Toxicological
Profile
for
NITROBENZENE
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
TP-90-19
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TOXICOLOGICAL PROFILE FOR
NITROBENZENE
Prepared by:
Life Systems, Inc.
Under Subcontract to:
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.
Wi ., M.P.H.
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 NITROBENZENE? 1
1.2 HOW MIGHT I BE EXPOSED TO NITROBENZENE? 2
1. 3 HOW CAN NITROBENZENE ENTER AND LEAVE MY BODY? 2
1.4 HOW CAN NITROBENZENE AFFECT MY HEALTH? 3
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE
BEEN EXPOSED TO NITROBENZENE? 8
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE
TO PROTECT HUMAN HEALTH? 8
1.8 WHERE CAN I GET MORE INFORMATION? 9
2. HEALTH EFFECTS 11
2 .1 INTRODUCTION 11
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 11
2.2.1 Inhalation Exposure 12
2.2.1.1 Death 12
2.2.1.2 Systemic Effects 12
2.2.1.3 Immunological Effects 18
2.2.1.4 Neurological Effects 18
2.2.1.5 Developmental Effects 18
2.2.1.6 Reproductive Effects 19
2.2.1.7 Genotoxic Effects 19
2.2.1.8 Cancer 20
2.2.2 Oral Exposure 20
2.2.2.1 Death 20
2.2.2.2 Systemic Effects 20
2.2.2.3 Immunological Effects 23
2.2.2.4 Neurological Effects 23
2.2.2.5 Developmental Effects 24
2.2.2.6 Reproductive Effects 24
2.2.2.7 Genotoxic Effects . 24
2.2.2.8 Cancer 24
2.2.3 Dermal Exposure 24
2.2.3.1 Death 25
2.2.3.2 Systemic Effects 25
2.2.3.3 Immunological Effects 26
2.2.3.4 Neurological Effects 26
2.2.3.5 Developmental Effects 26
2.2.3.6 Reproductive Effects . 26
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2.2.3.7 Genotoxic Effects 26
2.2.3.8 Cancer 26
2.3 TOXICOKINETICS "'.!!! 26
2.3.1 Absorption 26
2.3.1.1 Inhalation Exposure 26
2.3.1.2 Oral Exposure 26
2.3.1.3 Dermal Exposure 26
2.3.2 Distribution 27
2.3.2.1 Inhalation Exposure 27
2.3.2.2 Oral Exposure 27
2.3.2.3 Dermal Exposure 2g
2.3.3 Metabolism 2g
2.3.4 Excretion 2g
2.3.4.1 Inhalation Exposure 28
2.3.4.2 Oral Exposure 28
2.3.4.3 Dermal Exposure 2g
2.4 RELEVANCE TO PUBLIC HEALTH . 29
2.5 BIOMARKERS OF EXPOSURE AND EFFECT 33
2.5.1 Biomarkers Used to Identify and/or Quantify Exposure
to Nitrobenzene 34
2.5.2 Biomarkers Used to Characterize Effects Caused by
Nitrobenzene
2.6 INTERACTIONS WITH OTHER CHEMICALS '!!!'! 34
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE .... 35
2.8 ADEQUACY OF THE DATABASE 36
2.8.1 Existing Information on Health Effects of
Nitrobenzene 26
2.8.2 Identification of Data Needs 26
2.8.3 On-going Studies ^
3. CHEMICAL AND PHYSICAL INFORMATION 43
3.1 CHEMICAL IDENTITY ! 43
3.2 PHYSICAL AND CHEMICAL PROPERTIES .'!!!' 43
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION * 47
4.2 IMPORT • • • ¦
4.3 USE 47
4.4 DISPOSAL ! ! ! '. 48
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW '
5.2 RELEASES TO THE ENVIRONMENT ' /*
c*9
5.2.1 Air *
5.2.2 Water '
5.2.3 Soil " It
5.3 ENVIRONMENTAL FATE ^ ^
5.3.1 Transport and Partitioning __
5.3.2 Transformation and Degradation
5.3.2.1 Air
5.3.2.2 Water | ^
J J
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5.3.2.3 Soil 58
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 58
5.4.1 Air 58
5.4.2 Water 59
5.4.3 Soil 59
5.4.4 Other Media 60
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 60
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 60
5.7 ADEQUACY OF THE DATABASE 61
5.7.1 Identification of Data Needs 61
5.7.2 On-going Studies 63
6. ANALYTICAL METHODS 65
6.1 BIOLOGICAL MATERIALS 65
6.2 ENVIRONMENTAL SAMPLES 65
6.3 ADEQUACY OF THE DATABASE 67
6.3.1 Identification of Data Needs 67
6.3.2 On-going Studies 69
7. REGULATIONS AND ADVISORIES 71
8. REFERENCES 75
9. GLOSSARY 105
APPENDIX 109
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ix
LIST OF FIGURES
2-1 Levels of Significant Exposure to Nitrobenzene - Inhalation .... 16
2-2 Levels of Significant Exposure to Nitrobenzene - Oral 22
2-3 Existing Information on Health Effects of Nitrobenzene 37
5-1 Frequency of Sites with Nitrobenzene Contamination 50
5-2 Atmospheric Reactions Generating and Removing Nitrobenzene 56
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xi
LIST OF TABLES
1-1 Human Health Effects from Breathing Nitrobenzene 4
1-2 Animal Health Effects from Breathing Nitrobenzene 5
1-3 Human Health Effects from Eating or Drinking Nitrobenzene 6
1-4 Animal Health Effects from Eating or Drinking Nitrobenzene 7
2-1 Levels of Significant Exposure to Nitrobenzene - Inhalation .... 13
2-2 Levels of Significant Exposure to Nitrobenzene - Oral 21
2-3 Genotoxicity of Nitrobenzene In Vitro 32
3-1 Chemical Identity of Nitrobenzene 44
3-2 Physical and Chemical Properties of Nitrobenzene 45
6-1 Analytical Methods for Determining Nitrobenzene in Biological
Materials 66
6-2 Analytical Methods for Determining Nitrobenzene in Environmental
Samples 68
7-1 Regulations and Guidelines Applicable to Nitrobenzene 72
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1. PUBLIC HEALTH STATEMENT
This Statement was prepared to give you information about
nitrobenzene 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).
Nitrobenzene has been found at 7 of these sites. However, we do not
know how many of the 1,177 NPL sites have been evaluated for
nitrobenzene. As EPA evaluates more sites, the number of sites at which
nitrobenzene is found may change. The information is important for you
because nitrobenzene may cause harmful health effects and because these
sites are potential or actual sources of human exposure to nitrobenzene.
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 nitrobenzene,
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 NITROBENZENE?
Nitrobenzene is an oily yellow liquid with an almond-like odor. It
may be pale yellow-brown in appearance. It dissolves only slightly in
water, but very easily in some other chemicals.
Nitrobenzene is produced in large quantities for industrial use.
Approximately 98% of the nitrobenzene produced in the United States is
used to manufacture a chemical known as aniline. Nitrobenzene is also
used to produce lubricating oils such as those used in motors and
machinery. A very small amount of nitrobenzene is used in the
manufacture of dyes, drugs, pesticides, and synthetic rubber.
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2
1. PUBLIC HEALTH STATEMENT
Small amounts of nitrobenzene are released to the air and to bodies
of water by the industries that use this chemical. However,
broken down to other chemicals within a few days after it is released
Air and water in most areas contain no nitrobenzene or such lQw amounts
that they cannot be measured.
More information on the chemical and physical properties 0f
nitrobenzene can be found in Chapter 3. Its production, import ^ uses
and disposal are presented iri Chapter 4, and its occurrence arid fate in
the environment are described in Chapter 5.
1.2 HOtf MIGHT I BE EXPOSED TO NITROBENZENE?
Because nitrobenzene is not usually found at hazardous waste sites
it is unlikely that you will be exposed to nitrobenzene if you nea^
one of these sites. However, you may be exposed if you live near one of
the seven waste sites where it has been found or near a manu£acturing or
processing plant, such as those involved in petroleum refining and
chemical manufacturing. Persons in these areas may be exposed to
nitrobenzene in the air they breathe. However, even in these cases the
levels of nitrobenzene have been found to be extremely low, Usually less
than 1 ppb (one part nitrobenzene per billion parts of air). Levels of
nitrobenzene in the air of residential areas are even lower.
Nitrobenzene is almost never found in drinking water. There is no
information available on the levels of nitrobenzene in food,
The most common way that humans are exposed to this compound is by
occupational exposure. If you work in a plant or factory that produces
nitrobenzene or uses nitrobenzene to make other products such as dyes,
drugs, pesticides or synthetic rubber, you may be exposed to
nitrobenzene in the air that you breathe or through your slcin.
For more information on human exposure to nitrobenzene, see
Chapter 5.
1.3 HOW CAN NITROBENZENE ENTER AND LEAVE MY BODY?
Nitrobenzene can enter your body easily and quickly through your
lungs, through your skin, or if you eat or drink contaminated food or
water. Nitrobenzene is easily absorbed through the skin and this is a
frequent pathway of human exposure. Drinking alcoholic beverages may
result in nitrobenzene entering your body at a faster rate, no matter
how you are exposed.
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3
1. PUBLIC HEALTH STATEMENT
Nitrobenzene and its breakdown products leave the body within a few
days. These are eliminated mostly in the urine and to a smaller extent
in the feces.
More information on how nitrobenzene enters and leaves the body can
be found in Chapter 2.
1.4 HOW CAN NITROBENZENE AFFECT MY HEALTH?
Nitrobenzene can cause a wide variety of harmful health effects to
exposed persons. Direct contact of small amounts of nitrobenzene with
the skin or eyes may cause mild irritation. Repeated exposures to a
high concentration of nitrobenzene can result in a blood condition
called methemoglobinemia. This condition affects the ability of the
blood to carry oxygen. Following such an exposure, the skin may turn a
bluish color. "This may be accompanied by nausea, vomiting and shortness
of breath. Effects such as headache, irritability, dizziness, weakness,
and drowsiness may also occur. If the exposure level is extremely high,
nitrobenzene can cause coma and possibly death unless prompt medical
treatment is received. Consuming alcoholic beverages during
nitrobenzene exposure may increase the harmful effects of nitrobenzene.
In studies with laboratory animals, a single dose of nitrobenzene
fed to male rats resulted in damage to the testicles and decreased
levels of sperm. This suggests that decreased fertility may be a
concern in humans. There is very little information available about the
effects of long-term exposure of humans or animals to nitrobenzene, and
it is not known whether exposure to nitrobenzene can cause cancer.
Further information on the health effects of nitrobenzene in humans
and animals can be found in Chapter 2. More information on nitrobenzene
breakdown products can be found in Chapter 2. There are populations
that are unusually susceptible to nitrobenzene, and this is further
discussed in Chapter 2.
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Tables 1-1 through 1-4 show the relationship between exposure to
nitrobenzene at certain levels and known health effects. The exposure
of laboratory animals to nitrobenzene through skin contact has resulted
in harmful effects similar to those seen in laboratory animals by other
routes of exposure. In general, the longer the period of contact with
the skin, the more severe the effects.
Nitrobenzene can be smelled in water when it is present at
0.11 mg/L (milligrams of nitrobenzene per liter of water) or in air at
0.018 ppm (0.018 parts of nitrobenzene per million parts of air). It
has an odor characteristic of bitter almonds or shoe polish.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing Nitrobenzene
Short-term Kxpn.surc
(less than or equal to 1A d
»y«)
Length of Exposure
r i pt i on of Effects
^ " The health effects result-
ing 1rom short-term
exposure of humans Co
air containing specific
levels of nitrobenzene
are not known.
Long-term Exposure
(greater than 1A days)
Length of Exposure
Description of Effects
T,eve Is
The health effects result-
ing from long-term
exposure of humans to
air containing specific
levels of nitrobenzene
are not known.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing Nitrobenzene
Short-term Exposure
(less than or equal to 14
days)
Levels in Air
C DDdl)
Lenpth of Exposure
DescriDtion of Effects*
10
125
10 to 14 days
14 days
Increased liver, kidney
and spleen weights and
methemoglobinemia in
rats.
Brain lesions in mice;
death in rats.
Long-term Exposure
(greater than 14 days
)
Levels in Air
Conm)
Length of ExDosure
Description of Effects*
5
50
90 days
90 days
Damage to the kidneys
and increased methemo-
globinemia in rats.
Damage to the spleen,
liver, and testes of
rats.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking Nitrobenzene
Short-term Exposure
(less than or equal to l't
clays) |
Length of Exposure
Description of Effects 1
The health effects result- 1
ing from short-term 1
exposure of humans to I
food containing specific 1
levels of nitrobenzene 1
are not known. 1
Levels
in Water
The health effects result- I
in;', from short-term 1
exposure of humans to I
water containing specific!
levels of nitrobenzene 1
are not known. 1
Long-term Exposure
(greater than 1A day
I
Length of Exposure
Description of Effects 1
The health effects result- I
Ing from long-term I
exposure of humans to I
food containing specific 1
levels of nitrobenzene 1
are not known. 1
Levels
i n Water
The health effects result- I
ing from long-term I
exposure of humans to 1
water containing specific!
levels of nitrobenzene I
are not known. l
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal Health Effects from Eating or Drinking Nitrobenzene
Short-term Exposure
(less than or equal to 14
days)
Levels
in Food (ppm)
Length of Exposure
Description of Effects*
4,000
6 ,000
11,000
1 day
1 day
1 day
Methemoglobinemia in rats.
Testicle damage in rats.
Brain hemorrhage in rats.
Levels
in Water
The health effects result-
ing from short-term
exposure of animals to
water containing specific
levels of nitrobenzene
are not known.
Long-term Exposure
(greater than 14 days)
Levels
in Food
Length of Exposure
Description of Effects
Levels
in Water
The health effects result-
ing from long-term
exposure of animals to
food containing specific
levels of nitrobenzene
are not known.
The health effects result-
ing from long-term
exposure of animals to
water containing specific
levels of nitrobenzene
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 on Che health effects assoc i at ed with exposure to
nitrobenzene is presented in Chapter 2.
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
NITROBENZENE?
Nitrobenzene reacts with red blood cells in the body to produce
raethemoglobin. If you have recently been exposed to nitrobenzene, the
levels of methemoglobin in your blood will be elevated. Tins level can
be measured. However, many toxic chemicals produce methemoglobin, and
this method does not give specific information about nitrobenzene
exposure.
In cases of long-term exposure to nitrobenzene, t lie presence of its
breakdown products, p-nitropheno1 and p-aminoplienol , in the urine is an
indication of nitrobenzene exposure. These tests require special
equipment and cannot be routinely done in a doctor's office. The
results of these tests cannot, be used to determine the level of
nitrobenzene exposure or if harmful health effects can be expected to
occur.
