National Toxicology Program

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

Names (NTP)

• o-Toluidine
• 2-METHYLBENZENAMINE (9CI)

Human Toxicity Excerpts

• O-TOLUIDINE, A METABOLITE OF PROPITOCAIN, CAN CAUSE FETAL AS WELL AS MATERNAL METHEMOGLOBINEMA. [LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971., p. 95]**PEER REVIEWED**
  
• O-TOLUIDINE ... /CAUSES METHEMOGLOBINEMIA &/ TRANSIENT HEMATURIA. FOLLOWING ABSORPTION ... ONE OCCASIONALLY MAY OBSERVE SUFFICIENT RED BLOOD CELL COUNT IN URINE TO RENDER SPECIMEN GROSSLY SUSPECT. ... OFTEN URINARY SEDIMENT ... SHOWS NUMEROUS ERYTHROCYTES WITHOUT HAVING GROSSLY ALTERED ITS APPEARANCE. [Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963., p. 2123]**PEER REVIEWED**
  
• CLINICAL SIGNS OF /CNS DEPRESSION/ INCL PHYSIOLOGICAL & PSYCHICAL DISTURBANCES & MARKED IRRITATION OF KIDNEYS & BLADDER. [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. V16 358(1978)]**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**
  
• ... HEMATURIA ... OBSERVED IN MEN HANDLING TOLUIDINES ... THERE MAY BE A HEMORRHAGIC CYSTITIS WITH PAINFUL FREQUENT MICTURITION. THIS PROBLEM ... NO LONG-TERM SIGNIFICANCE & CLEARS ... ON CESSATION OF ... EXPOSURE. IF HEMATURIA PERSISTS ... OTHER PATHOLOGICAL URINARY TRACT PHENOMENA MUST BE CONSIDERED. [Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974., p. 311]**PEER REVIEWED**
  
• INTOXICATION MAY OCCUR FROM INHALATION, INGESTION, OR CUTANEOUS ABSORPTION. ACUTE TOXICITY: CYANOSIS, METHEMOGLOBINEMIA, VERTIGO, HEADACHE, MENTAL CONFUSION. /ANILINE/ [Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 111]**PEER REVIEWED**
  
• CHRONIC TOXICITY: ANEMIA, ANOREXIA, WT LOSS, CUTANEOUS LESIONS. /ANILINE/ [Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 111]**PEER REVIEWED**
  
• Chemicals from the International Program for Chemical Safety collaborative study on short-term tests were assayed for mutagenic activity in human lymphoblasts. Two distinct lines of human lymphoblasts were used in these assays; TK6, a human cell line which, like many cell lines, does not contain detectable mixed-function oxygenase activity; and AHH-1, a metabolically competent human cell line. Gene-locus mutations were measured at the thymidine kinase locus in TK6 cells and hypoxanthine-guanine phosphoribosyl transferase locus in AHH-1 cells. The samples were assayed under 3 different conditions of metabolic activation. These conditions were: first in TK6 cells without the addition of an extracellular metabolizing system; second, in TK6 cells with the addition of a rat liver homogenate metabolizing system; and third, in the AHH-1 metabolically competent human lymphoblast cell line. Samples yielding positive mutagenic responses included o-toluidine. [Crespi CL et al; Prog Mutat Res 5: 497-516 (1985)]**PEER REVIEWED**
  
• HIGHLY TOXIC WHEN ABSORBED THROUGH SKIN, INHALED AS VAPOR, OR SWALLOWED. [National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986., p. 49-88]**PEER REVIEWED**
  
• ... /CASE REPORTS OF EPIDEMIOLOGICAL STUDIES INVOLVING/ OCCUPATIONAL EXPOSURE ... TO TOLUIDINES ... IS SUGGESTIVE OF CARCINOGENIC EFFECT, BUT INFORMATION WAS INCOMPLETE. [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. V16 360(1978)]**PEER REVIEWED**
  
