National Toxicology Program

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

Names (NTP)

• p-Nitroaniline
• 4-NITROBENZENEAMINE (9CI)

Human Toxicity Excerpts

• Para-nitroaniline is a potent methemoglobin-inducing agent and given sufficiently high or prolonged exposures, hemolysis can occur. Prolonged exposure may also result in liver damage. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1094]**PEER REVIEWED**
  
• ... SEVERAL CASES OF POISONING AMONG MEN WHO SWEPT UP SPILLED ... POWDER IN ... HOLD OF A SHIP. ONE MAN, WHO ALREADY HAD LIVER DISEASE, BECAME JAUNDICED & DIED. THE OTHERS BECAME CYANOTIC & COMPLAINED OF HEADACHE, SLEEPINESS, WEAKNESS, & RESPIRATORY DISTRESS. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1094]**PEER REVIEWED**
  
• Symptomatology: 1. Lips, tongue, and mucous membranes navy blue to black; skin slate gray, all without signs of cardiac or pulmonary insufficiency. 2. Severe headache, nausea, sometimes vomiting, dryness of throat. 3. Central nervous symptoms: confusion, ataxia, vertigo, tinnitus, weakness, disorientation, lethargy, drowsiness, and finally, coma. Convulsions may occur but appear to be uncommon. 4. Cardiac effects: heart blocks, arrhythmias, and shock. 5. Death, although uncommon, is usually due to cardiovascular collapse and not resp paralysis. 6. Urinary signs and symptoms may incl painful micturition, hematuria, hemoglobinuria, and renal insufficiency (usually mild). 7. A late acute hemolytic episode should be anticipated at 6 to 8 days after ingestion. /Aniline/ [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-197]**PEER REVIEWED**
  
• ... P-NITROANILINE /FOUND/ IN SOME SAMPLES OF RED WAX CRAYONS AND IN SOME SAMPLES OF THE PARA-RED DYE ... /IS SUSPECTED OF BEING/ RESPONSIBLE FOR ... POISONING OF CHILDREN WHO ATE SUCH CRAYONS. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1094]**PEER REVIEWED**
  
• More toxic than aniline & probably more toxic than nitrobenzene. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-209]**PEER REVIEWED**
  
• A powerful methemoglobin former causing anoxia. ... Chronic exposure may cause jaundice and anemia. [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 2468]**PEER REVIEWED**
  
• Serious health hazard. May be harmful if absorbed through skin or inhaled. Symptoms of overexposure include irritability, vomiting, diarrhea, cyanosis, ataxia, tachycardia, convulsions, respiratory arrest, & anemia. [Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997., p. 49-96]**QC REVIEWED**
  

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Non-Human Toxicity Excerpts

• METHEMOGLOBIN WAS PRODUCED IN DOGS GIVEN SINGLE DOSE OF 15 MG/KG BY IV ADMINISTRATION. /FROM TABLE/ [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 2416]**PEER REVIEWED**
  
• ADMIN TO RAT INITIALLY DECR BLOOD SH GROUP, GLUTATHIONE, & OTHER THIOL SYSTEMS OF ERYTHROCYTE CYTOPLASM LEVELS. HEME OXIDN & HEMOGLOBIN DESTRUCTION LEADING TO ERYTHROCYTE HEMOLYSIS & ANEMIA FOLLOWED. FERROGEN GAVE FERROHEME, HEMOGLOBIN PPT AS HEINZ BODIES. [VASILENKO NM, ZVEZDAI VI; FIZIOL PATOL OBMENA PORFIRINOV GEMA, MATER SIMP 1ST: 60-3 (1974)]**PEER REVIEWED**
  
• 4-Nitroaniline was found to be a frameshift mutagen in Salmonella typhimurium strain TA1538. The chemical was also toxic to TA1538. [Malca-Mor L, Stark AA; Appl Environ Microbiol 44 (4): 801-8 (1982)]**PEER REVIEWED**
  