Information regarding tests for the detection of nitrobenzene in
the body is presented in Chapters 2 and 6.
1.7 TOAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
The federal government has developed regulations and guidelines in
order to protect individuals from the possible health effects of
nitrobenzene in drinking water. The Ktiv i ronment a 1 Protection Agency
(EPA) has concluded that the amount of nitrobenzene in drinking water
should not exceed 19.8 mg/L and that any release in excess of 1,000
pounds should be reported.
The Occupational Safety and Health Administration (0S1IA) has set a
legal limit (Permissible Exposure Limit, or PEL) of 1 ppm in workroom
air to protect workers during an 8-hour shift in a MJ-hour workweek.
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1. PUBLIC HEALTH STATEMENT
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
nitrobenzene. Its purpose is to present levels of significant exposure
for nitrobenzene 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 nitrobenzene and (2) a depiction of
significant exposure levels associated with various adverse health
effects.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the data in this section
are organized first by route of exposure -- inhalation, oral, and
dermal -- and then by health effect -- death, systemic, immunological,
neurological, developmental, reproductive, genotoxic, and carcinogenic
effects. These data are discussed in terms of three exposure periods --
acute, intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in
figures. The points in the figures showing no-observed-adverse-effect
levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs)
reflect the actual doses (levels of exposure) used in the studies.
LOAELs have been classified into "less serious" or "serious" effects.
These distinctions are intended to help the users of the document
identify the levels of exposure at which adverse health effects start to
appear, determine whether or not the intensity of the effects varies
with dose and/or duration, and place into perspective the possible
significance of these effects to human health.
The significance of the exposure levels shown on the tables and
figures may differ depending on the user's perspective. For example,
physicians concerned with the interpretation of clinical findings in
exposed persons or with the identification of persons with the potential
to develop such disease may be interested in levels of exposure
associated with "serious" effects. Public health officials and project
managers concerned with response actions at Superfund sites may want
information on levels of exposure associated with more subtle effects in
humans or animals (LOAEL) or exposure levels below which no adverse
effects (NOAEL) have been observed. Estimates of levels posing minimal
risk to humans (Minimal Risk Levels, MRLs) are of interest to health
professionals and citizens alike.
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12
2. HEALTH EFFECTS
2.2.1 Inhalation Exposure
Health effects in humans following inhalation exposure to
nitrobenzene have been described. However, as described in this
section, these studies are limited in detail and technical content.
There are several reliable animal studies using this route of exposure.
Table 2-1 and Figure 2-1 describe the health effects observed in
laboratory animals associated with inhalation of nitrobenzene at varying
exposure levels and durations; the results are discussed below.
2.2.1.1 Death
No studies were located regarding lethal effects of nitrobenzene in
humans after inhalation exposure.
Strain and species differences in response to nitrobenzene exposure
were demonstrated by Medinsky and Irons (1985). At an exposure level of
125 ppm nitrobenzene, there was a 40% rate of lethality in Sprague-
Dawley (CD) rats and morbidity necessitating early sacrifice of all
B6C3F1 mice. Fischer-344 rats, however, tolerated this level for
2 weeks without any adverse clinical signs. The relevance of these
findings to human exposure is not known.
2.2.1.2 Systemic Effects
Hematological Effects. The outstanding toxic effect of inhalation
exposure to nitrobenzene is methemoglobinemia. When the iron component
of hemoglobin is converted from the ferrous state to the ferric state
(oxidized), the resultant methemoglobin is no longer capable of
releasing oxygen to the tissues of the body. This lowered oxygen
capacity, or hypoxia, is generally associated with fatigue, weakness
dyspnea, headache, and dizziness as oxygen-poor blood reaches the brain.
Even under normal conditions, some (1 to 4%) methemoglobin is formed in
the lungs as blood is oxygenated. Toxic or "secondary", methemo-
globinemia can occur following exposure to nitrobenzene and other
chemicals.
Methemoglobinemia has been reported in three-week-old twins (a male
and a female) (Stevens 1928) and in a 12-month-old girl (Stevenson and
Forbes 1942) exposed to nitrobenzene in insect exterminator sprays. In
each case, the exposure lasted several hours and the exposure level was
neither known nor estimated. Severe methemoglobinemia was reported in a
47-year-old woman who was occupationally exposed to nitrobenzene at
unmeasured levels for 17 months (Ikeda and Kita 1964).
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TABLE 2-1. Levels of Significant: Exposure to Nitrobenzene - Inhalation
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key Species Duration Effect (ppn) (ppm) (ppm) Reference
ACUTE EXPOSURE
Death
1 Rat
14 d
5d/wk
6hr/d
125a (LD50 males)
Medinsky and
Irons 1985
Systemic
2 Rat
3 Rat
4 Rat
Mouse
1A d
5d/vk
6hr/d
10 d
Gd6-15
6hr/d
14 d
5d/vk
6hr/ d
14 d
5d/wk
6hr/d
14 d
5d/vk
6hr/d
Renal
Other
Hepatic
Hemato
Other
10a (incr. kidney vt.)
10a (incr. spleen wt.)
10a (incr. liver wt.)
10a (methemoglob-
inemia)
10 (splenic hemosid-
erosis)
35 (incr. WBC's)
Medinsky and
Irons 1985
Tyl et al. 1987
Medinsky and
Irons 1985
Medinsky and
Irons 1985
a:
w
>
EC oj
PI
*1
W
O
H
GO
35 (lymphoid aplasia) Medinsky and
Irons 1985
Neurological
7 Mouse
14 d
5d/vk
6hr/d
125a (cerebellar
lesions)
Medinsky and
Irons 1985
Deve 1 opoent al
8 Rat
10 d
Gd6-15
6hr/d
40
Tyl et al. 1987
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Figure
Key Species
Exposure
Frequency/
Duration Effect
NOAEL
(ppm)
INTERMEDIATE EXPOSURE
Systemic
9 Rat
10 Rat
11 Rat
12 Rat
13 Rat
14 Mouse
15 Mouse
16 Rat
Reproduct ive
17 Rat
21 d Other 50
5d/wk
6hr /d
90 d Renal
5d/vk
6hr/d
90 d Other
5d/vk
6hr/d
90 d Hemato
5d/vk
6hr/d
90 d Hepatic
5d/vk
6hr/d
90 d Other
5d/wk
6hr/d
90 d Hemato
5d/vk
6hr/d
10 wk Other 10
(2 gen)
5d/vk
6hr/d
90 d
5d/wk
6hr/d
TABLE 2-1 (Continued)
LOAEL (Effect)
Less Serious Serious
(ppm) (ppm) Reference
Kligerman et al.
1983
5a (nephrosis)
50 (necrosis)
Hanxn 1984
5 (splenic
hyperplasia)
5 (methemoglob-
inemia)
50 (splenic
les ions)
50a (necrosis)
5 (adrenal lesions)
Hanxn 1984
Hanxn 1984
Hanxn 1984
Hanxn 1984
N>
ac
P3
>
t-
H
sc
m
*1
w
o
H
in
50 (methemoglob-
inemia)
Hanxn 1984
Dodd et al. 1987
50a (testicular
degeneration)
Hamm 1984
-------
TABLE 2-1 (Continued)
Figure
Key
Species
Exposure
Frequency/ NOAEL
Duration Effect (ppm)
LOAEL (Effect)
Less Serious
(ppm)
Serious
(ppm)
Reference
18
Mouse
90 d
5d/vk
6hr/d
50
Hanm 1984
19
Rat
10 vk
(2 gen)
5d/wk
6hr/d
10
40 (testic. lesions,
deer, fertility)
Dodd et al. 1987
aPresented in Table 1-2.
LOAEL « lowest-observed-adverse-effect level; NOAEL « no-observed-adverse-effect level; ppm = parts per million; d « day;
LD5Q « lethal dose, 50* mortality; wk » week; hr — hour: incr. * increase; wt = weight; Gd ¦ gestation day; hemato —
hematological; UBC's * white blood cells; gen ~ generation; testic. « testicular; deer. - decreased.
W
>n
•n
M
n
H
t/i
-------
ACUTE
fc14 Days)
INTERMEDIATE
(15-364 Days)
/
so- £ f so-
?//s s // / //
/
(ppm) v _ _ _
1,000
/
~
/
~
100
10
1 L
llr
17m
Oar
MSm
|13f #10r O* #11r O • l7r#19f
Oir ®4f ®2r (Km ®3r
Ol6r
®12r ®10r ®i4m ®11r
Ol9r
Key
r Rat
¦ LD50
m Mouse
# LOAEL for senous effects (animals)
9 LOAEL for less serious effects (animals)
O NOAEL (animals)
The number next to
each point corresponds to entries in Table 2-1.
a:
m
>
r1
H
:i
m
•n
m
n
H
to
FIGURE 2-1. Levels of Significant Exposure to Nitrobenzene - Inhalation
-------
17
2. HEALTH EFFECTS
Increased levels of blood methemoglobin have been reported in rats
exposed to nitrobenzene at levels as low as 10 ppm for two weeks
(Medinsky and Irons 1985) or 5 ppm for 90 days (Hamm 1984).
Hepatic Effects. There is some evidence that the human liver is
damaged after chronic inhalation of nitrobenzene. The liver was
enlarged and tender and the results of liver function tests were
abnormal in a woman who was occupationally exposed to nitrobenzene for
17 months (exposure levels not measured or estimated) (Ikeda and Kita
1964) .
Liver lesions reported in animal studies include hepatocyte
necrosis in male Sprague-Dawley (CD) rats exposed to nitrobenzene at
35 ppm for 2 weeks (Medinsky and Irons 1985) and increased liver weight,
hepatocyte hyperplasia, and multinucleated hepatocytes in male B6C3F1
mice exposed to nitrobenzene at 16 ppm for 90 days (Hamm 1984).
Renal Effects. No studies were located regarding renal effects in
humans after inhalation exposure to nitrobenzene.
Dose-related increases in kidney weights were observed in
Fischer-344 rats (both sexes), but not in Sprague-Dawley (CD) rats
exposed to nitrobenzene at 10 to 125 ppm for 14 days (Medinsky and Irons
1985) . At 125 ppm, hydropic degeneration of the cortical tubular cells
was observed only in Sprague-Dawley rats (20% of males; 90% of females),
and hyaline nephrosis only in Fischer-344 rats (100% of males; 20% of
females). Renal effects reported in B6C3F1 mice in this study included
minimal to moderate multifocal degenerative changes in tubular
epithelium of males exposed to 35 ppm for 2 weeks. However, neither
hydropic degeneration of the cortical tubular cells nor hyaline
nephrosis was seen in mice even at the highest exposure level (125 ppm).
Using the same three animal models exposed to nitrobenzene at 5 to
50 ppm for 90 days, dose-related renal lesions were observed in both rat
strains but not in mice (Hanun 1984) .
Differences in species and possibly strain susceptibility to the
renal effects of nitrobenzene exposure may exist, but their relevance to
the potential renal effects in humans is not clear. The occurrence of
renal effects in male rats, but not female rats or mice of either sex,
in response to exposure to chemical toxicants is not unique to
nitrobenzene. These differences have also been found with exposure to
1,4-dichlorobenzene, isophorone, and unleaded gasoline (Charbonneau and
Swenberg 1988) and have been attributed to the production of high
concentrations of the protein alpha-2/i-globulin in the kidneys of male
rats, but not in female rats, mice, or humans. These observations
suggest that the severe renal effects observed in male rats exposed to
nitrobenzene will probably not occur in exposed humans.
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18
2. HEALTH EFFECTS
Other Systemic Effects. No studies were located regarding
cardiovascular, respiratory, gastrointestinal, musculoskeletal, dermal
or ocular effects in humans or animals after inhalation exposure to
nitrobenzene.
Dose-related splenic lesions have been reported to occur in B6C3F1
mice exposed to nitrobenzene at 10 to 125 ppm for 14 days (Medinsky and
Irons 1985) and in F-344 and Sprague-Dawley (CD) rats at 5 to 50 ppm for
90 days (Hamm 1984). These lesions were described as sinusoidal
congestion, an increase in extramedullary hematopoiesis and hemosiderin-
laden macrophages infiltrating the red pulp, and the presence of
proliferative capsular lesions. The results of these studies suggest
that the spleen may also be a sensitive organ in cases of human
inhalation exposure to nitrobenzene.
2.2.1.3 Immunological Effects
No studies were located regarding immunological effects in humans
or animals after inhalation exposure to nitrobenzene. Splenic lesions
observed in studies in rats and mice (see Section 2.2.1.2) suggest that
potential immunologic effects may warrant further attention.
2.2.1.4 Neurological Effects
Neurological effects have been noted in the case of a woman who was
occupationally exposed to nitrobenzene for 17 months at an unknown
level. These effects included headache, nausea, vertigo, confusion, and
paresthesia (Ikeda and Kita 1964).
Neurologic signs were not observed in mice or rats exposed to 5,
16, or 50 ppm nitrobenzene in air for 90 days. These animals were
observed twice daily for clinical abnormalities (Hamm 1984).
When Sprague-Dawley (CD) rats and B6C3F1 mice were exposed to
nitrobenzene at 125 ppm daily for two weeks, damage to the hindbrain
(cerebellar peduncle) , including bilateral cerebellar perivascular
hemorrhage and malacia (cell breakdown), was observed in 8/19 mice (both
sexes) and in 14/19 rats (both sexes) (Medinsky and Irons 1985). No
brain lesions were found in Fischer rats exposed to the same levels
The reason for these strain differences under similar conditions is not
apparent.
2.2.1.5 Developmental Effects
No studies were located regarding developmental effects in humans
after inhalation of nitr°benzene.
-------
19
2. HEALTH EFFECTS
Studies in animals indicate that inhalation exposure to
nitrobenzene does not result in fetotoxic, embryotoxic or teratogenic
effects at concentrations up to 40 ppm in rats (Tyl et al. 1987) and up
to 100 ppm in rabbits (Bio/dynamics Inc. 1984). While the mean numbers
of resorption sites and percentage of resorptions/implants in rabbits
were higher in the 100 ppm group than in concurrent controls, these
parameters were within the historical control range. However, animal
data from these studies indicate that nitrobenzene is maternally toxic.
In rats, spleen weights increased in the mothers (dams) at 10 ppm, and
there was transient reduction in body weight gain in the 40 ppm group
(Tyl et al. 1987). In rabbits, maternal effects noted at 40 ppm and
above were increased methemoglobin levels and increased liver weights
(Bio/dynamics Inc. 1983). Since no developmental toxic effects occurred
in animals even at doses producing some maternal toxicity, developmental
toxicity may not be a major concern in humans.
