Ethyl carbamate (EC), also known as urethane, is a compound found in fermented foods and beverages. It’s an ester of carbamic acid. It’s also a known carcinogen (cue ominous-sounding music), making it an important compound to know and understand in your distillery. There’s your Wikipedia lesson for the day. However, there’s so much more to this story.
As concerned citizens, we see the word “carcinogen” and think that’s some bad juju to be putting into a bottle. Our job as distillers is not simply to make booze, but also to ensure that it is produced and subsequently imbibed in a responsible way. Ensuring due diligence is performed when it comes to compounds such as ethyl carbamate is paramount to a happy and healthy customer.
Interestingly, EC has not always been seen as the chemical boogeyman. In what could be seen as an unbelievably twisted irony, prior to 1943 it was used as a medicine to fight cancer until it was discovered to cause cancer in mice. Note that causing cancer is generally considered the opposite of curing it. Once news of EC’s carcinogenicity came to light, most countries stopped using it on people. (Turns out EC is pretty good at anesthetizing rodents and other lab animals.) Japan, however, continued to use it until 1975. During that time it’s estimated that around 100 million injections of the stuff were administered. No formal studies have been performed to assess the effects of those injections on the EC-dosed patients.
The cancer risks of EC have been assessed over the years on mice, but no studies have been done on humans. Currently, EC is listed as a Group 2A carcinogen, meaning it’s “probably carcinogenic to humans.” This is just above the Group 1A rating of “fully carcinogenic to humans.” “Probably carcinogenic” is enough for me to say that I don’t want it in my drink.
During the 1980s, ethyl carbamate became a serious concern for distillers, brewers and winemakers due to its discovery in alcoholic beverages. This caused government regulators to get involved, and there are now regulatory limits on the amount of ethyl carbamate allowed in spirits. Fortunately, most products fall well below the allowable threshold in the US (125 ppb — voluntary limit used by the industry) and Canada (150 ppb — government mandated limit).
To understand ethyl carbamate in the context of distilled spirits, we have to ask a few questions:
How is it formed?
What are the precursors?
What can we do to lessen its formation in spirits?
Let’s start with how it’s formed. Industrially, EC is formed by heating urea and ethanol together and blam! You get ethyl carbamate.
CO(NH2)2 + C2H5OH + Heat CH3CH2OCNH2
Urea Ethanol Ethyl Carbamate
The astute reader will notice two very important words in that reaction. First is “ethanol,” which we have an abundance of in distilled spirits. The second is “urea,” which sounds an awful lot like “urine.” That’s no coincidence: Urea is a major constituent of urine.
One of the many things humans have in common with yeast is that we both produce urea. Yeast produce urea through the metabolism of amino acids. Specifically, the amino acid arginine is enzymatically broken down to ornithine and urea. It is understood that the enzyme responsible for this process is encoded by the CAR1 gene in Saccharomyces cerevisiae. Indeed, when this gene is knocked out, urea production goes down.
What Comes Before
If eliminating EC from distilled spirits were as simple as knocking a gene out of commission, then the problem would’ve been solved decades ago, and you would likely be playing Pokémon Go instead of reading this right now. (I assume.) There are a few issues with that strategy. One is that the CAR1 gene encodes for only one of the enzymes thought to be responsible for urea production. Second is that the use of a genetically modified yeast is dicey water for consumers and distillers to jump into due to the current cultural climate and concerns over long-term health effects of genetically modified organisms, or GMOs. Finally, urea is just one of the precursors for EC. As we’re about to see, there are other precursors we have to worry about.
In barley, the primary precursor is a glycosidic nitrile (GN) known as epiheterodentrin (EPH). EPH falls into a family of compounds called “cyanogenic glycosides.” Parse that out and what you have is a sugar (glycoside) attached to a cyanide-based compound (cyanogenic). (Now I realize the word “cyanide” just made things a whole lot scarier here, but hold onto your britches. It’s all going to be OK.) EPH is measured as a cyanide equivalent.
