TOXICOLOGICAL PROFILE FOR
 

NITROBENZENE
 

Agency for Toxic Substances and Disease Registry
 

U.S. Public Health Service
 

December 1990
 
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.
 










1
 

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.
 
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, it is
 

broken down to other chemicals within a few days after it is released.
 

Air and water in most areas contain no nitrobenzene or such low amounts
 

that they cannot be measured.
 

More information on the chemical and physical properties of
 

nitrobenzene can be found in Chapter 3. Its production, import, uses,
 

and disposal are presented in Chapter 4, and its occurrence and fate in
 

the environment are described in Chapter 5.
 

1.2 HOW 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 live near
 

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 manufacturing 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 skin.
 

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.
 
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.
 




8
 

1. PUBLIC HEALTH STATEMENT
 

More information on the health effects associated with exposure to
 

nitrobenzene is presented in Chapter 2.
 

1.6 	WHERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
 

EXPOSED TO NITROBENZENE?
 

Nitrobenzene reacts with red blood cells in the body to produce
 

methemoglobin. If you have recently been exposed to nitrobenzene, the
 

levels of methemoglobin in your blood will be elevated. This 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, the presence of its
 

breakdown products, p-nitrophenol and p-aminophenol, 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 	WHAT 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 Environmental 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 (OSHA) 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 40-hour workweek.
 
9
 

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.
 

11
 

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.
 
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-l and Figure 2-l 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
 

B6C3Fl 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", methemoglobinemia
 

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).
 




17
 

2. HEALTH EFFECTS
 

Increased levels of blood methemoglobin have been reported in rate
 

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 inhaltion 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 animals 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 hyperlasia, 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
 

Human 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 real lesions were observed in both rat
 

strains but not in mice (Hamm 1984).
 

Difference 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
 

Wwenberg 1988) and have been attributed to the production of high
 

Concentrations of the protein alpha-2μ-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.
 
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 B6C3Fl
 

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 hemosiderinladen 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 B6C3Fl 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 nitrobenzene.
 
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 F1
 

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 F1 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 B6C3Fl 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
 

condition, the blood releases less oxygen to the tissues and all general
 

body functions tend to be slowed 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 hours. Usually, the higher the dose, the
 

shorter the latency period.
 


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 of
 

nitrobenzene at 550 mg/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 after
 

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 after
 

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 ocated 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 in
 

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 Absorption
 

2.3.1.1 Inhalation Exposure
 

In humans, nitrobenzene was well absorbed through the lung in 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 by Albrecht and Neumann (1985). When Wistar rats were
 

administered 25 mg/kg radiolabeled nitrobenzene by gavage,
 

biotransformation was first seen in the intestine where nitrobenzene was
 

sequentially reduced to nitrosobenzene, phenylhydroxylamine and aniline.
 

These findings were also reported in Fischer-344 rats (Levin and Dent
 

1982a). The observation that germ-free rats do not develop
 

methemoglobinemia when administered nitrobenzene (Reddy et al. 1976) has
 

led to the speculation that a nitrobenzene metabolite such as aniline
 

may be involved in methemoglobinemia formation in this species. 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).
 

2.3.4 Excretion
 

2.3.4.1 Inhalation Exposure
 

Urinary excretion rates of p-nitrophenol were found in 7 volunteers
 

who had inhaled 6 ppm nitrobenzene for 6 hours (Salmowa et al. 1963).
 

The rate of urinary elimination varied considerably from individual to
 

individual, but showed a general dose dependence at 1 to 6 ppm
 

nitrobenzene. In general, excretion was most rapid during the first two
 

hours and then leveled off. In some cases, p-nitrophenol could be
 

detected for as long as 100 hours after exposure to 6 ppm for 6 hours.
 

In a 47-year-old woman who had been occupationally 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
 

is the urine. In most cases of human poisoning, the metabolites
 

excreted in the urine are p-aminophenol and p-nitrophenol (Myslak et al.
 

1971; 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 (Carter 1936; Leader 1932; Myslak
 

et al. 1971). There is no clear evidence that dermal exposure to
 

nitrobenzene results in methemoglobinemia in 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 hepatocytes 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.
 
 

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.
 

 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 BIOMAREERS 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
 
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 dea
 

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).
 
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 any 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).
 
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
 

are defined as substance-specific informational needs that, if met would
 

reduce or eliminate the uncertainties of human health assessment. In
 

the future, the identified data needs will be evaluated and prioritized,
 

and a substance-specific research agenda will be proposed.
 

2.8.1 Existing Information on Health Effects of 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
 

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 MEL 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 MELs 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 (CIIT) 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 CIIT 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.
 
39
 

2. HEALTH EFFECTS
 

There are no available carcinogenicity data in humans or animals
 

using any route of exposure. Data from the CIIT 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 CIIT 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 CIIT bioassay, however, may provide
 

some information on this end point.
 
40
 

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 CIIT 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.
 
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 CIIT 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.
 

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.
 



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 6 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).
 
48
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

4.4 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).
 
 

49
 

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-l.
 

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).
 

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 >lOO ppm in the organic and plastics
 
52
 

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 μg/L (Perry
 

et al. 1979). Reported nitrobenzene concentrations in raw and treated
 

industrial wastewaters from several industries range from 1.4 to
 

91,000 μg/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 the
 

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)], its
 

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 μg/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 μg/kg 

(CLPSD 1988). No further data on nitrobenzene levels released to soils 

were located. 
53
 

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, unionized
 

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 Hc = -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 (t 1/2 = > 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 (Ksed = 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)
 
54
 

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 Kow
 

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 -l. 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. A less satisfactory 3-day static
 

measurement gave a BCF of less than 10 for the golden ore (Freitag
 
55
 

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 (Physa 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 14C-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 NO2 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).
 

 

57
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Photolysis. Photochemical oxidation of nitrobenzene by hydrogen
 

peroxide yields p-, o-, and m-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)
 
 

58
 

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).
 
 

59
 

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 STORET 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.
 
 

60
 

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
 

(McFarlane 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. NIOSH (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/m3 (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.
 
 

61
 

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
 
 

62
 

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.
 
 

63
 

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 211°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
 

methemoglobin, 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-l.
 

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.
 

 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
 

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 μg/L in drinking water, 1 μg/L in surface waters, and 

10 μg/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-l.
 



 

 

75
 

8. REFERENCES


 Abrams EF, Derkics D, Fong CV, et al. 1975. Identification of organic


 compounds in effluents from industrial sources. Report to U.S.


 Environmental Protection Agency, Office of Toxic Substances, Washington,


 DC, by Versar, Inc., General Technologies Division, Springfield, VA.


 EPA-560/3-75-002.
 

* ACGIH. 1986. Documentation of the threshold limit values and


 biological exposure indices. 5th ed. American Conference of


 Governmental Industrial Hygienists. Cincinnati, OH.
 

* Albrecht W, Neumann H-G. 1985. Biomonitoring of aniline and


 nitrobenzene: Hemoglobin binding in rats and analysis of adducts. Arch


 Toxico157:1-5.


 Albright-Jones JA, Brieger H. 1947. Poisoning due to ingestion of wax


 Crayons: Report of a case. J Pediatr 30:422-427.
 

* Alexander M, Lustigman BK. 1966. Effects of chemical structure on


 microbial degradation of substituted benzenes. J Agric Food Chem


 14:411-413.


 AMA. 1973. AMA drug evaluations. 2nd ed. Acton, MA: Publishing


 Sciences Group, Inc., 266-267.
 

* Amoore JE, Hautala E. 1983. Odor as an aid to chemical safety: Odor


 thresholds compared with threshold limit values and volatilities for 214


 industrial chemicals in air and water dilution. J Appl Toxico1 3:272­

290.


 Anbar M, Neta P. 1967. A compilation of specific biomolecular rate


 constants for the reactions of hydrated electrons, hydrogen atoms and


 hydroxyl radicals with inorganic and organic compounds in aqueous


 solutions. Int J Appl Radiat Isot 18:493-523.
 

* Anderson D, Styles JA. 1978. The bacterial mutation test. Br J Cancer


 37:924-930.
 

* Anderson GE. 1983. Human exposure to atmospheric concentrations of


 selected chemicals. Vol. II. Research Triangle Park, NC: U. S.


 Environmental Protection Agency, Office of Air Quality Planning and


 Standards. NTIS No. PB83-265249.


 * = Cited in text.
 
 

76
 

8. REFERENCES
 

* Andersson K, Levin J-O, Lindahl R, et al. 1984. Influence of air
 

humidity on sampling efficiency of some solid adsorbents used for
 

sampling organics from work-room air. Chemosphere 13:437-444.
 

Arena JM, Drew RH. eds. 1986. Poisoning: Toxicology-symptomstreatments.
 

5th ed. Springfield, IL: Charles C. Thomas, Publisher,
 

252-256.
 

* Atkinson R, Tuazon EC, Wallington TJ, et al. 1987. Atmospheric
 

chemistry of aniline, N,N-dimethylaniline, pyridine, 1,3,5-triazine, and
 

nitrobenzene. Environ Sci Technol 21:64-72.
 

* Banerjee S, Yalkowsky SH, Valvani SC. 1980. Water solubility and
 

octanol/water partition coefficients of organics. Limitations on the
 

solubility-partition coefficient correlation. Environ Sci Technol
 

14:1227-1229.
 

Banning A, Harley JD, O'Gorman Hughes DW, et al. 1965. Prolonged
 

methaemoglobinaemia after eating a toy-shaped deodorant. Med J Aust
 

2:922-925.
 

* Barltrop JA, Bunce NJ. 1968. Organic photochemistry. Part VIII. The
 

photochemical reduction of nitro-compounds. J Chem Sot (Sec. C)
 

1968:1467-1474.
 

* Barnes D, Bellin J, DeRosa C, et al. 1987. Reference dose (RfD):
 

Description and use in health risk assessments. Vol. I, Appendix A:
 

Integrated risk information system supportive documentation.
 

Washington, DC: U.S. Environmental Protection Agency, Office of Health
 

and Environmental Assessment. EPA/600/8-86/032a.
 

* Barth EF, Bunch RL. 1979. Removability, biodegradation and
 

treatability of specific pollutants. Washington, DC: U.S.
 

Environmental Protection Agency. EPA-600/g-79-034. NTIS No. PB80-106­

438.
 