2.2.1.6 Reproductive Effects
No studies were located regarding reproductive effects in humans
following inhalation exposure to nitrobenzene.
In a two-generation study in rats, nitrobenzene exposure (10 weeks)
resulted in a decrease in fertility indices at 40 ppm for F0 and Fx
generations, while other reproductive parameters were unaltered (Dodd
et al. 1987). The study data suggested that the decrease was caused by
effects in males. Atrophy of seminiferous tubules, spermatocyte
degeneration and reduced testicular and epididymal weights were reported
in F0 and FL generations. A five-fold increase (above levels during
exposure) in the fertility index was reported after 9 weeks of recovery
from inhalation exposure to nitrobenzene, but reversibility was not
studied histologically. Maternal toxicity was not observed. Hamm
(1984) reported that both F-344 and Sprague-Dawley (CD) rats exposed to
nitrobenzene at 50 ppm for 90 days had testicular atrophy, bilateral
degeneration of the seminiferous tubules, and a reduction in or absence
of mature sperm in the epididymis. No testicular lesions were observed
in B6C3F1 mice under the same exposure conditions.
The testicular effects observed in these studies suggest that
reproductive toxicity may be an area of concern for occupationally
exposed humans.
2.2.1.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans after
inhalation exposure to nitrobenzene.
-------
20
2. HEALTH EFFECTS
Cytogenetic analyses of lymphocytes In the peripheral blood or in
splenic blood of rats exposed to nitrobenzene at 5 to 50 ppm for 21 days
did not reveal an increase in sister chromatid exchange (SCE) or
chromosome breakage (Kligerman et al. 1983).
2.2.1.8 Cancer
No studies were located regarding cancer in humans or animals after
inhalation exposure to nitrobenzene.
2.2.2 Oral Exposure
Table 2-2 and Figure 2-2 describe the health effects observed in
laboratory animals associated with oral exposure to nitrobenzene at
varying levels and exposure durations.
2.2.2.1 Death
Although the early literature describes many "poisonings" and
deaths that were attributed to nitrobenzene ingestion, the lack of
reliable chemical identification makes it impossible to determine the
actual cause of death in some of these cases. In early case studies
that describe such events, nitrobenzene may have been identified only by
its odor- in other cases, aniline may have been identified in the
stomach contents. Because nitrobenzene is reduced to aniline by the
microflora in the intestines, the presence of aniline in the stomach may
more reasonably be attributed to the ingestion of aniline. In addition,
due to prompt and aggressive medical attention when these incidents have
occurred most of the available case studies report that the victim has
survived' Therefore, firm conclusions cannot be drawn about the
potential lethal effects of nitrobenzene ingestion by humans.
An LD50 of 600 mg/kg in rats was reported by Smyth et al. (1969).
2.2.2.2 Systemic Effects
Hematological Effects. when nitrobenzene is ingested, the
outstanding systemic effect is methemoglobin formation. In this
mndition the blood releases less oxygen to the tissues and all general
body functions tend to be sloped down (WHO 1986). A latency period
(after ingestion and before any signs or symptoms occur) can be as short
as 30 minutes or as long as 12 *°urs. Usually, the higher the dose, the
shorter the latency period.
-------
TABLE 2-2. Levels of Significant Exposure to Nitrobenzene - 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
NeuroLogical
2 Rat
Reproduct ive
3 Rat
(G) 1*
(G) lx
(G) lx
Hemato
100
200a (methemoglobin-
emia)
550^ (malacia/
hemorrhage)
Goldstein et al.
1984
Morgan et al.
1985
300° (testic. necrosis, Levin et al.
deer, sperm) 1988
aConverted to an equivalent concentration of 4,000 ppm in food for presentation in Table 1-4.
^Converted to an equivalent concentration of 11,000 ppm in food for presentation in Table 1-4,
cConverted to an equivalent concentration of 6,000 ppm in food for presentation in Table 1-4.
LOAEL ¦ lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effeet level; cng = milligramsi kg ¦ kilograms;
(G) = gavage; x = time; hemato * hematological; testic. * testicular; deer. = decreased
SC
>
r1
H
rr
w
hrj
Tl
o
H
-------
ACUTE
(<14 Days)
(mg/kg/day)
1,000
/ / /
>2r
Mr
—: NJ>
»1r
Key
r Rat • LOAEL for serious effects (animals)
® LOAEL for less serious effects (animals)
O NOAEL (animals)
The number next to each point corresponds to entries in Table 2-2.
100
O if
FIGURE 2-2. Levels of Significant Exposure to Nitrobenzene - Oral
-------
23
2. HEALTH EFFECTS
No data are available to reliably estimate the level of human oral
exposure to nitrobenzene that results in methemoglobinemia. Two of the
case studies that were located indicate that some vague quantity, such
as a few drops or a partial spoonful, was swallowed and part of that
amount was vomited out before cyanosis and methemoglobinemia were
observed (Carter 1936; Leader 1932). Another study (Myslak et al. 1971)
estimated that a dose of 4.3 to 11 g was swallowed by a 19-year-old
woman, based on the urinary levels of p-nitrophenol.
Oral administration of nitrobenzene to rats and mice results in
methemoglobinemia (Goldstein et al. 1984a; Rickert 1984a).
The mouse is apparently more resistant to the methemoglobin forming
properties of nitrobenzene than are other species (Shimkin 1939; Smith
et al. 1967). The action of bacteria normally present in the small
intestine of the rat is an important element in the formation of
methemoglobin resulting from nitrobenzene exposure. Germ-free rats do
not develop methemoglobinemia when orally administered nitrobenzene
(Reddy et al. 1976). This observation leads to the speculation that a
nitrobenzene metabolite such as aniline (which is formed by the
bacterial reduction of nitrobenzene in the intestines of rats) may be
involved in methemoglobin formation in this species. In addition, diet
has been shown to play a role in the production of methemoglobin by
influencing the intestinal microflora. The presence of cereal-based
pectin in the diets of rats was shown to increase the ability of orally
administered nitrobenzene to induce methemoglobinemia (Goldstein et al.
1984a).
Other Systemic Effects. No studies were located regarding hepatic,
respiratory, cardiovascular, gastrointestinal, renal, musculoskeletal,
dermal, or ocular effects in humans or animals after oral exposure to
nitrobenzene.
2.2.2.3 Immunological Effects
No studies were located regarding immunological effects in humans
or animals after oral exposure to nitrobenzene.
2.2.2.4 Neurological Effects
Neurological effects following nitrobenzene ingestion by humans
have been reported as headache, nausea, vertigo, confusion,
unconsciousness, apnea and coma (Carter 1936; Leader 1932; Myslak et al.
1971). Levels of nitrobenzene associated with these effects cannot be
reliably estimated in most of the case studies from which these
descriptions have been derived.
-------
24
2. HEALTH EFFECTS
Brain pathology was reported after a single oral administration o
nitrobenzene at 550 rag/kg to male rats (Morgan et al, 1985).
Observations included petechial hemorrhages in the brain stem and
cerebellum and malacia (cell breakdown) in the fourth ventricle.
2.2.2.5 Developmental Effects
No studies were located regarding developmental effects in humans
or animals after oral exposure to nitrobenzene.
2.2.2.6 Reproductive Effects
No studies were located regarding reproductive effects in humans
after oral exposure to nitrobenzene.
No single or multigeneration reproduction studies in animals were
found. However, an acute systemic study in rats indicated that the
testes are sensitive to the toxic effects of nitrobenzene. Typical
signs included testicular degeneration and transiently decreased sperm
production following a single oral dose of 300 mg/kg (Levin et al.
1988).
Although no human studies were found and animal reproduction
studies have not been performed by oral administration, the testicular
degeneration in rats reported by Levin et al. (1988) suggests that
reproductive toxicity may be of concern in exposed humans.
2.2.2.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans afte
oral exposure to nitrobenzene.
Rats gavaged with nitrobenzene at 200 or 500 mg/kg were tested for
unscheduled DNA synthesis in liver slices (Mirsalis et al. 1982). No
significant increase in DNA synthesis was found.
2.2.2.8 Cancer
No studies were located regarding cancer in humans or animals afte
oral exposure to nitrobenzene.
2.2.3 Dermal Exposure
Cases of severe and nearly lethal toxic effects after dermal
exposure to aniline-based dyes have been reported as early as 1886.
These cases have involved mainly infants exposed to dye-stamped diapers
and persons wearing freshly dyed shoes. The resulting condition was
often termed "nitrobenzene poisoning", even though exposure to
-------
25
2. HEALTH EFFECTS
nitrobenzene did not necessarily occur. Several conclusions and
generalizations about the dermal absorption and toxic effects of
nitrobenzene, especially in infants, seem to have been based on these
studies which should more appropriately be considered as part of the
data base for aniline.
2.2.3.1 Death
No studies were located regarding death in humans after dermal
exposure to nitrobenzene.
Dermal applications of nitrobenzene to female C3H or male A-strain
mice resulted in the death of 12 of 18 and 8 of 10 animals, respectively
(Shimkin 1939). Although 2 or 3 applications were required for the C3H
mice, most animals were in partial collapse within 15 minutes and dead
by the third day. Most of the strain-A mice were dead within the first
day. The dermal dosage was not stated.
2.2.3.2 Systemic Effects
Hematological Effects. No studies were located regarding
hematological effects in humans after dermal exposure to nitrobenzene.
Dermal painting of C3H female or strain-A male mice with nitrobenzene
resulted in methemoglobinemia by 3 hours after application (Shimkin
1939).
Hepatic Effects. No studies were located regarding hepatic effects
in humans after dermal exposure to nitrobenzene. In mice dermally
exposed to nitrobenzene, the liver was the most severely affected organ.
There was diffuse necrosis in the outer two thirds of the lobules of the
liver (Shimkin 1939).
Renal Effects. No studies were located regarding renal effects in
humans after dermal exposure to nitrobenzene.
When mice were dermally painted with nitrobenzene for 1 to 3
applications, there was slight swelling of the glomeruli and tubular
epithelium upon histological examination {Shimkin 1939) .
Other Systemic Effects. No studies were located regarding other
systemic effects (respiratory, cardiovascular, gastrointestinal,
musculoskeletal, splenic, dermal, ocular) in humans or animals after
dermal exposure to nitrobenzene.
-------
26
2. HEALTH EFFECTS
No studies were located regarding the following health effects
humans or animals after dermal exposure to nitrobenzene.
2.2.3.3
Immunological Effects
2.2.3.4
Neurological Effects
2.2.3.5
Developmental Effects
2.2.3.6
Reproductive Effects
2.2.3.7
Genotoxic Effects
2.2.3.8
Cancer
2.3 TOXICOKINETICS
2.3.1 Absorpt ion
2.3.1.1 Inhalation Exposure
In humans, nitrobenzene was well absorbed through the lung ln the
one study located. During a 6-hour exposure of volunteers to
nitrobenzene, Salmowa et al. (1963) found absorption to average 80% (73
to 87%) in 7 men breathing 6 ppm nitrobenzene. The efficiency of uptake
was dose dependent, but showed considerable individual variation
No studies were located regarding the uptake of nitrobenzene by
animals after inhalation exposure.
2.3.1.2 Oral Exposure
No studies were located regarding the uptake of nitrobenzene by
humans after oral exposure.
After oral administration of 250 mg/kg of nitrobenzene by stomach
tube to rabbits, Parke (1956) recovered 0.5% (1.3 mg) of the
administered dose of nitrobenzene from the exhaled air of the rabbit
The amount of nitrobenzene in the blood was not measured. Unchanged
nitrobenzene in the urine was less than 0.1% (0.25 mg)
2.3.1.3 Dermal Exposure
The toxicokinetics of dermal exposure have not been well studied in
either humans or experimental animals. Piotrowski (1967) found that
approximately half of the dose of nitrobenzene was absorbed through the
skin when volunteers were exposed to either 1 or 5.5 ppm nitrobenzene in
air.
-------
27
2. HEALTH EFFECTS
In animal studies, nitrobenzene appears to be absorbed after dermal
application based on observations of toxic responses in the treated
animals. Shimkin (1939) reported that dermal painting of mice with
liquid nitrobenzene (dose not stated) resulted in the death of most test
animals after 1 to 3 applications. Dermal exposure of rabbits to
nitrobenzene (dose not stated) for 22 to 205 days resulted in greater
neural damage than did intravenous exposure (Matsumaru and Yoshida
1959) . Administration of alcohol (not further identified) by stomach
tube following exposure to nitrobenzene resulted in neurotoxicity by
both routes of exposure.
2.3.2 Distribution
2.3.2.1 Inhalation Exposure
No studies of the distribution of nitrobenzene or its metabolites
after inhalation exposure by humans or animals were found in the
literature.
2.3.2.2 Oral Exposure
Radiolabeled nitrobenzene has been followed after oral
administration in a number of studies in rats and mice (Goldstein and
Rickert 1984; Levin and Dent 1982a; Morgan et al. 1985). In summary,
these studies have shown that nitrobenzene is reduced to nitrosobenzene,
phenylhydroxylamine, and aniline by the bacteria of the intestine.
Metabolism of nitrobenzene resulted on covalent binding to the hepatic
microsomes. Nitrosobenzene and phenylhydroxylamine were bound to the
hemoglobin. Unaltered nitrobenzene was recovered from the brain at a
rate of 0.02% of the administered dose. The subcellular site of
nitrobenzene metabolism was not found. The major urinary metabolites
were p-aminophenol and p-nitrophenol together with the sulfate and
glucuronide conjugates.
In a study of rats that received radiolabeled nitrobenzene by
gavage, it became bound to the tissues after the first day according to
the following indices [mmol/mol Hb/dose (mmol/kg)]: blood-229,
liver-129, kidney-204, lung-62. By day 7, the same indices were: 134,
26.5, 48, 29. After the first day, 50% of the dose (radioactivity)
appeared in the urine and 4% in the feces. After the fifth day, 65% of
the dose had appeared in the urine and 16% appeared in the feces
(Albrecht and Neumann 1985). These studies confirmed the observation of
Rickert et al. (1983), that the excretion of nitrobenzene is delayed.
The binding indices also indicated that 4 to 5 times as much
nitrosobenzene is formed from nitrobenzene as from an equal amount of
aniline.
-------
28
2. HEALTH EFFECTS
2.3.2.3 Dermal Exposure
No studies were located regarding the distribution of nitrobenzene
or its metabolites after dermal exposure.
2.3.3 Metabolism
The covalent metabolism and binding of nitrobenzene to hemoglobin
was studied\y ftlbrecht and Neumann (1985). Hhen Wlstar rats were
administered 25 mg/kg radiolabeled nitrobenzene by gavage,
administer I g/ g f seen ln the intestine where nitrobenzene was
led to the speculation that a nrtrobenzene metabolite sue as ,iUne
u in metheraoElobmemia formation m this species. lhe
k n metabolites nitrosobenzene and phenylhydroxylamine have
iuhShe„6lobln 1„ the blood of orally exposed „lce
and rats (Goldstein and Rickert 1984).