• ... CMPD THAT CAN INFLUENCE LEVEL OF FERRIC HEMOGLOBIN SUCH AS ... TOLUIDINE ... /CONTRIBUTE/ TO ASPHYXIATION. /TOLUIDINE/ [Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975., p. 205]**PEER REVIEWED**
  
• RESULTS OF EXPTL, HYGIENIC & OCCUPATIONAL PATHOLOGY INVESTIGATIONS INDICATE CARCINOGENIC NATURE OF O-TOLUIDINE. [GENIN VA ET AL; GIG TR PROF ZABOL: ISS 7: 10 (1978)]**PEER REVIEWED**
  
• Epidemiologic evidence ... clearly associates occupational exposure to o-toluidine ... with an increased risk of bladder cancer among workers. The risk of bladder cancer ... was greatest among workers with possible and definite exposures to o-toluidine ... and the risk increased with duration of exposure. [NIOSH; NIOSH Alert: Preventing Bladder Cancer from Exposure to o-Toluidine and Aniline p.5 (1990)]**PEER REVIEWED**
  
• A retrospective cohort study of the incidence of bladder cancer was conducted in response to a union request for an evaluation of a possible excess number of cases of bladder cancer at a chemical plant in western New York State. Workers at the plant were exposed to two potential bladder carcinogens o-toluidine and aniline. Incidence rates of bladder cancer among workers at the plant were compared with those of the population of New York State (excluding New York City). Among all 1749 workers at the plant, 13 cases of bladder cancer were observed versus 3.61 expected (standardized incidence ratio = 3.60; 90% interval = 2.13-5.73). Among the 708 workers who worked in areas in which o-toluidine and aniline were used, 7 cases were observed versus 1.08 expected (standardized incidence ratio = 6.48; 90% confidence interval = 3.04-12.2). Among the 288 maintenance, shipping, and janitoral workers thought to have been possibly exposed, 4 cases were observed versus 1.09 expected (standardized incidence ratio = 3.66; 90% confidence interval = 1.25-8.37). Among the remaining 753 workers who were probably not exposed, 2 bladder cancers were observed versus 1.43 expected (standardized incidence ratio = 1.39; 90% confidence interval = 0.25-4.39). Increased risk of bladder cancer was strongly associated with increased duration of employment in the department where o-toluidine and aniline were used (P less than 0.001). Among workers with 10 or more years of employment in the department, the standardized incidence ratio was 27.2 (90% confidence interval = 11.8-53.7). o-Toluidine is an animal carcinogen more potent than aniline and is known to produce bladder tumors in rats; hence, it is more likely that o-toluidine is responsible for the observed excess number of cases of bladder cancer, although aniline may have played a role. [Ward E et al; J Natl Cancer Inst 83 (7): 501-6 (1991)]**PEER REVIEWED**
  
• Epidemiological aspects of aromatic amine cancers are discussed. Industrial exposure to aromatic amines has been linked with occupational bladder cancer since the end of the last century. Aromatic amines of industrial importance such as 1-naphthylamine, 1-naphthylthiourea, benzidine, 4-biphenylamine, 4,4'-methylenedianiline, 3,3'-dichlorobenzidine, diphenylamine, toluidine, o-toluidine, and p-toluidine are discussed. The epidemiology of bladder cancer is reviewed. Data for the United States in 1981 showes age adjusted incidence rates of bladder cancer per 100,000 of the male population ranging from 7.5 in Puerto Rico to 17.1 in Connecticut. It is noted that the incidence of bladder cancer has been increasing. The epidemiology of industrial bladder cancer is discussed. The historical development of bladder cancer epidemiology is summarized. Studies in the United Kingdom have indicated that 2-naphthylamine is the major carcinogenic amine in the British dyestuffs industry. No evidence of aniline carcinogenicity has been found. Screening as a means of protecting workers at risk is discussed. [Parkes HG, Evans AEJ; Epidemiology of Aromatic Amine Cancers p.277-301 in Chemical Carcinogens American Chemical Society Monograph No. 182 (1982)]**PEER REVIEWED**
  
