National Toxicology Program

National Toxicology Program
http://ntp.niehs.nih.gov/go/hsdb-62-75-9

CAS Registry Number: 62-75-9 Toxicity Effects

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

Names (NTP)

  • N-Nitrosodimethylamine
  • N-METHYL-N-NITROSOMETHANAMINE (9CI)
  • TGMX RAT LIVER EVALUATION (N-NITROSODIMETHYLAMINE)
  • N-NITROSO-DIMETHYLAMINE
  • N-Nitrosodimethylamine (TGMX rat liver evaluation)

Human Toxicity Excerpts

  • SIGNS AND SYMPTOMS: Potential symptoms of overexposure are nausea, vomiting, diarrhea and abdominal cramps; headache; fever; enlarged liver, jaundice; reduced function of liver, kidneys and lungs.[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1147] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: In persons with acute NDMA poisoning due to systemic exposure, headaches, a feeling of generalized malaise, fever, and weakness often occur. Gastrointestinal effects are frequent and include abdominal cramping and nausea. Vomiting and diarrhea occur within hours of absorption. Liver enlargement and jaundice may follow.[Haddad, L.M. (Ed). Clinical Management of Poisoning and Drug Overdose 3rd Edition. Saunders, Philadelphia, PA. 1998., p. 1277] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Has caused fatal liver disease in humans. Symptoms include headache, fever, weakness, nausea, vomiting, dizziness, diarrhea, GI hemorrhage, hepatomegaly, jaundice, and ascites.[Prager, J.C. Environmental Contaminant Reference Databook Volume 1. New York, NY: Van Nostrand Reinhold, 1995., p. 611] **PEER REVIEWED**
  • CASE REPORTS: At least one death and several cases of hepatic dysfunction have resulted from workers handling DMNA. No malignant tumors were reported among accidentally exposed humans; however, studies of the metabolism of DMNA by human liver slices in vitro suggested that humans may be as sensitive as the rat to the carcinogenic action of the compound.[American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-4148 2010.] **PEER REVIEWED**
  • CASE REPORTS: In four men, laboratory exposure to NDMA gave rise to acute liver necrosis which later developed into cirrhosis; in one case, the acute liver injury proved to be fatal.[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). Available at: http://monographs.iarc.fr/index.php, p. V17 151 (1978)] **PEER REVIEWED**
  • CASE REPORTS: In 8 hr period, five members of two kindred families suddenly became ill with nausea, vomiting and malaise. This was followed by acute liver disease, generalized bleeding, and low platelet count. 2 of the patients died four and five days after onset. DMNA had been added to beverages.[Cooper SW, Kimbrough RD; J Forensic Sci 25 (4): 874-82 (1980)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/7430995?dopt=Abstract" target=new>PubMed Abstract</a>
  • CASE REPORTS: Dimethylnitrosamine (NDMA) was detected at levels of about 32 ug/L in dialyzate from 5 of 16 dialysis units surveyed /NDMA entered dialysis units via plastic components of the dialyzer/. Blood drawn from patients at 1 of these units in which NDMA was raised in the dialyzate showed a significant increase in the amount of NDMA in the patient's blood when predialysis levels were compared with 15 min intradialysis levels.[Simenhoff ML et al; J Am Med Assoc 250 (15): 2020-4 (1983)] **PEER REVIEWED**
  • CASE REPORTS: DNA, isolated from two samples of human liver obtained from a suspected dimethylnitrosamine poisoning, contained 1363 to 1373 micromol of 7-methylguanine per mol of guanine and 273 to 317 micromol of O6-methylguanine per mol of guanine. Liver and kidney DNA obtained from unrelated cases contained no detectable methylated purines. From the DNA methylation levels, it is estimated that the dimethylnitrosamine-poisoning victim had been exposed to a dose of 20 mg or more of dimethylnitrosamine per kg of body weight. The results indicate for the first time that humans, like rodents, appear to activate dimethylnitrosamine metabolically to a strong methylating agent, resulting in methylation of liver DNA at both the 7- and O6 positions of guanine.[Herron DC, Shank RC; Cancer Res 40 (9): 3116-17 (1980)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/7427930?dopt=Abstract" target=new>PubMed Abstract</a>
  • CASE REPORTS: Two deliberate poisonings with NDMA resulted in deaths, one ... where the NDMA was eaten in a dish of raspberries and the other where is was drunk mixed in lemonade. In both cases, the NDMA caused liver necrosis.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 648] **PEER REVIEWED**
  • GENOTOXICITY: Unscheduled DNA synthesis ... observed ... in human fibroblasts in culture in presence of NDMA and mouse liver microsomal fraction[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). Available at: http://monographs.iarc.fr/index.php, p. V17 150 (1978)] **PEER REVIEWED**
  • ALTERNATIVE and IN VITRO TESTS: In the present study we examined a role of pro-apoptotic Bax and anti-apoptotic Mcl-1 proteins, participating in the regulation of intrinsic apoptosis pathway in human neutrophils (PMNs) exposed to N-nitrosodimethylamine (NDMA), the environmental xenobiotic. For the purpose comparison, the same studies were conducted in autologous peripheral blood mononuclear cells (PBMCs). The production of cytochrome c by PMNs was also determined. A deficit of anti-apoptotic Mcl-1 and overexpression of the pro-apoptotic protein Bax suggest that the apoptosis process in human neutrophils exposed to NDMA is dependent on changes in the expression of these proteins. PMNs were more sensitive to NDMA than PBMCs.[Jablonski J et al; Bull Environ Contam Toxicol 87 (6): 638-42 (2011)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/21947543?dopt=Abstract" target=new>PubMed Abstract</a>