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
. „„rof{or1 rates of p-nitrophenol were found in 7 volunteers
h ha?inhaled 6 ppm nitrobenzene for 6 hours (Salmowa et al. 1963).
Th! rate of urinary elimination varied considerably from individual to
• a- 'a ~\ but showed a general dose dependence at 1 to 6 ppm
mdivldua , eeneral excretion was most rapid during the first two
hours and^the-n leveled off. In some cases, p-nitrophenol could be
riptected for as long as 100 hours after exposure to 6 ppm for 6 hours.
T 47-year-old woman who had been accupationally exposed to
nitrobenzene for 17 months, p-nitrophenol and p-aminophenol were found
in the urine (Ikeda and Kita 1964).
2.3.4-2 Oral Exposure
After oral exposure to nitrobenzene, the major route of excretion
i the urine. In most cases of human poisoning, the metabolites
S d in the urine are p-aminophenol and p-nitrophenol (Myslak et al,
197V Von Oettingen 1941). Five days after oral administration to rats,
Albrecht and Neumann (1985) found 65% of the administered dose
^25 mg/kg) in the urine and 16% in the feces.
-------
29
2. HEALTH EFFECTS
2.3.4.3 Dermal Exposure
A unique apparatus was developed to measure skin absorption from
the nitrobenzene vapor in the air without inhalation of nitrobenzene
(Piotrowski 1967). At 1 ppm, about 8 mg is absorbed through the skin
and about 20% is excreted in the urine the first day.
2.4 RELEVANCE TO PUBLIC HEALTH
Studies in animals, combined with observations in humans, indicate
that the principal adverse health effects associated with short-term
inhalation or oral exposure to nitrobenzene are methemoglobinemia,
neurological effects, and liver injury. Data related to dermal exposure
and to long-term exposure by any route are not considered sufficient to
clearly assess the potential effects.
Death. Accidental poisonings and deaths in humans that were
attributed to the ingestion of nitrobenzene have been reported; but as
discussed in Section 2.2.2.1, these studies usually lack clear chemical
identification of nitrobenzene as the ingested substance. In those
inhalation case studies (Stevens 1928; Stevenson and Forbes 1942) and
oral case studies (Carter 1936; Leader 1932; Myslak et al. 1971) in
which the patients were apparently near death due to severe
methemoglobinemia, termination of exposure and prompt medical
intervention resulted in gradual improvement and recovery. Data
relating to dermal exposure to nitrobenzene, as discussed previously in
Section 2.2.3, are questionable since there may have been exposure to
aniline-based dyes and little or no exposure to nitrobenzene. Data in
animals indicate that nitrobenzene can be lethal via oral, inhalation or
dermal exposure. Although human exposure to sufficiently high
quantities of nitrobenzene can probably be lethal via any route of
exposure, it is considered unlikely that levels of exposure high enough
to cause death would occur except in cases of industrial accidents.
Systemic Effects. The chief systemic effect associated with human
exposure to nitrobenzene is methemoglobinemia. However, it is difficult
to locate clear evidence of this effect, since nitrobenzene was
identified only by its odor in several early case studies.
Methemoglobinemia was reported to occur in twin 3-week-old babies
(Stevens 1928), in a 12-month-old girl (Stevenson and Forbes 1942), and
in a 47-year-old woman (Ikeda and Kita 1964), all of whom were exposed
to nitrobenzene via inhalation. However, levels of exposure were
neither known nor estimated. In addition, the compound to which the
12-month-old girl was exposed also contained kerosene, turpentine, and
oil of lilacine. The 3-week-old twins were exposed to nitrobenzene in a
toilet deodorant called "Creco". No other ingredients were stated in
the study. Oral exposure to nitrobenzene at unspecified amounts has
-------
30
2. HEALTH EFFECTS
also resulted in methemoglobinemia (Garter 1936; Leader 1932; Myslak
et al. 1971). There is no clear evidence chat dermal exposure to
nitrobenzene results in methemoglobinemia iti humans. Reports of
methemoglobinemia resulting in dermal contact with dyes allegedly
containing nitrobenzene are complicated by the early confusion in
nomenclature for aniline and nitrobenzene.
Methemoglobinemia has also been reported in mice and rats exposed
to nitrobenzene via inhalation (Hamm 1984) and in rats and mice exposed
orally (Goldstein et al. 1984a; Rickert 1984a). Dermal painting studies
in mice resulted in the onset of methemoglobinemia within 3 hours after
nitrobenzene application (level not stated) (Shimkin 1939). This
finding suggests that methemoglobinemia may also occur in dermally
exposed humans.
Liver effects have been reported in both humans and animals exposed
to nitrobenzene. Hepatic enlargement and tenderness, jaundice, and
altered serum chemistries were reported in a 47-year-old woman who had
been occupationally exposed to nitrobenzene for 17 months (Ikeda and
Kita 1964). The authors considered these changes to be related to
increased destruction of hemoglobin and enlargement of the spleen.
Liver effects observed in animals following nitrobenzene exposure are
hepatocyte necrosis in rats (Medinsky and Irons 1985) and increased
liver weight, hepatocyte hyperplasia, and multinucleated h«;patocytes in
mice (Hamm 1984). Hepatic effects have not been reported in oral
studies. Dermal painting studies in mice resulted in diffuse necrosis
in the outer two-thirds of the lobules of the liver (Shimkin 1939).
There are no data on renal effects in humans exposed to
nitrobenzene by any route. In rats, strain-related differences in renal
effects have been reported as a result of inhalation exposure to
nitrobenzene (Hamm 1984; Medinsky and Irons 1985). Observed effects
have included increased kidney weights, hydropic degeneration of the
cortical tubules and hyaline nephrosis. Renal effects have not been
reported in studies of animals that were orally exposed to nitrobenzene.
In dermal painting studies in mice, slight swelling of the glomeruli and
tubular epithelium were reported (Shimkin 1939) . These findings suggest
that renal damage may also occur in exposed humans.
Splenic lesions reported in inhalation studies in mice and rats
have included sinusoidal congestion, an increase in extramedullary
hematopoiesis and hemosiderin-laden macrophages invading the red pulp,
and the presence of proliferative capsular lesions (Hamm 1984; Medinsky
and Irons 1985). These findings suggest that the spleen may also be a
target organ during human inhalation exposure to nitrobenzene.
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31
2. HEALTH EFFECTS
Little information is available on the effects of inhalation, oral
or dermal exposure of humans or animals to nitrobenzene on the
respiratory, cardiovascular or musculoskeletal systems or on the skin or
eyes .
Immunological Effects. No studies were located regarding
immunologic effects in humans or animals after inhalation, oral, or
dermal exposure to nitrobenzene. Splenic lesions reported in rodent
inhalation studies (Hamm 1984; Medinsky and Irons 1985) suggest that
this may be an area of potential concern.
Neurological Effects. Neurotoxic symptoms reported in humans after
inhalation exposure to nitrobenzene have included headache, confusion,
vertigo and nausea (Ikeda and Kita 1964); effects in orally exposed
persons have also included those symptoms as well as apnea and coma
(Carter 1936; Leader 1932; Myslak et al. 1971). Studies in animals
exposed via inhalation have shown morphological damage to the hindbrain
(cerebellar peduncle) (Medinsky and Irons 1985). Damage to the
brainstem, cerebellum and fourth ventricle was observed in orally
exposed animals. Thus, it is possible that similar neurological changes
may occur in humans as a result of nitrobenzene exposure.
Developmental Effects. No studies of developmental effects in
humans resulting from inhalation, oral or dermal exposure to
nitrobenzene have been reported. Studies conducted via inhalation
exposure did not result in fetotoxic or teratogenic effects in rats or
rabbits (Bio/dynamics 1984; Tyl et al. 1987). No studies have been
conducted using the oral or dermal routes. Developmental effects are
not expected to be of concern to humans exposed to the typical levels in
the environment or in occupational settings.
Reproductive Effects. The effects of nitrobenzene on reproduction
have not been studied in humans by inhalation, oral or dermal routes of
exposure. In rats, inhalation of nitrobenzene has resulted in
testicular degeneration and decreased sperm levels (Dodd et al. 1987;
Hamm 1984). Cessation of spermatogenesis, followed by a slow and
incomplete recovery, was observed in rats following a single oral dose
of nitrobenzene (Levin et al. 1988). These findings suggest that
reproductive effects may also be an area of concern for men exposed to
nitrobenzene in occupational settings.
Genotoxic Effects. The genotoxicity of nitrobenzene has been
investigated in both in vitro and in vivo studies. The results of
in vitro studies are presented in Table 2-3. In vivo studies are
described in Sections 2.2.1.7 and 2.2.2.7. The results of these studies
are generally negative and do not suggest potential human health
concerns.
-------
TABLE 2-3. Geootoxicity of nitrobenzene In Vitro
Results
End Point
Species (Test System)
With
Activation
Without
Activation
Reference
Prokaryotic organisms:
Gene mutation
Gene mutation
Gene mutation
Gene mutation
Gene mutation
Gene mutation
- = negative result; ND = no data.
Salmonella typhimurium
S. typhimurium
S. typhimurium
S. typhimurium
S. typhimurium
S. typhimurium
ND
ND
Garner and Nutraan 1977
Shimizu et al. 1983
Ho et al, 1981
Havorth et al. 1983
Anderson and Styles
1978
Hughes et al. 1984
SC
>
r1
H
sc
m
m
o
H
CO
to
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33
2. HEALTH EFFECTS
Cancer. No studies were located regarding carcinogenic potential
in humans or animals after inhalation, oral, or dermal exposure to
nitrobenzene.
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 result of exposures
from more than one source. The substance being measured may be a
metabolite of another xenobiotic (e.g., high urinary levels of phenol
can result from exposure to several different aromatic compounds).
Depending on the properties of the substance (e.g., biologic half-life)
and environmental conditions (e.g., duration and route of exposure), the
substance and all of its metabolites may have been eliminated from the
body by the time biologic samples can be taken. It may be difficult to
identify individuals exposed to hazardous substances that are commonly
found in body tissues and fluids (e.g., essential mineral nutrients such
as copper, zinc and selenium). Biomarkers of exposure to nitrobenzene
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 nitrobenzene 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
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34
2. HEALTH EFFECTS
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 and/or Quantify Exposure to
Nitrobenzene
The presence of p-nitrophenol in the urine can be used to indicate
exposure to nitrobenzene (Ikeda and Kita 1964). Measurement of
p-nitrophenol, however, cannot be used to determine the level of
nitrobenzene exposure or if harmful effects can be expected to occur
The nitrobenzene metabolites, nitrosobenzene and phenylhydroxylamine
have been found to bind with hemoglobin in the blood of orally exposed
mice and rats (Goldstein and Rickert 1984). The presence of these
hemoglobin adducts in human blood may also serve as a potential
biomarker of exposure to nitrobenzene.
2.5.2 Biomarkers Used to Characterize Effects Caused by Nitrobenzene
The presence of methemoglobinemia can indicate exposure to
nitrobenzene as well as to any of several other toxic substances.
Therefore, this condition in itself cannot be used as a biomarker of
effect for nitrobenzene.
2.6 INTERACTIONS WITH OTHER CHEMICALS
Synergism between orally administered nitrobenzene and six other
common industrial compounds was demonstrated in rat studies using death
as the end point (Smyth et al. 1969). The combinations of chemicals
showed increased lethality that varied from 20 to 47%. The compounds
were: formalin, 20%; butyl ether, 28%; aniline, 32%; dioxane, 39%-
acetone, 47%; and carbon tetrachloride, 47%.
Alcohol also has the potential for enhancing the toxicity of
nitrobenzene; however the toxicokinetic mechanism is not known. It is
clear, however, that alcohol does not simply enhance the absorption of
nitrobenzene. When alcohol was given orally and nitrobenzene is given
intravenously, there was increased toxicity in rabbits. Alcohol also
enhanced the neural toxicity of nitrobenzene in rabbits when
nitrobenzene was applied to the skin (Matsumaru and Yoshida 1959).
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35
2. HEALTH EFFECTS
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
Populations that are considered unusually susceptible to
nitrobenzene toxicity are those groups that are susceptible to
methemoglobinemia. The newborn infant is especially vulnerable to
methemoglobinemia due to the following factors (Goldstein et al. 1969;
Von Oettingen 1941):
1. Fetal hemoglobin, which remains in the blood for some time
after birth, is more prone to conversion to methemoglobin than
is adult hemoglobin.
2. Umbilical cord blood is deficient in the enzyme glucose-6-
phosphate dehydrogenase and thus cannot readily convert the
methemoglobin that is formed "naturally" back to hemoglobin as
is readily done in adults.
A condition described as "hereditary methemoglobinemia" may result
from a genetic defect (Goldstein et al. 1969). The enzyme methemoglobin
reductase is absent and persons are hypersensitive to arty substances
such as nitrite or aniline derivatives capable of producing
methemoglobinemia. The trait is inherited as an autosomal recessive
allele. Thus either sex may exhibit the trait which is ordinarily
detected by the presence of cyanosis at birth. Such individuals would
be extremely sensitive to the effects of nitrobenzene.
A more common genetic defect was also described in which the enzyme
glucose-6-phosphate dehydrogenase has decreased activity (Goldstein
et al. 1969). The pattern of inheritance of this trait is linked to one
of several alleles on the X chromosome. The phenotype is expressed as
an incomplete dominant trait. Thus, female heterozygotes are not known
to have severely depressed enzyme levels and males may have a wide range
of activity. These phenotypes express a wide range of levels of
glucose-6-phosphate dehydrogenase enzyme in the red blood cell. This
defect is ordinarily without adverse effects. It is only when these
individuals are challenged with compounds that oxidatively stress
erythrocytes (such as primaquine) that there is a hemolytic response.
Reactors to primaquine (and fava beans) are found predominantly among
groups that live in or trace their ancestry to malaria-hyperendemic
areas such as the Mediterranean region or Africa. The incidence of
"primaquine sensitivity" among Kurds, a Middle Eastern population, is
53%. Among American blacks, the incidence is 13%. Thus, individuals
already exhibiting primaquine sensitivity would be expected to be more
vulnerable to the additional hemolytic crisis that often follows 5 to
6 days after nitrobenzene exposure (Gosselin et al. 1984; Von Oettingen
1941) .
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36
2. HEALTH EFFECTS
The presence of susceptible populations in the workplace is
obviously of great concern since chronic and potentially high levels of
exposure to nitrobenzene combined with a genetic predisposition toward
methemoglobinemia can put certain individuals at very high risk (Linch
1974).
