N-Ethyl-N-nitrosourea

117.10700

117.11

212-072-2

P8M1T4190R

45403

2811|3077

DTXSID8020593

C26563

Very pale pink crystalline solid|Pale yellow, crystalline|Pale buff-yellow hexagonal plates

2924199090

75.76000

0.76870

N-nitroso-n-ethylurea appears as yellow-pink crystals or off-white powder. Sensitive to light.

1.35g/cm3

103-104 °C (decomp)

181.8ºC at 760 mmHg

63.8ºC

1.532

12.83g/L(room temperature)

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 b

2.0X10-2 mm Hg at 25 °C (est)

LD50 i.v. in rats: 240 mg/kg (Druckrey)

Henry's Law constant = 1.3X10-10 atm-cu m/mol at 25 °C (est)

Decomposes to diazoethane in alkaline solutions; stability in aqueous solutions is pH dependent: pH 4.0, half-life 190 hours; pH 6.0, half-life 31 hours; pH 7.0, half-life 1.5 hours; pH 8.0, half-life 0.1 hours; pH 9.0, half-life 0.05 hours (at 20 °C).|Hydroxyl radical reaction rate constant = 5.0X10-12 cu cm/mole-sec at 25 °C (est)

Water soluble. Sensitive to moisture--stability in aqueous alkaline solutions depends on pH.

Amides and Imides

Water-Reactive

N-NITROSO-N-ETHYLUREA is highly reactive. Sensitive to moisture and light. Its stability in aqueous solutions is pH-dependent. Incompatible with water and nucleophilic reagents. Alkaline hydrolysis produces a highly explosive gas. (NTP, 1992).

III

6.1(b)

UN 2811 6.1/PG 3

3

45-46-61-20/21/22

53-22-36/37/39-45

YT3150000

T

Unstable at RT, Contains approximately 40% Water, 2.0% Acetic Acid to stabilize

P201-P280-P301 + P310-P308 + P313

H301-H312-H332-H350-H360

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U176, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.|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/|For more Disposal Methods (Complete) data for N-Nitroso-N-ethylurea (9 total), please visit the HSDB record page.

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-ethylurea (759-73-9) 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]

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P280, P281, P301+P310, P302+P352, P304+P312, P304+P340, P308+P313, P312, P321, P322, P330, P363, P405, and P501|Aggregated GHS information provided by 40 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H301: Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P310, P308+P313, P321, P330, P405, and P501

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

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. STORAGE PRECAUTIONS: You should protect this chemical from exposure to light. Keep the container tightly closed under an inert atmosphere, and store it in a refrigerator. (NTP, 1992)

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)|Eye/face protection: Face shield and safety glasses. 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).|For more Personal Protective Equipment (PPE) (Complete) data for N-Nitroso-N-ethylurea (6 total), please visit the HSDB record page.

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 dry chemical, carbon dioxide, water spray, or foam extinguishers. ... If material or contaminated runoff enters waterways, notify downstream users of potentially contaminated waters. Notify local health and fire officials and pollution control agencies. From a secure, explosion-proof location, use water spray to cool exposed containers. If cooling streams are ineffective (venting sound increases in volume and pitch, tank discolors, or shows any signs of deforming), withdraw immediately to a secure position. ... The only respirators recommended for firefighting are self-contained breathing apparatuses that have full face-pieces and are operated in a pressure-demand or other positive-pressure mode.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. 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. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.|Evacuate persons not wearing protective equipment from area of spill or leak until cleanup is complete. Remove all ignition sources. Use HEPA vacuum or wet method to reduce dust during cleanup. Do not dry sweep. Collect powdered material in the most convenient and safe manner and deposit in sealed containers. Ventilate area after cleanup is complete. It may be necessary to contain and dispose of this chemical as a hazardous waste. If material or contaminated runoff enters waterways, notify downstream users of potentially contaminated waters.|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/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. 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.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.|Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.|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.|For more Preventive Measures (Complete) data for N-Nitroso-N-ethylurea (15 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

U176; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate.

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).

U176; As stipulated in 40 CFR 261.33, when N-nitroso-N-ethylurea, 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).

