N-메틸-N'-니트로-N-니트로소구아니딘

Nitrogen Compounds -> Other Nitrogen Compounds

Carcinogens

Crystals from methanol

Pale yellow to pink crystals

Yellow crystals from methanol.

Reacts with water violently (NTP, 1992)

Slightly soluble in water (less than 0.5%)

Soluble in polar organic solvents (often accompanied by decomposition)

Soluble in DMSO

Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx).

When heated to decomposition it emits very toxic fumes of ... /nitrogen oxides/.

244 °F (decomposes) (NTP, 1992)

118 °C (decomposes)

MP: 118-123.5 °C (with desomposition)

118 °C

N-methyl-n'-nitro-n-nitrosoguanidine appears as a yellow powder. Melting point 244 °F. Decomposes above 212 °F. A suspected carcinogen. Extremely hazardous as a mutagen. Avoid skin contact and inhalation of of vapors. Usually stored frozen (below 32 °F) in polyethylene bottles that are tightly closed and contained in a metal can. May decomposed during prolonged storage and develop sufficient pressure in a closed container to explode. Keep away from heat, sparks, and open flame.

Yellow solid; [Merck Index] Pale yellow to pink solid; Light sensitive, changes color to orange and green; [HSDB] Yellow crystals; [Aldrich MSDS]

Stable under recommended storage conditions.

Pure compound is sensitive to light, changing to orange and green colors. Degradation products arising from prolonged or inadequate storage include N-methyl-N'-nitroguanidine, N-nitroguanidine, nitrocyanamide and guanidine. N-Methyl-N'-nitro-n-nitroso-guanidine (MNNG) is more stable than comparable alkyl-nitrosoureas and alkylnitrosourethanes. Thus, at room temp, the half life at ph 8 is about 200 hr. At ph 7.0 (phosphate buffer) and 37 °C, the half life is 170 hr. ... /It was shown that/ tap water decomposes MNNG much more rapidly than does deionized water.

Although the crude product from the aqueous nitrosation is pyrophoric, recrystallized material is stable (though powerfully mutagenic).

At acid pH slowly releases nitrous acid to give N-methyl-N'-nitroguanidine; it is converted by concentrated aqueous alkali hydroxide to diazomethane; reactions with several nucleophiles are known, especially with amines

Reacts with aqueous KOH to form diazomethane: a.f. McKay, J Am Chem Soc 70, 1974 (1948); reacts at acid pH to give methylnitroguanidine.

Pure N-methyl-N'-nitro-N-nitrosoguanidine is sensitive to light, changing to orange and green colors.

Half-life at pH 8 is about 200 hours; at pH 7 (phosphate buffer) and 37 °C the half-life is 170 hours.

Danger

H315: Causes skin irritation [Warning Skin corrosion/irritation]

P203, P261, P264, P264+P265, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P317, P318, P321, P332+P317, P337+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement)

Danger

H228 (97.6%): Flammable solid [Danger Flammable solids]

P203, P210, P240, P241, P261, P264, P264+P265, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P317, P318, P321, P332+P317, P337+P317, P362+P364, P370+P378, P391, P405, and P501 (click each P-code to see the statement)

Hazard Traits - Carcinogenicity

S - indicates a substance that is identified in a final Significant New Use Rule.

Methylnitronitrosoguanidine: Does not have an individual approval but may be used under an appropriate group standard

The New Jersey Worker and Community Right to Know Act requires public and private employers to provide information about hazardous substances at their workplaces. (N.J.S.A. 34:5A-1 et. seq.)

