Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 98-95-3 Toxicity Effects

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Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • Nitrobenzene
  • OIL OF MIRBANE

Human Toxicity Excerpts

  • IN 2 INDUSTRIAL CASES THERE WAS SLIGHT ANEMIA ... CONSIDERED TO BE OF HEMOLYTIC TYPE, WITH MARKED IRREGULARITY IN SHAPE AND SIZE OF RED CELLS ... & SOMETIMES AN INTENSE POLYNUCLEOSIS. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 301]**PEER REVIEWED**
  • ... 21 INFANTS HAVE BEEN AFFECTED BY ... SKIN APPLICATION OF 'BITTER ALMOND OIL'; & ... A MIXTURE OF 2-10% NITROBENZENE AND ... COTTON SEED OIL. IN SIX CASES THE INFANTS WERE IN ... SHOCK, & SEMICOMATOSE WITH COLD EXTREMITIES AND RAPID PULSE, & OF THESE, TWO ENDED FATALLY, TERMINAL BRONCHO-PNEUMONIA HAVING DEVELOPED; THE REMAINING CASES RECOVERED, WITH ... /MINIMUM OR NO/ RESIDUAL CYANOSIS. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 302]**PEER REVIEWED**
  • NITROBENZENE & OTHER NITRO CMPD GENERATE METHEMOGLOBIN MORE SLOWLY /THAN ANILINE, DINITROBENZENE OR NITROANILINE/, BUT CYANOSIS IS MORE PERSISTANT. ONSET OF CYANOSIS IS OFTEN FIRST NOTED AT LIPS. ... SYMPTOMS MAY BE ABSENT, ALTHOUGH, EUPHORIA, FLUSHED FACE AND HEADACHE ARE COMMON. CYANOSIS IS USUALLY DETECTABLE WHEN PROPORTION OF CONVERTED HEMOGLOBIN APPROXIMATES 15%. METHEMOGLOBIN LEVELS OF 40% MAY EXIST WITHOUT SYMPTOMS OTHER THAN A SENSE OF WELL-BEING. AT HIGHER LEVELS, ... WEAKNESS, ATAXIA, AND LIGHTHEADEDNESS OCCUR. WITH INCR CONCN OF METHEMOGLOBIN, DYSPNEA, TACHYCARDIA AND ALARMING CYANOSIS ARE NOTED. [Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974., p. 306]**PEER REVIEWED**
  • REPEATED EXPOSURE MAY BE FOLLOWED BY LIVER IMPAIRMENT UP TO YELLOW ATROPHY, HEMOLYTIC ICTERUS AND ANEMIA OF VARYING DEGREES, WITH THE PRESENCE OF HEINZ BODIES IN THE RED CELLS. [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 1448]**PEER REVIEWED**
  • A RARE CASE OF ACCIDENTAL POISONING BY NITROBENZENE IS DESCRIBED. THIS POISONING WAS CHARACTERIZED BY SEVERE CLINICAL PICTURE, PROTRACTED COURSE WITH RELAPSES & OCCURRENCE OF HEMATOLOGICAL & NEUROLOGICAL COMPLICATIONS. [LARENG L ET AL; EUR J TOXICOL ENVIRON HYG 7 (1): 12-6 (1974)]**PEER REVIEWED**
  • The most reliable established ocular effects are secondary to discoloration of the blood from methemoglobinemia, & consist of brown discoloration of the vessels of the fundus & the conjunctiva. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 663]**PEER REVIEWED**
  • TOXIC BY ALL ROUTES INCLUDING SKIN ABSORPTION. ... SYSTEMIC EFFECTS MAY BE DELAYED A FEW HOURS. POISONING CLOSELY RESEMBLES ANILINE. MEAN LETHAL DOSE BY MOUTH PROBABLY LIES BETWEEN 1 AND 5 G. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-214]**PEER REVIEWED**
  • Methemoglobinemia, with cyanosis, headache, dyspnea, weakness and ultimately coma and death, is the main characteristic of acute nitrobenzene poisoning. Nitrobenzene may also induce hemolysis, which is, however, usually mild. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 395 (1996)]**PEER REVIEWED**
  • Methemoglobinemia was reported in three week old twins and in a 12 month old girl exposed to nitrobenzene from insect-exterminator sprays for several hours. Moreover, a woman who worked under bad hygienic conditions in a cable insulation factory for three months developed serious poisoning. Her methemoglobin level in the blood was 29.5% (37 g/l) up to 36 hours after the end of exposure. (Lethal at about 80%; 'normally' about 1% or 10 g/l; normal' half-life 15-20 hours.) She also developed hemolysis, as well as slight toxic hepatitis and peripheral neuropathy. It was discovered that she had a hereditary deficiency of NADH-methemoglobin reductase, which may have made her particularly sensitive, and which also probably explained the high methemoglobin level a long time after exposure. Development of toxic hepatitis after acute episodes of methemoglobinemia has been reported repeatedly. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 395 (1996)]**PEER REVIEWED**
  • In cultures of primary human hepatocytes in vitro, no unscheduled DNA synthesis was observed. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 398 (1996)]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • ... IN WHITE RATS POISONED BY SC INJECTION OF 0.64 G/KG NITROBENZENE ... CATALASE ACTIVITY FELL CONSISTENTLY DURING A PERIOD UP TO 96 HR AFTER INITIAL DOSE TO 86.6% OF INITIAL LEVEL. ... PEROXIDASE ACTIVITY ALSO DIMINISHED. ... [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 299]**PEER REVIEWED**
  • ... IN SLOW POISONING FROM CONTINUED LOW EXPOSURES THERE MAY BE INCREASE IN NUMBER OF ERYTHROCYTES; URINE BECOMES BROWN OR DARK RED, CONTAINS BILE PIGMENTS, METHEMOGLOBIN OR HEMOGLOBIN; THERE MAY ... BE ALBUMINURIA AND POSITIVE FEHLING'S REACTION /IN RABBITS/. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 300]**PEER REVIEWED**
  • OUTSTANDING TOXIC EFFECT ... IS ... FORMATION OF METHEMOGLOBIN, WITH RISK OF DEATH FROM RESPIRATORY FAILURE. ... [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 300]**PEER REVIEWED**
  • RESTLESSNESS, CYANOSIS OF SKIN, MUCOUS MEMBRANES; ONSET OF ... /CNS DEPRESSION/ ACCOMPANIED BY LOSS OF WEIGHT AND MARKED CYANOSIS /IN RABBITS/. METHEMOGLOBINEMIA ... /% DEPENDENT ON DOSE, IS/ GREATEST BY IP INJECTION. HEINZ BODIES /DEVELOPED/ IN 40 TO 60% OF RED CELLS. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 301]**PEER REVIEWED**
  • IN RABBITS, GIVEN SC INJECTIONS OF 0.75 G ... HEMATOCRIT AND HEMOGLOBIN LEVELS SHOWED MARKED DECREASE ... AND TENDENCY TO SPHEROCYTOSIS; HEINZ BODIES WERE PRESENT IN ... 17 ANIMALS OUT OF 27. ... CHANGES WERE ACCOMPANIED BY ... RETICULOCYTOSIS ... [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 301]**PEER REVIEWED**
  • IN RABBITS AFTER SC ADMIN: BONE MARROW SHOWED CHANGES RANGING FROM HYPERPLASIA TO HYPOPLASIA AND EVEN APLASIA, WITH AN INCREASE IN MACROBLASTS AND A DECREASE IN RETICULOCYTES AND MEGAKARYOCYTES. HYPEREMIA OF ABDOMINAL CAVITY & ALL ORGANS /WERE OBSERVED/. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 301]**PEER REVIEWED**
  • METHEMOGLOBINENIA WAS ... MAXIMUM (4%) ... 4 HR AFTER INITIAL DOSAGE FALLING GRADUALLY THEREAFTER ... SULFHEMOGLOBIN ROSE ... TO 14%. LEUCOPENIA WAS PRESENT IN SOME ANIMALS ... IN OTHERS LEUCOCYTOSIS ... WITH NEUTROPHILIA, IN MAJORITY THROMBOCYTOPENIA /DEVELOPED IN RABBITS GIVEN 0.75 G SUBCUTANEOUSLY/ [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 301]**PEER REVIEWED**
  • CHANGES IN RABBIT ORGANS WERE: LIVER: MACROSCOPIC APPEARANCE OF NUTMEG SIZE NODULES; MICROSCOPICALLY FATTY INFILTRATION; KIDNEYS: FATTY INFILTRATION; LUNGS: TENDENCY TO EXTRAVASATION OF BLOOD, VARYING FROM MINUTE PETECHIAE TO LARGER ECCHYMOSES OR EVEN LOBULAR HEMORRHAGE IN SEVERE POISONING. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 302]**PEER REVIEWED**
  • ... ONE RABBIT WHICH DIED AFTER RECEIVING ORALLY 200 MG/KG 30 HR LATER HAD LARGE DEPOSITS OF FAT IN TISSUES ... THIS WAS ALSO PRESENT IN GASTROINTESTINAL TRACT. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 302]**PEER REVIEWED**
  • NITROBENZENE WAS: ADMIN ... IN DOSES OF 125 MG/KG/DAY SC TO PREGNANT RATS DURING PREIMPLANTATION & PLACENTATION. DELAY OF EMBRYOGENESIS, ALTERATION OF NORMAL PLACENTATION, AND ABNORMALITIES IN FETUS WERE OBSERVED. GROSS MORPHOLOGIC DEFECTS WERE SEEN IN 4 OF THE 30 FETUSES EXAMINED. [National Research Council. Drinking Water & Health, Volume 4. Washington, DC: National Academy Press, 1981., p. 227]**PEER REVIEWED**
  • TESTS FOR MUTAGENIC ACTIVITY OF NITROBENZENE WERE DONE WITH RAT-LIVER S9 OR MOUSE-LIVER S9 FRACTIONS IN SALMONELLA TYPHIMURIUM STRAINS TA92, TA1535, TA100, TA1537, TA94 AND TA98. THERE WAS NO MUTAGENIC EFFECT OBSERVED. [MIYATA R ET AL; BULL NATL INST HYG SCI (TOKYO) 0 (99): 60-5 (1981)]**PEER REVIEWED**
  • ACUTE INTOXICATION OF SC INJECTION TO YOUNG RATS 6 MO OLD AND MATURE RATS 18 MO OLD PRODUCED A HIGH MORTALITY IN THE OLDER RATS AND NONE IN THE YOUNGER ANIMALS. DEATH IN OLDER RATS WAS MAINLY DUE TO ACUTE RENAL FAILURE. [VRABIESCU N SA ET AL; AN UNIV BUCUR BIOL 30 (0): 117 (1982)]**PEER REVIEWED**
  • MALE RATS WERE GIVEN SINGLE ORAL DOSES OF NITROBENZENE (50-450 MG/KG) AND AT THE TIME OF SACRIFICE, 25 TISSUES WERE REMOVED AND EXAMINED. HEPATIC CENTRILOBULAR NECROSIS APPEARED IN RATS GIVEN VARIOUS DOSES. TESTICULAR LESIONS WERE CONFINED TO SEMINIFEROUS TUBULES AND CONSISTED OF NECROSIS OF THE PRIMARY AND SECONDARY SPERMATOCYTES WITH APPEARANCE OF MULTINUCLEATED GIANT CELLS BETWEEN 1 & 4 DAYS AFTER ADMIN OF 300 MG/KG. [BOND JA ET AL; FUNDAM APPL TOXICOL 1 (5): 389-94 (1981)]**PEER REVIEWED**
  • THE REFRACTILE HEINZ BODIES ARE OFTEN FOUND AT THE PERIPHERY OF ERYTHROCYTES, AND SOMETIMES WITHIN, AS A RESULT OF POISONING BY ... NITROBENZENE ... . [Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972., p. 232]**PEER REVIEWED**
  • Toxicity threshold /as determined by/ (cell multiplication inhibition test): bacteria (Pseudomonas putida) 7 mg/l; algae (Microcystis aeruginosa) 1.9 mg/l; green algae (Scenedesmus quadricauda) 33 mg/l; protozoa (Entosiphon sulcatum) & (Uronema parduczi) 1.9 mg/l & 15 mg/l, respectively. [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 911]**PEER REVIEWED**
