N-Methyl-N-nitrosoharnstoff

Hazardous Air Pollutants (HAPs)

Nitrogen Compounds -> Nitrosamines

Carcinogens

log Kow = -0.03

-0.4

less than 1 mg/mL at 64 °F (NTP, 1992)

In water, 1.443X10+4 mg/l at 24 °C

Soluble in water

Soluble in ethanol, ether

Melting point: 124 °C (decomposition).

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

255 °F (decomposes) (NTP, 1992)

123 °C

Non-volatile (NTP, 1992)

0.02 [mmHg]

N-nitroso-n-methylurea appears as pale yellow crystals or light yellow moist powder. (NTP, 1992)

Colorless or yellow solid; [HSDB]

Decomposes to diazomethane in alkaline solutions; stability in aqueous solutions is pH-dependent (at 20 °C).

The pure compound is sensitive to humidity and light and should be refrigerated for storage.

This must be stored under refrigeration to avoid sudden decomposition after storage at ambient temp or slightly above (30 °C).

... N-methyl-N-nitrosourea (MNU) ... The kinetics of N-methyl-N-nitrosourea hydrolyses are shown to be first order in N-methyl-N-nitrosourea with a steep rise in rate above pH 8. ... base-induced hydrolysis of N-methyl-N-nitrosourea is initiated by deprotonation at the carbamoyl group. The critical reactive species are shown to be the methyldiazonium ion (Me-N2+) and cyanate (NCO-). Investigations of reactions of (13CH3) N-methyl-N-nitrosourea with 2'-deoxyguanosine (dGuo) and 2'-deoxyguanosine 5'-monophosphate (dGuo-5P) showed that: a) the site of methylation of 2'-deoxyguanosine is highly pH-dependent (relatively more N-1 and O-methylation compared to N-7 occurs at higher pH); b) the principal site of methylation of 2'-deoxyguanosine 5'-monophosphate by N-methyl-N-nitrosourea is at phosphate; c) incorporation of deuterium into methyl groups occurs in D20 at higher pH. Methylation of the oligonucleotide d(GT(15N)GCAC) by N-methyl-N-nitrosourea in D20 showed partial deuteriation of the N7-methyl groups of the guanines, whilst methylation by N-methyl-N-nitrosourea in water indicated no significant preference for either guanine with respect to N7-methylation.

Decomposes to diazomethane in alkaline solutions; stability in aqueous solutions is pH dependent: pH 4.0, half-life 125 hours; pH 6.0, half-life 24 hours; pH 7.0, half-life 1.2 hours; pH 8.0, half-life 0.1 hours; and pH 9, half-life 0.03 hours (at 20 °C).

Danger

H228 (100%): Flammable solid [Danger Flammable solids]

P203, P210, P240, P241, P264, P270, P280, P301+P316, P318, P321, P330, P370+P378, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 42 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H301: Toxic if swallowed [Danger Acute toxicity, oral]

Hazard Traits - Carcinogenicity; Dermatotoxicity

Urea, N-methyl-N-nitroso-: 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.)

SYMPTOMS: Exposure to this compound may cause nausea, vomiting, epigastric pain, diarrhea and leukopenia. It may also cause skin rashes. Eye contact may cause damage to the retina, degeneration of pigment epithelium and destruction of the rods and outer nuclear layer leading to thinning of the whole retina and migration of pigment. Retinal atrophy and cataracts have also been reported. It may cause acetonuria.

N-Nitroso-n-methylurea has been studied in mutagenicity and genetics studies and for use as a cancer chemotherapy agent. No commercial use of N-nitroso-n-methylurea is known. Acute (short-term) exposure toN-nitroso-n-methylurea in humans causes dermatitis. No information is available on the chronic (long-term), reproductive, developmental, or carcinogenic effects of N-nitroso-n-methylurea in humans or animals. Tumors have been reported in the offspring of animals treated with N-nitroso-n- methylurea during their pregnancy. Animal studies have reported tumors of the brain, spinal cord, nerves, stomach, pancreas, and kidneys from oral exposure to N-nitroso-n-methylurea. EPA has classified N- nitroso-n-methylurea as a Group B2, probable human carcinogen.

