAS - Chemical Abstracts Service;
NlOSH - National Institute for Occupational Safety and Health; RTECS -
Registry of Toxic Effects of Chemical Substances; EPA - Environmental
Protection Agency; OHM/TADS - Oil and Hazardous Materials/Technical Assistance
Data System; DOT/UN/NA/IMCO - Department of Transportation/United
Nations/North America/International Maritime Dangerous Goods Code; NCI -
National Cancer Institute; STCC - Standard Transport Commodity Code.
-------
96
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-5. Physical and Chemical Properties of Mixed Xylene
Value Reference
Property
Molecular weight
Melting point
Boiling point
Density
at 20°C/4°C
Physical state
Color
Odor
Odor threshold:
Air
Water
Solubility:
Water
at 25"C
Organic solvents
Partition coefficients:
Log octanol/water
Log KgC
Vapor pressure at 7.5°C
at 20'C
at 21"C
Henry's law constant
Autoignition temperature
Flashpoint
106.16
No data
137°-140°C
138.5°C
About 0.86
0,864
0.8685
Liquid
Clear
Sweet
0.0045 mg/L (1.0 ppm)
0.6 mg/m3 (0.1 ppm)
0.73 mg/m3 (0.17 ppm)
No data
Practically insoluble
0.013 g/100 g (130 ppm)
Miscible with absolute
alcohol, ether, and
other organic liquids
Very soluble in alcohol,
very soluble in ether
3.12-3.20
3.33
No data
2.5 mmHg
6-16 mmHg
6.72 mmHg
No data
464°C (867°F)
17°-25"C (C.C.)
27°-46®C (O.C.)
29°C
37.6'C (100"F) (T.0.C)
Windholz 1983
Windholz 1983
Sax and Lewis 1989
Windholz 1983
Sax and Lewis 1989
Dawson et al. 1974
Windholz 1983
Sax and Lewis 1989
Environment Canada
1981
Carpenter et al. 1975
Gusev 1967
Gusev 1965
Windholz 1983
Stephan and Stephen
1963
Windholz 1983
Sandmeyer 1981
Hansch and Leo 1979
Leo 1982
Dawson et al. 1974
Sandmeyer 1981
Sax and Lewis 1989
General Electric 1980
Maxwell 1978
Hawley 1977
Windholz 1983
Sax and Lewis 1989,
Sandmeyer 1981
-------
97
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-5 (Continued)
Property Value Reference
Flammability limits l%-7% General Electric
1980
Conversion factors 1 mg/m3 - 0,23 ppm Verschueren 1977
1 ppm - 4.41 mg/m3
T.O.C - tag open cup; C.C. - closed cup; and O.C. - open cup.
-------
98
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-6. Physical and Chemical Properties of m-Xylene
Property
Value
Reference
Molecular weight
Melting point
Boiling point
Density at 15°C
at 20°C
Physical state
Color
Odor
Odor threshold:
Air
Water
Solubility:
Water
at 25°C
at 20°C
at 25°C
at 25°C
at 20°C
at 25°C
Organic solvents
Partition coefficients:
Log octanol/water (Log
Kow)
Koe
106.16
-47.4°C
-47.9°C
-48°/53"C
139.3°C
139.1°C
0.8684
0.8642
Liquid
Colorless
Sweet
16 mg/m3 (3.7 ppm)
1.1 mg/L (1.1 ppm)
Insoluble
146 mg/L (146 ppm)
160 mg/L (160 ppm)
161 ppm
173 ppm
0.00003 g/lOOg (0.3 ppm)
134.0 ppm
Miscible with alcohol,
ether, and many other
organic solvents
3.09 (estimated)
3.20
3.28 (estimated)
166
Windholz 1983
Windholz 1983
Sax and Lewis 1989;
Weast 1988
Verschueren 1983
Windholz 1983
Weast 1988
Windholz 1983
Weast 1988
Windholz 1983
Windholz 1983
Environment Canada
1981
Verschueren 1977
Rosen et al. 1962
Windholz 1983
NAS 1980
Chernoglazova and
Simulin 1976
Sanemasa et al. 1982
Andrews and Keefer
1949
Mackison et al. 1981
Price 1976
Windholz 1983
Konemann 1981
Hansch and Leo 1979;
Verschueren 1983
Yalkowsky and Valvani
1976
Abdul et al. 1987
-------
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-6 (Continued)
Property
Value
Reference
Vapor pressure at 20°C
6 mmHg
Verschueren 1983
at 28.3°C
10 mmHg
Sax and Lewis 1989
at 30°C
11 mmHg
Verschueren 1983
Henry's law constant at
7.19xl0~3 atm-m3/mol
SRC 1988
25°C
Autoignition temperature
527°C
NFPA 1978
Flashpoint
25°C (C.C.)
Windholz 1983
27°C (C.C.)
NFPA 1978
Flamraability limits
1.l%-7.0%
NFPA 1978
Conversion factors
1 mg/m3 - 0.23 ppm
Verschueren 1983
1 ppm - 4.41 mg/m3
Verschueren 1983
C.C. — closed cup.
-------
100
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-7. Physical and Chemical Properties of o-Xylene
Value Reference
Property
Molecular weight
Melting point
Boiling point
Density at 20°C
Physical state
Color
Odor
Odor threshold:
Air
Water
Solubility:
Water
at 0°C
at 20°C
at 25°C
at 259C
at 25"C
Organic solvents
Partition coefficients:
Log octanol/water
Koc
at 25°C
at 110"C
Vapor pressure at 208C
at 25°G
at 30°C
Henry's law constant at
25°C
Autoignition temperature
106.16
-25°C
144°C
0.8801
Liquid
Colorless
Sweet
0.08 ppm
0.17 ppm
1.8 ppm
Insoluble
142 mg/L (142 ppm)
175 mg/L (175 ppm)
175 ppm
178 ppm
213 mg/L (213 ppm)
Miscible with alcohol,
ether
2.77
3.09 (estimated)
3.12
3.18 (estimated)
47.7-68.1
82.2-117
129
5 mmHg
6.8 mmHg
9 mmHg
5.19xl0"3 atm-m3/mol
463°C
463.89°C
464"C
465°C
Windholz 198 3
Windholz 1983
Windholz 1983
Windholz 1983
Windholz 1983
Windholz 1983
Verschueren 1983
Verschueren 1977
Gerarde 1959
Verschueren 1983
Windholz 1983
Polak and Lu 1973
Verschueren 1983
OHM/TADS 1988
Sanemasa et al. 1982
Polak and Lu 1973
Windholz 1983
Verschueren 1983
Konemann 1981
Hansch and Leo 1979
Yalkowsky and Valvani
1976
Nathwani and Phillips
1977
Nathwani and Phillips
1977
Abdul et al. 1987
Verschueren 1983
Sandmeyer 1981
Verschueren 1983
Sanemasa et al. 1982
UFPA 1978
OHM/TADS 1988
Hawley 1977
Sax 1979
-------
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-7 (Continued)
Property
Value
Reference
Flashpoint
17°C (C.C.)
Windholz 1983
17.20C (C.C.)
US DOT 1978
23.9°C (O.C.)
US DOT 1978
32 °C (C.C.)
NFPA 1978
32.2°C (C.C.)
Mackison et al. 1981;
Sax 1979
46.1°C (O.C.)
Hawley 1977
Flammability limits
1.0X-6.0X
NFPA 1978
Conversion factors
1 mg/cin3 - 0.23 ppm
1 ppm - 4.41 mg/m3
Verschueren 1983
C.C. - closed cup; and O.C. - open cup.
-------
102
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-8. Physical and Chemical Properties of 2-Xylene
Property
Molecular weight
Melting point
Boiling point
Density at 20-C
Physical state
at low temperatures
Color
Odor
Odor threshold:
Air
Water
Solubility:
Water at
25 °C
25 "C
25°C
Organic solvents
Partition coefficients:
Log octanol/water
Koc
Vapor pressure at 20°C
at 20"C
at 25°C
at 25°C
at 30°C
Value
106.16
13°-14°C
137°-138°C
0.86104
0.8611
Liquid
Solid (plates or prisms)
Monoclinic prisms
Colorless
Sweet
0.47 ppm
0.53 ppm
Insoluble
198 mg/L (198 ppm)
162.4 ppm
185 mg/L (185 ppm)
Soluble in alcohol,
ether, and other
organic solvents
3.08 (measured)
3.09 (estimated)
3.15 (estimated)
3.28 (estimated)
260
6.5 mmHg
9 mmHg
8.82 mmHg
8.84 mmHg
12 mmHg
Reference
Windholz 1983
Windholz 1983
Windholz 1983
Windholz 1983
Weast 1988
Hawley 1981
Windholz 1983
Weast 1988
Windholz 1983
US DOT 1978
Verschueren 1977
Rosen et al. 1962
Windholz 1983
Verschueren 1983
Sanemasa et al. 1982
Polak and Lu 1973
Windholz 1983
Hutchinson et al.
1978
Konemann 1981
Hansch and Leo 1979
Yalkowsky and Valvani
1976
Vowles and Mantoura
1987
Verschueren 1983
Mackison et al. 1981
Hine and Mookerjee
1975
Chao et al. 1983
Verschueren 1983
at 27.3°C
10 mmHg
OHM/TADS 1988
-------
103
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-8 (Continued)
Property
Value
Reference
Henry's law constant at
7.60xl0"3 atm-m3/mol
SRC 1988
25°C
Autoignition temperature
528°C
NFPA 1978
Flashpoint
25°C (C.C.)
Windholz 1983
27°C (C.C.)
NFPA 1978
27.2°C (T.O.C.)
Hawley 1981; Mackison
et al. 1981
Flammability limits
1.1X-7.0X
NFPA 1978
Conversion factors
1 mg/m3 - 0.23 ppm
Verschueren 1983
1 ppm - 4.41 mg/m3
T.O.C - tag open cup; and C.C. - closed cup.
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105
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION
Mixed xylene consists of a mixture of ethylbenzene and the m-, o-, and
£-isomers of xylene; m-xylene predominates. Mixed xylene may contain non-
xylene hydrocarbons in addition to ethylbenzene, such as benzene, toluene,
trimethylbenzene, phenol, thiophene, and pyridine (Gerarde 1960; Riihimaki and
Hanninen 1987; Sandmeyer 1981). However, the product has been relatively free
of benzene (less than 0.001%) since the late 1950s (Gosselin et al. 1984;
Riihimaki and Hanninen 1987). The exact composition of mixed xylene depends
°n the manufacturing method used. Currently, nearly all mixed xylene is
produced as a catalytic reformate of petroleum and consists of approximately
20% o-xylene, 44% m-xylene, 20% ^-xylene, and 15% ethylbenzene (HSDB 1988;
NIOSH 1975). Mixed xylene may also be manufactured from coal tar, yielding a
mixture of appro- 'mately 10%-15% o-xylene, 45%-70% m-xylene, 23% ^-xylene, and
6%-10% ethylben. .e; by gasoline pyrolysis, or by disproportionation of
toluene, producing a mixture free of ethylbenzene (HSDB 1988; NIOSH 1975;
Ransley 1984). U.S. manufacturers have an estimated annual capacity to
produce over one billion gallons of mixed xylene (SRI 1988). In 1987, U.S.
Petroleum refiners produced 649,428,000 gallons of high-purity (98%-100%)
mixed xylene (USITC 1988).
The isomers of xylene are produced from mixed xylene. m-Xylene is
obtained from mixed xylene via crystallization and fractionation or via
complexing with hydrofluoric acid and boron trifluoride (HSDB 1988). o-Xylene
is isolated from mixed xylene via distillation, but can also be produced by
the isomerization of the meta isomer (HSDB 1988). ^-Xylene is derived from
mixed xylene by crystallization, solvent extraction, or adsorption (HSDB 1988;
Hawley 1981). U.S. production capacity is estimated at 920 million and 5,525
million pounds annually for o-xylene and ^-xylene, respectively (SRI 1988).
In 1987, over 939 million pounds of 2_xylene anc* greater than 5,155 million
Pounds of ^-xylene were produced in the United States (USITC 1988). Current
values are not reported for sj-xylene; U.S. production of m-xylene was
estimated as 5.59xl010 gallons for 1980 (HSDB 1988).
4.2 IMPORT
In 1982, 1.31xl0u gallons of mixed xylene and 1.02xl09 gallons of
St-xylene were imported to the United States (HSDB 1988). In 1985, 1.48xl07
gallons of o-xylene and 6.53xl010 gallons of £-xylene were imported (HSDB
1988).
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106
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.3 USE
Approximately 70% of mixed xylene is used in the production of
ethylbenzene arid the meta, ortho, and para, isomers of xylene. The remaining
mixed xylene is used in solvents, such as for paints and coatings or is
blended into gasoline (HSDB 1988; Riihimaki and Hanninen 1987" Santodonato et
al. 1985).
The isomers of xylene are used as industrial solvents and serve as
intermediates in synthetic reactions. m-Xylene is a chemical intermediate in
the production of isophthalic acid, m-toluic acid, and isophthalonitrile;
isophthalic acid, in turn, is used in polyesters. o-Xylene is a chemical
intermediate in the synthesis of phthalic anhydride (for plasticizers)
phthalonitrile, 4,4-(trifluoro-1-(trifluoromethy1)ethylidene) diphthalic
anhydride ^(for polyimide polymers), terephthalic acid (for polyesters),
isophthalic acid, vitamins, and pharmaceuticals. ^-Xylene is a chemical
intermediate for the synthesis of dimethyl terephthalate, terephthalic acid
(for polyesters), dimethyl tetrachloroterephthalate, vitamins and
pharmaceuticals. Both o- and E-xylene are used as components'of insecticides
(HSDB 1988; Hawley 1981). F insecticides
4.4 DISPOSAL
Various methods of incineration are used in the disposal of xylene
isomers (EPA 1981b; HSDB 1988); the addition of a more flammable solvent has
been suggested to make the process easier (HSDB 1988)
Criteria for the disposal of xylenes are currently subject to
significant revision. Under the Resource Conservation and Recovery Act the
T'Vnnn^' °ff"sPeci^catlon batches, and spill residues of xylene greater
than 1,000 pounds are subject to handling, reporting, and recordkeeping
requirements; this applies also to spent xylene solvents and still bottoms
from the refining of these solvents (EPA 1980b, 1981c).
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5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Xylenes are released to the atmosphere primarily as fugitive emissions
from industrial sources (e.g., petroleum refineries, chemical plants), in
automobile exhaust, and through volatilization from their use as solvents.
Discharges into waterways and spills on land result primarily from use,
storage, and transport of petroleum products and waste disposal. Most of the
xylenes released to the environment partition to the atmosphere. Xylenes are
moderately mobile in soil and can leach into the groundwater, where they may
persist for several years. Xylenes are rapidly transformed in the troposphere
where photooxidation by hydroxyl radicals is the dominant process. Xylenes
are stable to hydrolysis and oxidation in the aquatic environment, but some
evidence indicates that they may be biotransformed by microorganisms in
groundwater. Biotransformation of xylene in surface waters is probably not
significant due to the volatility of the compound. Biotransformation will be
an important process mainly in subsurface soils, since xylenes in surface
soils will undergo photooxidation or will volatilize to the atmosphere.
Sorption of xylene to soils is more important in dry soils and will increase
in soils and sediments as organic matter content increases. Xylenes have been
found to bioaccumulate to very modest levels (e.g., bioconcentration factors
of less than 100), but food-chain biomagnification has not been observed.
Xylene or its metabolites have been detected in human urine, blood, and
expired air samples among members of the general population. Human exposure
to xylenes is believed to occur via inhalation of indoor and workplace air,
inhalation of automobile exhausts, ingestion of contaminated drinking water,
smoking, and inhalation and dermal absorption of solvents containing xylenes.
5.2 RELEASES TO THE ENVIRONMENT
Xylenes are ubiquitously distributed in the environment. They have been
detected in the atmosphere, rainwater, soils, surface waters and sediments,
drinking water, aquatic organisms, and human blood, urine, and expired breath.
Xylenes do not occur in the environment naturally except in smoke from forest
fires or as constituents of petroleum which may seep into the oceans from
underground deposits (Merian and Zander 1982). To date total xylenes have
been identified at 236 of the total 1,177 NPL sites (VIEW 1989). The
frequency of these sites within the United States can be seen in Figure 5-1.
Xylene has been detected at 38% of the 2,738 hazardous waste sites that have
had samples of all media analyzed by EPA's Contract Laboratory Program (CLP)
at a positive geometric mean concentration of 25 ppb (CLP 1988).
Releases of xylenes into the environment each year are estimated to
total nearly 3 million tons (2.7 million metric tons) (Merian 1982), In 1978,
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FIGURE 5-1. FREQUENCY QF SITES WITH TOTAL XYLENES CONTAMINATION
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5. POTENTIAL FOR HUMAN EXPOSURE
total U.S. emissions of mixed xylenes were estimated to be 480,000 tons
(435,000 metric tons) (SAI 1981). Major emissions of mixed xylenes occur
during production (principally from catalytic reforming of petroleum stock)
and end-use as a solvent in a variety of industrial applications. Total
emission of mixed xylenes from catalytic reformate production in the United
States in 1978 was estimated to have been approximately 9 million pounds
(4,500 tons) (Anderson et al. 1980). The breakdown of individual isomers in
these emissions was 16.7% g-xylene, 20.5% o-xylene, and 35.7% m-xylene. In
1978, the estimated U.S. mixed xylene emissions were 330,400 pounds from
pyrolysis gasoline production, 39,600 pounds from toluene disproportionation,
and 41,250 pounds from coal-derived production (Anderson et al. 1980).
Individual xylene isomers are produced by extraction of mixed xylenes
(Anderson et al. 1980). In 1978, U.S. emissions of xylene isomers from
extraction production processes were estimated to have been approximately 2.7
million pounds, 6.4 million pounds, and 176,000 pounds for o-, , and m-
xylene, respectively (Anderson et al. 1980).
5.2.1 Air
About 3 million tons of total xylenes are lost annually into the global
environment (Merian 1982). Volatilization is the dominant process which
governs the environmental behavior of xylenes, so most of the xylene released
will ultimately partition into the atmosphere. The total annual xylene loss
consists of 0.5 million tons from solvent losses, 2 million tons from refinery
losses into the atmosphere during the production, transportation, and
processing of petroleum, and 0.5-1 million tons as a component of automobile
exhaust gases (Merian and Zander 1982). Evaporation of gasoline into the air
during its transportation and distribution accounts for 10,000 tons of the
total annual xylene releases. Another 50,000 tons are released from the
chemical industry (Merian and Zander 1982).
5.2.2 Water
Xylenes may be introduced into groundwater by fuel oil, gasoline, or
solvent spills, by infiltration of polluted surface waters, by leaking
underground storage tanks, or by leaching from disposed wastes (Giger and
Schaffner 1981). It is estimated that over 10,000 water-polluting spills of
oil and hazardous substances occur annually in the United States (Faust 1977).
EPA ranked xylene as 16th out of the 20 most hazardous soluble substances
based on the lowest concentration range at which a material impairs any of the
beneficial uses of water, the quantity shipped annually by each mode of
transport, and the probability of an accidental spill to surface waters (Faust
1977) . Annual losses into the sea have been estimated to account for
approximately 0.6 million tons of the total global losses into the environment
(Merian and Zander 1982).
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110
5. POTENTIAL FOR HUMAN EXPOSURE
Total xylene and the individual o-, m- , and ^-xylene isomers have been
detected primarily in finished drinking water (at both the source and the
tap), effluent from chemical plants and oil rer'neries, well water (not
specified), river water, and landfill leachate affluent (Shackelford and Keith
1976). Xylenes have been detected in petroleum refinery effluents in the
United States at concentrations of 6 ^g/L (ppb) (CEC 1976). A total xylene
concentration (concentration includes ethylbenzene) of 1.2 ppb was detected in
effluent from containment ponds in the containment area of an oil spill that
accumulated along the banks of the Atigun River, Alaska (Lysyj et al. 1980).
Treated effluents from offshore oil drilling platforms in the Gulf of Mexico
contained an average concentration of 0.3 mg/L (ppm) (concentration includes
ethylbenzene) (Lysyj et al. 1980). Final effluent from the Los Angeles County
wastewater treatment plant sampled from November 1980 to August 1981 contained
o- and jj-xylene at concentrations of 40 and 30 £ig/L, respectively (Gosset et
al. 1983).
According to EPA's Contract Laboratory Program (CLP) statistical
database (CLP 1988), total xylenes have been detected in surface water and
groundwater samples of approximately 3.9% and 11.6%, respectively, of the
2,783 hazardous waste sites that have had samples analyzed through the CLP.
The geometric mean concentrations of the positive surface water and
groundwater samples were 11.4 and 216.6 /ig/L, respectively,
5.2.3 Soil
No quantitative information was available in the literature regarding
total releases of xylenes to soil. Atmospheric xylenes may reach soils either
by wet deposition in precipitation or dry deposition of material adsorbed to
particulate matter in air. Xylenes may also reach soils from the introduction
of man-made wastes (e.g. landfills) or as a result of accidental releases
(e.g., spills).
According to EPA's CLP database (CLP 1988), total xylenes have been
detected in the soil of approximately 22.5% of the 2,783 hazardous waste sites
that have had samples analyzed through the CLP. The geometric mean
concentration of xylene in the positive soil samples was 19 MgAg (ppb) .
5.3 ENVIRONMENTAL PATE
Volatilization is the dominant transport mechanism for xylene.
Therefore, most xylene releases will ultimately partition into the atmosphere.
The major transformation process in the atmosphere is photooxidation by
hydroxyl radicals. Hydrolysis and oxidation of xylenes in the aquatic
environment are not expected to be significant. Xylenes are relatively mobile
in soil and may leach into groundwater depending upon soil conditions (e.g.,
degree of saturation, percent of organic matter). Sorption is more important
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Ill
5. POTENTIAL FOR HUMAN EXPOSURE
in soils or sediments with high organic matter contents. Once in groundwater,
xylenes are known to persist for several years despite evidence that they
biodegrade in both soil and groundwater. Bioconcentration of xylenes has been
reported but is not expected to be significant.