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 nitrobenzene 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 nitrobenzene.
The following categories of possible data needs have been
identified by a joint team of scientists from ATSDR, NTP, and EPA. They
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 Nitrobenzene
The existing data on health effects of inhalation, oral, and dermal
exposure of humans and animals to nitrobenzene are summarized in
Figure 2-3. The purpose of this figure is to illustrate the existing
information concerning the health effects of nitrobenzene. 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.
2.8.2 Identification of Data Needs
Acute-Duration Exposure. Case studies of acute-duration human
exposure to nitrobenzene via inhalation and the oral route indicate that
methemoglobinemia is the major adverse effect found in humans. No data
are available on human dermal exposure. Acute-duration studies
conducted in rats via the inhalation and oral routes and in mice via the
dermal route have also resulted in methemoglobinemia as well as various
other systemic, neurological, and testicular effects. The data are not
considered to be appropriate to use in calculating an MRL by any route
because species- and strain-related differences in sensitivity have been
noted in intermediate-duration inhalation studies in mice and rats, and
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37
2. HEALTH EFFECTS
Inhalation
Oral
Dermal
HUMAN
Inhalation
Oral
Dermal
ANIMAL
0 Existing Studies
FIGURE 2-3. Existing Information on Health Effects of Nitrobenzene
SYSTEMIC
SYSTEMIC
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38
2. HEALTH EFFECTS
it is possible that human sensitivity to methemoglobin formation may
greatly exceed that of the test animals used in these studies. The
available toxicokinetic data do not provide insight as to the possible
reasons for the observed differences in rodent studies. However, there
is no apparent need for further animal studies by any route of exposure
for this duration period.
Intermediate-Duration Exposure. No data are available on human
exposure to nitrobenzene by any route for this duration period. Data in
animals are limited to two inhalation studies in rodents. Effects in
rats included methemoglobinemia, renal and hepatic necrosis, splenic
lesions, and testicular necrosis. Methemoglobinemia and adrenal lesions
were reported in mice. The available data were not considered to be
adequate to use in calculating an MRL for this route, because the
database is very limited and because the different levels of sensitivity
observed in mice and rats suggest that relative human sensitivity should
be closely studied before calculations of MRLs are attempted. There are
no toxicokinetic data that provide a potential explanation for these
differences. However, there is no apparent need for further inhalation
studies for this duration period. A 90-day study via the oral route may
provide useful information. However, the available information does not
clearly establish that oral or dermal exposure to nitrobenzene are
likely to occur in humans.
Chronic-Duration Exposure and Cancer. Available chronic-duration
studies in humans are limited to a case report of a woman who was
occupationally exposed to nitrobenzene and developed methemoglobinemia
and hepatic and neurological effects. Chronic duration data in animals
are limited to a two-generation inhalation study in rats that resulted
in testicular lesions. No studies using the oral or dermal routes have
been located and the available data are not considered appropriate to
use in calculating an MRL by any route. The results of a Chemical
Industry Institute of Toxicology (CUT) inhalation bioassay using rats
and mice which was completed in 1987 should provide useful information
on the potential risks associated with chronic exposure to nitrobenzene
in the vicinity of hazardous waste sites and, to a greater extent, in
the workplace. Although nitrobenzene appears to be well absorbed via
the oral route, there are no data to suggest that long-term oral
exposure would be of concern in these populations. Dermal absorption of
nitrobenzene in the air has been demonstrated in toxicokinetic studies
in humans. Based on the results of the CUT two-year inhalation study,
chronic-duration dermal application studies may be useful in assessing
the possible effects of dermal contact with nitrobenzene in the
workplace.
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39
2. HEALTH EFFECTS
There are no available carcinogenicity data in humans or animals
using any route of exposure. Data from the CUT inhalation bioassay
should provide valuable information on the carcinogenic potential of
airborne nitrobenzene. There is currently no apparent need for studies
using the oral or dermal route. However, as stated above, the results
of the CUT bioassay may provide insight into the possible need for
dermal application studies.
Genotoxicity. There are no data on the genotoxic potential of
nitrobenzene in humans exposed via any route. The results of in vivo
tests in rats exposed via inhalation or orally and in vitro tests have
generally been negative and do not suggest a potential concern for
exposed humans. Further studies in this area do not appear to be
needed.
Reproductive Toxicity. There are no data on the potential
reproductive effects in humans exposed to nitrobenzene via any route.
Data in animals include a 90-day inhalation study in rats that resulted
in testicular degeneration, a two-generation inhalation study in rats
that resulted in testicular lesions and decreased fertility, and a
single-dose gavage study in rats that resulted in testicular necrosis
and temporarily decreased sperm levels. These data suggest that similar
information on men exposed to nitrobenzene in the area of hazardous
waste sites or in the workplace would be extremely useful. In addition,
in any further animal studies conducted by any route and for any
duration period, data on reproductive organ histopathology resulting
from nitrobenzene exposure as well as toxicokinetic data on the
distribution of nitrobenzene to the reproductive organs would be
valuable information.
Developmental Toxicology. There are no available data on the
developmental effects of nitrobenzene in humans exposed via any route
for any duration period. The results of inhalation studies in rats and
rabbits have been negative. There is no apparent need for further
studies in this area. However, if any further developmental studies are
conducted, it would be useful to have data on animals exposed earlier in
the gestation period than day 6 (which was the earlier gestation day in
the two available inhalation studies).
Immunotoxicity. No studies were located relating to immunotoxic
effects in humans or animals exposed to nitrobenzene via any route.
However, splenic lesions have been reported in mice and rats exposed to
nitrobenzene via inhalation in both acute- and intermediate-duration
studies. These results suggest that a battery of immune function tests
in animals exposed via inhalation and orally would provide useful
information. The results of the CUT bioassay, however, may provide
some information on this end point.
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AO
2. HEALTH EFFECTS
Neurotoxicity. Neurological effects including headache, nausea,
vertigo, and confusion have been reported in case studies of humans
exposed to nitrobenzene by inhalation. In orally exposed persons, apnea
and coma have additionally been reported. No data are available in
humans exposed via the dermal route. In animal studies, brain lesions
have been observed in mice and rats exposed by inhalation and in rats
that received a single oral dose. No data are available in animals
exposed via the dermal route. Toxicokinetic studies in mice and rats
provide evidence that nitrobenzene is distributed to brain tissue. Both
the human and animal data provide clear evidence that nitrobenzene is a
neurotoxic substance. Further studies in this area do not appear to be
needed. In addition, results of the CUT two-year bioassay may provide
further information on this end point.
Epidemiological and Human Dosimetry Studies. No epidemiological
studies were located regarding human health effects from nitrobenzene
exposure. Studies of occupationally exposed populations would probably
provide useful information. Areas of major interest would include
methemoglobin levels, effects on reproductive function, immunological
status, and neurobehavioral function.
Biomarkers of Exposure and Effect. The presence of p-nitrophenol
in urine serves as a satisfactory biomarker of nitrobenzene exposure.
Because nitrobenzene metabolites, nitrosobenzene and
phenylhydroxylamine, bind to hemoglobin in the blood of rats and mice,
the presence of these hemoglobin adducts in human blood may also serve
as biomarkers of nitrobenzene exposure. More information on this
possibility would be useful.
The presence of increased levels of methemoglobin can indicate
exposure to nitrobenzene as well as to any of several other toxic
substances. Therefore, methemoglobinemia by itself would not serve as a
satisfactory biomarker of effect for nitrobenzene. Further study in
this area does not appear to be potentially useful.
Absorption, Distribution, Metabolism, Excretion. Absorption data
for humans exposed to nitrobenzene via inhalation and the dermal route
indicate that it is efficiently absorbed by these routes. Although
absorption studies using the oral route have not been located for
humans, the available case studies suggest that it can also be absorbed
via ingestion. However, quantitative data are lacking. Similarly, in
animals, quantitative absorption studies using inhalation or dermal
application are not available, but the available toxicity data using
these routes suggest that absorption does take place. This does not
appear to be a priority area for further research.
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41
2. HEALTH EFFECTS
No distribution data are available for humans exposed to
nitrobenzene via any route. Data in animals are limited to oral studies
in rats and mice that indicate that there is some distribution to the
blood, liver, brain, kidney, and lung. Not all tissues have been
analyzed in these studies. Comprehensive distribution studies for
nitrobenzene administered to mice and rats via all three routes would be
very helpful in predicting the organ systems at potential risk in
exposed humans.
Metabolism data available for nitrobenzene suggest that species
and/or strain differences in toxicity may be related to the metabolic
activities of intestinal bacteria that convert it to its toxic
metabolite aniline. This is an area in which further study may be
helpful in making comparisons of human sensitivity with that of other
animals and thus may aid in the interpretation of the currently
available animal studies and their relevance to humans.
Excretion data are available for humans exposed to nitrobenzene via
the inhalation, oral, and dermal routes. The available animal studies
have used the oral route. Urine appears to be the major route of
excretion, although this has not been clearly established. There is no
apparent need for further studies in this area.
Comparative Toxicokinetics. Species and strain differences in
response to nitrobenzene exposure have been noted in inhalation studies
using mice and rats. The reason for these differences and the
toxicokinetics involved are not understood. Additional toxicokinetic
studies in species other than rodents and attempts to estimate the
sensitivity of humans relative to these test species would be valuable
aids in interpreting the results of available toxicity studies and in
understanding individual differences noted in response to nitrobenzene
exposure.
2.8.3 On-going Studies
The CUT has been preparing a final report on their two-year
carcinogenicity studies of nitrobenzene administered to mice and rats
via inhalation. No other research activities on nitrobenzene are known
to be currently in progress.
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43
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Table 3-1 lists common synonyms, trade names and other pertinent
identification information for nitrobenzene.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Table 3-2 lists important physical and chemical properties of
nitrobenzene.
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44
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Nitrobenzene
Value Reference
Chemical name
Nitrobenzene
NLM 1988
Synonyms
Nitrobenzol;
MLM 1988
Oil of Mirbane
Trade name
Caswell No. 600
NLM 1988
Chemical formula
C6H5N02
NLM 1988
Chemical structure
IMC^
1
(Si
Identification numbers:
CAS Registry
98-95-3
NLM 1988
NIOSH RTECS
DA6475000
HSDB 1988
EPA Hazardous Waste
U169, F004
NLM 1988,
HSDB 1988
OHM/TADS
7216821
HSDB 1988
DOT/UN/NA/IMCO Shipping
UN 1662
NLM 1988
HSDB
104
NLM 1988
NCI
C60082
NLM 1988
CAS - Chemical Abstracts Service; NIOSH - National Institute for
Occupational Safety and Health; RTECS - Registry of Toxic Effects of
Chemical Substances; EPA - Environmental Protection Agency; OHM/TADS
Oil and Hazardous Materials/Technical Assistance Data System-
DOT/UN/NA/IMCO - Department of Transportation/United Nations/North
America/International Maritime Dangerous Goods Code; HSDB - Hazardous
Substances Data Bank; NCI «¦ National Cancer Institute.
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45
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of Nitrobenzene
Property
Value
Reference
Molecular weight
Color
Physical state
Melting point
Boiling point
Density at 20°C
Odor
Odor threshold:
Water
Air
Solubility:
Water at 20°C
Organic solvents
Partition coefficients:
Log Kow
Log Koc
Vapor Pressure at 20°C
Henry's law constant
Autoignition temperature
Flashpoint
Flammability limits
Conversion factors
123.11
Yellow
Liquid
5. 7°C
210.8°C
1.2037
Bitter almonds,
shoe polish
0.11 mg/L
0.092 mg/m3
1900 mg/L
Soluble in alcohol,
ether, acetone,
benzene
1.87
1.56
0.15 mmHg
1.31 x 10~5 atm-m3/mol
482°C
87.7° C
No data
1 ppm - 5.12 mg/m3
1 mg/m3 - 0.20 ppm
Weast 1985
Verschueren 1983
Verschueren 1983
Weast 1985
Weast 1985
Weast 1985
Verschueren 1983
Amoore and Hautala
1983
Amoore and Hautala
1983
Mabey et al. 1982
Weast 1985
Mabey et al. 1982
Mabey et al. 1982
Mabey et al. 1982
Mabey et al. 1982
Sax and Lewis 1987
Sax and Lewis 1987
Verschueren 1983
Verschueren 1983
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47
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION
Nitrobenzene is produced commercially by the exothermic nitration
of benzene with fuming nitric acid in the presence of a sulfuric acid
catalyst at 50 to 65°C. The crude nitrobenzene is passed through
washer-separators to remove residual acid and is then distilled to
remove benzene and water.
There has been a gradual increase in nitrobenzene production volume
in the United States from 73,600 metric tons (kkg) in 1960 to
434,900 kkg in 1986. Based on increased production capacity and
increased production of aniline (the major end-product of nitrobenzene)
in 1987, it is likely that nitrobenzene production volume will continue
to increase (Collins et al. 1982; Dunlap 1981; EPA 1985a; SRI 1985,
1986, 1987, 1988; USITC 1987, 1988).
Currently, there are four United States producers of nitrobenzene:
E. I. DuPont de Nemours & Company, Inc., Beaumont, Texas; Mobay
Corporation, New Martinsville, West Virginia; First Chemical
Corporation, Pascagoula, Mississippi; and ICI Americas, Inc., Geismar,
Louisiana (SRI 1988; USITC 1988).
4.2 IMPORT
No recent data documenting import or export volumes of nitrobenzene
were located. However, it is estimated that these quantities are
negligible, based on the 1978 import volume of 38 kkg and 1980 export
volume of 36 kkg, which represent less than 1% of United States
production during those years (Collins et al. 1982).
4.3 USE
The primary use of nitrobenzene Is in the captive production of
aniline, with about 97.5% of nitrobenzene production consumed in this
process. The major use of aniline is in the manufacture of
polyurethanes. Nitrobenzene is also used as a solvent in petroleum
refining, in the manufacture of cellulose ethers and acetate, and in
Friedel-Crafts reactions to hold the catalyst in solution. It is also
used in the synthesis of other organic compounds including
acetaminophen, which is an over-the-counter analgesic commonly known as
Tylenol®.
Nitrobenzene is used as a flavoring agent, a perfume for soaps and
as a solvent for shoe dyes (Collins et al. 1982; Dunlap 1981; EPA 1985a;
HSDB 1988).
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h 8
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.A DISPOSAL
Because nitrobenzene is listed as a hazardous substance, disposal
of waste nitrobenzene is controlled by a number of federal regulations
(see Chapter 7). Land disposal restrictions (treatment standards) apply
to wastes containing nitrobenzene. These wastes may be chemically or
biologically treated or incinerated by the liquid injection or fluidized
bed methods (EPA 1988a, 1989; HSDB 1988). No data were located on the
amounts of nitrobenzene disposed of by any of these methods. The EPA
does not believe that releases of nitrobenzene to the environment are
substantial (EPA 1984).
