Ethyl carbamate
Encyclopedia
Ethyl carbamate is a chemical compound
with the molecular formula C3H7NO2 first prepared in the nineteenth century. Structurally, it is an ester
of carbamic acid
. Despite its common name, it is not a component of polyurethane
s.
on ethyl chloroformate
or by heating urea nitrate
and ethyl alcohol
:
Prior to World War II, ethyl carbamate saw relatively heavy use in the treatment of multiple myeloma
before it was found to be toxic, carcinogenic and largely ineffective. By US FDA regulations, ethyl carbamate has been withdrawn from pharmaceutical use. However, small quantities of ethyl carbamate are also used in laboratories as an anesthetic for animals.
Ethyl carbamate was upgraded to a Group 2A carcinogen by IARC in 2007.
Formerly, crosslinking agents for permanent press textile treatments were synthesized from ethyl carbamate.
have also been found in wines, sake, beer, brandy, whiskey and other fermented alcoholic beverages.
It has been shown that ethyl carbamate forms from the reaction of alcohol (ethanol
) with urea
:
This reaction occurs much faster at higher temperatures, and therefore higher concentrations of ethyl carbamate are found in beverages that are heated during processing, such as brandy, whiskey, and other distilled beverages. Additionally, heating after bottling either during shipping or in preparation will cause ethyl carbamate levels to rise further.
The urea in wines results from the metabolism of arginine
or citrulline
by yeast or other organisms. The urea waste product is initially metabolised inside the yeast cell until it builds up to a certain level. At that point, it is excreted externally where it is able to react with the alcohol to create ethyl carbamate.
In 1988, wine and other alcoholic beverage manufacturers in the United States
agreed to control the level of ethyl carbamate in wine to less than 15 ppb, and in stronger alcoholic drinks to less than 125 ppb.
Although the urea cannot be eliminated, it can be minimized by controlling the fertilization of grape vines, minimizing their heat exposure, using self-cloning yeast and other actions.
Another important mechanism for ethyl carbamate formation in alcoholic beverages is the reaction from cyanide as precursor, which causes comparably high levels in spirits derived from cyanogenic plants (i.e. predominantly stone-fruit spirits and cachaca).
Studies with rats, mice, and hamsters has shown that ethyl carbamate will cause cancer when it is administered orally, injected, or applied to the skin, but no adequate studies of cancer in humans caused by ethyl carbamate has been reported due to the ethical considerations of such studies. However, in 2007, the International Agency for Research on Cancer raised ethyl carbamate to a Group 2A carcinogen that is "probably carcinogenic to humans," one level below fully carcinogenic to humans. IARC has stated that ethyl carbamate can be “reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals.” In 2006, the Liquor Control Board of Ontario in Canada rejected imported cases of sherry due to excessive levels of ethyl carbamate.
Alcoholic beverages, particularly certain stone-fruit spirits and whiskies, tend to contain much higher concentrations of urethane. Heating (e.g., cooking) the beverage increases the ethyl carbamate content, and some concern exists over shipping wines to overseas markets in containers that tend to overheat. In addition, urethane has a tendency to accumulate in the human body from a number of daily dietary sources, e.g., alcohols, bread and other fermented grain products, soy sauce, orange juice and commonly consumed foods. Hence, exposure risk to human health is increasingly evaluated on the total ethyl carbamate intake from the daily diet (WHO refers to this as "margin of exposure" or MOE), of which alcoholic beverages often provide the most significant portion.
Studies in Korea (2000) and Hong Kong (2009) outline the extent of the accumulative exposure to ethyl carbamate in daily life. Fermented foods such as soy sauce, kimchi, soybean paste, breads, rolls, buns, crackers and bean curd, along with wine, sake and plum wine, were found to be the foods with the highest ethyl carbamate levels in traditional Asian diets.
In 2005, the JECFA (Joint FAO/WHO Expert Committee On Food Additives) risk assessment evaluation of ethyl carbamate concluded that the MOE intake of ethyl carbamate from daily food and alcoholic beverages combined is of concern and mitigation measures to reduce ethyl carbamate in some alcoholic beverages should continue. There is little doubt that ethyl carbamate in alcoholic beverages is very important to health authorities, while the cumulative daily exposure in the typical diet is also an issue of rising concern that merits closer observation. The Korean study concluded, "It would be desirable to closely monitor ethyl carbamate levels in Korean foods and find ways to reduce the daily intake."
The IARC evaluation has led to the following US regulatory actions:
(urethylane, m. p. 52-54 °C), butyl carbamate, and phenyl carbamate (m. p. 149-152 °C), which can also be prepared from the corresponding chloroformate
and ammonia
. These esters are white, crystalline solids at room temperature. Except for the phenyl carbamate, they sublime at moderate temperatures; methyl carbamate sublimes at room temperatures. The first two and ethyl carbamate are very soluble in water, benzene, and ether. These other carbamates (methyl
, butyl, and phenyl) are only used in small quantities for research purposes.
