In vivo, urethane is a good clastogen in mammalian somatic cells, however in vitro, it has inconsistent effects on cells. In many different types of cells, urethane is an efficient inducer of sister chromatid exchange [2].

Tumor models and animal modeling both benefit from the usage of polyurethane.

Absorption, Distribution and Excretion
The distribution of radiolabelled urethane administered in water or ethanolic solution, was compared in mice by whole-body autoradiography. Two fasted male A/JAX mice were administered 6 uCi (ethyl-1-(14)C)urethane by oral intubation. One mouse received urethane in 1 mL of an aqueous solution, the other in a 12% ethanol solution. One hour after treatment, the mice were frozen and processed for whole body autoradiography. When urethane was administered in water, the radioactivity localized in the salivary, seromucous, and Harderian glands, medullary bone, liver, bile, and epithelia of the stomach and intestine. Lower levels were seen in brown fat, and in the thymus and esophagus. When urethane was administered in ethanol, localization of urethane at each of these sites was almost completely inhibited; high concentrations were still found in the lumen of the stomach and intestine. No evidence was found of transesterification at pH 1.5 in 12% ethanol.
In an attempt to understand route of administration dependency, (3)H-benzo(a)pyrene, (14)C-urethane and (14)C-acrylamide were administered as single doses orally or topically to male Sencar mice. Distribution in skin, stomach, liver, and lung was determined for time periods up to 48 hr. The binding of these compounds to DNA, RNA, and protein in these tissues was determined 6 and 48 hr after administration. For all three compounds, high concentrations were found in the skin following topical application, but very little material reached this target organ following oral administration. The internal organs generally contained more material after oral administration compared to topical application, whereas the opposite was true for the skin. Differences in distribution to the skin and binding to macromolecules following oral or topical administration cannot explain the greater tumorigenicity of urethane and acrylamide after oral administration in the Sencar mouse.
In mice, urethane is active by transplacental route & is passed to offspring in milk.
After oral administration to rats and mice, /carbamic acid, ethyl ester/ is completely absorbed from the GI tract and rapidly distributed throughout the body. ...Mice eliminated /carbamic acid, ethyl ester/ as /carbon dioxide/ more rapidly than rats.
For more Absorption, Distribution and Excretion (Complete) data for ETHYL CARBAMATE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
In rats, rabbits & humans (patients with multiple myeloma treated with urethane in conjunction with alkylating agent), urinary metabolites are: urethane (0.5-1.7% of admin dose), n-hydroxy urethane (0.02-0.15%), acetyl-n-hydroxy urethane (0.1-0.6%), ethyl mercapturic acid (0.1-0.2%) & N-acetyl-s-ethoxy carbonylcysteine (0.9-2.1%).
Reactivity of ... /n-hydroxyurethane/ in vitro and in vivo favors its consideration as being a proximal carcinogenic metabolite of ... /urethane/ ...
It is metabolized to ethyl alcohol and carbamic acid, and the latter acts as a weak diuretic.
Biotransformation of urethane in rats and rabbits and in man affords n-hydroxyurethane, N-acetyl-s-carboxyethylcysteine, and ethylmercapturic acid as urinary metabolites, and thus urethane is converted into an alkylating agent through n-hydroxylation.
For more Metabolism/Metabolites (Complete) data for ETHYL CARBAMATE (10 total), please visit the HSDB record page.
Urethane has known human metabolites that include Vinyl carbamate.
Ethyl carbamate is rapidly metabolized in the body with 95% being eliminated as carbon dioxide. It is readily absorbed from the gastrointestinal tract and the skin. Metabolism is mediated by cytochrome P450 2E1. Metabolites of ethyl carbamate include N-hydroxyethylcarbamate, alpha-hydroxyethylcarbamate and vinyl carbamate. After conjugation, N-hydroxyethylcarbamate is excreted in the urine, alpha-hydroxyethyl carbamate is metabolized to ammonia and CO2 and vinyl carbamate is converted to vinyl carbamate epoxide. The vinyl carbamate epoxide is thought to be the metabolite that is responsible for the carcinogenic properties of ethyl carbamate based on its ability to form etheno-DNA adducts (A15086)

Toxicity Summary
Ethyl carbamate is genotoxic and a potent carcinogen. It exerts its effects through the formation of DNA adducts (via its vinyl carbamate epoxide metabolite) that induce choromosomal aberrations, micronuclei and sister chromatid exchange. It also tends to induce specific mutations in the Kras oncogene in codon 61 of exon 2 including A:T transversions and A-->G transitions in the second base and A-->T transversions in the third base.