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5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Human exposure to nitrobenzene results from releases to air and
wastewater from industrial sources and from nitrobenzene as an air
pollutant in ambient air, especially in urban areas. Its low volatility
and weak sorption on soil suggest that surface waters and groundwater
could be a route of exposure for the general population. Exposure is
mitigated by environmental degradation, including photolysis and
microbial biodegradation. Nitrobenzene is poorly bioaccumulated and
not biomagnified through the food chain. A number of fairly stable
degradation products of nitrobenzene are formed during environmental
degradation; some have similar effects, while others operate by
different mechanisms. Moreover, whether or not nitrobenzene will be
completely broken down (mineralized) at a particular site seems to be
questionable. Nitrobenzene may not be degraded in a given sewage
treatment plant, and, when present at high concentrations, it also may
inhibit the biodegradation of other wastes.
Occupational exposure is of great concern, since nitrobenzene can
be taken up very readily through the skin as well as by inhalation.
Monitoring studies reveal low and highly variable exposures through air
and, more rarely, drinking water, with a generally downward trend in
exposure levels over the past two decades. At this time, nitrobenzene
has been found in 7 of the 1,177 NPL hazardous waste sites in the United
States (VIEW 1989). The frequency of these sites within the United
States can be seen in Figure 5-1.
Because of the relative ease of measurement of many of
nitrobenzene's properties and its ready detectability by both chemical
analysis and human olfaction (sense of smell), its release, transport
and fate, and the consequent exposure of human beings have been studied
over a considerable period of time. Thus, the potential for human
exposure to nitrobenzene is better understood than that of many other
chemicals.
5.2 RELEASES TO THE ENVIRONMENT
Most (97% to 98%) of the nitrobenzene produced is retained in
closed systems for use in synthesizing aniline and other substituted
nitrobenzenes and anilines (Dorigan and Hushon 1976; Chemical Marketing
Reporter 1987). Most of these products go into the manufacture of
various plastic monomers and polymers (50%) and rubber chemicals (27%);
a smaller proportion goes into synthesis of hydroquinones (5%), dyes and
intermediates (6%), drugs (3%), and pesticides and other specialty items
(9%) (Dunlap 1981). A small fraction of the production Is used directly
in other processes or in consumer products (principally metal and shoe
polishes).
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FREQUENCY ¦ I I 1 I I 1 SUE M 2 SITES
FIGURE 5-1. Frequency of Sites with Nitrobenzene Contamination
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51
5. POTENTIAL FOR HUMAN EXPOSURE
The nitration of benzene in air leads to variable ambient levels in
urban areas, making the assessment of releases to the air from waste
sites difficult. Nevertheless, limited studies of municipal waste
disposal facilities and the more complete evaluation of hazardous waste
sites have found nitrobenzene infrequently present and, when present,
concentrations have been generally low.
5.2.1 Air
Direct release of nitrobenzene to air during its manufacture is
minimized by the passage of contaminated air through activated charcoal
(EPA 1980a), and its subsequent use in closed systems as an intermediate
similarly limits direct exposure during industrial processing.
Nevertheless, as much as 8.3 million lbs/yr may be released from
industrial processes (Dorigan and Hushon 1976). The fraction of these
manufacturing losses to air is not known.
Use of nitrobenzene as a chemical intermediate or in consumer
products such as metal and shoe polishes could contribute to losses via
fugitive emissions, wastewater, spills, and end product usage. The
extent to which these sources contribute to human exposure has not been
evaluated quantitatively.
The third principal source of nitrobenzene is the atmospheric
photo-chemical reaction of nitrogen oxides with benzene, which
presumably is derived from automobile fuels and, to a lesser extent,
solvent uses of benzene (Dorigan and Hushon 1976). As benzene releases
decline, this source (not quantified) should diminish as well. The
contribution of this source is difficult to estimate since most
measurements of ambient atmospheric nitrobenzene have been made in urban
areas near sites of nitrobenzene manufacture, use, and disposal (see
Section 5.4.1). Seasonal variations and those associated with air
pollution episodes suggest that this source, although limited, may form
a significant proportion of nonoccupational human exposure.
5.2.2 Water
The effluent discharge produced during nitrobenzene manufacture is
the principal source of nitrobenzene release to water. Losses to
wastewater have been observed to be 0.09% of production in one plant and
2.0% in another (Dorigan and Hushon 1976).
The nitrobenzene in wastewater may be lost to the air, degraded by
sewage organisms or, rarely, carried through to finished water. The EPA
has surveyed nitrobenzene levels reported in effluents from
4,000 publicly-owned treatment works (POTWs) and industrial sites. The
highest value in effluent was >100 ppm in the organic and plastics
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5. POTENTIAL FOR HUMAN EXPOSURE
industry (Shackelford et al. 1983). Nitrobenzene was detected in one of
33 industrial effluents at a concentration greater than 100 /^g/L (perry
et al. 1979). Reported nitrobenzene concentrations in raw and treated
industrial wastewaters from several industries range from 1.4
91,000 fj.g/L (EPA 1983a). The highest concentrations are associated with
wastewaters from the organic chemicals and plastics industries .
Nitrobenzene was reported at above detectable levels in 1.8% of t^e
1,245 reporting industrial stations (Staples et al. 1985) and in the
finished effluent of only 3 of the POTWs and one oil refinery (Ellis
et al. 1982). In analysis of runoff samples from 51 catchments in
19 cities, the National Urban Runoff Program found no nitrobenzene (Cole
et al. 1984).
These results suggest that commercial and industrial users of
nitrobenzene are dispersed throughout the country, so that concern
regarding sources must extend beyond those four states in which
nitrobenzene is manufactured.
Although nitrobenzene is sparingly soluble in water [1,900 ppm at
20°C (Verschueren 1983); 2,090 ppm at 25°C (Banerjee et al. 1980)],
pungent, characteristic odor ["bitter almonds," (Windholz 1983); "shoe
polish," (Ruth 1986)] is detectable at water concentrations as low as
30 ppb (EPA 1980a). Hence, human exposures to large releases or
accumulations in the environment appear unlikely to escape unnoticed.
Nitrobenzene was detected in groundwater at 3 of 862 hazardous waste
sites at a geometric mean concentration of 1,400 j^g/L according to the
Contract Laboratory Program (CLP) Statistical Database (CLPSD 1988) .
Nitrobenzene was not detected in any surface water samples from the
862 sites.
5.2.3 Soil
As a source of nitrobenzene exposure of humans, soil appears to
rank a distant third in terms of its contribution. Nelson and Hites
(1980) reported 8 ppm in the soil of a former dye manufacturing site
along the Buffalo River, but failed to detect nitrobenzene in river
sediments, as noted above. The presence of nitrobenzene in the soils of
abandoned hazardous waste sites is inferred by its presence in the
atmosphere above several sites (Harkov et al. 1985; LaRegina et al.
1986). Nitrobenzene was detected in soil/sediment samples at 4 of 862
hazardous waste sites at a geometric mean concentration of 1,000 wg/kg
(CLPSD 1988). No further data on nitrobenzene levels released to soils
were located.
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5. POTENTIAL FOR HUMAN EXPOSURE
5.3 ENVIRONMENTAL FATE
Nitrobenzene has been scored in the Pre-Biologic Screen (PBS)
(Gillett 1983) which estimates the environmental fate of neutral, un-
ionized organic chemicals and the implications for ecotoxic and, to a
lesser extent, health effects. Based on a three-dimensional matrix [for
which the components are P (Log Kow), Hc (log of dimensionless Henry's
law constant), and t1/2 (log biodegradation half-life)], the PBS scores
a candidate chemical in each of the four following categories: A)
bioaccumulation and multi-species/multi-media effects; B)
bioaccumulation and chronic action; C) chronic action in the water
column, including plant uptake and soil leaching; and D) indirect
atmospheric action, including inhalation and plant fumigation. For
nitrobenzene, the values in the PBS are P - 1.83 (Banerjee et al. 1980)
and He = -3.02 (Hine and Mookerjee 1975). These values correspond well
with observations that nitrobenzene is not bioaccumulated, does not
accumulate in soils and sediments, can be taken up by plants, has been
reported in groundwater, and has not been associated with either direct
or indirect effects in the atmosphere. Half-life values for
nitrobenzene indicate that it can be readily biodegraded aerobically in
7 days (t1/2 = 0.06) (Tabak et al. 1981); it is degraded anaerobically
in 22 days (t1/2 - 1.34) (Hallas and Alexander 1983); and at high
concentrations in water is resistant to biodegradation (t1J2 - > 2)
(Korte and Klein 1982).
5.3.1 Transport and Partitioning
The movement of nitrobenzene in soil, water and air is predicted by
its physical properties: (1) water solubility (1,900 ppm) (Verschueren
1983); (2) moderate volatility (0.15 mmHg at 20°C) (Mabey et al. 1982);
(3) low octanol-water partition coefficient (log Kow - 1.84) (Geyer
et al. 1984); and (4) soil/sediment sorption coefficient (K3ed - 36)
(Mabey et al. 1982), (Kom - 50.1) (Briggs 1981). The dimensionless
Henry's law constant for nitrobenzene (9.6 x 10"4) suggests that
transfer from water to air will be significant, but not rapid (EPA
1985a; Lyman et al. 1982). Sediment sorption and bioconcentration into
aquatic and terrestrial animals are not likely to be significant (EPA
1985a). Plant uptake might be expected in terrestrial systems
(McFarlane et al. 1987a, 1987b). Leaching through soil may occur.
Vapor densities reported for nitrobenzene relative to air range
from 4.1 to 4.25 (Anderson 1983; Beard and Noe 1981; Dorigan and Hushon
1976; Dunlap 1981). Removal processes of nitrobenzene in air may
involve settling of vapor due to its higher density relative to air
(Dorigan and Hushon 1976). Washout by rainfall (either through solution
in rain drops or by removal of nitrobenzene sorbed onto particulates)
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5. POTENTIAL FOR HUMAN EXPOSURE
and dry fall of particulates are negligible, as estimated by Cupitt
(1980) and expressly measured in field releases (Dana et al. 1984).
Atmospheric residence time was estimated to be 190 days (Cupitt 1980)
Briggs (1981) compared the soil sorption coefficient (Kd) expressed
in terms of organic matter (Kom) , where Kom - 100xKd/(% organic matter),
for a wide variety of chemicals and soils to the octanol-water partition
coefficient Kow. Briggs (1973) classified soil mobility using log Kou
and log organic matter (om) content and compared this classification to
that of Helling and Turner (1968), based on soil thin layer
chromatography. Nitrobenzene would be in mobility class III
(intermediate).
Jury et al. (1984) also classified nitrobenzene as intermediately
mobile, but noted that its loss from soil would be enhanced by
evaporation of water. Moreover, because nitrobenzene has relatively
poor diffusive flux, the material would tend to move as a bolus within
soil. Jury et al. (1984) hypothesized that a deposit 10 cm deep in soil
would have a half-life of about 19 days.
Other results also indicate that nitrobenzene is intermediately
mobile in forest and agricultural soils (Seip et al. 1986). However,
nitrobenzene was somewhat more mobile in soil with lower organic carbon
content. The authors attribute this to hydrogen bonding interactions of
nitrobenzene with organic matter in the soil.
Piwoni et al. (1986) found that nitrobenzene did not volatilize in
their microcosms simulating land-application of wastewater, but was
totally degraded. Enfield et al. (1986) employed a calculated Henry's
law constant of 1.30 x 10~3 kPa m3 mol"1, and arrived at a biodegradation
rate coefficient greater than 8 day-1. They predicted that 0.2% of the
added nitrobenzene could be accounted for in volatiles. The EXAMS
computer model (Burns et al. 1981) predicts volatilization half-lives of
12 days (river) to 68 days (eutrophic lake) and up to 2% sediment
sorption for nitrobenzene.
In a laboratory-scale waste treatment study, Davis et al. (1981)
estimated that 25% of the nitrobenzene was degraded and 75% was lost
through volatility in a system yielding a loss of about 80% of initial
nitrobenzene in 6 days. In a stabilization pond study, the half-life by
volatilization was about 20 hours, with approximately 3% adsorbed to
sediments (Davis et al. 1983).
The measured bioconcentration factors (BCF) for nitrobenzene in
several organisms indicate minimal bioconcentration in aquatic
organisms. Veith et al. (1979) found the 28-day flow-through test for
fathead minnows yielded a BCF of 15. ^ less satisfactory 3-day static
measurement gave a BCF of less than 10 for the golden ore (Freitag
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5. POTENTIAL FOR HUMAN EXPOSURE
et al. 1982). In the Metcalf model "farm pond" microcosm (Lu and
Metcalf 1975), the Ecological Magnification Index (EM: ratio of
concentration of parent material in organism to concentration of parent
material in water) was about 8 in mosquitofish (Gambusia affinis") after
a 24-hr exposure. Longer exposures of other species, however, did not
increase the value; the EM in snails (Phvsa sp.) was 0.7, in mosquito
(Culex quinquifasciatus) larvae was 0.8, in Daphnia magna was 0.15, and
in alga (Oedogonium) was 0.03. Bioaccumulation from water is not
considered significant at values of less than 300 (Trabalka and Garten
1981) .
Nitrobenzene may bioconcentrate in terrestrial plants. The
relatively rapid uptake of UC-labeled nitrobenzene into mature soybean
(Glycine max L Merr) plants was reported by McFarlane et al. (1987a,
1987b) and Nolt (1988). Plant uptake is, therefore, a possible route of
human exposure to nitrobenzene.
5.3.2 Transformation and Degradation
5.3.2.1 Air
p-Nitrophenol and nitrosobenzene were reported to be the principal
photodegradation products of nitrobenzene vapors exposed to UV light in
air (Hastings and Matsen 1948). In another study, both o- and
p-nitrophenols were found when 02 was present and phenol was also found
when 02 was absent (Nojima and Kanno 1977). Photolysis by reaction with
hydroxyl radicals or ozone was found to be insignificant in the
troposphere (Atkinson et al. 1987). Based on laboratory studies, they
projected half-lives of nitrobenzene of 180 days by reaction with
hydroxyl radicals and more than 6 years by reaction with ozone in
"clean" air. In typical, moderately "dirty" air, these values would
decrease to 90 days and more than 2 years, respectively.
As noted earlier, nitrobenzene is formed by reaction of benzene
with N0Z, and Atkinson et al. (1987) reported that aniline is slowly
oxidized to nitrobenzene by ozone. Further nitration of nitrobenzene
appears to be negligible. These reactions are summarized in Figure 5-2.