  • Pregnant CD (Sprague-Dawley) rats were exposed to nitrobenzene vapor at 0, 1, 10, and 40 ppm (mean analytical values of 0.0, 1.06, 9.8, and 39.4 ppm, respectively) on gestational days 6 through 15 for 6 hr/day. At sacrifice on gestation days 21, fetuses were evaluated for external, visceral, and skeletal malformations and variations. Maternal toxicity was observed: weight gain was reduced during exposure (gestation days 6-9 and 6-15) to 40 ppm, with full recovery by gestation days 21, and absolute and relative spleen weights were increased at 10 and 40 ppm. There was no effect of treatment on maternal liver, kidney, or gravid uterine weights, on pre- or postimplantation loss including resorptions or dead fetuses, on sex ratio of live fetuses, or on fetal body weights (male, female, or total) per litter. There were also no treatment-related effects on the incidence of fetal malformations or variations. In summary, during organogenesis in CD rats, there was no developmental toxicity (including teratogenicity) associated with exposure to nitrobenzene concentrations that produced some maternal toxicity (10 and 40 ppm) or that produced no observable maternal toxicity (1 ppm). [Tyl RW et al; Fund Appl Toxicol 8 (4): 482-92 (1987)]**PEER REVIEWED**
  • A two-generation reproduction study was performed by exposure of Sprague-Dawley CD rats to concentrations of 0, 1, 10, or 40 ppm of nitrobenzene (NB) vapor. No NB related effects on reproduction were observed at 1 or 10 ppm. At 40 ppm, a decrease in the fertility index of the F(0) and F(1) generations occurred, which was associated with alterations in the male reproductive organs. Specifically, weights of testes and epididymides were reduced and seminiferous tubule atrophy, spermatocyte degeneration, and the presence of giant syncytial spermatocytes were observed. The only significant finding in the litters derived from rats exposed to 40 ppm was an approximate 12% decrease in the mean body weight of F(1) pups on postnatal day 21. Survival indices were unaltered. To examine the reversibility of this selective effect on male gonads, the F(1) males from the 40 ppm group were allowed a 9 week nonexposure period and mated to naive females. An almost five-fold increase in the fertility index was observed, indicating at least partial functional reversibility upon removal from NB exposure. The numbers of giant syncytial spermatocytes and degenerated spermatocytes were greatly reduced. The results of this study support the selection of 10 ppm of nitrobenzene as the no-observable-effect level for reproduction and fertility effects in rats. [Dodd DE et al; Fund Appl Toxicol 8 (4): 493-505 (1987)]**PEER REVIEWED**
  • The neurotoxic effects of nitrobenzene were studied morphologically and biochemically in rats. Male F344 rats received a single oral dose of 550 mg/kg radiolabeled nitrobenzene. ... Nitrobenzene induced petechial hemorrhages in the brain stem and cerebellum and malacia in the cerebellum and cerebellar peduncles within 48 hr after administration. ... Analysis of the distribution of radiolabeled nitrobenzene and HPLC analysis indicated that a very small proportion of the administered dose passed the blood brain barrier. In the brain it was present as the parent compound, accumulated in higher concentrations in gray matter than white matter, but there was no evidence of increased accumulation of nitrobenzene in the location in which malacia occurred. [Morgan KT et al; Neurotox 6 (1): 105-116 (1985)]**PEER REVIEWED**
  • NITROBENZENE INHIBITED THE OXIDATION OF TYPE II SUBSTRATES (ANILINE AND ZOXAZOLAMINE) BY CYTOCHROME P450 DEPENDENT ENZYMES IN LIVER MICROSOMES, BUT DID NOT AFFECT THE OXIDATIVE METAB OF TYPE I CMPD (HEXOBARBITAL AND AMINOPYRENE). [STERNSON LA, GAMMANS RE; J MED CHEM 19 (1): 174-7 (1976)]**PEER REVIEWED**
  • Nineteen nitro compounds, including nitrobenzene, were evaluated for mutagenicity, using a modification of the standard Salmonella typhimurium mutagenicity assay. A preincubation protocol was used which incorporated flavin mononucleotide to facilitate nitro reduction. Nitrobenzene was found to elicit a negative response in the modified preincubation assay with flavin mononucleotide despite extensive nitro reduction that occurred in the preincubation with flavin mononucleotide. [Dellarco VL, Prival MJ; Environ Mol Mutagen 13 (2): 116-27 (1989)]**PEER REVIEWED**
  • 21 day Daphnia reproduction tests were conducted in line with the provisional procedure proposed by the Federal Environmental Agency (Umweltbundesamt, FRG), as of Jan 1, 1984. Groups of 20, 24 hr old Daphnia magna were exposed to 1.6 to 200 mg/l nitrobenzene in semi-static test vessels. Parent animals in the test and control vessels had to be pipetted 3 times/wk in freshly prepared test and control media at the corresponding concn level. The no observed effect concn (NOEC) was determined from the parameters of mortality of the parent animals, reproduction rate and appearance of the first offspring during the test period. In preliminary acute Daphnia tests, the 24 hr EC50 was 60 mg/l for nitrobenzene, the EC0 was 19 mg/l. The nominal 21 day no observed effect concn was 13 mg/l, with the most sensitive parameter being the reproductive rate. [Kuhn R et al; Water Res 23 (4): 501-10 (1989)]**PEER REVIEWED**
  • Purified Sertoli cell cultures were used to determine whether the effects of nitrobenzene in cocultures are the result of a direct effect on the Sertoli cell. Testicular cell cultures were prepared from Alpk:Ap-rats. The exposure of Sertoli cells to nitrobenzene resulted in Sertoli cell vacuolation, the exfoliation of germ cells, and dose dependent increases in lactate and pyruvate secretion in the presence or absence of germ cells. Following exposure to concentrations greater than 0.0005 molar nitrobenzene resulted in an increase in the in-vitro secretion of lactate and pyruvate by Sertoli cells in a dose dependent manner, both in the presence and absence of follicle stimulating hormone (FSH) and in the presence and absence of germ cells. Following exposure of cocultures or Sertoli cell cultures to nitrobenzene, basal inhibin secretion exhibited a reproducible alteration in response in a biphasic pattern and was taken by the authors as a confirmation of germ cell modulation of Sertoli cell inhibin secretion. The finding that these effects of nitrobenzene on inhibin secretion were not evident in follicle stimulating hormone stimulated cultures does not support the use of inhibin as a specific indicator of the toxic actions of nitrobenzene on the Sertoli cells. The authors state this to be the first study to evaluate the potential of inhibin secretion by Sertoli cells as a marker of toxicant action. [Allenby G et al; Fundam Appl Toxicol 14 (2): 364-75 (1990)]**PEER REVIEWED**
  • The relative resistance of rodents (mice, rats, rabbits) to methemoglobin formation must be ascribed in part to greater methemoglobin reductase activity in red cells of these species than in the red cells of dogs /and/ cats. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-32]**PEER REVIEWED**
  • Groups of 70 male and 70 female B6C3F1 mice, 63 days of age, were exposed by inhalation to air containing target concentrations of 0, 5, 25 or 50 ppm (0, 25, 125 or 250 mg/cu m) nitrobenzene (> 99.8% pure) for 6 hours per day on five days per week for 24 months. Body weight of high-dose male mice were approximately 5-8% lower than those of controls throughout the study. Probability of survival at 24 months was 60% for males and 45% for females and was not affected by exposure to nitrobenzene, except that mid-dose females had better survival than controls (70%). The incidence of alveolar-bronchiolar neoplasms was increased in treated males (alveolar-bronchiolar adenomas and carcinomas: 9/68 in controls, 21/67 at the low dose, 21/65 at the mid dose and 23/66 at the high dose; p < 0.05, Cochran-Armitage trend test). The incidence of alveolar-bronchiolar hyperplasia was also increased in mid- and high-dose males and in mid-dose females. The incidence of thyroid follicular-cell adenomas was increased in treated males (0/65 in controls, 4/65 at the low dose, 1/65 at the mid dose, 7/64 at the high dose; p < 0.05 trend test) and that of thyroid follicular-cell hyperplasia was increased in mid- and high-dose males. The incidence of hepatocellular adenomas was increased in treated females (6/51 in controls, 5/61 at the low dose, 5/64 at the mid dose, 13/62 at the high dose; p < 0.05 trend test), although the incidence of hepatocellular adenomas and carcinomas combined was not increased (7/51, 7/61, 7/64, 14/62, respectively). Mammary gland adenocarcinomas were found in 5/60 (p < 0.05) high-dose females compared to 0/48 controls. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 390 (1996)]**PEER REVIEWED**
  • No standard reverse mutation test with Salmonella typhimurium showed mutagenic activity of nitrobenzene. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 398 (1996)]**PEER REVIEWED**