5.3.1 Transport and Partitioning
In a global sense, most (99.68%) of the xylenes released into the
environment will ultimately partition into the atmosphere as shown by the
applied calculations of fugacity (Jori et al. 1986). Table 5-1 shows the
calculated equilibrium distribution for releases of xylenes to the environ-
ment. As the magnitude of the Henry's Law Constant for xylenes presented in
Chapter 3 indicates, xylenes are highly volatile and are likely to partition
readily into the atmosphere from water. Because of their volatility, xylenes
are generally not persistent in surface water in high concentrations. The
half-life associated with volatilization from surface waters for o-xylene at a
depth of one meter is reported to be 5.6 hours but will vary in accordance
with turbulence and water depth (Mackay and Leinonen 1975).
When spilled on land, xylenes will volatilize or leach into the ground.
Volatilization half-lives for the three xylene isomers in soil are not
available in the literature. Using an estimated soil organic carbon partition
coefficient (Koc) of 2.40 x 102 and a dimensionless Henry's law constant (H)
of 2.12 x 10"1, the calculated air-soil partition coefficient (Kas) for total
xylene is 1,100, where Kas - Koc/H. In general, calculated Kas values of
10,000 or less correlate well with chemicals which volatilize completely from
soil in one year or less as determined by iterative modeling using a time
dependent soil volatilization model with reservoir depletion (Hwang et al.
1986). However, calculated air-soil partition coefficients for individual
soils suggest that as soil organic content increases beyond 1%, xylene
residence time in soil increases correspondingly. In soils and sediments,
xylene tends to be adsorbed to organic matter since the octanol:water
partition coefficient is about 1,100:1 (Chiou et al. 1982). A general
increasing trend for the relative retention of xylene in soil with increasing
soil organic matter has been observed by a number of investigators (Green et
al. 1981; Nathwani and Phillips 1977; Seip et al. 1986). In subsurface soils
with low organic carbon content, xylenes are more likely to infiltrate into
groundwater from soil (EPA 1985a). According to the Exposure Analysis
Modeling System (EXAMS) model of Burns et al. (1981), total steady state
xylene accumulation in bottom sediments from surface waters ranged from 4.5%
to 70% of the total xylene load from the model, depending upon the percent
organic matter present.
When xylene was spilled at an application depth of 7.2xl0"2 m or less on
loam-textured soil at moisture contents ranging from 0.15 to 0.26 kg/kg, l%-4%
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5. POTENTIAL FOR HUMAN EXPOSURE
TABLE 5-1. Characteristics of Different Environmental Compartments and
Xylene Concentrations on Emission of 100 mol
Concentration
Volume Amount
Compartment (m3) (%) (mol/m3) (ppm)
Air
1010
99.6837
0.99xl0"8
880xl0"6
Soil
9xl03
0.0089
98.88x10"®
70xl0"6
Water
7xl06
0.2656
3.79xl0"8
4xl0"6
Biomass
3.5
0,1261x10-*
360.28x10"®
382xl0"6
Suspended solids
35
0.6942x10"*
198 . 34xl0"8
140xl0~6
Sediments
2.1x10*
0.0416
198.09xl0"8
140xl0"6
Total amount
99.9999
. .
^ _
Source: Jori et al. 1986.
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5. POTENTIAL FOR HUMAN EXPOSURE
volatilized, 0.5X-35X leached, 50%-85% degraded, and 6%-12% remained after
about 80 days in the soil (Aurelius and Brown 1987). Most of the observed
volatilization occurred immediately after application. The fractions of
applied xylene that were retained, volatilized, or degraded were greatest in
the driest soil. Increased sorption of xylene in dry soils results in greater
retention and allows for subsequent loss by volatilization or degradation.
Estimated degradation rates ranged from 45.7 to 137.8 g/day, with the greatest
degradation in the soil with the highest application rate and the least
degradation in the wettest soil with the lowest application rate.
Xylene moves through unsaturated soil faster than water and other polar
solvents (Amoozegar et al. 1986; Barbee and Brown 1986). Additional field
data suggesting that concentrated organics may leach 10 to 1,000 times faster
than water in unsaturated soil were provided by Griffin et al. (1984). This
increased conductivity is probably due to the formation of cracks in the soil
through which the organics move rapidly (Aurelius and Brown 1987). At high
water contents, water displaces a number of organics from mineral surfaces
(Rhue et al. 1988). Because xylene is hydrophobic, it does not easily diffuse
through water films into the soil matrix (Barbee and Brown 1986), Thus, in
the presence of a hydraulic gradient, xylene likely moves as a separate
immiscible organic phase floating on the water films in the soil pores
(Aurelius and Brown 1987). Xylene moved as a relatively uniform front through
loamy sand; however, in silt loam and clay, xylene moved preferentially
through large pores in the soil structure (Barbee and Brown 1986). Because of
its ability to desiccate clays, xylene may have further opened these natural
macropores, thereby facilitating rapid movement. Even though xylene may move
slowly through a wet clay by diffusion and convection, there is, in principle,
a danger that it will eventually cause shrinking and cracking and thereby
allow fluid transmission in bulk (Green et al 1981).
The measured log octanol-water partition coefficients (as log Kow) are
reported by Chiou et al. (1982) as 2.77, 3.15, and 3.20 for o-, m-, and
E-xylene, respectively. Although bioaccumulation has been predicted for all
isomers of xylene because of their tendency to partition into the octanol
phase of the octanol-water system (EPA 1978b), the rapid oxidation of xylenes
to their corresponding polar metabolites seems to preclude bioaccumulation in
higher animal systems (NRC 1980). Bioconcentration factors (BCFs) for o-, in->
or jj-xylene have been estimated to be 45, 105, and 95, respectively (EPA
1985a). The calculated log BCF ?ange for fish is reported to be 2.14-2.20
(HSDB 1988). Bioconcentration of xylenes has been observed in shrimp
(Pandalus platvceros) (Sanborn and Malins 1980) , manila clams (Tapes
semidecussatal (Nunes and Benville 1979) , and eels (Anguilla iaponica't (Ogata
and Miyake 1978). A bioaccumulation factor of 6 has been reported for tissue
accumulation in clams throughout an 8-day exposure to o-, e-, and ^-xylene
(Nunes and Benville 1979), and bioaccumulation factors of 21.4, 23.6, and 23.6
have been reported for eels exposed to 50 ppm of c>-, m-, or g-xylene,
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5. POTENTIAL FOR HUMAN EXPOSURE
respectively (Ogata and Miyake 1978). Tissue accumulation reached a steady
state after 10 days.
5.3.2 Transformation and Degradation
Xylenes undergo photooxidation and biodegradation as their main
environmental transformation reactions. Phototransformation in the atmosphere
is believed to be the most quantitatively important transformation process for
xylene in terms of the percentage of substance transformed (an estimated
99.96%) (Jori et al. 1986). The remainder of the total xylene transformed is
primarily photooxidized in soils or biodegraded in groundwater and sediments
(Jori et al. 1986). Hydrolysis and oxidation are not significant
transformation processes for xylene in the aquatic environment.
5.3.2.1 Air
Xylenes are transformed in the atmosphere by photooxidation. Direct
photolysis is not expected because these compounds do not significantly absorb
light at wavelengths greater than 290 nm (Jori et al. 1986). Based on an
estimated rate constant of 0.0287 hr"1 (Jori et al. 1986), the half-life for
the photooxidation of xylene in the atmosphere is estimated to be 24 1 hour
The transformation of xylene by reaction with hydroxyl radicals prevails over
that of reaction with ozone or peroxy radical and is likely to be the only
significant atmospheric removal process for xylene (Atkinson et al 1982- Fox
et al. 1984; Mill 1980; Roberts et al. 1984). Reported half-lives for the
oxidation of o-, B-, and E-xylene by hydroxyl radicals range from 0 4 to
1.0 day (ECETOC 1986; Mill 1980). The reported half lives for the reaction
with ozone are much greater, ranging from 5,000 to 6,200 days (ECETOC 1986)
The products of photoreaction with hydroxyl radicals are ultimately degraded
to carbon dioxide and water after absorption in the hydrosphere (Guisti et al
1974).
5.3.2.2 Water
Oxidation reactions are not expected to be significant transformation
processes for xylene in aquatic systems (Mill 1980). In addition, xylenes are
reported to be resistant to hydrolysis (HSDB 1988). Biodegradation may be the
only significant transformation process for xylene in water, but it appears to
vary according to the source of the microbial population and whether or not
the microbial population was conditioned to utlize xylene by pre-exposure to
the chemical (acclimation) (Bridie et al. 1979). Acclimation increased
degradation in a filtered sewage seed to 57% and 74% from 52% and 44% of the
theoretical 5-day BOD value for o- and ^-xylene, respectively (Bridie et al.
1979). A concentration of 500 rag/L of o-, m-, or E-xylene was toxic to
unacclimatized activated sludge microorganisms during the first 24 hours of
aeration (Marion and Malaney 1964). In other studies, m-xylene was found to
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115
5. POTENTIAL FOR HUMAN EXPOSURE
be toxic to microorganisms, yielding only about 10% of the theoretical
Biological Oxygen Demand (BOD) after 8 days, while o-Xylene and ^-xylene were
more degradable, varying between 63% and 26% of the theoretical BOD (Malaney
1960; Malaney and McKinney 1966; Marion and Malaney 1964). The relatively
high concentrations of xylene used in some of these studies may account for
the low degradation rates as a result of toxicity to test microorganisms (EPA
1985a).
Although xylenes have been observed to completely degrade in groundwater
in one study (Kappeler and Wuhrmann 1978a), forming methylbenzyl alcohol
intermediates, xylenes appear to be only poorly to moderately biodegraded in
most aquatic systems. The estimated half-life for biodegradation of xylenes
in water (247,5 hr) (Jori et al. 1986) is considerably greater than most of
the half-lives predicted for volatilization of xylene from water (5.6 hr-264
hr). Xylene concentrations detected in tap water during several monitoring
studies were not significantly different than those at the source (Keith et
al. 1976; Otson et al. 1982a; Saunders et al. 1975; Williams et al. 1982),
which supports the conclusion that biodegradation of xylenes in water is
limited and that little or no oxidation or hydrolysis occurs. In addition,
xylenes are known to persist for many years in groundwater at least at sites
where the initial xylene concentration is quite high (HSDB 1988). In a field
study following an oil spill from the Trans-Alaskan Pipeline in the Atigun
Pass, Alaska on June 10, 1979, xylenes were not detected in the 40 km long
watershed of the containment area 18 days after the spill. This suggested
xylene persistence in the groundwater of the containment area as opposed to
movement in the groundwater to the watershed area (Lysyj 1980).
5.3.2.3 Soil
In surface soils, photo-induced oxidation is likely to be a significant
transformation process for xylenes. Based on an estimated rate constant of
0.0287 hr"1 (Jori et al, 1986), the half-life for the photooxidation of xylene
in soils is estimated to be 24.1 hr. No other quantitative information was
found in the available literature regarding photooxidation of xylenes in
surface soils.
Biodegradation is considered to be the only significant transformation
mechanism for xylene in sub-surface soil but is likely to be a slow process
based on its rate of degradation in other media (EPA 1984, 1985a).
Biodegradation half-lives for xylene in soil were not found in the available
literature; however, numerous bacteria (including several strains of
fseudomonas. Flavobacterium. and Norcardia) capable of utilizing p- and
Sa-xylene as a carbon source in the growth medium have been isolated from soils
(Davis et al. 1968; Gibson et al. 1974). According to several degradative
pathways that have been proposed, both s- and £- isomers are oxidized to their
respective intermediate products, which in turn undergo aromatic ring cleavage
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5. POTENTIAL FOR HUMAN EXPOSURE
(Davis et al. 1968; Davey and Gibson 1974; Gibson et al. 1974; Omori and
Yamada 1970). Since many of the decomposition products of microbial
degradation of xylene are hydrophilic (e.g., xylenols, benzoic acids, etc.),
they are easily subject to further microbial biodegradation (Herian and Zander
1982). The importance of the methyl group position to breakdown of xylene
isomers is indicated by the fact that ^-xylene grown cultures of Pseudomonas
were capable of oxidizing both m-xylene and toluene, but neither £- nor
m-xylene grown cultures were capable of oxidizing o-xylene (Davis et al.
1968).
Based on an estimated rate constant of 0.0028 hr"1 (Jori et al. 1986),
the half-life for the biodegradation of xylene in sediments is estimated to be
247.5 hr. Quantitative measurements of anaerobic breakdown of xylene in
sediments were not found in the available literature. However, field evidence
of xylene transformation during transport in anoxic groundwater at a landfill
in North Bay, Ontario, suggests that anaerobic transformation of xylene likely
occurs in landfills and their leachate plumes (Barker 1987).
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
As a result of its large production and widespread use as a solvent,
xylene is ubiquitously distributed in the environment. The compound has been
detected in indoor and outdoor air, surface water, groundwater, drinking
water, soils, and rainwater.
5.4.1 Air
Ambient air concentrations of xylenes in industrial and urban areas of
the United States range from 0.003 to 0.38 mg/m3 (Merian and Zander 1982).
Since one of the largest sources of xylene release into the atmosphere comes
from auto emissions, atmospheric concentrations are related to urbanization.
Median o-xylene concentrations calculated from a compilation of the available
published and unpublished atmospheric data on organic chemicals were 0.41
/ig/m3 in rural/remote areas (114 observations), 5.2 fig/m3 in urban/suburb an
areas (1,885 observations), and 3.5 jug/m3 in source dominated areas (183
observations) (Brodzinsky and Singh 1983). The median concentrations for the
combined isomers s- and ^-xylene were 0.38 Mg/m3 in rural/remote areas (115
observations), 12 Mg/m3 in urban/suburban areas (1,911 observations), and
7.4 /ig/m3 in source dominated areas (186 observations) (Brodzinsky and Singh
1983). The maximum concentrations reported for o-xylene and combined m- and
E-xylene were 38,000 and 43,000 Mg/m3, respectively (Oldham et al. 1979).
Both values were measured at a source dominated location.
Recent studies have revealed that xylene is also a common contaminant of
indoor air. Concentrations of m- and g-xylene measured in homes at 15
locations in the United States ranged from 10 to 47 Mg/m3 (Seifert and Abraham
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5. POTENTIAL FOR HUMAN EXPOSURE
1982). Similar results were reported during a 1981 study of the correlation
between breath concentration and personal and outdoor air concentrations of
350 New Jersey residents (Wallace et al. 1986). The weighted median indoor
air concentrations of o-xylene and the combined m- and i>-xylene isomers were
4.9 and 14 ng/m3, respectively. Breath concentrations showed significant
correlation with personal air concentrations but only weak correlation with
outdoor air concentrations. Concentrations in indoor air were usually higher
than in outdoor air, indicating that the source of the xylenes was building
materials or household products (e.g., cleaning agents) (Wallace et al. 1986,
1987a).
5.4.2 Water
Limited monitoring data are available on ambient concentration of
xylenes in surface waters. In view of the rapid volatilization of xylenes,
their presence in surface waters is unlikely to be significant. Surface
waters generally contain average xylene concentrations of <1 ppb total xylenes
except in areas where there are fuel processing activities, such as petroleum
refining (ECETOC 1986; Otson et al. 1982b; Sauer et al. 1978). Typical
surface water concentrations range from not detected to 2 ng/L (ppb) (Otson et
al. 1982b; Sauer et al. 1978).
Data on the occurrence of xylene in public drinking water supplies are
available from several federal, regional, and state surveys (EPA 1985a). In
most cases, less than 6% of the groundwater and surface water systems sampled
contained detectable levels of xylenes (EPA 1983b, 1985a; NJDEP 1984, 1985).
Typical xylene concentrations detected (all isomers) ranged from 0.2 to
9.9 ng/h (ppb) with mean concentrations of less than 2 fig/L (ppb) (EPA 1978a,
1985a; Keith et al. 1976; NJDEP 1984, 1985; Williams et al. 1982). However,
m-xylene was detected in public drinking water in Rhode Island with
concentrations ranging from 1 ppb to 30 ppb (RIDH 1989). Xylene was detected
in private well water in Rhode Island with concentrations ranging from 1 ppb
to 6,000 ppb (RIDH 1989).
5.4.3 Soil
Although several investigators (Aurelius and Brown 1987; Barbee and
Brown 1986; Griffin et al. 1984) refer to leaching of xylene from waste
disposal sites as a source of xylene levels in groundwater samples, very
little data are available on actual measurements of xylene in soil. Diluted
aliquots were made from samples (e.g., used oil, spent solvents, paint wastes,
and polymer formulations) collected under contract to the EPA Contract
Laboratory Program (CLP). These came from a variety of waste materials
including contaminated soils at 221 hazardous waste disposal sites. In these
samples, ^-xylene was detected 223 times out of 600 analyses (37.2% frequency
of detection) at a mean concentration of 8,388 ppm (mg/L) (Blackman et al.
-------
118
5. POTENTIAL FOR HUMAN EXPOSURE
1984) . o-Xylene was second among the most prevalent organic chemicals and. had
the third highest reported maximum concentration (790,000 mg/L) (Blackman et
al. 1984).
No other quantitative data on the presence of xylenes in soil were found
in the available literature. However, in view of the rapid volatilization of
xylenes, their presence in surface soils is unlikely to be significant. In
addition, much of the xylene that is present in sub-surface soils probably
becomes degraded by microorganisms or leached in groundwater.
5.4.4 Other Media
Xylene has been detected in both cigarette smoke and consumer products.
The gas phase delivery of ^-xylene in ultra-low tar delivery cigarette smoke
ranges from <0.01 to 8 /ig/cigarette, while the ranges for m- and o-xylene,
respectively, are from <0.01 to 20 jug/cigarette and from <0.005 to
10 jig/cigarette (Higgins et al. 1983). The 1,095 household products surveyed
by the Consumer Product Safety Commission (Fishbein 1985) contained an average
of 9.5% mixed xylenes. The largest number of mixed xylene-containing products
were found in household aerosols and paints, varnishes, shellac, and rust
preventatives.
Xylene has also been detected in distillates of rainbow trout, and carp
tissue samples from three rivers not known to be contaminated (Hiatt 1983).
The estimated tissue concentrations of m- and £"xylene in rainbow trout and
carp were 0.05 and 0.12 mg/kg, respectively (Hiatt 1983).
5.5 GENERAL POPULATION ANE 2CUPATI0NAL EXPOSURE
The principal population at risk of significant xylene exposure is the
occupational work force. This group can be exposed to mixed xylenes during
their production as well as their end use as an industrial solvent.
Occupational exposures result from inhalation or dermal exposure and are
usually associated with process, storage, or fugitive emissions at chemical,
paint, and plastics plants (Fishbein 1985). Average daily intake from
individual occupational exposure sources has not been estimated.
The National Occupational Hazard Survey (NOHS) conducted by the National
Institute for Occupational Safety and Health (NIOSH), ranked xylenes 13th in
concentration in workplace air out of approximately 7,000 chemicals (NIOSH
1976). The NOHS estimated that 1,016,020 workers in 99,920 U.S. plant sites
were potentially exposed to total xylenes in the workplace in 1970 (NIOSH
1976). An estimated 5,778 workers in 179 plants, 4,621 workers in 96 plants,
and 1,912 workers in 62 plants were potentially exposed to o-, nt-, and
2-xylene, respectively. These estimates were derived from observations of the
actual use of total xylenes and the individual isomers and the use of trade
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119
5. POTENTIAL FOR HUMAN EXPOSURE
name products known to contain xylenes (see Table 5-2 for composition
breakdown of the estimates). The largest numbers of workers exposed to total
xylenes were employed by automotive dealers, service stations, or special
trade contractors and in the chemical and allied products, transportation
equipment, machinery (except electrical), fabricated metal products, and
electrical equipment and supplies industries. In addition, the largest
numbers of workers exposed to single xylene isomers were employed in the
rubber and plastics products, printing and publishing, petroleum and coal
products, chemicals and allied products, and fabricated metal products
industries.
Preliminary data from a second workplace survey, the National
Occupational Exposure Survey (NOES), conducted by NIOSH from 1980 to 1983,
indicated that 1,106,789 workers, including 211,806 women, in 74,063 plants
were potentially exposed to total xylenes in the workplace in 1980 (NIOSH
1984). An estimated 5,596 workers (including 1,314 women) in 331 plants,
16,863 workers (including 1,194 women) in 1,610 plants, and 1,160 workers
(including 545 women) in 178 plants were potentially exposed to o-, m-, and
E-xylene, respectively. The largest numbers of workers exposed to total
xylenes were employed in the machinery (except electrical), special trade
contractors, fabricated metal products, and health services industries and as
assemblers, janitors, and cleaners, painting and paint-spraying machine
operators, and automobile mechanics. The largest numbers of workers exposed
to o-xylene were employed in the chemical and allied products industry and as
machine operators (not specified), chemical technicians, production
inspectors, checkers, and examiners. The largest numbers of workers exposed
to m-xylene were employed in the electric, gas, and sanitary services and
business services industries and as electrical power installers and repairers,
supervisors, plumbers, pipe fitters, and steam fitters, order clerks, and
chemists (except biochemists). The largest numbers of exposed workers exposed
to E"xylene were employed in the health services industries and as clinical
laboratory technologists and technicians. These estimates were derived from
observations of the actual use of xylenes and the individual isomers and the
use of trade name products known to contain xylenes (see Table 5-2 for
percentage breakdown).
Neither the NOHS nor the NOES databases contain information on the
frequency, level, or duration of exposure of workers to any of the chemicals
listed therein. The surveys only provide estimates of workers potentially
exposed to the chemicals.