Mutagenic to human cells; No expected human exposure outside of laboratories where it is used for research; Evidence of carcinogenicity and mutagenicity in experimental animals; [HSDB] Highly flammable, explosive, and violently reactive with water; [CAMEO] A skin and eye irritant; [eChemPortal: ESIS] Toxic to embryonic development in experimental animals; ]REPROTOX] Causes convulsions, acute pulmonary edema, and ulceration or bleeding from stomach in oral lethal-dose studies of rats; Causes changes to liver, GI tract, blood, and lipids in oral toxic-dose studies of mice; [RTECS] An irritant; [Aldrich MSDS]

Toxicology Review: Archiv Fuer Tosikologie 28: 135 (1971)

Toxicology Review: Basic Life Sciences 24: 129 (1983)

Toxicology Review: Nutrition and Cancer 3: 109 (1981)

USEPA; Ambient Water Quality Criteria Doc: Nitrosamines p.A-1 (1980) EPA-440/5-80-064

For more Special Reports (Complete) data for N-methyl-N'-nitro-N-nitrosoguanidine (8 total), please visit the HSDB record page.

U163; As stipulated in 40 CFR 261.33, when N-methyl-N'-nitro-N-nitrosoguanidine, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).

N-METHYL-N'-NITRO-N-NITROSOGUANIDINE will detonate under high impact. It is sensitive to heat. A sample has exploded when melted in a sealed capillary tube. Incompatible with acids, bases, oxidizing agents and reducing agents. Reacts with bases to release highly toxic, irritating and explosive gases. Reacts slowly with acids to release nitrous acid. Reacts with various nucleophiles, especially amines and thiols. Reacts with aqueous potassium hydroxide to form a highly reactive compound. The crude product from aqueous nitrosation is pyrophoric but recrystallized material is stable (NTP, 1992).

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

Use water spray to cool unopened containers.

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2 - 8 °C. Light sensitive. May explode when heated.

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired. ... Facilities for dispensing ... should be contiguous to storage area. /Chemical carcinogens/

ACCIDENTAL RELEASE MEASURES; Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Sweep up and shovel. Contain spillage, and then collect with an electrically protected vacuum cleaner or by wetbrushing and place in container for disposal according to local regulations. Keep in suitable, closed containers for disposal. Contain spillage, pick up with an electrically protected vacuum cleaner or by wet-brushing and transfer to a container for disposal according to local regulations.

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms. ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal. ... The plastic bag should be sealed immediately. ... The sealed bag should be labelled properly. ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated. ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical carcinogens/

Nitrosamine residues generated in laboratory research or accidental spills in research laboratories and diluted to concn of 10 mg/L or less are rapidly reduced to innocuous amines, ammonia, or alcohols by aluminum-nickel alloy powder and aqueous alkali. The method is applicable to a variety of media (water, mineral oil, olive oil, dimethylsulfoxide, soln of agar gel) but is not recommended for use with nitrosamines in acetone or dichloromethane because reactions are slow and incomplete. After the reduced reaction mixture is filtered, the liquid is disposed of by pouring it over sufficient absorbent material to convert it to a solid waste for incineration. /Nitrosamines/

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U163, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.

Product: Burn in a chemical incinerator equipped with an afterburner and scrubber but exert extra care in igniting as this material is highly flammable. Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Contaminated packaging: Dispose of as unused product.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Total destruction ... by incineration may be only feasable method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable. ... Most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical carcinogens/

For more Disposal Methods (Complete) data for N-methyl-N'-nitro-N-nitrosoguanidine (8 total), please visit the HSDB record page.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

Avoid contact with skin and eyes. Avoid formation of dust and aerosols.Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. Keep away from sources of ignition - No smoking. Take measures to prevent the build up of electrostatic charge.

ACCIDENTAL RELEASE MEASURES; Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.

Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

For more Preventive Measures (Complete) data for N-methyl-N'-nitro-N-nitrosoguanidine (14 total), please visit the HSDB record page.

0.04 [mg/m3]

0.50 [mg/m3]

3.0 [mg/m3]

Excerpt from ERG Guide 133 [Flammable Solids]:

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent ... Safety pipettes ... for all pipetting. ... In animal laboratory ... protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators ... when working with particulates or gases, & disposable plastic aprons ... gowns ... /should be/ of distinctive color. /Chemical carcinogens/