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Acute Exposure: Acute doses of 20 to 40 mg/kg bw NDMA administered orally in rats, rabbits, mice, guinea pigs and dogs caused severe liver necrosis that culminated in death.[Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 648] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: The influence of intestinal microflora on the hepatotoxic effects of dimethylnitrosamine (DMN) or dimethylamine (DMA) plus NaNO2 was studied by comparing the degree of liver necrosis and the levels of serum alanine aminotransferase (GPT) and aspartate aminotransferase (GOT) in germ-free and conventional male Wistar rats (320 to 340 g). In one experiment, both germ-free and conventional rats were intubated with DMN in respective doses of 8, 9, and 10 mg/kg bw, while in another experiment, both groups were intubated with DMA (1500 mg/kg) plus NaNO2 (100 mg/kg). In both experiments, 48 hr after intubation, there was a marked difference in the degree of liver necrosis and the levels of serum GPT and GOT between the groups. In particular, a dose of 8 mg of DMN or 1500 mg of DMA plus 100 mg of NaNO2 produced severe liver necrosis in the majority of germ-free rats, while the same dose did not produce any detectable liver necrosis in the majority of conventional rats. At a dose of 8 mg, serum GPT and GOT levels were raised to 22 and 15 times normal values, respectively, in germ-free rats, but only to about twice the normal values for both levels in conventional rats. At the combination dose of DMA plus NaNO2, the levels of serum GPT and GOT were raised to 40 and 30 times normal values, respectively, in germ-free rats, while both levels remained almost normal in conventional rats. Thus, the results indicated that the liver of the germ-free state was far more susceptible to the acute toxic effects of DMN as well as DMA plus NaNO2 administration at a certain dose range than was the liver of the conventional state, suggesting the influence of the absence of microflora.[Sumi Y, Miyakawa M; Cancer Res 43 (6): 2942-6 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6850604?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Acute Exposure: No evidence for liver necrosis was observed at 24, 48 or 72 hr after injection of dimethylnitrosamine (DMN) (70 mg/kg, i.p.) to pigeons. The assessment of possible liver necrosis was made by determination of isocitric dehydrogenase (ICD), glutamate oxalacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) in plasma. The ability of pigeon liver slices to metabolize CO2 or to give covalent binding of reactive metabolites to nucleic acids was 24 times smaller than that for rat. Similarly, the pigeon liver microsomes or 9000 X g supernatant have DMN-demethylase activity or ability to activate DMN to reactive metabolites that bind covalently to proteins very close to zero. Results suggest that resistance of pigeon liver to DMN acute effects is related to its lack of ability for DMN metabolic activation.[Diaz Gomez MI et al; Cancer Lett 18 (2): 157 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6403221?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Acute Exposure: Single doses of DMNA (dimethylnitrosamine) from 8 to 15 mg/kg body weight were given to 37 foxes. The course and intensity of the disease was not influenced by the application route, but was directly related to the amount of DMNA given per kg body weight, causing hemorrhagic centrolobular liver necrosis and acute vessel changes. ... The LD50 determined after 4 wk was 10 mg DMNA/kg body weight In a longer experiment 18 foxes in 3 groups were given 2 weekly doses of DMNA in food. They were treated with daily estimated doses of 1.0, 0.2 and 0.1 mg DMNA/kg body weight, respectively. The foxes in groups 1 and 2 developed ascites, jaundice, and liver failure after intake of 45-70 mg DMNA/kg body weight. The foxes treated with 1 mg DMNA/kg body weight showed centrolobular hemorrhagic liver necrosis and productive vessel changes in the hepatic vein system. The second group given 0.2 mg DMNA/kg body weight developed hemorrhagic centrolobular necrosis which healed with fibrosis leading to cirrhosis and chronic occlusion in many hepatic veins. Noduli of chondroid lamellae and foci of hematopoietic tissue and early stages of hemagiomatous liver tumors were found in the liver. The group exposed to 0.1 mg of DMNA/kg body weight/day developed thickening in the walls of the hepatic veins. After more than 3.5 yr of exposure, multiple hemangiosarcomas grew out from the changed vessel walls. In a shorter experiment with daily DMNA doses in the feed below 0.165 mg/kg body weight, all the foxes were completely healthy and only some showed beginning changes in the hepatic vein walls. Hematomas were often seen in foxes dying after a single DMNA dose. One fox treated with 0.1 mg DMNA/kg body weight died of brain bleeding after 220 days of treatment. Chronic vessel changes were found in the heart and kidneys of the DMNA treated foxes. DMNA produces vessel changes of a more general nature.[Koppang N et al; Acta Vet Scand 22 (3-4): 501-16 (1982)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: ... Single i.p. doses of N-nitrosodimethylamine (0.07 mg/kg) ... induced a statistically significant reduction of the time (t95) required for eta red to reach its maximal value. A dose-dependent decrease of t95 was observed for dosages markedly lower than those found to be effective in eliciting DNA fragmentation by the use of alkaline elution or alkaline sucrose gradient sedimentation. ...[Brambilla G et al; Cancer Res 43 (1): 202-9 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6847769?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Acute Exposure: A single admin of 50 mg N-nitrosodimethylamine/kg reduced the total protein content in the hepatic microsomes of rats. It reduced protein synthesis, particularly at the translational level, and thirdly its interaction with cell membrane lipid components resulted in the disintegration and conformational charges in membrane-bound proteins.[Tutelyan VA, Lashneva NV; Farmakol Toksikol (Moscow) 46 (2): 111-4 (1983)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Rats given a single injection of 18 mg/kg body wt either im, retroperitoneally or directly into the kidney, developed renal tumors.[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). Available at: http://monographs.iarc.fr/index.php, p. V1 100 (1972)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Administration by stomach tube of 1.6, 1.0 and 1.0 mg/animal NDMA over five weeks, or of one dose of 1.6 mg/animal, to Syrian golden hamsters induced cholangioadenomas, cholangiocarcinomas and hemangiosarcomas as well as hemangioendotheliomas of the liver.[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). Available at: http://monographs.iarc.fr/index.php, p. V17 137 (1978)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Weekly sc injections of 0.5-1.0 mg NDMA for 6-20 wk ... caused ... esthesioneuroepitheliomas of nasal cavity in Syrian golden hamsters.[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). Available at: http://monographs.iarc.fr/index.php, p. V17 139 (1978)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Male guinea pigs given 1-2 mg/kg body wt orally for 40-55 wk developed papillary cholangiomas and liver-cell carcinomas.[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). Available at: http://monographs.iarc.fr/index.php, p. V1 99 (1972)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Doses of 25 ppm and 50 ppm given to rabbits in diet for 17-51 wk resulted in hepatocellular carcinoma with lung metastases and benign papillary cholangiomas.