The Risk Assessment Information System

Toxicity Summary for NITROBENZENE

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

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EXECUTIVE SUMMARY

1. INTRODUCTION

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION
2.2 DISTRIBUTION
2.3 METABOLISM
2.4 EXCRETION

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES
3.2 INHALATION EXPOSURES
3.3 OTHER ROUTES OF EXPOSURE
3.4 TARGET ORGANS/CRITICAL EFFECTS

4. CARCINOGENICITY

4.1 ORAL EXPOSURES
4.2 INHALATION EXPOSURES
4.3 OTHER ROUTES OF EXPOSURE
4.4 EPA WEIGHT-OF-EVIDENCE
4.5 CARCINOGENICITY SLOPE FACTORS

5. REFERENCES

MARCH 1993

Prepared by: Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation Group, Biomedical Environmental Information Analysis Section, Health and Safety Research Division, ^*, Oak Ridge, Tennessee.

Prepared for: Oak Ridge Reservation Environmental Restoration Program.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Nitrobenzene (CAS Reg. No. 98-95-3) is a pale yellow liquid with an odor of bitter almonds (Dunlap, 1981). Most of the nitrobenzene produced is used as an intermediate in the synthesis of aniline. An anthropogenic environmental contaminant, nitrobenzene can be released to wastewater and air from industrial sources (ATSDR, 1990). It is primarily removed from the environment by photolysis, reaction with hydroxyl radicals, volatilization, and biodegradation (U.S. EPA, 1985).

Nitrobenzene can be absorbed by humans following oral, inhalation, or dermal exposure (U.S. EPA, 1980). When absorbed into the blood, nitrobenzene oxidizes the iron in hemoglobin to form methemoglobin, thus decreasing the oxygen carrying capacity of the blood. The primary systemic effect associated with human exposure to nitrobenzene is methemoglobinemia. Acute oral exposure has resulted in methemoglobinemia, cyanosis, and anemia, and neurological effects, including headache, nausea, vertigo, confusion, unconsciousness, apnea, coma, and death (Piotrowski, 1967; U.S. EPA, 1980; ATSDR, 1990). Methemoglobinemia has also been reported following subchronic to chronic occupational exposure to nitrobenzene. Additional effects included sulfhemoglobinemia, presence of Heinz bodies in erythrocytes, liver toxicity (hepatomegaly, jaundice, and altered serum chemistry), spleen enlargement, and neurological symptoms (headache, nausea, weakness, vertigo, numbness of legs, and hyperalgesia of hands and feet) (U.S. EPA, 1980; Ikeda and Kita, 1964). Dermal exposure to nitrobenzene has resulted in contact dermatitis (Beauchamp et al., 1982).

Effects observed in subchronic inhalation studies with rodents exposed to nitrobenzene at concentrations up to 50 ppm for 90 days included methemoglobinemia, splenic lesions (splenomegaly, increased hemosiderosis and hematopoiesis), liver toxicity (hepatocyte hyperplasia and focal necrosis), kidney nephrosis, and testicular degeneration. Morphologic changes of the adrenal cortex were reported for mice (CIIT, 1984). Effects on the spleen, kidneys, and liver were also reported in rodents exposed to concentrations up to 125 ppm for 14 days. In addition, there was morphologic damage to the hind brain (Medinsky and Irons, 1985). Testicular degeneration and decreased sperm levels were reported in a two-generation reproductive study with rats (Dodd et al., 1987).

A reference dose (RfD) of 5E-3 mg/kg/day for subchronic oral exposure and 5E-4 mg/kg/day for chronic oral exposure to nitrobenzene was calculated from a lowest-observed-adverse-effect level (LOAEL) of 25 mg/m³ derived from a 90-day inhalation study with F344 rats and B6C3F₁ mice (CIIT, 1984). The critical effects were hematological changes in F344 rats, and adrenal, renal, and hepatic lesions in B6C3F₁ mice (U.S. EPA, 1992a,b). Because this value is based on a route to route extrapolation, the RfD may change pending further review by EPA (U.S. EPA, 1992a). The same study (CIIT, 1984) served as the basis of a reference concentration (RfC) of 2E-2 mg/m³ for subchronic inhalation exposure and 2E-03 mg/m³ for chronic inhalation exposure to nitrobenzene (U.S. EPA, 1992b). This value is currently under review by an EPA work group (U.S. EPA, 1992a).