IDENTIFICATION AND USE: N-Nitroso-N-ethylurea (NEU) is a solid. It is used experimentally as mutagen, and as ethylating agent in the laboratory synthesis of diazoethane. Mutagenic effect has been studied for promoting growth of various plants. HUMAN STUDIES: Treatment of cultured human fibroblasts with NEU induced both chromatid and chromosome aberrations. The effect of NEU on human chromosomes from cultured blood lymphocytes was studied. The incidence of single chromatid and isochromatid breaks, exchanges and multiple breaks in human lymphocytes in vitro was dose-dependent, at doses ranging 25-200 ug/mL. Both O6-alkylguanine-DNA alkyltransferase and nucleotide excision repair play an important role in protecting human cells from the toxic and mutagenic effects of NEU. ANIMAL STUDIES: Rats were given single oral doses of 10, 20, 40 or 80 mg/kg bw NEU, and malignant neurogenic tumors were induced in the brain, spinal cord and peripheral nervous system in 75/80 animals. Even at the lowest dose, 23/26 animals died with neurogenic tumors (21 with brain tumors). At the highest dose, 9/16 rats had nephroblastomas. Among 39 rats given 60 mg NEU/L of drinking-water on 5 days/week for 52 weeks, the following tumors were observed: 7 tumors of the stomach (3 papillomas, 1 squamous-cell carcinoma and 3 sarcomas, all in males), 9 tumors of the large intestine (6 adenocarcinomas and 3 sarcomas, all in males), 9 adenocarcinomas of the mammary gland (8 in females and 1 in a male) and 12 myelocytic leukemias were observed. A variety of epithelial and mesenchymal embryonal neoplasms of the eye, liver, brain, kidney, muscle and jaw (including neuroectodermal tumors of the eye and nephroblastomas), closely analogous to tumors of human infancy, were found in opossums (Didelphis virginiana Kerr) treated orally from birth to 16 weeks of age with 100 mg/kg bw NEU in either single or split doses. One-day-old mice given single s.c. injections of NEU at dose levels ranging from 10-160 mg/kg bw developed a high incidence of tumors. Monthly i.p. injections of 10 mg/animal NEU for 3 months caused thymic lymphomas in 3/10 adult rats. Monthly treatment with 10 mg/animal for 5 months produced thymic lymphomas in 9/20 treated rats and myeloid leukemias in 5 others. When 30 mg/kg bw NEU were given by i.v. injection to Syrian golden hamsters on day 15 of pregnancy, 14/22 offspring developed tumors, mainly of the nervous system (5 tumors the trigeminal nerve and 11 tumors of the peripheral nerves). No tumors of the brain or spinal cord were observed. Teratogenic effects of NEU on craniofacial development were investigated in rat embryos in vivo, and in vitro using a whole-embryo culture technique. A single intraperitoneal injection of NEU into the pregnant rat on day 9.5 of gestation induced several types of craniofacial malformations. A functional defect (respiratory distress), in addition to morphological defects, was induced in the offspring of male mice treated with NEU before mating. NEU Induces mutations in Salmonella typhimurium, Escherichia coli, lower and higher plants, in Drosophila melanogaster and in other organisms. A mutation yield of 85% X-linked recessive lethal and visible mutations was seen in Drosophila exposed to 4-5 mg NEU.