[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). Available at: http://monographs.iarc.fr/index.php, p. V1 99 (1972)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Twice-weekly sc injections of 0.1 mg NDMA per rat for 10 to 44 weeks induced liver tumors in 6/36 males: 2 cholangiomas, 2 cholangiocarcinomas, 1 hemangioendothelioma and 1 hepatic cell carcinoma; none were seen in females. In controls, 4/82 liver tumors were seen in females and none in males.[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). Available at: http://monographs.iarc.fr/index.php, p. V17 140 (1978)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ... One week of culture was sufficient to induce colony growth in soft agar in some cultures of the dimethylnitrosamine (DMNA)-treated, but not in those of control, rats. ... Suspended colony growth was not observed in cultures of control rats stimulated successively by the 2 mitogens: thioglycollate and Al(OH)3. The incidence of rats showing transformed colonies in their cultures after a single DMNA dose of 20 mg/kg was nearly double that reported for rats developing tumors after a higher single dose of 30 mg/kg DMNA. ...[Nashed N, Chandra P; Cancer Lett 10 (2): 95-108 (1980)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/7459837?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Analbuminemic rats were found to be highly susceptible to induction of renal tumors. Thirty-nine weeks after N-dimethylnitrosamine administration, the incidence of renal tumors and average weight of kidneys (including tumors) were 76.0% and 10.8 +/- 4.1 g in male analbuminemic rats, respectively, whereas they were 37.1% and 3.5 +/- 0.1 g, respectively, in normal male SD rats.[Nagase S et al; Gann 74 (3): 317-8 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6884689?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In mice, single or repeated injections of 12.5-75 mg/kg bw NDMA during last days of pregnancy resulted in lung adenomas and hepatomas in offspring. NDMA induced a low frequency of kidney tumors in offspring of pregnant rats treated during last week or during the whole pregnancy (total dose, 11 mg).[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). Available at: http://monographs.iarc.fr/index.php, p. V17 142 (1978)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Single oral doses of N-nitrosodimethylamine or olive oil were given to nonpregnant and pregnant female Holtzman rats on different days of pregnancy (days 7-18, where day 0 was considered to be the sperm positive day). Serological and histopathological studies were performed on animals killed 2 days after treatment. In comparison with the values obtained in nonpregnant controls, the following parameters in pregnant controls were significantly increased: relative liver weights (days 9-20), liver ascorbic acid concentrations (day 12), blood urea nitrogen (days 16-20), serum triglyceride (days 14-20), serum inorganic phosphorus (days 12-18), and serum glutamic-pyruvic transaminase (days 14-20). The following parameters were decreased in pregnant rats compared with nonpregnant controls: relative organ weights (kidneys, adrenals and thyroids), serum glucose (days 12-20), total serum protein (days 9 and 16-20), and serum alkaline phosphatase (day 20). The serum cholesterol levels in pregnant rats were significantly decreased on days 9-15 of pregnancy and significantly increased on day 20. The numbers of mitotic cells in the livers of pregnant rats were greatly increased compared with nonpregnant rats on all days of pregnancy, while the adrenal cortex contained a significantly higher number of mitotic cells only on days 16 and 18. Compared with control values, NDMA given orally (15 or 20 mg/kg body weight) increased the following in both pregnant and nonpregnant rats: numbers of mitotic cells in the liver and adrenal cortex, relative adrenal weights, serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase. NDMA treatment decreased liver ascorbic acid and total serum protein in both pregnant and nonpregnant rats. In nonpregnant rats NDMA also increased relative liver weights (not significant) and serum alkaline phosphatase levels. NDMA increased serum alpha-hydroxybutyric dehydrogenase in pregnant rats on day 20 and decreased foetal weights (in rats treated on days 13 and 18). NDMA treatment was not lethal to nonpregnant rats or to pregnant rats up to day 16 of pregnancy, but single oral doses of 15 and 20 mg NDMA/kg killed 9.4 and 35.3%, respectively, of rats treated on day 18 of pregnancy. In general, the acute toxic effect of NDMA, as measured by changes in the above parameters, was greater in pregnant than in nonpregnant rats, especially near the end of pregnancy.[Nishie K; Food Chem Toxicol 21 (4): 453-62 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6684627?dopt=Abstract" target=new>PubMed Abstract</a>
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Dimethylnitrosamine given on the last day of pregnancy produced only a few uncharacteristic tumors. Dimethylnitrosamine was not teratogenic in rats when 30 mg was given orally in single days during gestation.[Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 199] **PEER REVIEWED**
  • GENOTOXICITY: Cytogenetic changes were investigated during the early stages of hepatic adenocarcinoma development in Chinese hamsters injected with single dose of N-nitrosodimethylamine (NDMA). Aneuploidy, tetraploidy, and chromosome aberrations increased significantly in the hepatic cells of NDMA-treated animals in vivo, with no significant change over the 7- to 35-wk period. The importance of increased aneuploidy in early carcinogenesis and the differences between the in vivo and in vitro results are discussed.[Swindell JA, Ockey CH; Cancer Genet Cytogenet 10 (1): 23-36 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6883298?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: A major and previously undetected carcinogen-DNA adduct was found in the livers of rats given N,N-dimethylnitrosamine or 1,2-dimethylhydrazine. This adduct, which accounted for 55% of the total methyl residues in DNA at 72 hours after carcinogen treatment, was chromatographically identical to a synthetic purine ring-opened derivative of 7-methylguanine and could be released from the isolated hepatic DNA by a specific E. coli glycosylase. The synthetic ring-opened adduct was characterized by mass and NMR spectroscopy as N5-methyl-N5-formyl-2,5,6-triamino-4-hydroxypyrimidine and appears to exist in two rotameric forms.[Beranek DT et al; Biochem Biophys Res Commun 110 (2): 625-31 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6838542?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: Dimethylnitrosamine requires mammalian metabolic activation before showing mutagenic activity. Using a complement-resistant escherichia coli strain injected into mice given a single dose of DMN, a linear response curve was established using ampicillin and nalidixic acid as 2 forward mutation markers.[Neale S, Solt AK; Chem-Biol Interact 31 (2): 221-26 (1980)] **PEER REVIEWED**
  • GENOTOXICITY: Combined intrasanguineous and urinary mutagenic assay in vivo was tested with dimethylnitrosamine, using Schizosaccharomyces pombe. Dose of 0, 250 and 405 mg/kg cyclophosphamide or 5, 10, or 100 mg/kg dimethylnitrosamine were given to mice and rats immediately after they were injected with the yeast cells. Tested; lung and kidneys were more active than spleen and testes. DMNA was inactive in urine.[Bauer C et al; Mutat Res 74 (4): 291-302 (1980)] **PEER REVIEWED**
  • GENOTOXICITY: Induction of single-strand breaks in the DNA of 3 organs of BD-VI rats and Syrian golden hamsters was exam 4 hr after dosage. Rats received 40 to 80 mg/kg ip dose of N-nitrosodimethylamine (NDMA) and hamsters received 30 mg/kg NDMA. DNA damage occurred in the liver and kidney of rats and in the liver and lungs of hamsters. Damage was monitored in vivo by alkaline elution method, fluorometrically.[Barbin A et al; Carcinogenesis (London) 4 (5): 541-5 (1983)] **PEER REVIEWED**