• A survey of the incidence of industrial chemical cyanosis in the United Kingdom was conducted. All records of aniline poisoning as received by Her Majesty's Factory Inspectorate from 1961 through 1980 were reviewed. Additional details about each case were obtained where possible by the reporting factory inspector and verifying physician. A total of 325 notifications of poisoning affecting 299 individuals, 279 males, occurred. For 44 of 325 notifications, at least one previous incident affecting that person had been recorded. Age was recorded in 311 cases and ranged from 17 to 63 years, mean 33.2 years. Notifications were received from 43 different workplaces, 94.5% occurring during chemical or dyestuff manufacture. One chemical manufacturing facility was responsible for 118 (36%) notification and one dyestuff producing facility for 111 (34 %) notifications. A substantially large number of notifications, 169, occurred in the summer. Aniline was responsible for 30% of 312 cases in which the compound responsible was identified. Other compounds producing more than 10 cases per year were chloroaniline, paratoluidine, nitrobenzene, and nitrochlorobenzene. A total of 141 cases resulted from skin absorption, 90 from inhalation, and 49 from absorption through both the skin and lungs. Aniline, paratoluidine, and chloroaniline tended to produce early poisoning symptoms, and nitrochlorobenzene and nitrobenzene produced late symptoms. The most predominant symptom was methemoglobinemia, 321 cases. Other common symptoms included headache, weakness, dizziness, and vertigo. Methemoglobin was detected in 147 cases and ranged up to 65%. /Results indicated/ that increased peripheral vasodilation, perspiration, and wearing fewer clothes are as important as increased volatility of the compounds in causing the increased incidence of poisoning cases in summer months. [Sekimpi DK, Jones RD; Br J Ind Med 43 (4): 272-279 (1986)]**PEER REVIEWED**
  
• It has been determined experimentally that a concentration of about 100 ppm is the maximum endurable for 1 hr without serious consequences and that 6-23 ppm is endurable for several hours without serious disturbances. [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 3198]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• O-TOLUIDINE ... TESTED BY APPLICATION TO RABBITS EYES WAS FOUND INJURIOUS TO CORNEAL EPITHELIUM, GRADED 8 ON SCALE OF 1 TO 10, BUT WHEN APPLIED AS 0.02 MOLAR SOLN AT PH 6 FOR 10 MIN AFTER REMOVAL OF EPITHELIUM ... /IT WAS FOUND/ TO BE INNOCUOUS TO RABBIT CORNEA. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 929]**PEER REVIEWED**
  
• O-TOLUIDINE WAS FED TO 6 MALE & 6 FEMALE ALBINO RATS IN INITIAL DOSAGES OF 2 G OF 7.5% SOLN IN PEANUT OIL (REDUCED AFTER 64 DAYS TO 1/2 DOSE) ADDED TO SYNTHETIC DIET FOR UP TO 91 DAYS; IT PRODUCED EPITHELIAL CHANGES IN BLADDER, WHICH INCL KERATOSIS, METAPLASIA & IN 3 CASES, TENDENCY TO INCIPIENT PAPILLOMATOSIS. [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. V16 358(1978)]**PEER REVIEWED**
  
• WHEN RATS WERE GIVEN 1/20 OF INTRAGASTRIC LD50 FOR 2.5 MO ... /THEY DEVELOPED/ RETICULOCYTOSIS, METHEMOGLOBINEMIA & ERYTHROPENIA. [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. V16 357(1978)]**PEER REVIEWED**
  
• 15 RABBITS & 10 GUINEA PIGS WERE INJECTED SC WITH 1.0 & 0.5 ML, RESPECTIVELY, OF 2% SOLN ... IN OLIVE OIL 6 TIMES/WK. ANIMALS THAT SURVIVED MORE THAN 100 DAYS DEVELOPED PAPILLOMAS IN BLADDER ... . [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. V16 357(1978)]**PEER REVIEWED**
  
• O-TOLUIDINE DID NOT INDUCE REVERSE MUTATIONS IN SALMONELLA TYPHIMURIUM TA1535, TA1537, TA1538, TA98, OR TA100 IN PRESENCE OR ABSENCE OF RAT LIVER PREPN. [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. V16 358(1978)]**PEER REVIEWED**
  