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 pretreatment 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-N-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-N-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 06-methylguanine repair in rat liver when compared with 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.|BD rats were given simultaneous s.c. administrations of 10 mg/kg bw NEU and 1 mg/kg bw anhydrous cobalt chloride or anhydrous cupric sulfate once weekly; all of 24 rats treated with cobalt and NEU developed local sarcomas at the injection site, and, in addition, 2 malignant neurinomas were seen. Of those treated with copper and NEU, 4 animals developed local sarcomas. A single i.p. injection of 25-90 mg/kg bw NEU with 5-10 mg/kg bw anhydrous cupric sulfate or anhydrous cobalt chloride caused local sarcomas in the abdominal cavity in 6/20 animals. Rats treated with NEU or with cobalt or copper salts alone did not develop local sarcomas.|Ethylnitrosourea /was administered/ intraperitoneally in doses of 0, 5, or 20 mg/kg bw to 15-day-old outbred CD-1 Swiss mice. At weaning, at 5 weeks of age, 23 to 29 mice at each dose level were given drinking water containing 1,800 ppm concentrations of chloroform. Other groups of 25 to 36 of the ENU-treated mice were given sodium phenobarbital in water at concentrations of 500 ppm. After 46 weeks of exposure, that is, at 51 weeks of age, the mice were killed for necropsy. There was dose-related development of liver adenomas and hepatocellular carcinomas in males and of lung tumors (mostly adenomas) in both sexes that were attributable to ethylnitrosourea alone. The administration of chloroform seemed to inhibit tumor development in male mice that had received ethylnitrosourea. Phenobarbital seems to have increased the incidence of liver tumors among ethylnitrosourea treated mice. A significant effect of chloroform or phenobarbital on lung-tumor incidence was not evident.

LD50 Rat oral 300 mg/kg|LD50 Rat sc 240 mg/kg|LD50 Rat iv 240 mg/kg|LD50 Mouse oral 960 mg/kg|LD50 Mouse ip 490 mg/kg

/PLANTS/ Three-year long investigations were conducted for the purpose of assessing the effect of N-nitroso-N-ethylurea treatment applied single or in combination with gamma irradiation (4 krad) on the variability of some quantitative characteristics in beans cv. No. 564. It was found that in the two generations investigated (M1 and M2) th effect of the factors year (A) and treatment (B) and of their interaction (A treatment with 0.0031 M N-nitroso-N-ethylurea, as compared to the control, had a stimulating effect on the quantitative characteristics studied in M1 generation. Combined treatment (4 krad gamma rays + 0.0031 M N-nitroso-N-ethylurea), as compared to the control, produced as stimulating effect in M1 generation on the characteristic plant height, number of fruit bearing branches and number of pods per plant. No significant differences were found between treated and non-treated plants in M2 for the quantitative characters investigated.

N-Nitroso-N-ethylurea's 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-ethylurea is produced or used commercially(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a log Kow of 0.23(2) and a regression-derived equation(3), indicates that N-nitroso-N-ethylurea is expected to have very high mobility in soil(SRC). Volatilization of N-nitroso-N-ethylurea from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). N-Nitroso-N-ethylurea is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.0X10-2 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 10(SRC), determined from a log Kow of 0.23(2) and a regression-derived equation(3), indicates that N-nitroso-N-ethylurea 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 1.3X10-10 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-ethylurea, which has an estimated vapor pressure of 2.0X10-2 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-ethylurea 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 3 days(SRC), calculated from its rate constant of 5.0X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). N-Nitroso compounds, like N-nitroso-N-ethylurea , commonly absorb at wavelengths of approximately 330 nm(3) and, therefore, N-nitroso-N-ethylurea may be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

The rate constant for the vapor-phase reaction of N-nitroso-N-ethylurea with photochemically-produced hydroxyl radicals has been estimated as 5.0X10-12 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). N-Nitroso-N-ethylurea may undergo hydrolysis in the environment; stability in aqueous solutions at 20 °C was reported to be pH dependent; at pH 4.0, hydrolysis half-life 190 hours; pH 6.0, half-life 31 hours; pH 7.0, half-life 1.5 hours; pH 8.0, half-life 0.1 hours; pH 9.0, half-life 0.05 hours(2). N-Nitroso compounds, like N-nitroso-N-ethylurea, commonly absorb at wavelengths of approximately 330 nm(3) and, therefore, N-nitroso-N-ethylurea may be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

An estimated BCF of 3 was calculated in fish for N-nitroso-N-ethylurea(SRC), using a log Kow of 0.23(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Koc of N-nitroso-N-ethylurea is estimated as 10(SRC), using a log Kow of 0.23(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that N-nitroso-N-ethylurea is expected to have very high mobility in soil(SRC).

