Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 79-46-9 Toxicity Effects

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

Names (NTP)

  • 2-Nitropropane
  • DIMETHYLNITROMETHANE

Human Toxicity Excerpts

  • HUMAN EXPOSURE STUDIES: The acute effects of exposure to 2-nitropropane at 20-45 ppm on workmen were anorexia, nausea, vomiting, diarrhea and severe occipital headache. Complete recovery occurred overnight. [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. 395]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: ... Prolonged repeated exposure to concentrations of 20 to 45 ppm (73 to 164 mg/cu m) of 2-nitropropane produced nausea, vomiting, diarrhea, anorexia, and severe headache. Toxic hepatitis was found in construction workers applying epoxy resins to the walls of the nuclear power plant. ... However, exposure to 2-nitropropane occurred when the workers washed the epoxy resins from their skin. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 3]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: 2-Nitropropane /effects primarily/ the respiratory and central nervous systems. [Sittig, M. Handbook of Toxic And Hazardous Chemicals. Park Ridge, NJ: Noyes Data Corporation, 1981., p. 501]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Symptoms: Irritation of eyes; headache, depressed appetite, nausea, vomiting, diarrhea. [ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988., p. 377]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Human volunteers noted eye irritation from nitropropane at a concentration of 150 ppm in air. /Nitropropane/ [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 669]**PEER REVIEWED**
  • CASE REPORTS: Chronic exposure to concentrations above 25 ppm has produced anorexia, nausea, vomiting, headache, and diarrhea in industrial workers. ... High acute industrial exposures in poorly ventilated areas have been associated with acute hepatic failure and death, although these exposures include a variety of solvents. In one case of fulminant hepatic failure in a worker, the serum 2-nitropropane level on admission was 13 ug/mL; it was 8.5 ug/mL in a coworker with mild hepatic dysfunction. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 967]**PEER REVIEWED**
  • CASE REPORTS: Ten fatalities have been reported among workmen overexposed to solvent mixtures. All cases involved the application of coatings in poorly ventilated, confined spaces. The one agent common to all was 2-NP, which occurred in the solvent mixtures at concentrations of 11 to 28%. All patients showed typical signs of 2-NP overexposure, headache, nausea, vomiting, diarrhea, and chest and abdominal pains, but the prodromal signs were somewhat nonspecific and similar to those from overexposure to any variety of solvents. The characteristic lesion in the fatal cases was destruction of hepatocytes. In all cases, liver failure was the primary cause of death. This was well documented by antemortem findings of elevations in serum enzymes and postmortem findings of microscopic evidence of liver changes. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 p. 571]**PEER REVIEWED**
  • CASE REPORTS: High concentrations are acutely toxic and 7 industrial fatalities have been attributed to inhalation of 2-NP vapor. ...The actual concentrations of 2-NP that caused deaths were not measured, but were thought to be high and in one case estimated at 2.18 g/cu m (600 ppm), as determined by GC-FID from the 2-NP content of the victim's blood (0.013 g/L). Initial symptoms requiring medical treatment appeared during exposure or within a few hours following exposure and included headache, nausea, dizziness, drowsiness, weakness, anorexia, vomiting, diarrhea, and neck, thoracic, and abdominal pain. Victims were hospitalized and in general initially showed improvement, in some cases to the point of being discharged after a day or less. But improvement, where present, was temporary and in all 7 cases was followed within a few days by worsening condition and rehospitalization of those previously discharged. Later symptoms included persistent nausea, vomiting, anorexia, jaundice, reduced urine output, diarrhea, bloody stools, mental confusion, restlessness, loss of reflexes, and increases in serum aminotransferases and other indicators of hepatic lesions. Death occurred within 4 to 26 days (average, 10 days) following exposure. In all cases the primary cause was acute hepatic failure. Contributing factors included lung edema, gastrointestinal bleeding, and respiratory and kidney failure. Postmortem microscopic examination of the liver revealed necrosis of hepatic tissue and in some cases fatty degeneration. None of the victims had a past history of liver disease or drank /ethanol/ excessively. [WHO; Environ Health Criteria 138: 2-Nitropropane p.74 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**
  • CASE REPORTS: In addition to ... fatalities, there have been four additional serious but nonlethal cases attributed to acute exposure to 2-NP. All but one were colleagues of the deceased described above, but may have received lesser doses. Initial symptoms were similar to those of the deceased, but were followed by full recovery rather than decline and death. Serum enzyme levels, however, remained mildly elevated for months following exposure. As in the case of the deceased, the actual concentrations of 2-NP to which these workers were exposed are unknown. One of the survivors had a 2-NP serum concentration of 8.5 mg/L when hospitalized. Since his coworker hospitalized at the same time with a serum concentration of 13 mg/L subsequently died, /it was/ speculated that either 2-NP has a very steep dose-response curve or that there are substantial differences in individual susceptibility. [WHO; Environ Health Criteria 138: 2-Nitropropane p.50 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**
  • CASE REPORTS: ... Two construction workers... were exposed to 2-nitropropane while applying epoxy resin coating. One man died 10 days after exposure from fulminant hepatitis, the other man had persistently elevated serum aminotransferase activity. Serum concentrations of 2-nitropropane on admission were 13 mg/L in the man who died and 8.5 mg/L in his co-worker. [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. V71 1083 (1999)]**PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: A retrospective mortality study of a group of 1481 employees and former employees of a 2-nitropropane production facility... with up to 27 years of exposure were reported. ... When mortalities for all males (regardless of job title) were combined, there were 4 deaths from lymphatic cancer where only 1 was expected. Among the 147 women, there were 8 deaths from all causes (compared to an expected 2.9 deaths) and 4 deaths from cancer compared with 0.8 expected. Seven of the total number of deaths were attributed to sarcomatous cancers. ... Lack of individual exposure data, the limited number of workers with long term exposures (15 years), and the small number of deaths among the group studied, prohibit the conclusion from these data that 2-nitropropane is without carcinogenic activity in humans. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 3]**PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: An occupational health examination program was carried out in workers exposed to 2-nitropropane, generally at levels <25 ppm, during an 8-hr workday. The period of exposure ranged from <1 yr to 40 years. Of the 28 exposed workers examined (out of a total workforce of 46 examined), no excess abnormalities of the skin, blood, renal, liver, pulmonary and cardiac systems were noted that could be associated with exposure to 2-nitropropane. [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Acute Exposure: Cats that died following several exposures at 328 ppm had microscopic evidence of focal necrosis and parenchymal degeneration in the liver and slight to moderate degeneration of the heart and kidneys. The lungs showed pulmonary edema, intraalveolar hemorrhage, and interstitial pneumonitis. Cats also developed 25 to 35% methemoglobin when exposed at 750 ppm for 4.5 hr and about 15 to 25% methemoglobin during repeated, daily, 7 hr exposures at 280 ppm. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 p.570]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Acute exposures of rats, guinea pigs, rabbits, and cats to 2-NP via inhalation.../at/ high concentrations produced dyspnea, cyanosis, prostration, convulsions, lethargy, and weakness, proceeding to coma and death. Some animals that survived the acute exposure died in 1 to 4 days later. These high concentrations of 2-NP caused pulmonary edema and hemorrhage, selective disintegration of brain cells, hepatocellular damage, and general vascular endothelial injury in all tissues. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 p.568]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Dermal exposure to 2,000 mg/kg 2-nitropropane did not cause death, clinical signs of toxicity or skin irritation in rabbits. [EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Program's Robust Summaries and Test Plans. Available from: http://www.epa.gov/chemrtk/viewsrch.htm on 2-Nitropropane as of July 11, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: BALB/c mice //were treated// intraperitoneally with a single dose of 9 mmol/kg bw 2-nitropropane. In male mice, plasma activities of the hepatic enzymes sorbitol dehydrogenase, alanine aminotransferase and aspartate aminotransferase were significantly elevated, while doses of 6.7 mmol/kg bw were ineffective. In female mice, a dose of 6.7 mmol/kg bw was sufficient to cause hepatotoxicity. Histopathological evaluation revealed hepatic damage, particularly in the periportal region. [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. V71 1081 (1999)]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Tested in rabbits ... slightly more toxic than nitromethane or nitroethane. Mildly irritating to mucous membranes but not skin. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-213]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Severity and time of onset of symptoms varied ... In most ... animals lethargy and prostration appeared before dyspnea and occasional convulsions. ... Cats and rats /showed/ coma and death ... in a short time; rabbits and guinea pigs, after apparent partial recovery, died 1-4 days later. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 287]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: With non-lethal but high concentrations, unsteady gait and partial loss of coordination in cats, but no signs of intoxication ... observed in any animals subjected to 83 ppm. Cats showed lacrimation, salivation and gastric regurgitation. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 287]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Methemoglobin formation ... 60-80% was developed by cats with severe exposure, and 25-35% with exposure to 780 ppm for 4-5 hr. With latter ... 1/5 ... amount received by rabbits was necessary to produce same amount ... methemoglobin in cats. Heinz bodies ... more frequent and at lower concentrations in cats ... [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 287]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: In cats exposed to 328 ppm /heart and kidneys/ ... showed some toxic degeneration. In other species this concentration caused none of these lesions. In the brain all animals exposed to ... higher concentrations showed disintegration of cerebral neurons. Lungs ... showed pulmonary edema, intra-alveolar hemorrhage and interstitial pneumonitis. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 288]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Ip injection (50 mg/kg) induced lipid accumulation, centrilobular necrosis, degranulation of rough and proliferation of smooth endoplasmic reticulum and mitochondrial abnormalities in rat liver 24 hr after exposure. [Zitting A et al; Toxicol Lett (Amst) 9 (3): 237-46 (1981) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Ip injection (50 mg/kg) in rat elevated serum alanine aminotransferase, depressed hepatic cytochrome P450 and microsomal monooxygenase while epoxide hydratase, UDP-glucuronosyltransferase and cytosolic glutathione peroxidase were enhanced, as was brain acetycholinesterase. [Zitting A et al; Toxicol Lett (Amst) 9 (3): 237-46 (1981) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Wistar rats were divided into 4 groups (5 males and 5 females per group) and dosed by gavage with 2-nitropropane as an emulsion in 1% methyl cellulose at 0, 20, 200 or 400 mg/kg bw/day for 28 days. In the high dose group, all male rats died within 1 day and all female rats within 10 days. At 200 mg/kg bw/day, all male rats died within 7 days while all females survived. Effects in the surviving females of the high dose group included reduced body weight gain, higher alanine aminotransferase, aspartate aminotransferase and total bilirubin, and lower serum total protein and albumin levels. In addition, there was an increase in liver weights and multiple hepatic changes including multifocal single cell necrosis and Kupffer cell pigmentation. In the lowest dose group multifocal centrilobular hepatocellular hypertrophy was observed. There were no changes in blood biochemistry values. The authors concluded that the changes in the low dose group were metabolic adaptations. [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rats and rabbits exposed to 2-NP for 6 months via inhalation at 27 and 207 ppm showed very few classical signs of nitroparaffin toxicity. No effects on body weight gain or hematology were observed at either concentrations. Liver weights from rats exposed at 27 ppm were comparable to those of controls. However, severe neoplastic changes were observed in the livers of male rats exposed to 207 ppm 2-NP for 6 months. The only effect reported for rabbits exposed to 207 ppm 2-NP was elevation in ornithine carbamyl transferase after 1 and 3 months. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 p.570]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In a drinking water study, Fischer 344 rats (10 males and 10 females per group) were dosed with 1000, 100, 10, 1.0 or 0.1 or 0 mg/L of 2-nitropropane for 4 weeks (equivalent to 128 and 99 mg/kg bw/day for female and male rats in the 1000 mg/L groups, respectively, and 17 and 14 mg/kg bw/day for male and female rats in the 100 mg/L groups, respectively, based on daily fluid consumption). Reduced food and fluid consumption and reduced body weight gain were observed in the highest dose group, as well as elevated organ weights. In the 100 mg/L group there was a slight elevation in liver weights in males. The authors concluded that there were no treatment-related effects at 10 mg/L (estimated to be 1 to 2 mg/kg bw/day). [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Prothrombin content of blood showed some reduction in ... 2 cats only, time ... for clotting during repeated exposure to about 328 ppm increased from 24.0 and 23.5 to 40 and 50 sec respectively. No changes ... observed in ... peripheral blood picture. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 287]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rats, rabbits, and guinea pigs survived inhalation of 2-nitropropane at a concentration of 328 ppm for 7 hr/day for 130 days. Cats survived only a few days; methemoglobinemia and Heinz body formation were present along with early evidence of hepatic necrosis. [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. 395]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Liver weights were elevated in rats exposed to 207 ppm for 1, 3, and 6 months. Liver neoplasms were seen in rats killed following 6 months of exposure to 207 ppm. [Lewis TR et al, J Environ Pathol Toxicol 2 (5): 233 (1979) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Sprague-Dawley rats (125 of each sex per group) were exposed to 0 or 25 ppm 2-NP for 7 hr/day, 5 days/week, for 2 months. Interim sacrifices were conducted (10 of each sex) after 1, 3, 6, and 12 months, and recovery groups were initiated (10 of each sex) after 3 and 12 months of exposure. No effects on body weight, clinical signs, clinical chemistries, or hematology and no methemoglobinemia were observed. There were no tumors in any organ or tissue, including the liver. Relative liver weights were slightly elevated in males, and focal areas of hepatocellular nodules were seen with greater incidence in males (2/125 for controls, 10/125 for 2-NP at 25 ppm). No indication of hepatoxicity was observed. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 p.571]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Male and female Sprague-Dawley rats, four to six days of age, were exposed by whole-body inhalation to concentrations of 0, 25, 40, 50, 80 and 125 ppm [0, 91, 146, 182, 292 and 456 mg/m3] 2-nitropropane (99% pure) for 6 h per day on five days per week for three weeks. One week later, a polychlorinated biphenyl (Clophen A50) was administered orally at a dose of 10 mg/kg bw twice per week for eight weeks. Thirteen weeks after the start of the experiment, the number of preneoplastic adenosine-5- triphosphatase-deficient foci in the liver was found to increase linearly with the exposure concentration, demonstrating the initiating activity of 2-nitropropane. [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. V71 1081 (1999)]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: A group of male and female rats were exposed to 2-nitropropane at a concentration of 200 ppm, 7 hr/day 5 days/wk for up to 6 months. Groups were killed after 10 days, 1 month, 3 months and 6 months. One group was held for an additional 6-month postexposure period. Morphological changes occurred more extensively in males that included hepatocellular nodules, hyperplasia, necrosis and multivacuolated fatty metamorphosis. The livers of six of ten rats had pre-neoplastic foci and metastasizing tumors were apparent in nine out of ten rats that were held 6 months post-exposure. Similar findings were observed after exposing rats to 2-nitropropane at a concentration of 100 ppm for 18 months. Hepatocellular carcinoma occurred in males after 12 months of exposure and in females after 18 months. [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Cats, rabbits, rats, guinea pigs and monkeys ... exposed ... to 328 and 83 ppm for 7 hr/day. Cats died following several days exposure to 328 ppm, but rabbits, rats, and guinea pigs survived 130 exposures and a monkey survived 100. No signs or symptoms ... observed in any animals during 130 exposures to 83 ppm. [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. 4159]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Rats exposed by inhalation at 25 ppm for 7 hr/day, 5 days/wk over a period of 22 months showed no methemoglobinemia, no malignancies or any significant pathologic changes in liver. [Griffin TB et al, Ecotoxicol Environ Saf 4 (3): 267-81 (1980) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In a NIOSH sponsored inhalation study, male Sprague-Dawley rats and New Zealand male rabbits were exposed to commercial grades of 2-nitropropane for 7 hours/day, 5 days/week for 6 months. One group of 50 rats and 15 rabbits was exposed to 207 ppm (750 mg/cu m), a second group of the same size was exposed at 27 ppm (98 mg/cu m), and a third group served as controls. Liver neoplasms, described as hepatocellular carcinoma or hepatic adenoma, were observed in all ten rats killed after six months of exposure at 207 (750 mg/cu m) of 2-NP. No tumors were observed in any other animals (rabbits or low-dose rats) in this study, including controls. Hepatocellular hypertrophy, hyperplasia, and necrosis were reported in rats exposed at 207 ppm for three months; elevated liver weights occurred in rats exposed at 207 ppm for one, three, and six months. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Male Wistar rats, three to four weeks of age, received six intraperitoneal injections of 25, 50 or 100 mg/kg bw 2-nitropropane (95% pure) every two days. Between the 42nd and 56th day of the experiment, 2-acetylaminofluorene (2-AAF) dissolved in corn oil was added to the diet at a concentration of 50 mg/kg diet (ppm). In the middle of the 2-AAF treatment period (on day 49), rats were subjected to partial hepatectomy. From day 56, phenobarbital sodium was added to the diet at a concentration of 500 ppm for two weeks. After 70 days of the experiment, rats were killed and the livers examined for gamma-glutamyltranspeptidase (gamma-GT) and for glutathione S-transferase (GST) foci. The numbers of gamma-GT positive foci per cm2 were 0.6, 3.7, 5.5 and 22.2 in the control, low-dose, mid-dose and high-dose groups, respectively. The numbers of GST-positive foci were 1.4, 10.8, 10.7 and 29.9 in the four groups, respectively [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. V71 1081 (1999)]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: 2-NP was a hepatic carcinogen for male, but not female rats of the Sprague-Dawley derived strain following a 6 month daily, 7 hr exposure at 207 ppm. Multiple hepatic carcinomas and numerous neoplastic nodules were present in the livers of all 10 rats exposed at 207 ppm 2-NP for 6 months but not at 27 ppm. Blood-filled cysts were occasionally seen in the neoplasm, and mitotic figures were frequently present. The hepatocellular carcinomas were rapidly growing and severely compressing the surrounding parenchyma. No metastatic hepatocellular carcinomas were seen in any of the other tissues examined. The difference between male and female rats in their response to 2-nitropropane is another important clue. The compound is more potent in males for liver toxicity, carcinogenicity, and induction of DNA repair synthesis. Differences in saturable metabolism between the two sexes point to a key role for metabolites produced by a first order pathway. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 p. 570]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: 2-NP also causes hepatocarcinogenicity in rats given oral exposure. Sprague-Dawley rats (29 controls, 22 treated) were given gavage doses of vehicle or 2-NP (1 mmol/kg) three times per week for 16 weeks. Animals were sacrificed in the 77th week after treatment was initiated. 2-NP decreased body weight gain and caused massive hepatocellular carcinomas. Metastases were also seen in the lungs of four animals. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 p.571]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: 2-Nitropropane (redistilled) was administered by gavage to weanling male Sprague-Dawley rats at a dose of 1 mmol/kg bw three times per week for 16 weeks. All surviving rats were killed at week 77. Benign liver tumours appeared in 4/22 treated animals versus 1/29 controls and malignant liver tumors occurred in 22/22 treated rats versus 0/29 controls (p < 0.001). [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. V71 1081 (1999)]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: This study was carried out on groups of 25 male Sprague-Dawley rats. An untreated group was administered 100 mg/day glutathione by gavage, another group was administered diethyl maleate (0.6 mL/kg) ip, and a third group served as a control. The test groups were exposed to 200 ppm 2-nitropropane by inhalation, 7 hr/day, 5 days/week. The glutathione-treated animals in the test group were treated 5 days/week prior to exposure to 2-nitropropane, and the diethyl maleate group were exposed 5 days/week and later 3 days/week to 2-nitropropane. Interim sacrifices (5 rats/group) were carried out at 3 months and 6 months, and the remaining animals were sacrificed at 7 months. Glutathione did not have any effect on the progressive development of nodular hyperplasia and hepatocellular carcinoma. Diethyl maleate, which causes a marked reduction in blood glutathione levels, delayed the appearance of hepatic cell injury and no hepatocellular carcinomas were observed at terminal sacrifice in this group. [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Rats were exposed to 170 mg 2-nitropropane/kg bw by ip injections on days 1-15 of gestation. The treatment caused developmental abnormalities in the cardiovascular system of pups from mothers treated with 2-nitropropane. [Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000., p. 773]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: A dominant lethal test was carried out in male rats with exposure to atmospheres containing 25 ppm or 200 ppm 2-nitropropane for 7hr/day for 5 consecutive days. There were no effects attributable to 2-nitropropane on pregnancy frequency, numbers of corpora lutea or implantations, or the frequency of early deaths. Reductions to 75% were seen, however, in pregnancy frequencies in weeks 1 and 5 of the 200 ppm atmosphere group and in the frequencies of live implantations and late deaths in week 2 of the 200 ppm atmosphere group. A sperm abnormality test was carried out in male mice with exposure to atmospheres containing 25 ppm or 200 ppm 2-nitropropane for 7 hr/day for 5 consecutive days. Sperm abnormality frequency was not increased by 2-nitropropane treatment neither was the frequency increased by EMS treatment. These results were therefore consideredto be inconclusive. [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Neurotoxicity: Observations ... indicated that a single intraperitoneal injection of 0.05 g 2-NP/kg to rats can produce significant changes in the fine structure of the liver and in the physiology of both liver and brain. ...The major observed neurochemical effect was a significant increase in acetylcholine esterase activity in the cerebrum and in isolated synaptosomes. There was little or no change in RNA, 2',3'-cyclic nucleotide 3'-phosphohydrolase, or acid proteinase in the brain. [WHO; Environ Health Criteria 138: 2-Nitropropane p.50 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**
  • GENOTOXICITY: One set of genotoxicity tests using rats... yielded strongly positive results. In both in vivo and in vitro tests, 2-NP induced DNA repair synthesis in rat liver cells. In the in vitro experiments, cultures of rat hepatocytes were incubated with 2-NP, while in the in vivo experiments rats were injected intraperitoneally with 2-NP, sacrificed 4 hr later, and cultures of their hepatocytes were examined for DNA repair synthesis. Exposure of hepatocyte cultures for 18 to 20 hr to concentrations of 2-NP as low as 2.7 mg/L (30 umol/L) induced a detectable (approximately 2-fold above the control level) increase in repair synthesis. The highest concentration tested, i.e. 89 mg/L (10 mmol/L), induced a 12- to 15-fold increase above control levels in hepatocytes from male rats and a 25- to 30-fold increase in hepatocytes from female rats. The in vivo experiments also demonstrated the existence of a sexual difference in susceptibility to 2-NP. In males, the lowest dose (20 mg/kg) induced a doubling in repair synthesis and the highest dose (80 mg/kg) a 3.6-fold increase, whereas in females these doses induced a very small increase and a doubling, respectively. In contrast to 2-NP, 1-NP given in vivo had no effect on DNA repair synthesis and did not increase in vitro repair synthesis above that expected from its contamination with 2-NP. .../The/ results from the in vivo experiments were in agreement with the observed greater hepatocarcinogenicity of 2-NP in male rats than in females. Their observation that 2-NP did not induce any increase in repair synthesis in any of nine non-hepatic cell lines derived from human, mouse, hamster, and rat tissues led the authors to suggest that 2-NP is not a direct-acting genotoxic agent but rather requires metabolic activation by liver-specific metabolism. [WHO; Environ Health Criteria 138: 2-Nitropropane p.68 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**