Members of the general population are exposed to low levels of xylenes
primarily by breathing ambient air, particularly in areas with heavy traffic,
near filling stations, near industrial sources such as refineries, or where
xylenes are used as solvents. Exposure may also arise from ingestion of
contaminated drinking water. Common activities identified with increased
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120
5. POTENTIAL FOR HUMAN EXPOSURE
TABLE 5-2. Percentage Breakdown of NIOSH Occupational Exposure Estimates from
the NOHS and NOES Databases*
NOHS NOES
Actualb
Trade Name0
Actual
Trade Name
Chemical
(%)
(%)
(%)
(%)
o-Xylene
14
86
96
4
Eg-Xylene
100
23
77
E-Xylene
41
59
75
25
Total Xylene
9d
35d
19
81
aSource: NIOSH 1976, 1984.
"Actual observations are surveyor observations in which the surveyor observed
the use of the specific agent,
cTrade name observations are surveyor observations in which the
surveyor observed the use of a trade name product known to contain the
specific agent.
"Remainder is composed of generic observations (i.e., observations of the use
of generic products suspected of containing xylene), which are not Included
in the total exposure estimates provided.
NIOSH - National Institute for Occupational Safety and Health; NOES - National
Occupational Hazard Survery; NOHS - National Occupational Exposure Survey
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121
5. POTENTIAL FOR HUMAN EXPOSURE
potential exposure include pumping gasoline, visiting service stations,
traveling in a car, painting, scale model building, pesticide use, and smoking
(Wallace et al. 1986; 1987a). The level of exposure associated with living
near hazardous waste sites has not been assessed, but it is expected to be
elevated above ambient background levels determined in areas not near
hazardous waste sites.
General population exposure to xylene can also occur through dermal
contact with the many consumer products containing xylene, including cleaning
solvents, insecticides, lacquers, paint thinners and removers, and pesticides
(Gleason et al. 1969; Fishbein 1985; EPA 1985a). Dermal absorption is
reported to be minor following exposure to xylene vapor but may be significant
following contact with the liquid (EPA 1985a). The percutaneous absorption
rate of m-xylene in humans was approximately 2 ^g/cra2/niin through the skin of
the hands (Engstrom et al. 1977).
Assuming a daily intake of 2 liters drinking water and that total xylene
(sum of m-, o-, and ^-xylene isomer concentrations) is present at the highest
concentration reported, the adult maximum daily intake for total xylene
through consumption of drinking water is estimated to be 2,760 jig/day or
39.4 /xg/kg/day (EPA 1985a). Assuming a typical xylene concentration in
drinking water of 0-1 ppb, the average daily intake of xylenes from drinking
water is estimated to be 2 pg or less than 0,03 ^g/kg/day (HSDB 1988).
Based on the estimates of Brodzinsky and Singh (1983) of median
atmospheric concentrations of xylene in rural, urban, and source dominated
areas (see Section 5.4.1) and assuming inhalation of 23 m3/d by a 70-kg adult,
the daily o-xylene intake from air for adults exposed to the median levels in
rural, urban, and source dominated areas would be 0.1, 1.7, and 1.2 /ig/kg/day,
respectively. The median 3- and E-xylene intake would be 0.1, 3.9, and
2.4 /ig/kg/day, respectively (EPA 1985a). Assuming a typical ambient air
xylene concentration of 4.0 ppb, the average daily intake of xylenes from air
is estimated to be 353 fig (HSDB 1988) .
Exposure to xylenes in indoor environments can constitute a significant
source of human exposure (Krotoszynski et al. 1979; Seifert and Abraham 1983;
Wallace et al. 1986, 1987b). Xylene isomers were consistently present in
personal air (indoor air) and breath samples at higher concentrations than in
outdoor samples in recent surveys of approximately 400 residents of New
Jersey, North Carolina, and North Dakota. They appeared in exhaled breath at
approximately 50% of their average concentration in the air inhaled during the
previous 12 hours (Wallace et al. 1986, 1987a). The major reason for the high
levels of personal exposures seen in these studies appears to be elevated
indoor air levels at work and at home caused by a variety of sources,
including consumer products, building materials, and personal activities such
as smoking (Wallace et al. 1986, 1987a). In most cases, exposures to indoor
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122
5. POTENTIAL FOR HUMAN EXPOSURE
air levels at work and at home were greater than exposures to outdoor air
levels found near traditional "major" point sources (e.g., chemical plants,
petroleum refineries, petrochemical plants) and area sources (e.g., dry
cleaners and service stations) (Wallace et al. 1987a).
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
Workers in certain occupational groups appear to have the greatest
potential for exposure to high concentrations of xylenes. Based on the
available case reports of xylene toxicity in humans, painters (or paint
industry workers) and laboratory workers appear to be most frequently affected
(EPA 1985a). In general, workers involved in the distillation and
purification of xylene or employed in industries using xylene as a raw
material (e.g., gasoline blending) may be at higher risk of exposure (EPA
1985a). The use of xylene in improperly ventilated areas is often the cause
for toxic levels of exposure. Significant relationships with increased
exposures or breath concentrations have been observed for wood processing
plant workers, gas station employees, metal workers, and furniture
refinishers. Among the general population, individuals who smoke or routinely
come into contact with solvent products appear to be potentially exposed to
the highest concentrations of xylenes. Populations living near chemical waste
sites where xylene is improperly stored are also likely to be at risk of
increased exposure.
5.7 ADEQUACY OF THE DATABASE
Section 104(i) 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 xylene 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 xylene.
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 xylene have been well studied, and reliable values for key parameters are
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123
5. POTENTIAL FOR HUMAN EXPOSURE
available for use in environmental fate and transport models. On this basis,
further studies of the physical-chemical properties of xylene are not
essential at the present time.
Production, Use, ReLease, and Disposal. Potential for human exposure to
xylenes is expected to be quite high based on the high volume of production
and the widespread use of xylenes in the home and industry.
Recent estimates of production capacity of xylenes indicate that over
1 billion gallons of mixed xylenes and over 50 billion gallons of xylene
isomers may be produced in the United States each year. Information on the
actual production levels, however, is limited. More information on current
production levels as well as past and projected production volumes would be
helpful in estimating potential human exposure.
Xylenes are widely used in industry as solvents and as precursors of
other products (i.e., polyester). Exposure of individuals may occur as a
result of releases to the environment (approximately 3 million tons per year)
and as a result of the presence of xylenes in gasoline, paint products,
insecticides and cigarette smoke. No information was obtained on the
occurrence of xylenes in food. Consequently, dietary intake and its
contribution to total exposure could not be evaluated. This information would
be helpful in estimating potential human exposure.
Because of their widespread use and release into the environment,
xylenes have been distributed to most environmental media. They have been
detected in air, rainwater, soil, surface water and sediments, drinking water,
and aquatic organisms. Reports of levels in the various environmental media
are dated within the last 10 years, with some as current as 1989. Information
on the most recent distribution of xylenes would be helpful in estimating
exposure.
According to the Emergency Planning and Community Right-to-Know Act of
1986 (EPCRTKA), (Pub. L. 99-499, Title III, §313), industries are required to
submit release information to the EPA. The Toxics Release Inventory (TRI),
which contains release information for 1987, became available in May of 1989.
This database will be updated yearly and should provide a more reliable
estimate of industrial production and emission.
Incineration is the primary method for disposal of xylenes, although
information on the disposal methods is not detailed. Information on the
amount of xylenes disposed of by incineration as well as the amount of xylene
disposed of or abandoned at hazardous waste sites is important for estimating
the potential human exposure. Criteria for the disposal of xylenes are
currently subject to frequent revision.
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5. POTENTIAL FOR HUMAN EXPOSURE
Environmental Fate. The information available regarding transport and
partitioning of xylene among environmental compartments indicates that
volatilization is the most important fate process. Xylene released to surface
water will primarily volatilize. Xylene will also sorb to soils and sediments
and leach into groundwater; however, there is considerable variation and
uncertainty in estimates of persistence in these media. Photooxidation
appears to be the most important transformation process in the atmosphere and
in surface soils. Biodegradation is likely to be the only significant
degradation process for xylene in subsurface soils and aquatic systems.
Additional data on the partitioning of xylene released to soil and groundwater
and on the rates of biotransformation in soils, sediments, and groundwater
would be useful to further define potential pathways of human exposure and to
estimate ambient concentrations in environmental media.
Bioavailability from Environmental Media. Xylenes are absorbed during
inhalation, oral, and dermal contact. Approximately 50% of the xylene that is
inhaled is absorbed into the body. However, limited information was found in
the available literature regarding the uptake of xylene components by living
organisms from contaminated media such as soil and sediments to which the
xylenes are sorbed or from contaminated surface waters. Information on uptake
would be helpful in estimating human exposure from contaminated environmental
media.
Food Chain Bioaccuroulation. Xylenes are bioconcentrated in aquatic
organisms to variable extents. The degree of concentration is believed to be
limited by the rapid metabolism and excretion of xylenes from some aquatic
species. However, additional data on the bioconcentration of xylene by
aquatic organisms from contaminated surface waters and sediments would be
useful. No information was found in the available literature regarding the
bioconcentration of xylenes in plants or biomagnification of xylene among food
chain trophic levels. Although bioaccumulation has been predicted for all
isomers of xylene because of their tendency to partition into the octanol
phase of the octanol-water system, the rapid oxidation of xylenes during
metabolism seems to preclude bioaccumulation in higher animal systems. Thus,
biomagnification is not expected to be important for xylenes. However, data
on the bioaccumulation of xylene in commercially important fish and shellfish
would be useful, since consumption of contaminated fish and shellfish may be a
potential source of human exposure.
Exposure Levels in Environmental Media. The presence of xylenes in the
environment has been assessed mainly together with other volatile organic
compounds and characteristic components of oil. There is thus little data
available on environmental levels of total xylenes, and data on the individual
isomers are even scarcer. In particular, very few estimates of the levels of
xylenes in soils and surface waters in the vicinity of industrial sites (such
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125
5. POTENTIAL FOR HUMAN EXPOSURE
as fuel processing plants) were found in the available literature. More
monitoring data are needed to better characterize ambient concentrations of
xylene in soils, surface water, and groundwater, particularly in the vicinity
of hazardous waste sites and petroleum refineries. These data would be useful
to estimate the exposure of populations coming into contact with xylene
through inhalation of contaminated air or consumption of contaminated surface
water or groundwater.
The available data allow characterization of human exposure to xyle s
from most exposure pathways. Estimates of human intake of xylenes from
contaminated air and drinking water have been made based on background levels
that have been recorded in the environment. In addition, estimates exist for
the absorption from dermal contact that results from immersion in xylenes.
More information of the levels of xylenes in contaminated media in the
vicinity of hazardous waste sites is necessary before estimates of human
intake from these sites may be calculated.
Exposure Levels in Humans. Xylenes have been detected in human blood,
urine, and exhaled breath. However, exposure associated with living or
working near hazardous waste sites and refineries has not been assessed. The
most important human exposure sources, inhalation of workplace and ambient
air, are reasonably well understood. Additional monitoring programs involving
analysis of human breath or urine would be useful in assessing the magnitude
of environmental exposures and in estimating the average daily dose associated
with various sources, particularly for populations exposed in the vicinity of
hazardous waste sites.
Exposure Registries. Several sectors of the occupational work force
have the greatest levels of exposure to xylenes. Total xylene exposure has
been found to be greatest among those employed in the machinery (except
electrical), special trade contracting, fabricated metal products, and health
services industries and as assemblers, janitors and cleaners, painting and
paint-spraying machine operators, and automobile mechanics. Exposure to
o-xylene is greatest among those employed in the chemical and allied products
industry and as machine operators; chemical technicians; and production
inspectors, checkers, and examiners. Exposure to ai-xylene is greatest among
those employed in the electrical, gas, and sanitary services and as electrical
power installers, repairers, and supervisors; plumbers; pipe fitters; steam
fitters; order clerks; and chemists. Exposure to ^-xylene is greatest among
those employed in the health services industries and as clinical laboratory
technologists and technicians.
No exposure registries for xylene 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
-------
126
5. POTENTIAL FOR HUMAN EXPOSURE
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
No on-going studies on the environmental fate of xylene or of
occupational or general population exposures to xylene were located in the
available literature. However, remedial investigations and feasibility
studies on the 236 NPL sites which are known to be contaminated with total
xylene should add to the current knowledge regarding the transport and
transformation of the compound in the environment. In addition, environmental
monitoring and human exposure assessments conducted in conjunction with these
should add to the current database on environmental levels of xylene in media
and humans.
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 and Injury Control, Centers for Disease
Control, will be analyzing human blood samples for total xylenes and other
volatile organic compounds. These data will give an indication of the
frequency of occurrence and background levels of these compounds in the
general population.
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127
6. ANALYTICAL METHODS
The purpose of this chapter is to describe briefly the analytical
methods that are available for detecting and/or measuring and monitoring
xylene 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 xylene concentrations. Rather, the intention is to identify well
established or common analytic techniques that are used as the standard
methods of analysis. Some of the reported methods in this section are
currently used by EPA or by State environmental agencies to detect xylene in
environmental samples. On-going research efforts to develop new or improved
analytical methods have also been identified.
The analytical methods used to quantify xylene in biological and
environmental samples are summarized below. Table 6-1 lists the applicable
analytical methods used for determining xylene in biological fluids and
tissues, and Table 6-2 lists the methods used for determining xylene in
environmental samples.
6.1 BIOLOGICAL MATERIALS
Extensive commercial, industrial, and domestic use of volatile organic
chemicals such as xylene virtually assures that the general population will be
exposed to some extent to this class of chemicals. The determination of trace
amounts of xylene in biological tissues and fluids has been restricted to only
a limited number of analytical methods. These include gas chromatography
coupled with mass spectrometry (GC/MS), gas chromatography coupled with
hydrogen flame ionization detection (GC/FID), and high-performance liquid
chromatography (HPLC).
Recent work conducted by Cramer et al. (1988) indicates that gi-xylene
can be detected at parts-per-trillion (ppt) levels in whole human blood using
a GC/MS technique. Antifoam agents do not have to be used in this technique;
however, the use in this method of a dynamic headspace purge at room
temperature reduces the absolute recoveries of the late eluting compounds. An
advantage of this GC/MS technique is that it can be used in conjunction with
limited mass scanning (LMS) to obtain better sensitivity of target compounds
(such as National Priority List Pollutants) at ppt levels. LMS is a technique
which involves scanning for a smaller number of ions than in the full-scan
GC/MS method. Some analytes (including ^-xylene) can be detected by LMS but
not by full-scan GC/MS because of the inherent differences in sensitivity
between the two methods (Cramer et al. 1988).
The use of GC/FID followed by a combination of packed and open tubular
capillary GC and GC/MS to detect and quantify the isomers of xylene in human
-------
TABLE 6-1. Analytical Methods for Dstemining Xylene in Biological Materials
Sample
Detection
Sample Matrix Sample Preparation Analytical Method Limit Accuracy Reference
Hunan blood Purge-and-trap sample on Tenax TA trap
Purge-and-trap sample on sorbent
Tissues and Saturate sample with sodium chloride and
body fluids seal in a vial; inject into GC
Urine
Acidify sample and extract with ethyl
acetate and methylating solution
Adjust pH of sample to 2.0; extract with
ethylacetate
Acidify sample with RCL and extract with
ethylacetate; add MeOH to ethylacetate
extract; methylate extract with diazome-
thane in diethyl ether solution
Acidify sample with HCL; extract with
n-butyl chloride: isopropanol (9:1)
Adjust pfl of sample to 2.0; extract with
methyl ethyl ketone; add phenacyl bromide
solution to extract and heat
GC/MS
GC/MS
GC/FID and GC/MS
GC/FID
GC/FID
GC/FID
HPLC
HPLC
m-xylene
1 ng/ral
5.2 ng/ml
m, j-
xylene
0.05
mg/100 g
o-xylene
0.01
mg/100 g
5 mg/L
No data
No data
m-MHA 0.1
mg/ml
m-MHA
0.02
Mg/sample
e-mha
0.02
fig/sample
No data
No data
No data
o-MHA 81.5%
recovery
m-MHA B2.2Z
recovery
p-MHA 8<« .81
recovery
m-MHA 98X
recovery
m-MHA 88.71-
95Z recovery
E-mha 79.3-
821 recovery
No data
No data
No data
Cramer et al. 1988
Antoine et al 198b
Bellanca et al. 1982
Caperos and
Fernandez 197 7
H
t—I
O
>
r
s
m
3C
Kngstrom et al. 1976 (31
Morin et al. 19S1
Po&gi et al. 1982
Sugihara and Ogata
1978
1-0
00
-------
TABLE 6-1 (Continued)
Sample
Detection
SaapLe Matrix Sample Preparation Analytical Method Limit Accuracy Reference
Whole body
(ale*)
Add sample specimen to MeOH; centrifuge
HPLC
o-MHA
o-MHA 1021
Ogata and Ta&uclu
6 mg/L
recovery
1987
m-MHA
m-MHA 102.-41
8 tng/L
recovery
e-mha
e-mha 99.51
8 mg/L
recovery
Acidify saaple; extract with chloroform
TLC
m-MHA
m-MHA 1001
Bieniek and Wilczok
and concentrate
6 «ig/ml
recovery
1981
Kill mica and inject with aolvent saapla;
GC/FID
No data
m-xylene 861
Tsurata and Iwasaki
homogenize sample in liquid nitrogen;
recovery
1984
evaporate liquid nltrogan and extract
with carbon dlsulfida
>
r-
~<
H
i—i
o
>
r-
s
w
•-j
:c
o
o
c/5
GC/KS ¦ gaa chraaatography/aaas apectroawtry; GC/FID
chroaatography; TLC » thin layer chromatography; (OA
gaa chromatography/fla
aethylhippuric acid.
ionization detector; HPLC = high performance liquid
-------
TABLE 6-2. Analytical Methods for Detealning Xylene in Environmental Sables
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit Accuracy
Ref-erence
Air
Draw sample through copper tubing with a
diaphragm pump
GC/PID
0 .3 p pb
No data
Hester and Meyer
1979
Absorption on Tenax GC air sampler GC/ftS
Collect vulcanized air on activated char- GC/FID
coal; desorb with carbon disulfide
No data
0.1-1.5
ppm
No data
No data
Hampton et al. 1982
Rappaport and Fraser
1977
Pump air sample through charcoal tubes;
extract charcoal with carbon disulfide
GC/FID
o-xylene
<0.05 ppm
o-xylene 511-
86i recovery
Otson et al. 1963
g-xylene'
<0.05 ppm
j>-xylene 511-
B6I recovery
Collect sample In tedlar bags by means of
an automated sequential large air sampler
Collect air on activated charcoal; desorb
with carbon disulfide; shake with 751
h2so4
Collect saaqpla in pressurized stainless
steel cannister
GC/FID
GC/FID
LC/UV
GC-FID/PID
No data
1 ns/tiL
No data
o-xylene
1.3
pg/s ample
Ko data
92S-100I re-
covery
921-1041 re-
c overy
No data
Loniieman et al. 197 4
>
Esposito and Jacobs
1977 o
>
r1
s
ca
'—j
Nutmagul et al. 1983 q
O
C/5
U)
o
Fish
Collect a ample in a pressurized camnister
Freeze sample; homogenize in liquid ni-
trogen; Vacuum distillation
GC-FIE/ECD and GC/HS ppm No data
GC/HS equipped with No data No data
fused-silica capillary
column
Pleil et al 1968
Hiatt 1983
Sediment Shake sample with water; purge-and-trap
(clay) on porapak N cartridges; elute with MeOH
GC-ECD/PID
^ ng/s
j>-xylene 70Z-
77X recovery
Amin and Narang 1985
o-xylene 681-
791 recovery
GC/ECD
1 ng/g
No data
-------
TABLE 6-2 (Continued)
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit
Accuracy
Reference
Drinking
water
Haste
Purge-and-trap on sorbent
Extract sample in hexane
GC/FID
GC/FID
Purge saaple with a counter-current flow
of heliuB gas
Purge-and-trap on sorbent
Mo data
GC/MS
GC/PID
GC/PID and GC/MS
Extract waste with hexane
Add saaple to a aaall volme of ethanol
and dilute with water or raw wastewater;
adjust tbe pH; extract with Freon-TF
GC/MS
GC/FID
o-xylene
<1 (rg/L
m-xylene
<1 Mg/L
oxylene
2 (ig/L
m-xylene
2 Mg/L
g-xylene
2 Mg/L
<5 ppb
0.05 M6/L
m-xylene
0.2-2.0
ppb
o-xylene
0.2-2.0
ppb
£-0.2-3.0
ppb
No data
Ho data
o-xylene 7 51
recovery
m-xylene 871
recovery
o-xylene 802
961 recovery
m-xylene 801-
831 recovery
£-xylene 78X-
851 recovery
No data
No data
No data
No data
No data
Otson and Williams
1982
Otson and Williams
1981
Saunders et al, 1975
EPA 1981a
NJDEP 1985 (EPA
method 602/503.1 and
625)
>
H
>—i
O
>
r-
X
m
H
x
o
o
C/J
Austern et al. 1975
Austern et al. 1975
GC/MS " gas chroaatograpfay/Bass spectrometry; GC/FID " gas chromatography/flame ionization detector; GC/PID - gas chromatography/photoioniza-
tion detector; LC/UV " liquid chromatography/ultraviolet spectrometry, and GC/ECD = gas chromatography/electron capture detector.
-------
132
6, analytical methods
tissues and fluids has been reported in the literature. Brain, liver, lung,
kidney, and blood samples of individuals who died following occupational
exposure to several organic solvents were analyzed using a. combination of
capillary columns (Bellanca et al. 1982). The sensitivity and resolution of
the Isomers of xylene were increased and detection limits of 0.05 mg, 0,05 mg,
and 0.01 mg per 100 gram of sample were obtained for m-, o-, or E-Xylen®>
respectively (Bellanca et al. 1982). Despite this increased resolving power,
adequate separation of m-xylene and ^-xylene was unattainable.