The Henry's Law constant for N-nitroso-N-ethylurea is estimated as 1.3X10-10 atm-cu m/mole(SRC) developed using a fragment constant estimation method(1). This Henry's Law constant indicates that N-nitroso-N-ethylurea is expected to be essentially nonvolatile from water surfaces(2). N-Nitroso-N-ethylurea's Henry's Law constant indicates that volatilization from moist soil surfaces is not likely to occur(SRC). N-Nitroso-N-ethylurea is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.0X10-2 mm Hg(SRC), determined from a fragment constant method(1).

Occupational exposure to N-nitroso-N-ethylurea may occur through inhalation and dermal contact with this compound at workplaces where N-nitroso-N-ethylurea is produced or used. Use data indicate that general population exposure should be low or non-existent since N-nitroso-N-ethylurea is used in small quantities in research laboratories. (SRC)

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. (See all compounds classified as Alkylating Agents.)

NEU was rapidly lost from the blood after its i.v. injection, with a half-life of 5-6 minutes. The high chemical reactivity of NEU renders it unlikely that enzymic catalysis is involved in its decomposition.|The tissue-disposition and fate of N-[(14)C]ethyl-N-nitrosourea has been studied in mice. A large part of the injected N-[(14)C]ethyl-N-nitrosourea radioactivity was found to be exhaled as (14)CO2. Whole-body autoradiography showed evenly distributed radioactivity in most tissues shortly after the administration of N-[(14)C]ethyl-N-nitrosourea which probably is due to the homogeneously distributed substance and the non-enzymatically formed ethyl-carbonium ions which have reacted with the tissues. The blood-brain barrier seemed to have a capacity to partially prevent the uptake of the substance in the central nervous system. A high radioactivity was observed in the liver, which may imply that N-[(14)C]ethyl-N-nitrosourea is enzymatically decomposed in this tissue. An observed labelling of kidneys may be connected with urinary excretion of radioactivity. The radioactivity in the liver and kidney decreased at later survival intervals and a distribution pattern appeared, which was characterized by a labelling of tissues with a high protein or steroid synthesis and of fat containing tissues. The distribution pattern corresponded to the one seen after the administration of [(14)C]acetaldehyde and is probably due to normal biosynthetic incorporation of radioactivity in the 2-carbon pool. Pretreatments with pyrazole, nialamide and diethyldithiocarbamate caused a marked inhibition of the exhalation of (14)CO2 and of the incorporation of radioactivity in the liver. This effect may be directed towards the decomposition of N-[(14)C]ethyl-N-nitrosourea itself, but an effect on the metabolism of formed 2-carbon fragments is also possible. The incorporation of radioactivity in other tissues was not influenced by the pretreatments.

In the ethylation of tRNA from calf liver with (14)C-labeled ENU in vitro, 1,7-diethylguanine was obtained as the main product. ... After in vivo ethylation, the main reaction product isolated from rat liver tRNA was 7-ethylguanine and a pyrimidine nucleotide-like fraction containing a 1,7-diethylguanine derivative with an opened imidazole ring.|NEU is a direct alkylating agent and has been shown to ethylate nucleic acids both in vitro and in vivo. 7-Ethylguanine, 06-ethylguanine, 3-ethyladenine and 7-ethyladenine and ethylphosphate triesters have been detected in rat tissues after administration of NEU in vivo. 06-Ethylguanine was lost from DNA of brain (a target organ) much more slowly than from liver DNA, whereas no such difference was observed for the rate of loss of the other ethylated products.

NEU was rapidly lost from the blood after its i.v. injection, with a half-life of 5-6 minutes.