  • GENOTOXICITY: Structural analysis by chromatography on benzoylated-DEAE-cellulose (BD-cellulose) has been made of hepatic DNA from rats treated for up to 21 weeks with dimethylnitrosamine (DMN). The carcinogen (1 mg/kg body wt) was administered on a daily basis by intraperitoneal injection. By comparison with preparations from saline-treated controls, the proportion of DNA retained by benzoylated-DEAE-cellulose in the presence of 1.0 M NaCl was increased by administration of the carcinogen. Variation in the result, dependent upon the time after the final dose, suggested a complex relationship between structural damage to DNA and duration of treatment. Structural damage was confirmed by S1 nuclease digestion. The observations imply that in the course of chronic administration, increasing time is required to complete DNA repair processes operative in rat liver.[Kosic J, Stewart BW; Cancer Lett 20 (1): 5-12 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6318966?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: An in vivo intrasanguine host-mediated assay revealed that mutations occurred at significant rate in Salmonella typhimurium G-46 employed as indicator organisms recovered from liver, lung, kidney and spleen of NDMA-treated mice, compared to negative control animals.[Bakshi K, Brusick D; Mutat Res 72 (1): 79-89 (1980)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/7003367?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: Dimethylnitrosamine was activated to mutagen on incubation with drosophila melanogaster microsomes. Mutagenicity was observed in Chinese hamster ovary cells, Escherichia coli strains 343/113/R-9 and 343/113/UVRB, and Salmonella typhimurium TA1538. Drosophila microsomes appeared to be at least as active as rat liver microsomes when compared in this type of mutagenicity testing.[Baars AJ et al; Mutat Res 72 (2): 257-64 (1980)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6777691?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: Male rats received a single injection of dimethylnitrosamine (NDMA). Significant increases in frequencies of sister chromatid exchanges (SCE) in lymphocytes and incidence of micronucleated hepatocyte were observed. NDMA-induced preclastogenic damage in hepatocytes was lost between 28 and 56 days after injection.[Tates AD et al; Mutat Res 107 (1): 131-51 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6828034?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: ... Mutagenesis studies on drosophila oogonial cells with dimethylnitrosamine revealed high rates of sex-linked recessive lethals relative to other male and female germ cell stages. Indeed, the oogonial mutation rates with chemicals are higher than with massive X-ray or neutron exposures of oogonia. Analysis of the distribution of lethals per treated female suggests most of the mutations recovered are of independent origin, with very small levels of clustering of identical mutations. In the male stem cell population (spermatogonia) on the other hand, the distribution of lethals is primarily nonrandom and highly clustered. The nature of the mutational endpoint and the different pattern of germ cell development in the two sexes are the probable causes of this difference. ...[Abrahamson S et al; Environ Mutagen 5 (6): 891-905 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6653508?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: DNA repair was elicited by dimethylnitrosamine in hepatocytes from B6C3F1 mice and Syrian hamsters.[McQueen CA et al; Environ Mutagen 5 (1): 1-8 (1983)] **PEER REVIEWED**
  • GENOTOXICITY: Deuterated and non-deuterated N-nitrosodimethylamine, epichlorohydrin and dimethyl sulfate were evaluated for the ability to induce DNA single-strand breaks in rat hepatocytes as measured by alkaline elution. Non-deuterated nitrosodimethylamine induced twice the amount of DNA-strand breaks as the deuterated form. No evidence of a deuterium isotope effect was seen for the direct-acting alkylating agents epichlorohydrin and dimethyl sulfate.[Sargent EV et al; Mutation Res 263 (1): 9-12 (1991)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/2034243?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: ... The indirect-acting alkylating agent, dimethylnitrosamine (DMN) induced DNA damage only when an NADPH generating system was included in the incubation mixture. ...[Cohen AM, Prabhakar H; Cancer Lett 18 (2): 163-7 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6831392?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: IN ALKALINE CONDITIONS (PH 12.5), THE REDUCED VISCOSITY OF KIDNEY & LUNG DNA FROM CONTROL RATS INCR SLOWLY WITH TIME REACHING MAX AFTER 9-12 HR. CARCINOGENS, BY INDUCING DNA STRAND BREAKS EITHER CHEMICALLY OR INDIRECTLY BY EXCISION REPAIR OR DURING INCUBATION IN ALKALI, CAUSE A REDN OF DNA SUPERCOILING WHICH CAN BE SENSITIVELY MEASURED BY MONITORING CHANGES IN VISCOSITY. COMPUTERIZED ANALYSES OF TIME-VISCOSITY CURVES SHOWED 95% OF ITS MAX VALUE (T-95) WAS INDUCED BY IP DOSES OF N-NITROSODIMETHYLAMINE: KIDNEY 0.07 MG/KG, LUNG 0.28 MG/KG. THE DECREASE IN T-95 WAS DOSE-RELATED.[CARLO P ET AL; CARCINOGENESIS 4 (2): 137-40 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6825203?dopt=Abstract" target=new>PubMed Abstract</a>
  • GENOTOXICITY: DNA breaks induced by dimethylnitrosamine in cultured liver cells were more detectable from rat treated with phenobarbital. Treatment for 24 hr with 60 and 13.5 umolar dimethylnitrosamine (NDMA) of hepatocytes from untreated and phenobarbital treated rats, respectively, decreased the molecular wt of DNA by 50%. It is more genotoxic for hepatocytes from phenobarbital-treated rats, probably due to augumented metabolism of NDMA by these cultures.[Mendoza-Figueroa T et al; Toxicol 27 (1): 55-69 (1983)] **PEER REVIEWED**
  • ALTERNATIVE and IN VITRO TESTS: The biotransformation potential of six nitrosamines and their precursor secondary amines by a mixed methanogenic culture was investigated. Among the six nitrosamines tested, N-nitrosodimethylamine (NDMA) ... was almost completely degraded but only when degradable electron donors were available. ... A bioassay conducted to elucidate the biotransformation pathway of NDMA in the mixed methanogenic culture using H(2) as the electron donor showed that NDMA was utilized as an electron acceptor and transformed to dimethylamine (DMA), which in turn was degraded to ammonia and methane. The H(2) threshold concentration for NDMA bioreduction ranged between 0.0017 and 0.031 atm. Such a high H(2) threshold concentration suggests that in mixed methanogenic cultures, NDMA reducers are weak competitors to other, H(2)-consuming microbial species, such as homoacetogens and methanogens. ...[Tezel U et al; Environ Sci Technol 45 (19): 8290-7 (2011)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/21863807?dopt=Abstract" target=new>PubMed Abstract</a>