No suitable cancer bioassays or epidemiological studies are available to assess the carcinogenicity of nitrobenzene. Therefore, U.S. EPA (1992a,b) has placed nitrobenzene in weight-of-evidence group D, not classifiable as to human carcinogenicity.

1. INTRODUCTION

Nitrobenzene (CAS Reg. No. 98-95-3), also known as nitrobenzol or oil of mirbane, is a pale yellow liquid with an odor of bitter almonds (Dunlap, 1981). The compound's characteristic odor can be detected in water at a threshold concentration as low as 30 g/L (U.S. EPA, 1980). Nitrobenzene has a melting point of 5.85C and a boiling point of 210.9C. It is slightly soluble in water, readily soluble in organic solvents such as alcohol, ether, and benzene (Dunlap, 1981), and very soluble in lipids. Nitrobenzene is prepared by direct nitration of benzene in the presence of nitric and sulfuric acids (U.S. EPA, 1980). About 98% of all nitrobenzene produced is used in the synthesis of aniline; the major use of aniline is in the manufacture of polyurethanes. Nitrobenzene is also used as a solvent and in the refining of some lubricating oils, in the manufacture of cellulose ethers and acetate, as a chemical intermediate in the synthesis of N-acetyl p-aminophenol (Tylenol®) and other chemicals, as a flavoring agent, a perfume for soaps, and as a solvent for shoe dyes (Beauchamp et al., 1982; Beard and Noe, 1981; U.S. EPA, 1985; ATSDR, 1990).

An anthropogenic environmental contaminant, nitrobenzene can be released to wastewater and air from industrial sources. Nitrobenzene is formed in ambient air, particularly in urban areas, as a result of photochemical reactions of nitrogen oxides with benzene derived from automobile fuels (ATSDR, 1990). Photolysis, volatilization, and biodegradation are significant removal processes affecting the fate of nitrobenzene in water. Reaction with hydroxyl radicals and photolysis appear to be the primary removal mechanisms in ambient air (U.S. EPA, 1985). Principal degradation products of nitrobenzene in air include p-nitrophenol and nitrosobenzene (ATSDR, 1990).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Although nitrobenzene can be absorbed by the gastrointestinal tract, it is most commonly absorbed through the respiratory tract and skin (U.S. EPA, 1980, 1985). Humans breathing air containing 5-30 g nitrobenzene/L retained approximately 80% in the respiratory tract, and the amount of retained nitrobenzene remained fairly constant over a period of 6 hours (Beauchamp et al., 1982). Humans exposed to 5 mg/m³ for 6 hours absorbed 18 mg through the lungs and 7 mg through the skin (Piotrowski, 1967). Nitrobenzene can be absorbed through the skin in both vapor and liquid state. The rate of vapor absorption depends on the air concentration, ranging from 1 mg/hr at 5 mg/m³ to 9 mg/hr at 30 mg/m³. Air temperature does not affect dermal absorption rates, but an increase in humidity from 33 to 67% will increase the absorption rate by 40%. Maximal dermal absorption of liquid nitrobenzene was 0.2-3 mg/cm²/hr, depending on skin temperature. Absorption was increased with elevated skin temperature and duration of contact (Piotrowski, 1977). Based on toxic responses observed in mice and rabbits following skin application, nitrobenzene appears to be absorbed in dermally treated animals (ATSDR, 1990).

2.2. DISTRIBUTION

No studies were available concerning the tissue distribution of nitrobenzene in humans. Two days after gavage administration of 0.25 mL of radiolabeled nitrobenzene to rabbits, approximately 54% of the radioactivity was found in tissues, accumulating primarily in adipose tissue and the intestinal tract. Eight days following dosing, 8% of the radioactivity remained in the animals, mostly in adipose tissue (Parke, 1956). An oral study with rats showed that nitrobenzene is bound to blood, liver, kidneys, and lungs one day after administration by gavage. Nitrobenzene metabolites were shown to be bound to blood proteins, both in hemoglobin and in plasma (Albrecht and Neumann, 1985). One hour after intravenous administration of nitrobenzene to rats, the ratio of the concentration of nitrobenzene in adipose tissue vs. blood in internal organs and muscle was 10:1 (Piotrowski, 1977). No studies were found addressing the distribution of nitrobenzene following inhalation or dermal exposure.

2.3. METABOLISM

The metabolites identified and measured in the urine of humans exposed to nitrobenzene indicate that metabolism proceeds by a series of oxidation (hydroxylation) and reduction reactions, resulting primarily in the excretion of p-nitrophenol and p-aminophenol (Beauchamp et al., 1982).

