Cinnamyl acetate
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Cinnamyl acetate (3-phenylprop-2-enyl acetate) is a chemical compound of the cinnamyl ester family, in which the variable R group is substituted by a
methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
. As a result of the non-aromatic carbon-carbon double bond, cinnamyl acetate can exist in a ''Z'' and an ''E'' configuration: Cinnamyl acetate naturally occurs in fresh bark of
cinnamon Cinnamon is a spice obtained from the inner bark of several tree species from the genus ''Cinnamomum''. Cinnamon is used mainly as an aromatic condiment and flavouring additive in a wide variety of cuisines, sweet and savoury dishes, breakfa ...
(''Cinnamomum zeylanicum Blume'' and other Cinnamomum species), with concentrations of 2,800–51,000 ppm. Cinnamyl acetate is used as a flavour ester in for example bread and animal feed and has a sweet floral-fruity fragrance. Moreover, it is used in several cosmetics, some toiletries but also in non-cosmetic products, for example detergents.


Legislation and control

Cinnamyl acetate, used in fragrances and as flavour ingredient, has been discussed by several institutions. In 1965, the compound was annotated as 'Generally Recognized as Safe as a flavor ingredient’ by the Flavor and Extract Manufacturers" Association (
FEMA The Federal Emergency Management Agency (FEMA) is an agency of the United States Department of Homeland Security (DHS), initially created under President Jimmy Carter by Presidential Reorganization Plan No. 3 of 1978 and implemented by two Exec ...
). The association determined the average maximum use levels in several products that were considered to be safe: The
European Parliament The European Parliament (EP) is one of the legislative bodies of the European Union and one of its seven institutions. Together with the Council of the European Union (known as the Council and informally as the Council of Ministers), it adopts ...
registered cinnamyl acetate as both a flavouring substance and a cosmetic compound in 1996. The Joint (
FAO The Food and Agriculture Organization of the United Nations (FAO)french: link=no, Organisation des Nations unies pour l'alimentation et l'agriculture; it, Organizzazione delle Nazioni Unite per l'Alimentazione e l'Agricoltura is an intern ...
/
WHO Who or WHO may refer to: * Who (pronoun), an interrogative or relative pronoun * Who?, one of the Five Ws in journalism * World Health Organization Arts and entertainment Fictional characters * Who, a creature in the Dr. Seuss book '' Horton He ...
) Expert Committee on Food Additives (
JECFA The Joint FAO/WHO Expert Committee on Food Additives (JECFA) is an international scientific expert committee that is administered jointly by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO). ...
) described in 2000 that “the substance does not present a safety concern at current levels of intake when used as a flavouring agent”. In 2009, the
EFSA The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...
Panel on Food Contact Materials, Enzyme, Flavourings and Processing Aids (CEF) concluded that cinnamyl acetate does not give rise to safety concerns when used as flavour ingredient in food. Cinnamyl acetate is also permitted by the U.S. Food & Drug administration for use as flavouring agent in food if the minimum quantity needed for its effect is used.


Production and intake

Estimates of the average annual production and daily intake of cinnamyl acetate as flavouring agent are reported by the
WHO Who or WHO may refer to: * Who (pronoun), an interrogative or relative pronoun * Who?, one of the Five Ws in journalism * World Health Organization Arts and entertainment Fictional characters * Who, a creature in the Dr. Seuss book '' Horton He ...
. According to this report, the annual volume of production in Europe is 1498 kg, and in the USA 2255 kg. The daily intake per person in Europe is estimated to be 210 μg, and in the USA 300 μg. Per kg body weight the daily intake is estimated for Europeans to be 4 μg/kg and for Americans to be 5 μg/kg.