The present study provides experimental evidence of in vivo reduction of genotoxic and mutagenic activities of potent carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by the strain Lactobacillus rhamnosus Vc. In vitro studies revealed that coincubation of MNNG with viable cells of L. rhamnosus Vc resulted in the detoxification of the parent compound accompanied with reduction in genotoxicity (69%) and mutagenicity (61%) as evaluated by SOS-Chromotest and Ames test, respectively. Oral feeding of probiotic bacteria L. rhamnosus Vc (10(9) cfu) to Gallus gallus (chicks) for 30 days provided protection against MNNG-induced damage as evidenced from the significant decrease (P = 0.009) in glutathione S-transferase activity in the L. rhamnosus Vc+MNNG-treated chicks in comparison to the MNNG-treated chicks. Histopathology of colon and liver showed intact cells and mild inflammation in the L. rhamnosus Vc+MNNG-treated chicks, whereas heavy inflammation and degenerative changes were observed in MNNG-treated chicks. The results indicate that the probiotic L. rhamnosus Vc provided in vivo protection against MNNG-induced colon damage by detoxification of MNNG to less toxic metabolites.

OBJECTIVES: To investigate if oral omeprazole application induces cancers of fore and glandular stomach in mice. METHODS: A total of 66 eligible male mice were randomly divided into 6 groups, which were treated with control reagent, low (6 mg/kg) and high dose omeprazole (30 mg/kg), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 100 mg/L water), and MNNG plus low and high dose omeprazole, respectively. After 24 weeks, concentrations of acid phosphatase (ACP) and N-acetyl-beta-D-glucosaminidase(NAG) in serum and spleen was examined, and p21 and mTOR levels in stomach were detected. RESULTS: The mouse spleen weight index was smaller in the omeprazole group than the control group, and in the MNNG plus omeprazole groups than the MNNG group. In the fore-stomach, more carcinomas were observed in the MNNG plus omeprazole groups than in the MNNG group. In the glandular stomach, there existed more atypical hyperplasia cases in the MNNG plus omeprazole groups than the MNNG-treated group, and one carcinoma was induced in the MNNG plus high dose omeprazole group. Omeprazole alone caused minor gastric pathological changes. Omeprazole treatment lowered both serum and spleen ACP and NAG levels in both the non-MNNG-treated and MNNG-treated subgroups. In fore-stomach, there existed decreased p21 and mTOR levels in the omeprazole-treated groups than in the control group, and in the MNNG plus omeprazole groups than the MNNG-treated group. CONCLUSION: Omeprazole promotes carcinogenesis of the mouse fore-stomach but not the glandular stomach following treatment with MNNG. Lysosomal hydrolase activity was inhibited and some cancer-associated proteins was dysregulated, which requires further explorations.

Mega-ascorbate intake in diet was more beneficial in alleviating development of gastric cancer in rats when it was commenced after middle of long-term experimental period (initiation of adenomatous hyperplasia but no appearance of malignant lesions) rather than from the beginning of MNNG drinking. A remarkable effect of mega-ascorbate intake was to reinforce surrounding connective tissues to retard the malignant growth.

Hydroxyurea (HU) protected KB (human oral carcinoma) cells specifically against the toxic effect of MNNG.