Thirty-day-old Sprague--Dawley rats were used to study the persistence of DNA lesions (e.g., O6-alkylguanine) induced by various doses of ethylnitrosourea (ENU). Cellular proliferation was measured as an increment of DNA content per organ at 7 days post-treatment. We observed that the persistence of O6-EtGua was not affected by the various dose levels. Comparing the 3 organs, the persistence of O6-EtGua ranked in the order of brain greater than kidney greater than liver, while the percent increase in DNA content was measured as liver greater than kidney greater than brain. When the target specificity of ENU carcinogenesis in 30-day-old rats was compared to that following transplacental exposure in terms of its relationship to the persistence of DNA lesions and the rate of target cellular proliferation, it permitted the conclusion that induction of neoplasia in target cells is not only determined by persistent DNA lesions but also by the rate of proliferation of target cells at the time of exposure.|O6-Alkylguanine-DNA alkyltransferase (AGT) is responsible for repairing the O6-alkylguanine lesion in DNA. There is wide variation in the levels of alkylguanine-DNA alkyltransferase between organ and cell types, which appears to correlate with cell and tissue type sensitivity to the mutagenic and carcinogenic effects of alkylating agents. ... to investigate the role of alkylguanine-DNA alkyltransferase in modulating the frequency and types of mutations induced in one type of normal human parenchymal cells, we examined the types and frequency of mutations in the hypoxanthine (guanine) phosphoribosyltransferase (hprt gene in 116 mutants derived from two N-ethyl-N-nitrosourea (ENU)-treated normal human skin keratinocyte cell lines. O6-Benzylguanine (O6-BZ; 5 um x 2 hr) was used to specifically inhibit alkylguanine-DNA alkyltransferase activity before N-ethyl-N-nitrosourea treatment (0 to 5 mM x 1 hr). O6-Benzylguanine increased both the cytotoxic and mutagenic effects of N-ethyl-N-nitrosourea by 1.8- and 3- to 5-fold, respectively. In both treatment groups, most of the mutations were base substitutions (72%). The proportion of GC to AT transitions in the O6-Benzylguanine group (14/31) was twice that in the group treated with N-ethyl-N-nitrosourea alone, consistent with the loss of alkylguanine-DNA alkyltransferase activity in these cells. There was no strand specificity of GC to AT and AT to GC transitions in both groups. Base transversions accounted for 28% of total base substitutions. A lower than expected proportion of AT to TA transversions were observed in both cell lines, which decreased in the O6-Benzylguanine pretreated group. A strand bias was observed for GC to TA and AT to TA transversions. Most of the G to A and G to T base substitutions had one or more purines flanking 3' to the mutated deoxyguanosines. There were more deletion mutants with the deletion of exon 1,4,6, and 8 in the BZ group than in the control group. These data, characterizing the mutational spectra of N-ethyl-N-nitrosourea in normal human keratinocytes treated in vitro, indicate that GC to AT and AT to GC transition mutations predominate in these cells depleted or not depleted of alkylguanine-DNA alkyltransferase.|The experiments investigated the induction of ethylations to DNA in yeast cells exposed to the chemical mutagen ethylnitrosourea. A similar level of alkylation was seen at the N7 and O6 of guanine and at the N3 of adenine in either log phase cells or in temperature sensitive cdc4 and cdc7 cells growth arrested at their specific G1 positions. Hence, the changes in chromosome structure associated with the above cdc phenotypes do not modify the amount of DNA damage induced by ethylnitrosourea.|NEU is a direct alkylating agent and has been shown to ethylate nucleic acids both in vitro and in vivo. 7-Ethylguanine, 06-ethylguanine, 3-ethyladenine and 7-ethyladenine and ethylphosphate triesters have been detected in rat tissues after administration of NEU in vivo. 06-Ethylguanine was lost from DNA of brain (a target organ) much more slowly than from liver DNA, whereas no such difference was observed for the rate of loss of the other ethylated products.|For more Mechanism of Action (Complete) data for N-Nitroso-N-ethylurea (7 total), please visit the HSDB record page.

ACUTE/CHRONIC HAZARDS: This compound is extremely unstable at high pH. It will decompose to extremely unstable decomposition products if acidic conditions are not maintained. When heated to decomposition it emits toxic fumes of nitrogen oxides. Decomposition products may be explosive. (NTP, 1992)|Carcinogens, Mutagens, Teratogens

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. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR as necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Nitrates, nitrites, and related compounds/|Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat as necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Nitrates, nitrites, and related compounds/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or is in severe respiratory distress. Monitor cardiac rhythm and treat arrhythmias if necessary. Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. If unresponsive to these measures, vasopressors may be helpful. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Nitrates, nitrites, and related compounds/|Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Nitrogen Oxides (NOx) and Related Compounds/|For more Antidote and Emergency Treatment (Complete) data for N-Nitroso-N-ethylurea (7 total), please visit the HSDB record page.