In addition to direct measurement of xylene in biological tissues and
fluids, it is also possible to determine the concentration of metabolites in
biological fluids. A simple, sensitive and specific automated HPLC technique
was developed for direct and simultaneous quantification of o-, m-, and
£-methylhippuric acids, the metabolites of o-, m-, and g.-xylene, respectively
(Ogata and Taguchi 1987, Sugihara and Ogata 1978). The authors noted that a
possible disadvantage of the HPLC technique is that at low concentrations
(less than 0.6 mg/liter) in urine, these methylhippuric acids may not be
distinguishable from other compounds closely resembling these acids.
Other techniques that have been successful in quantitatively determining
urinary concentrations of metabolites of xylene include GC/FID, GC/MS, and
thin layer chromatography (TLC).
GC/FID and GC/MS offer the possibility of excellent analytical
sensitivity and specificity for urinary metabolites of xylene. However, all
GC analytical methods require the urinary metabolites to be chemically
transformed into methyl esters or trimethyl silyl derivatives. This
transformation is a very critical reaction and may subsequently cause low
reproducibility (Caperos and Fernandez 1977; Engstrom et al. 1976; Morin et
al. 1981; Poggi et al. 1982).
A simple and highly reproducible TLC method has been developed for the
detection and separation of m- or 2"methylhippuric acid in the urine of
individuals exposed to a mixture of volatile organic solvents (Bieniek and
Wilczok 1981). However, the authors noted that this analytical technique is
time-consuming. Furthermore, the developing agent used in this technique
(j>-dime thy lamine benzaldehyde in acetic acid) has a disadvantage in that it is
irritating to the eyes and mucous membranes.
6.2 ENVIRONMENTAL SAMPLES
A gas chromatograph equipped with an appropriate detector is the basic
analytical method used for determining the levels of xylene in soil, water,
air, and fish. Precautions in the isolation, collection, and storage of
xylene in environmental media are necessary to prevent loss of the volatile
xylene compounds to the air.
-------
133
6. ANALYTICAL METHODS
An automated gas chroraatograph with photoionization detector (GC/PID)
has been developed by Hester and Meyer (1979) to identify gas-phase
hydrocarbons (including xylene) for complex systems such as vehicle exhaust
gas. The GC/PID method allows for measurement of sub-part-per billion level
concentrations of air contaminants and does not require trapping or freeze-
concentration of samples before analysis. These latter preconcentration steps
are usually necessary because of the limited sensitivity of flame ionization
detection (FID) techniques commonly used in the analysis of environmental
samples. A limitation of the GC/PID technique is that m- and ja-xylene isomers
are detected but not well separated. A GC/PID in tandem with a flame
ionization detector was constructed to obtain a more sensitive method to
determine xylene levels in the air (Nutmagul et al. 1983). A detection limit
of 1.3xl0"12 g of o-xylene per sample was achieved.
A purge-and-trap gas chromatographic method involving photoionization
detection has been developed by EPA to analyze volatiles in drinking water
(EPA 1981a). A confirmatory analysis by a second analytical column or by
GC/MS is advised by EPA. The purge-and-trap gas chromatographic method (EPA
method 602/503.1 and 625) can detect the isomers of xylene and has a detection
limit for o-, m-, and ^-xylene of 0.2 ppb (NJDEP 1985; Otson and Williams
1981, 1982; Saunders et al. 1975).
A gas chromatograph equipped with both electron capture and
photoionization detectors (GC-ECD/PID) has been employed to determine xylene
levels in sediment samples (Amin and Narang 1985). The authors indicated that
their method involved transfer of samples between containers and a
considerable loss of volatile compounds was obtained.
A procedure has been developed to characterize volatile xylene compounds
from fish samples by GC/MS using a fused-silica capillary column (FSCC) and
vacuum distillation (Hiatt 1983). FSCC provides a more attractive approach
than packed columns for chromatographic analysis of volatile aromatic organic
compounds. A FSCC can be heated to a higher temperature (350°C) than that
recommended for packed column, thereby improving the resolution (in ppb
levels) of compounds and reducing column retention times. A physical
limitation for compounds that can be detected, however, is that the vapor
pressure of the compound 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 xylene is available. Where adequate information is not available,
ATSDR, in conjunction with NTP, is required to assure the initiation of a
-------
134
6. ANALYTICAL METHODS
program of research designed to determine the health effects (and techniques
for developing methods to determine such health effects) of xylene.
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 Biomarkers of Exposure and Effect. The methods
for determining xylene levels in blood and tissue samples, GC/MS or GC/FID,
have sufficient sensitivity to measure xylene levels associated with
background levels of exposure as well as exposure levels at which biological
effects occur. GC/MS has been employed to detect o-xylene at ppm levels in
the blood. However, development of a GC/MS method that incorporates a less
rigorously heated purge would be useful. Heated purges currently used in
GC/MS have the disadvantage of reducing the absolute recoveries of volatile
organic solvents. Better resolution and sensitivity are achievable with the
application of a capillary GC/MS column and selection of an appropriate
detector or detector combination as an alternative to the packed column
approach currently in use. Also, there is a growing need for analytical
methods to efficiently separate and quantify trace levels of the isomers of
xylene in biological media.
Analytical methods are also available to detect and quantify the xylene
metabolites present in the urine. These methods, GC/MS, GC/FID, and HPLC,
have been well characterized with respect to their precision, accuracy,
reliability, and specificity and have sufficient sensitivity to measure xylene
metabolite levels associated with biological effects. However, these methods
may not be sensitive enough to measure metabolite levels associated with
background exposure levels.
Currently, no methods are available to quantitatively correlate
monitored levels of xylene in tissues or fluids with exposure levels or toxic
effects in humans. These methods would provide the ability to evaluate
possible health effects in humans resulting from exposure to xylene.
No specific biomarkers of effect have been clearly associated with
xylene exposure. Some biological parameters such as hepatic microsomal enzyme
activities and central nervous system activity (measured by evoked potentials
or tests of memory and reaction time) have been tentatively linked with xylene
-------
135
6. ANALYTICAL METHODS
exposure, but insufficient data exist to adequately assess the analytical
methods associated with measurement of these potential biomarkers.
Methods for Determining Parent Compounds and Degradation Products in
Environmental Media. Methods for determining xylene and its degradation
products in environmental media are necessary to identify contaminated areas
and to determine whether the levels at contaminated sites constitute a concern
for human health. Standardized methods are available to detect xylene in air,
waste water, drinking water, fish, and clay sediments. There is growing need
for simultaneously achieving lower (< ppb) detection limits, separating meta
and para isomers of xylene, and obtaining an adequate sample recovery. Such
methods would provide useful information for assessing the biological effects
of exposure to xylene and to delineate dose-response relationships. A
combination of capillary gas chromatography coupled to a multi-detector
system, nuclear magnetic resonance (NMR) spectroscopy, and infra-red (IR)
spectroscopy, would be useful for the accurate identification and measurement
of the isomers of xylene in complex environmental systems.
6.3.2 On-going Studies
Two on-going studies concerning the identification of xylene in
biological samples were reported in the Federal Research in Progress File
(FEDRIP) database. R.A. Glaser of NIOSH is developing analytical techniques
to establish the identities and concentrations of contaminants within the
workplace. A prototype solid sorbent device for the direct collection of
exhaled breath samples will be evaluated; this prototype will permit further
refinement of its design and use. A complete analytical method for
identification of m-xylene in breath will be developed. R.E. Letz of the
Mount Sinai School of Medicine in New York is estimating the central nervous
system concentrations of various solvents (including xylene) in industrial
spray painters. This investigator proposes using industrial hygiene sampling
and exhaled breath and urine analyses coupled with biomathematical dose models
to estimate these concentrations.
No on-going studies concerning the identification of xylene in
environmental samples were identified.
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 total xylenes 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.
-------
137
7. REGULATIONS AND ADVISORIES
Xylenes are 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 1987a).
The national and state regulations and guidelines pertaining to xylenes
in air, water, and other media are summarized in Table 7-1. No international
regulations or guidelines applicable to xylenes were found.
-------
138
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to Xylenes
Agency
Description
Value
References
IARC
Regulations:
a. Air:
OSHA
b. Water:
- EPA
EPA OSW
EPA OWRS
c. Other:
EPA
EPA OEM
EPA OSW
National
Carcinogen classification
PEL TWA (8-hr)
STEL (15 min)
m-xylene
o-xylene
g-xylene
Xylene is exempted from the requirement
of a tolerance when used as an aquatic
herbicide applied to irrigation
conveyance systems in accordance with
specified conditions
Ground water monitoring list (Appendix
IX) (xylenes)
General permits under NPDES
Residues of xylene are exempted from the
requirement of a tolerance when used in
accordance with good agricultural
practice as an ingredient in pesticide
formulations applied to growing crops
or to raw agricultural conmodities
after harvest
Chemical information rules require
manufacturers to report production,
use, and exposure-related information
on mixed xylene, gpxylene, g-xylene,
and £-xylene
Health and safety data reporting rules
require manufacturers, processors, etc.
to submit lists and copies of
unpulished health and safety studies
for 8"> 2"• •*"* fi-xylene
Reportable Quantity
xylenes
spent xylene solvents and still
bottoms from the recovery of these
solvents
distillation bottoms from production
of phthalic anhydride from ^-xylene
Hazardoua waste:
xylene the caonarclal chemical
products, manufacturing chemical
interaediate*, or off-specification
coumercial chemical products
spent xylene solvents and still bottoms
. from the recovery of these solvents
distillation light ends snd bottoms
from production of pthallc anhydride
from 2-xylene
Group 3a
100 ppm
150 ppm
NA
NA
NA
NA
NA
NA
1000 lb
1000 lb
5000 lb
IARC 1989
OSHA 1989 (29 CFR
1910)
EPA 1985b (40 CFR
180.1025)
EPA 1987c
EPA 1983a (AO CFR
122) Appendix D
EPA 1971 (AO CFR
180.1001)
EPA 1982b (AO CFR
712.30)
EPA 1982a (AO CFR
716)
EPA 1983d (CFR
302.A)
EPA 1981c (AO CFR
261.31)
EPA 1981d (AO CFR
261.32)
-------
139
7. REGULATIONS AND ADVISORIES
TABLE 7-1 (Continued)
A%ency
Description
Value
References
FDA
Substance for use only as component of
adhesives intended for use in
packaging, transporting, or hoLding
food in accordance with specified
conditions
xylene
xylene alkylated with
dicyclopentadiene
Resin safe for use as a coating for
articles intended for use in contact
with food
xylena-formaldehyde resins condensed
with 4,4'-isopropylidene- diphenol-
epichlorohydrin epoxy resins
NA
NA
FDA 197?b (21 CFR
175.105)
FDA 1977a (21 CFR
175.380)
Advisories:
a. Air:
ACGIH
NIOSH
b. Water:
EPA ODW
HAS
TLV TWA
STEL.
REL TWA (10 hr>
ceiling (10 min.)
IDLH
Health advisory
1-day (10 kg child)
10-day (10 kg child)
Longac-texm (70 kg adult)
(10 kg child)
Lifetime
MCLG (proposed)
SNARL
1-day (70 kg adult)
7-day (70 kg adult)
100 ppra
(=435
mg/m3)
150 ppm
(=655
mg/m3)
100 ppm
200 ppm
10,000 ppm
12 mg/L
7.8 mg/L
27.3 mg/L
7.8 mg/L
0.4 mg/L
0.44 mg/L
21 mg/L
11.2 mg/L
ACGIH 1986
ACGIH 1986
NIOSH 1985
NIOSH 1985
EPA 1987b
EPA 1985c
NRC 1980
c. Other:
ACGIH
EPA
BEI
End of shift
Over last four hours of shift
Carcinogenic classification
RfD (oral)
1.5 g/g
creatinine
2 mg/min
Group Db
2 mg/kg/day
ACGIH 1986
IRIS 1989
IRIS 1989
J1
o\
-------
140
7. REGULATIONS AND ADVISORIES
TABLE 7-1 (Continued)
Agency
Description
Value
References
State
Regulations and Advisories:
a. Air: Acceptable ambient air concentration
(mixed xylene)
Connecticut
Indiana
North Caro-
lina
North Da-
kota
Nevada
New York
Rhode
Island
South Da-
kota
8680 iig/m3
(8 hr)
2175 jig/tn3
(8 hr)
65.5 mg/m3
(15 min)
2.6 mg/ra3
(24 hr)
4.35 mg/m3
<8 hr>
6.55 mg/m3
<1 hr)
10.357
mg/m3 (8
hr)
1450 Mg/m3
<1 yr)
700 fig/o3
<24 hr)
8700 itg/m3
(8 hr)
NATICH 1988
Massachu-
setts
11.8 ng/m3
(24 hr)
11.8 m/m3
(annual
average)
MDEQE 1989
New York
South Caro-
lina
Virginia
Acceptable ambient air concentration
(m-xylene)
1450 Mg/m3
<1 yr)
4350 Mg/m3
(24 hr)
73 MS/m3
(24 hr)
NATICH 1988
New York
South Caro-
lina
Virginia
Acceptable ambient air concentration (o-xylene)
1450 Mg/m3
(1 yr)
4350 nt/m3
(24 hr)
73 ug/m3
(24 hr)
NATICH 19aa
-------
141
TABLE 7-1 (Continued)
Agency
Description
Value
References
New Vork
South Caro-
lina
Virginia
b. Water:
Arizona
Kansas
Mains
Minnesota
New Mexico
New York
Vermont
Wisconsin
Massachu-
setts
New Jersey
Rhode
Island
Massachu-
setts
California
Acceptable ambient air concentration
(g-xylene)
NATICH 1938
Drinking water (mixed xylene)
Drinking water (SIAL) (1 yr)
Drinking water
Groundwater standard
Drinking water (g-xylene)
Drinking water (g-xylene)
Drinking water (p-rylene)
1450 ng/m3
(1 yr)
4350 ng/m*
(24 hr)
73 (ig/m3
(24 hr)
440 /ig/L
440 |ig/L
620 wg/L
440 ag/L
620 m/L
SO /ig/L
620 jig/L
620 Mg/L
1,000 /ig/L
44
-------
143
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. Hazardous Waste and Hazardous Materials 4:211-222.
*Abu Al Ragheb S, Salhab AS, Amr SS. 1986. Suicide by xylene ingestion: A
case report and review of literature. Am J Forensic Med Pathol 7:327-329.
*ACGIH. 1986. Documentation of the threshold limit values and biological
exposure indices. 5th ed. American Conference on Governmental
Industrial Hygienists, Inc., Cincinnati, Ohio.
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.
*Amin TA, Narang RS. 1985. Determination of volatile organics in sediment at
nanogram-per-gram concentrations by gas chromatography. Anal Ghem 57:648-651.
*Amoozegar A, Warrick AW, Fuller WH. 1986. Movement of selected organic
liquids into dry soils. Hazardous Waste and Hazardous Materials 3:29-41.
*Anderson C, Sundberg K, Groth 0. 1986. Animal model for assessment of skin
irritancy. Contact Dermatitis 15:143-151.
^Anderson GE, Liu CS, Holman HY, et al. 1980. Human exposure to atmospheric
concentrations of selected chemicals. Report to Environmental Protection
Agency, Office of Air Quality Planning and Standards, Resarch Triangle Park,
NC, by Systems Applications, Inc, San Rafael, CA.
*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 Appl Pharmacol 60:535-548.
^Andrews L, Keefer R. 1949. Cation complexes of compounds containing
carbon-carbon double bonds. IV. The argentation of aromatic hydrocarbons. J
Amer Chem Soc 71:3644-3647.
* Cited in text
-------
144
8. REFERENCES
Anonymous. 1971. Xylene, (Xylol, Dimethyl Benzene), Hygienic Guide Series.
Am Ind Hyg Assoc J 29:702-705.
*Antoine SR, DeLeon IR, 0'Dell-Smith RM. 1986. Environmentally significant
volatile organic pollutants in human blood. Bull Environ Contam Toxicol
36:364-371.
Appuhn E, Goldeck H. 1957. Fruh- und spatschaden der blutbildung durch
benzol und seine homologen. Arch Gewerbe Path Gewerbehyg 15:399. (German)
*Arp EW Jr, Wolf PH, Chekoway H. 1983. Lymphocytic leukemia and exposures to
benzene and other solvents in the rubber industry. J Occup Med 25:598-602.
^Arthur LJ, Curnock DA. 1982. Xylene-induced epilepsy following innocent
glue sniffing. Br Med J 284:1787.
*Askergren A. 1981. Studies on kidney function in subjects exposed to
organic solvents: III. Excretion of cells in the urine. Acta Med Scand
210:103-106.
*Askergren A. 1982. Organic solvents and kidney function. In: Mehlman MA,
ed. Advances in modern environmental toxicology. Vol, 2, Princeton Junction,
NJ: Senate Press, 157-172.
Askergren A, Allgen L-G, Bergstrom J. 1981a. Studies on kidney function in
subjects exposed to organic solvents: II. The effect of desmopressin in a
concentration test and the effect of exposure to organic solvents on renal
concentrating ability. Acta Med Scand 209:485-488.
*Askergren A, Allgen L-G, Karlsson C, et al. 1981b. Studies on kidney
function in subjects exposed to organic solvents: I. Excretion of albumin
and beta-2-microglobulin in the urine. Acta Med Scand 209:479-483.
*Askergren A, Brandt R, Gullquist R, et al. 1981c. Studies on kidney
function in subjects exposed to organic solvents: IV. Effect on 51-Cr-EDTA
clearance. Acta Med Scand 210:373-376.
*Astrand I. 1982. Work load and uptake of solvents in tissues of man. In:
Mehlman MA, ed. Advances in modern environmental toxicology. Vol. 2,
Princeton Junction, NJ: Senate Press, 141-152.
*Astrand I, Engstrom J, Ovrum P. 1978. Exposure to xylene and ethylbenzene:
I. Uptake, distribution and elimination in man. Scand J Work Environ Health
4:185-194.
-------
145
8. REFERENCES
^Atkinson R, Aschmann SM, Fitz DR, et al. 1982. Rate constants for the
gas-phase reactions of 03 with selected organics at 296 K. Int J Chem Kinet
14:13-18.
Au WW, Ward JB, Ramanujam VMS, et al. 1988. Genotoxic effects of a sub-acute
low-level inhalation exposure to a mixture of carcinogenic chemicals. Mutat
Res 203:103-115.
*Aurelius MW, Brown KW. 1987. Fate of spilled xylene as influenced by soil
moisture content. Water Air Soil Pollut 36:23-31.
*Austern BM, Dobbs RA, Cohen JM. 1975. Gas chromatographic determination of
selected organic compounds added to wastewater. Environ Sci Technol
9:588-590.
Babeu L, Vaishnav DD. 1987. Prediction of biodegradability for selected
organic chemicals. J Indust Microb 2:107-115.
*Bakke OM, Scheline RR. 1970. Hydroxylation of aromatic hydrocarbons in the
rat. Toxicol Appl Pharmacol 16:691-700.
*Balogh T, Tatrai E, Barczai G, et al. 1982. [Study of the embryotoxic
effect of xylene mixtures.] Egeszsegtudomany 26: 42-48. (Hungarian)
*Barbee GC, Brown KW. 1986. Movement of xylene through unsaturated soils
following simulated spills. Water Air Soil Pollut 29:321-331.
*Barker JF. 1987. Volatile aromatic and chlorinated organic contaminants in
groundwater at six Ontario landfills. Water Pollut Res J Can 22:33-48.
*Barlow SM, Sullivan FM. 1982. Reproductive hazards of industrial chemicals:
An evaluation of animal and human data. London: Academic Press, 1-42.
*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.
Batchelor JJ. 1927. The relative toxicity of benzol and its higher
homologues. Am J Hyg 7:276-298.
-------
146
8, REFERENCES
*Bellanca JA, Davis PL, Donnelly B, et al, 1982, Detection and
quantitation of multiple volatile compounds in tissues by GC and GC/MS. J
Anal Toxicol 6:238-240,
*Berenblum I. 1941. The cocarcinogenic action of croton resin. Cancer Res
1:44-48.
*Bernardelli BC, Gennari MC. 1987. Death caused by ingestion of endosulfan.
J Forensic Sci 32:1109-1112.
Bertsch W, Chang RC, Zlatkis A. 1974. The determination of organic volatiles
in air pollution studies: Characterization of profiles. J Chroraatogr 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.
*Bieniek G, Wilczok T. 1981. Thin-layer chromatography of hippuric and
m-methylhippuric acid in urine after mixed exposure to toluene and xylene. Br
J Ind Med 38:304-306.
*Bio/dynamics Inc. 1983. File with FYI-AX-0982-0209: Parental and fetal
reproduction toxicity study. EPA/0TS Public Files. Submitted by American
Petroleum Institute. Document # FYI-AX-0983-0209 .
*Blackman WJ, Garnas RL, Preston JE, et al. 1984. Chemical composition of
drum samples from hazardous waste sites. Fifth National Conference on
Management of Uncontrolled Hazardous Waste Sites, Washington, DC:39-44.
*Bonnet P, Raoult G, Gradiski D. 1979. [Lethal concentration 50 of main
aromatic hydrocarbons]. Arch Mai Prof Med Trav Secur Soc 40:805-810.
(French).
Boorman GA, Eustis SL. 1984. Proliferative lesions of the exocrine pancreas
in male F344/N rats. Environ Health Perspect 56:213-217.
*Bos RP, Brouns RME, Van Doom R, et al. 1981. Nonmutagenieity of toluene,
o-xylene, m-xylene, p-xylene, o-methylbenzylalcohol and o-methyl benzylsulfate
in the Ames assay. Mutat Res 88:273-280.
*Bowers DJ, Cannon MS, Jones DH. 1982. Ultrastructural changes in livers of
young and aging rats exposed to methylated benzenes. Am J Vet Res 43:679-683.
Brass HJ. 1982. Procedures for analyzing organic contaminants in drinking
water. J Am Water Works Assoc 74:107-112.
-------
147
8. REFERENCES
*Bray HG, Humphris BG, Thorpe WV. 1949. Metabolism of derivatives of
toluene: 3. o-, m-, and p-xylenes. Biochem J 45:241-244.