Numerous metabolites have been identified in the urine of laboratory animals. Following gavage administration of radiolabeled nitrobenzene to rabbits, Parke (1956) recovered 1% of a 250-mg/kg dose as CO₂, and 0.6% was exhaled as unchanged nitrobenzene. The total excretion of radioactivity in the expired air, urine, and feces accounted for nearly 70% of the dose 4-5 days after administration of nitrobenzene. p-Aminophenol in the urine accounted for 31% of the administered radioactivity within 4 or 5 days after dosing. Smaller amounts of m-aminophenol, o-aminophenol, p-nitrophenol, and m-nitrophenol, each comprising 3-9% of the administered radioactivity, were also identified in the urine. Less than 1% of the radioactivity was identified as aniline, o-phenol, o-nitrophenol, 4-nitrocatechol, nitroquinol, or p-nitrophenylmercapturic acid.

Human and animal studies have shown that nitrobenzene is involved in the formation of methemoglobin, resulting in methemoglobinemia. Although not completely understood, reduced nitrobenzene metabolites are believed to be responsible for nitrobenzene-induced methemoglobinemia. Studies with rats and mice demonstrated that orally administered nitrobenzene is reduced in the intestinal tract and that intestinal microfloral metabolism is essential for the production of methemoglobin (Goldstein et al., 1984; Albrecht and Neumann, 1985).

2.4. EXCRETION

Urinary excretion appears to be the major route of nitrobenzene elimination in humans after oral or inhalation exposure. In most cases of oral nitrobenzene poisoning, the metabolites p-aminophenol and p-nitrophenol were excreted in the urine (ATSDR, 1990). Ikeda and Kita (1964) identified the same two metabolites in the urine of a woman who had been occupationally exposed to nitrobenzene for 17 months. In volunteers who had inhaled 6 ppm nitrobenzene for 6 hours, the urinary excretion of p-nitrophenol was most rapid during the first two hours following exposure. The metabolite was still detectable 100 hours after cessation of exposure (Salmova et al., 1963).

Following oral administration of radiolabeled nitrobenzene to rabbits, Parke (1956) recovered only small amounts of a 250-mg/kg dose as CO₂ or as unchanged compound in expired air. The total excretion of radioactivity in the expired air, urine, and feces accounted for nearly 70% of the dose 4-5 days after administration of nitrobenzene. Urinary radioactivity was still detected ten days after dosing. Delayed excretion was also apparent in a more recent gavage study with rats (Albrecht and Neumann, 1985). One day after treatment, 50% of the dose appeared in the urine and 4% in the feces; after the fifth day, 65% of the dose appeared in the urine and 16% in the feces. A gavage study with rabbits showed that all phenolic compounds were excreted in conjugated form as glucuronide or sulfate (Beauchamp et al., 1982). Bile is a minor route of excretion of nitrobenzene and its metabolites in rats; 2-4% of an oral dose was excreted by this route in 12 hours (Rickert et al., 1983). Ikeda and Kita (1964) identified p-aminophenol and p-nitrophenol in the urine of rats that had been exposed to nitrobenzene by inhalation.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Acute effects have been reported following accidental or intentional ingestion of liquid nitrobenzene or false bitter almond oil in food or medicine (U.S. EPA, 1980). Following absorption into the blood, nitrobenzene oxidizes the iron in hemoglobin to form methemoglobin, thus decreasing the oxygen carrying capacity of the blood. Methemoglobinemia with resulting cyanosis is the most characteristic symptom of nitrobenzene poisoning in humans. If cyanosis is severe or prolonged, coma and death may occur. Anemia may be seen 1-2 weeks after acute poisoning as a result of the hemolytic effect of nitrobenzene (Piotrowski, 1967; U.S. EPA, 1980). Neurological effects, including headache, nausea, vertigo, confusion, unconsciousness, apnea, and coma have been reported following ingestion of nitrobenzene (ATSDR, 1990). However, no data were available to reliably estimate the levels of nitrobenzene associated with methemoglobinemia or neurological effects.