For more Interactions (Complete) data for N-methyl-N'-nitro-N-nitrosoguanidine (23 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 70(SRC), determined from a structure estimation method(2), indicates that N-methyl-N'-nitro-N-nitrosoguanidine is expected to have high mobility in soil(SRC). Volatilization of N-methyl-N'-nitro-N-nitrosoguanidine from moist soil surfaces is not expected(SRC) given an estimated Henry's Law constant of 1.2X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). N-Methyl-N'-nitro-N-nitrosoguanidine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018). Hydrolysis is expected to occur in moist soil(SRC) based on a neutral hydrolysis half-life of 19 hours at 25 °C(3).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 70(SRC), determined from a structure estimation method(2), indicates that N-methyl-N'-nitro-N-nitrosoguanidine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.2X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). A measured hydrolysis half-life of 19 hours at 25 °C and pH 7 indicate that N-methyl-N'-nitro-N-nitrosoguanidine is expected to hydrolyze under environmental conditions(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of -0.92(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data in water were not available(SRC, 2018).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), N-methyl-N'-nitro-N-nitrosoguanidine, which has an estimated vapor pressure of 1.2X10-4 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase N-methyl-N'-nitro-N-nitrosoguanidine may be removed from the air by wet or dry deposition(SRC). N-Methyl-N'-nitro-N-nitrosoguanidine absorbs light at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a solid. It is used experimentally as a carcinogen and mutagen. It was formerly used in preparation of diazomethane. HUMAN STUDIES: MNNG can induce DNA damages and many cellular defensive events, such as DNA repair, G2/M-phase arrest and apoptosis. Noticeably, diverse cellular responses were observed to occur following MNNG treatment, including nontargeted mutations at undamaged DNA bases, endoplasmic reticulum stress induction and the activation of several signal transduction pathways. ANIMAL STUDIES: Tumors of the forestomach or glandular stomach were observed in rats exposed to MNNG in the drinking water, by stomach tube, and by ip injection; in mice exposed by stomach tube; and in male hamsters and dogs exposed via the drinking water. MNNG also caused tumors of the large intestine in rats exposed by intrarectal instillation. MNNG caused tumors of the small intestine in rats exposed via the drinking water, sc injection, or ip injection and in mice exposed by ip injection. In addition, MNNG caused tumors of the liver and peritoneum in rats exposed orally (by stomach tube or drinking water) and injection-site tumors (fibrosarcoma and rhabdomyosarcoma) in rats exposed by sc injection. In mice, MNNG administered by sc injection caused benign tumors of the liver, lung, and blood vessels (hemangoendothelioma) and by dermal application caused benign and malignant skin tumors (papilloma and carcinoma). MNNG is a potent inducer of cellular stress leading to chromosomal aberrations, point mutations, and cell killing. A high frequency of mutation was induced in O6-methylguanine-DNA methyltransferase-/- cells on exposure to a relatively low dose of MNNG.

/AQUATIC SPECIES/ Cells derived from rainbow trout gonad (RTG-2) and bluegill fry tissues (BF-2) were used as model cell systems to measure cytotoxicity and genotoxicity following exposure to Puget Sound sediment extracts, benzo(a)pyrene and MNNG (N-methyl-N'-nitro-N-nitrosoguanidine). Sediment was collected from several sites withing Puget Sound (Wasington USA) known to be contaminated with compounds such as polycyclic aromatic hydrocarbons, polychlorinated biphenyls, chlorinated hydrocarbons and heavy metals. Each of the sediment samples was extracted with organic solvents and added to cultures of the 2 model cell systems in DMSO (dimethyl sulfoxide). Following exposure the cultures were evaluated for cell death, mitotic inhibition, stimulatory effects and chromosomal damage. These cell cultures responded to the sediment extracts much as they did to known mutagenic/carcinogenic chemicals which were used as model compounds.

/AQUATIC SPECIES/ Three different developmental stages of embryonated eggs of Oryzias latipes were exposed to 2-hr pulses of a number of different concentrations of MNU, MNNG, and DENA. Lethality and teratogenic endpoints were assessed through 24 hr posthatch. MNU (greater than or equal to 2.5 mM) and MNNG (greater than or equal to 0.75 mM) exposure at the multicell stage was lethal, but the same exposure during early organogenesis was largely teratogenic. Four days before hatching, embryos were very resistant to MNU and proceeded to hatch normally; 7.5 mM MNU was required to significantly reduce the percent normal hatch. Effects of DENA were equivocal and only seen at the multicell stage. In order to differentiate between potential changes in chorion permeability, and toxicity per cell, the same three stages were exposed to a series of radiolabeled compounds of varying hydrophobicity, and apparent uptake measured. There were no differences in uptake rate or equilibrium concentration between any of the compounds at the different stages. These results suggest that, as in mammals, certain stages of development are more susceptible than others, and that these differences are a result of embryo sensitivity rather than chemical bioavailability. The most sensitive indicator of exposure was posthatch inflation of the swimbladder. Other terata included pericardial edema, anisophthalmia, and partial rupture of the chorion.