Bray HG, Humphris BG, Thorpe WV. 1950. Metabolism of derivatives of toluene:
5. The fate of the xylenols in the rabbit, with further observations on the
metabolism of the xylenes. Biochem J 47:395-399.
*Bridie AL, Wolff CJM, Winter M. 1979. BOD and COD of some petrochemicals.
Water Research 13:627-630.
Broda P, Bayley S, Duggleby CJ, et al. 1977. Plasmid-coded degradation of
toluene and xylenes in soil pseudomonads. Plasmids: Medical and theoretical
aspects:403-406.
*Brodzinsky R, Singh HB. 1983. Volatile organic chemicals in the atmosphere.
An assessment of available data. Prepared by SRI International, Menlo Park,
CA for US Environmental Protection Agency, Office of Research and Development,
Environmental Sciences Research Laboratory, Research Triangle Park, NC.
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.
*Burns LH, Cline DM, Lassiter RR. 1981. Exposure analysis modeling system
(EXAMS). Athens, GA: US Environmental Protection Agency, Office of Research
and Development, Environmental Research Lab.
*Bushnell, PJ. 1989. Behavioral effects of acute jj-xylene inhalation in
rats: Autoshaping, motor activity, and reversal learning. Neurotoxicol
Teratol 10:569-577.
Bushnell PJ, Peele DB. 1988. Conditioned flavor aversion induced by inhaled
E-xylene in rats. Neurotoxicol Teratol 10:273-277.
*Calabrese AJ. 1978. Pollutants and high-risk groups. New York, NY: John
Wiley & Sons, Inc., Pp. 4-8.
Camarasa JG. 1983. Contact dermatitis from dimethylformamide. Contact
Dermatitis 16:234.
*Cameron GR, Paterson JLH, DeSaram GSW, et al. 1938. The toxicity of some
methyl derivatives of benzene with special reference. J Pathol Bacteriol
46:95-107.
-------
148
8. REFERENCES
*CampbelL L, Wilson HK, Samuel AM, et al. 1988. Interactions of m-xylene and
aspirin metabolism in man. Br J Ind Med 45:127-132.
*Caperos JR, Fernandez JG. 1977. Simultaneous determination of toluene and
xylene metabolites in urine by gas chromatography. Br J Ind Med 34:229-233.
*Carlone MF, Fouts JR. 1974. In vitro metabolism of p-xylene by rabbit lung
and liver. Xenobiotica 4:705-715.
*Carlsson A. 1981. Distribution and elimination of 14C-xylene in rat. Scand
J Work Environ Health 7:51-55.
^Carpenter CP, Kinkead ER, Geary DJ, et al. 1975. Petroleum hydrocarbon
toxicity studies. V. Animal and human response to vapors of mixed xylenes.
Toxicol Appl Pharmacol 33:543-558.
Carpenter CP, Kinkead ER, Geary DJ, et al. 1975. Petroleum hydrocarbon
toxicity studies. I. Methodology. Toxicol Appl Pharmacol 32:246-262.
*CEC 1976. Commission of the European Communities. Cost Project 64b.
Analysis of organic micropollutants in water management committee. A
comprehensive list of following substances which have been identified in
various fresh waters, effluent discharges, aquatic animals and plants and
bottom sediments. EVCO/MDV/73/76, XII/476/76.
CESARS. 1988. Chemical evaluation search and retrieval system [Database].
Chemical Information Systems, Inc., Baltimore, MD. April 1982.
*Chao J, Lin CT, Chung TH. 1983. Vapor pressure of coal chemicals. J Phys
Chem Ref Data 12:1033-1063.
CHEMFATE. 1988. [Database]. Syracuse Research Corporation, Syracuse, NY.
December 1988.
*Chernoglazova FS, Simulin YN. 1976. [Mutual solubility in the
m-xylene-water system]. Zh Fiz Khim 50:809. (Russian). As cited in CHEMFATE
1988.
*Chiou CT, Schmedding DW, Manes M. 1982. Partitioning of organic compounds
in octanol-water systems. Environ Sci Technol 16:4-10.
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.
-------
149
8. REFERENCES
Clark AI, 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.
*CLP. 1988. Contract laboratory program statistical database. US
Environmental Protection Agency, August 17, 1988.
*Condie LW, Hill JR, Borzelleca JF. 1988. Oral toxicology studies with
xylene isomers and mixed xylenes. Drug Chem Toxicol 11: 329-354.
Cone JE. 1986. Health hazards of solvents. State Art Rev Occup Med 1:69-87.
*Cormor TH, Theiss JC, Hanna HA, et al. 1985. Genotoxicity of organic
chemicals frequently found in the air of mobile homes. Toxicol Lett 25:33-40.
Cox RA, Derwent RG, Williams MR. 1980. Atmospheric photooxidation reactions.
Rates, reactivity, and mechanism for reaction of organic compounds with
hydroxyl radicals. Environ Sci Technol 14:57-61.
*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.
*Davey JF, Gibson DT. 1974. Bacterial metabolism of para- and meta-xylene:
Oxidation of a methyl substituent. J Bacterid 119:923-929.
*David A, Flek J, Frantik E, et al, 1979. Influence of phenobarbital on
xylene metabolism in man and rats. Int Arch Occup Environ Health 44:117-125.
*Davis RS, Hossler FE, Stone RW. 1968. Metabolism of p- and m-xylene by
species of Pseudomonas. Can J Microbiol 14:1005-1009,
*Dawson GW, et al. 1974. Determination of harmful quantities and rates of
penalty for hazardous substances. Volume III. Washington, DC: US
Environmental Protection Agency. As cited in CESARS 1988.
Dean BJ . 1978. Genetic toxicology of benzene, toluene, xylenes and phenols.
Mutat Res 47:75-97.
Dean BJ. 1985. Recent findings on the genetic toxicology of benzene,
toluene, xylenes and phenols. Mutat Res 154:153-181.
*De Ceaurriz JC, Micillino JC, Bonnet P, et al. 1981. Sensory irritation
caused by various industrial airborne chemicals. Toxicol Lett 9:137-143.
-------
150
8. REFERENCES
*De Ceaurriz J, Desiles JP, Bonnet P, et al. 1983. Concentration-dependent
behavioral changes in mice following short-term inhalation exposure to various
industrial solvents. Toxicol Appl Pharmacol 67:383-389.
*Desi I, Kovacs F, Zahumenszky Z, et al. 1967. Maze learning in rats exposed
to xylene intoxication. Psychopharmacologia (Berl) 11:224-230.
Dewalle FB, Chian ESK. 1981. Detection of trace organics in well water near
a solid waste landfill. J Am Water Works Assoc 73:206-211.
Dilling WL, Bredeweg CJ, Tefertiller NB. 1976. Simulated atmospheric
photodecomposition rates of methylene chloride, 1,1,1-trichloroethane,
trichloroethylene, tetrachloroethylene, and other compounds. Environ Sci
Technol 10:351-356.
Dobecki M, Czerczak S. 1987. [Gas chromatographic determination of offset
lacquer organic solvents in air], Med Pr 38:357-363. (Polish).
Dodge MC. 1984. Combined effects of organic reactivity and NMHC/NOx ratio on
photochemical oxidant formation--a modeling study. Atmos Environ
18:1657-1666.
*Dolara P, Lodovici M, Buffoni F, et al. 1982. Variations of some parameters
of enzyme induction in chemical workers. Ann Occup Hyg 25:27-32.
Dore M, Brunet N, Legube B. 1975. [Participation of various organic
compounds in the evaluation of global pollution criteria]. Trib Cebedeau
28:3-11. (French).
Dowty BJ, Laseter JL, Storer J. 1976. The transplacental migration and
accumulation in blood of volatile organic constituents. Pediat Res
10:696-701.
Driscoll JN, Warneck P. 1973. The analysis of PPM levels of gases in air by
photoionization mass spectrometry. J Air Pollut Control Assoc 23:858-863.
Dunovant VS, Clark CS, Quehee SS, et al. 1986. Volatile organics in the
wastewater and airspaces of three wastewater plants. J Water Pollut Control
Fed 58:886-895.
Dworzanski JP, Debowski MT. 1981. Semiautomated preparation technique of
urine samples for gas chromatographic determination of toluene and xylene
metabolites. Cheroia Anal 26:319-325.
-------
151
8. REFERENCES
*Dyer RS, Bercegeay MS, Kayo LM. 1988. Acute exposures to p-xylene and
toluene alter visual information processing. Neurotoxicol Teratol 10:147-153.
*ECETOC. 1986. Joint assessment of commodity chemicals: No. 6: Xylenes.
Brussels, Belgium: European Chemical Industry Ecology and Toxicology Centre.
Eckardt RE. 1976. Recommendations for a xylene standard. Commentary 2. J
Occup Med 18:572.
Ehrenreich T. 1977. Renal disease from exposure to solvents. Ann Clin Lab
Sci 7:6-16.
Elovaara E. 1982. Dose-related effects of m-xylene inhalation on the
xenobiotic metabolism of the rat. Xenobiotica 12:345-352.
*Elovaara E, Collan Y, Pfaffli P, et al. 1980. The combined toxicity of
technical grade xylene and ethanol in the rat. Xenobiotica 10:435-445.
Elovaara E, Engstrom K, Vainio H. 1982. Unaltered metabolism of m-xylene in
the presence of ethylbenzene. Biochem Biophys Environ Implic 23:765-768.
Elovaara E, Pfaffli P, Savolainen H, et al. 1982. Marginal role of impaired
aldehyde metabolism in m-xylene vapour-induced biochemical effects in the rat.
J Appl Toxicol 2:27-33.
Elovaara E, Engstrom 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, Zitting A, Nickels J, et al. 1987. m-Xylene inhalation destroys
cytochrome P-450 in rat lung at low exposure. Arch Toxicol 61:21-26.
*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 J, Riihimaki V. 1979. Distribution of m-xylene to subcutaneous
adipose tissue in short-term experimental human exposure. Scand J Work
Environ Health 5:126-134.
*Engstrom K, Husman K, Rantanen J. 1976. Measurement of toluene and xylene
metabolites by gas chromatography. Int Arch Occup Environ Hlth 36:153-160.
*Engstrom K, Husman K, Riihimaki V. 1977. Percutaneous absorption of
m-xylene in man. Int Arch Occup Environ Hlth 39:181-189.
-------
152
8. REFERENCES
*Engstrom K, Husman K, Pfaffli P, et al. 1978. Evaluation of occupational
exposure to xylene by blood, exhaled air and urine analysis. Scand J Work
Environ Health 4:114-121.
*Engstrom K, Riihimaki V, Laine A. 1984. Urinary disposition of ethylbenzene
and in-xylene in man following separate and combined exposure. Int Arch Occup
Environ Health 54:355-363.
^Environment Canada. 1981. Tech info for problem spills: Xylenes (draft).
As cited in HSDB 1988.
*EPA. 1971. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 180.1001.
*EPA. 1978b. Initial report of the TSCA interagency testing committee to the
administrator, Environmental Protection Agency. Washington, D.C.: National
Science Foundation and Environmental Protection Agency. EPA 560-10-78/001.
EPA. 1980a. Guidelines and methodology used in the preparation of health -
effect assessment chapters of the consent decree water criteria documents.
Federal Register. US Environmental Protection Agency., 79347-79357.
*EPA. 1980b. US Environmental Protection Agency. Code of Federal
Regulations. 40 GFR 261.33.
*EPA. 1981a. Advisory opinion for xylenes (Dimethylbenzenes). An Office of
Drinking Water health effects advisory. Washington, D.C: US Environmental
Protection Agency, Office of Drinking Water, 1-11.
*EPA. 1981b. Engineering handbook for hazardous waste incineration. EPA
68-03-3025., 3-16. As cited in HSDB 1988.
*EPA. 1981c. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 261.31.
*EPA. 1981d. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 261.32.
*EPA. 1982a. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 716.
*EPA. 1982b. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 712.30.
*EPA. 1983a. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 122 Appendix D.
-------
153
8. REFERENCES
EPA. 1984. Health effects assessment for xylene. Cincinnati, OH, and
Washington, DC: US Environmental Protection Agency, Environmental Criteria
and Assessment Office, Office of Health and Environmental Assessment, Office
of Research and Development, and Office of Emergency and Remedial Response.
EPA 540/1-86-006.
*EPA. 1985a. Drinking water criteria document for xylenes. Report to US
Environmental Protection Agency, Office of Drinking Water, Washington, DC, by
Environmental Criteria and Assessment Office, Cincinnati, OH.
EPA-600/X-84-185 PB86-117942.
*EPA. 1985b. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 180.1025.
*EPA. 1985c. US Environmental Protection Agency Federal Register 50:46936.
*EPA. 1985d. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 302.4.
*EPA. 1986. 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. Federal Register
52:21152-21208.
*EPA. 1987b. Health advisory for xylenes. US Environmental Protection
Agency, Office of Drinking Water, Washington, DC.
*EPA. 1987c. US Environmental Protection Agency. Federal Register 52:25942.
*Epler JL, Rao TK, Geurin MR. 1979. Evaluation of feasibility of mutagenic
testing of shale oil products and effluents. Environ Health Perspect
30:179-184.
*Esposito GG, Jacobs BW. 1977. Chromatographic determination of aromatic
hydrocarbons in ambient air. Am Ind Hyg Assoc J 38:401-407.
Fabacher DL, Hodgson E. 1977. Hepatic mixed-function oxidase activity in
mice treated with methylated benzenes and methylated naphthalenes. J Toxicol
Environ Health 2:1143-1146.
Fabre R, Truhaut R, Laham S. 1960. [Study of metabolism of xylenes or
dimethylbenzenes in the rat, the guinea pig, and the rabbit]. Hebd Seances
Acad Sci 250:2655-2659. (French).
-------
154
8. REFERENCES
Fairhall LT. 1969, Industrial toxicology. 2nd ed. New York: Hafner
Publishing Co, 357-358.
*Faust SD. 1977. Chemical mechanisms affecting the fate of organic
pollutants in natural aquatic environments. In: Suffet IH, ed. Advances in
Environmental Science and Technology. Vol. 8, New York, NY: John Wiley &
Sons, Inc, 317-365.
*FDA. 1977a. US Food and Drug Administration. Code of Federal Regulations.
21 CFR 175.380.
*FDA. 1977b. US Food and Drug Administration. Code of Federal Regulations.
21 CFR 175.105.
*Feldt EG. 1986. [Evaluation of the mutagenic hazards of benzene and some of
its derivatives.] Gig Sanit: 1-8. (Russian)
*Fishbein L. 1985. An1 overview of environmental and toxicological aspects of
aromatic hydrocarbons: III. Xylene. Sci Total Environ 43:165-183.
*Florin I, Rutberg L, Curvall M, et al. 1980. Screening of tobacco smoke
constituents for mutagenicity using the Ames1 test. Toxicol 18:219-232.
Forde JP. 1973. Xylene affected platelet count. Occ Health 11:429-433.
*Fox DL, Gary M, Jeffries HE. 1984. Organic aerosol formation: OH vs. ozone
oxidation pathways. Report to Coordinating Research Council, Inc., Atlanta,
GA, by Department of Environmental Sciences and Engineering, University of
North Carolina, Chapel Hill, NC.
*Franchini I, Cavatorta A, Falzoi M, et al. 1983. Early indicators of renal
damage in workers exposed to organic solvents. Int Arch Occup Environ Health
52:1-9.
Freed VH, Chiou CT. 1982. Physicochemical factors in routes and rates of
human exposure to chemicals. In: McKinney JD, ed. Environmental health
chemistry. Ann Arbor, MI: Ann Arbor Science, 59-74.
*Freundt KJ, Romer KG, Federsel RJ. 1989. Decrease of inhaled toluene, ethyl
benzene, m-xylene, or mesitylene in rat blood after combined exposure to ethyl
acetate. Bull Environ Contain Toxicol 4-2: 495-498.
*FSTRAC. 1988. Summary of state and federal drinking water standards and
guidelines. Federal-State Toxicology and Regulatory Alliance Committee.
March 1988.
-------
155
8. REFERENCES
*Furnas DW, Hine CH. 1958. Neurotoxicity of some selected hydrocarbons. AMA
Arch Ind Health 18:9-15.
Galloway SM, Bloom AD, Resnick M, et al. 1985, Development of a standard
protocol for in vitro cytogenetic testing with Chinese hamster ovary cells:
Comparison of results for 22 compounds in two laboratories. Environ Mutagen
7:1-51.
*Gamberale F, Annwall G, Hultengren M. 1978. Exposure to xylene and
ethylbenzene: III. Effects on central nervous functions. Scand J Work
Environ Health 4:204-211.
Gart JJ, Chu KC, Tarone RE. 1979. Statistical issues in interpretation of
chronic bioassay tests for carcinogenicity. JNCI 62:957-974.
^General Electric Co. 1980. Material safety data sheet ¦//318. As cited in
HSDB 1988.
*Gerarde HW. 1959. Toxicological studies on hydrocarbons. III. The
biochemorphology of the phenylalkanes and phenylalkenes. AMA Arch Ind Health
19:403-418.
*Gerarde HW. 1960. Toxicology and biochemistry of aromatic hydrocarbons.
London: Elsevier Publishing Co., 171-180.
*Gerner-Smidt P, Friedrich U. 1978. The mutagenic effect of benzene, toluene
and xylene studied by the SCE technique. Mutat Res 58:313-316.
*Ghantous H, Danielsson BR. 1986. Placental transfer and distribution of
toluene, xylene and benzene, and their metabolites during gestation in mice.
Biol Res Pregnancy Perinatol 7:98-105.
*Ghosh TK, Copeland RJ, Parui RN, et al. 1987. Effects of xylene inhalation
on fixed-ratio responding in rats. Pharmacol Biochem and Behav 27:653-657.
Giammarinaro G. 1956. Mielosi aplastica globale con osteosclerosi diffusa
da intossicazione cronica da xilolo. Osped Maggiore 44:281. (Italian).
*Gibson DT, Mahadevan V, Davey JF. 1974. Bacterial metabolism of para- and
meta-xylene: Oxidation of the aromatic ring. J Bacteriol 119:930-936.
*Giger W, Schaffner C. 1981. Groundwater pollution by volatile organic
chemicals. Stud Environ Sci 17:517-522.
-------
156
8. REFERENCES
Gitelson S, Aladjemoff L, Ben Hador S, et al. 1966. Poisoning by a
malathion-xylene mixture. JAMA 197:819-821.
Glaser RA, Arnold JE, Shulman SA. 1988. Direct sampling of organic solvents
in expired breath with a new solid sorbent sampling device. Scand J Work
Environ Health 14 (Suppl 1):63-65.
*Gleason MN, Gosselin RE, Hodge HC, et al. 1969. Clinical toxicology of
commercial products: Acute poisoning. 3rd ed. Baltimore, MD: Williams and
Wilkins, 227-230.
Glibert D. 1935. Les mefaits de 11 heliogravure. Brux Med 16:194. (French).
*Goldie I. 1960. Can xylene (xylol) provoke convulsive seizures. Ind Med
Surg 29:33-35.
*Gosselin RE, Smith RP, Hodge HC. 1984. Clinical toxicology of commercial
products. 5th ed. Baltimore, MD: Williams & Wilkins, 397-404.
*Gossett RW, Brown DA, Young DR. 1983. Predicting the bioaccumulation of
organic compounds in marine organisms using octanol/water partition
coefficients. Marine Pollution Bulletin 14:387-392.
Grasso P, Sharrat M, Davies D, Irvine M. 1984. Neurophysiological and
psychological disorders and occupational exposure to organic solvents. Food
Chem Toxicol 22:819-852.
Gray DC. 1974. Solvent evaporation rates. Am Ind Hyg Assoc J 35:695-710.
*Green WJ, Lee GF, Jones RA. 1981. Clay-soils permeability and hazardous
waste storage. J Water Pollut Control Fed 53:1347-1354.
Green WJ, Lee GF, Jones RA, et al. 1983. Interaction of clay soils with
water and organic solvents: Implications for the disposal of hazardous
wastes. Environ Sci Technol 17:278-282.
*Griffin RA, Hughes RE, Follmer IR, et al. 1984. Migration of industrial
chemicals and soil-waste interactions at Wilsonville, Illinois. Land disposal
of hazardous waste, proceedings of the tenth annual research symposium at Ft.
Mitchell, KY. 61.
*Guisti DM, Conway RA, Lawson CT. 1974. Activated carbon adsorption of
petrochemicals. J Water Pollut Control Fed 46:947-965.
Gupta BN, Shanker R, Viswanathan PN, et al. 1987. Safety evaluation of a
barrier cream. Contact Dermatitis 17:10-12.
-------
157
8. REFERENCES
*Gusev I. 1965. Reflective effects of microconcentrations of benzene,
toluene, xylene and their comparative assessment. Hyg Sanit 30(Pt 2):331. As
cited in CESARS 1988.
*Gusev I. 1967. Comparative toxicity of benzene, toluene, and xylene. Biol
Deistvie Gig Znachenie Atmos Zagryaznenii 10:96. (Russian). As cited in
CESARS 1988.
*Gut I. 1981. [Inhibition of the metabolism of benzene, toluene and
acrylonitrile by some organic compounds]. Prac Lek 33:202-208.
(Czechoslovakian).
*Haglund U, Lundberg I, Zech L. 1980. Chromosome aberrations and sister
chromatid exchanges in Swedish paint industry workers. Scand J Work Environ
Health 6:291-298.
*Hake CLR, Stewart RD, Wu A, et al. 1981. p-Xylene: Development of a
biological standard for the industrial worker. Report to the National
Institute for Occupational Safety and Health, Cincinnati, OH, by the Medical
College of Wisconsin, Inc., Milwaukee, WI. PB82-152844.
Haider CA, Van Gorp GS, Hatoum NS, et al. 1986. Gasoline vapor exposures.
Part I. Characterization of workplace exposures. Am Ind Hyg Assoc J
47:164-172.
Hampel CA, Hawley GG. 1973. The encyclopedia of chemistry. 3rd ed. New
York, NY: Van Nostrand Reinhold Company, 819-820.