• p-Nitroaniline was evaluated for developmental toxicity in a proposed new short-term in vivo animal bioassay. In this assay, pregnant mice are dosed with the test agent in mid-pregnancy and allowed to go to term. Observations are then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Fifty pregnant CD-1 mice were given 1200 mg/kg/day p-nitroaniline in corn oil by gavage on days 6-13 of gestation and were allowed to deliver. p-Nitroaniline caused maternal death and reduced body weight. It decreased the number of viable litters and reduced pup viability and percent survival. [Hardin BD et al; Teratog Carcinog Mutagen 7: 29-48 (1987)]**PEER REVIEWED**
  
• The teratogenic potential of para-nitroaniline and para-nitrochlorobenzene was studied in rats and rabbits. Pregnant Sprague-Dawley rats were administered 25 to 250 mg/kg per day para-nitroaniline or 5 to 45 mg/kg/day para-nitrochlorobenzene on days 6 through 19 of gestation. All animals were observed for clinical signs of toxicity. Surviving rats and rabbits were killed on days 20 or 30, respectively. Maternal spleen weights were recorded. The uterine horns were examined for the number and location of viable and non viable fetuses and resorptions. Fetuses were removed and examined for decreased body weight gain, urogenital staining, and increased spleen weights. An increased number of resorptions and decreased fetal body weights were observed. Fetal skeletal and soft tissue abnormalities were seen. The lower doses caused no teratogenic effects but caused signs of maternal toxicity. In rabbits, the 125 mg/kg/day dose of para-nitroaniline caused a high degree of maternal mortality. No fetotoxic or teratogenic effects were observed. Para-nitrochlorobenzene caused no fetotoxicity or teratogenic effects. Fetal effects were observed with para-nitroaniline and para-nitrochlorobenzene only at doses that caused severe maternal toxicity. This suggests that there is a causal relationship between toxicity and subsequent fetal effects. Para-nitrochlorobenzene and para-nitroaniline should not be labeled as teratogenic as the fetal effects cannot be dissociated from the maternal effects. [Nair RS et al; Toxicity of Nitroaromatic Compounds 61-85 (1985)]**PEER REVIEWED**
  
• For evaluation of subchronic toxicity of the two single-ring nitroaromatics, p-nitroaniline and p-nitrochlorobenzene, groups of 10 male and 10 female Sprague-Dawley rats were exposed to an aerosol/vapor of p-nitroaniline in isopropanol at target concentrations of 0, 10, 30, or 90 mg/cu m or to p-nitrochlorobenzene vaporized from a solution in ethylene glycol monoethyl ether at target concentrations of 0, 5, 15, or 45 mg/cu m for 6 hr/day, 5 days/week for 4 weeks. Clinical signs of toxicity, body weights, results of ophthalmoscopic exam, hematology and clinical chemistry tests, organ weights, gross and histopathological changes were recorded. Exposure to p-nitroaniline or p-nitrochlorobenzene resulted in a dose-related increase in blood methemoglobin levels. Mean spleen weights (absolute and relative to body weight) were significantly increased at the high dose levels in the two studies. A slight increase in spleen weights was also observed at the low concentration level in the p-nitroaniline study. Microscopic changes were observed mainly in the spleen and included and increase in intensity of extramedullary hematopoiesis and hemosiderosis with both compounds. Neither p-nitroaniline nor p-nitrochlorobenzene exhibited significant toxicological effects other than those of methemoglobinemia, anemia, and splenic changes classically associated with nitroaromatics at levels significantly above presently accepted occupational standard. ... Data suggest that the current threshold limit values for p-nitroaniline which is 3 mg/cu m will provide adequate protection to the workers. [Nair RS et al; Fundam Appl Toxicol 6 (4): 618-27 (1986)]**PEER REVIEWED**
  