  • GENOTOXICITY: 2-Nitropropane (2-NP) was evaluated for cytogenetic effects in cultured human lymphocytes at concentrations of 0, 15, 30, 60 and 80 mM. Experiments were performed with and without metabolic activation. Without activation, the frequency of gaps was significantly increased at the 80 mM dose level. With activation, the frequency of gaps and chromatid-type aberrations (primarily breaks) were significantly increased at the 60 and 80 mM dose levels. Sister chromatid exchanges were evident in the presence of metabolic activation at or above the 30 mM dose level. Thus, 2-NP was positive in these tests and the lowest effective dose tested was 30 mM. [Bauchinger M et al; Mutat Res 190: 217-19 (1987) ]**PEER REVIEWED**
  • GENOTOXICITY: A putative reduced metabolite, 2-aminopropane, showed no mutagenic activity, suggesting that its reduction in vivo is not necessary for 2-nitropropane to exert its mutagenic effect. [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. 396]**PEER REVIEWED**
  • GENOTOXICITY: In the Salmonella typhimurium/mammalian microsome (Ames) test increased revertants in the Salmonella tester strains. In an in vivo mutagenic (micronucleus) test, negative results were obtained. [Hite M, Skeggs H; Environ Mutagen 1 (4): 383-9 (1979) ]**PEER REVIEWED**
  • GENOTOXICITY: Negative results in Drosophila sex-linked recessive lethal. [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. V29 336 (1982)]**PEER REVIEWED**
  • GENOTOXICITY: 2-Nitropropane is considered genotoxic. 2-NP modifies rat and rabbit liver DNA and RNA nucleosides in vitro. Base modifications include 8-aminodeoxyguanosine, 8-oxodeoxyguanosine in DNA, and 8-aminoguanosine and 8-oxoguanosine in RNA. 2-NP was active both with and without metabolic activations when tested for mutagenicity in the Ames assay. Generally metabolic activation had no effect or slightly reduced the number of revertants. One report the Ames strain TA 100 indicated that the mutagenicity of 2-NP was attributed to the formation of the metabolite 2-nitropropionate. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 p.572]**PEER REVIEWED**
  • GENOTOXICITY: An unscheduled DNA synthesis (UDS) assay was carried out in human diploid fibroblasts with exposures of 3 hours duration and concentrations up to 5,000 ug/mL of culture medium. There was no increase in UDS in cells treated with 2-nitropropane. [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • GENOTOXICITY: In vitro, in the absence of an exogenous metabolic system, 2-nitropropane induced unscheduled DNA synthesis in rat and mouse liver cells. It induced gene mutations in Chinese hamster cells and rat hepatoma cells in the absence of an exogenous metabolic system. In the absence of an exogenous metabolic system, 2-nitropropane induced micronuclei in three rat hepatoma cell lines but not in Chinese hamster cells. [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. V71 1084 (1999)]**PEER REVIEWED**
  • GENOTOXICITY: Observations ...suggest that cytochrome P-450-dependent monooxygenases are important in the activation of 2-nitroprpane (2-NP) in liver. /One study/... found an increase in damage to liver DNA in rats pretreated with phenobarbital or beta-naphthoflavone, inducers of cytochrome P-450-dependent monooxygenases, and a reduction in liver DNA damage in rats pretreated with methoxsalen, an inhibitor of cytochrome P-450. /Another study/... examined the effect of 2-NP on rat hepatoma cell lines that express various forms of cytochrome P-450-dependent monooxygenases and V79 Chinese hamster cells that lack these enzyme activities. 2-NP increased DNA repair synthesis, micronuclei formation, and the frequency of mutants resistant to 6-thioguanine in hepatoma cells pretreated with dexamethasone, an inducer of various liver-specific cytochrome P-450 forms. Genotoxicity was reduced or absent in hepatoma cells not treated with the inducer. In the V79 cells, 2-NP produced only mutations to 6-thioguanine resistance. [WHO; Environ Health Criteria 138: 2-Nitropropane p.69 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**
  • ALTERNATIVE IN VITRO TESTS: ...In vitro studies with guinea-pig tissues suggest that 2-NP may have several pharmacological effects. A 0.1 uM (8.9 ug/L) solution inhibited oxygen consumption of polymorphonuclear leucocytes by 50%. These authors further reported that, with increasing concentrations of 2-NP, respiration of heart homogenate was initially depressed and subsequently stimulated. 2-NP also produces two opposite neural effects on smooth muscle preparations. Contraction is induced partly by ganglionic stimulation and partly by direct liberation of a transmitter from nerve endings, but at the same time 2-NP inhibits the response to acetylcholine and other smooth muscle stimulants. ...The action of nitroparaffins on smooth muscle was /found to be/ similar to that of nicotine in that their ability to induce contraction was inhibited by morphine and by high, but not low, concentrations of atropine. [WHO; Environ Health Criteria 138: 2-Nitropropane p.73 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: ... Lethal dose was found to be a product of concentration and length of exposure, death ... from shorter ... exposure to higher concentrations. Susceptibility of different species was also a factor, decreasing in the following order: cats, rats, rabbits, and guinea pigs. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 287]**PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Sprague-Dawley Rat oral 720 mg/kg [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 1]**PEER REVIEWED**
  • LC50 Sprague-Dawley Rat (male) inhalation 400 ppm/6 hr [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 1]**PEER REVIEWED**
  • LC50 Rat inhalation 1513 ppm/4.5 hr /from table/ [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LC50 Rat inhalation 3712 ppm/1 hr /from table/ [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LD50 Rabbit oral 500 mg/kg bw [Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 1642]**PEER REVIEWED**
  • LC50 Rabbit inhalation 2381 ppm/4.5 hr /from table/ [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LD50 Rabbit dermal >2000 mg/kg bw [European Chemicals Bureau; IUCLID Dataset, 2-Nitropropane (79-46-9) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of July 11, 2005. ]**PEER REVIEWED**
  • LC50 Guinea pig inhalation 4622 ppm/5.5 hr /from table/ [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LD50 Mouse oral 0.40 g/kg/14 days [WHO; Environ Health Criteria 138: 2-Nitropropane p.44 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LC50 Mouse (male) inhalation 2031 mg/cu m (558 ppm)/6 hr [WHO; Environ Health Criteria 138: 2-Nitropropane p.44 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LC50 Mouse (female) inhalation 2038 mg/cu m (560 ppm)/6 hr [WHO; Environ Health Criteria 138: 2-Nitropropane p.44 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**