EPH is enzymatically converted to cyanide in a two-step process. First a β-glucosidase (naturally present in the grain) cleaves off the glucoside component and leaves isobutyraldehde cyanohydrin (IBAC). Add a little heat to IBAC from a frothy fermentation or during distillation and you get cyanide.
For some brandy distillers, cyanide is something they are accustomed to being careful about. The so-called “stone fruit” brandies based on fruits such as cherries, peaches, apricots and plums all carry this concern with their production. The pits or stones of these fruits contain a compound called amygdalin. Amygdalin was once believed to be a cancer cure. Amygdalin can be enzymatically broken down by glycosidase during fermentation to glucose, benzaldehyde and — you guessed it — cyanide. Since amygdalin is contained within the stones, the stones need to be broken for the reaction to occur.
What about rum? Surely there are no EC precursors in sugarcane to worry about, right? Unfortunately, sugarcane is considered to have a number of cyanogenic glycosides, and these can get into the pressed juice. Comparisons on EC levels in over 500 Brazilian cachaça samples have shown that ethyl carbamate contamination averages
380 ppb, well above Brazil’s federally mandated limit of 210 ppb.
Why would plants produce such potentially dangerous compounds? The prevailing assumption is that cyanogenic glycosides are an ancient defense mechanism for plants that has never evolved away. Of course, cyanide on its own is dangerous stuff. It interferes with the body’s ability to take up oxygen at the cellular level. A 200-mg dose is almost certainly fatal and there have been stories of lethal doses considerably lower than that.
Well, this is just great. It sounds like we have a bunch of cyanide on our hands (which are words I never thought I would find myself typing). How does cyanide become EC? Studies have shown that EC formation from cyanide requires three things: ethanol, heat and copper. Sounds an awful lot like the inside of a still, doesn’t it? Heat causes the reaction between ethanol and cyanide to take place while copper acts as a catalyst. This reaction doesn’t seem to take place in stainless steel stills.
Some research has suggested that EC will continue to form in the barrel and in the bottle. It’s a lot like John Mayer’s music in that it just keeps coming. However, unlike JM’s buttery-smooth Starbucks-loungy croon, there are ways to prevent it.
Tackling the problem
Most scientists agree that the best way to prevent EC formation is to limit the existence of precursors. For cereals, this means using barley varieties bred to have low glycosidic nitrile levels. In the UK, the Institute of Brewing and Distilling offers a list of acceptable brewing and distilling barleys every year, many of which are low GN producers. It’s worth checking out (www.ibd.org.uk).
In the world of brandy production, best practices are to be careful when processing stone fruits. In his 2004 book Artisan Distilling: A Guide for Small Distilleries, Kris Berglund recommends allowing no more than 5% of the pits of the fruits to break during processing. This is as simple as taking a few random samples of fruit pits, visually assessing them for breakage and doing some simple math. If the fruit is being milled, like say through a roller mill, then carefully adjusting the gap setting to ensure that stones can easily move through will eliminate a lot of concern.
Other suggestions researchers offer are the use of glass or steel stills, but this is a somewhat less viable option for many craft distillers, as copper confers so many other benefits to the distillation process. Let’s leave the pretty copper alone.
Finally it’s worth sending in the occasional sample to a lab for EC testing. Have them check for precursors and copper as well. If copper remains in the distillate and finds its way into the bottle, it is conceivable that it could catalyze further EC formation.
Ethyl carbamate doesn’t get talked about much anymore. Thirty years ago there was a whole generation of distillers, brewers and winemakers that had EC at the front of their minds and quality control programs. Unfortunately, the problem and risk have never gone away; they’ve just been temporarily forgotten. As an industry with a lot of responsibility on its shoulders, we owe it to our customers to shoulder just this little bit more. We’ve always tried to regulate ourselves before the government steps in to do it for us. Proactively protecting our customers from EC-contaminated spirits is the right thing to do.