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
with the molecular formula C3H7NO2 first prepared in the nineteenth century. Structurally, it is an ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
of carbamic acid
Carbamate
Carbamates are organic compounds derived from carbamic acid . A carbamate group, carbamate ester, and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes.-Synthesis:Carbamic acids are derived...
. Despite its common name, it is not a component of polyurethane
Polyurethane
A polyurethane is any polymer composed of a chain of organic units joined by carbamate links. Polyurethane polymers are formed through step-growth polymerization, by reacting a monomer with another monomer in the presence of a catalyst.Polyurethanes are...
s.
Synthesis
Ethyl carbamate is a white crystalline substance produced by the action of ammoniaAmmonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
on ethyl chloroformate
Ethyl chloroformate
Ethyl chloroformate is the ethyl ester of chloroformic acid. It is a reagent used in organic synthesis for the introduction of the ethyl carbamate protecting group and for the formation of carboxylic anhydrides....
or by heating urea nitrate
Urea nitrate
Urea nitrate is a fertilizer-based high explosive that has been used in improvised explosive devices in Israel, Iraq, and various other terrorism acts elsewhere in the world, like the 1993 World Trade Center bombings...
and ethyl alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
:
Uses
Ethyl carbamate has been produced commercially in the United States for many years. Although reports made to the USEPA for the Toxics Release Inventory indicate that over 100,000 pounds of urethane was used in 2004 (USEPA 2006), this is probably in error, because of incorrect reporting. None of the TRI reports list that any urethane is manufactured or imported, which suggests that the submitters are confusing urethane with polyurethane. It has been used as an antineoplastic agent and for other medicinal purposes but this ended after it was discovered to be carcinogenic in 1943. However, Japanese usage in medical injections continued and from 1950 to 1975 an estimated 100 million 2 ml ampules of 7 to 15% solutions of ethyl carbamate were injected into patients as a co-solvent in water for dissolving water-insoluble analgesics used for post-operation pain. These doses were estimated by Nomura (Cancer Research, 35, 2895–2899, October 1975) to be at levels that are carcinogenic in mice. This practice was stopped in 1975. "This regrettable medical situation appears to have involved the largest number (millions) of humans exposed to the largest doses of a pure carcinogen that is on record" (Japanese Journal of Cancer Research, 82, 1323–1324, December 1991). The author, U.S. cancer researcher James A. Miller, called for studies to determine the effects on Japanese cancer rates to be performed but apparently none were ever done.Prior to World War II, ethyl carbamate saw relatively heavy use in the treatment of multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
before it was found to be toxic, carcinogenic and largely ineffective. By US FDA regulations, ethyl carbamate has been withdrawn from pharmaceutical use. However, small quantities of ethyl carbamate are also used in laboratories as an anesthetic for animals.
Ethyl carbamate was upgraded to a Group 2A carcinogen by IARC in 2007.
Formerly, crosslinking agents for permanent press textile treatments were synthesized from ethyl carbamate.
Occurrence in beverages and food
The discovery of the widespread presence of ethyl carbamate in alcoholic beverages first occurred during the mid-1980s. In 1987, the U.S. Center for Science in the Public Interest published Tainted Booze: The Consumer's Guide to Urethane in Alcoholic Beverages to raise public awareness of this issue. Studies have shown that most, if not all, yeast-fermented alcoholic beverages contain traces of ethyl carbamate (15 ppb to 12 ppm). Other foods and beverages prepared by means of fermentation also contain ethyl carbamate. For example, bread has been found to contain 2 ppb; as much as 20 ppb has been found in some samples of soy sauce. Amounts of both ethyl carbamate and methyl carbamateMethyl carbamate
Methyl carbamate is an organic compound and the simplest ester of the hypothetical carbamic acid . Its sum formula is C2H5NO2....
have also been found in wines, sake, beer, brandy, whiskey and other fermented alcoholic beverages.
It has been shown that ethyl carbamate forms from the reaction of alcohol (ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
) with urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
:
This reaction occurs much faster at higher temperatures, and therefore higher concentrations of ethyl carbamate are found in beverages that are heated during processing, such as brandy, whiskey, and other distilled beverages. Additionally, heating after bottling either during shipping or in preparation will cause ethyl carbamate levels to rise further.
The urea in wines results from the metabolism of arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
or citrulline
Citrulline
The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated in 1930.It has the idealized formula H2NCNH3CHCO2H...
by yeast or other organisms. The urea waste product is initially metabolised inside the yeast cell until it builds up to a certain level. At that point, it is excreted externally where it is able to react with the alcohol to create ethyl carbamate.