* Beard RR, Noe JT. 1981. Aromatic nitro and amino compounds. In:
 

Clayton GD, Clayton FE, eds. Patty's industrial hygiene and toxicology.
 

3rd ed. Vol. 2A: Toxicology. New York, NY: John Wiley and Sons,
 

2416-2417, 2430-2434, 2469, 2484-2489.
 

Beauchamp RO Jr, Irons RD, Rickert DE, et al. 1982. A critical review
 

of the literature on nitrobenzene toxicity. CRC Crit Rev Toxicol
 

Vol 11: 33-84.
 

Beutler E. 1966. Drug-induced hemolytic anemia. Pharmacol Rev
 

21:73-103.
 
 

77
 

8. REFERENCES


 Bhatia K. 1975. Hydroxyl radical induced oxidation of nitrobenzene. J


 Phys Chem 79:1032-1038.
 

*Bio/dynamics Inc. 1983. A range-finding study to evaluate the toxicity


 of nitrobenzene in the pregnant rabbit. Final Report. East Millstone,


 NJ: Bio/dynamics Inc. Project Report 83-2723.
 

*Bio/dynamics Inc. 1984. An inhalation teratology study in rabbits with


 nitrobenzene. Final Report. East Millstone, NJ: Bio/dynamics Inc.


 Project Report 83-2725.


 Birge WJ, Cassidy RA. 1983. Structure-activity relationships in


 aquatic toxicology. Fundam Appl Toxicol 3:359-368.


 Blaauboer BJ, Holsteijn CW. 1983. Formation and disposition of


 N-hydroxylated metabolites of aniline and nitrobenzene by isolated rat


 hepatocytes. Xenobiotica 13:295-302.


 Bodansky O. 1951. Methemoglobinemia and methemoglobin-producing


 compounds. Pharmacol Rev 3:144-196.


 Bodansky O, Gutmann H. 1947. Treatment of methemoglobinemia. J


 Pharmacol Exp Ther 90:46-56.


 Bond JA, Chism JP, Rickert DE, et al. 1981. Nitrobenzene-induced


 hepatic and testicular lesions in Fischer-344 rats following oral


 administration [Abstract]. Pharmacologist 23:213.


 Bozzelli JW, Kebbekus BB. 1979. Analysis of selected volatile organic


 substances in ambient air. Trenton, NJ: New Jersey Department of


 Environmental Protection, Program on Environmental Cancer and Toxic


 Substances. NJDEP-79/02. NTIS No. PB80-144694.
 

* Bozzelli JW, Kebbekus BB. 1982. A study of some aromatic and


 halocarbon vapors in the ambient atmosphere of New Jersey. J Environ


 Sci Health A17:693-711.
 

* Bozzelli JW, Kebbekus BB, Greenberg A. 1980. Analysis of selected


 toxic and carcinogenic substances in ambient air in New Jersey.


 Trenton, NJ: New Jersey Department of Environmental Protection, Office


 of Cancer and Toxic Substances Research.
 

* Branson DR. 1978. Predicting the fate of chemicals in the aquatic


 environment from laboratory data. In: Cairns J Jr, Dickson KL, Maki


 AW, eds. Estimating the hazard of chemical substances to aquatic life.


 Philadelphia, PA: American Society for Testing and Materials, 55-70.
 
 

78
 

8. REFERENCES


 Brieger H. 1949. Poisoning due to ingestion of wax crayons. Am J


 Public Health 39:1023-1024.
 

* Briggs GG. 1973. A simple relationship between soil adsorption of


 organic chemicals and their octanol/water partition coefficients.


 Proceedings of the British Insecticide Fungicide Conference 7:83-85.
 

* Briggs GG. 1981. Theoretical and experimental relationships between


 soil adsorption, octanol-water partition coefficient, water


 solubilities, bioconcentration factors and the parachor. J Agric Food


 Chem 29:1050-1059.


 Brodzinsky R, Singh HB. 1983. Volatile organic chemicals in the


 atmosphere: An assessment of available data. Research Triangle Park,


 NC: U.S. Environmental Protection Agency, Office of Research and


 Development. EPA-600/3-83-027(A).


 Bronaugh RL, Maibach HI. 1985. Percutaneous absorption of


 nitroaromatic compounds: In vivo and in vitro studies in the human and


 monkey. J Invest Dermatol 84:180-183.


 Bruusgaard A. 1963. Suicide attempts with benzene derivatives. Dan


 Med Bull 10:142-144.


 Buikema AL Jr, McGinnis MJ, Cairns J Jr. 1979. Phenolics in aquatic


 ecosystems: A selected review of recent literature. Marine Environ Res


 2:87-181.


 Burmistrov W. 1967. Fatal nitrobenzene poisoning. Kazan Med Zh 1:63.


 (Russian)
 

* Burns LH, Cline DM, Lassiter RR. 1981. Exposure analysis model system


 (EXAMS). (Draft). Athens, GA: U. S. Environmental Protection Agency,


 Athens Environmental Research Laboratory.


 Bus JS. 1983. Aniline and nitrobenzene: Erythrocyte and spleen


 toxicity. In: CIIT activities. Vol. 3, No. 12. Research Triangle


 Park, NC: Chemical Industry Institute of Toxicology, 1,6.


 Bushy Run Research Center 1984. Teratogenicity evaluation of inhaled


 nitrobenzene in the CD rat. Final Report. Submitted to Nitrobenzene


 Association. Project Report 47-522. Unpublished.


 Bushy Run Research Center 1985. Potential effects of nitrobenzene


 inhalation on reproduction and fertility in rats. Submitted to


 Nitrobenzene Association. Project Report 47-524. Unpublished.
 
 

79
 

8. REFERENCES
 

* Callahan MA, Slimak MW, Gabel NW, et al. 1979. Water-related


 environmental fate of 129 priority pollutants. Vol. II. Washington,


 DC: U.S. Environmental Protection Agency, Office of Water Planning and


 Standards. EPA-440/4-79-029b.
 

* Canton JH, Slooff W, Kool HJ, et al. 1985. Toxicity, biodegradability,


 and accumulation of a number of Cl/N-containing compounds for


 classification and establishing water quality criteria. Regul Toxico1


 Pharmacol 5:123-131.
 

* Carter FW. 1936. An unusual case of poisoning, with some notes on


 non-alkaloidal organic substances. Med J Aust (October 24):558-564.


 Chambers CW, Tabak HH, Kabler PW. 1963. Degradation of aromatic


 compounds by phenol-adapted bacteria. J Water Pollut Control Fed


 35:3517-1528.
 

* Charbonneau M, Swenberg JA. 1988. Studies on the biochemical mechanism

 of α-2μ-globulin nephropathy in rats. CIIT Activities 8:1-7. 

* Chemical Marketing Reporter. 1987. Chemical profiles: Nitrobenzene.


 (August 3):50.


 Childs B, Zinkham W, Browne EA, et al. 1957. A genetic study of a


 defect in glutathione metabolism of the erythrocyte. Med J Aust


 1:21-147
 

.


 Chism JP, Bond JA, Levin AA, et al. 1982. Species and strain


 differences in the susceptibility of rats and mice to the hepatic and


 testicular toxicity of orally administered nitrobenzene (NB)


 [Abstract]. In: Abstracts, the fifth CIIT conference on toxicology:


 Toxicity of nitroaromatic compounds. Raleigh, NC: Chemical Industry


 Institute of Toxicology, 12.


 Chism JP, Rickert DE, Hamm TE Jr, et al. 1984. The effect of diet on


 the excretion and toxicity of nitrobenzene [Abstract]. Fed Proc 43:360.
 

* Chiu CW, Lee LH, Wany CY, et al. 1978. Mutagenicity of some


 commercially available nitro compounds for Salmonella tvphimurium.
 Mutat Res 58:11-22.
 

* Chou WL, Speece RE, Siddiqi RH. 1978. Acclimation and degradation of


 petrochemical wastewater components by methane fermentation. Biotechnol


 Bioeng Symp 8:391-414.


 CIIT. 1984. Ninety day inhalation toxicity study of nitrobenzene in


 F-344 rats, CD rats, and B6C3Fl mice. Chemical Industry Institute of


 Toxicology, Research Triangle Park, NC.
 
 

80
 

8. REFERENCES


 Clansky KB, ed. 1986. Chemical guide to the OSHA hazard communication


 standard. Burlingame, CA: Roytech Publications, Inc., 63, 653-655,


 657.


 Clark EB. 1947. Poisoning due to ingestion of wax crayons. JAMA


 135:917-918.


 CLC. 1988. Coordinated List of Chemicals. U.S. Environmental


 Protection Agency, Office of Research and Development, Washington, DC.
 

* CLPSD. 1988. Contract Laboratory Program (CLP) Statistical Database.


 Viar and Company, Management Services Division, Alexandria, VA.


 December 1988.


 Cohen GM, ed. 1986. Target organ toxicity. Vol. I. Boca Raton, FL:


 CRC Press, Inc., 12, 15, 72, 86, 125.
 

* Cole RH, Frederick RE, Healy RP, et al. 1984. Preliminary findings of


 the Priority Pollutant Program of the Nationwide Urban Runoff Program.


 J Water Pollut Control Fed 56:898-908.
 

* Collins JV, Mayo DR, Riordan BJ. 1982. Economic impact analysis of


 proposed test rule for nitrobenzene. Washington, DC:


 U.S. Environmental Protection Agency, Office of Pesticides and Toxic


 Substances.


 Connell DW, Hawker DW. 1988. Use of polynomial expressions to describe


 the bioconcentration of hydrophobic chemicals by fish. Ecotoxicol


 Environ Saf 16:242-257.


 Costlow RD, Hirskorn JM, Stiratelli RG, et al. 1983. The effects on
 

rat pups when nitrofen (4-(2,4-dichlorophenoxy)nitrobenzene) was
 

applied dermally to the dam during organogenesis. Toxicology 28:37-50.


 Crabtree HC. 1983. Relative risk assessment; an aid to planning. Ann


 Occup Hyg 27:213-219.
 

* Cupitt LT. 1980. Fate of toxic and hazardous materials in the air


 environment. Washington, DC: U.S. Environmental Protection Agency.


 EPA-600/3-80-084. NTIS No. PB80-221948.
 