  • ALTERNATIVE and IN VITRO TESTS: The aim of the study was to determine the tumorigenic potential of two cell lines established from N-nitrosodimethylamine induced rat hepatocarcinoma (HeDe) and mesenchymal renal tumors (NeDe). The basis of the distinction is that human cancers are known to overexpress facilitative GLUT transporters and TGF-beta1 protein. These proteins are linked to the increased metabolic energy consumption indicating uncontrolled growth and proliferation. We have assayed not only the expression of GLUT-1, GLUT-3 and TGF-beta1 proteins, but also the uptake of 2-fluoro-[18F]-2-deoxy-D-glucose (18FDG), a tracer for cancer diagnosis. Western blot analysis and whole body autoradiography were used to measure the 18FDG uptake of tumor cells. Elevated 18FDG uptake was measured in both tumor cell lines. Whole body autoradiography provided evidence that the uptake of 18FDG was lower in the necrotic inner part than in the more vascularized outer parts of primary hepatocarcinoma and mesenchymal renal tumors. GLUT-1 overexpression in hepatocarcinoma tumor, and high levels of GLUT-3 were found in the NeDe cell line and in the mesenchymal renal tumor. TGF-beta-1 was overexpressed in hepatocarcinoma and mesenchymal renal tumors. In vitro and in vivo parameters support the view that the tumorigenic potential of cancer cells cannot be determined by the expression of a single parameter such as the expression of either GLUT-1, GLUT-3 or 18FDG uptake. Besides the tumorigenic potential of the hepatocarcinoma, the high metabolic activity of the renal tumor indicated by its 18FDG uptake, GLUT-3 and TGF-beta1 expression, the mesenchymal renal tumor induced by N-nitroso-dimethylamine is not a benign, but an an aggressive renal carcinoma.[Trencsenyi G et al; Histol Histopathol 25 (3): 309-20 (2010)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/20054803?dopt=Abstract" target=new>PubMed Abstract</a>
  • ALTERNATIVE and IN VITRO TESTS: Whole cell preparations derived from collagenase-treated rat liver were cocultivated overnight with stationary cultures of L5178Y/TK+/- cells in N-nitrosodimethylamine. Substantial dose-dependent increases in trifluorothymidine-resistant variants were observed after 20 hr total exposure time.[Amacher DE, Paillet SC; Mutat Res 113 (1): 77-88 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6828044?dopt=Abstract" target=new>PubMed Abstract</a>
  • ALTERNATIVE and IN VITRO TESTS: Cell-mediated assays were used to study organ (liver, lung, kidney, and bladder) and species (rat and hamster) specificity of nitrosodimethylamine (NDMA) and other chemicals. NDMA was highly active in liver cell-mediated system. With regard to species specificity, hamster hepatocytes were 3-4 times as active at metabolizing NDMA to mutagenic intermediates as were rat hepatocytes.[Langenbach R, Nesnow S; Usepa, Res Dev, (Rep) EPA (EPA-600/9-83-008, Organ Species Specif Chem Carcinog; Pb83-220137): 377-90 (1983)] **PEER REVIEWED**
  • ALTERNATIVE and IN VITRO TESTS: Alterations in gene expression by carcinogens were analyzed on three unstable alleles of the white (w+) locus of Drosophilia melanogaster: white-crimson (wc); white-ivory 16 (wi16); and white-unstable 11 (wu11). Two of these alleles (wi16 and wu11) were spontaneous mutant derivatives of wc, which is known to harbor a transposable element. The compounds studied were dimethylnitrosamine, 7,12-dimethylbenz(a)anthracene, and aflatoxin B1. These carcinogens were topically applied on the early larval stages, and the genetic effects assayed were the alterations in eye color either to wild-type (w+) or to other w mutants, initiated both somatically and germinally, as well as the simultaneously induced X-chromosome recessive mutations. The tested compounds influenced the different unstable w alleles in a highly selective manner, both as a function of the inducing agent and the organization of the genome in the target cells. The same treatments raised the somatic reversions to w+ above the corresponding controls for wc and wi16, but not for wu11, whereas the simultaneous induction of other w mutant phenotypes occurred appreciably only with wc. Furthermore, these treatments gave high and variable somatic reversions to w+ with wi16, whereas the simultaneously induced germinal events were uniformly very low. The frequencies of altered expression at the unstable test loci, whether in the soma or germ line, were quantitatively uncorrelated with the mutagenic effects of the treatments in terms of the yield of X-chromosome recessive mutations assayed in the progeny of males emerging from the same treated larvae. There was also an association between the time of the induction of these alterations by the tested carcinogens in the soma and the cellular stage in genomic differentiation. Reversions to w+ were induced preferentially after the onset of genetic determination, whereas changes to the w mutant phenotypes occurred predominantly during the predetermination phases. The genetic properties of transposable elements and the manner of their response to carcinogens supported the hypothesis that nonviral cancer might arise from molecular processes similar to those involved in the evolution of retroviruses.[Fahmy MJ, Fahmy OG; Cancer Res 43 (2): 801-7 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6401223?dopt=Abstract" target=new>PubMed Abstract</a>
  • ALTERNATIVE and IN VITRO TESTS: ... In vitro RNA synthesis and methylation were proportional to time and nuclear concentration and dependent on exogenous nucleoside triphosphates and S-adenosylmethionine. Of the in vitro synthesis, 60-70% was inhibited by 1 ug/mL alpha-amanitin. Total liver nuclear RNA systhesis was increased after dimethylnitrosamine exposure but, unlike RNA synthesis in nuclei after partial hepatectomy, alpha-amanitin sensitive and resistant synthesis were increased. Differences were found between dimethylnitrosamine-treated liver and kidney nuclear RNA synthesis which was sensitive to inhibition by 1-10 ug/mL alpha-amanitin, presumably a product of RNA polymerase III. Nuclear RNA methylation with S-adenosylmethionine, which was dependent on new RNA synthesis, differed between dimethylnitrosamine-treated rat liver and kidney nuclei. The endogenous RNA methyl substituents labeled in vitro showed differences in levels of methylation of bases, the 2'-O position of ribose and caps in comparisons between control and dimethylnitrosamine-treated nuclei from liver and kidney. Significant differences were obtained in nuclear RNA transcription and methylation in vitro between the 2 tissues in response to pretreatment of the rat in vitro with dimethylnitrosamine.[Winicov I; Biochim Biophys Acta 654 (1): 31-41 (1981)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6168289?dopt=Abstract" target=new>PubMed Abstract</a>
  • OTHER TOXICITY INFORMATION: NDMA is metabolized by microsomal enzyme system that requires NADPH and oxygen. This metabolism leads to unstable products which decompose to yield reactive alkylating species. Alkylation of cellular components, particularly DNA, is the critical event in initiation of tumors. When small doses are given, the capacity of liver to metabolism the carcinogen is sufficient that nitrosamine is effectively cleared in 'first-pass' effect, leaving very little to interact with other organs. This has 2 consequences: 1. Levels of NDMA found in peripheral blood may be significantly lower than those expected because of rapid metabolism and effective clearance of carcinogen by liver; 2. Physiological factors leading to reduction of metabolism activation in liver may result in more of carcinogen being metabolized in other tissues and increase the risk of cancer developing in those tissues.[Pegg AE; IARC Sci Publ (27): 3-22 (1980)] **PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Spongiosis hepatis, a characteristic pathomorphologic entity originating from the perisinusoidal liver cells, was observed in rats after administration of relatively low doses of the hepatocarcinogens dimethylnitrosamine (DMNA) and nitrosopyrrolidine (NO-Pyr), but not after application of the urinary bladder carcinogen butyl-butanolnitrosamine (BBNA). The results support the conception that spongiosis is a persisting liver lesion due to specific changes of the perisinusoidal liver cells by hepatotropic carcinogens.[Zerban H, Bannasch P; Cancer Lett 19 (3): 247-52 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6883311?dopt=Abstract" target=new>PubMed Abstract</a>