*Hampton CV, Pierson WR, Harvey TM, et al. 1982. Hydrocarbon gases emitted
from vehicles on the road. 1. A qualitative gas chromatography/mass
spectrometry survey. Environ Sci Technol 16:287-298.
*Hansch C, Leo A. 1979. Substituent constants for correlation analysis in
chemistry and biology. New York, NY: John Wiley & Sons, 232.
Hansen DA, Atkinson R, Pitts JJ. 1975. Rate constants for the reaction of OH
radicals with a series of aromatic hydrocarbons. • Journal of Physical
Chemistry 79:1763-1766.
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 Total Environ 38:259-274.
Harmsen J. 1983. Identification of organic compounds in leachate from a
waste tip. Water Research 17:699-705.
-------
158
8. REFERENCES
*Harper C, Drew RT, Fouts JR. 1975. Benzene and p-xylene: A comparison of
inhalation toxicities and in vitro hydroxylations. In: Jollow J, et al.,
eds. Biological reactive intermediates. Formation, toxicity, and
inactivation. Proceedings of an international conference. Turku, Finland,
July 26-27, 1975. New York, NY: Plenum Press, 302-311.
Harton EJ, Rawl RR, ed. 1976. Toxicological and skin corrosion testing of
selected hazardous materials. Report to US Department of Transportation,
Office of Hazardous Materials Operations, Washington, D.C., by Biological
Services Division, United States Testing Company, Inc., Hoboken, NJ.
D0T/MTB/0HM0-76/2, PB-264 975.
Hartwell TD, Pellizzari ED, Perritt RL, et al. 1987. Comparison of volatile
organic levels between sites and seasons for the total exposure assessment
methodology (TEAM) study. Atmospheric Environment 21:2413-2424.
Hasanen E, Karlsson V, Leppamaki E, et al. 1981. Benzene, toluene and
xylene concentrations in car exhausts and in city air. Atmospheric
Environment 15:1755-1757.
Haseman JK, Tharrington EC, Huff JE, et al. 1986. Comparison of
site-specific and overall tumor incidence analyses for 81 recent National
Toxicology Program carcinogenicity studies. Regul Toxicol Pharmacol
6:155-170.
^Hastings L, Cooper GP, Burg W. 1986. Human sensory response to selected
petroleum hydrocarbons. In: MacFarland HN, et al. eds. Advances in modern
environmental toxicology. Vol. 6. Applied toxicology of petroleum
hydrocarbons. Princeton, NJ: Princeton Scientific Publishers, 255-270.
Hauser TR, Bromberg SM. 1982. Environmental Protection Agency monitoring
program at Love Canal New-York, USA 1980. Environ Monit Assess 2:249-272.
*Hawley GG. 1977. The condensed chemical dictionary. 9th ed. New York, NY:
Van Nostrand Reinhold Co., pp. 931-932.
*Hawley GG. 1981. The condensed chemical dictionary. 10th ed. New York,
NY: Van Nostrand Reinhold Co., 1101.
*Haworth S, Lawlor T, Mortelmans K, et al. 1983. Salmonella mutagenicity
test results for 250 chemicals. Environ Mutagen (Suppl) 1:3-142.
*Hazleton Labs. 1988a. Subchronic toxicity study in rats with m-xylene.
Report by Hazleton Laboratories America, Inc., Rockville MD for Dynamac
Corporation, Rockville, MD.
-------
159
8. REFERENCES
*Hazleton Labs. 1988b. Subchronic toxicity study in rats with p-xylene.
Report by Hazleton Laboratories America, Inc., Rockville MD for Dynamac
Corporation, Rockville, MD.
*Hejtmankova N, Simanek V, Holcik J, et al. 1979. Antifungal and mutagenic
activity of phenolic substances with different alkyl groups II. A study of the
relationship between the biological activity and the constitution of the
investigated compounds. Acta Univ Palacki Olomuc Fac Med 90:75-87.
Hendry DG, Mill T, Piszkiewicz L, et al. 1974. A critical review of H-atom
transfer in the liquid phase: Chlorine atom, alkyl, trichloromethyl, alkoxy,
and alkylperoxy radicals. J Phys Chem Ref Data 3:937-978.
^Hester NE, Meyer RA. 1979. A sensitive technique for measurement of benzene
and alkylbenzenes in air. Environ Sci Technol 13:107-109,
*Hiatt MH. 1983. Determination of volatile organic compounds in fish samples
by vacuum distillation and fused silica capillary gas chromatography/mass
spectrometry. Anal Chem 55:506-516.
*Higgins E, Griest WH, Olerich G. 1983. Applications of Tenax trapping to
analysis of gas phase organic compounds. J Assoc Off Anal Chem 66:1074-1083.
*Hine CH, Zuidema HH. 1970. The toxicological properties of hydrocarbon
solvents. Industrial Medicine 39:39-44.
*Hine J, Mookerjee P. 1975. The intrinsic hydrophilic character of organic
compounds. Correlations in terms of structural contributions. J Org Chem
40:292-298.
*Hipolito RN. 1980. Xylene poisoning in laboratory workers: Case reports
and discussion. Lab Med 11:593-595.
Hites RA, Lopez-Avila V. 1980. Sedimentary accumulation of industrial
organic compounds discharged into a river system. In: Baker RA, ed.
Contaminants and sediments. Vol. 1, Ann Arbor, MI: Ann Arbor Science, 53-66.
*Hodge HC, Sterner JH. 1949. Tabulation of toxicity classes. Am Indus Hug
Quart 10:93-96.
Hollowell CD, Miksch RR. 1981. Sources and concentrations of organic
compounds in indoor environments. Bull NY Acad Med 57:962-977.
-------
160
8. REFERENCES
Holmberg PC. 1979. Central-nervous-system defects in children born to
mothers exposed to organic solvents during pregnancy. Lancet 2:177-179.
*Holmberg PC, Nurminen M. 1980. Congenital defects of the central nervous
system and occupational factors during pregnancy, case-referent study. Am J
Ind Hed 1:167-176.
Hood RD, Ottley MS. 1985. Developmental effects associated with exposure to
xylene: A review. Drug Chem Toxicol 8:281-297.
Hormes JT, Filley CM, Rosenberg NL. 1986. Neurologic sequelae of chronic
solvent vapor abuse. Neurology 36:698-702.
*HSDB. 1988. Hazardous substances data bank. National Library of Medicine,
National Toxicology Information System, Bethesda, MD. July 6, 1988.
*Hudak A, Ungvary G. 1978. Embryotoxic effects of benzene and its methyl
derivatives: toluene, xylene. Toxicol 11:55-63.
Hudak A, Tatrai E, Lorincz M, et al. 1980. [Study of the embryotoxic effect
of o-xylene]. Morphol Igazsagugyi Orv Sz 20:204-209. (Hungarian).
*Hutchinson TC, et al. 1978. The correlation of the toxicity to algae of
hydrocarbons and halogenated hydrocarbons with their physical-chemical
properties. In: Afgan BK, Mackay D, eds. Hydrocarbons and halogenated
hydrocarbons in the aquatic environment. New York, NY: Plenum Press,
577-586.
*Hwang ST, Falco JW, Navman CH. 1986. Development of advisory levels for
polychlorinated biphenyls (PCBs). Washington, DC: US Environmental
Protection Agency, Office of Health and Environmental Assessment.
IARC. 1988. International Agency for Research on Cancer. Environmental
Carcinogens. Methods of Analysis and Exposure Measurement. Volume 10:
Benzene and Alkylated Benzenes: L. Fishbein and I.K. O'Neil, editors, IARC
Publications No. 85. Lyon, France.
*IARC. 1989. International Agency for Research on Cancer. IARC monographs
on the evaluation of carcinogenic risks to humans. Vol. 47: Some organic
solvents, resin monomers and related compounds, pigments and occupational
exposures in paint manufacturing and painting. World Health Organization,
Lyon, France.
Imbriani M, Ghittori S, Pezzagno G, et al. 1987. [Urinary elimination of
xylene in experimental and occupational exposure]. Med Lav 78:239-249.
(Italian).
-------
161
8. REFERENCES
*IRIS. 1989. Integrated Risk Information System [Database]. US
Environmental Protection Agency, Washington, D.C. February 1, 1989.
ISHOW. 1988. Information System for Hazardous Organics in Water.
[Database]. Chemical Information Systems Inc. Baltimore, MD.
Jamison VW, Raymond RL, Hudson JO. 1969. Microbial hydrocarbon
co-oxidation: III. Isolation and characterization of an alpha,
alpha*-dimethyl-cis, cis-muconic acid-producing strain of Nocardia corallina.
Appl Microbiol 17:853-856.
Jeltes R, Burghardt E, Thijsse TR, et al. 1977. Application of capillary gas
chromatography in the analysis of hydrocarbons. Chromatographia 10:430-437.
*Jenkins LJ, Jones RA, Siegel J. 1970. Long-term inhalation screening
studies of benzene, toluene, o-xylene, and cumene on experimental animals.
Toxicol Appl Pharmacol 16:818-823.
Johansson I. 1978. Determination of organic compounds in indoor air with
potential reference to air quality. Atmos Environ 12:1371-1377.
Johnson EM, Gabel BEG, Christian MS, et al. 1986. The developmental toxicity
of xylene and xylene isomers in the hydra assay. Toxicol Appl Pharmacol
82:323-328.
*Jori A, Calamari D, Di Domenico A, et al. 1986. Ecotoxicological profile of
xylenes: Working party on ecotoxicological profiles of chemicals. Ecotoxicol
Environ Safety 11:44-80.
Junk GA, Ford CS. 1980. A review of organic emissions from selected
combustion processes. Chemosphere 9:187-230.
*Kappeler T, Wuhrmann K. 1978a. Microbial degradation of the water-soluble
fraction of gas oil-I. Water Research 12:327-333.
Kappeler T, Wuhrmann K. 1978b. Microbial degradation of the water fraction
of gas oil-II Bioassays with pure strains. Water Research 12:335-342.
Karickhoff SW, Brown DS, Scott TA. 1979. Sorption of hydrophobic pollutants
on natural sediments. Water Research 13:241-248.
Kashin L, Kulinskaya I, Mikhailovskaya L. 1968. [Changes in animals under
the effect of small concentrations of xylene]. Vrach Delo 8:109-112.
(Russian).
-------
162
8. REFERENCES
Kawamura K, Kaplan 1R. 1983. Organic compounds in the rainwater of Los
Angeles. Environ Sci Technol 17:497-501.
*Keith LH, Garrison AW, Allen FR, et al. 1976. Identification of organic
compounds in drinking water from thirteen U.S. cities. In: Keith LH, ed.
Identification and analysis of organic pollutants in water, Ann Arbor, MI
329-373.
Kimura ET, Ebert DM, Dodge PW. 1971. Acute toxicity and limits of solvent
residue for 16 organic solvents. Toxicol Appl Pharmacol 19:699-704.
Kira S. 1977. Measurement by gas chromatography of urinary hippuric acid
and methylhippuric acid as indices of toluene and xylene exposure. Br J Ind
Med 34:305-309.
*Klaucke DN, Johansen M, Vogt RL. 1982. An outbreak of xylene intoxication
in a hospital. Am J Ind Med 3:173-178.
*Klimisch H-J, Pauluhn J, Hollander HW, et al. 1988. Inhalation hazard test:
Interlaboratory trial with OECD method 403. Arch Toxicol 61:318-320.
Kol'Kovski P. 1968. [A linear colorimetric method of determining benzene,
toluene and xylene vapor in the air]. Gig Sanit 33:50-53. (Russian).
*Konemann H. 1981. Quantitative structure-activity relationships in fish
toxicity studies: Part 1: Relationship for 50 industrial pollutants.
Toxicology 19:209-221.
Kool HJ, van Kreijl CF, Zoeteman BCJ. 1982. Toxicology assessment of organic
compounds in drinking water. CRC Crit Rev Environmental Control 12:307-357.
Kopecky J, Bocek K, Vlachova D. 1965, Chemical structure and biological
activity on m- and p-disubstituted derivations of benzene. Nature 207:981.
Kopfler FC, Melton RG, Mullaney JL, et al. 1977. Human exposure to water
pollutants. Adv Environ Sci Technol 8:419-433.
Korte F, Boedefeld E. 1978. Ecotoxicological review of global impact of
petroleum industry and its products. Ecotoxicol Environ Safety 2:55-103.
Krotoszynski BK, O'Neill HJ. 1982. Involuntary bioaccumulation of
environmental pollutants in nonsmoking heterogeneous human population. J
Environ Sci Health (Part A) 17:855-883.
-------
163
8. REFERENCES
*Krotoszynski BK, Bruneau BM, O'Neill HJ. 1979. Measurement of chemical
inhalation exposure in urban population in the presence of endogenous
effluents. J Anal Toxicol 3:225-234.
*Kucera J. 1968. Exposure to fat solvents: A possible cause for sacral
agenesis in man. J Pediatr 72:857-859.
*Kurppa K, Husman K. 1982. Car painters' exposure to a mixture of organic
solvents. Serum activities of liver enzymes. Scand J Work Environ Health
8:137-140.
*Kyrklund T, Kjellstrand P, Haglid K. 1987. Brain lipid changes in rats
exposed to xylene and toluene. Toxicology 45:123-133.
Lachnit V, Reimer EE. 1959. Panmyelopathien durch aromatische
losungsmittel. Wien Klin Wochenschr 71:365. (German).
Laham S. 1960. Comparative metabolism of benzene homologs in the Syrian
golden hamster. Proc Intern Congr Occup Health 13:735-738.
Laham S. 1970. Metabolism of industrial solvents: 1. The biotransformations
of benzene and benzene substitutes. Occup Health Rev 21:24-28.
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.
*Leo AJ. 1982. Log P values calculated using the CLOGP program for compounds
in ISHOW files. Pomona College Medicinal Chemistry Project. Seaver Chemistry
Laboratory, Claremont, CA. As cited in ISHOW 1988.
Leo A, Hansch C, Elkins D. 1971. Partition coefficients and their uses.
Chemical Reviews 71:525-616.
*Liira J, Riihimaki V, Engstrom K, et al. 1988, Coexposure of man to m-
xylene and methyl ethyl ketone: Kinetics and metabolism. Scand J Work
Environ Health 14: 322-327.
*Litton Bionetics. 1978a. Teratology study in rats xylene final report.
EPA/OTS Public Files. Submitted by American Petroleum Institute. Document
#878210350.
*Litton Bionetics. 1978b. Mutagenicity evaluation of xylene with cover
letter. EPA/OTS Public Files. Submitted by American Petroleum Institute.
Document #878210347.
-------
164
8. REFERENCES
*Lonnemati WA, Kopczynski SL, Darley PE, et al. 1974. Hydrocarbon composition
of urban air pollution. Environ Sci Technol 8:229-236.
Lundberg I, Sollenberg J. 1986. Correlation of xylene exposure and methyl
hippuric acid excretion in urine among paint industry workers. Scand J Work
Environ Health 12:149-153.
Lundberg I, Ekdahl M, Kronevi T, et al. 1986. Relative hepatotoxicity of
some industrial solvents after intraperitoneal injection or inhalation
exposure in rats. Environ Res 40:411-420.
*Lysyj I, Perkins G, Farlow JS. 1980. Trace analysis for aromatic
hydrocarbons in natural waters. Environ Int 4:407-416.
*Mackay D, Leinonen PJ. 1975. Rate of evaporation of low-solubility
contaminants from water bodies to atmosphere. Env Sci Technol 9:1178-1180.
Mackay D, Paterson S. 1981. Calculating fugacity, Environ Sci Technol
15:1006-1014.
Mackay D, Wolkoff AW. 1973. Rate of evaporation of low-solubility
contaminants from water bodies to atmosphere. Environ Sci Technol 7:611-614.
*Mackison R, Stricoff R, Partridge U Jr, ed. 1981, Occupational health
guidelines for chemical hazards. Vol. 3. Washington, DC: US Department of
Health and Human Services, Public Health Service, Centers for Disease Control,
and US Department of Labor.
*Malaney GW. 1960. Oxidative abilities of aniline-acclimated activated
sludge. J Water Pollut Control Fed 32:1300-1311.
Malaney GW, Gerhold RM. 1969. Structural determinants in the oxidation of
aliphatic compounds by activated sludge. J Water Pollut Control Fed (Pt 2)
41:R18-R33,
*M.alaney GW, McKinney RE. 1966. Oxidative abilities of benzene-acclimated
activated sludge. Water Sewage Works 113:302-309.
*Maltoni C, Conti B, Cotti G. 1983. Benzene: A multipotential carcinogen.
Results of long-term bioassays performed at the Bologna Institute of Oncology.
Am J Ind Wed 4:589-630.
*Maltoni C, Conti B, Cotti G, et al. 1985. Experimental studies on benzene
carcinogenicity at the Bologna Institute of Oncology: Current results and
ongoing research. Am J Ind Med 7:415-446,
-------
165
8. REFERENCES
*Marion CV, Malaney GW. 1964. Ability of activated sludge microorganisms to
oxidize aromatic organic compounds. Proc 18th Ind Waste Conf Eng
Bull:297-308. As cited in EPA 1985a.
*Marks TA, Ledoux TA, Moore JA. 1982. Teratogenicity of a commercial xylene
mixture in the mouse. J Toxicol Environ Health 9:97-105.
*Martinez JS, Sala JJG, Vea AM, et al. 1989. Renal tubular acidosis with an
elevated anion gap in a 'glue sniffer.' Human Toxicol 8: 139-140. (Letter to
Editor)
^Maxwell MH. 1978. Safer substitutes for xylene and propylene oxide in
histology, haemotology, and electron microscopy. Med Lab Sci 35:401.
*McCarroll NE, Keech BJ, Piper CE. 1981a. A microsuspension adaptation of
the Bacillus subtilis "rec" assay. Environ Mutagenesis 3:607-616.
*McCarroll NE, Piper CE, Keech BH. 1981b, An E coli microsuspension assay
for the detection of DNA damage induced by direct-acting agents and
promutagens. Environ Mutagenesis 3:429-444.
McConnell EE, Solleveld HA, Swenberg JA, et al. 1986. Guidelines for
combining neoplasms for evaluation of rodent carcinogenesis studies. JNCI
76:283-289.
McCreary JJ, Jackson JG, Zoltek JJ. 1983. Toxic chemicals in an abandoned
phenolic waste site. Chemosphere 12:1619-1632.
¦*McDougal JN, Jepson GW, Clewell III HJ, et al. 1990. Dermal absorption of
organic chemical vapors in rats and humans. Fund Appl Toxicol 14:299-308.
*MDEQE. 1989. Written communication regarding Massachusetts guidelines for
xylene. Boston, Mass: Department of Environmental Quality Engineering,
Office of Research & Standards. (May 8).
*Merian E. 1982. The environmental chemistry of volatile hydrocarbons.
Toxicol Environ Chem 5:167-175.
*Merian E, Zander M. 1982. Volatile aromatics. In: Hutzinger G, ed.
Handbook of environmental chemistry. Vol. 3 (Pt B), Berlin: Springer,
117-161.
Mikulski PR, Wiglusz R, Dublewska A, et al. 1972. Investigation of exposure
of ships' painters to organic solvents. Br J Ind Med 29:450-453.
-------
166
8. REFERENCES
*Mill T. 1980. Chemical and. photo oxidation. In: Hutzinger 0, ed.
Handbook of environmental chemistry. Vol. 2, Springer-Verlag, Berlin 77-105.
Mill T. 1982. Hydrolysis and oxidation processes in the environment.
Environ Toxicol Chem 1:135-141.
*Mirkova E, Hinkova L, Vassileva L, et al. 1979. Xylene neurotoxicity in
pregnant rats and fetuses. Activ Nerv Supp (Praha) 21:265-268.
*Mirkova E, Antov G, Zajhov H, et al. 1982. [Assessment of inhalation
toxicity of the organic solvent xylene in experiment on pregnant rats], Prob
Khig 7:60-67. (Russian).
*Mirkova E, Zaikov C, Antov G, et al. 1983. Prenatal toxicity of xylene. J
Hyg Epidemiol Microbiol Immunol 27:337-343.
*Mohtashamipur E, Northpoth 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 behavior
during 4-hr inhalation exposure to prenarcotic concentrations of benzene and
its derivatives. Acta Physiol Hung 67:349-354.
Monnet R, Boiteau HL, Corneteau H. 1967. [A method for the identification
and titration of benzene, toluene and xylenes in complex solvents using
infra-red spectrophotometry]. Arch Mai Prof 28:861-866. (French).
*Morin M, Chambon P, Chambon R, et al. 1981. Measurement of exposure to
xylenes by separate determination of m- and p- methyl hippuric-acid in urine.
J Chromatogr 210:346-349.
*Morley R, Eccleston DW, Douglas CP, et al. 1970. Xylene poisoning: A
report on one fatal case and two cases of recovery after prolonged
unconsciousness. Br Med J 3:442-443.
*Morvai V, Hudak A, Ungvary G, et al. 1976. ECG changes in benzene, toluene
and xylene poisoned rats. Acta Med Acad Sci Hung 33:275-286.
*Morvai V, Ungvary G, Herrmann HJ, et al. 1987. Effects of quantitative
undernourishment, ethanol and xylene on coronary microvessels of rats. Acta
Morphol Hung 35:199-206.
Moser VC, Coggeshall EM, Balster RL. 1985. Effects of xylene isomers on
operant responding and motor performance in mice. Toxicol Appl Pharmacol
80:293-298.
-------
167
8. REFERENCES
Moszczynski P. 1980. [Results of rosette tests in persons having
professional contact with organic solvents containing benzene and its
homologues]. Immunol Pol 4:321-327. (Polish).
*Moszczynski P, Lisiewicz J. 1983. Occupational exposure to benzene, toluene
and xylene and the T lymphocyte functions. J Clin Hematol Oncol 13:37-41.
Moszczynski P, Lisiewicz J. 1984. [Cytochemical and immunological tests of
those exposed to paint-and-varnish organic solvents: IV. Activity of
nonspecific esterase in lymphocytes]. Med Pr 35:273-278. (Polish).