* Dana MT, Lee RN, Hales JM. 1984. Hazardous air pollutants: Wet


 removal rates and mechanisms. Research Triangle Park, NC: U.S.


 Environmental Protection Agency. EPA 600/3-84-113.
 

* Dangwal SK, Jethani BM. 1980. A simple method of determination of


 nitrobenzene and nitrochlorobenzene in air and urine. Am Ind Hyg Assoc


 J 41:847-850.
 
 

81
 

8. REFERENCES
 

* Davis EM, Murray HE, Liehr JG, et al. 1981. Basic microbial
 

degradation rates and chemical byproducts of selected organic
 

compounds. Water Res 15:1125-1127.
 

* Davis EM, Turley JE, Casserly DM, et al. 1983. Partitioning of


 selected organic pollutants in aquatic ecosystems. Biodeterioration


 5:176-184.


 Debethizy JD, Goldstein RS. 1985. The influence of fermentable dietary


 fiber on the disposition and toxicity of xenobiotics. In: Finley JW,


 Schwass DE, eds. American Chemical Society Symposium Series 277.


 Xenobiotic metabolism: Nutritional effects. Washington, DC: American


 Chemical Society, 37-50.


 Deneer JW, Sinnige TL, Seinen W, et al. 1987. Quantitative structure-


activity relationships for the toxicity and bioconcentration factor of


 nitrobenzene derivatives towards the guppy (Poecilia reticulata). Aqua


 Toxico110:115-129.
 

* Dodd DE, Fowler EH, Snellings WM, et al. 1987. Reproduction and


 fertility evaluations in CD rats following nitrobenzene inhalation.


 Fundam Appl Toxicol 8:493-505.


 Doelle HW. 1969. Bacterial metabolism. New York, NY: Academic Press,


 157.


 Donovan WM. 1920. The toxicity of nitrobenzene with report of a fatal


 case. JAMA 74:1647.
 

* Dorfman IM, Adams GE. 1973. Reactivity of the hydroxyl radical in


 aqueous solutions. Washington, DC: Department of Commerce, National


 Bureau of Standards. COM-73-50623.
 

* Dorigan J, Hushon J. 1976. Air pollution assessment of nitrobenzene.


 Report to U.S. Environmental Protection Agency, Office of Air Quality


 and Planning Standards, Washington, DC, by Mitre Corporation, McLean,


 VA. NTIS No. PB-257776.
 

* Draper WM, Crosby DG. 1984. Solar photooxidation of pesticides in


 dilute hydrogen peroxide. J Agric Food Chem 32:231-237.
 

* Dreisbach RH, Robertson WO. 1987. Nitrogen compounds. In: Handbook


 of poisoning: Prevention, diagnosis and treatment. 12th ed. Norwalk,


 CT: Appleton and Lange, 141-147.
 

* Dunlap KL. 1981. Nitrobenzene and nitrotoluenes. In: Grayson M,


 Eckroth D, eds. Kirk Othmer encyclopedia of chemical technology. 3rd


 ed. Vol. 15. New York, NY: John Wiley and Sons, Inc., 916-932.
 
82
 

8. REFERENCES


 Dura G, Krasovski GN, Zholdakova ZI, et al. 1985. Prediction of


 toxicity using quantitative structure-activity relationships. Arch


 Toxico1 Supp 8:481-487.
 

* Eckert JW. 1962. Fungistatic and phytotoxic properties of some


 derivatives of nitrobenzene. Phytopathol 52:642-649.
 

* Ellis DD, Jones CM, Larson RA, et al. 1982. Organic constituents of


 mutagenic secondary effluents from wastewater treatment plants. Arch


 Environ Contam Toxicol 11:373-382.
 

* Enfield CG, Walters DM, Wilson JT, et al. 1986. Behavior of organic


 pollutants during rapid-infiltration of wastewater into soil: III.


 Mathematical description of transport and transformation. Hazardous


 Waste and Hazardous Materials 3:57-76.
 

* EPA. 1980a. Ambient water quality criteria for nitrobenzene.


 Washington, DC: U.S. Environmental Protection Agency, Office of Water


 Regulations and Standards, Environmental Criteria and Assessment


 Office. EPA 440/5-80-061. NTIS PB81-117723.
 

* EPA. 1980b. U.S. Environmental Protection Agency. Federal Register.


 45:33084-33133.
 

* EPA 1982a. Test method: Nitroaromatics and isophorone - method 609.


 In: Longbottom JE, Lichtenberg 53, eds. Test methods: Methods for


 organic chemical analysis of municipal and industrial wastewater.


 Cincinnati, OH: U.S. Environmental Protection Agency, Environmental


 Monitoring and Support Laboratory. EPA-600/4-82-057.
 

* EPA. 1982b. Test method: Base/neutrals and acids - method 625. In:


 Longbottom JE, Lichtenberg JJ, eds. Test methods: Methods for organic


 chemical analysis of municipal and industrial wastewater. Cincinnati,


 OH: U.S. Environmental Protection Agency, Environmental Monitoring and


 Support Laboratory. EPA-600/4-82-057.
 

* EPA. 1982c. U.S. Environmental Protection Agency. Federal Register.


 47:26992-27008.
 

* EPA. 1983a. Nitrobenzene. In: Treatability manual: Volume I.


 Treatability data. Washington, DC: U.S. Environmental Protection


 Agency, Office of Research and Development. EPA-600/2-82-OO1a.


 EPA 1983b. Reportable quantity document for benzene, nitro-.


 Cincinnati, OH: U.S. Environmental Protection Agency, Office of Solid


 Waste and Emergency Response. External Review Draft ECAO-CIN-R036.
 
83
 

8. REFERENCES
 

* EPA. 1984. U.S. Environmental Protection Agency. Federal Register.


 49:25013-25017.
 

* EPA. 1985a. Health and environmental effects profile for nitrobenzene.


 Cincinnati, OH: U.S. Environmental Protection Agency, Office of


 Research and Development. EPA/600/X-85/365 NTIS No. PB88-180500.
 

* EPA. 198513. U.S. Environmental Protection Agency. Part II. Federal


 Register. 50:13456-13522.
 

* EPA. 1986a. Reference values for risk assessment. Final draft.


 Cincinnati, OH: U.S. Environmental Protection Agency, Office of Solid


 Waste. ECAO-CIN-477.
 

* EPA. 1986b. Method 8090: Nitroaromatics and cyclic ketones. In:


 Test methods for evaluating solid waste. SW-846. 3rd ed. Washington,


 DC: U.S. Environmental Protection Agency, Office of Solid Waste and


 Emergency Response.
 

* EPA. 1986c. Method 8250: Gas chromatography/mass spectrometry for


 semivolatile organics: Packed column technique. In: Test methods for


 evaluating solid waste. SW-846. 3rd ed. Washington, DC: U.S.


 Environmental Protection Agency, Office of Solid Waste and Emergency


 Response.
 

* EPA. 1986d. Method 8270: Gas chromatography/mass spectrometry for


 semivolatile organics: Capillary column technique. In: Test methods


 for evaluating solid waste. SW-846. 3rd ed. Washington, DC: U.S.


 Environmental Protection Agency, Office of Solid Waste and Emergency


 Response.
 

* EPA. 1986e. Method 8410: Capillary column analysis of semi-volatile


 organic compounds by gas chromatography/Fourier transform infrared


 (GC/FT-IR) spectrometry. In: Test methods for evaluating solid waste.


 SW-846. 3rd ed. Washington, DC: U.S. Environmental Protection Agency,


 Office of Solid Waste and Emergency Response.
 

* EPA. 1987a. U.S. Environmental Protection Agency: Part II. Federal


 Register. 52:13378-13410.
 

* EPA. 198713. U.S. Environmental Protection Agency: Part II. Federal


 Register. 52:25942-25953.


 EPA. 1987c. Health effects assessment for nitrobenzene. Cincinnati,


 OH: U.S. Environmental Protection Agency, Office of Research and


 Development. EPA/600/8-88/049. NTIS No. PB88-178975.
 
 

84
 

8. REFERENCES


 EPA. 1987d. Toxic air pollutant/source crosswalk: A screening tool


 for locating possible sources emitting toxic air pollutants. Research


 Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air


 Quality Planning and Standards. EPA-450/4-87-023a.
 

* EPA. 1988a. U.S. Environmental Protection Agency: Part II. Federal


 Register. 53:31138-31222.
 

* EPA. 1988b. U.S. Environmental Protection Agency: Part II. Federal


 Register. 53:38642-38654.


 EPA. 1988c. U.S. Environmental Protection Agency: Part II. Federal


 Register. 53:4500-4539.
 

* EPA. 1989. U.S. Environmental Protection Agency: Part II. Federal


 Register. 54:1056-1119.


 Etteldorf JN. 1951. Methylene blue in the treatment of


 methemoglobinemia in premature infants caused by marking ink. J Pediatr


 38:24-27.


 Everitt JI, Popp JA, Mangum JB, et al. 1986. Pulmonary lesions in mice


 associated with chronic inhalation exposure to nitrobenzene [Abstract].


 Proceedings of the Annual Meeting of the American College of Veterinary


 Pathologists and American Society for Veterinary Clinical Pathology


 (December l-5):39.


 Eyer P, Kampffmeyer H, Maister H, et al. 1980. Biotransformation of


 nitrosobenzene, phenylhydroxylamine, and aniline in the isolated


 perfused rat liver. Xenobiotica 10:499-516.


 Feldstein M. 1968. Syllabus of analytical toxicology for laboratory


 technologiest. Clin Toxico1 1:341-378.


 Fouts JR, Brodie BB. 1957. The enzymatic reduction of chloramphenicol,


 p-nitrobenzoic acid and other aromatic nitro compounds in mammals. J


 Pharmacol Exp Ther 119:197-207.


 Franke JF, Hermann ER. 1980. Toxicity of substances in combination


 [Abstract]. Toxico1 Lett (Spec Iss 1):112.
 

* Freitag D, Geyer H, Kraus A, et al. 1982. Ecotoxicological profile


 analysis. VII. Screening chemicals for their environmental behavior by


 comparative evaluation. Ecotoxicol Environ Safety 6:60-81.


 Freitag D, Ballhorn L, Geyer H, et al. 1985. Environmental hazard


 profile of organic chemicals. Chemosphere 14:1589-1616.
 