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Interactions
It was ... shown to enhance leukemogenic effects of x-irradiation.
The antipellagratic vitamin, nicotinamide, significantly suppressed urethane induced malformations, when it was given intraperitoneally to pregnant JCL:ICR mice immediately after a single subcutaneous injection of urethane (1.0 mg/g) on the 9th day of gestation. The level of inhibition increased with the doses of nicotinamide: 33.0, 55.8, and 70.0% at doses of 0.2, 0.3, and 0.5 mg/g, respectively. Polydactyly and tail anomalies were markedly suppressed by the post treatment with nicotinamide, while cleft palates were less effectively suppressed. Nicotinamide was still effective, when it was given during the period of 24-48 hr after urethane treatment. The level of inhibition was 39.4 and 61.1% at 0.5 and 1.0% of nicotinamide in the diet, respectively. Higher doses of nicotinamide (3 and 5% in diet) also inhibited urethane induced malformations, but not so effectively as lower doses. The inhibiting effects of nicotinamide on the spontaneous incidence of cleft lips and palates in CL/Fr mice were significant at a low dose (0.5% in diet), but not at a higher dose (1.0%).
The progression of papillomas to squamous cell carcinomas (malignant conversion) was studied in the skin of Sencar and Charles River CD-1 mice, using a three stage treatment protocol. After initiation with 7,12-dimethylbenz(a)anthracene (stage 1) and limited promotion by 12-O-tetradecanoylphorbol-13-acetate (stage II), papilloma bearing mice were treated (stage III) with either tumor initiators, such as urethane, N-methyl-N'-nitro-N-nitrosoguanidine or 4-nitroquinoline-n-oxide; the promoter 12-O-tetradecanoylphorbol-13-acetate, or solvent (acetone). Treatment with tumor initiators in stage III increased both the rate of appearance and the final yield of carcinomas. Similar results were obtained in both Sencar and CD-1 mice. A papilloma stage appears to be necessary for carcinoma development since elimination of 12-O-tetradecanoylphorbol-13-acetate treatment in stage II greatly reduced the incidence of both papillomas and carcinomas in both stocks of mice. The carcinomas that develop using the three stage regimen vary in metastatic potential. In CD-1 mice, the frequency of metastases to lymph nodes were similar in groups treated in stage III with N-methyl-N'-nitro-N-nitrosoguanidine, urethane, 4-nitroquinoline-n-oxide, 12-O-tetradecanoylphorbol-13-guanidine or acetone, but treatment with urethane substantially increased metastases to the lung.
N-homocysteine thiolactonyl retinamide was synthesized from trans-retinoic acid and the free base of homocysteine thiolactone. In doses of 90-1800 mg/kg given ip in mixed lipid vehicle over nine weeks, the compound decreased to 60% of controls the number of lung tumors which was induced in A/J mice by 20 mg of ethyl carbamate. The highest dose also decreased the mean volume of lung tumors to 505 of controls, resulting in a total tumor volume of 30% of controls. Retinoic acid itself of 450 mg/kg was toxic, and no chemopreventive activity was observed. The free base and the lipophilic perchlorate salt of homocysteine thiolactone both increased the number of lung tumors to 114-117% of controls, indicating a co-carcinogenic effect. In C57BL/6N mice with transplanted MUO4 rhabdomyosarcoma, N-homocysteine thiolactonyl retinamide in a dose of 1000 mg/kg given over 11-21 days decreased the weight of the tumors to 30-70% of controls. Therefore, N-homocysteine thiolactonyl retinamide has chemopreventive activity against chemical carcinogenesis and antineoplastic activity against a transplanted neoplasm.
For more Interactions (Complete) data for ETHYL CARBAMATE (23 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 1809 mg/kg
LD50 Rat ip 1500 mg/kg
LD50 Rat im 1400 mg/kg
LD50 Mouse oral 2500 mg/kg
For more Non-Human Toxicity Values (Complete) data for ETHYL CARBAMATE (7 total), please visit the HSDB record page.

[1]. K J Field, et al. Hazards of urethane (ethyl carbamate): a review of the literature. Lab Anim. 1988 Jul;22(3):255-62.
[2]. R E Sotomayor, et al. Mutagenicity, metabolism, and DNA interactions of urethane. Toxicol Ind Health. 1990 Jan;6(1):71-108.

Therapeutic Uses
Anesthetics, Intravenous; Antineoplastic Agents; Carcinogens
/It was/ ... reported in 1968 that urethane had found use in human medicine as an anti-neoplastic agent & formerly was used as a hypnotic, an adjunct to sulfonamide therapy, a component (with quinine) of sclerosing soln for varicose veins, & as a topical bacteriocide.
A more recent source states that large doses of urethane produce bone marrow depression, & that for a time it was used in treatment of chronic leukemia & multiple myeloma. No evidence was found that urethane presently finds use in USA in human medicine.
Medication (vet): reported ... exposures of urethane incl its infrequent use as a hypnotic & its more frequent use as an anesthetic for lab animals.
For more Therapeutic Uses (Complete) data for ETHYL CARBAMATE (7 total), please visit the HSDB record page.

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Drug Warnings
Overdosage with any /anticancer agents which include urethane/ causes leukopenia, granulocytopenia, thrombocytopenia, hypoplasia of all elements of bone marrow, nausea ... & anorexia. /From table/
Medication (vet): ... Hepatotoxic. Contraindicated in nephritis or hepatitis. Hematopoietic depressant. May be teratogenic (hamsters) & carcinogenic (rats & mice). Continued use may depress white cell counts. May increase blood glucose levels. ... Usually reserved for terminal experiments, as pulmonary edema may occur during long lasting anesthesia and recovery periods.
Although positive evidence of teratogenicity in humans is not available for all antineoplastic agents, it is considered that they are best avoided during pregnancy, especially during the first trimester, and should not be used in mothers who are breast feeding. /Anti-neoplastic agents/
... Urethane can occur as a contaminant in two anticonvulsant drugs (trimethadione and paramethadione), with an allowable limit of 1 ppm; these anticonvulsant drugs may be used only to treat epilepsy ... .

C3H7NO2

89.0932

89.047

51-79-6

Urethane-d5;73962-07-9

5641

Colorless, columnar crystals or white, granular powder
Prisms from benzene and toluene

1.1±0.1 g/cm3

105.7±23.0 °C at 760 mmHg

48-50 °C(lit.)

17.7±22.6 °C

15.9±0.4 mmHg at 25°C

1.423

0.07

1

2

2

6

52.8

0

O(C(N([H])[H])=O)C([H])([H])C([H])([H])[H]

JOYRKODLDBILNP-UHFFFAOYSA-N

InChI=1S/C3H7NO2/c1-2-6-3(4)5/h2H2,1H3,(H2,4,5)

ethyl carbamate

NSC-746; NSC 746; Urethane

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~1122.46 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (23.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (23.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: 2.08 mg/mL (23.35 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 50 mg/mL (561.23 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)