  • LD50 Mouse (Swiss ICR/HQ) ip 0.80 g/kg /from table/ [WHO; Environ Health Criteria 138: 2-Nitropropane p.47 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • Following absorption by the gastro-intestinal tract and the lungs, part is eliminated unchanged in the expired air, part excreted in the urine as nitrite and nitrate. There is no evidence of absorption by the skin sufficient to cause systemic injury. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 286]**PEER REVIEWED**
  • The pharmacokinetics of [14C]-2-nitropropane (2-NP) were studied in male rats exposed for 6 hr to 20 or 154 ppm. At least 40% of the inhaled compound was absorbed. Blood concentrations of 2-NP measured by gas chromatographic analysis decreased in an apparent first order manner (half life = 48 min). Half lives for the biphasic elimination of radioactivity from blood were two to four times longer, indicating that metabolites have a greater potential to accumulate. The major route of excretion was the expired air. About half of the administered radioactivity was recovered as 14CO2. Numerous differences in kinetic parameters observed at the two exposure concentrations indicated nonlinear kinetics at 154 ppm and higher.There were no differences in uptake or exhalation processes between males and females, but metabolic processes differed. A first-order, low-affinity but high capacity metabolic pathway was more than twice as active in females. The saturable pathway was predominant in females at exposure concentrations up to 180 ppm but only up to 60 ppm in males. Because males are more sensitive to hepatoxicity, genotoxicity, and carcinogenicity produced by inhalation of 2-NP, /it was/ concluded that these effects are produced by the metabolite resulting from the first-order pathway. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4 p.569]**PEER REVIEWED**
  • ...Immediately following exposure to 728 mg/cu m (200 ppm) for 3 hr, plasma contained approximately 0.4% as 2-nitropropane (2-NP) and 7.2% as metabolitesof the 2-NP inhaled. The metabolites were mainly acetone but also included a small amount of isopropanol. These percentages were estimated from the results ... and normative data for the laboratory rat, and support rapid pulmonary uptake of 2-NP since 2-NP and its metabolites sequestered elsewhere in the body and loss of metabolized 2-NP during exposure were not considered. [WHO; Environ Health Criteria 138: 2-Nitropropane p.34 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 8, 2005. ]**PEER REVIEWED**
  • The rate of 2-nitropropane (2-NP) uptake by rats from intraperitoneal injection was examined. Ten minutes after an injection of 25 mg/kg, the blood plasma contained 3.3% of the dose as 2-NP and 1.9% as metabolites, acetone, and isopropanol, indicating an uptake of >5.2% since presumably some of the dose was already lost from the body and to other tissues in the body during this initial period. These percentages were estimated from the data ... and normative data for the laboratory rat. A dose of 50 mg/kg yielded partially dissimilar results. The 10-min average value was low and also had a very large standard deviation. This may have reflected large differences among the rats in their initial uptake rates for 2-NP or an experimental problem such as injection into the gastrointestinal tract rather than the peritoneal cavity. Blood plasma contained, 10 min after injection, only 1.4% of the dose as 2-NP and 1.3% as acetone and isopropanol. These data indicate that uptake from the peritoneal cavity is fairly rapid, and suggest that the relatively slower uptake of the 50-mg/kg dose may have reflected saturation of the uptake mechanisms, since initial concentrations in the plasma did not exceed those following the 25-mg/kg dose. [WHO; Environ Health Criteria 138: 2-Nitropropane p.34 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 8, 2005. ]**PEER REVIEWED**
  • Absorption of 2-nitropropane (2-NP) via the gastrointestinal tract was investigated with male Wistar rats. They found that the systemic availability of orally administered 2-NP from a water solution was very high (90%) and absorption was rapid, maximum plasma values being reached within 15 min after dosage. Absorption of 2-NP given in olive oil was much slower and availability was only 34% during the initial 3 hr following dosage.The authors suggested that absorption from oil was incomplete at 3 hr and might ultimately be much higher, since the olive oil was absorbed and the 2-NP redistributed between the oil and aqueous phases. [WHO; Environ Health Criteria 138: 2-Nitropropane p.35 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 8, 2005. ]**PEER REVIEWED**
  • Groups of 8-10 Wistar rats were administered 2-nitropropane by intraperitoneal injection or inhalation. Injection of 1.7 g/kg bw caused death in two hours and 89% blood methemoglobin. Quantities of nitrite (1-2.5 mg/100 g tissue) were found in the heart, lungs, kidney, spleen and liver. There was no trace in the other organs and pulmonary excretion amounted to 76% of the injected dose. Injection of 0.11 g/kg bw/day for 15 days followed by sacrifice 36 hours after the last injection produced no methemoglobin, but nitrite was found in all organs examined except the liver. 2-nitropropane was found in the liver and lungs at concentrations of 18.7 and 360 mg/100 g tissue,respectively. Urinary excretion of nitrite was also noted. [JECFA; WHO Food Additive Series 26: Toxicological Evaluation of Certain Food Additives and Contaminants- 2-Nitropropane (1990). Available from: http://www.inchem.org/documents/jecfa/jecmono/v26je09.htm as of July 11, 2005. ]**PEER REVIEWED**
  • Although workers are cautioned against dermal contact with 2-nitropropane (2-NP), there appear to be no quantitative data on dermal absorption. The solubility of 2-NP in both polar and non-polar solvents, together with its small molecular size, suggests that it should be absorbed readily through the skin. Dermal application of 2 g 2-NP/kg to rabbits produced no obvious symptoms; however, ...the rabbit is relatively resistant to the toxicity of 2-NP. [WHO; Environ Health Criteria 138: 2-Nitropropane p.35 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 8, 2005. ]**PEER REVIEWED**
  • The distribution of 2-nitropropane (2-NP) and its carbon-containing metabolites among the organs and tissues in Sprague-Dawley rats was examined... via inhalation, and ... via intraperitoneal injection. Both utilized 14C-labelled 2-NP and thus their data do not reveal the distribution of nitrite and other nitrogen-containing metabolites generated from the nitro portion of the 2-NP molecule. One hour after intraperitoneal injection, radioactivity was concentrated in fat; there were intermediate amounts in the blood, liver, and kidney, and lower amounts in other organs and tissues. By 40 hr, the highest concentrations were in bone marrow and adrenal tissue, intermediate amounts being found in the kidney, liver, spleen, lungs, and omental fat, and by 8 days only the concentration of 14C in adrenal tissue was noticeably greater than elsewhere in the body. However, /a different study/... found, both immediately and 48 hr after a 6-hr period of 2-NP inhalation, that highest concentrations of carbon from 2-NP were in the liver and kidney and relatively little in the fat. [WHO; Environ Health Criteria 138: 2-Nitropropane p.36 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 8, 2005. ]**PEER REVIEWED**