85
 

8. REFERENCES
 

* FSTRAC. 1988. Summary of state and federal drinking water standards


 and guidelines. Washington, DC: Federal-State Toxicology and


 Regulatory Alliance Committee, Chemical Communication Subcommittee.


 Furihata C, Matsushima T. 1987. Use of in vivo/in vitro unscheduled


 DNA synthesis for identification of organ-specific carcinogens. CRC


 Crit Rev Toxico117:245-277.


 Garg SK. 1975. Antifertility effects of substituted nitrobenzene


 derivatives in female albino rats. Bulletin Postgraduate Institute


 9:66-67.
 

* Garner RC, Nutman CA. 1977. Testing of some azodyes and their


 reduction products for mutagenicity using Salmonella typhimurium TA


 1538. Mutat Res 44:9-19.


 Garrett RH, Nason A. 1969. Further purification and properties of


 Neurospora nitrate reductase. J Biol Chem 244:2870-2882.
 

* Geyer H, Politzki G, Freitag, D. 1984. Prediction of ecotoxicologic


 behavior of chemicals: Relationship between n-octanol/water partition


 coefficient and bioaccumulation of organic chemicals by alga Chlorella.


 Chemosphere 13:269-284.


 Ghess MJ, Wilbourn J, Tossavainen A, et al. 1986. Information bulletin


 on the survey of chemicals being tested for carcinogencity. No. 12.


 Lyon, France: International Agency for Research on Cancer, 202-203.
 

* Gillett JW. 1983. The pre-biologic screen for ecotoxicologic effects.


 Environ Toxicol Chem 2:463-476.
 

* Gitchell A, Simonaitis R, Heicklen J. 1974. The inhibition of


 photochemical smog: II. Inhibition by hexafluorobenzene, nitrobenzene,


 naphthalene, and 2,6-di-tert-butyl-4-methylphenol. J Air Pollut Control


 Assoc 24:772-775.
 

* Goldstein A, Aronow L, Kalman SM. 1969. Principles of drug action:


 The basis of pharmacology. New York, NY: Harper and Row, Publishers,


 274-452.


 Goldstein I. 1975. Quantitative evaluation of the effect of aromatic


 nitro and amino compounds on the respiration of cerebral tissue. In:


 Horvath M, ed. Adverse effects of environmental chemicals and


 psychotropic drugs: Neurophysiological and behavioral tests. Vol 2:


 New York, NY: Elsevier Scientific Publishing Company, 229-233.
 
86
 

8. REFERENCES
 

* Goldstein RS, Rickert DE. 1984. Macromolecular covalent binding of


 [14C]nitrobenzene in the erythrocyte and spleen of rats and mice. Chem


 Biol Interact 50:27-37.


 Goldstein RS, Rickert DE. 1985. Relationship between red blood cell


 uptake and methemoglobin production by nitrobenzene and dinitrobenzene


 in vitro. Life Sci 36:121-125.


 Goldstein RS, Dyroff MC, Rickert DE, et al. 1983a. Characterization of


 covalent binding of orally administered nitrobenzene to erythrocytic


 macromolecules [Abstract]. Pharmacologist 25:116.


 Goldstein RS, Irons RD, Rickert DE, et al. 1983b. Pathophysiology of


 splenic toxicity in mice and rats following oral nitrobenzene (NB)


 administration [Abstract]. Toxicologist 3:125.
 

* Goldstein RS, Chism JP, Sherrill JM, et al. 1984a. Influence of


 dietary pectin on intestinal microfloral metabolism and toxicity of


 nitrobenzene. Toxicol Appl Pharmacal 75:547-553.


 Goldstein RS, Chism JP, Hamm T Jr. 1984b. Influence of diet on


 intestinal microfloral metabolism and toxicity of nitrobenzene


 [Abstract]. Toxicologist 4:143.
 

* Gosselin RE, Smith RP, Hodge HC, et al. 1984. Clinical toxicology of


 commercial products. 5th ed. Baltimore, MD: Williams and Wilkins,


 11-214.


 Graubarth J, Bloom CJ, Coleman FC, et al. 1945. Dye poisoning in the


 nursery: A review of seventeen cases. JAMA 128:1155-1157.


 Graves GW. 1928. Shoe-dye poisoning. Med Clin North Am 12~673-677.


 Green DR, Le Pape D. 1987. Stability of hydrocarbon samples on


 solid-phase extraction columns. Anal Chem 59:699-703


 Greenberg HB. 1964. Syncope and shock due to methemoglobinemia. Arch


 Environ Health 9:762-764.


 Gregory CH. 1906. Notes on another case of poisoning by nitrobenzol.


 Lancet 1:1242.


 Gross EA, Bond JA, Lyght O, et al. 1982. Characterization of


 nitrobenzene-induced cerebellar malacia in F-344 rats [Abstract]. In:


 Abstracts, the Fifth CIIT conference on toxicology: Toxicity of


 nitroaromatic compounds. Raleigh, NC: Chemical Industry Institute of


 Toxicology.
 
87
 

8. REFERENCES


 Guy RH, Hadgraft J, Maibach HI. 1985. Percutaneous absorption in man:


 A kinetic approach. Toxico1 Appl Pharmacol 78:123-129.
 

* Hallas LE, Alexander M. 1983. Microbial transformation of


 nitroaromatic compounds in sewage effluent. Appl Environ Microbial


 4:1234-1241.


 Hallowell M. 1959. Acute haemolytic anaemia following the ingestion of


 paradichlorobenzene. Arch Dis Child 34:74-75.
 

* Hamm TE. 1984. Ninety day inhalation toxicity study of nitrobenzene in


 F-344 rats, and CD rats and B6C3Fl mice. Chemical Industry Institute of


 Technology, Research Triangle Park, NC.


 Harada N, Omura T. 1980. Participation of cytochrome P-450 in the


 reduction of nitro compounds by rat liver microsomes. J Biochem


 87:1539-1554.
 

* Harkov R, Kebbekus B, Bozzelli JW, et al. 1983. Measurement of


 selected volatile organic compounds at three locations in New Jersey


 during the summer season. J Air Pollut Control Assoc 33:1177-1183.
 

* Harkov R, Kebbekus B, Bozzelli JW, et al. 1984. Comparison of selected


 volatile organic compounds during the summer and winter at urban sites


 in New Jersey. Sci Total Environ 38:259-274.
 

* Harkov R, Gianti SJ Jr, Bozzelli JW, et al. 1985. Monitoring volatile


 organic compounds at hazardous and sanitary landfills in New Jersey. J


 Environ Sci Health A20:491-501.


 Harley JD, Celermajer JM. 1970. Neonatal methaemoglobinaemia and the


 "red-brown" screening-test. Lancet 2:1223-1225.


 Harrington JM, Waldron HA. 1981. The effects of work exposures on


 organ systems I - liver, kidney and bladder, and skin. In: Schilling


 RS, ed. Occupational Health Practice. 2nd edition. Woburn, MA:


 Butterworths, 89-114.


 Harrison MR. 1977. Toxic methaemoglobinaemia: A case of acute


 nitrobenzene and aniline poisoning treated by exchange transfusion.


 Anaesthesia 32:270-272.
 

* Hashimoto S, Kano K. 1970. Photochemical reduction of u-substituted


 nitrobenzenes in isopropanol. Tetrahedron Lett 40:3509-3512.
 

* Hastings SH, Matsen FA. 1948. The photodecomposition of nitrobenzene.


 J Am Chem Sot 70:3514-3515.
 
 

88
 

8. REFERENCES
 

* Haworth S, Lawlor T, Mortelmans K, et al. 1983. Salmonella


 mutagenicity test results for 250 chemicals. Environ Mutagen Suppl


 1:3-38, 46, 114.
 

* Hawthorne SB. 1988. 1988 Workshop on supercritical fluid


 chromatography. American Laboratory (August):6-8.
 

* Helling CS, Turner BC. 1968. Pesticide mobility: Determination by


 soil thin-layer chromatography. Science 162:562-563.


 Henderson Y, Haggard HW. 1943. Noxious gases and the principles of


 respiration influencing their action. 2nd ed. New York, NY: Reinhold


 Corporation, 227-228.


 Heukelekian H, Rand MC. 1955. Biochemical oxygen demand of pure


 organic compounds. J Water Pollut Control Assoc 27:1040-1053.
 

* Hine J, Mookerjee PK. 1975. The intrinsic hydrophilic character of


 organic compounds. Correlation in terms of structural contributions.


 J Org Chem 40:292-298.
 

* Ho C-H, Clark BR, Guerin MR, et al. 1981. Analytical and biological


 analyses of test materials from the synthetic fuel technologies: IV.


 Studies of chemical structure-mutagenic activity relationships of


 aromatic nitrogen compounds relevant to synfuels. Mutat Res 85:335-345.


 Hollingsworth RL, Rowe VK, Oyen F, et al. 1956. Toxicity of


 paradichlorobenzene: Determinations on experimental animals and human


 subjects. AMA Arch Ind Health 14:138-147.


 Houk VS, DeMarini DM. 1988. Use of the microscreen phage-induction


 assay to assess the genotoxicity of 14 hazardous industrial wastes.


 Environ Mole Mutagen 11:13-29.
 

* HSDB. 1988. Hazardous Substances Data Bank. National Library of


 Medicine, National Toxicology Information Program, Bethesda, MD.


 December 1988.


 Hughes JP, Proctor NH, Adams RM. 1978. The treatment of occupational


 diseases. In: Proctor NH, Hughes JP, eds. Chemical hazards of the


 workplace. Philadelphia, PA: J.B. Lippincott Co., 55-65.
 

* Hughes TJ, Sparcino C, Frazier S. 1984. Validation of chemical and


 biological techniques for evaluation of vapors in ambient


 air/mutagenicity testing of twelve (12) vapor-phase compounds. U.S.


 Environmental Protection Agency, Research Triangle Park, NC. EPA


 600/l-84-005. NTIS PB84-164219.
 
 

89
 

8. REFERENCES
 

* Hurley R, Testa AC. 1966. Photochemical n->pi* excitation of
 

nitrobenzene. J Am Chem Sot 88:4330-4332.
 

* Hurley R, Testa AC. 1967. Nitrobenzene photochemistry. II.
 

Protonation in the excited state. J Am Chem Sot 89:6917-6919.
 