Atmospheric photochemical decomposition is, therefore, thought to
be an important removal route of nitrobenzene itself (EPA 1985a).
5.3.2.2 Water
There is no known mechanism of hydrolysis of nitrobenzene; however,
photolysis and biodegradation are significant nitrobenzene degradation
pathways in water (Callahan et al. 1979; Mabey et al. 1982).
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57
5. POTENTIAL FOR HUMAN EXPOSURE
Photolysis. Photochemical oxidation of nitrobenzene by hydrogen
peroxide yields p-, o-, and ra-nitrophenols (Draper and Crosby 1984) with
an estimated half-life of 250 days (Dorfman and Adams 1973). Direct
photolysis, measured by Zepp and Scholtzhauer (1983), has a half-life of
2.5 to more than 6 days near the surface of bodies of water in the
vicinity of 40°N latitude.
Under laboratory conditions, direct photolysis of nitrobenzene in
solvents such as isopropanol yields phenylhydroxylamine, which can be
oxidized to nitrosobenzene by oxygen (Hurley and Testa 1966, 1967).
Phenylhydroxylamine and nitrosobenzene can then combine to form
azoxybenzene. However, these reactions may not be important under
natural conditions in the absence of hydrogen donors (Mabey et al.
1982). Callahan et al. (1979) proposed that sorption of nitrobenzene to
humics could enhance photolytic destruction of nitrobenzene. Simmons
and Zepp (1986), however, found that photolysis of nitrobenzene was not
appreciably enhanced by either a natural humic-containing water or a
commercial humic sample. Zepp et al. (1987a) reported that hydrated
electrons from dissolved organic matter could significantly increase
photoreduction of compounds such as nitrobenzene, and that photolysis of
nitrate ions to hydroxyl radicals increased nitrobenzene
photodegradation (Zepp et al. 1987b). Algae do not enhance photolysis
of nitrobenzene (Zepp and Scholtzhauer 1983). Photolysis may be an
important pathway in natural waters (EPA 1985a), but probably only under
conditions where biodegradation is poor or absent and where both UV
irradiance and appropriate facilitating molecules occur in relatively
clear waters.
Biodegradation. Nitrobenzene may be almost completely removed by
activated sludge treatment (EPA 1983a). Pitter (1976) obtained 98%
removal of chemical oxygen demand (COD) at a rate of 14 mg COD/hr/g dry
weight of activated sludge with nitrobenzene as the sole carbon source,
Tabak et al. (1981) obtained 100% biodegradation in settled domestic
wastewater in 7 days. Hallas and Alexander (1983) reported 100%
degradation in 10 days after a 6-day lag under aerobic conditions with
municipal sewage effluent. Similar results have been reported by a
number of researchers (Davis et al. 1981, 1983; Kincannon et al. 1983;
Patil and Shinde 1988; Stover and Kincannon 1983) using a variety of
model sewage treatment reactors and wastewater sources, including
adapted industrial sludges.
Nitrobenzene is also degradable by anaerobic processes, but more
slowly than described above. Chou et al. (1978) reported that
nitrobenzene was 81% removed in 110 days by acclimated domestic sludge
in an anaerobic reactor, and Hallas and Alexander (1983) found that 50%
was degraded in 12 days under similar conditions. Canton et al. (1985)
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5. POTENTIAL FOR HUMAN EXPOSURE
measured an 8% decrease in nitrobenzene after 8 days in unadapted media
but reported a half-life of less than 2 weeks in adapted media.
Nitrobenzene was either highly resistant to degradation or
inhibited biodegradation of other components of the waste in several
biodegradation studies (Barth and Bunch 1979; Davis et al. 1981; Korte
and Klein 1982; Lutin et al. 1965; Marion and Malaney 1963). However
these effects were observed at concentrations (^50 mg/L) of nitrobenzene
much higher than those detected in ambient waters (see Section 5.4 2)
5.3.2.3 Soil
There is a paucity of studies of nitrobenzene in soil.
Decomposition of nitrobenzene in a 1% suspension of Niagara silt loam
took more than 64 days, while aniline and phenol, commonly metabolites
of nitrobenzene, were completely degraded in 4 and 1 days, respectively
(Alexander and Lustigman 1966). In contrast, a study of the efficacy of
soil infiltration along the Rhine River in the Netherlands showed that
nitrobenzene was removed completely in moving 50 cm through a peat-sand
artificial dune (Piet et al. 1981).
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
Monitoring of nitrobenzene in the environment reveals variably low
levels in air, very infrequent occurrence in surface waters, and
infrequent occurrence but higher levels in industrial wastewaters.
Nitrobenzene may be present in soils at hazardous waste sites.
5.4.1 Air
Most of the information on nitrobenzene levels in air is derived
from a series of reports from New Jersey, in which ambient air in urban
rural, and waste disposal areas were monitored extensively. In the
initial study (Bozzelli et al. 1980), nitrobenzene was not detected
above the level of 0.01 ppb in about 260 samples collected in 1979. In
1978, nitrobenzene levels averaged 0.40 ppb in industrial areas, and
0.02 and 0.09 ppb in two residential areas, but that in 1982, levels in
residential areas were approximately 0.3 ppb or less, while levels in
industrial areas were 0.9 ppb or more (Bozzelli and Kebbekus 1982).
Again, most of the samples were negative for nitrobenzene. The highest
values were 3.5 to 5.7 ppb.
Harkov et al. (1983) reported low levels of nitrobenzene (0.07 to
0.1 ppb) in approximately 85% of air samples of nitrobenzene in their
study of airborn toxic chemicals in summer. Nitrobenzene was not
detected during the winter (Harkov et al. 1984; Lioy et al. 1983).
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5. POTENTIAL FOR HUMAN EXPOSURE
Studies of air over waste disposal sites (Harkov et al. 1985) are
confounded by weather and timing. Air at one landfill showed a mean
nitrobenzene concentration of 1.32 ppb and another of 0.3 ppb; but at
two other sites (measured during snow and/or rain), nitrobenzene was not
detected. LaRegina et al. (1986) summarized these studies by noting
that the highest value for nitrobenzene was 14.48 ppb at a hazardous
waste site, whereas nitrobenzene was often undetectable elsewhere
(especially in rural areas or at sanitary landfills) or anywhere in the
air during the winter.
Very little information is available for other areas of the United
States. Pellizzari (1978b) found only one positive value of 107 ng/m3
(20 ppb) at a plant site in Louisiana. Early data (summarized in EPA
1985a) show less than 25% of United States air samples positive with a
median concentration of about 0.01 ppb.
5.4.2 Water
A nitrobenzene concentration of about 20 ppb in the final effluent
of a Los Angeles County municipal wastewater treatment plant in 1978 and
less than 10 ppb in 1980 was reported (Young et al. 1983). Nitrobenzene
was not reported in runoff samples in 1982 in a nation-wide project
(Cole et al. 1984). Kopfler et al. (1977) list nitrobenzene as one of
the chemicals found in finished tap water in the United States, but do
not report its concentrations or locations. Levins et al. (1979)
reported only one positive sample (total sample number not stated) in
Hartford, Connecticut, sewage treatment plant influents, and no
nitrobenzene was detected in samples taken from three other major
metropolitan areas. Nitrobenzene was detected in only 0.4% of the 836
ambient surface water stations involved in EPA's ST0RET database
(Staples et al. 1985). No data were located on occurrence of
nitrobenzene in groundwater.
Nitrobenzene is detected more frequently and at higher
concentrations in effluents from industrial sources. The STORET
database shows that 1.8% of the 1,245 reporting stations on industrial
wastewaters have had measurable values (Staples et al. 1985).
5.4.3 Soil
The only measurement of nitrobenzene in soil located was a value of
8 ppm detected is soil at one of two sampling sites along the bank of
the industrially polluted Buffalo River in New York (Nelson and Hites
1980). Nitrobenzene was not detected at any of three sediment sampling
sites in this study.
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5. POTENTIAL FOR HUMAN EXPOSURE
5.4.4 Other Media
Nitrobenzene has not been found in other environmental media. It
has not been detected as a bioaccumulated material in fish samples
(Staples et al. 1985). No monitoring of plant tissues has been
reported, even though uptake of nitrobenzene by plants has been observed
(WcFarlane et al. 1987a, 1987b). Data on nitrobenzene occurrence in
foods were not located in the available literature.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
Apparently general exposure of the population to nitrobenzene is
limited to variable concentrations in air and possibly drinking water
Air levels can be high in the vicinity of manufacturing or production
facilities (especially petroleum refining, leather finishing and some
chemical manufacturers). Urban areas have much higher levels in the
summer than winter due to both the formation of nitrobenzene by
nitration of benzene (from motor vehicle fuels) and the higher
volatility of nitrobenzene during the warmer months. Ambient exposure
in the winter may be negligible.
Occupational exposure can be significantly higher than the exposure
of the general population. N10SH (1988) identified about 10,600 workers
(mainly chemists, equipment servicers, and janitorial staff) as
potentially exposed workers in facilities where nitrobenzene is used
Because nitrobenzene is readily absorbed through the skin, as well as
taken up by inhalation and ingestion, industrial exposure necessitates
worker protection, and this has been recognized for decades. At an
industrial exposure level of 5 mg/mJ (1 ppm), a worker would receive
about 25 mg during an 8-hour day (Dunlap 1981).
5, 6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
Based on the New Jersey air studies and on estimates of releases
during manufacture, only populations in the vicinity of manufacturing
activities (i.e., producers and industrial consumers of nitrobenzene for
subsequent synthesis) and petroleum refining plants are likely to have
any significant exposure to anthropogenic nitrobenzene. However
consideration of possible groundwater and soil contamination and uptake
of nitrobenzene by plants expands the potentially high exposure group to
include people living in and around abandoned hazardous waste sites
The numbers of people actually exposed to ambient concentrations of
nitrobenzene are unknown. Based on the locations of production and
other manufacturing facilities, tens of millions of people might be
exposed to low levels of this compound.
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5. POTENTIAL FOR HUMAN EXPOSURE
5.7 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of nitrobenzene is available. Where adequate information
is not available, ATSDR, in conjunction with the NTP, is required to
assure the initiation of a program of research designed to determine the
health effects (and techniques for developing methods to determine such
health effects) of nitrobenzene.
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. No specific data needs are
identified for these properties, for which available values are
generally accepted.
Production, Use, Release and Disposal. Available data indicate
that most nitrobenzene produced in the United States is consumed in the
production of aniline, but current quantitative data on the amount of
nitrobenzene released to the environment during nitrobenzene production
and use are sparse. Collection of this information would be helpful in
evaluating the effect of current industrial practices on environmental
levels of nitrobenzene.
According to the Emergency Planning and Community Right to Know Act
of 1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313), industries
are required to submit release information to the EPA. The Toxic
Release Inventory (TRI), which contains release information for 1987,
became available in May of 1989. This database will be updated yearly
and should provide a more reliable estimate of industrial production and
emission.
Environmental Fate. The environmental fate of nitrobenzene is
fairly well understood within the context of recognition of the
importance of conditions in estimating or modelling environmental
concentrations. The most critical condition is the presence/absence of
a viable, competent and functioning population of microorganisms for
biodegradation. The next most critical factor is the amount of
sunlight. For exposure assessment modelling accuracy, more data are
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5. POTENTIAL FOR HUMAN EXPOSURE
needed on fate in soil, both in the root zone where plants are exposed
and in the saturated and unsaturated zones where groundwater may become
contaminated. Metabolism in plants is poorly characterized to date, so
that information on the nature and quantity of plant metabolites would
assist assessment of exposure via that route.
Bioavailability from Environmental Media. The available
information indicates that nitrobenzene is well absorbed following
inhalation, oral or dermal exposure. It is expected to be well absorbed
by persons breathing or having dermal contact with contaminated air or
ingesting water, soil, plants or any environmental materials that
contain it. It would be useful to have information on its absorption
after dermal contact with contaminated soil or plant material.
Food Chain Bioaccumulation. Uptake and accumulation of
nitrobenzene through food chains are well understood regarding animal
tissues, especially fish. However, more information about plant tissues
would be helpful.
Exposure Levels in Environmental Media. Because nitrobenzene is a
priority pollutant, extensive data are available on its occurrence in
surface waters, sediments, and aquatic animals. It would be useful to
have data on its presence in soils and groundwater and correlations of
measured air concentrations to soil levels and of plant levels to soil
concentrations.
Exposure Levels in Humans. There is very little information on
human exposure to nitrobenzene outside of the workplace. More detailed
exposure analyses that take transformation pathways into account need to
be performed for local sites and the potentially impacted populations.
Further, it would be useful to know more about the relationship of the
organoleptic properties of nitrobenzene with respect to tolerable
exposures. For example, it would be useful to know whether its taste
and aroma are deterents to high levels of human exposure.
Exposure Registries, No exposure registries for nitrobenzene were
located. This compound is not currently one of the compounds for which
a subregistry has been established in the National Exposure Registry.
The compound will be considered in the future when chemical selection is
made for subregistries to be established. The information that is
amassed in the National Exposure Registry facilitates the
epidemiological research needed to assess adverse health outcomes that
may be related to the exposure to this compound.
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5. POTENTIAL FOR HUMAN EXPOSURE
5.7.2 On-going Studies
No long-term research projects or other on-going studies of
occupational or general population exposures to nitrobenzene were
identified.
As part of the Third National Health and Nutrition Evaluation
Survey (NHANES III), the Environmental Health Laboratory Sciences
Division of the Centers for Disease Control, will be analyzing human
urine samples for p-nitrophenol and other phenolic compounds. Since
p-nitrophenol is a major metabolite of nitrobenzene, the presence of
p-nitrophenol in the urine can be used to indicate exposure to
nitrobenzene. These data will give an indication of the frequency of
occurrence and background levels of these compounds in the general
population.
-------
65
6. ANALYTICAL METHODS
The purpose of this chapter is to describe the analytical methods
that are available for detecting and/or measuring and monitoring
nitrobenzene 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 nitrobenzene. Rather, the
intention is to identify well-established methods that are used as the
standard methods of analysis. Many of the analytical methods used to
detect nitrobenzene in environmental samples are the methods approved by
federal agencies such as EPA and the National Institute for Occupational
Safety and Health (NIOSH). Other methods presented in this chapter are
those that are approved by a trade association such as the Association
of Official Analytical Chemists (AOAC) and the American Public Health
Association (APHA). Additionally, analytical methods are included that
refine previously used methods to obtain lower detection limits, and/or
to improve accuracy and precision.