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for N-methyl-N'-nitro-N-nitrosoguanidine is available.[Available from, as of February 1, 2019: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

PRECAUTIONS FOR "CARCINOGENS": ... In relation specifically to cancer hazards, there are at present no health monitoring methods that may ensure the early detection of preneoplastic lesions or lesions which may prelude them. Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning additional tests that might become useful or mandatory. /Chemical carcinogens/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of N-methyl-N'-nitro-N-nitrosoguanidine can be estimated to be 70(SRC). According to a classification scheme(2), this estimated Koc value suggests that N-methyl-N'-nitro-N-nitrosoguanidine is expected to have high mobility in soil(SRC).

/GENOTOXICITY/ Fibroblast cell strains were obtained from skin biopsies taken from patients with adenomatoses of the colon and rectum (ACR), and their relatives. A total of 50 different fibroblast strains were tested for their frequencies of sister chromatid exchange in vitro. These strains included nine from patients with the Gardner syndrome, 21 from patients with non-Gardner ACR, and 20 cell strains from healthy relatives who were not at an increased risk for ACR. In 23 strains, the sister chromatid exchange frequencies after in vitro exposure to N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) were also determined. Both with and without MNNG induction, sister chromatid exchange values in the Gardner strains were found to be significantly higher than in the control strains (p< 0.02 and p< 0.03, respectively). Non-Gardner ACR strains differed only slightly from controls, thus making the difference between the control group and the pooled Gardner + non-Gardner ACR group not significant. In all groups, there was a significant increase in sister chromatid exchange after MNNG exposure, and those strains which had low sister chromatid exchange values spontaneously, also tended to have relatively moderate sister chromatid exchange values after MNNG induction. There was no significant difference between the ratios of SCE values with and without MNNG exposure in the different groups.

/GENOTOXICITY/ Induction of 6-thioguanine (YG) resistance by chemical mutagens was examined in P3 cells, a line of cells derived from a human epithelial teratocarcinoma cell clone which have a stable diploid karyotype with 46(XX) chromosomes, including a translocation between chromosomes 15 and 20. Efficient recovery of TG-resistant mutants induced by the direct-acting mutagens N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), ... the TG-resistant mutant cells induced by MNNG maintained their resistant phenotype 4-6 wk after isolation. This mutant phenotype was assoc with a >10-fold reduction in hypoxanthine-guanine phosphoribosyl transferase (HGPRT) activity relative to that of the parental P3 cell line, which catalyzed the formation of 4.6 pmol inosine-5'-monophosphate/min/ug protein. ... Thus, P3 cells can be useful for the study of mutagenesis at the HGPRT locus by direct-acting chemical mutagens, as well as by chemicals activated in a cell-mediated assay.

/GENOTOXICITY/ To determine the relationship between neoplastic transformation and increased genetic instability, spontaneous and induced mutation rates were compared in a nontumorigenic, immortalized human bronchial epithelial cell line (NL20) and a tumorigenic cell line (NL20T) spontaneously derived from the NL20 line. Using the hypoxanthine phosphoribosyltransferase (HPRT) locus as a marker for determining mutation rate, fluctuation analysis was utilized to evaluate the spontaneous mutation rate. Induced mutation rates were determined for each cell line after N-methyl-N'-nitro-N-nitrosoguanidine exposure. Both the spontaneous and induced mutation rates were noted to be significantly higher in the nontumorigenic NL20 cell line, These findings suggest that increasing genetic instability, as measured by spontaneous or induced mutation rate in the HPRT locus, does not correlate with tumorigenicity in these cells.