* Ikeda M, Kita A. 1964. Excretion of p-nitrophenol and p-aminophenol in
 

the urine of a patient exposed to nitrobenzene. Br J Ind Med
 

21:210-213.
 

IRIS. 1988. Integrated Risk Information System. U.S. Environmental
 

Protection Agency, Washington, DC. December 1988.
 

Irons RD, Hamm TE Jr, Rickert DE. 1985. Effect of dietary pectin on
 

the target organ toxicity of nitrobenzene (NB) [Abstract]. Toxicologist
 

5:91.
 

IRPTC. 1989. IRPTC data profile on: Nitrobenzene. International
 

Register of Potentially Toxic Chemicals, United Nations Environment
 

Programme, Geneva, Switzerland. January 1989.
 

Jenner P, Testa B, eds. 1981. Concepts in drug metabolism. Part B.
 

New York, NY: Marcel Dekker, Inc., 267, 298, 303-304, 317, 363.
 

* Johnson LD, Young JC. 1983. Inhibition of anaerobic digestion by
 

organic priority pollutants. J Water Pollut Control Fed 55:1441-1449.
 

Josephson J. 1980. The workplace: Reproductive hazards. Environ Sci
 

Tech 14:1418. 1427-1429.
 

* Jury WA, Spencer WF, Farmer WJ. 1984. Behavior assessment model for
 

trace organics in soil. III. Application of screening model. Journal
 

of Environmental Quality 13:573-579.
 

Kaplan AM, Khanna KL. 1975. The role of microsomal metabolism of
 

nitrobenzene in methemoglobin formation [Abstract]. Toxicol Appl
 

Pharmacol 33:131.
 

Katsumura Y, Tanaka J, Ichikawa H, et al. 1986. Persistent light
 

reaction: Induction in the guinea pig. J Invest Dermatol 87:330-333.
 

Kawai A, Goto S, Matsumoto Y, et al. 1987. Mutagenicity of aliphatic
 

and aromatic nitro compounds: Industrial materials and related
 

compounds. Jpn J Ind Health 29:34-54.
 

Khoury MJ, Stewart W, Beaty TH. 1987. The effect of genetic
 

susceptibility on casual inference in epidemiologic studies. Am J
 

Epidemiol 126:561-567.
 
 

90
 

8. REFERENCES


 Kiese M, Lorcher W, Weger N, et al. 1972. Comparative studies on the


 effects of toluidine blue and methylene blue on the reduction of


 ferrihaemoglobin in man and dog. Europ J Clin Pharmacol 4:115-118.
 

* Kincannon DF, Stover EL, Nichols V, et al. 1983. Removal mechanisms of


 toxic priority pollutants. J Water Pollut Control Fed 55:157-163.


 Kirkman HN. 1968. Glucose-6-phosphate dehydrogenase variants and


 druginduced hemolysis. Ann NY Acad Sci 151:753-764.


 Kirkman HN, Doxiadis SA, Valaes T, et al. 1965. Diverse


 characteristics of glucose-6-phosphate dehydrogenase from Greek


 children. J Lab Clin Med 65:212-221.
 

* Kligerman AD, Erexson GL, Wilmer JL, et al. 1983. Analysis of


 cytogenetic damage in rat lymphocytes following in vivo exposure to


 nitrobenzene. Toxico1 Lett 18:219-226.


 Kligerman AD, Erexson GL, Wilmer JL. 1984. Development of rodent


 peripheral blood lymphocyte culture systems to detect cytogenetic


 damage in vivo [Abstract]. Proceedings of the International Symposium on


 Sister Chromatid Exchange, Brookhaven National Laboratory, Upton, NY,


 Session X.


 Klopman G, Raychaudhury C. 1988. A novel approach to the use of graph


 theory in structure-activity relationship studies. Application to the


 qualitative evaluation of mutagenicity in a series of nonfused ring


 aromatic compounds. Journal of Computational Chemistry 9:232-243.


 Koegel W, Iatropoulos MJ, Mueller WF, et al. 1978. Metabolism, body


 distribution, and histopathology of pentachloronitrobenzene in rhesus


 monkeys [Abstract]. Toxico1 Appl Pharmacol 45:283.
 

* Kopfler FC, Melton RG, Mullaney JL, et al. 1977. Human exposure to


 water pollutants. Adv Environ Sci Technol 8:419-433.
 

* Korte F, Klein W. 1982. Degradation of benzene in the environment.


 Ecotoxicol Environ Saf 6:311-327.
 

* LaRegina J, Bozzelli JW, Harkov R, et al. 1986. Volatility of organic


 compounds at hazardous waste sites and a sanitary landfill in New


 Jersey. An up-to-date review of the present situation. Environ Prog


 5:18-27.
 

* Lauwerys RR. 1983. Industrial chemical exposure: Guidelines for


 biological monitoring. Davis, CA: Biomedical Publications, 97-100.
 
 

91
 

8. REFERENCES


 Lauwerys RR. 1986. Occupational toxicology. In: Klaasen CD, Amdur


 MD, Doull J, eds. Casarett and Doull's toxicology: The basic science


 of poisons. 3rd ed. New York, NY: Macmillan Publishing Company,


 902-916.


 Layne WR, Smith RP. 1969. Methylene blue uptake and the reversal of


 chemically induced methemoglobinemias in human erythrocytes. J


 Pharmacol Exp Ther 165:36-44.
 

* Leader SD. 1932. Nitrobenzene poisoning: Report of an unusual case in


 a child. Arch Pediatr 49:245-250.


 Leinoff HD. 1936. Methylene blue therapy in nitrobenzene poisoning. N


 Engl J Med 215:191-193.


 Lentner C, ed. 1984. Geigy scientific tables. 8th ed. Vol 3:


 Physical chemistry, composition of blood, hematology, somatometric


 data.


 West Caldwell, NJ: Ciba-Geigy Corporation, Medical Education Division,


 76-77, 200-201, 264, 285, 287.


 Levin AA, Dent JG. 1981. Metabolism of 14C-nitrobenzene by liver


 microsomes and cecal microflora from Fischer-344 rats [Abstract].


 Pharmacologist 23:171.
 

* Levin AA, Dent JG. 1982a. Comparison of the metabolism of nitrobenzene


 by hepatic microsomes and cecal microflora from Fischer-344 rats in


 vitro and the relative importance of each in vivo. Drug Metab Dispos


 10:450-454.


 Levin AA, Dent JG. 1982b. Nitrobenzene metabolism in vitro:


 Comparison of cecal microflora and hepatic microsomes from Fischer-344


 rats [Abstract]. Proceedings of the 5th CIIT Conference of Toxicology:


 Toxicity of Nitroaromatic Compounds, January 28-29, Raleigh, NC.


 Levin AA, Dent JG. 1982c. Nitrobenzene metabolism in vivo: The role


 of gut flora [Abstract]. Toxicologist 2:A22.


 Levin AA, Dent JG. 1982d. Nitrobenzene metabolism in vivo: The role


 of gut flora [Abstract]. Proceedings of the 5th CIIT Conference on


 Toxicology: Toxicity of Nitroaromatic Compounds, January 28-29,


 Raleigh, NC.


 Levin AA, Bus JS, Dent JG. 1982a. Interactions of nitrobenzene with


 hepatic microsomes: Evidence for cytochrome P450 uncoupling [Abstract].


 Toxicologist 2:17.


 Levin AA, Popp JA, Dent JG. 1982b. The role of gut microflora in


 nitrobenzene-induced testicular necrosis [Abstract]. Toxicologist 2:77.
 
 

92
 

8. REFERENCES


 Levin AA, Earle LL, Butterworth BE. 1983. Reversibility of


 nitrobenzene-induced testicular degeneration: Application of a novel


 technique [Abstract]. Toxicologist 3:20.
 

* Levin AA, Bosakowski T, Earle LL, et al. 1988. The reversibility of


 nitrobenzene-induced testicular toxicity: Continuous monitoring of


 sperm output from vasocystotomized rats. Toxicology 53:219-230.


 Levin SJ. 1927. Shoe-dye poisoning-relation to methemoglobin


 formation: Report of a case in a two-year-old child. JAMA


 89:2178-2180.


 Levin SJ. 1931. Shoe-dye poisoning: Report of a case in an


 eight-month-old infant. JAMA 96:681.
 

* Levins P, Adams J, Brenner P, et al. 1979. Sources of toxic pollutants


 found in influents to sewage treatment plants. AD Little, Inc.,


 Boston, MA. ADL 81099-63.
 

* Linch AL. 1974. Biological monitoring for industrial exposure to


 cyanogenic aromatic nitro and amino compounds. Am Ind Hyg Assoc J


 35:426-432.
 

* Lioy PJ, Daisey JM, Atherholt T, et al. 1983. The New Jersey Project


 on airborne toxic elements and organic substances (ATEOS): A summary of


 the 1981 summer and 1982 winter studies. J Air Pollut Control Fed


 33:649-657.


 Longo LD. 1980. Environmental pollution and pregnancy: Risks and


 uncertainties for the fetus and infant. Am J Obstet Gynecol


 137:162-173.
 

* Lu PY, Metcalf RL. 1975. Environmental fate and biodegradability of


 benzene derivatives as studied in a model aquatic ecosystem. Environ


 Health Perspect 10:269-284.
 

* Lutin PA, Cibulka JJ, Malaney GW. 1965. Oxidation of selected


 carcinogenic compounds by activated sludge. Purdue University


 Engineering Extension Series 118:131-145.
 

* Lyman WJ, Reehe WF, Rosenblatt DH. 1982. Handbook of chemical property


 estimation methods. In: Environmental behavior of organic compounds.


 New York, NY: McGraw-Hill Book Co. p. 960.
 

* Mabey WR, Smith JH, Pod011 RT, et al. 1982. Aquatic fate process data


 for organic priority pollutants. Washington, DC: U.S. Environmental


 Protection Agency, Office of Water Regulations and Standards. EPA


 440/4-81-014.
 
 

93
 

8. REFERENCES


 MacDonald WB. 1951. Methaemoglobinaemia resulting from poisoning in


 children. Med J Aust 1:145-147.


 MacMath IF, Apley J. 1954. Cyanosis from absorption of marking-ink in


 newborn babies. Lancet 2:895-896.