  • In Fischer 344 rats, no significant increase in sister chromatid exchange frequency or chromosomal aberrations was found in peripheral blood lymphocytes. No significant increase in sister chromatid exchange was observed in the isolated splenic lymphocytes after in vivo exposure to up to 50 ppm nitrobenzene for 6 hours per day for 21 days during a 29 day period; the toxicity of the dosing regimen was demonstrated by cell cycle inhibition and mitotic depression in the lymphocytes. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 398 (1996)]**PEER REVIEWED**
  • Groups of 70 male and 70 female Fischer 344 rats, 62 days of age, were exposed by inhalation to air 125 mg/cu m nitrobenzene (> 99.8% pure) for 6 hr per day on five days per week for 24 months. Groups of 10 rats per sex and per group were killed for an interim evaluation at 15 months. Body weights of high-dose males were slightly lower than those of controls during the study. Probability of survival at 24 months was 75% for males and 80% for females and was not affected by exposure to nitrobenzene. Increased incidences were noted for hepatic eosinophilic foci in mid- and high-dose males and in high-dose females, and for hepatocellular neoplasms in both treated males (adenomas and carcinomas: l/69 in controls, 4/69 at the low dose, 5/70 at the mid dose, 16/70 at the high dose; p < 0.05, Cochran-Armitage trend test) and treated females (0/70 in controls, 2/66 at the low dose, 0/66 at the mid dose, 4/70 at the high dose; p < 0.05 trend test). Thyroid follicular-cell hyperplasia occurred with a positive exposure-related trend in males and the incidences of thyroid follicular-cell adenomas and adenocarcinomas were increased in exposed males (2/69 in controls, 1/69 at the low dose, 5/70 at the mid dose, 8/70 at the high dose; p < 0.05 trend test). The incidence of endometrial stromal polyps was increased in exposed females (11/69 in controls, 17/65 at the low dose, 15/65 at the mid dose, 25/69 at the high dose; p < 0.05); that of renal tubular-cell adenomas was increased in exposed males (0/69 in controls, 0/68 at the low dose, 0/70 at the mid dose, 5/70 at the high dose; p < 0.05, Fisher exact test) and one renal tubular-cell carcinoma occurred in another high-dose male. There was an increased severity of nephropathy in exposed males and females. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 390-1 (1996)]**PEER REVIEWED**
  • Groups of 70 male Charles River CD rats, 62 days of age, were exposed by inhalation to air containing target concentrations of 0, 1, 5 or 25 ppm (O, 5, 25 or 125 mg/cu m) nitrobenzene (> 99.8% pure) for 6 hr/day on five days per week for 24 months. Groups of 10 rats per sex and per group were killed for an interim evaluation at 15 months. Body weights and survival were not affected by exposure to nitrobenzene during the study. The incidence of hepatocellular neoplasms was increased in treated groups (adenomas and carcinomas: 2/63 in controls, 1/67 at the low dose, 4/70 at the mid dose, 9/65 at the high dose; p < 0.05, Cochran-Armatage trend test). The incidence of spongiosis hepatis was increased in high-dose rats, and that of centrilobular hepatocytomegaly was increased in mid- and high-dose groups. The incidence of Kupffer-cell pigmentation was increased in all treated groups. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 391 (1996)]**PEER REVIEWED**
  • Single acute exposures of male Fischer 344 rats to > 200 mg/kg bw nitrobenzene resulted in significantly elevated (> 20%) methemoglobin, while higher single oral exposures (550 mg/kg bw) resulted in encephalomalacia and hemorrhage of the brainstem and cerebellum in male Fischer 344 rats. Necrosis of seminiferous tubules and hepatocellular nucleolar enlargement in male Fischer 344 rats following single oral exposure have also been reported. The latter liver lesions were observed at doses as low as 110 mg/kg bw whereas the testicular lesions occurred at doses > 300 mg/kg bw. Acute exposure by injection of nitrobenzene has been reported to cause methemoglobinemia, neurotoxicity and death in a variety of animal species. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 396 (1996)]**PEER REVIEWED**
  • Moderate bronchiolar hyperplasia was observed in male and female mice exposed to 125 ppm nitrobenzene; mild hyperplasia was present in animals examined three days after the last exposure to 35 ppm. Perivascular oedema and vascular congestion were found in lungs taken from dead or moribund Sprague-Dawley rats after three to five days of exposure to 125 ppm nitrobenzene. No histopathology was found in the lungs from Fischer 344 rats exposed to 125 ppm nitrobenzene. Sprague-Dawley rats also exhibited moderate-to-severe hydropic degeneration of cortical tubular cells. Minimal degenerative changes were noted in the kidneys of some mice. The only renal lesion in Fischer 344 rats was a moderate to severe hyaline nephrosis in males that regressed in animals allowed to recover for 14 days. Splenic lesions were evident in all rats and mice in all groups exposed to nitrobenzene. Lesions consisted of increased extramedullary hematopoiesis and acute congestion. Thus for nitrobenzene, the most sensitive organ after 14 day inhalation exposure was the spleen. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 396-7 (1996)]**PEER REVIEWED**
  • Methemoglobinemia and anemia were observed in both species at > or = 25 ppm (100 mg/ml) exposure concentrations. Other effects included lesions of the nose, liver, testis and lung. In mice, degeneration and loss of olfactory epithelium were observed at > 5 ppm; the incidence of pigment deposition in olfactory epithelium was increased in mice and rats. Cytomegaly of centrilobular hepatocytes was induced in mice and rats, particularly males, at > 5 ppm; in male mice multinucleation of hepatocytes was also induced. An increased incidence of testicular atrophy and epididymal hypospermia was observed in male CD (but not Fischer 344) rats at 25 ppm. In mice, an unusual pulmonary lesion, alveolar bronchialization, was frequently induced by exposure to > or = 5 ppm nitrobenzene. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 397 (1996)]**PEER REVIEWED**
  • Groups of 26 pregnant Sprague-Dawley rats were exposed by inhalation to 0, l, 10 and 40 ppm (5, 50 and 200 mg/cu m) nitrobenzene vapor for 6 hour per day on gestational days 6-15. Maternal weight gain was reduced during exposure to 40 ppm, with full recovery by gestational day 21. Absolute and relative spleen weights were increased at 10 and 40 ppm. There was no effect of treatment on resorptions or dead fetuses, on the sex ratio of live fetuses or on fetal body weights per litter. No treatment-related effect on the incidence of fetal malformations or variations was observed. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 397 (1996)]**PEER REVIEWED**
  • Groups of 30 male and 30 female rats were exposed to concentrations of 0, 1, 10 or 40 ppm nitrobenzene vapor for 6 hours per day on five days per week for 10 weeks. Fl rats were produced from the F0 rats and at least one male and one female were picked randomly from each litter to form a group size of 30 per sex. F1 rats remained in the same exposure group as their F0 parents. Additional female rats were used for a second mating with the recovery group high-dose and control F1 males. No effect on reproduction was observed at doses of 1 or 10 ppm nitrobenzene. At 40 ppm, a decrease in the fertility index of the F0 and Fl generations occurred, and this was associated with reduced testicular and epididymal weight, atrophy of the seminiferous tubules, spermatocytic degeneration and the presence of giant syncytial spermatocytes. The only significant observation in the litter derived from rats exposed to 40 ppm was an approximate 12% decrease in the mean body weights of Fl rats on postnatal day 21. Survival indices were unaltered. In the F1 rats, males of the high-dose and control groups were allowed a nine week nonexposure recovery period. At the end of this period, the Fl males were mated with virgin females, which had never been exposed to nitrobenzene. An almost five-fold increase in the fertility index was observed, indicating at least partial functional reversibility upon removal from nitrobenzene exposure. In addition, the numbers of giant syncytial spermatocytes and degenerated spermatocytes were greatly reduced; testicular seminiferous tubule atrophy persisted. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 397 (1996)]**PEER REVIEWED**