• p-Dinitrobenzene, p-nitroaniline, and p-nitroacetanilide were examined for mutagenic action in Salmonella typhimurium strains TA98, TA98NR, TA1538NR. p-Nitroaniline and p-nitroacetanilide were not mutagenic in these tester strains. [Corbett MD et al; Carcinog 6 (5): 727-32 (1985)]**PEER REVIEWED**
  
• Heme metabolism and porphyrin metabolism disorders caused by poisoning by aromatic nitro compounds and amino compounds were investigated. The pathological nature of such disorders was assessed. Contents of methemoglobin, sulfhemoglobin, oxyhemoglobin, sulfhydryl blood groups, and Heinz bodies in the blood were determined. The concentration of coproporphyrin-3 was determined as an indicator porphyrin metabolism. Compounds having the most hematoxic effect were aniline; meta-chloroaniline; para-chloroaniline; meta-nitroaniline; para-nitroaniline; aminotoluenes; and nitrochlorobenzenes. Least hemotoxic were isomer nitrotoluenes, o-chloro-p-nitroaniline, and isomer nitrochlorobenzenes. Intoxication with aniline, nitrobenzene, p-chloroaniline, m-chloroaniline, and isomer nitrochlorobenzenes most affected porphyrin in metabolism. [Vasilenko NM, Zvezdai VI; Fiziol Patol Obmena Porfirinov Gema Mater Simp 60-3 (1974)]**PEER REVIEWED**
  
• Three nitroanilines and 9 nitroaminophenols were tested for their ability to induce mutations in Salmonella typhimurium strains TA1535, TA100, TA1537, TA1538, and TA98. The compound p-nitroaniline was also inactive in all tests with the possible exception of that in strain TA98 in the presence of S9 mix, where it was either very weakly mutagenic or nonmutagenic. [Shahin MM; Imt J Cosmet 7 (6): 277-89 (1985)]**PEER REVIEWED**
  
• The toxic effects of aniline, p-chloroaniline, nitrobenzene (NB), p-nitrochlorobenzene, p-nitroaniline, o-nitroaniline, o-chloroparanitroaniline, p-chloro-o-nitroaniline, o-nitrotoluene, m-nitrotoluene, dinitrotoluene, and trinitrotoluene were investigated on the hemoglobin content of rats. Male white rats were administered 20% of the median lethal dose (LD50) of compounds daily for 30 days; dinitrotoluene and trinitrotoluene were administered as 10% of the LD50. After 5 days, most of the compounds inactivated the respiratory blood pigment. Based on the intensity of methemoglobinemia, compounds were ranked according to their effect from greater to lesser: p-nitroaniline, p-nitrochlorobenzene, p-chloroaniline, aniline, nitrobenzene, aniline, dinitrotoluene. All of the compounds studied with the exception of o-nitrotoluene and o-nitroaniline suppressed the respiratory function of the blood. [Vasilenko NM et al; Sovremennye Problemy Biokhim Dykhaniza Klin Mater Voes Konf 1: 411-3 (1972)]**PEER REVIEWED**
  
• Nineteen nitro compounds, including p-nitroaniline, were evaluated for mutagenicity, using a modification of the standard Salmonella typhimurium mutagenicity assay. A preincubation protocol was used which incorporated flavin mononucleotide (FMN) to facilitate nitro reduction. The mutagenic activity of p-nitroaniline was greater in Salmonella typhimurium TA98 than TA100. In the standard plate test, little or no mutagenicity was detected with or without rat liver S9. p-Nitroaniline was more mutagenic when hamster rather than rat liver S9 was used. The presence of flavin mononucleotide in the S9 mix was a necessary condition for optimal mutagenic activity. [Dellarco VL, Prival MJ; Environ Mol Mutagen 13 (2): 116-27 (1989)]**PEER REVIEWED**
  