Reported cause of allergic contact dermatitis; Mutagenic to human cells; Evidence of carcinogenicity in experimental animals; Teratogenic and embryotoxic; [HSDB] Sensitive to moisture and light; Decomposed slowly by water; A skin irritant; May cause skin rashes, leukopenia, and permanent eye injury; [CAMEO] Causes endocrine changes and decreased humoral immune response in intraperitoneal lethal-dose and toxic-dose studies of mice; Causes structural nerve changes in 6-day, intravenous study of rats; Causes changes in teeth in 16 week intermittent oral study of hamsters; [RTECS] May cause irritation; [Aldrich MSDS] See NITROSAMINES.

DHHS/National Toxicology Program; Report on Carcinogens, Fourteenth Edition: Chloramphenico (November 2016). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. N-Nitroso-N-methylurea (684-93-5) is listed as reasonably anticipated to be a human carcinogen.[Available from, as of December 10, 2018: http://ntp.niehs.nih.gov/pubhealth/roc/index-1.html]

U177; As stipulated in 40 CFR 261.33, when N-nitroso-N-methylurea, 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-NITROSO-N-METHYLUREA is incompatible with strong acids and bases. Also incompatible with water and nucleophilic reagents. Alkaline hydrolysis produces a highly toxic, irritating and explosive gas. Can detonate with (potassium hydroxide + methylene chloride) (NTP, 1992).

Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. N-Nitroso-N-methylurea is included on this list.

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.

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical 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/

The pure compound is sensitive to humidity and light and should be refrigerated for storage.

The kinetics of N-methyl-N-nitrosourea hydrolyses are shown to be first order in N-methyl-N-nitrosourea with a steep rise in rate above pH 8. ... base-induced hydrolysis of N-methyl-N-nitrosourea is initiated by deprotonation at the carbamoyl group. The critical reactive species are shown to be the methyldiazonium ion (Me-N2+) and cyanate (NCO-). Investigations of reactions of (13CH3) N-methyl-N-nitrosourea with 2'-deoxyguanosine (dGuo) and 2'-deoxyguanosine 5'-monophosphate (dGuo-5P) showed that: a) the site of methylation of 2'-deoxyguanosine is highly pH-dependent (relatively more N-1 and O-methylation compared to N-7 occurs at higher pH); b) the principal site of methylation of 2'-deoxyguanosine 5'-monophosphate by N-methyl-N-nitrosourea is at phosphate; c) incorporation of deuterium into methyl groups occurs in D20 at higher pH. Methylation of the oligonucleotide d(GT(15N)GCAC) by N-methyl-N-nitrosourea in D20 showed partial deuteriation of the N7-methyl groups of the guanines, whilst methylation by N-methyl-N-nitrosourea in water indicated no significant preference for either guanine with respect to N7-methylation.

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/

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with 5% acetic acid, then transfer the dampened material to a suitable container. Use absorbent paper dampened with 5% acetic acid to pick up any remaining material. Your contaminated clothing and the absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with 5% acetic acid followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U177, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.

A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 °C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 °C and residence times of seconds for liquids and gases, and longer for solids.

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": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The 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-Nitroso-N-methylurea (8 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for N-Nitroso-N-methylurea (9 total), please visit the HSDB record page.

0.33 [mg/m3]

3.6 [mg/m3]

22 [mg/m3]

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear 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 may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Rats were pretreated for a number of weeks with ... N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea ... . A subsequent challenge with a single, low-dose of radioactivity labeled dimethylnitrosamine was given to assay the capacity of the liver for O6-methlyguanine repair. ... Pretreatment for 2 weeks with N-ethyl-N-nitrosourea resulted in strongly enhanced O6-methylguanine repair, as did a similar pretreament with diethylnitrosamine, which was included as a positive control. The same pretreatment scheme which was highly effective in the case of N-ethyl-N-nitrosourea, was found to be totally ineffective in the case of N-methyl-N-nitrosourea. When N-methyl-nitrosourea was admin for 8 wk instead of 2, a small but statistical incr in O6-methylguanine repair was observed. ... Two factors are responsible for the low effectivity of N-methyl-nitrosourea. The first is the relatively low extent of liver DNA methylation by this cmpd when compared with dimethylnitrosoamine. The second is the low efficiency of methylating agents to induce O6-ethylating agents. ... It is concluded that the capacity of an agent to enhance O6-methylguanine repair in rat liver ... reflects the hepato(co)carcinogenic capacity of that agent.