• ... /O-TOLUIDINE/ VAPOR TOXICITY WAS MUCH LIKE THAT OF ANILINE (SLIGHT SYMPTOMS AFTER SEVERAL HR AT 6 TO 23 PPM & 7 TO 53 PPM RESPECTIVELY). ... EFFECT ON CNS WAS REPORTEDLY LESS, & THAT ON VASCULAR SYSTEM MORE MARKED WITH TOLUIDINE THAN WITH ANILINE. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979), p. 261]**PEER REVIEWED**
  
• O-TOLUIDINE-HYDROGEN CHLORIDE ADMIN IN FEED AT 3,000 OR 6,000 PPM TO RATS FOR 101-104 WK INDUCED SARCOMAS OF SPLEEN IN MALES & FEMALES, MESOTHELIOMAS OF ABDOMINAL CAVITY, OF SCROTUM IN MALES TRANSITIONAL-CELL CARCINOMAS OF URINARY BLADDER IN FEMALES, INCR INCIDENCES OF FIBROMAS OF SC TISSUE IN MALES & HEPATOCELLULAR CARCINOMAS OR ADENOMAS IN FEMALES. /O-TOLUIDINE-HYDROGEN CHLORIDE/ [REPORT; ISS DHEW/PUB/NIH-79-1709; PB-290908, 132 (1978)]**PEER REVIEWED**
  
• O-TOLUIDINE-HYDROGEN CHLORIDE ADMIN TO MICE AT 1,000 OR 3,000 PPM IN FEED FOR 101-104 WK INDUCED HEMANGIOSARCOMAS AT VARIOUS SITES IN MALES & HEPATOCELLULAR CARCINOMAS OR ADENOMAS IN FEMALES. /O-TOLUIDINE-HYDROGEN CHLORIDE/ [REPORT; ISS DHEW/PUB/NIH-79-1709; PB-290908, 132 (1978)]**PEER REVIEWED**
  
• o-Toluidine-hydrogen chloride admin to CD-1 mice in feed at either 16,000 or 32,000 mg/kg for 3 months and then 8,000 or 16,000 mg/kg for 15 months, respectively, showed significantly increased incidence of hemangiosarcomas and hemangiomas of abdominal viscera. /o-Toluidine-hydrogen chloride/ [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. V27 164(1982)]**PEER REVIEWED**
  
• Anilines, such as o-toluidine, are usually more potent carcinogens than aniline. [USEPA; Subst Risk Notice, 8EHQ-0680-0348 (1980)]**PEER REVIEWED**
  
• The NCI bioassay of o-toluidine hydrochloride was conducted by administering the test chemical in feed to F344 and B6C3F1 mice. Groups of 50 rats ... and 50 mice of each sex were administered o-toluidine hydrochloride at one of several doses, either 3,000 or 6,000 ppm for the rats and either 1,000 or 3,000 for the mice, for 101 to 104 weeks. There were control gorups of 20 untreated rats ... and mice of each sex. Mean body weights of dosed male and female rats and mice were lower than those of corresponding matched controls and were dose related. Mortalities of the male and female mice were not, however, significantly affected by administration of test chemical. [USEPA; Subst Risk Notice, 8EHQ-0680-0348 (1980)]**PEER REVIEWED**
  
• Unscheduled DNA synthesis in HeLa S3 cells was measured ... in which (3)H-thymidine uptake into DNA was measured after treating with the test compounds. ... o-Toluidine induced increases in unscheduled DNA synthesis in the presence of S9. [Barrett RH; Prog Mutat Res 5: 347-52 (1985)]**PEER REVIEWED**
  