*Muller J, Greff G. 1984. Recherche de relations entre toxicite de molecules
d'interet industrial et proprietes physico-chimiques: Test d'irritation des
voies aeriennes superieures applique a quatre families chimiques. Food Chem
Toxic 22:661-664. (French).
Munnecke DM, Hsieh DPH. 1975. Microbial metabolism of a parathion-xylene
pesticide formulation. Appl Microbiol 30:575-580.
*Muralidhara, Krishnakumari MK. 1980. Mammalian toxicity of aromex & xylene
used in pesticidal formulations. Indian J Exp Biol 18:1148-1151.
*Nakajima T, Sato A. 1979. [Metabolic antagonism among benzene, toluene and
m-xylene in vitro]. Jpn J Ind Health 21:546-547. (Japanese).
¦*NAS. 1980. The alkyl benzenes. Washington, DC: National Academy of
Sciences. As cited in CHEMFATE 1988.
*NAS/NRC. 1989. Biological markers in reproductive toxicology. National
Academy of Sciences/National Research Council. Washington, DC: National
Academy Press, 15-35.
*Nathwani JS, Phillips CR. 1977. Adsorption-desorption of selected
hydrocarbons in crude oil in soils. Chemosphere 4:157-162.
*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 Planning
and Standards, Emissions Standards Division, Research Triangle Park, NC, by
Radian Corporation, Austin, TX. EPA 450/5-88-007.
National Cancer Institute (NCI). 1976. Guidelines for carcinogen bioassay in
small rodents. NCI Carcinogenesis Technical Report Series No. 1. Department
of Health, Education, and Welfare, Public Health Service, National Institutes
of Health.
-------
168
8. REFERENCES
Natusch DFS. 1978. Potentially carcinogenic species emitted to the
atmosphere by fossil- fueled power plants. Environ Health Perspect 22:79-90.
Nelson PF, Quigley SM. 1983. The m,p-xylenes: Ethylbenzene ratio. A
technique for estimating hydrocarbon age in ambient atmospheres. Atmos
Environ 17:659-662.
*Nelson KW, Ege JF Jr, Ross M, et al. 1943. Sensory response to certain
industrial solvent vapors. J Ind Hyg Toxicol 25:282-285.
*Nersesian W, Booth H, Hoxie D, et al. 1985. Illness in office attributed to
xylene [Letter]. Occup Health Saf 54:88.
*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.
*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.
*NFPA. 1978. Fire protection guide on hazardous materials. 7th ed. National
Fire Protection Association. Boston, MA. As cited in HSDB 1988.
Nilsen 0G, Toftgard R. 1980. The influence of organic solvents on cytochrome
P-450-mediated metabolism. 4th International Symposium: Microsomes, Drug
Oxidations, and Chemical Carcinogenesis 2:1235-1238.
*N10SH. 1975. Criteria for a recommended standard--occupational exposure to
xylene. Rockville, MD: U.S. Department of Health, Education, and Welfare,
Public Health Service, Center for Disease Control, National Institute for
Occupational Safety and Health. NIOSH 75-168, PB246-702.
*NI0SH. 1976. National occupational hazard survey (1970) [database].
Cincinnati, OH: National Institute for Occupational Safety and Health,
Department of Health and Human Services.
*NI0SH, 1984. National occupational exposure survey (1980-83) [database].
National Institute for Occupational Safety and Health, Department of Health
and Human Services.
*NI0SH. 1985. NIOSH pocket guide to chemical hazards. Washington, D.C: US
Department of Health and Human Services, Public Health Service, Centers for
Disease Control, National Institute for Occupational Safety and Health. DHEW
(NIOSH) Publ. No. 78-210., 236-237.
-------
169
8. REFERENCES
*NJDEP. 1984. Annual report for the governor and the legislature on the
amendments to the New Jersey safe drinking water act (A-280). Trenton, NJ:
NJ Department of Environmental Protection, Office of Science and Research.
*NJDEP. 1986. Results of initial testing for contaminants in public water
supplies under Assembly Bill A-280 through January 9, 1985. Trenton, NJ:
Office of Science and Research and Division of Water Resources.
*NJDEP. 1989. Written communication regarding New Jersey guidelines for
xylene. Xylene: Short-Term Action Level Document. Trenton, NJ: New Jersey
Department of Environmental Protection, Division of Science and Research.
(June 5).
*Norppa H, Vainio H. 1983. Induction of sister-chromatid exchanges by
styrene analogues in cultured human lymphocytes. Mutat Res 116:379-387.
*Norstrom A, Andersson B, Levin JO,et al. 1989. Biological monitoring of o-
xylene after experimental exposure in man: Determination of urinary excretion
products. Chemosphere 18: 1513-1523.
NPL. 1988. National priorities listing technical database. US
Environmental Protection Agency, August 1988.
*NRC. 1980. Drinking water and health. Vol. 3. Washington, DC: National
Academy Press, 178-181, 231-261.
*NTP. 1986. National Toxicology Program technical report on the toxicology
and carcinogenesis studies of xylenes (mixed) (60% m-xylene, 14% p-xylene, 9%
o-xylene, and 17% ethylbenzene) (CAS no. 1330-20-7) in F344/N rats and B6C3F1
mice (gavage studies). US Department of Health and Human Services, Public
Health Service, National Institutes of Health, National Toxicology Program.
NTP TR 327, NIH Publication No. 87-2583.
*NTP. 1988. National Toxicology Program: Review of current DHHS, DOE, and
EPA research related to toxicology: Fiscal year 1988. US Department of
Health and Human Services, Public Health Service, National Toxicology Program.
NTP-88-201.
*Nunes P, Benville PJ. 1979. Uptake and depuration of petroleum hydrocarbons
in the manila clam, Tapes semidecussata reeve. Bull Environ Contam Toxicol
21:719-726.
*Nutmagul W, Cronn DR, Hill HJ. 1983. Photoionization/flame-ionization
detection of atmospheric hydrocarbons after capillary gas chromatography.
Anal Chem 55:2160-2164.
-------
170
8. REFERENCES
*Nylen P, Ebendal T, Eriksdotter-Nilsson M, et al. 1989. Testicular atrophy
and loss of nerve growth factor-immunoreactive germ line in rats exposed to n-
hexane and a protective effect of simultaneous exposure to toluene or xylene.
Arch Toxicol 63: 296-307.
Ogata M. 1981. Quantitative determination of urinary metabolites in subjects
exposed to organic solvents. Acta Med Okayama 35:385-394.
*Ogata M. 1984. Estimation of solvent concentrations in ambient air from
urinary metabolite levels of workers exposed to solvents [Letter]. Ind Health
22:319-324.
Ogata M, Fugii T. 1979. Urinary excretion of hippuric acid and
m-methylhippuric acid after administration of toluene and m-xylene mixture to
rats. Int Arch Occup Environ Health 43:45-51.
Ogata M, Hobara T. 1979. A new direct method for colorimetric determination
of hippuric acid and methylhippuric acid as indices of toluene and m-xylene,
and its application to workers using thinner. Ind Health 17:61-72.
Ogata M, Miyake Y. 1975. Compound from floating petroleum accumulating in
fish. Water Research 9:1075-1078.
*0gata M, Miyake Y. 1978. Disappearance of aromatic hydrocarbons and organic
sulfur compounds from fish flesh reared in crude oil suspension. Water
Research 12:1041-1044.
*0gata M, Taguchi T. 1987. Quantitation of urinary metabolites of toluene,
xylene, styrene, ethylbenzene, benzene and phenol by automated high
performance liquid chromatography. Int Arch Occup Environ Health 59:263-272.
Ogata M, Tomokuni K, Takatsuka Y. 1969. Quantitative determination in urine
of hippuric acid and m- or p- methylhippuric. acid, metabolites of toluene and
m- or p-xylene. Brit J Ind Med 26:330-334.
*0gata M, Tomokuni K, Takatsuka Y. 1970. Urinary excretion of hippuric acid
and m- or p-methylhippuric acid in the urine of persons exposed to vapours of
toluene and m- or p-xylene as a test of exposure. Br J Ind Med 27:43-50.
*0gata M, Yamazaki Y, Sugihara R, et al. 1980. Quantitation of urinary
o-xylene metabolites of rats and human beings by high performance liquid
chromatography. Int Arch Occup Environ Health 46:127-139.
*0HM/TADS. 1988. Oil and hazardous materials/technical assistance data
system. [Database]. Baltimore, MD: Chemical Information System, Inc.
December 1985.
-------
171
8. REFERENCES
*01dham RG, Spraggins RL, Parr JL, et al. 1979. Analysis of organics in
ambient air. Austin, TX: Radian Corporation.
*01son BA, Gamberale F, Iregren A. 1985. Coexposure to toluene and p-xylene
in man: central nervous functions. Br J Ind Med 42:117-122.
*Omori T, Yamada K. 1970. Studies on the utilization of hydrocarbons by
microorganisms Part XVI. Detection of metabolic intermediates of xylene and
pseudocumene. Agric Biol Chem 34:659-663.
*0SHA. 1989. US Department of Labor, Occupational Safety and Health
Administration. Code of Federal Regulations. 29 CFR 1910.
*Otson R, Williams DT. 1981. Evaluation of a liquid-liquid extraction
technique for water pollutants. J Chromatogr 212:187-197.
*0tson R, Williams DT. 1982. Headspace chromatographic determination of
water pollutants. Anal Chem 54:942-946.
*0tson R, Williams DT, Biggs DC. 1982a. Relationships between raw water
quality, treatment, and occurrence of organics in Canadian potable water.
Bull Environ Contam Toxicol 28:396-403.
*0tson R, Williams DT, Bothwell PD. 1982b. Volatile organic compounds in
water at thirty Canadian potable water treatment facilities. J Assoc Off Anal
Chem 65:1370-1374.
*0tson R, Williams DT, Bothwell PD. 1983. Charcoal tube technique for
simultaneous determination of selected organics. Am Ind Hyg Assoc J
44:489-494.
*Padilla SS, Lyerly DP. 1989. Effects of p-xylene inhalation on axonal
transport in the rat retinal ganglion cells. Toxicol Appl Pharmacol 101: 390-
398.
Paksy KA, Molnar J, Nary M, et al. 1982. Comparative study on the acute
effects of benzene, toluene and m-xylene in the rat. Acta Physiol Acad Sci
Hung 59:317-324.
Pannwitz K-H. 1984. Sampling and analysis of organic solvent vapours in the
atmosphere: Comparison of active and passive sampling devices. Drager Review
52:19-28.
*Pap M, Varga C. 1987. Sister-chromatid exchanges in peripheral lymphocytes
of workers occupationally exposed to xylenes. Mutat Res 187:223-225.
-------
172
8. REFERENCES
*Parkin DM, Wahrendorf J, ed. 1987. Directory of on-going research in cancer
epidemiology 1987. Lyon, France: International Agency for Research on
Cancer, 219.
*Patel JM, Harper C, Drew RT. 1978. The biotransformation of p-xylene to a
toxic aldehyde. Drug Metab Dispos 6:368-374.
*Patel JM, Harper C, Gupta BN, et al. 1979. Changes in serum enzymes after
inhalation exposure of p-xylene. Bull Environ Contam Toxicol 21:17-24.
Pathiratne A, Puyear RL, Braramer JD. 1986. A comparative study of the
effects of benzene, toluene, and xylenes on their in vitro metabolism and
drug-metabolizing enzymes in rat liver. Toxicol Appl Pharmacol 82:272-280.
Pedersen PS, Ingwersen J, Nielsen T, et al. 1980. Effects of fuel,
lubricant, and engine operating parameters on the emission of polycyclic
aromatic hydrocarbons. Environ Sci Technol 14:71-79.
*Pleil JD, Oliver KD, McClenny WA. 1988. Ambient air analyses using
nonspecific flame ionization and electron capture detection compared to
specific detection by mass spectrometry. J Air Pollut Control Assoc
38:1006-1010.
*Poggi G, Giusiani M, Palagi U, et al. 1982. High-performance liquid
chromatography for the quantitative determination of the urinary metabolites
of toluene, xylene, and styrene. Int Arch Occup Environ Health 50:25-31.
*Polak J, Lu BCY. 1973. Mutual solubilities of hydrocarbons and water at 0
and 25 C. Can J Chem 51:4018-4033.
*Pool BL, Lin PZ. 1982. Mutagenicity testing in the Salmonella typhimurium
assay of phenolic compounds and phenolic fractions obtained from smokehouse
smoke condensates. Food Chem Toxicol 20:383-391.
*Pound AW. 1970. Induced cell proliferation and the initiation of skin
tumour formation in mice by ultraviolet light. Pathology 2:269-275.
*Pound AW, Withers HR. 1963. The influence of some irritant chemicals and
scarification on tumour initiation by urethane in mice. Br J Cancer
17:460-470.
*Price L. 1976. Aqueous solubility of petroleum as applied to its origin and
primary migration. Amer Assoc Petrol Geol Bull 60:213-244. As cited in
CESARS 1988.
-------
173
8. REFERENCES
*Pryor GT, Rebert CS, Howd RA. 1987. Hearing loss in rats caused by-
inhalation of mixed xylene and styrene. J Appl Toxicol 7:55-61,
*Pyykko K. 1980. Effects of methylbenzenes on microsomal enzymes in rat
liver, kidney and lung. Biochim Biophys Acta 633:1-9.
Pyykko K, Paavilainen S, Metsa-Ketela T, et al. 1987. The increasing and
decreasing effects of aromatic hydrocarbon solvents on pulmonary and hepatic
cytochrome P-450 in the rat. Pharmacol Toxicol 60:288-293.
*Rank J. 1985. Xylene induced feeding and drinking behavior and central
adrenergic receptor binding. Neurobehav Toxicol Teratol 7:421-426.
*Ransley DL. 1984. Xylenes and ethylbenzene. In: Grayson M, ed.
Kirk-Othmer encyclopedia of chemical technology. Vol. 24, 3rd ed. New York:
John Wiley & Sons, 709-744.
*Rappaport SM, Fraser DA. 1977. Air sampling and analysis in a rubber
vulcanization area. Am Ind Hyg Assoc J 38:205-210.
Ravishankara AR, Wagner S, Fischer S, et al. 1978. A kinetics study of the
reactions of OH with several aromatic and olefinic compounds. Int J Chera
Kinetics 10:783-804.
Raymond RL, Jamison VW, Hudson JO. 1971. Hydrocarbon cooxidation in
microbial systems. Lipids 6:453-457.
*Recchia G, Perbellini L, Prati GF, et al. 1985. [Coma due to accidental
ingestion of xylene. Treatment with charcoal hemoperfusion]. Med Lav
76:67-73. (Italian).
Reinhard M, Goodman NL, Barker JF. 1984. Occurrence and distribution of
organic chemicals in two landfill leachate plumes. Environ Sci Technol
18:953-961.
*Rhue RD, Rao PSC, Smith RE. 1988. Vapor-phase adsorption of alkylbenzenes
and water on soils and clays. Chemosphere 17:727-741.
*RIDH. 1989. Written communication regarding xylene levels in private well
water, public drinking water and health-based guidelines. Providence, RI:
Rhode Island Department of Health (June 19).
*Riihimaki V. 1979. Percutaneous absorption of m-xylene from a mixture of
m-xylene and isobutyl alcohol in man. Scand J Work Environ Health 5:143-150.
Riihimaki V. 1979. Conjugation and urinary excretion of toluene and m-xylene
metabolites in a man. Scand J Work Environ Health 5:135-142.
-------
174
8. REFERENCES
*Riihimaki V, Hanninen 0. 1987. Xylenes. In: Snyder R, ed. Toxicity and
metabolism of industrial solvents. Vol. 1, 2nd ed. Amsterdam: Elsevier
Science Publishers B.V., 64-84.
*Riihimaki V, Pfaffli P. 1978. Percutaneous absorption of solvent vapors in
man. Scand J Work Environ Health 4:73-85.
*Riihimaki V, Savolainen K. 1980. Human exposure to m-xylene. Kinetics and
acute effects on the central nervous system. Ann Occup Hyg 23:411-422.
*Riihimaki V, Pfaffli P, Savolainen K. 1979a. Kinetics of m-xylene in man:
Influence of intermittent physical exercise and changing environmental
concentrations on kinetics. Scand J Work Environ Health 5:232-248.
*Riihimaki V, Pfaffli P, Savolainen K, et al. 1979b. Kinetics of m-xylene in
man: General features of absorption, distribution, biotranformation and
excretion in repetitive inhalation exposure. Scand J Work Environ Health
5:217-231.
*Riihimaki V, Laine A, Savolainen K, et al. 1982a. Acute solvent-ethanol
interactions with special references to xylene. Scand J Work Environ Health
8:77-79.
*Riihimaki V, Savolainen K, Pfaffli P, et al. 1982b. Metabolic interaction
between m-xylene and ethanol. Arch Toxicol 49:253-263.
^Roberts JM, Fehsenfeld FC, Liu SG, et al. 1984. Measurements of aromatic
hydrocarbon ratios and NOx concentrations in the rural troposphere:
Observation of air mass photochemical aging and NOx removal. Atmos Environ
18:2421-2432.
^Roberts FP, Lucas EG, Marsden CD, et al. 1988. Near-pure xylene causing
reversible neuropsychiatric disturbance [Letter]. Lancet 2:273.
"*Romer KG, Federsel RJ, 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, et al. 1962. Odor thresholds of mixed organic chemicals. J Water
Pollut Control Fed 34:7-14.
Rosen MB, Crofton KM, Chernoff N. 1986. Postnatal evaluation of prenatal
exposure to p-xylene in the rat. Toxicol Lett 34:223-229.
-------
175
8. REFERENCES
*Rosengren LE, Kjellstrand P, Aurell A, et al. 1986. Irreversible effects of
xylene on the brain after long term exposure: A quantitative study of DNA and
the glial cell marker proteins S-100 and GFA. Neurotoxicology 7:121-136.
*Rumsey TS, Cabell CA, Bond J. 1969. Effects of an organic phosphorus
systemic insecticide on reproductive performance in rats. Am J Vet Res 30:
2209-2214.
*SAI. 1981. Human exposure to atmospheric concentrations of selected
chemicals. Vol. 2. Research Triangle Park, NC: US Environmental Protection
Agency, Office of Air Quality Planning and Standards., 29.
Saita G, Moreo L. 1959. [Thalassemia and occupational blood disease: I.
Thalassemia and chronic benzol poisoning]. Med Lav 50:25. (Italian).
Samini B, Falbo L. 1982. Monitoring of workers exposure to low levels of
airborne monomers in a polystyrene production plan. Am Ind Hyg Assoc J
43:858-862.
*Sanborn HR, Malins DC. 1980. The disposition of aromatic hydrocarbons in
adult spot shrimp (Pandalus piatyceros) and the formation of metabolites of
naphthalene in adult and larval spot shrimp. Xenobiotica 10:193-200.
*Sandmeyer EE. 1981. Aromatic hydrocarbons. In: Clayton GD, Clayton FE,
eds. Patty's Industrial Hygiene and Toxicology. Vol. 2B, 3rd revised ed.
New York, NY: John Wiley & Sons, 3253-3431.
*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,
*Santodonato J, Bosch S, Meylan W, et al. 1985. Monograph on human exposure
to chemicals in the workplace: Xylene. Report to National Cancer Institute,
Division of Cancer Etiology, Bethesda, MD, by Syracuse Research Corporation,
Syracuse, NY. SRC-TR-84-1126, PB86-155124.
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.
*Sauer TJ, Sackett WM, Jeffrey LM. 1978. Volatile liquid hydrocarbons in the
surface coastal waters of the Gulf of Mexico. Mar Chem 7:1-16.
*Saunders RA, Blachly CH, Kovacina TA, et al. 1975, Identification of
volatile organic contaminants in Washington, D.C. municipal water. Water
Research 9:1143-1145.
-------
176
8. REFERENCES
Savage GM, Sharpe H. 1987. Assessment of non-regulated hazardous wastes in
the Seattle area. Waste Management and Research 5:159-171.
*Savolainen K. 1980. Combined effects of xylene and alcohol on the central
nervous system. Acta Pharmacol Toxicol 46:366-372.
*Savolainen K, Linnavuo M. 1979. Effects of m-xylene on human equilibrium
measured with a quantitative method. Acta Pharmacol Toxicol 44:315-318.
*Savolainen K, Pfaffli P. 1980. Dose-dependent neurochemical changes during
short-term inhalation exposure to m-xylene. Arch. Toxicol. 45(2):117-122.
Savolainen K, Riihimaki V. 1981a. Xylene and alcohol involvement of the
human equilibrium system. Acta Pharmacol Toxicol 49:447-451.
*Savolainen K, Riihimaki V. 1981b. An early sign of xylene effect on human
equilibrium. Acta Pharmacol Toxicol 48:279-283.
*Savolainen H, Seppalainen AM. 1979. Biochemical and physiological effects
of organic solvents on rat axon membranes isolated by a new technique.
Neurotoxicology 1:467-477.
*Savolainen H, Vainio H, Helojoki M, et al. 1978. Biochemical and
toxicological effects of short-term, intermittent xylene inhalation exposure
and combined ethanol intake. Arch Toxicol 41:195-205.
^Savolainen K, Pfaffli P, Helojoki M, et al. 1979a. Neurochemical and
behavioral effects of long-term intermittent inhalation. Acta Pharmacol
Toxicol 44:200-207.
*Savolainen K, Riihimaki V, Linnoila M. 1979b. Effects of short-term xylene
exposure on psychophysiological functions in man. Int Arch Occup Environ
Health 44:201-211.
*Savolainen K, Riihimaki V, Vaheri E, et al. 1980. Effects of xylene and
alcohol on vestibular and visual functions in man. Scand J Work Environ
Health 6:94-103.
Savolainen K, Riihimaki V, Seppalainen AM, et al. 1980. Effects of
short-term m-xylene exposure and physical exercise on the central nervous
system. Int Arch Occup Environ Health 45:105-121.