6.1 BIOLOGICAL MATERIALS
Nitrobenzene is volatile; it has a boiling point of 211C,C and a
vapor pressure (20°C) of 0.15 mmHg. Its water solubility (20°C) is
1,900 mg/L. It has a log octanol/water partition coefficient value of
1.85, implying a relatively weak affinity for lipids. These properties
affect the manner in which biological samples are analyzed for
nitrobenzene. Albrecht and Neumann (1985) discussed the difficulty of
analysis of nitrobenzene and its metabolite aniline in animals.
Excretion of the parent compounds or some metabolites in urine has been
determined, but apparently this kind of biological monitoring has so far
not produced satisfactory results due to practical and methodological
reasons. Nitrobenzene metabolites are bound to blood proteins, both in
hemoglobin and in plasma (Albrecht and Neumann 1985). Acute poisoning
by nitrobenzene is usually monitored by measuring levels of methemo-
globin, which is produced by the metabolic products of nitrobenzene.
However, many toxicants produce methemoglobin, and this analysis is not
specific enough to be a satisfactory method for monitoring nitrobenzene
in animals.
Analytical methods for the determination of nitrobenzene in
biological materials are given in Table 6-1.
6.2 ENVIRONMENTAL SAMPLES
Nitrobenzene is determined in environmental samples by collection,
extraction with an organic solvent and gas chromatographic analysis (EPA
1982a, 1982b; NIOSH 1984). Flame ionization detection or mass
spectrometry may be used for detection.
-------
TABLE 6-1. Analytical Methods for Determining Nitrobenzene In Biological Materials
Sample
Detection
Sample Matrix Sample Preparation Analytical Method Limit Accuracy Reference
Urine (spiked
with
nitrobenzene)
Reduce nitrobenzene, form
coupled dye, extract in
carbon tetrachloride
Colorimetrie
at 450 nm
0.8 mg/L
No data
Dangwal and
Jethani 1980
Urine
Measure p-nitrophenol
metabolite in urine
Ho data
Ho data
No data
Ikeda and
Kita 1964
Urine
Measure p-nitrophenol
metabolite in urine
No data
No data
No data
Lauverys
1983
Blood
Measure methemoglobin
formation in blood
No data
No data
No data
Albrecht
and Neumann
1985
Blood
Blood
Measure methemoglobin
formation in blood
Measure methemoglobin
formation in blood
No data
Photometric
No data
No data
No data
No data
Lauverys
1983
Dreisbach and
Robertson 1987
>
5
H
t—i
O
>
r
s
n
n
rr
o
o
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67
6. ANALYTICAL METHODS
Analytical methods for the determination of nitrobenzene in
environmental samples are given in Table 6-2.
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 nitrobenzene is available. Where adequate information
is not available, ATSDR, in conjunction with the NTP, is required to
assure the initiation of a program of research designed to determine the
health effects (and techniques for developing methods to determine such
health effects) of nitrobenzene.
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.
Sensitive and selective methods are available for the qualitative and
quantitative measurement of nitrobenzene after it is separated from its
sample matrix. Capillary gas chromatography, also known broadly as
high-resolution gas chromatography (HRGC), has greatly facilitated the
analysis of compounds such as nitrobenzene that can be measured by gas
chromatography and has resulted in vast improvements in resolution and
sensitivity. It has made the choice of a stationary phase much less
crucial than was the case with packed columns. The instrumental
capability to separate volatile analytes by HRGC is no longer the
limiting factor in their analysis. Further development of methods for
the transfer of isolated analytes, quantitatively and in a narrow band,
to the HRGC, and the identification and accurate measurement of
compounds in the HRGC peaks would be useful. Mass spectrometry (MS) has
been outstanding for the detection of various organic compounds but
other techniques, particularly Fourier transform infrared spectroscopy
(FTIR) may be superior for nitrobenzene. Because nitrobenzene is
metabolized in biological systems, it is difficult to accurately
determine in most biological samples after enough time has elapsed for
these metabolic processes to take place. Therefore, although
nitrobenzene itself can be easily determined in biological samples, it
is rarely found in its unchanged form In these samples. Metabolites of
nitrobenzene in biological materials are difficult to determine in
-------
TABLE 6-2. Analytic*! Methods for Determining nitrobenzene In Environmental Samples
Sample
Detection
Sample Matrix Sample Preparation. Analytical Method Limit Accuracy Reference
Air at landfill
sites
Air
Air
Adsorption on Tenax-GC car-
ttidKes, thermal desorption
Adsorption on silica gel,
extraction with methanol
Adsorption on silica gel,
extraction with methanol
HRGC/FID
GC/FID
GC/FID
0.05 ppb
0.02 mgI
sample
0.5 mg/m3
No data
No data
No data
Harkov et al.
1985
NIOSH 1984
NIOSH 1977
Wastewater
Wastewater
Water
Soil and solid
waste
Soil and solid
waste
Soil and solid
waste
Soil and solid
waste
Direct injection of aqueous
sample
Extract with dichloromethane,
exchange to hexane, concentrate
Extract with dichloromethane
at pH 11 and 2, concentrate
Extract from sample,
cleanup
Extract from sample,
cleanup
Extract from sample,
cleanup
Extract from sample,
cleanup
GC/FID
GC/FID
GC/MS
GC/FID
GC/MS
GC/FID
HRGC/FTIR
No data
3.6 ^g/L
1.9 ,ug/L
137
mg/k&b
19
mg/kgk
660
£
H
m cr>
O CO
>
r
s
w
H
O
O
w
aRelative recovery, percent, + standard deviation.
bApproximate detection limit in high-level soil and sludges.
cApproximate detection limit in low-level soil and sediments.
^Detection limit in water. Detection limit in solids and wastes is several orders of Tiagnltude higher.
HRGC « high resolution gas chromatography; FID « flame ionization detector; ppb = s per billion; GC = gas chromatography;
mg * milligram: m3 * cubic meter; yg/L = micrograms/literj MS = mass spectrometry; ku = kilogram; FTIR « fourier transform
infrared spectrometry.
-------
69
6. ANALYTICAL METHODS
routine practice because of the lack of standardized methods for
measuring these compounds and because of the difficulty of correlating
the presence or levels of these metabolites directly with exposure to
nitrobenzene.
The development of supercritical fluid (SCF) extraction combined
with chromatographic analysis will probably be useful for meeting the
goals of quantitative, rapid, easily performed, low cost and safe
procedures for the determination of poorly volatile organic analytes
such as nitrobenzene and its metabolites in biological samples
(Hawthorne 1988).
Methods for the determination of biomarkers of effect for
nitrobenzene are largely confined to measurement of methemoglobin, which
is also produced by numerous toxicants other than nitrobenzene. More
specific methods for biomarkers of exposure would be helpful in
toxicological studies of nitrobenzene.
Methods for Determining Parent Compounds and Degradation Products
in Environmental Media. Methods for determining the parent compound,
nitrobenzene, in water, air, and waste samples with excellent
selectivity and sensitivity are well developed and constantly improving.
It is desirable to have the means to measure organic compounds such as
nitrobenzene in situ in water and other environmental media without the
need for sampling and extraction procedures to isolate the analyte prior
to analysis.
6.3.2 On-going Studies
Research is ongoing to develop a Master Analytical Scheme for
organic compounds, including nitrobenzene, in water (Michael et al.
1988). The overall goal is to detect and quantitatively measure organic
compounds at 0.1 /ig/L in drinking water, 1 Mg/L in surface waters, and
10 Mg/L in effluent waters. Analytes are to include numerous
nonvolatile compounds and some compounds that are only "semi-soluble" in
water, as well as volatile compounds (bp < 150°C). Improvements
continue to be made in chromatographic separation and detection,
including the areas of supercritical fluid extraction and supercritical
fluid chromatography (Smith 1988). An important aspect of supercritical
fluid chromatographic analysis of compounds such as nitrobenzene is
detection. Fourier transform Infrared flow cell detectors are promising
for this application (Wieboldt et al. 1988). Immunoassay methods of
analysis are promising for the determination of various organic
pollutants and toxicants, and nitrobenzene may be a candidate for
immunoassay techniques.
-------
70
6. ANALYTICAL METHODS
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 nitrobenzene and
other compounds. These methods use high resolution gas chromatography
and magnetic sector mass spectrometry.
-------
71
7. REGULATIONS AND ADVISORIES
Because of its potential to cause adverse health effects in exposed
people, a number of regulations and guidelines have been established for
nitrobenzene by various international, national and state agencies.
These values are summarized in Table 7-1.
-------
12
7. REGULATIONS AND ADVISORIES
Agency
TABLE 7-1. Regulations and Guidelines Ajppl liable to Hi t rob*»nsen«
Dcscript ion
Nat 1ona[
Vah
Refer
Regulations:
a. Air:
OS FLA
b. Water-.
EPA OWRS
PEL TWA
General permits under NPDES
General pretreatroent regulations for
existing and new sources of pollution
1 ppm
<5 mg/m3)
NA
OSHA 1989. (29
cm i9io.iooo)
Table Z-l-A
40 CFR 122,
Appendix D,
Table II
AO CFR 403
c. Nonspecific media:
EPA 0£RR Reportable quantity
Extremely hazardous substance
threshold planning quantity
EPA OSW
EPA OTS
Hazardous waste constituent
(Appendix VIII)
Land disposal restrict-ions
Groundwater monitoring list
(Appendix IX)
Preliminary assessment Information
rule
Health and safety data reporting
rule
Toxic chemical release reporting
1000 lb
10 . 000 lb
NA
NA
HA
NA
NA
NA
EPA 1985b, (40
CFR 302.4>
EPA 1987a, <40
CFR 155)
EPA 1980b, (40
CFR 261)
EPA 1988a, 1989
(40 CFR 26S)
EPA 1987b, (AO
CFR 264)
EPA 1982c, (40
CFR 712.30)
EPA 1988b, (40
CFR 716,120)
EPA 1988c, (40
CFR 372)
Guidelines:
a. Air:
ACGIH
NIOSH
TLV TWA
IDLH
1 ppm
200 ppm
ACGIH 1986
(5 mg/ro^)
NIOSH 1985
Water:
EPA OWRS
Other;
EPA
Ambient water quality criteria
Ingesting water and organisms
Oral RfD
Carcinogenic class ificat ion
19.8 mg/L
0. 0005
mg/kg/day
Group
EPA 1980b
IRIS 1989
CPA 1988c
-------
73
REGULATIONS AND ADVISORIES
TABLE 7-1 (Continued)
Agency
Description
Value
Refer
State
Reguiat ions:
a. A i r :
Connect icut
Massachusetts
Nevada
Hew York
North Carolina
North Dakota
South Carolina
Virginia
Acceptable ambient air concentration
100 pg/m3 (8 hr)
6.80 pg/m^ (24 hr)
0.1190 mgfm3 (8 hr)
16.70 (1 yr)
25.0 (24 hr)
0.05 mg/m3 (8 hr)
25.0 £ig/m3 (24 hr)
80.0 jjg/m3 (24 hr)
NATICH 1988
b. Water:
Kansas
Maine
Drinking water
5 /ig/L
1.4 pg/L
FSTRAC 1988
a Numerical values are provided in this column, when available. However, many regulations list
chemicals and/or involve requirements too complex for Inclusion here. In these cases, NA (Not
Applicable) is inserted in this column. The cited references provide details of the regulations,
k Group D: Not classifiable as to human carcinogenicity.
OSHA - Occupational Safety and Health Administration; PEL = Permissible Exposure Limits TWA » Time-
Weighted Averages £PA = Environmental Protection Agency; OWRS = Office of Water Regulations and
Standards? NPDES - National Pollutant Discharge Elimination System; NA « Not Applicable; OERR «
Office of Emergency and Remedial Response; OSW =» Office of Solid Wastes; OTS » Office of ToxLc
Substances; ACGIH = American Conference of Governmental Industrial Hyglenists; TLV = Threshold Limit
Value; NIOSH - National Institute for Occupational Safety and Health; IDLH » Immediately Dangerous
to Life or Health Level.
-------
75
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9. GLOSSARY
Acute Exposure - - Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Adsorption Coefficient (K,,,.) -- 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 time period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
group of studies which produces significant increases in incidence of
cancer (or tumors) between the exposed population and its appropriate
control.
Carcinogen -- A chemical capable of inducing cancer.
Ceiling value (CL) -- 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 Concentration^) (LClo) -- 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 DoseC^) (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(50) (LD50) -- The dose of a chemical which has been
calculated to cause death in 50% of a defined experimental animal
population.
Lethal Time(50) (LT50) -- A calculated period of time within which a
specific concentration of a chemical is expected to cause death in 50%
of a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
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9. GLOSSARY
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level (MRL) --An estimate 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 a chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at
which there are 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 (K^,) -- 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.
-- The upper-bound estimate of the low-dose slope of the dose-
response curve as determined by the multistage procedure. The q:* 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.
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9. GLOSSARY
Reportable Quantity (RQ) -- The quantity of a hazardous substance that
is considered reportable under CERCLA. Reportable quantities are: (1)
1 lb or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-hour period.
Reproductive Toxicity -- The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL) -- The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
Target Organ Toxicity -- This term covers a broad range of adverse
effects on target organs or physiological systems (e.g., renal,
cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.
Teratogen -- A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV) -- A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA) --An allowable exposure concentration
averaged over a normal 8-hour workday or 40-hour workweek.
Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a
route other than inhalation, which is expected to cause a specific toxic
effect in 50% of a defined experimental animal population.
Uncertainty Factor (UF) - - A factor used in operationally deriving the
RfD from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population, (2)
the uncertainty in extrapolating animal data to the case of humans, (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 nitrobenzene. The panel
consisted of the following members: Dr. Lloyd Hastings, Research
Associate Professor, Department of Environmental Health, University of
Cincinnati; Dr. Judith Marquis, Associate Professor, Department of
Pharmacology, Boston University School of Medicine; Dr. James Popp,
Head, Department of Environmental Pathology, Chemical Industry Institute
of Toxicology; Dr. Rajender Abraham, Private Consultant, Brookview, NY;
and Dr. Martin Alexander, Professor, Department of Agronomy, Cornell
University. These experts collectively have knowledge of nitrobenzene's
physical and chemical properties, toxicokinetics, key health end points,
mechanisms of action, human and animal exposure, and quantification of
risk to humans. All reviewers were selected in conformity with the
conditions for peer review specified in Section 104(i)(13) of the
Comprehensive Environmental Response, Compensation, and Liability Act,
as amended.
Scientists from ATSDR have reviewed the peer reviewers' comments
and determined which comments will be included in the profile. A
listing of the peer reviewers' comments not incorporated in the profile,
with a brief explanation of the rationale for their exclusion, exists as
part of the administrative record for this compound. A list of
databases reviewed and a list of unpublished documents cited are also
included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
of the content of this profile lies with the Agency for Toxic Substances
and Disease Registry.
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