3.1.1.2. Animal

Smyth et al. (1969) reported an LD₅₀ of 600 mg/kg in rats. Damage to the brain stem, cerebellum, and fourth ventricle was reported in male rats following administration of a single 50- mg/kg dose of nitrobenzene (Morgan et al., 1985). Histopathologic lesions of the liver and testes were consistently observed in male F344 rats given single oral doses of nitrobenzene (Bond et al., 1981). Hepatocellular nucleolar enlargement was seen after administration of 110 mg/kg, the lowest dose tested, while hepatic centrilobular necrosis occurred in all rats receiving 450 mg/kg and in some receiving the lower doses of nitrobenzene. Testicular lesions developed within one to four days after administration of 300-450 mg/kg; one rat exhibited a cerebellar lesion at 450 mg/kg. Oral administration of 200-600 mg nitrobenzene/kg to rats resulted in methemoglobinemia. Diet has been shown to affect the production of methemoglobin by influencing the intestinal microflora (Goldstein et al., 1984).

3.1.2. Subchronic Toxicity

Information on the subchronic oral toxicity of nitrobenzene in humans or animals was not available.

3.1.3. Chronic Toxicity

Information on the chronic oral toxicity of nitrobenzene in humans or animals was not available.

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on the developmental or reproductive toxicity of nitrobenzene in humans following oral exposure was not available.

3.1.4.2. Animal

A single oral dose of 300 mg/kg nitrobenzene produced a transient decrease of sperm production and testicular degeneration in rats (Levin et al., 1988). Testicular lesions in rats, confined to the seminiferous tubules with necrosis of primary and secondary spermatocytes and appearance of multi-nucleated giant cells, developed within one to four days following administration of 300-450 mg nitrobenzene/kg (Bond et al., 1981).

3.1.5. Reference Dose

3.1.5.1. Subchronic

ORAL RfD_s: 5E-3 mg/kg/day (U.S. EPA, 1992b)

UNCERTAINTY FACTOR: 1000

NOAEL: None

LOAEL: 25 mg/m³, converted to 4.6 mg/kg/day

PRINCIPAL STUDY: CIIT, 1984

COMMENTS: The same study (Section 3.2.2.2) applies to both the subchronic and chronic RfD derivations. The LOAEL was based on hematologic effects in F344 rats and on adrenal, renal, and hepatic lesions in B6C3F₁ mice exposed by inhalation to 25 mg/m³ of nitrobenzene for 90 days. The uncertainty factor of 1000 includes two factors of 10 for intra- and interspecies variability and a factor of 10 for estimating an effect from a LOAEL rather than a NOAEL (U.S. EPA, 1992a).

3.1.5.2. Chronic

ORAL RfD: 5E-4 mg/kg/day (U.S. EPA, 1992a)

UNCERTAINTY FACTOR: 10,000

NOAEL: None

LOAEL: 25 mg/m³, converted to 4.6 mg/kg/day

CONFIDENCE:

Study: Medium

Data Base: Low

RfD: Low

VERIFICATION DATE: 07/08/85

PRINCIPAL STUDY: CIIT, 1984

COMMENTS: The LOAEL was based on hematologic effects in F344 rats and on adrenal, renal, and hepatic lesions in B6C3F₁ mice exposed by inhalation to 25 mg/m³ of nitrobenzene for 90 days. The LOAEL was converted to mg/kg/day by multiplying by the following factors: 6 hr/24 hr x 5 days/7 days (adjustment for discontinuous exposure); 0.039 cm³/day/0.03 kg (mouse breathing rate/body weight); and 0.8 (absorption). The uncertainty factor of 10,000 includes two factors of 10 for intra- and interspecies variability, a factor of 10 for estimating an effect from a LOAEL rather than a NOAEL, and a factor of 10 for extrapolation from subchronic to chronic exposure. Because the RfD is based on route to route extrapolation, the value may change pending further review by EPA (U.S. EPA, 1992a).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Methemoglobinemia has been reported after acute, short-term occupational exposure to nitrobenzene. Additional effects include sulfhemoglobinemia and anemia (Beauchamp et al., 1982; U.S. EPA, 1985). OSHA (1978) reported that human exposure to nitrobenzene vapor at concentrations of 6 ppm resulted in headache, vertigo, and a low degree of methemoglobinemia; exposure to 40 ppm caused intoxication. Alcohol has the potential to enhance the toxicity of nitrobenzene. For example, ingestion of an alcoholic beverage induced immediate acute symptoms, including coma, in a worker who had apparently recovered from the effects of chronic nitrobenzene exposure (U.S. EPA, 1980).