  • Male and female Fischer 344 rats, Sprague-Dawley (CD) rats and B6C3F1 mice (910 weeks old) were exposed by inhalation to 10, 35 or 125 ppm (50, 175 or 625 mg/cu m) nitrobenzene vapors for 6 hours per day on five days per week for up to two weeks. Animals were sacrificed at three or 14 days following the last exposure. Early morbidity among male and female mice exposed to 125 ppm necessitated euthanasia between two and four days of exposure. Some male and female Sprague-Dawley rats were found dead after the fourth day of exposure, but the remaining animals in the group exhibited rapid shallow breathing, wheezing and an orange discoloration around the urogenital orifice. In contrast, Fischer 344 rats exposed to 125 ppm exhibited no adverse clinical signs over the entire two-week period. The presumptive cause of death of the Sprague-Dawley rats exposed to 125 ppm nitrobenzene was perivascular hemorrhage in the cerebellar peduncle. Species and sex related differences in liver pathology were also observed in animals exposed to 125 ppm nitrobenzene. Male mice exhibited centrilobular necrosis, superimposed on severe central lobular hydropic degeneration. In contrast, no necrosis was observed in livers from female mice at the same concentration. Liver pathology observed in Sprague-Dawley rats was similar but not as severe as that described for the mice. Livers from Sprague-Dawley rats that died early exhibited centrilobular hydropic degeneration and basophilic hepatocytic degeneration in periportal areas. No significant histological findings was observed in the livers from male and female Fischer 344 rats. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 396 (1996)]**PEER REVIEWED**
  • Groups of 22 pregnant rabbits were exposed by inhalation to 0, 9.9, 41 and 101 ppm (50, 207 and 509 mg/cu m) nitrobenzene for 6 hours per day on gestational days 7-19. The dams were sacrificed on gestational day 30 and the fetuses were evaluated for external, visceral and skeletal malformations. No adverse effect was associated with the lowest dose. At the two higher doses (41 and 101 ppm), liver weights were slightly higher and methemoglobin levels were significantly increased compared with controls. At the highest dose, a slight increase in fetal resorption was observed. No teratogenic effect was apparent at any of the exposure levels investigated. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 398 (1996)]**PEER REVIEWED**
  • Nitrobenzene is known as a spermatogenesis inhibitor in mature rats. ... /The authors/ examined differences of treat-start ages and durations. Male SD rats (5 rats per group) at 6, 8, 10 or 40-week old were treated with nitrobenzene at 50 mg/kg for 2 or 4 weeks. Control animals were treated with a vehicle (sesame oil). All rats were examined for testis/epididymis weights, morphology, activity, and number of sperms obtained from the cauda epididymidis. The testis was examined microscopically. Rats treated from 6-week old showed depressed sperm activity. Eight-week old rats showed depressed sperm activity and testis weight, and 10-week old rats showed depressed sperm activity, a smaller number of sperm and testis weights. Sperm activity appeared unchanged between different durations of treatment, but number of sperms and testis weight decreased in the longer duration of treatment. Microscopical changes in 6-week old rats were weaker than in 8 or 10-week old rats. The results suggest that effects on sperm and testis treated with nitrobenzene might change depending on treat-start age and duration, and that they are related with the developmental stage of testis and degree of spermatogenetic disorder. Therefore, treat-start age and duration are important when ... /estimating/ the testicular toxicity of a chemical. [Koida M et al; Teratology 52 (4): 39B (1995)]**PEER REVIEWED**
  • The effect of dietary pectin on nitrobenzene induced methemoglobinemia were investigated. Male Fischer 344 rats were fed a purified diet containing 5 percent cellulose (diet 1), diet 1 with a 5 percent pectin replacing the cellulose (diet 2), or a cereal based diet containing 8.4 percent cellulose (diet 3) for 28 days. Rats were then administered 50 to 600 milligrams per kilogram nitrobenzene by mouth. Methemoglobin concentrations were determined from 1 to 24 hours later. The total number of anaerobic cecal bacteria was examined. In-vitro cecal metabolism of radiolabeled nitrobenzene was also measured, and metabolism products were examined using high pressure liquid chromatography. Administration of 50 to 150 mg/kg nitrobenzene did not result in significant methemoglobinemia in any group. Treatment with 200 mg/kg nitrobenzene produced 40 percent methemoglobinemia in rats fed diet 3 at 4 to 8 hours, compared with 30 percent for the diet 2 group, and 5 percent for the diet 1 group. Similar but dose dependent results occurred at 400 and 600 mg/kg. At 600 mg/kg nitrobenzene, the highest methemoglobin concentration, 64 percent, was seen in diet 3 animals. Those fed diet 1 had 20 percent methemoglobinemia, and those fed diet 2 had an intermediate methemoglobin concentration of 44 percent. The total number of viable cecal anaerobes was elevated 2 to 2.5 times in rats fed diets 2 or 3, compared with those fed diet 1. In-vitro, cecal metabolism of nitrobenzene was greatest in animals fed diet 3, least in those fed diet 1, and intermediate in those fed diet 2. Metabolites of nitrobenzene produced by cecal contents from animals fed diets 2 and 3 included aniline, nitrosobenzene, and azoxybenzene; only aniline was detected in animals fed diet 1. The authors conclude that nitrobenzene induced methemoglobinemia is significantly different in animals fed purified or cereal based diets. These diet related differences are probably related to dietary composition of fermentable carbohydrates and are mediated by dietary alterations in intestinal microflora. [Goldstein RS et al; Toxicol Appl Pharmacology 75 (3): 547-553 (1984)]**PEER REVIEWED**
  • Quantitative differences in the toxicity of 1,2-dichloroethane , nitrobenzene, and carbon disulfide on cultured human epidermoid carcinoma and African-green-monkey kidney cells were estimated. Toxicants were dissolved in dimethyl sulfoxide and diluted in Eagle's minimum essential medium immediately before final use. Cell counts indicated that cell viability of both cell lines was decreased with increasing concentrations of these toxicants, indicating dose dependent cell viability. Nitrobenzene was more toxic than carbon disulfide and 1,2-dichloroethane to both cell lines. African-green-monkey kidney cells were much more sensitive than human epidermoid carcinoma cells to all three chemicals. Concentrations reducing viability by 50 percent were 1500, 42 and 160 micrograms/milliliter for 1,2-dichloroethane, nitrobenzene and carbon disulfide, respectively, in human epidermoid carcinoma cells. These concentrations were 1000, 30 and 90 micrograms/milliliter for 1,2-dichloroethane, nitrobenzene and carbon disulfide, respectively, in African-green-monkey kidney cells. The authors point out that this assay does not correlate with acute toxicity studies in rats, which have found a 50 percent lethal dose for oral 1,2-dichloroethane of 770 mg/kg. [Mochida K et al; J Pharmaceut Sci 75 (12): 1190-1191 (1986)]**PEER REVIEWED**

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Human Toxicity Values

  • MEAN LETHAL DOSE BY MOUTH PROBABLY LIES BETWEEN 1 AND 5 G. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-214]**PEER REVIEWED**

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Non-Human Toxicity Values

  • ... /CNS DEPRESSANT/ DOSE, BY IP INJECTION, FOR RATS, 0.18 G/KG. ... [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 300]**PEER REVIEWED**
  • LD50 Rat oral 640 mg/kg [Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1042]**PEER REVIEWED**
  • LD50 Rat oral 600 mg/kg [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 396 (1996)]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • IN RABBIT AND GUINEA PIG MAIN METABOLITE IS P-AMINOPHENOL ... EXCRETED IN URINE MAINLY IN CONJUGATED FORM (AMINOPHENYL GLUCURONIDE) AMOUNTS TO 31% ORAL DOSE. ... /NITROBENZENE IS/ READILY ABSORBED BY SKIN ... AND INHALATION ... ONLY 0.5% IS ELIMINATED UNCHANGED IN THE EXPIRED AIR, THOUGH 1% OF CO2, ONE OF ITS BREAKDOWN PRODUCTS, IS ELIMINATED BY THIS ROUTE AND 0.1% IN THE URINE. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 299]**PEER REVIEWED**
  • NITROBENZENE IS HIGHLY FAT-SOLUBLE AND CAN BE ABSORBED THROUGH HUMAN SKIN @ RATES AS HIGH AS 2 MG/SQ M/HR. MEDICAL LITERATURE CONTAINS MANY REPORTS OF POISONING FROM ABSORPTION OF NITROBENZENE IN SHOE DYES & LAUNDRY MARKING INK. ... CYANOSIS & POISONING OF NEWBORN WHO CAME INTO CONTACT WITH DIAPERS OR PADS CONTAINING MARKING INK WERE ALSO VERY COMMON. THIS GENERALLY OCCURRED WHEN DIAPERS OR PADS WERE FRESHLY STAMPED BY HOSPITAL LAUNDRY ... TOXICITY WAS OFTEN SEVERE IN PREMATURE INFANTS WHO WERE IN AN INCUBATOR & SURROUNDED BY FUMES ... & DYE IN CLOTH. GENERAL ABSORPTION ... IS CAUSE OF MANY OF CHRONIC & ACUTE TOXIC EFFECTS OBSERVED IN ... WORKERS. AMT OF CUTANEOUS ABSORPTION IS FUNCTION OF AMBIENT CONCN ... CLOTHING WORN, & RELATIVE HUMIDITY, WHICH INCR ABSORPTION AS IT BECOMES HIGHER. A WORKER EXPOSED TO TLV OF 5 MG/CU M COULD ABSORB UP TO A TOTAL OF 33 MG/DAY, APPROX 9 MG OF WHICH IS ABSORBED CUTANEOUSLY. [National Research Council. Drinking Water & Health, Volume 4. Washington, DC: National Academy Press, 1981., p. 225]**PEER REVIEWED**
  • Workers exposure to nitrobenzene can be monitored by measuring p-nitrophenol in the urine. Levels reach a maximum 4 hr after exposure and may be detected up to 100 hr later. [Dorigan J, Hushon J: Air Pollution Assessment Of Nitrobenzene NTIS PB 257-776 Mclean, VA: MITRE Corp pp. 96 (1976)]**PEER REVIEWED**