• F344 rats were fed doses: aniline, 6,000 and 3,000 ppm; p-chloroaniline, 500 and 250 ppm; o-toluidine, 600 and 300 ppm; dapsone, 1,200 and 600 ppm; azobenzene, 400 and 200 ppm; and red dye number 9, 3,000 and 1,500 ppm. Dose related decreases in body weight occurred in animals treated with azobenzene, aniline, dapsone, and o-toluidine. A dose related decrease in survival occurred in males and females given o-toluidine. All compounds caused dose dependent incidences of splenic sarcomas and fibrosis, the incidences being higher in male rats. Larger tumors metastasized to the peritoneal cavity and abdominal organs. Splenic sarcomas often appeared to arise in association with fibrosis. Fatty infiltration was also observed in the spleen. The origin of the fat in splenic lesions could not be determined. [Goodman DG et al; JNCI 73 (1): 265-73 (1984)]**PEER REVIEWED**
  
• o-Toluidine produced activity when tested without exogenous metabolic activation in the Syrian hamster embryo-adenovirus transformation assay. [Hatch CG, Anderson TM; Prog Mutat Res 5: 629-38 (1985)]**PEER REVIEWED**
  
• The alkaline elution assay (which detects small changes in DNA molecular weight/rat hepatocyte assay) was used to test selected chemicals. The carcinogenic compounds that induced DNA single-strand breaks in rat hepatocytes /included/ o-toluidine. [Bradley MD; Prog Mutat Res 5: 353-7 (1985)]**PEER REVIEWED**
  
• Male Wistar-rats were administered o-toluidine, m-toluidine, and p-toluidine ip for 3 consecutive days at 75 mg/kg. On day four, liver, kidneys, and lung were excised and homogenized. Homogenates were centrifuged and the microsomal fraction was then sedimented from the resultant supernatant. Activities of 5 enzymes as well as the concentrations of cytochrome p450 and cytochrome b5 were determined. No marked differences were observed in cytochrome contents after administration of toluidines. Liver cytochrome p450 content was decreased only by p-toluidine whereas o-toluidine increased the cytochrome b5 content. Cytochrome content in the kidney was not affected by any of the toluidines. Only o-toluidine increased reduced nicotinamide adenine dinucleotide cytochrome c-reductase activity in the liver and m-toluidine caused a decrease in this enzyme activity in the kidney. o-Toluidine increased the activity of aryl hydrocarbon hydroxylase in all studied tissues while p-toluidine decreased aryl hyrdocarbon hydroxylase in the liver only. p-Toluidine also lowered aminopyrine demethylase activity in the liver and increased activities of microsomal epoxide hydrolase and cytosolic glutathione-S-transferase in the liver. [Gnojkowski J et al; Toxicology 32 (4): 335-42 (1984)]**PEER REVIEWED**
  
• The relationship between toxicity and physicochemical indexes of derivatives of 4 chemical groups: of phenol, benzene, aniline, and aliphatic amines were studied. Using the Hansch model, the feasibility of using the octanol/water partition coefficient, electronic, and steric constants was estimated. The acute LDs and no effect levels for rats were predictable using these parameters. The molecular connectivity indexes, which describe the topology of the molecule structure have shown a closer relation to toxicity, than the physicochemical parameters. The application of physicochemical and molecular connectivity indexes provided the best correlations and has been recommended for prediciton of toxicological parameters. [Dura G et al; Arch Toxicol 8: 481-7 (1985)]**PEER REVIEWED**
  
• Seven of the 8 carcinogens induced morphologic transformation of Syrian hamster embryo cells including o-toluidine, was also active at high doses. Results indicate a good correlation between the induction of cell transformation in this system and carcinogenicity in rodents. [Barrett JC, Lamb PW; Prog Mutat Res 5: 623-8 (1985)]**PEER REVIEWED**
  