3.2.1.2. Animal

Inhalation of air saturated with nitrobenzene for 5.5 hours induced nystagmus and paralysis in dogs (Beauchamp et al., 1982).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Ikeda and Kita (1964) reported neurotoxic and hepatotoxic effects in a 47-year-old woman who had been occupationally exposed to nitrobenzene for 17 months. The effects included headache, nausea, vertigo, general weakness, numbness of legs, hyperalgesia of hands and feet, cyanosis, hypotension, spleen enlargement, liver enlargement and tenderness, jaundice, and altered serum chemistry.

3.2.2.2. Animal

In a subchronic inhalation study, F344 rats, CD rats, and B6C3F₁ mice were exposed to nitrobenzene at concentrations of 0, 25, 81, or 252 mg/m³ (0, 5, 16, or 50 ppm) 6 hours/day, 5 days/week for 90 days (CIIT, 1984). In both strains of rats, there were concentration-related increased levels of methemoglobin; increased hemosiderosis and hematopoiesis of the spleen; toxic nephrosis of the kidneys; and liver lesions, increasing in severity from hepatocellular hypertrophy to focal necrosis. At 25 mg/m³, the incidence of spleen, kidney, and liver lesions was similar to controls. At 81 mg/m³, rats exhibited changes in hematological parameters indicative of hemolytic anemia, and increased spleen and liver weights. At 252 mg/m³, male rats exhibited decreased testicular weights, severe degeneration of the testicular spermatogenic epithelium, and bilateral testicular atrophy. A low incidence of these testicular lesions was also seen at 25 and 81 mg/m³. In mice, the lowest concentration caused increased hemosiderosis of the spleen, which became more severe at higher concentrations. Female mice exposed to 25 mg/m³ had increased incidences and severity of vacuolization of the zona reticularis of the adrenal gland. Mice also had hepatocellular hyperplasia at 81 mg/m³ and increased liver and spleen weights and methemoglobinemia at 252 mg/m³.

Strain and sex differences in response to nitrobenzene exposure were demonstrated in studies conducted by Medinsky and Irons (1985). F344 rats, CD rats, and B6C3F₁ mice were exposed to concentrations of nitrobenzene ranging from 10 to 125 ppm for 14 days. At 125 ppm, there was 40% mortality in CD rats, and morbidity necessitated the sacrifice of nearly all mice before the end of the exposure period. F344 rats, however, tolerated this concentration without any clinical signs of toxicity. Histological renal lesions were seen at 125 ppm and included hydropic degeneration of the cortical tubular cells in 20% of male and 90% of female CD rats, and hyaline nephrosis in 100% of male and in 20% of female F344 rats. In mice, multifocal degenerative changes of the tubular epithelium was observed in males at 35 ppm, but not at the higher concentrations. Species- and sex-related differences in liver pathology were also observed in animals exposed to 125 ppm: severe centrilobular necrosis and degeneration occurred in male mice but not in female mice; in CD rats, the hepatic effects were similar but not as severe; and no significant liver lesions were seen in F344 rats. Splenic lesions, such as sinusoidal congestion, increased extramedullary hematopoiesis, hemosiderin-laden macrophages, infiltration of red pulp, and presence of proliferative capsular lesions, were present to varying degrees in all three species and exposure groups. Brain lesions (damage to the hindbrain, including bilateral cerebellar perivascular hemorrhage and malacia), was observed in both sexes of CD rats and in mice exposed to 125 ppm.

3.2.3. Chronic Toxicity

3.2.3.1. Human

Chronic toxic effects in humans usually result from industrial exposure to nitrobenzene vapor that is absorbed through the lungs or the skin (U.S. EPA, 1980). Recorded symptoms include cyanosis, methemoglobinemia, jaundice, anemia, sulfhemoglobinemia, presence of Heinz bodies in the erythrocytes, and dark colored urine (U.S. EPA, 1980).

3.2.3.2. Animal

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

Dorigan and Hushon (1976) reported chorionic and placental changes in pregnant women who used nitrobenzene in the production of a rubber catalyst. Also reported were menstrual disturbances after chronic exposure.

3.2.4.2. Animal

Tyl et al. (1987) exposed pregnant CD rats to 0, 1, 10, or 40 ppm nitrobenzene, 6 hours/day on gestational days 5 through 15. Exposure to nitrobenzene did not result in developmental effects at any exposure concentration. However, maternal toxicity was observed; absolute and relative spleen weights were increased at 10 and 40 ppm, and weight gain was reduced at 40 ppm, with full recovery after cessation of exposure.