  • To study percutaneous absorption of nitrobenzene: radiolabeled nitrobenzene was applied to excised human skin at a dose of 4 ug/sq cm using a diffusion cell technique. Penetration of radioactivity through the skin was monitored for the next 24 hours. The compound rapidly penetrated excised human skin, the greatest penetration occuring in the first 2 hours after exposure. ... [Bronaugh RL, Maibach HI; Chem Ind Tox Series, Toxicity of Nitroaromatic Compounds 141-8 (1985)]**PEER REVIEWED**
  • ... The dermal absorption rate depends on the concn of the agent at the application site and increases with increasing skin temperature. Aniline and nitrobenzene are absorbed at rates of 0.2 to 0.7 mg/sq cm/hr. It is noted that skin contact with aniline or nitrobenzene is unlikely to cause intoxication under normal conditions (in the absence of an accidental widespread skin contamination). Normal working clothes offer little protection. Metabolism and metabolic kinetics of phenol, aniline, and nitrobenzene are reviewed. [Piotrowski JK; Biological Monitoring of Selected Misc Compds; p.165-75 (1984)]**PEER REVIEWED**
  • (14)C-Nitrobenzene /was injected/ intravenously into volunteers. Excretion in the urine was 60.5% of the dose over five days. The elimination half-life was 20 hours. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 392 (1996)]**PEER REVIEWED**
  • The percutaneous absorption of 4 ug/sq m nitrobenzene in an acetone vehicle in monkeys /was studied/. In vitro, 6.2 + or - 1.0% of the applied dose was absorbed percutaneously, in vivo, 4.2 + or - 0.5% of the applied dose was excreted in urine after five days. Loss of nitrobenzene due to volatilization could have affected the amount of nitrobenzene absorbed. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 392 (1996)]**PEER REVIEWED**
  • Tissue dosimetry and hemoglobin binding /were measured/ in Wistar rats following a 0.20 mmol/kg body weight (24.6 mg/kg body weight) oral dose of (14)C-nitrobenzene. Radioactivity in tissues (pmol/mg/dose (mmol/kg)) after one day was as follows: blood, 229 + or - 24; liver, 129 + or - 9.5; kidney, 204 + or - 27; and lung, 62 + or - 14. The binding index (mmol/mol hemoglobin/dose (mmol/kg)) was 72.8 + or - 10. Specific binding (pmol/mg/dose) was 1030 + or - 137 for hemoglobin and 136 + or - 34 for plasma proteins. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 394 (1996)]**PEER REVIEWED**
  • Species differences /was determined/ in the covalent binding of (14)C-nitrobenzene to erythrocytes and spleen of male Fischer 344 and male B6C3F1 mice following an oral dose of 75, 150, 200 or 300 mg/kg body weight nitrobenzene in corn oil. Total radioactivity in erythrocytes, as a percentage of dose, averaged 0.57 + or - 0.11% and 0.08 + or - 0.01% in rats and mice, respectively, following treatment with 200 mg/kg nitrobenzene. In both species, total and bound concentrations of (14) were four to six times greater in erythrocytes than in spleen. All of the covalently bound nitrobenzene-related material in hemoglobin was recovered in the protein fraction, suggesting that nitrobenzene or its metabolites bind specifically to the globin moiety. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 394 (1996)]**PEER REVIEWED**
  • (14)C-nitrobenzene /was administered/ to male Fischer 344 rats (22.5 or 225 mg/kg bw, 20 uCi, in corn oil orally or 225 mg/kg bw intraperitoneally), male CD rats (22.5 or 225 mg/kg bw orally), male B6C3F1 mice (225 mg/kg bw orally) and germfree male Fischer 344 rats (225 mg/kg bw orally). No significant effect of route of administration or strain was observed for the excretion of radioactivity in urine, feces or expired air following administration of 225 mg/kg bw nitrobenzene. Following oral administration of 225 mg/kg bw to Fischer 344 rats, excretion of radioactivity was distributed as follows: urine, 63.2%; feces, 14.2%; expired air, 1.6%. At this same dose, but following intraperitoneal administration, the distribution of excretion of radioactivity was very similar: urine, 56.8%; feces, 13.7%; expired air, 1.4%. A smaller dose of 22.5 mg/kg bw administered orally to Fischer 344 rats, resulted in a significantly higher proportion of radioactivity excreted in feces (21.4%). Following a similar treatment pattern, B6C3F1 mice excreted a smaller percentage of the dose in urine (34.7%) than did rats, but similar percentages in feces (18.8%) and expired air (0.8%). [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 393 (1996)]**PEER REVIEWED**
  • Soybeans were grown in the presence of nitrobenzene in hydroponic solution; this compound was rapidly bound to the root system. Less than 1.5% of the nitrobenzene was translocated to the plant shoots(1). In a second study, soybeans subjected to nitrobenzene during hydroponic growth were believed to have lost much of the incorporated nitrobenzene through transpiration from plant leaves(2). [(1) McFarlane JC et al; J Environ Qual 16: 372-76 (1987) (2) Fletcher JS et al; Chemosphere 20: 513-23 (1990)]**PEER REVIEWED**

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Metabolism/Metabolites

  • NITROBENZENE IS METABOLIZED VIA 2 MAIN PATHWAYS: REDUCTION TO ANILINE FOLLOWED BY HYDROXYLATION TO AMINOPHENOLS & DIRECT HYDROXYLATION OF NITROBENZENE TO FORM NITROPHENOLS. FURTHER REDUCTION OF NITROPHENOLS TO AMINOPHENOLS MAY ALSO OCCUR. [National Research Council. Drinking Water & Health, Volume 4. Washington, DC: National Academy Press, 1981., p. 223]**PEER REVIEWED**
  • REDUCTION TO ANILINE OCCURS VIA UNSTABLE NITROSOBENZENE & PHENYL HYDROXYLAMINE WHICH ARE TOXIC & HAVE PRONOUNCED ABILITY TO FORM METHEMOGLOBIN. REDUCTIONS OCCUR IN CYTOPLASMIC & ENDOPLASMIC RETICULUM REGIONS OF CELL CATALYZED BY NITROREDUCTASE ENZYME SYSTEM. [National Research Council. Drinking Water & Health, Volume 4. Washington, DC: National Academy Press, 1981., p. 223]**PEER REVIEWED**
  • ... METABOLISM OF (14)C-NITROBENZENE IN RABBITS /WAS STUDIED/. APPROX 55% OF DOSE WAS EXCRETED AS METABOLITES IN URINE DURING 2 DAYS AFTER DOSING- 20% IN FORM OF NITRO CMPD & 35% AS AMINO CMPD. NITRO CMPD FOUND IN URINE WERE NITROBENZENE, O-NITROPHENOL, & 4-NITROCATECHOL IN VERY SMALL AMT, & M- & P-NITROPHENOL IN RELATIVELY LARGE AMT. [National Research Council. Drinking Water & Health, Volume 4. Washington, DC: National Academy Press, 1981., p. 223]**PEER REVIEWED**
  • ALL OF THE PHENOLS /IN RABBITS/ WERE EXCRETED AS EITHER GLUCURONIDE OR SULFATE CONJUGATES. APPROX 1% OF DOSE WAS EXPIRED FROM RABBITS AS (14)CO2. [National Research Council. Drinking Water & Health, Volume 4. Washington, DC: National Academy Press, 1981., p. 224]**PEER REVIEWED**
  • IN RABBITS: UNCHANGED NITROBENZENE WAS ELIMINATED BY EXPIRATION (0.5%) & IN URINE (LESS THAN 0.1%). ... URINARY METABOLITES INCLUDED P-AMINOPHENOL (31%), M-AMINOPHENOL (4%), O-AMINOPHENOL (3%), ANILINE (0.3%), O-NITROPHENOL (0.1%), M-NITROPHENOL (9%), P-NITROPHENOL (9%), 4-NITROCATECHOL (0.7%), NITROQUINOL (0.1%), and P-NITROPHENOL MERCAPTURIC ACID (0.3%). [National Research Council. Drinking Water & Health, Volume 4. Washington, DC: National Academy Press, 1981., p. 224]**PEER REVIEWED**
  • OXIDATIVE METAB OF (14)C-LABELED NITROBENZENE BY RAT LIVER MICROSOMES OCCURRED AT RATES GREATER THAN 0.022 NMOL OF PRODUCT/MIN/MG OF PROTEIN. THE MAJOR PRODUCT OF HEPATIC MICROSOMAL METAB OF NITROBENZENE WAS AN UNIDENTIFIED METABOLITE WHICH COELUTED WITH A URINARY EXCRETION PRODUCT AFTER NITROBENZENE EXPOSURE TO FISCHER-344 RATS. [LEVIN AA, DENT JG; DRUG METAB DISPOS 10 (5): 450-4 (1982)]**PEER REVIEWED**
  • IN MALE FISCHER-344 RATS, AND CD RATS THE URINARY METABOLITES AFTER AN ORAL DOSE OF NITROBENZENE WERE P-HYDROXYACETANILIDE, P-NITROPHENOL, AND M-NITROPHENOL. FISCHER-344 RATS EXCRETED THE METABOLITES AS SULFATE ESTERS, BUT CD RATS EXCRETED THEM BOTH AS SULFATE ESTERS AND GLUCURONIDES. IN ADDITION TO THESE METABOLITES, FISCHER-344 RATS EXCRETED 1, AND CD RATS 2 VERY POLAR UNIDENTIFIED METABOLITES IN THE URINE. B6C3F1 MICE EXCRETED THE SAME METABOLITES (EXCEPT GLUCURONIDE OF M-NITROPHENOL) IN THE URINE AS DID CD RATS. IN ALL 3 STRAINS, URINARY EXCRETION OF NITROBENZENE METABOLITES PEAKED 12-24 HR AFTER ORAL ADMIN OF NITROBENZENE. [RICKERT DE ET AL; TOXICOL APPL PHARMACOL 67 (2): 206-14 (1983)]**PEER REVIEWED**
  • ... Cecal contents obtained and incubated in an anaerobic environment are capable of reducing nitrobenzene. Incubation of radioactive nitrobenzene with isolated rat hepatocytes under aerobic conditions produces no metabolites detectable by counting fractions of eluate from a high pressure liquid chromatographic system and no measurable disappearance of the parent compound. ... Conventional rats excrete an oral dose of nitrobenzene in the urine as an unknown metabolite, p-hydroxyacetanilide-sulfate, p-nitrophenol-sulfate, and m-nitrophenol-sulfate. It was concluded that it is clear that metabolism by both mammalian and bacterial enzyme systems is important to the expression of toxicity of nitroaromatic compounds. [Rickert DE; Mammalian and Bacterial Metabolism of Nitroaromatic Compounds; p.87-101 (1985)]**PEER REVIEWED**