• ... Groups of male and female mice were administered the chemical in corn oil by gavage at doses of 0, 10, 30, 100, 300, or 1000 mg/kg bw, 5 days/wk for 2 wk (14-day studies) or 0, 1, 3, 10, 30, or 100 mg/kg day, 5 days/wk for 13 wk (13-wk studies). In the 14-day studies, all mice that received 1000 mg/kg/day died from cmpd-related toxicity by day 4. The hematologic and pathologic findings in the mice receiving p-nitroaniline were characteristic of a process of accelerated erythrocyte destruction associated with methemoglobinemia and Heinz body formation and a physiologic, compensatory reaction to maintain erythrocyte mass. The methemoglobin concentrations of all dosed groups were significantly greater than those of the concurrent controls. The total erythrocyte counts of male and females receiving 100 or 300 mg/kg/day and of females receiving 30 mg/kg/day were significantly reduced compared with the concurrent controls. The reticulocyte counts of male mice receiving 300 mg/kg and of females receiving 100 or 300 mg/kg/day were significantly greater than those of the controls. No gross lesions associated with p-nitroaniline administration were observed. Increased extramedullary hematopoeisis in males and females and in the Heinz bodies as well as increased Kuppfer cell pigmentation were the only histopathologic changes associated with exposure to p-nitroaniline. In the 13-wk studies, there were no deaths associated with exposure to p-nitroaniline. The hematologic finding were consistent with those of the 14-day studies; most of the changes occurred in the 30 and 100 mg/kg/day dose groups. Histopathologic changes associated with administration of p-nitroaniline occurred in the spleen (hematopoiesis and pigmentation), liver (golden-brown pigment in Kuppfer cells of male mice), and bone (bone marrow hyperplasia in male mice but not in females). [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1093]**PEER REVIEWED**
  
• ... Gave p-nitroaniline in corn oil by gavage to rats at doses of 0, 0.25, 1.5, or 9 mg/kg/day for 2 yr. This chronic administration of p-nitroaniline produced statistically significant increases in methemoglobin concentrations and decreased erythrocyte counts at 1.5 and 9 mg/kg/day. None of the doses studied produced either a general increase in tumors or any increase in splenic fibrosarcomas. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1093]**PEER REVIEWED**
  
• Following intubation of 30 or 100 mg/kg/day in male mice, an increased incidence of hepatic hemangiosarcomas and an increased incidence of hemangioma or hemangiosarcoma (combined) at all sites were recorded. ... Concluded that there was equivocal evidence for the carcinogenicity of p-nitroaniline in male mice. There was no evidence of carcinogenicity of p-nitroaniline in female mice at any or the doses. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1094]**PEER REVIEWED**
  
• ... Evaluated the potential reproductive toxicity of oral p-nitroaniline by administering 0, 0.25, 1.5, or 9 mg/kg/day to groups of male and female rats (F0) for 14 wk before mating, during mating, throughout gestation, and during lactation. Rats from the F1 generation were given the same dose levels of p-nitroaniline for 18 wk through lactation; F2 pups were observed through weaning. A slight reduction in the rate of pregnancy was observed in the high-dose F0 group, but no other differences between F0 and F1 groups were observed. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1094]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• None found

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Absorption, Distribution and Excretion

• It is absorbed through the skin. [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 2468]**PEER REVIEWED**
  
• ... ABSORBED ... BY INHALATION OF DUST OR VAPOR. [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 145]**PEER REVIEWED**
  
• The disposition of 14(C)-labeled p-nitroaniline was studied in male rats following oral or iv admin. The clearance of 14(C) p-nitroaniline-derived radioactivity from various tissues was rapid and followed a 2-component decay curve. The whole-body half-life of p-nitroaniline was approximately 1 hr. Within 3 days, clearance of p-nitroaniline-derived radioactivity from the body was almost complete. 14(C) p-nitroaniline was rapidly cleared by metabolism to 9 metabolites which were excreted primarily in the urine and to a lesser extent in the feces. Most (56%) of the urinary radioactivity was in the form of sulfate conjugates of 2 metabolites of p-nitroaniline. [Chopade HM, Matthews HB; Fundam Appl Toxicol 4 (3): 485-93 (1984)]**PEER REVIEWED**
  