In 1988, wine and other alcoholic beverage manufacturers in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
agreed to control the level of ethyl carbamate in wine to less than 15 ppb, and in stronger alcoholic drinks to less than 125 ppb.
Although the urea cannot be eliminated, it can be minimized by controlling the fertilization of grape vines, minimizing their heat exposure, using self-cloning yeast and other actions.
Another important mechanism for ethyl carbamate formation in alcoholic beverages is the reaction from cyanide as precursor, which causes comparably high levels in spirits derived from cyanogenic plants (i.e. predominantly stone-fruit spirits and cachaca).
Hazards
Ethyl carbamate is not acutely toxic to humans, as shown by its use as a medicine. Acute toxicity studies show that the lowest fatal dose in rats, mice, and rabbits equals 1.2 grams/kg or more. When ethyl carbamate was used medicinally, about 50 percent of the patients exhibited nausea and vomiting, and long time use led to gastroenteric hemorrhages. The compound has almost no odor and a cooling, saline, bitter taste.Studies with rats, mice, and hamsters has shown that ethyl carbamate will cause cancer when it is administered orally, injected, or applied to the skin, but no adequate studies of cancer in humans caused by ethyl carbamate has been reported due to the ethical considerations of such studies. However, in 2007, the International Agency for Research on Cancer raised ethyl carbamate to a Group 2A carcinogen that is "probably carcinogenic to humans," one level below fully carcinogenic to humans. IARC has stated that ethyl carbamate can be “reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals.” In 2006, the Liquor Control Board of Ontario in Canada rejected imported cases of sherry due to excessive levels of ethyl carbamate.
Alcoholic beverages, particularly certain stone-fruit spirits and whiskies, tend to contain much higher concentrations of urethane. Heating (e.g., cooking) the beverage increases the ethyl carbamate content, and some concern exists over shipping wines to overseas markets in containers that tend to overheat. In addition, urethane has a tendency to accumulate in the human body from a number of daily dietary sources, e.g., alcohols, bread and other fermented grain products, soy sauce, orange juice and commonly consumed foods. Hence, exposure risk to human health is increasingly evaluated on the total ethyl carbamate intake from the daily diet (WHO refers to this as "margin of exposure" or MOE), of which alcoholic beverages often provide the most significant portion.
Studies in Korea (2000) and Hong Kong (2009) outline the extent of the accumulative exposure to ethyl carbamate in daily life. Fermented foods such as soy sauce, kimchi, soybean paste, breads, rolls, buns, crackers and bean curd, along with wine, sake and plum wine, were found to be the foods with the highest ethyl carbamate levels in traditional Asian diets.
In 2005, the JECFA (Joint FAO/WHO Expert Committee On Food Additives) risk assessment evaluation of ethyl carbamate concluded that the MOE intake of ethyl carbamate from daily food and alcoholic beverages combined is of concern and mitigation measures to reduce ethyl carbamate in some alcoholic beverages should continue. There is little doubt that ethyl carbamate in alcoholic beverages is very important to health authorities, while the cumulative daily exposure in the typical diet is also an issue of rising concern that merits closer observation. The Korean study concluded, "It would be desirable to closely monitor ethyl carbamate levels in Korean foods and find ways to reduce the daily intake."
The IARC evaluation has led to the following US regulatory actions:
- NESHAP: Listed as a Hazardous Air Pollutant (HAP)
- Comprehensive Environmental Response, Compensation, and Liability Act: Reportable Quantity (RQ) = 100 lb
- Emergency Planning and Community Right-To-Know Act, EPA’s Toxics Release Inventory: A listed substance subject to RCRA reporting requirements
- RCRA Listed Hazardous Waste: substance - U238
Related compounds
Other carbamates include methyl carbamateMethyl carbamate
Methyl carbamate is an organic compound and the simplest ester of the hypothetical carbamic acid . Its sum formula is C2H5NO2....
(urethylane, m. p. 52-54 °C), butyl carbamate, and phenyl carbamate (m. p. 149-152 °C), which can also be prepared from the corresponding chloroformate
Chloroformate
Chloroformates are a class of chemical compounds which are esters of chloroformic acid. They are widely used as reagents in organic chemistry. For example, benzyl chloroformate is used to introduce the CBZ protecting group and fluorenylmethyloxycarbonylchloride is used to introduce the FMOC...
and ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
. These esters are white, crystalline solids at room temperature. Except for the phenyl carbamate, they sublime at moderate temperatures; methyl carbamate sublimes at room temperatures. The first two and ethyl carbamate are very soluble in water, benzene, and ether. These other carbamates (methyl
Methyl carbamate
Methyl carbamate is an organic compound and the simplest ester of the hypothetical carbamic acid . Its sum formula is C2H5NO2....
, butyl, and phenyl) are only used in small quantities for research purposes.