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LC50 Rat inhalation 78 ppm/4 hr[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1128] **PEER REVIEWED**
  • LD50 Mouse intraperitoneal 19 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2709] **PEER REVIEWED**
  • LC50 Mouse inhalation 57 ppm/4 hr[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1128] **PEER REVIEWED**
  • Ip LD50 rat = 34 mg/kg[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1147] **PEER REVIEWED**
  • LD50 Rat oral 27-41 mg/kg[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1128] **PEER REVIEWED**
  • LD50 Rat intraperitoneal 26.5 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2709] **PEER REVIEWED**
  • LD50 Rat subcutaneous 45 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2709] **PEER REVIEWED**
  • LD50 Rat oral 37 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2709] **PEER REVIEWED**

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Absorption, Distribution and Excretion

  • In order to elicit the characteristic toxicities, DMNA has required activation to a proximate mutagenic and carcinogenic metabolite. DMNA has undergone oxidative demethylation as catalyzed by rodent and human hepatic microsomes; this reaction has given rise to reactive intermediates. Alkylation of guanine (to 7-methylguanlic acid) and of cytosine (to 3-methylcytosine) has been thought to underlie the biochemical basis of DMNA-induced carcinogenesis. Methylation of the messenger ribonucleic acid (mRNA) in DMNA poisoning inhibited transIation. Although 7- methylguanylic acid has served as a normal nucleotide for RNA polymerase activity, the incorporation of 3-methylcytosine reduced efficiency. The alkylation of DNA by the reactive metabolites of DMNA resulted in a change in base sequence and deletion of one or more base pairs, changes indicative of the genotoxic mechanism of DMNA-induced carcinogenesis.[American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-4148 2010.] **PEER REVIEWED**
  • It is absorbed from gastrointestinal tract and lung ... Skin absorption is slow. When administered to rats, mice, and rabbits, it is distributed uniformly in tissue ... Although the liver is main organ concerned with its metabolism and is site of selective toxicity, dimethylnitrosamine does not concentrate there. Only a small percentage is excreted unchanged in rat urine after oral and iv doses of 50 to 100 mg/kg. A large proportion ... Appears in the expired air as ... Carbon dioxide (approx 60% in 24 hr).[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. 2787] **PEER REVIEWED**
  • N-nitrosodimethylamine (NDMA) reached equal max concn in the maternal and fetal blood and tissues within 5-15 min and 30-60 min, respectively, after an iv injection of 50 mg/kg into mice and rats on days 21-23 of pregnancy. The subsequent exponential decr in NDMA was more rapid in mice than in rats. Increasing the NDMA level in maternal blood by increased doses, linearly increased the fetal blood NDMA to a peak of 120 mug/mL in mice and 220 ug/mL in rats, whereas the level of NDMA in maternal blood continued to increase as doses were increased to 300 mg/kg.[Shendrikova IA et al; Farmakol Toksikol (Moscow) 46 (6): 53-7 (1983)] **PEER REVIEWED**
  • N-Nitrosodimethylamine (DMN) was shown to be assimilated by the roots and translocated to the tops of lettuce and spinach plants.[Dean-Raymond D, Alexander M; Nature 262: 394-6 (1976)] **PEER REVIEWED**
  • The acute toxicities of dimethylnitrosamine and diethylnitrosamine were evaluated in adult male crayfish. Toxicokinetic studies of (14)C dimethylnitrosamine and (14)C diethylnitrosamine in Austropotamobius pallipes (crayfish), administered by iv injection, show high concns of (14)C in abdominal muscle and hepatopancreas. Excretion is greater with dimethylnitrosamine, and retention in tissues, especially the hepatopancreas, is greater with diethylnitrosamine.[Alibaud R et al; Xenobiotica 15 (12): 1103-10 (1985)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/4090529?dopt=Abstract" target=new>PubMed Abstract</a>