Dodd et al. (1987) conducted a two-generation reproductive study by exposing CD rats to 1, 10, or 40 ppm nitrobenzene for 4 weeks. No compound-related effects on reproduction were observed at 1 or 10 ppm. In litters derived from rats exposed to 40 ppm, there was a decrease of fertility indices of the F₀ and F₁ generations, associated with atrophy of seminiferous tubules, spermatocyte degeneration, and reduced testicular and epididymal weights. Other reproductive parameters remained unaltered and maternal toxicity was not observed. Testicular atrophy, degeneration of seminiferous tubules, and a reduction or absence of mature sperm in the epididymis was also reported in F344 and CD rats exposed to 50 ppm nitrobenzene for 90 days (CIIT, 1984).

3.2.5. Reference Concentration

3.2.5.1. Subchronic

INHALATION RfC_s: 2E-2 mg/m³ (6E-4 mg/kg/day) (U.S. EPA, 1992b)

UNCERTAINTY FACTOR: 1000

NOAEL: None

LOAEL: 25 mg/m³

PRINCIPAL STUDY: CIIT, 1984

COMMENTS: The same study applies to both the subchronic and chronic RfC derivations and was used for the derivation of the oral RfD (see Sections 3.1.5. and 3.2.2.2). The uncertainty factor of 1000 includes two factors of 10 for intra- and interspecies variability and a factor of 10 for estimating an effect from a LOAEL rather than a NOAEL. The RfC was derived from methodology (dose conversions from mg/kg/day to mg/m³) that is not current with the interim inhalation methodology used by the RfD/RfC Work Group (U.S. EPA, 1992b).

3.2.5.2 Chronic

INHALATION RfC: 2E-3 mg/m³ (6E-4 mg/kg/day) (U.S. EPA, 1992b)

UNCERTAINTY FACTOR: 10,000

NOAEL: None

LOAEL: 25 mg/m³

PRINCIPAL STUDY: CIIT, 1984

COMMENTS: The uncertainty factor of 10,000 includes two factors of 10 for intra- and interspecies variability, a factor of 10 for estimating an effect from a LOAEL rather than a NOAEL, and a factor of 10 for extrapolation from subchronic to chronic exposure. The RfC was derived from methodology (dose conversions from mg/kg/day to mg/m³) that is not current with the interim inhalation methodology used by the RfD/RfC Work Group (U.S. EPA, 1992b). The RfC, not currently available in IRIS, is under review by an EPA work group (U.S. EPA, 1992a).

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Contact dermatitis has been reported in workers who used nitrobenzene as a preservative in cutting oils (Beauchamp et al. (1982).

3.3.1.2. Animal

U.S. EPA (1980) reported dermal and intraperitoneal LD₅₀ values of 2100 mg/kg and 640 mg/kg, respectively, for rats. According to Shimkin (1939), methemoglobinemia occurred in mice within 3 hours following dermal application of nitrobenzene (concentration not reported). Also observed was diffuse necrosis of the liver and slight swelling of glomeruli and tubular epithelium.

3.3.2. Subchronic Toxicity

3.3.2.1. Human

Information on the subacute toxicity of nitrobenzene by other routes of exposure in humans was not available.

3.3.2.2. Animal

Rabbits that received a subcutaneous dose of 840 mg nitrobenzene/kg/day for 3 months exhibited a decrease of erythrocytes and hemoglobin content soon after treatment started; the values increased during the three months of treatment but did not return to normal levels during this time period (Yamada, 1958).

3.3.3. Chronic Toxicity

Information on the chronic toxicity of nitrobenzene by other routes of exposure in humans or animals was not available.

3.3.4. Developmental and Reproductive Toxicity

3.3.4.1. Human

Information on the developmental or reproductive toxicity of nitrobenzene in humans by other routes of exposure was not available.

3.3.4.2. Animal

An abstract of a Russian study (Kazanina, 1968) reported delayed embryogenesis, disorders of organogenesis, and alterations in placentation in rats injected subcutaneously with 125 mg/kg/day of nitrobenzene during preimplantation and placentation periods.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organ(s)

1. Blood: Methemoglobinemia in humans resulting in reduced oxygen carrying capacity of the blood and cyanosis has been reported following accidental or intentional ingestion of nitrobenzene, however, chronic exposure data were not available. Anemia may occur as a result of the hemolytic effect of nitrobenzene. Single oral doses of nitrobenzene induced methemoglobinemia in rats.

2. Nervous system: Chronic exposure data were not available. In humans, headache, nausea, vertigo, confusion, unconsciousness, apnea, and coma were reported following acute oral exposure to nitrobenzene. Single oral doses produced pathologic changes of the brain in rats.