  • (14)C-Labeled nitrobenzene administered to female Wistar rats and hemoglobin binding indices determined. After mild acid or alkaline hydrolysis, 90% of the bound material was released and identified as aniline by radio thin layer chromatography . Nitroso aryl derivatives, common intermediates in the metabolism of N-substituted aryl compounds, apparently react with SH-groups of hemoglobin to yield sulfinic acid amides. Aniline was furthermore identified and quantified by capillary gas chromatography, using hemoglobin from animals treated with unlabeled aniline and nitrobenzene. Although nitrobenzene is known to produce less methemoglobin than aniline, hemoglobin binding is higher. Hemoglobin binding may be a better index of body burden than methemoglobin levels in biomonitoring N-substituted aryl compounds. [Albrecht W, Neumann HG; Arch Toxicol 57 (1): 1-5 (1985)]**PEER REVIEWED**
  • The reductive products of several nitroaromatic compounds have been found to be toxic, mutagenic, and carcinogenic. The nitro reductases present in intestinal microflora have been implicated in the biotransformation of these compounds to their deleterious metabolites. A "classical" nitro reductase has been purified from Enterobacter cloacae 587-fold using a protocol which yields approximately 1 mg of purified nitro reductase from 10 liters of cell culture. An analysis of the physical properties of the nitro reductase indicates that the enzyme is active as a monomer with a calculated molecular mass of 27 kDa. FMN has been identified as a required flavin cofactor and is present at a stoiciometry of 0.88 mol of FMN bound/mol of active enzyme. The enzyme was found capable of reducing nitrofurazone under aerobic conditions indicating that the mechanism involves an obligatory two-electron transfer. Thus, this enzyme can be classified as an oxygen-insensitive nitro reductase. The purified nitroreductase can utilize either NADH or NADPH as a source of reducing equivalents and can reduce a variety of nitroaromatic compounds including nitrofurans and nitrobenzenes as well as quinones. Studies in which the rates of nitro reduction for a series of para substituted nitrobenzene derivatives were determined suggest that a linear free energy relationship exists between the rate and the redox midpoint potential of the substrate. [Bryant C, Deluca M; J Biol Chem 266 (7): 4119-25 (1991)]**PEER REVIEWED**
  • The metabolism of nitrobenzene and substituted nitrobenzenes appears to be accomplished by two routes. The first is a reduction of the nitro group to yield aniline or substitute anilines. For nitrobenzene and perhaps for pentachloronitrobenzene, a reduction of the nitro group to the amine is accomplished in the intestinal tract by the bacteria residing there. When the compound has a second nitro group, the reduction is easier as the compound can be reduced under aerobic conditions by hepatic and erythrocyte enzymes. For dinitrobenzenes the bacterial reduction is probably not that important. The second pathway involves the replacement of a nitro group by glutathione. For mononitrotoluenes the most important metabolic pathway is methyl group oxidation. Nitropolycyclic aromatic hydrocarbons are apparently metabolized by both nitro reduction and ring oxidation. Evidence indicated that, at least in 1-nitropyrene and 6-nitrobenzo(a)pyrene, the nitro reduction occurs in the intestinal microflora. [Rickert DE; Drug Metab Rev 18 (1): 23-53 (1987)]**PEER REVIEWED**
  • In a case of nitrobenzene poisoning in a woman using a paint containing nitrobenzene as solvent (99.7%, 0.27% benzene in distillate), the urinary level of 4-nitrophenol was 1056 nmol/ml (142 mg/l) one day after the end of exposure. Simultaneously, a concentration of 400 nmol/ml (39.6 mg/l) p-aminophenol was detected. The levels decreased with an estimated half-life of a few days. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 392 (1996)]**PEER REVIEWED**
  • ... 250 mg/kg body weight (14)C-nitrobenzene /was administered/ by stomach tube to rabbits and measured metabolites in expired air, urine and feces. Nearly 70% of the administered radioactivity was excreted within five days. Major metabolic products were 3- and 4-nitrophenols and 4-aminophenol. Minor metabolites included aniline, 2-aminophenol, 3-aminophenol, 4-nitrocatechol and 4-nitrophenyl mercapturic acid. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 392 (1996)]**PEER REVIEWED**
  • The metabolism of nitrobenzene /was studied/ using hepatic microsomes and cecal microflora from male Fischer 344 rats invitro. Oxidative metabolism of 100 uM (14)C-nitrobenzene occurred at a rate of 0.008 + or - 0.003 nmol/mg protein/min. The major product was unidentified and accounted for nearly 40% of the metabolites formed. Metabolism of nitrobenzene was also studied under anaerobic conditions, in which microsomal reduction occurred much more rapidly than did oxidation (0.33 versus 0.022 nmol/mg protein/min). The rate of reduction by cecal contents was 150 fold that in microsomes. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 394 (1996)]**PEER REVIEWED**
  • Four major metabolites were found in the urine of Fischer 344 rats: 4-hydroxyacetanilide sulfate; 4-nitrophenol sulfate; 3-nitrophenol sulfate; and an unidentified metabolite. 4-Hydroxyacetanilide sulfate and 4-nitrophenol sulfate were excreted in approximately equal proportions (20% of dose). 3-Nitrophenol sulfate and the unidentified metabolite each made up 10% of the dose. 4-Hydroxyacetanilide, 4-nitrophenol and 3-nitrophenol were found in the urine of B6C3F1 mice and CD rats but not of Fischer 344 rats. B6C3F1 mice and CD rats also excreted each of the above metabolites as glucuronides (except 3-nitrophenol in mice) and sulfates. Mice excreted nearly 10% of the dose as 4-aminophenol sulfate, whereas rats did not excrete this metabolite. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 393 (1996)]**PEER REVIEWED**
  • Bile collected from Fischer 344 and CD rats over the first 12 hours after oral administration of 225 mg/kg bw nitrobenzene contained 1.8% and 3.8% of the dose, respectively. Of six peaks detected, three co-eluted with 4-hydroxy-3-methylthioacetanilide, 2-acetamido-3-(5'-acetanido-2'-hydroxyphenylthio)propanoic acid and S-(5'-acetamido-2'hydroxyphenyl)glutathione. Another co-eluted with glutathione sulfinanilide. None of the metabolites recovered in bile of conventional Fischer 344 rats was found in bile of germ-free Fischer 344 rats. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. ]**PEER REVIEWED**
  • In-vivo experiments determined the role of microflora in nitrobenzene metabolism in control and animals treated with antibiotics. Antibiotic treatment totally inhibited in-vitro metabolism of nitrobenzene by caecal contents and decreased the expected level of methemoglobin formation after a single oral dose of 300 mg/kg bw nitrobenzene. The excretion of (14)C was not altered by antibiotic treatment; however, the pattern of urinary metabolites was changed. Antibiotic treatment decreased the urinary excretion of the reduced metabolite, 4-hydroxyacetanilide, to 6% of control values and that of an unidentified metabolite to 14% of control values; excretion of 3-nitrophenol was increased over control values. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 393 (1996)]**PEER REVIEWED**
  • Nitrobenzene is reduced to aniline in in-vitro hepatic microsome systems via the intermediate products nitrosobenzene and phenylhydroxylamine. ... /Authors/ investigated the formation and disposition of N-hydroxylated metabolites of nitrobenzene (phenylhydroxylamine and nitrosobenzene) by isolated rat hepatocytes. Apparent kinetic parameters for nitrobenzene reduction by hepatocytes, as measured by secretion of N-oxygenated products into the incubation medium, were Vmax 1.44 + or - 0.21 nmol/min/ml and Km 4.2 + or - 1.4 mM. Phenobarbital pretreatment stimulated the secretion of hydroxylated metabolites 2.8-fold. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V65 393 (1996)]**PEER REVIEWED**

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TSCA Test Submissions

  • The teratogenicity of nitrobenzene was evaluated in timed-pregnant female CD rats (26/group) exposed to nitrobenzene by inhalation at nominal concentrations of 0, 1, 10 or 40 ppm for 6 hrs/day on gestation days (GD) 6-15. Dams were sacrificed at GD 21. Significant differences between treated and control animals were observed in the following: maternal body weight gain (decreased in high-dose group during treatment period with full recovery by GD 21), increased spleen weight (high- and mid-dose groups), increase in total fetal malformations (low-dose group only), incidence of litters with one or more fetuses with variations or ecchymoses on the trunk (high-dose group), incidence of skeletal malformations including split (bipartite) anterior arch of the atlas (increased at low-dose only), bilobed thoracic centrum 9 (decreased at high-dose), parietal skull plate with a hole in the bone (increased at high-dose), and poorly ossified premaxillary bone (increased at low-dose only). No significant differences between treated and control animals were observed in the following: mortality, early deliveries, abortions, pregnancy rates, maternal body weight, clinical observations, gravid uterine weight, liver or kidney weights, reproductive parameters, number of litters with one or more affected fetuses for individual and total external, visceral and skeletal malformation.[Bushy Run Research Center, Union Carbide; Teratogenicity Evaluation of Inhaled Nitrobenzene in the CD Rat. (1984), EPA Document No. 40-8424493, Fiche No. OTS0510652 ]**UNREVIEWED**