• The percutaneous absorption of nitrobenzene, p-nitroaniline, 2,4-dinitrochlorobenzene, 2-nitro-p-phenylenediamine, and 4-amino-2-nitrophenol was studied in vivo and in vitro. The compounds were applied to shaved abdominal skins of Rhesus-monkeys at a concentration of 4 ug/sq cm. Five day urine samples were collected and analyzed for the compounds. Radiolabeled nitrobenzene, p-nitroaniline, 2-4-dinitrochlorobenzene, 2-nitro-p-phenylenediamine, or 4-amino-2-nitrophenol were 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 compounds rapidly penetrated excised human skin, the greatest penetration occurring in the first 2 hours after exposure. The ability of the compounds to penetrate human skin ranked in decreasing order of permeability and corrected for evaporation was 4-amino-2-nitrophenol, nitrobenzene, p-nitroaniline, 2,4-dinitrochlorobenzene, and 2-nitro-p-phenylenediamine. The corresponding rank for penetration of monkey skin was 4-amino-2-nitrophenol, p-nitroaniline, 2,4-dinitrochlorobenzene, 2-nitro-p-phenylenediamine, and nitrobenzene. [Bronaugh RL, Maibach HI; Toxicity of Nitroaromatic Compounds 141-8 (1985)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• GIVEN ORALLY OR IP IN DOSES OF 20-40 MG/KG IN RATS, ANALYSIS OF 24-HR URINE SAMPLES SHOWED THAT 4-NITROANILINE WAS EXCRETED PARTLY UNCHANGED & ALSO AS 4-PHENYLENEDIAMINE & 2-AMINO-5-NITROPHENOL. [MATE C ET AL; FOOD COSMET TOXICOL 5 (5): 657-63 (1967)]**PEER REVIEWED**
  
• The principal rat liver microsomal metabolite of 4-nitroaniline was isolated by high performance liquid chromatography and characterized as 2-amino-5-nitrophenol. Pretreatment of rats with phenobarbital and 3-methylcholanthrene increased the rate of conversion of 4-nitroaniline to 2-amino-5-nitrophenol by 2- and 4-fold, respectively. [Anderson MM et al; Drug Metab Dispos 12 (2): 179-85 (1984)]**PEER REVIEWED**
  
• 14(C) labeled m-dinitrobenzene was administered to rabbits in oral doses or by subdermal injection of 50 to 100 mg/kg. Within 2 days, 65 to 93 percent of 14(C)-dinitrobenzene was excreted in urine and 1 to 5 percent was excreted in feces. The major metabolites found in urine were m-nitroaniline and m-phenylenediamine, which comprised 35 percent of the m-dinitrobenzene dose, and 2,4-diaminophenol and 2-amino-4-nitrophenol, with 31 and 14 percent of the dose, respectively. Only trace amounts of 2,4-dinitrophenol were found in urine. The remaining metabolites were: 4-amino-2-nitrophenol, m-nitrophenylhydroxylamine, and unchanged m-dinitrobenzene. Subcutaneous administration of m-dinitrobenzene did not lessen the amounts of reduction products appearing in the urine, indicating that reduction was not caused by intestinal bacteria. [Parke DV; Biochem J 78: 262-71 (1981)]**PEER REVIEWED**
  
• The metabolism of radiolabeled dinitrobenzene isomers was compared in hepatocytes and hepatic subcellular fractions isolated from male rats. Under aerobic conditions, reduction was the major metabolic pathway for m-dinitrobenzene and p-dinitrobenzene in hepatocytes with m-nitroaniline and p-nitroaniline accounting for 74.0 and 81.0% respectively, of the radioactivity present after a 30-minute incubation. The major metabolite of o-nitrobenzene in similar incubations was S-(2-nitrophenyl)glutathione which represented 48.1% of the total radioactivity. o-Nitroaniline accounted for 29.5% of the radioactivity. [Cossum PA, Rickert DE; Drug Metab Dispos 13 (6): 664-8 (1985)]**PEER REVIEWED**
  