-------
177
8. REFERENCES
*Savolainen K, Riihimaki V, Laine A. 1982a. Biphasic effects of inhaled
solvents on human equilibrium. Acta Pharmacol Toxicol 51:237-242.
*Savolainen K, Riihimaki V, Laine A, et al. 1982b. Short-term exposure of
human subjects to m-xylene and 1,1,1-trichloroethane. Arch Toxicol (Suppl)
5:96-99.
*Savolainen K, Kekoni J, Riihimaki V, et al. 1984. Immediate effects of
m-xylene on the human central nervous system. Arch Toxicol Suppl 7:412-417.
*Savolainen K, Riihimaki V, Luukkonen R, et al, 1985. Changes in the sense
of balance correlate with concentrations of m-xylene. Br J Ind Med
42:765-769.
Savolainen K, Riihimaki V, Muona 0, et al. 1985. Conversely exposure-related
effects between atmospheric m-xylene concentrations and human body sense of
balance. Acta Pharmacol Toxicol 57:67-71.
*Sax NI. 1979. Dangerous properties of industrial materials, 5th ed. New
York, NY: Van Nostrand Reinhold Co. As cited in CESARS 1988.
Sax NI, Lewis RJ Sr. 1986. Rapid guide to hazardous chemicals in the
workplace. New York, NY: Van Nostrand Reinhold Co., 178-179.
*Sax NI, Lewis RJ Sr. 1989. Dangerous properties of industrial materials.
Vol. Ill, 7th ed. New York, NY: Van Nostrand Reinhold Company, 3495-3497.
Schramm M, Warrick AW, Fuller WH, 1986. Permeability of soils to four
organic liquids and water. Hazardous Waste & Hazardous Materials 3:21-27.
Schumaker H, Grandjean E. 1960. [Comparative investigations on the
anesthetic effect and acute toxicity of 9 solvents]. Arch Gewerbepathol
Gewerbehyg 18:109-119. (German).
Schwarzenbach RP, Westall J. 1981. Transport of nonpolar organic compounds
from surface water to groundwater. Laboratory Sorption Studies. Environ Sci
Technol 15:1360-1367.
Sedivec V, Flek J. 1976a. Exposure test for xylenes, Int Arch Occup
Environ Health 37:219-232.
*Sedivec V, Flek J. 1976b. The absorption, metabolism, and excretion of
xylenes in man. Int Arch Occup Environ Health 37:205-217.
-------
178
8. REFERENCES
Seidenberg JM, Anderson DG, Becker RA. 1986. Validation of an in vivo
developmental toxicity screen in the mouse. Teratogenesis, Carcinogenesis,
and Mutagenesis 6: 361-374.
*Seidenberg JM, Becker RA. 1987. A summary of the results of 55 chemicals
screened for developmental toxicity in mice. Teratogenesis, Carcinogenesis,
and Mutagenesis 7:17-28.
*Seifert B, Abraham H-J. 1982. Indoor air concentrations of benzene and some
other aromatic hydrocarbons. Ecotoxicol Environ Safety 6:190-192.
*Seifert B, Abraham H-J. 1983. Use of passive samplers for the determination
of gaseous organic substances. Int J Environ Anal Chem 13:237-253.
Seila RL. 1979. Non-urban hydrocarbon concentrations in ambient air north of
Houston, Texas. Research Triangle Park, NC: US Environmental Protection
Agency, Office of Research and Development, Environmental Sciences Research
Laboratory-RTP, NC. EPA 600/3-79-010 PB 293227., 38.
*Seip HM, Alstad J, Carlberg GE, et al. 1986. Measurement of mobility of
organic compounds in soils. Sci Total Environ 50:87-101.
*Senczuk W, Orlowski J. 1978. Absorption of m-xylene vapours through the
respiratory track and excretion. Br J Ind Med 35:50-55.
Seppalainen AM. 1988. Neurophysiological approaches to the detection of
early neurotoxicity in humans. CRC Crit Rev Toxicol 18:245-298.
Seppalainen AM, Savolainen K, Kovala T. 1981. Changes induced by xylene and
alcohol in human evoked potentials. Electroencephalogr Clin Neurophysiol
51:148-155.
*Seppalainen AM, Salmi T, Savolainen K, et al. 1983. Visual evoked
potentials in short-term exposure of human subjects to m- xylene and
1,1,1-trichloroethane. Appl Behav Pharmacol Toxicol (Lect Workshop):349-352.
*Seppalainen AM, Laine A, Salmi T, et al. 1989. Changes induced by short-
term xylene exposure in human evoked potentials. Int Arch Environ Health
61:443-449.
*Shackelford WM, Keith LH. 1976. Frequency of organic compounds identified
in water. Athens, GA: Environmental Protection Agency. EPA 600/4-76-062.
Shen TT. 1982. Air quality assessment for land disposal of industrial
wastes. Environ Management 6:297-305.
-------
179
8. REFERENCES
*Shimizu H, Suzuki Y, Takemura N, et al. 1985. The results of microbial
mutation test for forty-three industrial chemicals. Jpn J Ind Health
27:400-419.
*Sikora H, Gala J. 1957. [Effects of acute xylene poisoning on heart muscle
discussed]. Med Pr 18:75-77. (Polish).
Singh HB, Salas LJ, Smith AJ, et al. 1981. Measurements of some potentially
hazardous organic chemicals in urban environments. Atmos Environ 15:601-612.
Sittig M. 1981. Handbook of toxic and hazardous chemicals. Park Ridge, NJ:
Noyes Publications, 714.
Sittig M. 1985. Handbook of toxic and hazardous chemicals and carcinogens.
Park Ridge, NJ: Noyes Publications, 931-933.
Smith BR, Bend JR. 1981. Metabolic Interactions of hydrocarbons with
mammalian lung. Reviews in Biochemical Toxicology 3:77-122.
*Smith BR, Plummer JL, Wolf CR, et al. 1982. p-Xylene metabolism by rabbit
lung and liver and its relationship to the selective destruction of pulmonary
cytochrome P-450. J Pharmacol Exp Ther 223:736-742.
*Smolik R, Grzybek-Hryncewicz K, Lange A, et al. 1973. Serum complement
level in workers exposed to benzene, toluene and xylene. Int Arch Arbeitsmed
31:243-247.
*Smyth HJ, Carpenter CP, Weil CS, et al. 1962. Range-finding toxicity data:
List VI. Am Ind Hyg Assoc J 23:95-107.
Speck B, Moeschlin S. 1968. [Effect of toluene, xylene, chloramphenicol, and
thiouracil on bone marrow. Experimental autoradiographic study with
thymidine-3H]. Schweiz Med Wochensch 42:1684-1686. (German).
*SRC. 1988. Calculated values. Syracuse Research Corporation. As cited in
CHEMFATE 1988.
*SRI. 1988. Directory of chemical producers: United States of America.
Menlo Park, CA: SRI, International, 1052-1053.
Stedman DH, Niki H. 1973. Ozonolysis rates of some atmospheric gases.
Environ Lett 4:303-310.
*Stephan H, Stephen T. 1963. Solubilities of inorganic and organic
compounds. Volume I. Binary systems. New York, NY: Macmillan. As cited in
ISHOW 1988.
-------
180
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.
*Sugihara R, Ogata M. 1978. Quantitation of urinary m- and p-methylhippuric
acids as indices of m- and p-xylene exposure. Int Arch Occup Environ Health
41:281-286.
*Sukhanova VA, Makar'eva LM, Bo'iko VI. 1969. [A study of the functional
properties of leukocytes in workers engaged in the production of xylene]. Gig
Sanit 34:130-132. (Russian).
*Szybalski W. 1958, Special microbiological systems II. Observations on
chemical mutagenesis in microorganisms. Ann NY Acad Sci 76:465-489.
Tabacova S. 1986. Maternal exposure to environmental chemicals.
Neurotoxicology 7:421-440.
*Taskinen H, Anttila A, Lindbohm ML, et al. 1989. Spontaneous abortions and
congenital malformations among the wives of men occupationally exposed to
organic solvents. Scand J Work Environ Health 15: 345-352.
*Tatrai E, Ungvary G. 1980. Changes induced by o-xylene inhalations in the
rat liver. Acta Med Acad Sci Hung 37:211-216.
Tatrai E, Hudak A, Barcza G, et al. 1979. [Embryotoxic effect of
m-xylene], Egeszsegtudomany 23:147-151. (Hungarian).
*Tatrai E, Ungvary G, Horvath E, et al. 1980. Embryotoxic effect of
para-xylene. Acta Physiol Acad Sci Hung 56:90-91.
*Tatrai E, Ungvary G, Cseh IR, et al. 1981. The effects of long-term
inhalation of ortho-xylene on the liver. Ind Enviv Xenobiotica, Proc Int Conf
:293-300.
Tham R, Bunnfors I, Eriksson B, et al. 1984. Vestibulo-ocular disturbances
in rats exposed to organic solvents. Acta Pharmacol Toxicol 54:58-63.
Thorburn S, Colenutt BA. 1979. A gas chromatographic comparison of volatile
organic compounds in urban and rural atmospheres. Int J Environ Stud
13:265-271.
*Toftgard R, Gustafsson J-A. 1980. Biotransformation of organic solvents: A
review. Scand J Work Environ Health 6:1-18.
-------
181
8. REFERENCES
*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.
*Toftgard R, Nilsen OG, Gustafsson J-A. 1981. Changes in rat liver
microsomal cytochrome P-450 and enzymatic activities after the inhalation of
n-hexane, xylene, methyl ethyl ketone and methylchloroform for four weeks.
Scand J Work Environ Health 7:31-37.
Toftgard R, Halpert J, Gustafsson JA. 1983. Xylene induces a cytochrome
P-450 isozyme in rat liver similar to the major isozyme induced by
phenobarbital. Mol Pharmacol 23:265-271.
Toftgard R, Nilsen OG, Glaumann H, et al. 1983. Induction of cytochrome
P-450 in the rat liver after exposure to xylenes, dose-response relationship
and dependence on endocrine factors. Toxicology 27:119-137.
Toftgard R, Haaparanta T, Halpert J. 1986. Rat lung and liver cytochrome
P-450 isozymes involved in the hydroxylation. Toxicology 39:225-231.
Triebig G, Schaller K-H. 1986. Air monitoring of solvent exposed workers
with passive samplers in comparison to "biological monitoring (BM)".
Toxicological and Environmental Chemistry 12:285-312.
*Tsuruta H. 1982. Percutaneous absorption of organic solvents: III. On the
penetration rates. Ind Health 20:335-345.
*Tsuruta H, Iwasaki K. 1984. A procedure for determining volatile solvents
in mouse whole body. Ind Health 22:219-222.
Tuazon EC, Atkinson R, MacLeod H, et al, 1984. Yields of glyoxal and
methylglyoxal from the N0x--air photooxidations of toluene and m- and
p-xylene. Environ Sci Technol 18:981-984.
*Ungvary G. 1985. The possible contribution of industrial chemicals (organic
solvents) to the incidence of congenital defects caused by teratogenic drugs
and consumer goods--an experimental study. Prog Clin Biol Res 160: 295-300,
Ungvary G, Donath T. 1984. Effect of benzene and its methyl-derivatives
(toluene, para-xylene) on postganglionic noradrenergic nerves. Z Mikrosk-Anat
Forsch (Leipz) 98:755-763.
-------
182
8. REFERENCES
*Ungvary G, Tatrai E. 1985. On the embryotoxic effects of benzene and its
allkyl derivatives in mice, rats, and rabbits. Arch Toxicol [Suppl]
8:425-430.
Ungvary G, Tatrai E, Barcza G, et al. 1979. [Acute toxicity of toluene, o-,
m- and p-xylene, and of their mixtures, in rats]. Munkavedelem 25:37-38,
(Hungarian).
*Ungvary G, Cseh J, Manyai S, et al. 1980a. Enzyme induction by o-xylene
inhalation. Acta Med Acad Sci Hung 37:115-120.
*Ungvary G, Tatrai E, Hudak A, et al. 1980b. Studies on the embryotoxic
effects of ortho-, meta- and para-xylene. Toxicology 18:61-74.
*Ungvary G, Varga B, Horvath E, et al. 1981. Study on the role of maternal
sex steroid production and metabolism in the embryotoxicity of para-xylene.
Toxicology 19:263-268.
*USD0T. 1978. Chemical hazard response information system (CHRIS). Manuals
1 and 2. Washington, DC: US Coast Guard. As cited in CESARS 1988.
*USITC. 1988. Synthetic organic chemicals: United States production and
sales, 1987. Washington, DC: US International Trade Commission. USITC
Publication 2118.
Utidjian H. 1976. I. Recommendations for a xylene standard. J Occ Med
18:567-572.
*van Doom R, Bos RP, Brouns RME, et al. 1980. Effect of toluene and xylenes
on liver glutathione and their urinary excretion as mercapturic acids in the
rat. Arch Toxicol 43:293-304.
van Doom R, Leijdekkers CM, Bos RP, et al. 1981. Alcohol and sulfate
intermediates in the metabolism of toluene and xylenes to mercapturic acids.
J Appl Toxicol 1:236-242.
Van Roosmalen PB, Drummond I. 1978. Simultaneous determination by gas
chromatography of the major metabolites. Br J Ind Med 35:56-60.
Veith GD, Defoe DL, Bergstadt BV. 1979. Measuring and estimating the
bioconcentration factor of chemicals in fish. J Fish Res Board Can
36:1040-1048.
Venkataramani ES, Ahlert RC. 1984. Rapid aerobic biostabilization of
high-strength industrial landfill leachate. J Water Pollut Control Fed
56:1178-1184.
-------
183
8. REFERENCES
*Verschueren K. 1977. Handbook of environmental data on organic chemicals.
New York, NY: Van Nostrand Reinhold Co. As cited in CESARS 1988.
*Verschueren K. 1983. Handbook of environmental data on organic chemicals.
2nd ed. New York, NY: Van Nostrand Reinhold Company, 1188-1195.
*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 Burg R. 1982. Toxicology updates: Xylene. J Appl Toxicol 2:269-271.
*Vowles PD, Mantoura RFC. 1987. Sediment-water partition coefficients and
HPLC retention factors of aromatic hydrocarbons. Chemosphere 16:109-116.
Wallace LA. 1986. Personal exposures, indoor and outdoor air concentrations
and 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 L, Clayton CA. 1987. Volatile organic chemicals in 600 U.S. homes:
Major sources of personal exposure. Report to US Environmental Protection
Agency, Office of Acid Deposition, Environmental Monitoring and Quality
Assurance, Washington, D.C,, by Research Triangle Institute, Research Triangle
Park, NC. EPA/600/D-87/155.
Wallace LA, Pellizzar ED, Hartwell TD, Sparacino CM, Sheldon LS, Zelon H.
1985. Personal exposures, indoor-outdoor relationships, and breath levels of
toxic air pollutants measured for 355 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.
-------
184
8. REFERENCES
¦^Wallace L, Jungers R, Sheldon L, et al. 1987b. Volatile organic chemicals
in 10 public-access buildings. Report to US Environmental Protection Agency,
Office of Research and Development, Office of Deposition, Environmental
Monitoring and Quality Assurance, Washington, D.C., by Research Triangle
Institute, Research Triangle Park, NC. EPA/600/D-87/152.
Wallace L, Pellizzari E, Hartwell TD, et al. 1987. Exposures to benzene and
other volatile compounds from active and passive smoking. Arch Environ Health
42:272-279.
*Wallen M, Holm S, Byfalt Nordqvist M. 1985. Coexposure to toluene and
p-xylene in man: uptake and elimination. Br J Ind Med 42:111-116.
^Washington WJ, Murthy RC, Doye A, et al. 1983. Induction of morphologically
abnormal sperm in rats exposed to o-xylene. Arch Andrology 11:233-237.
Wathne BM. 1983. Measurements of benzene, toluene and xylenes in urban air.
Atmos Environ 17:1713-1722.
*Weast RC, ed. 1988. CRC handbook of chemistry and physics. 6th ed. Boca
Raton, FL: CRC Press, Inc, C548-C550.
Weiss G, ed. 1986. Hazardous chemicals data book. 2nd ed. Park Ridge, NJ:
Noyes Data Corporation, 1023-1025.
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.
WHO. 1981. Recommended health-based limits in occupational exposure to
selected organic solvents. Geneva, Switzerland: World Health Organization,
84.
*Wilcosky TC, Checkoway H, Marshall EG, Tyroler HA. 1984. Cancer mortality
and solvent exposures in the rubber industry. Am Ind Hyg Assoc J 45:809-811.
Williams PA, Morsey MJ. 1976. Ubiquity of plasmids in coding for toluene and
xylene metabolism in soil bacteria: Evidence for the existence of new TOL
plasmids. J Bacteriol 125:818-828.
*Williams DT, Nestmann ER, LeBel GL, et al. 1982. Determination of mutagenic
potential and organic contaminants of Great Lakes drinking water. Chemosphere
11:263-276.
-------
185
8. REFERENCES
*Wimolwattanapun S, Ghosh TK, Mookherjee S, et al. 1987. Effect of
inhalation of xylene on intracranial self-stimulation behavior in rat.
Neuropharmacology 26:1629-1632.
*Windholz M, ed. 1983. The merck index. 10th ed. Rahway, NJ: Merck & Co.,
Inc., 1447-1448.
*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.
*Yalkowsky SH, Valvani SC. 1976. Partition coefficients and surface areas of
some alkylbenzenes. J Med Chem 19:727-728.
Yamada C. 1980. [Experimental studies on the pathomorphological changes in
the poisoning of hydrocarbons: Benzene, toluene, p-xylene and n-heptane].
Tokyo Med Coll 38:591-606. (Japanese).
Yanagihara S, Shimada I, Shinoyama E, et al. 1977. Photochemical
reactivities of hydrocarbons. Proc Int Clean Air Congr:472-477.
*Zhong B, Baozhen, Tang, et al. 1980, A comparative study of the cytogenetic
effects of benzene, toluene and xylene. Chlung 2: 29-31,
-------
187
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.
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9. GLOSSARY
EPA Health Advisory --An estimate of acceptable drinking water levels for a
chemical substance based on health effects information. A health advisory is
not a legally enforceable federal standard, but serves as technical guidance
to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental
concentration of a contaminant from which one could escape within 30 min
without any escape-impairing symptoms or irreversible health effects.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days
as specified in the Toxicological Profiles.
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 Coneentration(L0) (LClq) -- The lowest concentration of a chemical in
air which has been reported to have caused death in humans or animals.
Lethal Concentration{50) (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{Ii0, (LD^,) -- 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(30) (LDS0) -- The dose of a chemical which has been calculated to
cause death in 50% of a defined experimental animal population.
Lethal Time(S0) (LT50) -- A calculated period of time within which a specific
concentration of a chemical is expected to cause death in 50% of a defined
experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in
a study, or group of studies, that produces statistically or biologically
significant increases in frequency or severity of adverse effects between the
exposed population and its appropriate control.
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.
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189
9. GLOSSARY
Minimal Risk Level --An estimat, of daily human exposure to a chemical that
is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen -- A substance that causes mutations, A mutation is a change in the
genetic material in a body cell. Mutations can lead to birth defects,
miscarriages, or cancer.
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which
there were no statistically or biologically significant increases in frequency
or severity of adverse effects seen between the exposed population and its
appropriate control. Effects may be produced at this dose, but they are not
considered to be adverse.
Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the
concentrations of a chemical in n-octanol and water, in dilute solution.
Permissible Exposure Limit (PEL) --An allowable exposure level in workplace
air averaged over an 8-hour shift.
qx* -- 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 /ig/L for water, mg/kg/day for food, and
/ig/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.
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190
9. GLOSSARY
Reproductive Toxicity -- The occurrence of adverse effects on the reproductive
system that may result from exposure to a chemical. The toxicity may be
directed to the reproductive organs and/or the related endocrine system. The
manifestation of such toxicity may be noted as alterations in sexual behavior,
fertility, pregnancy outcomes, or modifications in other functions that are
dependent on the integrity of this system.
Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers
can be exposed for up to 15 min continually. No more than four excursions are
allowed per day, and there must be at least 60 min between exposure periods.
The daily TLV-TWA may not be exceeded.
Target Organ Toxicity -- This term covers a broad range of adverse effects on
target organs or physiological systems (e.g., renal, cardiovascular) extending
from those arising through a single limited exposure to those assumed over a
lifetime of exposure to a chemical.
Teratogen -- A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV) -- A concentration of a substance to which most
workers can be exposed without adverse effect. "The TLV may be expressed as a
TWA, as a STEL, or as a CL.
Time-Weighted Average (TWA) --An allowable exposure concentration averaged
over a normal 8-hour workday or 40-hour workweek.
Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route
other than inhalation, which is expected to cause a specific toxic effect in
50% of a defined experimental animal population.
Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD
from experimental data. XJFs 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 xylene. The panel consisted of
the following members: Dr. Sanford W. Bigelow, President, MultiSciences,
Inc.; Dr. Harvey Checkoway, Department of Environmental Health, School of
Public Health, University of Washington; Dr. Lloyd Hastings, Department of
Environmental Health, College of Medicine, University of Cincinnati;
Dr. Ronald Hood, Biology Department, The University of Alabama; and
Dr. Charles 0. Ward, private consultant. These experts collectively have
knowledge of xylene's physical and chemical properties, toxicokinetics, key
health end points, mechanisms of action, human and animal exposure, and
quantification of risk to humans. All reviewers were selected in conformity
with the conditions for peer review specified in Section 104(i)(13) of the
Comprehensive Environmental Response, Compensation, and Liability Act, as
amended.
Scientist from the Agency for Toxic Substances and Disease Registry
(ATSDR) have reviewed the peer reviewers' comments and determined which
comments will be included in the profile. A listing of the peer reviewers'
comments not incorporated in the profile, with a brief explanation of the
rationale for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to imply
its approval of the profile's final content. The responsibility for the
content of this profile lies with the Agency for Toxic Substances and Disease
Registry.
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