Urethane: Synthesis and Cancer Studies

Urethane is commonly used as a sealant, but it has several other uses because it is resistant to water, oil, and oxidation. As an elastomer, it has outstanding tensile and tear strength. It is also resistant to abrasion and retains its durability in a wide range of temperature extremes.

Synthesis of Urethane

A 500 mL 3-neck round bottom flask was equipped with an overhead stirrer, temperature probe, and nitrogen line. The amino alcohol 3 (35.38 mmol, 10.25 g) and MTBE (100 mL) were charged, forming a light slurry. The water (100 mL) was charged, followed by potassium bicarbonate (2 equ, 7.08 g). Ethyl chloroformate (2 equiv., 6.76 mL) was charged via syringe, and the biphasic mixture was stirred vigorously at 20-25° C. Samples were assayed by HPLC until <2% amino alcohol 3 remained (approximately 30 hours). The layers were separated, and the organic layer was washed with brine (100 mL) and dried over magnesium sulfate. After filtration, a solvent switch (50-60° C. under vacuum) was carried out into a MTBE--heptane mixture (approx. 5% MTBE by volume as measured by 1 H NMR) of 102 mL (10 mL/g starting material) total volume. The ethyl carbamate 5 crystallized readily during the solvent switch. After aging the slurry at 20-25° C. for approx. 30 min, the material was filtered. The solid was washed with the mother liquors, and then with one cake volume of heptane. The dry Urethane was isolated in 92% yield (11.77 g). 1-2% was lost to the mother liquors.[1]

Cancer Studies of Urethane in Experimental Animals

Urethane caused tumors in several rodent species at several different tissue sites and by several different routes of exposure. It was carcinogenic following administration of a single dose and by prenatal exposure, and neonatal or infant mice generally were more susceptible than adult mice. Malignant and/or benign tumors of the lung, liver, and blood vessels were seen in many studies, along with lymphoma, leukemia, or melanoma.[2]

Urethane caused benign and/or malignant lung tumors (adenoma or squamous-cell carcinoma) in (1) mice exposed orally (by stomach tube or via the drinking water), by inhalation or intratracheal administration, by intraperitoneal injection, by dermal administration, prenatally, or by lactation, (2) newborn mice exposed by subcutaneous or intraperitoneal injection, (3) hamsters exposed orally or by subcutaneous injection, and (4) newborn hamsters exposed by subcutaneous injection. Urethane caused liver cancer (hepatocellular carcinoma) in (1) adult and newborn mice exposed orally (by stomach tube), by intraperitoneal injection, by subcutaneous injection, and/or prenatally, (2) newborn rats exposed by intraperitoneal injection, (3) female rats exposed orally, and (4) hamsters exposed orally.

Benign and/or malignant blood-vessel tumors (hemangioma or hemangiosarcoma of the liver, spleen, uterus, or unspecified sites) resulted from exposure to urethane via the drinking water in mice and hamsters of both sexes and in female rats. Malignant lymphoma (in some cases of thymic origin) or leukemia resulted from (1) oral exposure (by stomach tube or via the drinking water) in mice and hamsters of both sexes and in female rats and (2) exposure by intraperitoneal injection or subcutaneous injection in newborn mice. In hamsters, melanoma (primarily of the skin) occurred in adults exposed via the drinking water or by subcutaneous injection and in newborns exposed by intraperitoneal or subcutaneous injection. Other types of skin tumors were observed in mice following dermal or oral administration of urethane. In addition, urethane caused tumors at the following tissue sites: The mammary gland in female mice, rats, and hamsters exposed orally, female mice exposed dermally, and female rats exposed by intraperitoneal injection. The Harderian gland in mice exposed dermally and in newborn mice exposed by intraperitoneal or subcutaneous injection; some tumors were also observed following oral exposure. The forestomach in adult hamsters exposed orally and in adult and newborn hamsters exposed by subcutaneous injection.

Tumors were found less consistently in rodents at other tissue sites, including the ovary, Zymbal gland, adrenal cortex of the kidney, and gastrointestinal tract. Since urethane was listed in the Third Annual Report on Carcinogens, additional studies in rodents have been identified. Many of these studies confirmed the findings of the earlier studies or found that urethane caused similar tumors by additional routes of exposure or in additional species. Administration of urethane in the drinking water caused benign and/or malignant tumors of the blood vessels, liver, lung, and Harderian gland in mice of both sexes, the ovary and mammary gland in female mice, and the forestomach and skin in male mice. Urethane administered to mice by intraperitoneal injection caused tumors of the thymus (thymoma) in both sexes and the blood vessels in females, in addition to liver and lung tumors, as observed in earlier studies.[3]

References

[1] MERCK SHARP DOHME - US5922864, 1999, A

[2] National Toxicology Program; 2021 Dec 21. ISSN: 1551-8280

[3] Dahl GA, Miller EC, Miller JA. 1980. Comparative carcinogenicities and mutagenicities of vinyl carbamate, ethyl carbamate, and ethyl N-hydroxycarbamate. Cancer Res. 40(4):1194–1203.

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