  • Reproductive toxicity was evaluated in a range finding study using groups of 12 pregnant New Zealand white female rabbits exposed by inhalation to 0,10,40 and 80 ppm nitrobenzene (99.9% purity) for 6 hrs/day on days 13- 19 of gestation. No statistically significant differences were observed in mean body weight among the control and treated groups during the exposure period. Clinical observations of animals under treatment included yellowish staining of fur in the ano-genital area, soft stool, and alopecia. Mean numbers of corpora lutea, implantation and resorption sites, and mean percentage of resorptions to implants, were not significantly different among controls and treated groups. On day 19 methemoglobin levels in the 80 ppm exposure group were significantly higher than controls; this effect was not observed at other exposure levels. No significant differences in organ weights were observed among control and treated groups.[Biodynamics Inc.; A range finding study to evaluate the toxicity of nitrobenzene in the pregnant rabbit. (1983), EPA Document No. 40+8324347, Fiche No. OTS0509345 ]**UNREVIEWED**
  • The embryotoxicity and teratogenicity of nitrobenzene were evaluated in mated female New Zealand White rabbits (22/group) exposed by inhalation to nitrobenzene at nominal concentrations of 0, 10, 40 or 100 ppm for 6 hrs/day during gestation days (GD) 7-19. The animals were sacrificed on the day evidence was observed that they aborted or delivered prematurely or on GD 30, whichever occurred sooner. Significant differences between treated and control animals were observed in the following: increased absolute and relative liver weight and methemoglobin values (mid- and high-dose groups). No significant differences between treated and control animals were observed in the following: mortality, pregnancy, abortion or premature delivery rates, body weights, corpora lutea and uterine implantation data, fetal weight, crown-rump distance, fetal sex distribution, and external, visceral and skeletal evaluation of fetuses.[Biodynamics Inc.; An Inhalation Teratology Study in Rabbits with Nitrobenzene. (1984), EPA Document No. 40-8424492, Fiche No. OTS0510651]**UNREVIEWED**
  • In a two-generation reproduction study, male and female Sprague Dawley CD rats (F0 generation) (30/sex/group) were exposed to nitrobenzene at nominal concentrations of 0, 1, 10 or 40 ppm for 6 hrs/day, 5 days/week, for 10 ten weeks. Exposure was increased to 7 days/week during a two-week mating period, a 19-day gestation period (females only), and a 17-day postpartum period (dams only). F1 generation rats (5-7 weeks of age, 30/sex/group) were exposed to the same concentrations, exposure regimen and mating period as their parents. High-dose level and control F1 males were then allowed a 9 week nonexposure recovery period (F1 male recovery groups) followed by a mating period with nonexposed virgin females. F2 generation rats were sacrificed on postnatal day (PN) 21 and were never exposed to nitrobenzene. Significant differences between F0 and control animals were observed in the following: decrease in relative and absolute testes and epididymides weights and testes size and increase in atrophy of the testes and epididymides including degenerate spermatocytes and reduced numbers of spermatids (high-dose level males). Significant differences between F1 and control animals were observed in the following: body weights of F1 pups (high-dose level on PN 21), decrease in size of testes and increase in atrophy of the testes and epididymides including degenerate spermatocytes and reduced numbers of spermatids (high-dose males). Significant differences between F1 male high-dose and control recovery groups were observed in the following: decrease in relative and absolute testes and epididymides weights (high-dose level after several weeks of recovery), and increase in atrophy of the testes and epididymides including degenerate spermatocytes and reduced numbers of spermatids (high-dose males, but much less severe than for F0 and F1 high-dose groups without recovery). Significant differences between all treated groups and control animals were observed in the following: decreased fertility index (high-dose groups, mostly recovered in the high-dose recovery group), and number of dropped vaginal plugs (high-dose groups). No significant differences between any of the treated groups and control animals were observed in the following: clinical signs of toxicity, mortality, body weights or weight gain, duration of gestation, number of implantations, resorptions, or postimplantation losses, litter data, and survival index for postnatal days 1, 4, and 21, and most pup indices including ecchymosis, hypoactivity, hypothermia and partial cannibalism.[Bushy Run Research Center, Union Carbide; Potential Effects of Nitrobenzene Inhalation on Reproduction and Fertility in Rats. (1985), EPA Document No. 40-8524494, Fiche No. OTS0510653]**UNREVIEWED**
  • Nitrobenzene (CAS# 98-95-3) was evaluated for chronic toxicity and carcinogenicity. The test substance was administered via inhalation to male and female F344 rats and male CD rats at a concentration of 0, 1, 5, or 25 ppm for 6 hrs/day, 5 days per week for 107 weeks with a total of 505 exposure days. In male F344 rats, the incidence of hepatocellular adenoma, hepatocellular adenoma or carcinoma, and renal tubular adenoma were increased. They also had a marginally increased incidence of thyroid follicular neoplasia (adenoma or adenocarcinoma). In female 344 rats, the incidence of endometrial stromal polyp was increased. In male CD rats, the incidence of hepatocellular adenoma and hepatocellular adenoma or carcinoma was increased. Chronic toxicity included effects of the nasal mucosa, blood, liver, and testis, including an increased incidence of nasal inflammatory lesions and methemoglobinemic anemia. In male F344 rats, hepatic effects were evident as enlargement of centrilobular hepatocytes. In male CD rats, testicular effects were characterized by testicular atrophy. The test substance was determined to be carcinogenic.[MALLINCKRODT; Initial Submission: A Chronic Inhalation Toxicity Study of Nitrobenzene in B6C3F1 Mice, Fischer 344 Rats and Sprague-Dawley (CD) Rats with Cover Letter Dated 02/18/93; 01/22/93; EPA Doc. No. 88-930000171; Fiche No. OTS0538400]**UNREVIEWED**
  • Nitrobenzene (CAS# 98-95-3) was evaluated for chronic toxicity and carcinogenicity. The test substance was administered via inhalation to male and female B6C3F1 mice (50/sex/group) at a concentration of 0, 5, 25, or 50 ppm for 6 hrs/day, 5 days per week for 107 weeks with a total of 505 exposure days. In males, the incidence of alveolar/bronchiolar adenoma, alveolar/bronchiolar carcinoma, and thyroid adenoma were increased. In females, the incidence of mammary gland adenocarcinomas was increased and had a marginally increased incidence of hepatocellular adenoma. Chronic toxicity included effects of the nasal mucosa, blood, liver, and testis, including an increased incidence of nasal inflammatory lesions, methemoglobinemic anemia and nasal olfactory epithelial degeneration. In males, hepatic effects were evident as enlargement of centrilobular hepatocytes and multinucleated hepatocytes. Testicular effects were characterized by epididymal hypospermia. The test substance was determined to be carcinogenic.[MALLINCKRODT; Initial Submission: A Chronic Inhalation Toxicity Study of Nitrobenzene in B6C3F1 Mice, Fischer 344 Rats and Sprague-Dawley (CD) Rats with Cover Letter Dated 02/18/93; 01/22/93; EPA Doc. No. 88-930000171; Fiche No. OTS0538400]**UNREVIEWED**
  • Acute inhalation toxicity was evaluated in groups of 10 male Crl:CD rats exposed to nitrobenzene at measured (mean) concentrations of 439, 514, 542, 555, 578, and 714 ppm for 4 hours. Mortality was observed in 1 rat in the 542 ppm dose group, in 7 rats in the 555 ppm dose group, in 8 rats in the 578 ppm dose group and in all rats in the 714 ppm dose group; the LC50 was determined to be 556 ppm (546-568 ppm confidence limits). Clinical observations during exposure included cyanosis, weakness, chromodacryorrhea, slight reddish-brown nasal discharge, slight corneal clouding, yellowish-brown stained perineal area and lacrimation, and post-exposure, hyperactive aggressive behavior, pallor, stained-wet perineal area, tremors, tachypnea, weight loss, diarrhea, corneal clouding, prostration, labored breathing, rales, and white foamy discharge from the mouth and nose. Gross necropsy observations were not reported.[E.I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine; Inhalation Median Lethal Concentration (LC50) with cover letter (1981), EPA Document No. 878220423, Fiche No. OTS0215040]**UNREVIEWED**