  • Pulmonary excretion of 2-nitropropane (2-NP), like loss of the 14C label from plasma, is dose dependent, biphasic, and follows first-order kinetics. Fifty times more 2-NP was exhaled during the first hour following exposure to 560.6 mg/cu m (154 ppm) than during the first hour following exposure to 73 mg/cu m (20 ppm). Following exposure to 73 mg/cu m, 2-NP was excreted for the first 7 hr at a rate which decreased by one half every 64 min,and subsequently decreased by one half every 16 hr, whereas following exposure to 560.6 mg/cu m, the half-times of excretion were 71 min for the first 12 hr, and 16 hr for the subsequent period. Changes in the rates of pulmonary excretion of 14C-labelled carbon dioxide were similar for 48 hr following exposure to 73 and 560.6 mg/cu m. 87% of the total was eliminated during the first 12 hr after exposure; loss was somewhat less rapid thereafter. The dose-dependent nature of pulmonary excretion of 2-NP suggests that greater concentrations of 2-NP in the blood markedly increase exhalation of the unchanged compound and reduce the percentage metabolized. Thus exposure of the tissues to 2-NP and its metabolites may not be a linear function of the inhaled dose. [WHO; Environ Health Criteria 138: 2-Nitropropane p.40 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 8, 2005. ]**PEER REVIEWED**
  • ...Following iv injection of 14C-labelled 2-nitropropane (2-NP) (10 mg/kg) into male chimpanzees; the concentration of 2-NP in plasma declined exponentially with time, the half-life being 92 min. The concentration of acetone reached a maximum 6 hr after injection and remained high for at least 48 hr. The concentration of isopropanol peaked 3 hr after injection when it approached that of acetone, but otherwise was a third to a quarter that of acetone. The concentration of 2-NP and its carbon-containing metabolites (i.e.the concentration of 14C) in plasma declined exponentially with a half-life of 5.5 hr for the initial 10 hr, and a half-life of 48 hr thereafter. As in rats, exhalation was the major means of elimination of 2-NP and its carbon-containing metabolites. During the first 3 days after injection, only 5-6% of the 14C in the dose was recovered in urine and only 0.4-0.5% in feces. Acetone, isopropanol, and 2-NP were mainly eliminated via renal excretion; urine collected during 6 to 24 hr after injection contained 3.1 mg acetone/L, 7.2 mg isopropanol/L, and 1.8 mg 2-NP/L. Isopropanol may thus be maintained at low concentrations in the plasma both by oxidation to acetone and by rapid excretion. In addition to acetone, isopropanol, and 2-NP, 14C was excreted as an unidentified polar metabolite which by 24 hr after injection contained 90% of the radioactivity in the urine. The one striking difference between results with rats and with chimpanzees, i.e. the relatively much higher plasma concentrations of isopropanol in comparison to acetone, might indicate interspecific variation in the excretion of 2-NP and its metabolites. [WHO; Environ Health Criteria 138: 2-Nitropropane p.41 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 8, 2005. ]**PEER REVIEWED**
  • The test material was dermally applied to the shaved backs of 2 female rhesus monkeys. A single dermal dose of the test material was applied to the intact skin. The test site was covered for 12 hours... . ...Neither animal showed any signs of toxicity. Urine and feces output was very low during the 12 hours immediately post-dosing. Urine output normalized after 12 hours, and feces output normalized after 48 hours. There was no effect of exposure on body weights. Excretion of the total dose of test material was 0.693% in 72 hours, and 96.6% of it was through the urine. Approximately 3.6% was excreted in the feces. Exhaled air was not trapped as part of this experiment. Blood levels of 2-NP reached a maximum of 39.3 ng after 2 hours, but dropped to essentially zero at 24 hours post-dosing. Excised skin contained 0.3% of the total dose, and 0.001% in the subcutaneous fat and tissue. Approximately 30% of the dose was recovered from the swabs used to wipe the skin after the 12-hour occluded exposure. The high loss of test material (98.2% of the total dose) can be attributed to the high volatility of the material. Absorption of the 2-NP through the skin occurred in very low amounts. [European Chemicals Bureau; IUCLID Dataset, 2-Nitropropane (79-46-9) (2000 CD-ROM edition). Available from the database query page: http://ecb.jrc.it/esis/esis.php as of July 11, 2005. ]**PEER REVIEWED**
  • 2-Nitro[14C]propane /were administered/ to rats by inhalation at levels of 73 or 562 mg/cu m for 6 hr. Over 40% of the administered dose was retained in the body and the bulk of the absorbed dose was rapidly metabolized and excreted. The elimination of total 14C from the blood and by exhalation was biphasic and the two sets of parameters were broadly comparable at the two dose levels. The two elimination half-lives from blood were 71 min and 13.2 hr at the high dose and 64 min and 16.4 hr at the low dose, while for exhalation the corresponding values were 172 min and 36 hr (high dose) and 354 min and 35 hr (low dose). At the high dose, the elimination half-life of 2-nitropropane from blood was 48 min; the value could not be calculated at the low dose, since 2- nitropropane levels were 1/12th of those at the high dose and only two levels could be measured before the concentration fell below the detection limit. The blood levels of 2- nitropropane and 14C at the end of the 6-hr inhalation exposure at the high dose were 12 and 9 times those after the low dose, values to be compared with the 7.5-fold difference between the doses. A 100% recovery of the absorbed dose was obtained in excretion balance studies conducted 48 hr after the 6-hr inhalation exposure. Some 10% of the dose was excreted in the urine, with a further 5% (high dose) or 10% (low dose) in the feces. 50% of the dose was exhaled as 14CO2 and 3% (low dose) or 22% (high dose) as 2-nitropropane. The balance of the dose (25%, low dose; 11%, high dose) was present in the carcass. [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. V71 1082 (1999)]**PEER REVIEWED**

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Metabolism/Metabolites

  • 2-Nitropropane has been shown to be metabolized to nitrous acid and acetone in 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. V29 338 (1982)]**PEER REVIEWED**
  • Liver microsomes from phenobarbital pretreated rats can convert 2-nitropropane to acetone and nitrate in the presence of NADPH and oxygen. [Sakurai H et al; Biochem Pharmacol 29 (3): 341-6 (1980) ]**PEER REVIEWED**