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Metabolism/Metabolites

  • Formation of n-nitrosodimethylamine (NDMA) in the stomachs of rats and mice after simultaneous oral administration of (14)C-labeled dimethylamine and potassium nitrite was determined by measuring the methylation of liver DNA. Simultaneous administration of 50 mg ascorbate/kg inhibited the nitrosation by approximately 80%. 50 mg alpha-tocopherol acetate/kg reduced the nitrosation by approximately 50%.[Meier-Bratschi A et al; Food Chem Toxicol 21 (3): 285-9 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6683225?dopt=Abstract" target=new>PubMed Abstract</a>
  • A method for quantitative estimation of the formation of N-nitrosodimethylamine (NDMA) in mice was developed. When 0.25 umole of aminopyrine and 0.25-2.0 umole of sodium nitrite were simultaneously administration orally to mice, the amt of NDMA formed in 20 min was 8.2-60.3 nmol. These values are equal to approximately 30-200 ug/kg of body wt which are nearly daily doses expected to cause carcinogenic effect in mice or rats.[Kawanishi T et al; Arch Toxicol 54 (4): 323-30 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6667123?dopt=Abstract" target=new>PubMed Abstract</a>
  • Available evidence suggests that NDMA requires metabolic activation to exert its toxic and carcinogenic effects. Rate of metabolism ... in vivo has been exam by measuring rate of loss of NDMA from blood and exhalation of (14)CO2 following administration of (14)C-NDMA. In rats ... 30 mg/kg administration by ip injection is metabolized within 6 hr. Rate of metab of NDMA in vitro ... Measured by use of slices of liver and other organs ... from rats, hamsters, monkeys, trout, goldfish and various amphibians. ... Oxidative N-demethylation to form formaldehyde has been demonstrated with liver microsomes from rats, mice and hamsters. Microsomal oxidn has been suggested to result in unstable N-nitroso-n-methyl-n-hydroxymethylamine, which decomp to yield methylating species and formaldehyde. ...[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). Available at: http://monographs.iarc.fr/index.php, p. V17 146 (1978)] **PEER REVIEWED**
  • ... In the metabolism ... one of the intermediary products is diazomethane.[International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 621] **PEER REVIEWED**
  • Nitrosodimethylamine (NDMA) and 2 of its metabolites, methylhydrazine and 1,1-dimethylhydrazine, were metabolized to carbon dioxide by liver slices obtained from rats. Rat liver microsomes or 9,000xg supernatants transformed NDMA to formaldehyde. NDMA led to covalent binding to proteins in incubation mixtures containing microsomes or 9,000xg supernatants. In the case of NDMA, the process was enzymic and required NADPH in both cellular fractions.[Godoy HM et al; J Natl Cancer Inst 71 (5): 1047-51 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6580481?dopt=Abstract" target=new>PubMed Abstract</a>
  • Maximal rates of metabolic oxidation of N-nitrosodimethylamine (NDMA) and NDMA-D6 in vivo were measured by following (14)CO2 exhalation in rats after ip injection of 2 (14)C-labeled carcinogens at doses of 20 or 40 mg/kg. Complete deuteration of NDMA reduced only slightly the maximal rate of metabolism when the 2 substrates were administration separately. However, much larger deuterium isotope effects were observed when mixtures of NDMA with NDMA-D6 were injected. These results are tentatively interpreted as evidence that c-h bond cleavage is not a rate-limiting feature of overall metabolism, but that the complex between NDMA and the principal enzyme(s) metabolizing it in vivo freely equilibrates with unbound substrate.[Swann PF et al; Carcinogenesis (London) 4 (7): 821-5 (1983)] **PEER REVIEWED**
  • Highly purified NADPH-cytochrome p450 reductase and the other major forms of cytochrome p450 induced by phenobarbital and beta-naphthoflavone were used in reconsitituted systems to study the demethylation and activation of dimethylnitrosamine to mutagenic intermediates. Both forms of cytrochrome p450 were active in the demethylation of dimethylnitrosamine, but cytochrome p450 from phenobarbital treated rats was more active and produced nearly twice as much formaldehyde per mole of hemoprotein.[Masson HA et al; Toxicol Lett 17 (1-2): 131-5 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6414108?dopt=Abstract" target=new>PubMed Abstract</a>
  • The demethylation of NDMA by rat hepatic microsomes was not changed by pretreatment with phenobarbital and methylcholanthrene.[Kawanishi T et al; Cancer Lett (Shannon, Irel) 20 (2): 157-64 (1983)] **PEER REVIEWED**
  • Fasting for 1-3 days causes a 2- or 3-fold enhancement of the reduced NADP-dependent nitrosodimethylamine demethylase (NDMAD) activity. The cytochrome p450 (p450) content and activities of reduced NADP p450 reductase and benzphetamine demethylase, however, are only modestly increased. Electrophoretic analysis revealed the induction of a 50,000-dalton protein band during fasting.[Tu YY, Yang CS; Cancer Res 43 (2): 623-9 (1983)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/6401221?dopt=Abstract" target=new>PubMed Abstract</a>
  • Metabolites identified inexcreta /from Austropotamobius pallipes, crayfish/ include monomethylnitrosamine from dimethylnitrosamine, and (hydroxyethyl)ethyl, bis(hydroxyethyl), and (carboxyethyl)ethylnitrosamine from diethylnitrosamine.[Alibaud R et al; Xenobiotica 15 (12): 1103-10 (1985)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/4090529?dopt=Abstract" target=new>PubMed Abstract</a>