3. Liver: Chronic exposure data were not available. Liver enlargement and necrosis were reported in rats that received single oral doses of nitrobenzene.

4. Testis: Chronic exposure data were not available. Single oral doses of nitrobenzene produced testicular lesions and a transient decrease of sperm production in rats.

3.4.1.2. Other Target Organ(s)

Information concerning other target organs following oral exposure to nitrobenzene was not identified.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organ(s)

1. Blood: Nitrobenzene-induced methemoglobinemia resulting in reduced oxygen capacity of the blood and cyanosis has been reported following short-term, subchronic, and chronic exposure. Also reported in occupational exposures were anemia, sulfhemoglobinemia, and presence of Heinz bodies in erythrocytes. Methemoglobinemia occurred in rodents following subchronic exposure.

2. Nervous system: Occupational exposure to nitrobenzene has resulted in headache, nausea, vertigo, general weakness, numbness of legs, and hyperalgesia of hands and feet. Pathologic changes of the brain were reported in a subchronic animal study.

3. Liver: Evidence of liver toxicity (liver enlargement, jaundice, and altered serum chemistry) has been reported following occupational exposure. In animals, hepatic effects including liver enlargement, hepatocyte hyperplasia, hepatocyte necrosis, pigmentation of Kupffer cells, periportal basophilia, and enlarged nucleoli have been reported following subchronic exposure.

4. Testis: Testicular damage (atrophy and degeneration of spermatogenic epithelium) and a reduction of mature germ cells have been reported in animals following subchronic exposure.

5. Reproduction: Chorionic and placental changes as well as menstrual disturbances have been reported in women occupationally exposed to nitrobenzene.

6. Spleen: Increased spleen weights with hemosiderin deposits and extramedullary hematopoiesis have been reported in animals after subchronic exposure to nitrobenzene.

3.4.2.2. Other Target Organ(s)

1. Kidneys: Observed kidney effects following subchronic exposure to nitrobenzene included increased kidney weights, degeneration of the cortical tubules, and hyaline nephrosis.

2. Adrenal gland: Pathologic changes of the adrenal cortex were reported in mice following subchronic exposure to nitrobenzene.

3.4.3. Other Routes of Exposure

3.4.3.1. Primary Target Organs

1. Blood: Chronic exposure data were not available. Dermal applications of nitrobenzene produced methemoglobinemia in mice. Decreased erythrocyte counts and hemoglobin values were reported in rabbits subcutaneously injected with nitrobenzene.

2. Liver: Chronic exposure data were not available. Dermal applications of nitrobenzene caused necrosis of the liver in animals.

3. Reproduction: Chronic exposure data were not available. Subcutaneous administration of nitrobenzene caused delayed embryogenesis, alterations of normal placentation, and abnormalities in the fetus of rats.

4. Skin: Chronic exposure data were not available. Contact dermatitis has been reported following dermal occupational exposure to nitrobenzene.

3.4.3.2. Other Target Organs

Kidneys: Chronic exposure data were not available. Dermal applications of nitrobenzene produced a slight swelling of the glomeruli and tubular epithelium in animals.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

Information on the carcinogenicity of nitrobenzene in humans or animals following oral exposure was not available.

4.2. INHALATION EXPOSURES

Information on the carcinogenicity of nitrobenzene in humans or animals following inhalation exposure was not available.

4.3. OTHER ROUTES OF EXPOSURE

Information on the carcinogenicity of nitrobenzene in humans or animals following other routes of exposure was not available.

4.4. EPA WEIGHT-OF-EVIDENCE

Classification D -- Not classifiable as to human carcinogenicity (U.S. EPA, 1992a,b).

Basis -- Based on the lack of human or animal data.

4.5. CARCINOGENICITY SLOPE FACTORS

Data were insufficient to derive carcinogenicity slope factors.

5. REFERENCES

Albrecht, W. and H.-G. Neumann. 1985. Biomonitoring of aniline and nitrobenzene: Hemoglobin binding in rats and analysis of adducts. Arch. Toxicol. 57: 1-5. (Cited in ATSDR, 1990).

ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for Nitrobenzene. Prepared by Life Systems, Inc., under Subcontract to Clement Associates, Inc., for ATSDR, U.S. Public Health Service under Contract 205-88-0608. ATSDR/TP-90-19.