The administration of nicotine during the perinatal stages of life resulted in a significant decrease in tumors occurring after transplacental induction by NMU. The overall tumor incidence following po application of NMU to dams was 85% in rats of the F1-generation, the main occurrence being related to the neurogenic system. Regular injections of nicotine before or after birth resulted in a reduction of malignancies by 17% and 22%, resp. ... These findings suggest that nicotine is capable of modulating the expression of chemically induced tumors of the neurogenic system in a favorable way.

MNU applied to fertilized egg cells /of Oryza sativa L/ induced an increased range of variation for aluminum tolerance in M2. For the M3, the induced variability in M2 was heritable; 50 variants expressed different degrees of tolerance for aluminum toxicity, some of which did not show growth inhibition even at 30 ppm aluminum. Tolerance for aluminum toxicity and longer root development were interrelated.

Ellagic acid ... inhibits the activity of the direct-acting mutagen N-methyl-N-nitrosourea in Salmonella typhimurium TA100. Ellagic acid at 0.10, 0.25, 0.50, and 1.0 mM inhibited the mutagenicity of N-methyl-N-nitrosourea (0.40 mM) by 3, 13, 45, and 60%, respectively ... Ellagic acid inhibition of N-methyl-N-nitrosourea induced mutagenicity is due to specific inhibition of methylation at the O6 position of guanine through an ellagic acid-duplex DNA affinity-binding mechanism.

For more Interactions (Complete) data for N-Nitroso-N-methylurea (18 total), please visit the HSDB record page.

LC50; Species: Oryzias latipes (Japanese medaka) embryo, 66 hr post-fertilization; Conditions: freshwater, static; Concentration: 206.1612 mg/L for 2 hr (95% confidence interval: 164.92896-257.7015 mg/L)

EC50; Species: Oryzias latipes (Japanese medaka) embryo, 66 hr post-fertilization; Conditions: freshwater, static; Concentration: 154.6209 mg/L for 2 hr (95% confidence interval: 134.00478-185.54508 mg/L); Effect: abnormal growth

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8(SRC), determined from a log Kow of -0.03(2) and a regression-derived equation(3), indicates that N-nitroso-N-methylurea is expected to have very high mobility in soil(SRC). Volatilization of N-nitroso-N-methylurea from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.9X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). N-Nitroso-N-methylurea is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-2 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegradation data in soil were not available(SRC, 2018).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8(SRC), determined from a log Kow of -0.03(2) and a regression-derived equation(3), indicates that N-nitroso-N-methylurea is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 9.9X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). 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-nitroso-N-methylurea, which has an estimated vapor pressure of 3.0X10-2 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase N-nitroso-N-methylurea is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 10 days(SRC), calculated from its rate constant of 1.6X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). N-Nitroso compounds, like N-nitroso-N-methylurea, commonly absorb at wavelengths of approximately 330 nm(3) and, therefore, N-nitroso-N-methylurea may be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