  • ... Reduction of nitrate to nitrite /in the gastrointestinal tract/ permits the formation of highly carcinogenic nitrosamines by reaction with secondary amines from the diet. /Nitrosamines/[National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 33] **PEER REVIEWED**
  • The metabolism of N-nitrosodimethylamine by liver microsomes from acetone-induced rats as well as by a reconstituted system containing purified cytochrome p450IIE1 was examined. The products consisted of methylamine, formaldehyde, methanol, methylphosphate and formic acid from N-nitrosodimethylamine. Compared to liver microsomes from untreated rats, the metabolic activity of acetone induced microsomes was approximately 4 times higher for N-nitrosodimethylamine. Using the reconstituted system, the enzyme activities (nmol substrate metabolized/nmol p450/min) N-nitrosodimethylamine was 9.47. Incubations carried out in the presence of a monoclonal antibody to cytochrome p450IIE1 resulted in a 85-90% inhibition in this system. The results indicate that N-nitrosodimethylamine is metabolized by the same form of rat liver cytochrome p450. The stoichiometry of N-nitrosodimethylamine products formed in these reactions indicates that denitrosation, a presumed detoxication process, and alpha-hydroxylation, an activation reaction, are also catalyzed by the same cytochrome p450 isozyme.[Sohn OS et al; Carcinogenesis 12 (1): 127-31 (1991)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/1988172?dopt=Abstract" target=new>PubMed Abstract</a>
  • A study was conducted on the mechanism by which hepatic N-nitrosodimethylamine demethylase, also known as cytochrome p450-IIE1, is induced by acetone treatment in the rat. Acetone was fed at a concentration of 5% volume/volume in drinking water to male Sprague-Dawley rats for at least 10 days before experiments. Tritiated leucine was given to some animals, which were killed 3, 8 or 15 minutes later to measure the rate of synthesis of N-nitrosodimethylamine demethylase. Another group of animals received (14)C labeled acetate and were killed at 21, 24, 48 and 72 hours later for determination of the rate of degradation of N-nitrosodimethylamine demethylase. N-nitrosodimethylamine demethylase was purified from solubilized liver microsomal protein by an immunoaffinity column coupled to mouse monocolonal antibody raised against N-nitrosodimetylamine demethylase. Acetone treatment did not alter the rate of synthesis of N-nitrosodimethylamine demethylase. In control rats, the degradation of N-nitrosodimethylamine demethylase was biphasic, with the fast and slow phases having half-lives of approximately 7 and 37 hours, respectively. In rats given acetone, the degradation curve for labeled N-nitrosodimethylamine demethylase showed only one phase, corresponding to the slower one in control rats. The mechanism for the acetone induction of N-nitrosodimethylamine demethylase is that acetone stabilizes the N-nitrosodimethylamine demethylase protein, thereby slowing its degradation.[Song BJ et al; J Biological Chem 264 (6): 3568-72 (1989)] **PEER REVIEWED**
  • The metabolism of N-nitrosodimethylamine was investigated in incubations with human liver microsomes from alcoholics and control patients who suffered from other diseases, but had a histological normal liver. All of the microsomal samples studied were able to metabolize N-nitrosodimethylamine at various concentrations to both formaldehyde and nitrite. Analysis of the liver microsomes from alcoholics revealed that both enzymatic activities, formaldyhyde and nitrite formation, were enhanced several times as compared to the control patients. Alcoholics metabolize N-nitrosodimethylamine at a higher rate probably due to the induction of one or more ethanol-inducible human liver cytochromes p450.[Amelizad S et al; Cancer Letters 46 (1): 43-9 (1989)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/2736507?dopt=Abstract" target=new>PubMed Abstract</a>
  • The metabolic activation of N-nitrosodimethylamine to an active metabolite is important in its carcinogenic effect. The lung and liver were compared for their responses to the induction of N-nitrosodimethylamine demethylation by 10% ethanol in the drinking water and by repeated bolus injections. Ethanol in the drinking water increased NDMA metabolism several-fold in both the liver and the lung. Repeated ip injections with 0.6 and 3.0 ml ethanol/kg for 7 days also enhanced this activity in a dose-dependent fashion. These results suggest that in the lung, as in the liver, ethanol may influence the metabolic activation of this nitrosamine.[Carlson GP; Cancer Letters 54 (3): 153-6 (1990)] **PEER REVIEWED** <a href="http://www.ncbi.nlm.nih.gov/pubmed/2224843?dopt=Abstract" target=new>PubMed Abstract</a>
  • The product(s) of metabolism of N-nitrosamines are thought to be responsible for the mutagenicity and/or carcinogenicity of many of these compounds. One hypothesis is that these active intermediates alkylate DNA at specific sites. Although the liver appears to be the major site of decomposition, other organs, such as kidney and lung, possess varying capacity to metabolize nitrosamines. The relative metabolic activity of different organs toward the same compound varies among species. /Nitrosamines/[USEPA; Ambient Water Quality Criteria Doc: Nitrosamines p.C-23 (1980) EPA-440/5-80-064] **PEER REVIEWED**

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TSCA Test Submissions

  • None found

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 12/12/2012.

The NTP is located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.