/GENOTOXICITY/ Treatment of cultured human fibroblasts with NEU induced both chromatid and chromosome aberrations. The effect of NEU on human chromosomes from cultured blood lymphocytes ... was studied. The incidence of single chromatid and isochromatid breaks, exchanges and multiple breaks in human lymphocytes in vitro was dose-dependent, at doses ranging 25-200 ug/mL.|/GENOTOXICITY/ The concentration dependent mutagenic, clastogenic and cytocidal activities of Mitomycin C, methylnitrosourea, and ethylnitosourea were measured 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.|/GENOTOXICITY/ We have developed a recombinant DNA shuttle vector that permits the molecular analysis of mutations induced in human cells by chemical or physical mutagens. The vector is able to replicate as a plasmid in Escherichia coli and in Epstein-Barr virus (EBV)-transformed human lymphoblastoid cell lines and contains the herpes simplex virus type 1 thymidine kinase gene (HSV tk) as the target for mutagenesis studies. After introduction of the vector into an EBV-transformed lymphoblastoid cell line (LCL-721) by electroporation, approximately equal to 2% of the transfected cells expressed the vector-encoded gene for hygromycin resistance. Plasmid DNA isolated from cells immediately after selection for hygromycin resistance (10 population doublings posttransfection) contained mutations in the HSV tk gene at a frequency of 6 x 10(-5). Treatment of plasmid-bearing LCL-721 cells with N-ethyl-N-nitrosourea resulted in a dose-dependent increase of up to 15-fold in the frequency of mutations in the HSV tk gene. The dose-response for the induction of mutations in the plasmid-encoded gene closely paralleled that for the induction of mutations in the cellular gene for hypoxanthine (guanine) phosphoribosyltransferase.|/GENOTOXICITY/ ... The toxicity, mutagenicity, and mutational spectra of N-ethyl-N-nitrosourea in three Epstein-Barr virus-transformed human lymphoblastoid cell lines, each with a different DNA repair phenotype /were examined/. One cell line lacks O6-alkylguanine-DNA alkyltransferase activity; another, derived from a patient with xeroderma pigmentosum, complementation group A, lacks nucleotide excision repair capability, and the third is competent in both repair functions. N-Ethyl-N-nitrosourea induced toxicity and mutagenicity at the hypoxanthine-guanine phosphoribosyltransferase locus were increased to a similar degree relative to the repair-competent cells in both O6-alkylguanine-DNA alkyltransferase deficient and nucleotide excision repair-deficient cells. We determine the mutational spectra for N-ethyl-N-nitrosourea by identifying DNA sequence changes at the hypoxanthine-guanine phosphoribosyltransferase locus in at least 26 clones resistant to 6-thioguanine from each cell line. Of the characterized mutations, 89% were single-base pair substitutions. Transitions and transversions were found at AT and GC base pairs in all three cell lines. The biggest difference within the spectra was in the rate of transitions at GC base pairs. Compared to the repair-competent cell line, this mutation was elevated about 8-fold in the O6-alkylguanine-DNA alkyltransferase deficient cells and about 3-fold in the nucleotide excision repair-deficient cells. We conclude that both O6-alkylguanine-DNA alkyltransferase and nucleotide excision repair play an important role in protecting human cells from the toxic and mutagenic effects of N-ethyl-N-nitrosourea. Furthermore, the mutational spectra suggest that both of these repair systems participate in the repair of O6-ethylguanine adducts.|For more Human Toxicity Excerpts (Complete) data for N-Nitroso-N-ethylurea (6 total), please visit the HSDB record page.

Ethylnitrosourea

Urea, N-ethyl-N-nitroso-: ACTIVE|There is no information that ENU /N-nitroso-N-ethylurea/ was manufactured commercially, but it has been used in laboratories to prepare the ethylating agent, diazoethane.|Although N-nitroso-N-ethylurea is available in small quantities for research purposes, no evidence was found that it has been produced commercially.

Determination of N-nitroso-N-ethylurea by using high performance liquid chromatography.

Health Hazards -> Carcinogens, Mutagens, Teratogens