 Malaney GW, McKinney RE. 1966. Oxidative abilities of benzeneacclimated


 activated sludge. Water and Sewage Works 113:302-309.


 Mangelsdorff AF. 1956. Treatment of methemoglobinemia. AMA Arch Ind


 Health 14:148-153.


 Maples KR, Eyer P, Mason RP. 1990. Aniline-, phenylhydroxylamine-,


 nitrosobenzene-, and nitrobenzene-inuced hemoglobin thiyl free radical


 formation in vivo and in vitro. Mol Pharmcol 37:311-318.
 

* Marion CV, Malaney GW. 1963. Ability of activated sludge


 microorganisms to oxidize aromatic organic compounds. Purdue University


 Engineering Extension Series 115:297-308.


 Matheson D. 1972. Nitrobenzene. In: Encyclopaedia of occupational


 health and safety. Vol. 2. New York, NY: McGraw-Hill Book Company,


 1448-1449.
 

* Matsumaru H, Yoshida T. 1959. Experimental studies of nitrobenzol


 poisoning. Kyushu J Med Sci 10:259-264.


 McCormick NG, Feeherry FE, Levinson HS. 1976. Microbial transformation


 of 2,4,6-trinitrotoluene and other nitroaromatic compounds. Appl


 Environ Microbial 31:949-958.
 

* McFarlane JC, Nolt C, Wickliff C, et al. 1987a. The uptake,


 distribution and metabolism of four organic chemicals by soybean plants


 and barley roots. Environm Toxico1 Chem 6:847-856.
 

* McFarlane JC, Pfleeger T, Fletcher J. 1987b. Transpiration effect on


 the uptake and distribution of bromacil, nitrobenzene, and phenol in


 soybean plants. J Environ Qual 16:372-376.
 

* Medinsky MA, Irons RD. 1985. Sex, strain, and species differences in


 the response of rodents to nitrobenzene vapors. In: Rickert DE, ed.


 Chemical Industry Institute of Toxicology Series. Toxicity of


 nitroaromatic compounds. New York, NY: Hemisphere Publishing


 Corporation, 35-51.
 

* Michael LC, Pellizzari ED, Wiseman RW. 1988. Development and


 evaluation of a procedure for determining volatile organics in water.


 Environ Sci Technol 22:565-570.
 
 

94
 

8. REFERENCES


 Miner CS. 1919. Methemoglobinemia due to poisoning by shoe dye


 [Letter]. JAMA 72:1593.
 

* Mirsalis JC, Tyson CK, Butterworth BE. 1982. Detection of genotoxic


 carcinogens in the in vivo-in vitro hepatocyte DNA repair assay.


 Environ Mutagen 4:553-562.


 Miyata R, Nohmi T, Yoshikawa K, et al. 1982. Metabolic activation of


 p-nitrotoluene and trichloroethylene by rat liver S9 or mouse liver S9


 fractions in Salmonella tvphimurium strains [Abstract]. Chemical


 Abstracts 96 (March 29-April 12):209-210.


 Mochida K, Ito Y, Saito K, et al. 1986. Cytotoxic effects of


 1,2-dichloroethane, nitrobenzene, and carbon disulfide on human KB and


 monkey AGMK cells. J Pharm Sci 75:1190-1191.


 Monnier J. 1947. [Acute intoxication with nitrobenzene]. Toulouse Med


 48:728. (French)
 

* Monsen RM, Davis EM. 1984. Microbial responses to selected organic


 chemicals in industrial waste treatment units. Drug Chem Toxicol


 1:233-249.
 

* Morgan KT, Gross EA, Lyght O, et al. 1985. Morphologic and biochemical


 studies of a nitrobenzene-induced encephalopathy in rats.


 Neurotoxicology 6:105-116.


 Morrissey RE, Schwetz BA, Lamb JC IV, et al. 1988. Evaluation of


 rodent sperm, vaginal cytology and reproductive organ weight data from


 National Toxicology Program 13-week study. Fundam Appl Toxicol


 111343-358.


 Motulsky AG. 1957. Drug reactions, enzymes, and biochemical genetics.


 JAMA 165:835-837.


 Motulsky AG. 1972. Hemolysis in glucose-6-phosphate dehydrogenase


 deficiency. Fed Proc 31:1286-1292.
 

Muehlberger CW. 1925. Shoe dye poisoning. JAMA 84:1987-1991.
 

Mulvihill JJ, Czeizel A. 1983 ICPEMC working paper 5/6: Perspectives
 

in mutation epidemiology, 6: A 1983 view of sentinel phenotypes. Mutat
 

Res 123:345-361.
 

* Myslak Z, Piotrowski JK, Musialowicz E. 1971. Acute nitrobenzene


 poisoning: A case report with data on urinary excretion of


 p-nitrophenol and p-aminophenol. Arch Toxikol 28:208-213.
 
95


 8. REFERENCES


 Nabarro JD. 1948. A case of acute mononitrobenzene poisoning. Br Med


 J. (May 15):929-931.
 

* NAS/NRC. 1989. Biologic markers in reproductive toxicology. National


 Academy of Sciences/National Research Council. Washington, DC: National


 Academy Press, 15-35.
 

* NATICH. 1988. Natich Database Report on State, Local and EPA Air


 Toxics Activities, Research Triangle Park, NC: U.S. Environmental


 Protection Agency, Office of Air Quality, Planning, and Standards,


 National Air Toxics Information Clearing House.


 NCI. 1977. Bioassay of technical-grade pentachloronitrobenzene (PCNB)


 for possible carcinogenicity. Bethesda, MD: National Cancer Institute,


 Division of Cancer Cause and Prevention. NCI-CG-TR-61. NTIS


 No. PB-281732.
 

* Nelson CR, Hites RA. 1980. Aromatic amines in and near the Buffalo


 River. Environ Sci Technol 14:1147-1149.


 Neumann H-G. 1984. Analysis of hemoglobin as a dose monitor for


 alkylating and arylating agents. Arch Toxico1 56:1-6.
 

* NIOSH. 1977. Nitrobenzene-method S217. In: NIOSH manual of


 analytical methods. Vol 3. Cincinnati, OH; National Institute for


 Occupational Safety and Health, S217-l-S217-9.
 

* NIOSH. 1984. Nitrobenzene-method 2005. In: NIOSH manual of


 analytical methods. 3rd ed. Cincinnati, OH: National Institute for


 Occupational Safety and Health, 2005-l-2005-5.
 

* NIOSH. 1985. Pocket guide to chemical hazards. Cincinnati, OH:


 National Institute for Occupational Safety and Health.


 NIOSH. 1988. National occupational exposure survey. Cincinnati, OH:


 National Institute of Occupational Safety and Health.
 

* NLM. 1988. Chemline. National Library of Medicine, Bethesda, MD.


 December 1988.
 

* Nojima K, Kanno S. 1977. Studies on photochemistry of aromatic


 hydrocarbons. IV. Mechanisms of formation of nitrophenols by the


 photochemical reaction of benzene and toluene with nitrogen oxides in


 air. Chemosphere 6:371-376.
 
 

96
 

8. REFERENCES
 

* Nolt CL. 1988. Uptake and translocation of six organic chemicals in a


 newly-designed plant exposure system and evaluation of plant uptake


 aspects of the prebiologic screen for ecotoxicologic effects. MS


 Thesis. Cornell University, Ithace, NY.


 NTP. 1987. Toxicology and carcinogenesis studies of


 pentachloronitrobenzene (CAS No. 82-68-8) in B6C3F1, mice (feed


 studies). TR No. 325. Research Triangle Park, NC: U.S. Department of


 Health and Human Services, Public Health Service, National Toxicology


 Program. National Institutes of Health. NIH Publication No. 87-2581.


 Nystrom DD, Rickert DE. 1987. Metabolism and excretion of


 dinitrobenzenes by male Fischer-344 rats. Drug Metab Dispos 15:821-825.


 O'Hara GP, Chan PK, Harris JC, et al. 1983. The effect of nitrogen


 [4-(2,4-dichlorophenoxy)nitrobenzene] on the reproductive performance


 of male rats. Toxicology 28:323-333.
 

* OSHA. 1989. U.S. Department of Labor, Occupational Safety and Health


 Administration: Part III. Federal Register 54:2332-2959.


 Pacseri I, Magos L, Batskor IA. 1958. Threshold and toxic limits of


 some amino and nitro compounds. AMA Arch Ind Health 18:1-8.
 

* Pankow D, Ponsold W. 1976. Effect of methemoglobinemia on carbon


 tetrachloride hepatotoxicity. Toxico1 Appl Pharmacol 36:143-150.
 

* Parke DV. 1956. Studies in detoxication: The metabolism of


 [14C]nitrobenzene in the rabbit and guinea pig. Biochem J 62:339-346.


 Parkes WE, Neil 1 DW. 1953. Acute nitrobenzene poisoning with transient


 amino-aciduria. Br Med J (March 21):643-655.
 

* Patil S, Shinde VM. 1988. Biodegradation studies of aniline and


 nitrobenzene in aniline plant waste waters by gas chromatography.


 Environ Sci Technol 22:1160-1165.


 Pellizzari ED. 1978a. Measurement of carcinogenic vapors in ambient


 atmospheres. Research Triangle Park, NC: U.S. Environmental Protection


 Agency, Office of Research and Development. EPA-600/7-78-062.
 

* Pellizzari ED. 1978b. Quantification of chlorinated hydrocarbons in


 previously collected air samples. Research Triangle Park, NC: U.S.


 Environmental Protection Agency. EPA-450/3-78-112.
 
 

97
 

8. REFERENCES
 

* Perry DL, Chuang CC, Jungclaus GA, et al. 1979. Identification of


 organic compounds in industrial effluent discharges. Athens, GA: U.S.


 Environmental Protection Agency, Office of Research and Development.


 EPA-600/4-79-016.


 PHRED. 1988. Public Health Risk Evaluation Database. U.S.


 Environmental Protection Agency, Washington, DC. March 1988.
 

* Piet GJ, Morra CH, De Kruijf HA. 1981. The behavior of organic


 micropollutants during passage through the soil. Stud Environ Sci


 17:557-564.
 

* Piotrowski J. 1967. Further investigations on the evaluation of


 exposure to nitrobenzene. Br J Ind Med 24:60-65.