• Both hemosiderosis and hematopoiesis were increased in the spleens of rats treated with 225 mg/kg/day ... In addition, mild renal hemosiderosis and increased density of bone marrow cells were observed. [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.48 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• Methemoglobinemia has been reported in cats after iv administration, ... in rats after intragastric administration, ... and in mice after intraperitoneal injection. ... Catalase and succinic dehydrogenase activity decreased, while cytochrome oxidase activity increased, in rats, rabbits, and dogs exposed to 2-methylaniline. [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.48 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• The micronucleus test using erythrocytes of Pleurodeles walt1 larvae (Amphibian, Salamandridae) was used to detect the genotoxic activity of various substances. Most of them were known (or suspected) to be mutagenic or carcinogenic in mammals. Larvae were reared in water containing either a test chemical (experimental group) or in control water and the levels of micronucleated red blood cells (RBCs) compared between the two groups. o-Toluidine gave positive response. The results were compared with published data from other tests used to detect the clastogenic or mutagenic properties of chemicals. [Fernandez M et al; Mutagenesis 4 (1): 17-26 (1989)]**PEER REVIEWED**
  
• Dermal application of o-toluidine in rats for 4 mos affected the ovarian cycle, ovary morphostructure, the ability to reproduce, and the progeny. Males treated similarly have stimulated spermatogenesis. [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 205]**PEER REVIEWED**
  
• o-Toluidine caused sc fibromas or fibrosarcomas and hepatomas in male rats fed for 2 yr. [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 205]**PEER REVIEWED**
  
• ANILINE & O-TOLUIDINE SHOWED NO MUTAGENIC ACTIVITY IN SALMONELLA TYPHIMURIUM. HOWEVER, COMBINATION OF NORHARMAN WITH EITHER CMPD RESULTED IN SIGNIFICANT MUTAGENICITY. [NAGAO M ET AL; PROC JPN ACAD, SER B: 53 (1): 34 (1977)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat oral 0.94 g/kg [Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996., p. 1627]**PEER REVIEWED**
  
• LD50 Mouse oral 515 mg/kg [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.46 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• LD50 Mouse ip 150 mg/kg [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.46 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• LD50 Cat oral 300 mg/kg [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.46 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• LD50 Rabbit oral 844 mg/kg [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.46 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• LD50 Rabbit dermal 3250 mg/kg [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.46 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• LD50 Rat oral 670 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 3198]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• ORTHO-TOLUIDINE IS ABSORBED BY RESP TRACT & SKIN. [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. V16 358 (1978)]**PEER REVIEWED**
  
• o-Toluidine ... is readily absorbed through the skin, or inhaled as dust, fume, or vapor. [International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998., p. 104.97]**PEER REVIEWED**
  
• The relations between absorption rate constants found in rat colon and lipophilicity were investigated for a homologous series of xenobiotics (4-alkylanilines) in the presence of a nonionic surfactant, Polysorbate 80, at its critical micellar concn and at concn clearly supramicellar. The results were compared with those obtained in the absence of surfactant in order to substantiate the effects of this additive in the absorption of xenobiotics. At supramicellar concn, the solubilization of compounds decreases their absorption rate constants relative to that found at critical micellar concn, this effect being more marked as the surfactant concn and the solute lipophilicity increase. [Pla-Delfina JM et al; Int J Pharm 37 (1-2): 49-64 (1987)]**PEER REVIEWED**
  
• Urinary levels in rats of o-, m-, and p-toluidine (20, 100, or 200 mg/kg, intragastric administration) were positively correlated with the toluidine dose; 26, 10, and 10% of the unchanged toluidines, respectively, were excreted after 24 hr. After chronic administration of m-toluidine, excretion rate of the unchanged toluidine increased with duration of the experiment. [Senczuk W, Rucinska H; Bromatol Chem Toksykol 17 (1): 57-62 (1984)]**PEER REVIEWED**
  
• In /male F344/ rats given 50 mg/kg /of 2-(methyl-(14)-C)aniline HCl in 0.9% saline as a single sc injection/, the /livers, kidneys, lungs, spleens, colons, and bladders/ contained the following average percentages of administered radioactivity, respectively: 0.125, 0.016, 0.0035, 0.002, not done, and 0.00035%. In rats given 400 mg/kg, these organs contained 0.325, 0.055, 0.015, 0.04, 0.005, and 0.015% of the administered radioactivity, respectively. [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.19 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• Rats treated subcutaneously with (14)C-2-methylaniline excreted 79, 3.3, and 1.4% of the dose in the urine, feces, and expired air within 48 hours. [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.24 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• Absorption of o-toluidine from the GI tract in rats is rapid with peak blood values at 1 hr; blood values were near zero in 24 hr. The urine was the main excretory rout; > 92% in 24 hr. At an oral dose of 20 mg/kg, 26% was excreted in the urine in 24 hr as o-toluidine. [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 204]**PEER REVIEWED**
  