• P-NITROANILINE WAS FOUND IN LIVER IN A CASE OF HUMAN POISONING WITH ... RODENTICIDE VACOR 1-(3-PYRIDYLMETHYL)-3-(4-NITROPHENYL)UREA. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979., p. 438]**PEER REVIEWED**
  

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TSCA Test Submissions

• The teratogenicity of 4-nitroaniline (NA) was evaluated in pregnant New Zealand White rabbits (18 females/group) orally exposed to NA in corn oil vehicle by gavage at dose levels of 0, 15, 75 or 125 mg/kg/day on gestation days (GD) 7-19. Surviving females were sacrificed on GD 30. No significant differences between treated and control animals were observed in the following: maternal mortality, pregnancy rates, mean maternal body weight change, uterine implantation data, mean percentages of resorptions, live fetuses to implants ratios, maternal spleen weight, mean number of fetuses and fetal weight, number of fetuses with ossification variations, fetal externally visible malformations, fetal skeletal malformations, and most fetal soft tissues examined (see below). Two high-dose group fetuses did not have a gallbladder (11.1% frequency) whereas the reported frequency of gallbladder variations was 0.9% (representing data for 8000 fetuses) and the historical frequency of rabbit fetuses with no gallbladders in the laboratory which performed these tests is 0.1% (representing 3541 fetuses). It is unclear in the report whether this observation was determined to be statistically significant.[Bio/dynamics Inc.; A Teratogenicity Study in Rabbits with p-Nitroaniline, Final Report. (1982)), EPA Document No. 878211841, Fiche No. OTS0206222 ]**UNREVIEWED**
  
• Teratogenicity was evaluated in pregnant Charles River CD rats (24 mated females/group) orally exposed to 4-nitroaniline (NA) in corn oil vehicle at dose levels of 0, 25, 85 or 250 mg/kg/day on gestation days (GD) 6-19. All females were sacrificed on GD 20. Significant differences between treated and control animals were observed in the following: decreased maternal body weight gain (high-dose group), increased incidence of yellow staining of the fur (mid- and high-dose groups), increased mean number of resorptions and percentage of resorptions to implants (high-dose group), increased absolute and relative maternal spleen weights and frequency of spleen lesions, including dark coloration and/or pitted surface (mid- and high dose groups), decreased mean fetal weights of both sexes (mid- and high dose groups), increased incidence of fetal ossification variations (high-dose group), and increased incidence of fetuses with external, soft tissue or skeletal malformations (high-dose group; predominant effects included kinked or shortened tails, absence of kidney or ureter, and fused ribs). No significant difference between treated and control animals was observed with respect to maternal mortality.[Bio/dynamics Inc.; A Teratogenicity Study with p-Nitroaniline in Rats, Final Report. (1980), EPA Document No. 878211846, Fiche No. OTS0206222 ]**UNREVIEWED**
  
• p-Nitroaniline was examined for mutagenic activity in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 with and without Aroclor-induced rat liver S9 fraction metabolic activation. In plate incorporation assays, significant ( Bartletts and Students-T tests, p < 0.01 ) mutagenic activity was observed at test article concentrations of 1.5, 3, 4, and 5 mg/plate in the absence of activation. In the presence of activation, a mutagenic effect was observed at p-Nitroaniline concentrations of 1 and 3 mg/plate, however, statistical evaluation of results showed significance only at the p < 0.03 level. The test article was reported not to elicit toxicity to tester strain TA100 at levels up to and including 10 mg/ml, which was the highest dose tested. In spot tests using tester strains TA100, TA1535, TA1537, or TA98, p-nitroaniline was not mutagenic in the presence or absence of Aroclor-induced rat liver, or CD-1 strain mouse liver S9 fraction metabolic activation.[ Monsanto Co.; Salmonella Mutagenicity Assay of p-Nitroaniline, DA-79-257 (1980), EPA Document No. 878211039, Fiche No. OTS0206222 ]**UNREVIEWED**
  