  • 14C-labeled 2-nitropropane was administered to chimpanzees and rats, the 14C-labeled biotransformation metabolites were principally carbon dioxide, acetone and isopropanol. ... It has been postulated that N-nitro compounds and oxygen radicals are reactive intermediates in the denitrification of 2-nitropropane. [American Conference of Governmental Industrial Hygienists. Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001., p. 2]**PEER REVIEWED**
  • The enzymatic system oxidizing 2-nitropropane (2-NP) to acetone and nitrite was identified through in vitro experiments using microsomes isolated from mammalian liver. /It was/ determined that cytochrome P-450, in liver microsomes from phenobarbital-pretreated rats, bound 2-NP. /It was/ subsequently reported that liver microsomes from rats pretreated with phenobarbital or 3-methylcholanthrene rapidly catalysed the oxidation of 2-NP to acetone and nitrite. The latter were produced in roughly equal quantities. Surprisingly, however, the rate of this reaction was not diminished under conditions of reduced oxygen pressure. The activity of preparations from untreated control rats was generally very low. /It was/ demonstrated that this enzyme system in rats was active in metabolizing other aliphatic nitro compounds. ...Working with mice, /researchers/ obtained somewhat different results. They reported rapid denitrification of 2-NP to nitrite and acetone by liver microsomes from untreated mice,and an acetone production at least twice the nitrite release. These authors suggested that multiple forms of cytochrome P-450 are involved, and claimed that nitrite is sequestered in the reaction mixture and that denitrification of 2-NP may involve a reductive or at least non-oxidative pathway as well as an oxidative pathway. They also noted large differences in the rates of hepatic microsomal enzymatic nitrite release among the five strains of mice tested. ...Hepatic microsomes from uninduced rabbits could denitrify a compound related to 2-NP, 2-nitro-1-phenylpropane. In addition to oxidative denitrification, a reductive pathway has been shown to occur in cultured hepatocytes from Wistar rats and in V79 Chinese hamster cells. Nitroreduction was indicated by the fact that the cells formed acetone oxime, the tautomeric form of nitrosopropane. [WHO; Environ Health Criteria 138: 2-Nitropropane p.38 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 8, 2005. ]**PEER REVIEWED**
  • Evidence for the involvement of more than one pathway for the metabolism of 2-nitropropane (2-NP) in the rat was also obtained... . Experiments on the pharmacokinetics of 2-NP in rats exposed by inhalation suggested that there are two different pathways both in male and female animals, a saturable one of low capacity and high affinity according to Michaelis-Menten kinetics and a non-saturable one following first-order kinetics. First-order kinetics was similar in the two sexes, but striking differences between sexes were observed in the kinetics of the saturable pathway. The authors showed that in females more 2-NP was metabolized by the non-saturable pathway at concentrations above 655 mg/cu m (180 ppm), and in males at concentrations above 218 mg/cu m (60 ppm), and linked their observations to the reported higher susceptibility to liver damage of males as compared to females. /It was/ suggested that it is the first-order metabolic process which results in the formation of toxic products whereas the saturable pathway was suggested to lead to less toxic metabolites.These observations on the hepatic metabolism of 2-NP and related compounds by rats, mice, and rabbits indicate differences among species and even strains. It is probable that more than one enzyme system is involved. In mice as well as rats hepatic cytochrome P-450 may be important in the metabolism of this xenobiotic. [WHO; Environ Health Criteria 138: 2-Nitropropane p.39 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 8, 2005. ]**PEER REVIEWED**
  • ...The microsomal metabolism of 2-nitropropane in mice resulted in the release of nitrite in a cytochrome P450- dependent reaction. In contrast to earlier results in rats, enzymatic denitrification in mice did not require enzyme induction. [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. V71 1082 (1999)]**PEER REVIEWED**
  • ...2-NP is indeed metabolized to nitrite in vivo and ... the metabolism is increased by phenobarbital (PB) pretreatment. Two hours after 2-NP administration, rat blood serum nitrate plus nitrite levels were approximately 1600 microM (PB-pretreated) and 940 microM (vehicle-pretreated controls). The PB-pretreated and control rats, respectively, excreted 250 and 120 micromol nitrate/nitrite in the 24-hr urine post 2-NP treatment. [Sohn OS, Fiala ES; Anal Biochem 279 (2): 202-8 (2000) ]**PEER REVIEWED** PubMed Abstract
  • There is no evidence that 2-nitropropane (2-NP) is retained for more than a few hours in the body. It is rapidly lost by exhalation and metabolic transformation. The known carbon-containing metabolites, acetone and isopropanol, are excreted rapidly and are also transformed into compounds which are normal to the body and enter into its general intermediary metabolism. There is less information on nitrite, the major metabolite of the nitro moiety. In rats much of the nitrite is excreted as such in the urine. There is no evidence for excessive accumulation of 2-NP or its metabolites in any organ or tissue. [WHO; Environ Health Criteria 138: 2-Nitropropane p.43 (1992). Available from: http://www.inchem.org/documents/ehc/ehc/ehc138.htm as of July 11, 2005. ]**PEER REVIEWED**

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TSCA Test Submissions

  • The histological results of a study of rats (97 female, 86 male rats examined, starting number of rats, number of rats exposed or unexposed controls, or strain of rats not reported) exposed to 2-nitropropane at 100 ppm via inhalation (no exposure time data reported) were reported with respect to oncogenicity. The total number of tumors/number of tumor bearing animals were higher in the control group (43/38) compared to the treated group (25/23). The most common benign tumors in the exposed and control female rats were pituitary adenomas (8 and 21, respectively) and the most common malignant tumors were mammary gland adenocarcinomas (2 and 3, respectively). The most common benign tumors in the exposed and control male rats were pituitary adenomas (1 and 6, respectively). The most common (7) malignant tumors in exposed male rats were hepatocellular carcinoma and in the male controls, there was one malignant fibrosarcoma of the skin and subcutis.[Coulston International Corporation; Histologic Study of Selected Tissues From Rats Exposed to 2-Nitropropane at 100 ppm, Pathology Final Report. (1985), EPA Document No. 88-8500816, Fiche No. OTS0200504-1 ]**UNREVIEWED**

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Footnotes

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

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