/GENOTOXICITY/ BACKGROUND: N-nitroso compounds (NOC) can cause cancers in a wide variety of animal species, and many of them are also potential human carcinogens. However, their underlying genotoxic mechanisms occurred within the context of chromatin, such as aberrant histone modifications, remained elusive. METHODS: We investigated the dynamic landscapes of histone modifications after N-nitroso compound N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitroso-urea (MNU) exposure. Among the altered histone modifications, we also investigated the control mechanisms of histone H3 phosphorylation changes and its possible implications on transcriptional repression. RESULTS: ... We find a specific biphasic reduction of histone H3 phosphorylation at serine 10 (H3S10ph) and serine 28 (H3S28ph), and a rapid decrease of histone H4 acetylation upon MNNG and MNU exposure. Further investigations reveal that the first hypophosphorylation of H3 occurs in a poly(ADP-ribosyl)ation enzyme PARP-1 (Poly(ADP-Ribose) Polymerase 1) dependent manner, whereas the second decline of H3 phosphorylation is at least partially under the control of histone kinase VRK1 (vaccinia-related kinase 1) and dependent on the tumor suppressor protein p53. In addition, DNA damage induced down-regulation of H3S10/S28 phosphorylation also functions in transcriptional repression of genes, such as cell-cycle regulators. CONCLUSIONS: Alkylating damage induced by NOC elicits a biphasic reduction of histone H3 phosphorylation with distinct control mechanisms, which is contributing to DNA damage responses such as the repair-facilitated transcriptional repression. GENERAL SIGNIFICANCE: Identification of the dynamic changes and underlying mechanisms of histone modifications upon NOC exposure would be of great help in understanding the epigenetic regulations of NOC induced DNA damage responses.

For more Human Toxicity Excerpts (Complete) data for N-methyl-N'-nitro-N-nitrosoguanidine (20 total), please visit the HSDB record page.

N-Methyl-N'-nitro-N-nitrosoguanidine's limited production and use experimentally as a carcinogen and mutagen(1) may result in its release to the environment through various waste stream(SRC). Its former use in the production of diazomethane(1) may have resulted in its release to the environment through various waste stream(SRC).

No evidence was found that N-methyl-N'-nitro-N-nitrosoguanidine is produced commercially except as a research chemical(1).

N-Methyl-N´-nitro-N-nitrosoguanidine (MNNG)

Group 2A: Probably carcinogenic to humans

Volume 4: (1974) Some Aromatic Amines, Hydrazine and Related Substances, N-Nitroso Compounds and Miscellaneous Alkylating Agents

1987

1987

NB Overall evaluation upgraded to Group 2A with supporting evidence from other relevant data

U163; As stipulated in 40 CFR 261.33, when N-methyl-N'-nitro-N-nitrosoguanidine, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).

Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b).

Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Nitrosamines/

The levels for nitrosamines through ingestion of contaminated water and contaminated aquatic organisms ... which may result in incremental increase of cancer risk over the lifetime are estimated at 1X10-5, 1X10-6, and 1X10-7. The corresponding recommended criteria are 8.0 ng/L, 0.8 ng/L, and 0.08 ng/L, respectively. If these estimates are made for consumption of aquatic organisms only, excluding consumption of water, the levels are 12,400 ng/L, 1,240 ng/L, and 124 ng/L, respectively. /Nitrosamines/

In vitro and in vivo, MNNG causes methylation of nucleic acids, forming mainly 7-methylguanine with smaller amounts of 3-methyladenine, 1-methyladenine, 3-methylcytosine and (6)o-methylguanine. ... MNNG can modify proteins by transferring its nitroguanidine residue, eg, by converting lysine into nitrohomoarginine. Cytochrome C thus modified no longer acts as an electron acceptor. Histones from ascites tumor cells contained nitrohomoarginine after MNNG treatment.

After oral administration of MNNG about 90% is excreted in the urine, mostly as N-methyl-N'-nitro-guanidine, in the first 9 hr. There is evidence that denitrosation of MNNG is effected by enzymes occurring in the stomach, liver and kidney. ...

Following an oral dose of (14)C-labeled N-methyl-N'-nitro-N-nitrosoguanidine, most of the radioactivity was excreted in the urine within 24 hrs and less than 3 percent in the feces. Less than 3 percent of the radioactivity remained in the body as acid-insoluble materials at 24 to 48 hrs.

Used as experimental carcinogen and mutagen; Used formerly to make diazomethane; [Merck Index]

Experimentally as a carcinogen and mutagen. Formerly used in preparation of diazomethane.

(1977) NOT PRODUCED COMMERCIALLY IN USA

(1982) NOT PRODUCED COMMERCIALLY IN USA