• The frequency of mutations at the HGPRT locus was determined in Chinese Hamster Ovary cells exposed to concentrations of 62.5, 125, 250, 500 and 750 ug/ml p-nitroaniline in the absence and presence of Aroclor-induced rat liver S9 fraction metabolic activation. In an initial assay, a slight but statistically significant ( Snee and Irr, p <= 0.01 ) increase in mutation frequency was observed at the 62.5 and 500 ug/ml level with activation, and at the 62.5 ug/ml level without activation, however, dose response was not observed. The experiment was repeated and no significant mutagenic effects were observed in the presence or absence of activation. In a preliminary cytotoxicity screen, p-nitroaniline was reported to cause 100% cell death at concentrations of 1000 ug/ml with activation, while 13.2% relative survival was observed at this concentration without activation.[ Pharmakon Research International, Inc.; CHO/HGPRT Mammalian Cell Forward Gene Mutation Assay (1984), EPA Document No. 878214479, Fiche No. OTS0206580 ]**UNREVIEWED**
  
• The frequency of forward mutations was determined at the thymidine kinase (TK) locus of the mouse lymphoma L5178Y cell line exposed in vitro to p-nitroaniline with and without the presence of Aroclor induced rat liver S9 metabolic activation. A significant ( Students T-test, p < 0.01 ) mutagenic response was observed in cells exposed to concentrations ranging from 5 to 50 ug/ml in the presence of activation, while exposure to 100 and 200 ug/ml was excessively cytotoxic. In the absence of activation, p-nitroaniline was tested at concentrations ranging from 200 to 800 ug/ml and a significant mutagenic effect was observed at the 650 and 700 ug/ml concentrations, while 800 ug/ml proved excessively cytotoxic. Differential toxicity of the test article in the presence and absence of rat liver S9 was also reported in preliminary range finding assays.[ Stanford Research Institute International; An Evaluation of Mutagenic Potential of p-Nitroaniline Employing the L5178Y TK +/- Mouse Lymphoma Assay (1982), EPA Document No. 878211853, Fiche No. OTS0206222 ]**UNREVIEWED**
  
• The effect of 4-nitroaniline was examined in the rat hepatocyte primary culture/DNA repair assay. Fischer F344 rat liver hepatocytes were exposed to concentrations of test article ranging from 0.1665 to 5,000 ug/ml for 18 to 20 hours. Net grain counts greater than 5 were observed at concentrations of 1.665 and 5 ug/ml, however, the effect was not dose related. 4-Nitroaniline was observed to be toxic to cells at concentrations of 500 ug/ml and higher during the test.[ Pharmakon Research Intl, Inc.; Rat Hepatocyte Primary Culture/DNA Repair Test (1983), EPA Document No. 878214478, Fiche No. OTS0206580 ]**UNREVIEWED**
  
• The fate of 14-C-4-nitroaniline (14C-NA) was studied in male and female Sprague-Dawley rats (3/sex) exposed by gavage to a dose level of 6.10-7.76 mg/kg (14C-NA). Urine, feces, and expired air were collected at intervals of 0-8, 8-16, 16-24, 24-48, and 48-72 hrs following dosing. Animals were sacrificed at 72 hrs following dosing. The majority of the 14C-activity was found in the urine (98.24-97.96% of the dose) and most of this was excreted in the 0-8 hr period. The amount of 14-activity found in the feces ranged from 3.78-5.83% of the dose. The total amount of 14C-activity found in the expired air ranged from 0.01-0.07% of the dose. The tissues were not analyzed for 14C-activity at necropsy since the entire dose was excreted in the urine and feces.[Bio/Dynamics Inc.; Absorption, Distribution and Elimination of 14C-Labeled p-Nitroaniline in the Rat. (1980), EPA Document No. 878211843, Fiche No. OTS0206222 ]**UNREVIEWED**
  

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Footnotes

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