IDENTIFICATION AND USE: N-Nitroso-N-methylurea (NMU) is a solid. NMU was once widely used to synthesize diazomethane in the laboratory, it has been replaced by other reagents for this use. NMU has been studied as a chemotherapeutic agent in cancer treatment, either alone or in combination with cyclophosphamide. Small quantities are used in research to study its mutagenic effects on plants. HUMAN STUDIES: Nausea and vomiting were seen after iv injection of 4 mg/kg body wt NMU to patients. NMU produced mutations in human lymphoblast cell line TK6. The malignant transformation of adult human prostate epithelial cells has been reported after multiple exposures to the NMU. ANIMAL STUDIES: The major toxic effects of NMU in animals result from severe damage to hematopoietic, lymphoid and other tissues that have rapid rates of cell turnover. Acute treatment with NMU has been shown to inhibit protein and nucleic acid synthesis in tissues. NMU acutely induced rod-dominant photoreceptor degeneration in monkey retinas, but the photoreceptor function was impaired in both the rods and cones. The intraperitoneal application of NMU led to moderate systemic side effects in mice and to selective photoreceptor degeneration. Intravitreal injections of NMU also induced photoreceptor degeneration; however, no systemic side effects were observed. In rabbits, the intravitreal injection of 3 mg/kg bw MNU leads to selective but inhomogeneous photoreceptor degeneration. Carcinomas of the forestomach were seen in rats at doses of 10 mg/kg bw given once every 2 weeks and 20 mg/kg bw given once every 4 weeks over a period of 9 months. Malignant tumors of the brain (sarcomas, gliomas) and the peripheral nervous system (described as neurosarcomas) were also observed. Odontogenic neoplasms were found in 2/10 rats after a single i.g. administration of 90 mg/kg bw. Minipigs received 10 mg/kg bw NMU at fortnightly intervals for 4.5 years. All of the 9 animals that lived 50 months developed benign and some malignant tumors of the stomach. Three species of monkeys, Macaca mulatta, M. fascicularis and Cercopithecus aethiops were administered NMU orally, and were found to have squamous-cell carcinomas of the oropharynx and/or esophagus. One skin application of 50-100 mg/kg bw to 125 newborn mice induced mainly lymphatic leukemias in about 50% of treated animals. Application of a 0.5% solution of NMU 3 times/week for 30 weeks (1.75 mg/dose) to rats produced multiple squamous- and basal-cell carcinomas of the skin in 9/9 animals. The first tumor appeared at 20 weeks. Skin application to 20 Syrian golden hamsters with 0.5% solution of NMU 3 times/week for 13 weeks (0.35 mg/dose) produced squamous-cell carcinomas of skin in 18/18 animals, the first tumor appearing at 8 weeks. Tumors of the nervous system and kidney were observed in the offspring of rats treated with NMU during the last third of pregnancy. Mammary tumors also occurred in the treated mothers. Congenital defects in the offspring of mice following paternal treatment with NMU also occurred. A model of retinal degeneration has been developed in mice using NMU. In mice, ectrodactyly was the predominant effect after treatment on day 11 of pregnancy. Treatment on day 12 triggered especially double-sided microdactyly. The genetic activity of NMU has been demonstrated in bacterial phage, Escherichia coli, Salmonella typhimurium, Saccharomyces cerevisiae, Serratia marcescens, Chinese hamster cells and Drosophila melanogaster, inducing forward and reverse mutations and gene conversions.

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-nitroso-N-methylurea 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": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

The Koc of N-nitroso-N-methylurea is estimated as 8(SRC), using a log Kow of -0.03(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that N-nitroso-N-methylurea is expected to have very high mobility in soil(SRC).

/HUMAN EXPOSURE STUDIES/ Nausea and vomiting were seen after iv injection of 4 mg/kg body wt NMU to patients.

/GENOTOXICITY/ The concentration-dependent mutagenic, clastogenic and cytocidal activities of Mitomycin C, methylnitrosourea, and ethylnitrosourea were measuresd in the human lymphoblast cell line TK6. For treatments resulting in fewer than 2 lethal hits methylnitrosourea, ethylnitrosourea, and Mitomycin C gave rise to apparently linear dose-response curves for gene mutations (hgprt and tk genes) as well as for chromosomal aberrations. The numbers of induced mutants at the tk and hgprt loci were similar between the two loci for each compound. However, the ratio of mutagenic activity relative to the clastogenic activity (aberrations/cell) was lowest for Mitomycin C, intermediate for methylnitrosourea, and highest for ethylnitrosourea. These results confirm in human cells the general observation that the processes of mutagenesis and clastogenesis are nonidentical: compounds vary independently in their mutagenic and clastogenic potentials.

/ALTERNATIVE and IN VITRO TESTS/ Loss of expression of the hMLH1 and HPMS2 subunits of the MutL alpha-mismatch repair complex is a frequent event (9/10) in independent cisplatin resistant derivatives of a human ovarian carcinoma cell line. ... Furthermore, cisplatin and doxorubicin-resistant ovarian lines deficient in hMLH1 expression are cross-resistant to 6-thioguanine and the methylating agent N-methyl-N-nitrosourea (MNU). Depletion of O6-alkylguanine-DNA-alkyltransferase (ATase) activity confers only limited increased sensitivity to N-methyl-N-nitrosourea. Thus the mismatch repair deficient lines retain DNA damage tolerance even after ATase depletion. ...