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Metabolism/Metabolites

• METAB TO 4-AMINO-M-CRESOL IN RABBIT. /FROM TABLE/ [Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. T-18]**PEER REVIEWED**
  
• o-Toluidine is: metabolized to various aminomethylphenols and excreted as acid- hydrolyzable conjugates. [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**
  
• Abalone and flatfish excreted 2-nitrosotoluene and N-acetyl-o-toluidine, respectively, as the only biotransformation products of o-toluidine. The elimination of o-toluidine over a 4 hr period was high for both species (80%), whereas the total extent of metabolism was low. [Knezovich JP, Crosby DG; Environ Toxicol Chem 5 (4): 387-92 (1986)]**PEER REVIEWED**
  
• The in vivo fate and metabolism of o-toluidine was determined for mussels (Mytilus edulis) and oysters (Crassostrea gigas). o-Toluidine was found to be relatively nontoxic and was rapidly turned over in mollusk tissues. The biotranformation of o-toluidine was determined by the extraction and analysis of eliminated metabolites. The metabolism of (14)C o-toluidine in both bivalve species resulted in the formation of 2-nitrosotoluene, N-methyl-o-toluidine and N-formyl-o-toluidine. Small amounts of N-hydroxy-o-toluidine were detected in experiments with Mytilus edulis. The total extent of o-toluidine biotransformation in mussels from pristine waters was found to be greater than in mussels from contaminated waters. [Knezovich JP, Crosby DG; Environ Toxicol Chem 4 (4): 435-46 (1985)]**PEER REVIEWED**
  
• Ring hydroxylation with subsequent conjugation is the primary metabolic pathway of 2-methylaniline in the rat. In rats treated by gavage with 50 mg/kg 2-methyl-(14)C-aniline HCl in distilled water, approximately 37% of the dose was identified as unchanged 2-methylaniline and approximately 52% was identified as 4-amino-3-methylphenol conjugates in the urine collected for 72 hours after dosing. [USEPA/ECAO; Health and Environmental Effects Profile for 2-Methylaniline and 2-Methylaniline Hydrochloride p.20 (1987) ECAO Pub. EPA/600/X-87/092]**PEER REVIEWED**
  
• ... In rats, the major metabolic routes are N-acetylation and 4-hydroxylation. [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 204]**PEER REVIEWED**
  
• The primary metabolism of o-toluidine takes place in the endoplasmic reticulum. [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 204]**PEER REVIEWED**
  
• An assay was developed to measure the concentration of a metabolite of o-toluidine in urine for use in the biological monitoring of exposed workers. The method involved separation by capillary gas chromatography (GC) and quantification by mass spectrometry (MS). No derivatization or extraction of the urine samples was required prior to analysis. Rats were dosed with 1 or 500 mg/kg body weight carbon-14 labeled o-toluidine and urine samples were collected for analysis of metabolites over a 48 hour period after dosing. Urine samples were incubated overnight with glucuronidase-sulfatase enzymes and subjected to liquid chromatography/MS, which identified N-acetyl-4-amino-m-cresol as the major metabolite excreted in the urine. High performance liquid chromatography was not found to be a viable means for quantitation of N-acetyl-4-amino-cresol, GC was assessed and found to be adequate. Reproducibility of the analysis was evaluated by running a control urine sample with reference standards of the metabolite 12 times. The use of an internal standard improved the coefficient of variation from 21.1% to 9.3% on a day to day, between run basis. The limit of detection was calculated to be less than 3 micrograms/liter (ug/l) in diluted samples, and the limit of quantitation was found to be less than 10 ug/l in undiluted urine. [Williamson JA et al; J of Analytical Toxicol 19 (4): 256-60 (1995)]**PEER REVIEWED**
  