 Piotrowski JK. 1984. Phenol, aniline, and nitrobenzene. In: Aitio A,


 eds. Biological monitoring and surveillance of workers exposed to


 chemicals. New York, NY: Hemisphere Publishing Company.
 

* Pitter P. 1976. Determination of biological degradability of organic


 substances. Water Res 10:231-235.


 Pitts JN Jr, Atkinson R, Winer AM. 1985. Formation and fate of toxic


 chemicals in California's atmosphere. Riverside, CA: Statewide Air


 Pollution Research Center, California Air Resources Board. NTIS No.


 PB88-133038.
 

* Piwoni MD, Wilson JT, Walters DM, et al. 1986. Behavior of organic


 pollutants during rapid-infiltration of wastewater into soil. I.


 Processes, definition, and characterization using a microcosm.


 Hazardous Waste and Hazardous Materials 3:43-55.


 Popp JA. 1989. Written communication (March 14) to Dr. Arthur Gregory,


 Techto Enterprises. Chemical Industry Institute of Toxicology, Research


 Triangle Park, NC.


 Price Evans DA. 1983. Pharmacogenetics. In: Emery AE, Rimoin DL,


 eds. Principles and practice of medical genetics. Vol 2. Edinburgh,


 Scotland: Churchill Livingstone, 1389-1400.


 Proctor NH, Hughes JP, Fischman ML. 1988. Chemical hazards of the


 workplace. 2nd ed. Philadelphia, PA: J.B. Lippincott Company,


 367-368.
 

* Reddy BG, Pohl LR, Krisha G. 1976. The requirement of the gut flora in


 nitrobenzene-induced methemoglobinemia in rats. Biochem Pharmacol


 25:1119-1122.
 
 

98
 

8. REFERENCES


 Reynolds ES, Yee AG. 1968. Liver parenchymal cell injury: VI.


 Significance of early glucose 6-phosphatase suppression and transient


 calcium influx following poisoning. Lab Invest 19:273-281.
 

* Rickert DE. 1984a. Mammalian and bacterial metabolism of nitroaromatic


 compounds. In: Rickert DE, ed. Toxicity of nitroaromatic compounds.


 New York, NY: Hemisphere Publishing Corporation, 87-101.


 Rickert DE. 1984b. Reductive reactions. In: Caldwell J, Paulson GD,


 eds. Foreign Compound Metabolism. London, England: Taylor and


 Francis, 227-234.


 Rickert DE. 1986. The effects of diet on the toxicity of nitroaromatic


 chemicals in rodents [Abstract]. Toxico1 Lett 31(Suppl):S2-3.


 Rickert DE. 1987. Metabolism of nitroaromatic compounds. Drug Metab


 Rev 18:23-53.


 Rickert DE, Chism JP, Long RM, 1981. Metabolism and excretion of


 14C-nitrobenzene in male, Fischer 344 rats [Abstract]. Pharmacologist


 23:172.
 

* Rickert DE, Bond JA, Long RM, et al. 1983. Metabolism and excretion of


 nitrobenzene by rats and mice. Toxico1 Appl Pharmacol 67:206-214.


 Rickert DE, Irons RD, Popp JA, et al. 1986. The effects of diet on the


 toxicity of nitroaromatic chemicals in rodents. Dev Toxicol Environ Sci


 12:107-114.


 Rieders F, Brieger H. 1953. Mechanism of poisoning from wax crayons.


 JAMA 151:1490.


 Robinson D, Smith JN, Williams RT. 1951. The metabolism of


 nitrobenzene in the rabbit o-, m- and p-nitrophenols, o-, m- and


 p-aminophenols and 4-nitrocatechol as metabolites of nitrobenzene.


 Biochem J 50:228-235.


 Ross JD, Ciccarelli RF. 1962. Acquired methemoglobinemia due to


 ingestion of acetophenetidin: Report of a case in an infant. N Engl J


 Med 266:1202-1204.


 Roy WR, Griffin RA. 1985. Mobility of organic solvents in watersaturated soil materials. Environ Geol Water Sci 7:241-247.
 

* Ruth JH. 1986. Odor thresholds and irritation levels of several


 chemical substances: A review. Am Ind Hyg Assoc J 47:A-142-151.
 
 

99
 

8. REFERENCES


 Salmowa J, Piotrowski J. 1960. Attempt at quantitative evaluation of


 nitrobenzene absorption in experimental conditions. 13th Proceedings of


 the International Congress on Occupational Health, 780-782.
 

* Salmowa J, Piotrowski J, Neuhorn U. 1963. Evaluation of exposure to


 nitrobenzene: Absorption of nitrobenzene vapour through lungs and


 excretion of p-nitrophenol in urine. Br J Ind Med 20:41-46.


 Sanders FG. 1920. Nitrobenzene poisoning with cyanosis: Report of


 case. JAMA 74:1518-1519.
 

* Sax NI, Lewis RJ Sr. 1987. Hawley's condensed chemical dictionary.


 11th ed. New York, NY: Van Nostrand Reinhold Company, 826.


 Schwartz L. 1941. Dermatitis from cutting oils. Public Health Rep


 56:1947-1953.
 

* Seip HN, Alstad J, Carlberg GE, et al. 1986. Measurement of mobility


 of organic compounds in soils. Sci Total Environ 50:87-101.


 Sekimpi DK, Jones RD. 1986. Notifications of industrial chemical


 cyanosis poisoning in the UK 1961-80. Br J Ind Med 43:272-279.
 

* Shackelford WM, Cline DM, Faas L, et al. 1983. An evaluation of


 automated spectrum matching for survey identification of wastewater


 components by gas chromatography-mass spectrometry. Anal Chim Acta


 146:15-27.
 

* Shimizu M, Yasui Y, Matsumoto N. 1983. Structural specificity of


 aromatic compounds with special reference to mutagenic activity of


 Salmonella typhimurium - a series of chloro or fluoro-nitrobenzene


 derivatives. Mutat Res 116:217-238.
 

* Shimkin MB. 1939. Acute toxicity of mononitrobenzene in mice. Proc


 Sot Exp Biol Med 42:844-846.
 

* Simmons MS, Zepp RG. 1986. Influence of humic substances on photolysis


 of nitroaromatic compounds in aqueous systems. Water Res 20:899-904.


 Sittig M. 1985. Handbook of toxic and hazardous chemicals and


 carcinogens. 2nd ed. Park Ridge, NJ: Noyes Publications, 652-654.
 

* Smith RM. 1988. Supercritical fluid chromatography. Royal Society of


 Chemistry, Letchword, England.


 Smith RP, Olson MV. 1973. Drug-induced methemoglobinemia. Semin


 Hematol 10:253-268.
 
 

100
 

8. REFERENCES
 

* Smith RP, Alkaitis AA, Shafer PR. 1967. Chemically induced


 methemoglobinemias in the mouse. Biochem Pharmacol 16:317-328.
 

* Smith RV, Rosazza JP. 1974. Microbial models of mammalian metabolism.


 Aromatic hydroxylation. Arch Biochem Biophys 161:551-558.
 

* Smyth HF Jr, Weil CS, West JS, et al. 1969. An exploration of joint


 toxic action: Twenty-seven industrial chemicals intubated in rats in


 all possible pairs. Toxicol Appl Pharmacol 14:340-347.
 

* Speece RE. 1983. Anaerobic biotechnology for industrial wastewater


 treatment. Environ Sci Technol 17:416A-427A.


 Spencer PS, Schaumburg HH. 1985. Organic solvent neurotoxicity: Facts


 and research needs. Stand J Work Environ Health ll(Supp11):53-60.
 

* SRI. 1985. Directory of chemical producers: United States of America.


 Menlo Park, CA: SRI International.
 

* SRI. 1986. Directory of chemical producers: United States of America.


 Menlo Park, CA: SRI International
 

* SRI. 1987. Directory of chemical producers: United States of America.


 Menlo Park, CA: SRI International.
 

* SRI. 1988. Directory of chemical producers: United States of America.


 Menlo Park, CA: SRI International.
 

* Staples CA, Werner A, Hoogheem T, et al. 1985. Assessment of priority


 pollutant concentrations in the United States using the STORET


 database.Environ Toxicol Chem 4:131-142.


 Sternson LA, Gammans RE. 1975. Interaction of aromatic nitro compounds


 with reduced hepatic-microsomal cytochrome P-450. Drug Metab Dispos


 3:266-274.


 Stevens AM. 1928. Cyanosis in infants from nitrobenzene. JAMA 90:116.
 

* Stevenson A, Forbes RP. 1942. Nitrobenzene poisoning: Report of a


 case due to exterminator spray. J Pediatr 21:224-228.


 Stifel RE. 1919. Methemoglobinemia due to poisoning by shoe dye:


 Report of a series of cases at an army camp. JAMA 72:395-396.


 Stolk JM, Smith RP. 1966. Species differences in methemoglobin


 reductase activity. Biochem Pharmacol 15:343-351.
 
 

101
 

8. REFERENCES


 Stone WJ. 1904. Fatal poisoning due to skin adsorption of liquid shoe


 blacking (nitrobenzol) with autopsy report. JAMA 43:977-980.
 

* Stover EL, Kincannon DF. 1983. Biological treatability of specific


 organic compounds found in chemical industry wastewaters. J Water


 Pollut Control Fed 55:97-109.


 Suzuki J, Koyami T, Suzuki S. 1983. Mutagenicities of mononitrobenzene


 derivatives in the presence of norharman. Mutat Res 120:105-110.


 Suzuki J, Takahashi N, Kobayashi Y, et al. 1987. Dependence on


 Salmonella tvphimurium enzymes for mutagenicities of nitrobenzene and


 its derivatives in the presence of rat-liver S9 and norharman. Mutat


 Res 178:187-193.


 Tabak HH, Chambers CW, Kabler PW. 1964. Microbial metabolism of


 aromatic compounds: I. Decomposition of phenolic compounds and aromatic


 hydrocarbons by phenol-adapted bacteria. J Bacterial 87:910-919.
 

* Tabak HH, Quave SA, Mashni CI, et al. 1981. Biodegradability studies


 with organic priority pollutant compounds. J Water Pollut Control Fed


 53:1503-1518.


 Tarlov AR, Brewer GJ, Carson PE, et al. 1962. Primaquine sensitivity:


 Glucose-6-phosphate dehydrogenase deficiency: An inborn error of


 metabolism of medical and biological significance. Arch Intern Med


 109:137-162.
 