/ALTERNATIVE and IN VITRO TESTS/ /The authors/ report the malignant transformation of adult human prostate epithelial cells after multiple exposures to the chemical carcinogen N-nitroso-N-methylurea. Such transformants showed morphological alterations and anchorage-independent growth in soft agar and induced carcinomas when transplanted into nude mice. No p53 or ras mutations were observed. Stepwise chromosomal changes in the progression to tumorigenicity were observed. Loss of the p arms of chromosome 8 (p10 > pter) and chromosome 10 (p10 > pter) and gain of the q arm of chromosome 8 (q10 >qter) were only observed in the tumor outgrows. ...

/ALTERNATIVE and IN VITRO TESTS/ For DNA-reactive chemicals, a low dose linear assessment of cancer risk is the science policy default. In the present study, we quantitated the endogenous and exogenous N7-methyl-G and O(6)-methyl-dG adducts in human lymphoblastoid cells exposed to low dose [D3]-methylnitrosourea. Endogenous amounts of both adducts remained nearly constant, while the exogenous adducts showed linear dose-responses. The data show that O(6)-methyl-dG adducts >/=1.8/10(8) dG correlated with published studies that demonstrated significant increases of mutations under these conditions. The combined results do not support linear extrapolations to zero when data are available for science-based regulations.

N-Nitroso-N-methylurea's limited production and use in laboratory synthesis for research purposes(1,2) may result in its release to the environment through laboratory waste streams. No evidence was found that N-nitroso-N-methylurea is produced or used commercially(SRC).

N-Methyl-N-nitrosourea

Group 2A: Probably carcinogenic to humans

Volume 17: (1978) Some N-Nitroso Compounds

1987

1987

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

An estimated BCF of 3 was calculated in fish for N-nitroso-N-methylurea(SRC), using a log Kow of -0.03(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

U177; As stipulated in 40 CFR 261.33, when N-nitroso-N-methylurea, 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).

Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. N-Nitroso-N-methylurea is included on this list.

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 1 lb or 0.454 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).

The role of oncogene ras in carcinogen-induced neoplastic transformation was examined. Rat mammary carcinomas induced by N-nitroso-N-methylurea and 7,12-dimethylbenzanthracene showed mutations in codons 12 and 61, resp, of the gene H-ras-1. The mutation at codon 12 was a guanine-guanine-adenine to guanine-adenine-adenine transition.

The cyanate ion produced by decomposilion of NMU at physiological pH can react with proteins by carbanoylation.

In vivo formation of NMU was shown by methylation of guanine at N7 after feeding of the precursors methylurea and sodium nitrite. /Species not specified/

Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.

The high chemical reactivity of NMU renders it unlikely that enzymic catalysis is involved in its decomposition. NMU is a direct alkylating agent and alkylates nucleic acids both in vitro and in vivo. Such alkylation has been detected in a number of tissues, including brain, lung, kidney, liver, intestine, thymus and spleen, in a number of species, including mice, rats, hamsters and mini-pigs. All three hydrogen atoms in the methyl group of NMU are retained in the methylated nucleosides formed in nucleic acids after alkylation by NMU in vivo.

N-Nitroso-n-methylurea was used in the past for the laboratory synthesis of diazomethane, but it has been largely replaced by other reagents. N-Nitroso-n-methylurea has been studied in mutagenicity and genetics studies and for use as a cancer chemotherapy agent (alone or in combination with cyclophosphamide).

Used as research chemical for its mutagenic effects on various plants; Formerly used to synthesize diazomethane in the laboratory; Not commercially produced in significant amounts; [HSDB]

For N-nitroso-N-methylurea (USEPA/OPP Pesticide Code: 035511) there are 0 labels match. /SRP: Not registered for current use in the USA, but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

N-Nitroso-N-methylurea was once widely used to synthesize diazomethane in the laboratory; however, it has been replaced by other reagents for this use. N-Nitroso-N methylurea has been studied as a chemotherapeutic agent in cancer treatment, either alone or in combination with cyclophosphamide. Small quantities are used in research to study its mutagenic effects on plants.

(1977) NOT PRODUCED COMMERCIALLY IN USA

(1979) NOT PRODUCED COMMERCIALLY IN USA

Urea, N-methyl-N-nitroso-: ACTIVE

Although N-nitroso-N-methylurea is available in small quantities for research purposes, no evidence was found that it has been produced in significant commercial quantities.