Beard, R.R. and J.T. Noe. 1981. Aromatic nitro and amino compounds. In: Clayton, G.D. and F. E. Clayton, Eds., Patty's Industrial Hygiene and Toxicology, 3rd. ed., Vol. 2A. John Wiley and Sons, New York, NY, pp. 2469-2434.

Beauchamp, R.O., Jr., R.D. Irons, D.E. Rickert, D.B. Couch and T.E. Hamm, Jr. 1982. A critical review of the literature on nitrobenzene toxicity. CRC Crit. Rev. Toxicol. 11: 33-84.

Bond, J.A., J.P. Chism, D.E. Rickert and J.A. Popp. 1981. Induction of hepatic and testicular lesions in Fischer-344 rats by single oral doses of nitrobenzene. Fund. Appl. Toxicol. 1: 389-394.

CIIT (Chemical Industry Institute of Toxicology). 1984. Ninety-day inhalation toxicity study of nitrobenzene in F-344 Rats, CD Rats, and B6C3F₁ Mice. Chemical Industry Institute of Toxicology, Research Triangle Park, NC. (Cited in U.S. EPA, 1980, 1992a,b; ATSDR, 1990)

Dodd, D.E., E.H. Fowler, W.M. Snellings, et al. 1987. Reproduction and fertility evaluations in CD rats following nitrobenzene inhalation. Fundam. Appl. Toxicol. 8: 493-505.

Dorigan, J. and J. Hushon. 1976. Air pollution assessment of nitrobenzene. U.S. Environmental Protection Agency. (Cited in U.S. EPA, 1980)

Dunlap, K.L. 1981. Nitrobenzene and nitrotoluenes. In: M. Grayson and D. Eckroth, Eds., Kirk-Othmer Encyclopedia of Chemical Technology, 3rd. ed., Vol. 15. John Wiley and Sons, New York, NY, pp. 916-925.

Goldstein, R.S., J.P. Chism, J.M. Sherill and T.E. Hamm, Jr. 1984. Influence of dietary pectin on intestinal microfloral metabolism and toxicity of nitrobenzene. Toxicol. Appl. Pharmacol. 75: 547-553.

Ikeda, M. and A. Kita. 1964. Excretion of p-nitrophenol and p-aminophenol in the urine of a patient exposed to nitrobenzene. Br. J. Ind. Med. 21: 210-213.

Kazanina, S.S. 1968. The morphology and histochemistry of hemochorial placentas of rats after nitrobenzene intoxication of the mother. Bull. Exp. Biol. Med. (USSR) 65: 93-96. [CA 69(17): 65819t] (Cited in U.S. EPA, 1985)

Levin, A.A., T. Bosakowski, L.L. Earle and B.E. Butterworth. 1988. The reversibility of nitrobenzene-induced testicular toxicity: Continuous monitoring of sperm output from vasocystotomized rats. Toxicology 53: 219-230.

Medinsky, M.A. and R.D. Irons. 1985. Sex, strain, and species differences in the response to nitrobenzene vapors. In: Rickert, D.E., Ed., Chemical Industry Institute of Toxicology Series. Toxicity of nitroaromatic compounds. Hemisphere Publishing Corporation, New York, NY, pp. 35-51. Morgan, K.T., E.A. Gross, O. Lyght, et al. 1985. Morphologic and biochemical studies of a nitrobenzene-induced encephalopathy in rats. Neurotoxicology 6: 105-116. (Cited in ATSDR, 1990)

OSHA (Occupational Safety and Health Administration). 1978. Occupational Health Guideline for Nitrobenzene. U.S. Department of Health and Human Services. (Cited in U.S. EPA, 1985)

Parke, D.V. 1956. Studies in detoxication: The metabolism of [¹⁴C]nitrobenzene in the rabbit and guinea pig. Biochem. J. 62: 339-346.

Piotrowski, J. 1967. Further investigations on the evaluation of exposure to nitrobenzene. Br. J. Ind. Med. 24: 60-67. (Cited in U.S. EPA, 1980)

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Rickert, D.E., J.A. Bond, R.M. Long and J.P. Chism. 1983. Metabolism and excretion of nitrobenzene by rats and mice. Toxicol. Appl. Pharmacol. 67: 206-214.

Salmova, J., J. Piotrowski and U. Neuhorn. 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. (Cited in ATSDR, 1990)

Shimkin, M.B. 1939. Acute toxicity of mononitrobenzene in mice. Proc. Soc. Exp. Biol. Med. 42: 844-846. (Cited in ATSDR, 1990)

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