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TSCA Test Submissions

• Acute inhalation toxicity was evaluated in groups of 10 male Crl:CD rats exposed to o-toluidine vapor at measured concentrations of 492, 606, 722, 799, 848, 931 and 1000 ppm for a single 4 hour period. Atmospheres were generated by passing nitrogen over test article heated to 115-120 degrees C. Mortality was observed in one animal exposed to 722 ppm, in 2 animals exposed to 799 ppm, in 6 animals exposed to 848 ppm, in 5 animals exposed to 931 ppm, and in all 10 animals exposed to 1000 ppm. The LC50 was determined to be 862 ppm (between 816 and 913 ppm at the 95% confidence level). Clinical observations included cyanosis, tremors, muscle spasms, labored breathing, corneal opacity, prostration, nasal discharge, weight loss, lethargy, stained wet perinea, hypothermia, and pallor.[Haskell Laboratory for Toxicology and Industrial Medicine; Inhalation Median Lethal Concentration (LC50), EPA Document No. FYI-OTS-1183-0266, Fiche No. OTS0000266-1]**UNREVIEWED**
  
• o-Toluidine (CAS # 95-53-4) was evaluated for urinary bladder toxicity in groups of Fisher-344 rats (10-15/sex/group) fed target doses of 0, 500, 3,000, and 6,000 ppm by dietary inclusion for 14 days. Urothelial cell proliferation (CP) and unscheduled DNA synthesis (UDS) each served as measures of urinary bladder toxicity in 5 rats/sex/group necropsied immediately following end of the treatment (males on Day 15, females on Day 16). Additionally, blood methemoglobinuria levels (metHb) and urinary excretion of N-acetyl-4-amino-m-creosol (NAAC), an o-toluidine metabolite, were examined as potential biological markers of toxic exposure. Treatment was associated with no mortality and small, but statistically significant, weight loss (males and females; 3000, 6000 ppm) in the first week of treatment; other clinical observations were sporadic and not considered treatment-related. Treatment was also associated with statistically significant (p < 0.05), dose-related elevations of metHb and dose-related increases in urinary NAAC, o-Toluidine induced UDS and statistically significant CP in 6,000 ppm males and females. Mild hyperplasia and minimal thickening of the urothelial layer characterized the histopathology of high dose females and males, respectively, while minimal thickening of the urothelial layer was noted occasionally among both males and females of an intermediate exposure. The study authors cited a weak correlation of increases in both metHb and urinary NAAC and/or CP indices with dietary levels of o-toluidine.[E I Dupont de Nemours & Co; Urinary Bladder Toxicity, 14-Day Feeding Study with o-Toluidine in Rats; 06/03/94; EPA Document No. 86940001153; Fiche No. OTS0557449]**UNREVIEWED**
  
• Tissue distribution and the degree of covalent binding to hepatic macromolecules were investigated in male Crl:CDBR rats (number not reported) administered by gavage a single dose of 500 mg ortho-toluidine/kg body weight. The level of covalent binding of o-toluidine to hepatic DNA and RNA was generally low (<1 pmol/ug) and plateaued after 24-48 hours. The level of binding to hepatic proteins was 2.0 (+/- 0.1) pmol/ug. After 72 hours, the highest organ concentration of test material remaining in the body was in whole blood (22.6 ug equivalents/gram tissue), followed by the spleen, kidneys, and liver with 19.2, 17.2, and 16.3 ug equivalents/gram tissue, respectively. The routes of elimination, and metabolism, of the test substance were not monitored.[E.I. DuPont De Nemours & Co.; Hepatic Macromolecular Binding and Tissue Distribution on ortho-Toluidine and para-Toluidine in Rats (1989), EPA Document No. 86-890001413S, Fiche No. OTS0521029]**UNREVIEWED**
  

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Footnotes

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