* Trabalka JR, Garten CT Jr. 1981. Development of predictive models for


 xenobiotic bioaccumulation in terrestrial systems. Oak Ridge, TN: Oak


 Ridge National Laboratory, Environmental Sciences Division #2037.


 ORNL-5869.
 

* Tyl RW, France KA, Fisher LC, et al. 1987. Developmental toxicity


 evalution of inhaled nitrobenzene in CD rats. Fundam Appl Toxico1


 8:482-492.


 Uchrin CG, Katz J, Mangels G, et al. 1985. Characterization of the


 sorption of toxic and hazardous organic substances to groundwater


 aquifer solids. Stud Environ Sci 29:663-676.


 Urano K, Kato Z. 1986. Evaluation of biodegradation ranks of priority


 organic chemicals. J Haz Materials 13:147-159.
 

* USITC. 1987. Synthetic organic chemicals: United States Production


 and Sales, 1986. Washington, DC: United States International Trade


 Commission.
 
 

102
 

8. REFERENCES
 

* USITC. 1988. Synthetic organic chemicals: United States Production


 and Sales, 1987. Washington, DC: United States International Trade


 Commission. USTIC Publication 2118.
 

* Veith GD, DeFoe DL, Bergstedt BV. 1979. Measuring and estimating the


 bioconcentration factor of chemicals in fish. J Fisheries Res Board Can


 36:1040-1048.


 Veith GD, Macek KJ, Petrocelli SR, et al. 1980. An evaluation of using


 partition coefficients and water solubility to estimate bioconcentration factors for organic chemicals in fish. In: Eaton JG, Parrish PR,


 Hendrick AC, eds. Aquatic Toxicology. Philadelphia, PA: American


 Society for Testing and Materials, 116-129.
 

* Verschueren K. 1983. Handbook of environmental data on organic


 chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Company,


 910-913.
 

* VIEW Database. 1989. Agency for Toxic Substances and Disease Registry


 (ATSDR), Office of External Affairs, Exposure and Disease Registry


 Branch, Atlanta, GA. June 20, 1989. (Map based on VIEW Database,


 June 12, 1989).
 

* Von Oettingen WF. 1941. The aromatic amino and nitro compounds, their


 toxicity and potential dangers: A review of the literature.


 Washington, DC: U.S. Public Health Service. Public Health Bulletin


 No. 271.


 Wallingford KN, Yodaiken RE. 1983. Health hazard evaluation report:


 HETA 82-338-1266, Center for Molecular Nutrition and Sensory Disorders,


 Washington, DC. Cincinnati, OH: U.S. Department of Health and Human


 Services, Public Health Service, Centers for Disease Control, National


 Institute for Occupational Safety and Health. NTIS No. PB84-209725.


 Walsh DB, Claxton LD. 1987. Computer-assisted structure-activity


 relationships of nitrogenous cyclic compounds tested in Salmonella


 assays for mutagenicity. Mutat Res 182:55-64.
 

* Watanabe T, Ishihara N, Ikeda M. 1976. Toxicity of and biological


 monitoring for 1,3-diamino-2,4,6-trinitro-benzene and other nitro-amino


 derivatives of benzene and chlorobenzene. Int Arch Occup Environ Health


 37:157-168.


 Weant GE, McCormick GS. 1984. Nonindustrial sources of potentially


 toxic substances and their applicability to source apportionment


 methods. Research Triangle Park, NC: U.S. Environmental Protection


 Agency. EPA-450/4-84-003. NTIS No. PB84-231232.
 
 

103
 

8. REFERENCES
 

* Weast RC, ed. 1985. CRC handbook of chemistry and physics: A


 ready-reference book of chemical and physical data. 66th ed. Boca


 Raton, FL: CRC Press, Inc., C-115.


 Weinberg AA. 1931. Aniline poisoning in the newborn with a report of


 thirteen cases. Am J Obstet Gynecol 21:104-108.


 Welch RM, Conney AH, Burns JJ. 1966. The metabolism of acetophenetidin


 and n-acetyl-R-aminophenol in the cat. Biochem Pharmacol 15:521-531.


 Wetherhold JM, Linch AL, Charsha RC. 1960. Chemical cyanosis - causes,


 effects, and prevention. Arch Environ Health 1:353-361.


 Wheeler LA, Soderberg FB, Goldman P. 1975. The relationship between


 nitro group reduction and the intestinal microflora. J Pharmacol Exp


 Ther 194:135-144.
 

* WHO. 1986. Diseases caused by toxic nitro and amino derivatives of


 benzene and its homologues. Chaper 9. In Early Detection of


 Occupational Diseases. World Health Organization, Geneva.
 

* Wieboldt, RC, Adams GE, Later DW. 1988. Sensitivity improvement in


 infrared detection for supercritical fluid chromatography. Anal Chem


 60:2422-2427.


 Wilson JT, Enfield CG, Dunlap WJ, et al. 1981. Transport and fate of


 selected organic pollutants in a sandy soil. J Environ Qua110:501-506.


 Windholz M. 1983. The Merck index: An encyclopedia of chemicals,


 drugs and biologicals. 10th ed. Rahway, NJ: Merck and Company, Inc.,


 945.


 Wirtschafter ZT, Wolpaw R. 1944. A case of nitrobenzene poisoning.


 Ann Intern Med 21:135-140.


 Wislocki PG, Bagan ES, Lu AY, et al. 1986. Tumorigenicity of nitrated


 derivatives of pyrene, benz[a]anthracene, chrysene and benzo[a]pyrene


 in the newborn mouse assay. Carcinogenesis 7:1317-1322.
 

* Wisniewska-Knypl JM, Jablonska JK, Piotrowski JK. 1975. Effect of


 repeated exposure to aniline, nitrobenzene, and benzene on liver


 microsomal metabolism in the rat. Br J Ind Med 32:42-48.


 Wuertz RL, Frazee WH Jr, Hume WG, et al. 1964. Chemical cyanosis ­

anemia syndrome: Diagnosis, treatment, and recovery. Arch Environ


 Health 9:478-491.
 
 

104
 

8. REFERENCES


 Yamada Y. 1958. Studies on the experimental chronic poisoning of


 nitrobenzene. Kobe J Med Sci 4:227-239.
 

* Young DR, Gossett RW, Baird RB, et al. 1983. Wastewater inputs and


 marine bioaccumulation of priority pollutant organics off southern


 California. In: Jolley RL, Brungs WA, Cotruvo JA, eds. Water


 chlorination: environmental impact and health effects. Vol 4, Book 2:


 Environment, health, and risk. Ann Arbor, MI: Ann Arbor Science


 Publishers, 871-884.


 Zachariah PK, Juchau MR. 1974. The role of gut flora in the reduction


 of aromatic nitro-groups. Drug Metab Dispos 2:74-78.


 Zeligs M. 1929. Aniline and nitrobenzene poisoning in infants. Arch


 Pediatr 46:502-506.


 A Zen RG, Schlotzhauer PF. 1983. Influence of algae on photolysis rates


 of chemicals in water. Environ Sci Technol 17:462-468.
 

* Zepp RG, Braun AM, Hoigne J, et al. 1987a. Photoproduction of hydrated


 electrons from natural organic solutes in aquatic environments. Environ


 Sci Technol 21:485-490.
 

* ( Zepp RG, Hoigne J, Bader H. 1987b. Nitrate-induced photooxidation of


 trace organic chemicals in water. Environ Sci Technol 21:443-450.


 Zoldak JJ, Dumdei BE. 1985. Characterization of toxic air emissions


 from TSDF's in heavily industrialized areas using a mobile MS/MS


 laboratory. Proceedings of the 78th annual meeting of the Air Pollution


 Control Association, Detroit, Michigan, June 16-21, 1985,


 (85-17.8):2-14.
 
105
 

9.GLOSSARY
 

Acute Exposure -- Exposure to a chemical for a duration of 14 days or
 

less, as specified in the Toxicological Profiles.
 

Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical
 

adsorbed per unit weight of organic carbon in the soil or sediment to
 

the concentration of the chemical in solution at equilibrium.
 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment
 

or soil (i.e., the solid phase) divided by the amount of chemical in the
 

solution phase, which is in equilibrium with the solid phase, at a fixed
 

solid/solution ratio. It is generally expressed in micrograms of
 

chemical sorbed per gram of soil or sediment.
 

Bioconcentration Factor (BCF) -- The quotient of the concentration of a
 

chemical in aquatic organisms at a specific time or during a discrete
 

time period of exposure divided by the concentration in the surrounding
 

water at the same time or during the same 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.
 
106
 

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(LO) (LCLO) -- The lowest concentration of a chemical
 

in air which has been reported to have caused death in humans or
 

animals.
 

Lethal Concentration(50) (LC50) -- A calculated concentration of a
 

chemical in air to which exposure for a specific length of time is
 

expected to cause death in 50% of a defined experimental animal
 

population.
 

Lethal Dose(LO) (LDLO) -- The lowest dose of a chemical introduced by a
 

route other than inhalation that is expected to have caused death in
 

humans or animals.
 

Lethal Dose(50) (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.
 
 

107
 

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 (Kow) -- The equilibrium ratio of
 

the concentrations of a chemical in n-octanol and water, in dilute
 

solution.
 

Permissible Exposure Limit (PEL) -- An allowable exposure level in
 

workplace air averaged over an 8-hour shift.
 

q1* -- The upper-bound estimate of the low-dose slope of the doseresponse
 

curve as determined by the multistage procedure. The q1* can
 

be used to calculate an estimate of carcinogenic potency, the
 

incremental excess cancer risk per unit of exposure (usually μg/L for 

water, mg/kg/day for food, and μg/m3 for air). 

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps
 

an order of magnitude) of the daily exposure of the human population to
 

a potential hazard that is likely to be without risk of deleterious
 

effects during a lifetime. The RfD is operationally derived from the
 

NOAEL (from animal and human studies) by a consistent application of
 

uncertainty factors that reflect various types of data used to estimate
 

RfDs and an additional modifying factor, which is based on a
 

professional judgment of the entire database on the chemical. The RfDs
 

are not applicable to nonthreshold effects such as cancer.
 
 

108
 

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.
 
109
 

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.