  • Subchronic inhalation toxicity was evaluated in groups of 16 male Crl:CD rats exposed to nitrobenzene at analytical concentration of 12, 39 or 112 ppm, 6 hours/day, 5 days/week, for 2 weeks. The test atmosphere was generated by passing nitrogen over heated (70 - 80 degrees Celcius) nitrobenzene; the vapor was then diluted with humidified, oxygen-enriched air and passed into a 35 L glass exposure chamber. Mortality was observed in 7 of the 10 animals in the 112 ppm exposure group. Significant decreases (Dunnett test, LSD, p <= 0.05) in body weights were observed in animals in the 112 ppm exposure group. Clinical observations included cyanosis, hind leg ataxia, labored breathing, and semiprostration. Hematological analysis revealed dose-dependant increases in red blood cell counts, platelet counts, methemoglobin levels, MCV, MCH, relative neutrophil and monocyte counts, serum choloesterol, white blood cell counts, immature erythrocytes, mean cell volume, mean cell hemoglobin, and serum proteins, while decreases were observed for hemoglobin content, erythrocyte count, relative lymphocyte counts, serum alkaline phosphates, and creatine levels. Urinalysis findings included increased urine volumes with decreased osmolalities and increased urinary urobilinogen levels. Gross necropsy revealed small and soft testes, small thymus, and dark-brownish colored blood. Incresed relative spleen, kidney, liver, and heart weights were observed in all exposure groups. Histopathological examination revealed: hemosiderin deposition in the spleen; hemorrhage and edema of the cerebral peduacle, medulla oblongata and cervical spinal cord; atrophy of the germinal cells of the testes; atrophy and decreased sperm within the epididymides; lyphoid cell atrophy of the thymus and spleen; pulmonary edema; and ocular keratitis.[EI Dupont De Nemours & Co.; Subacute Inhalation Toxicity Study of Nitrobenzene in Rats, (1980), EPA Doc. No. 878221372, Fiche No. OTS0215211]**UNREVIEWED**
  • Subchronic inhalation toxicity was evaluated in groups of 20 Fischer F344 rats (10 male and 10 female) exposed to measured average concentrations of 5.0, 15.8, or 48.7 ppm nitrobenzene, 6 hours/day, 5 days/week for 90 days. Treatment related mortality, and treatment related clinical observations of toxicity, were not observed in any dose group. Additionally, statistically significant (Dunnett's t-test, p < 0.05) changes in body weight gain were not observed in any dose group. Observations of significant (p < 0.05) changes in relative organ weights included increased spleen and liver weights in males in the 15.8 and 48.7 ppm groups, decreased testicular weights in males in the 48.7 ppm group, increased spleen weights in the 48.7 ppm group females, and increased liver weights in the 15.8 and 48.7 ppm group females. Treatment related pathology observed on gross necropsy included pale brown and red areas on the surface of livers, pale circumscribed foci consistent with necrosis on the cut surface of liver, and enlarged spleens in 48.7 ppm dose group males and females. Methemoglobin was significantly (p < 0.05) elevated in 5, 15.8, and 48.7 ppm dose group males, and in 15.8 and 48.7 ppm dose group females. Dose related hematologic changes were consistent with hemolytic anemia, accompanied by an increase in erythropoiesis; a significant increase in circulating Howell Jolly bodies were observed in males exposed to 48.7 ppm test article. Females in the 48.7 ppm dose group exhibited an increase in the specific gravity of the urine, while values for males in this group were decreased. Histopathological examination revealed the following treatment related pathology: congestion and increased extramedullary hematopoiesis in the spleen; proliferative capsular lesions in the spleen (observed primarily in the 48.7 ppm dose group); toxic nephrosis in the kidneys in rats from all dose groups; degeneration of the tubular epithelial cells, and reduced mature sperm in the testes of 48.7 ppm dose group males; disorganization of hepatic cord architecture in livers in all dose groups; and erythroid hyperplasia in the bone marrow obtained from 48.7 ppm dose group rats. Additional pathology observed that may have been treatment related included increased basophilia of the medullary cells in the adrenal glands in the 48.7 ppm dose group, reactive lymphoid hyperplasia in the lymph nodes primarily in the 15.8 and 48.7 dose groups, and inflammatory lesions in the lungs.[Chemical Industry Institute of Toxicology; Ninety Day Inhalation Toxicity Study of Nitrobenzene in F-344 Rats, CD Rats, and B6C3F1 Mice (1984), EPA Document No. 878214291, Fiche No. OTS0206507]**UNREVIEWED**
  • Subchronic inhalation toxicity was evaluated in groups of 20 CD rats (10 male and 10 female) exposed to measured average concentrations of 5.0, 15.8, or 48.7 ppm nitrobenzene, 6 hours/day, 5 days/week for 90 days. Treatment related mortality, and treatment related clinical observations of toxicity, were not observed in any dose group. Additionally, statistically significant (Dunnett's t-test, p < 0.05) changes in body weight gain were not observed in any dose group. Observations of significant (p < 0.05) changes in relative organ weights included increased spleen, liver, and kidney weights and decreased testes weights in the 48.7 ppm dose group males, and increased spleen and liver weights in the 48.7 and 15.8 ppm group females. Treatment related pathology observed on gross necropsy included prominent lobular markings on the livers of 48.7 ppm dose group males, and enlarged spleens in both males and females in this dose group. Methemoglobin was significantly (p < 0.05) elevated in 15.8, and 48.7 ppm dose group males, and in 48.7 ppm dose group females. Dose related hematologic changes were consistent with hemolytic anemia, accompanied by an increase in erythropoiesis. Males and females exhibited an increase in the specific gravity of the urine, however, the largest increase was observed in the 5 ppm dose group. Treatment related lesions were observed in the spleen, kidneys and liver in all dose groups. Histopathological examination revealed the following: congestion, increased extramedullary hematopoiesis, and an increase in thickness of the splenic capsule in the spleen in the 48.7 ppm dose group; toxic nephrosis in the kidneys in rats from the 48.7 ppm dose group; bilateral testicular atrophy, loss of seminiferous epithelium, and complete absence of mature sperm in the testes of 48.7 ppm dose group males; an increase in basophilic cytoplasm, centrilobular hepatocyte hypertrophy, and an increase in pigment-laden Kupffer cells in livers; erythroid hyperplasia in the bone marrow obtained from 15.8 and 48.7 ppm dose group rats; and rhinitis associated with epithelial and goblet cell hyperplasia in the nasal turbinates. Additional pathology observed that may have been treatment related included reactive lymphoid hyperplasia in the lymph nodes primarily in the 15.8 and 48.7 dose groups, and inflammatory lesions in the lungs.[Chemical Industry Institute of Toxicology; Ninety Day Inhalation Toxicity Study of Nitrobenzene in F-344 Rats, CD Rats, and B6C3F1 Mice (1984), EPA Document No. 878214291, Fiche No. OTS0206507]**UNREVIEWED**
  • Subchronic inhalation toxicity was evaluated in groups of 20 B6C3F1 mice (10 male and 10 female) exposed to measured average concentrations of 5.0, 15.8, or 48.7 ppm nitrobenzene, 6 hours/day, 5 days/week for 90 days. Treatment related mortality, and treatment related clinical observations of toxicity, were not observed in any dose group. Additionally, statistically significant (Dunnett's t-test, p < 0.05) changes in body weight gain were not observed in any dose group. Observations of significant (p < 0.05) changes in relative organ weights included increased spleen, and liver weights in the 48.7 ppm dose group males, and increased spleen weights in the 48.7 ppm group females. Enlarged spleens were observed in both males and females on gross necropsy. Methemoglobin was significantly (p < 0.05) elevated in 48.7 ppm dose group males and females, and an increase in the specific gravity of the urine was observed in both males and females at all dose levels. Histopathological examination revealed the following: congestion and increased extramedullary hematopoiesis in the spleen of animals from all dose groups; an adrenal lesion in females from all dose groups which consisted of a prominent cellular vacuolization that was restricted to the zona reticularis; sex related differences in liver necrosis as indicated by the observation of centrilobular hepatocyte hyperplasia with basophilic cytoplasm and multinucleated hepatocytes in 15.8 and 48.7 ppm dose group males, and less severe centrilobular hyperplasia and hypertrophy resulting in disorganization of the chord structure in the liver of 48.7 ppm dose group females; and mild hyperplasia of the bronchial epithelium and generalized bone marrow hyperplasia in all animals from the 48.7 ppm dose group.[Chemical Industry Institute of Toxicology; Ninety Day Inhalation Toxicity Study of Nitrobenzene in F-344 Rats, CD Rats, and B6C3F1 Mice (1984), EPA Document No. 878214291, Fiche No. OTS0206507]**UNREVIEWED**

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.

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Web page last updated on May 14, 2008