Synthesis

Since cinnamyl acetate is naturally occurring in plants, it can be extracted and purified to obtain the compound. However, this has a low yield and therefore the production costs are high. The use of chemical methods can offer more efficient strategies to produce cinnamyl acetate. There are multiple ways to synthesize cinnamyl acetate 2. One way is the synthesis from
cinnamyl alcohol Cinnamyl alcohol or styron is an organic compound that is found in esterified form in storax, Balsam of Peru, and cinnamon leaves. It forms a white crystalline solid when pure, or a yellow oil when even slightly impure. It can be produced by the h ...
1 and
vinyl acetate Vinyl acetate is an organic compound with the formula CH3CO2CH=CH2. This colorless liquid is the precursor to polyvinyl acetate and ethene-vinyl acetate copolymers, important industrial polymers. Production The worldwide production capacity of v ...
. This reaction is catalyzed by the enzyme triacylglycerol ester hydrolase, which is a
lipase Lipase ( ) is a family of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually tr ...
that is very specific towards the ester bond. The byproduct of this reaction is
acetaldehyde Acetaldehyde (IUPAC systematic name ethanal) is an organic chemical compound with the formula CH3 CHO, sometimes abbreviated by chemists as MeCHO (Me = methyl). It is a colorless liquid or gas, boiling near room temperature. It is one of the mos ...
. The reaction equation for this reaction is: :: Since acetaldehyde has an unfavourable deactivating effect on the lipase used in the synthesis,
ethyl acetate Ethyl acetate ( systematically ethyl ethanoate, commonly abbreviated EtOAc, ETAC or EA) is the organic compound with the formula , simplified to . This colorless liquid has a characteristic sweet smell (similar to pear drops) and is used in glues ...
can be used as reactant instead of vinyl acetate. In this
transesterification In organic chemistry, transesterification is the process of exchanging the organic group R″ of an ester with the organic group R' of an alcohol. These reactions are often catalyzed by the addition of an acid or base catalyst. The reaction can ...
reaction cinnamyl alcohol 1 reacts with ethyl acetate to form cinnamyl acetate 2 and
ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
. This synthesis requires the lipase Novozym 435, and is performed in a solvent-free system. The reaction is as follows: :: Cinnamyl acetate 2 can also be synthesized via a non-enzymatic reaction. An example of such a reaction is one with the use of cinnamyl bromide 3 and
sodium acetate Sodium acetate, CH3COONa, also abbreviated Na O Ac, is the sodium salt of acetic acid. This colorless deliquescent salt has a wide range of uses. Applications Biotechnological Sodium acetate is used as the carbon source for culturing bacteria ...
as reactants. Since these compounds are immiscible substrates, solid-liquid phase transfer catalysis (PTC) can be used, using quaternary ammonium bromide as a
phase transfer catalyst In chemistry, a phase-transfer catalyst or PTC is a catalyst that facilitates the transition of a reactant from one phase into another phase where reaction occurs. Phase-transfer catalysis is a special form of heterogeneous catalysis. Ionic reac ...
. This is shown in the following reaction: :: Besides these three examples, there are many more ways to synthesize cinnamyl acetate. The
addition reaction In organic chemistry, an addition reaction is, in simplest terms, an organic reaction where two or more molecules combine to form a larger one (the adduct).. Addition reactions are limited to chemical compounds that have multiple bonds, such as ...
of
dinitrogen trioxide Dinitrogen trioxide is the chemical compound with the formula N2O3. It is one of the simple nitrogen oxides. It forms upon mixing equal parts of nitric oxide and nitrogen dioxide and cooling the mixture below −21 °C (−6 °F): :NO ...
to cinnamyl acetate produces an intermediate in the synthesis of
chloramphenicol Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections. This includes use as an eye ointment to treat conjunctivitis. By mouth or by injection into a vein, it is used to treat meningitis, plague, cholera, a ...
.


Metabolism

Cinnamyl acetate belongs to the group of cinnamyl derivatives. In general, these cinnamyl derivatives are absorbed from the gut very quickly, after which they are metabolized and excreted as polar metabolites in the urine or feces within 24 hours. Within the cinnamyl derivatives, cinnamyl acetate belongs to the group of cinnamyl esters. After absorption from the gut, this group of compounds is first
hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...
to cinnamyl alcohol by carboxylesterases. Carboxylesterases are a group of enzymes. The most important enzymes within this group are the A-esterases. These are present in most body tissues, but they are prevalent in the
hepatocytes A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, b ...
. Subsequently, the
cinnamyl alcohol Cinnamyl alcohol or styron is an organic compound that is found in esterified form in storax, Balsam of Peru, and cinnamon leaves. It forms a white crystalline solid when pure, or a yellow oil when even slightly impure. It can be produced by the h ...
is
oxidized Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
which leads to the formation of
cinnamaldehyde Cinnamaldehyde is an organic compound with the formula(C9H8O) C6H5CH=CHCHO. Occurring naturally as predominantly the ''trans'' (''E'') isomer, it gives cinnamon its flavor and odor. It is a phenylpropanoid that is naturally synthesized by the shik ...
. This reaction is catalyzed by human NAD+-dependent
alcohol dehydrogenase Alcohol dehydrogenases (ADH) () are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to N ...
. Now, there are two routes for the further
biotransformation Biotransformation is the biochemical modification of one chemical compound or a mixture of chemical compounds. Biotransformations can be conducted with whole cells, their lysates, or purified enzymes. Increasingly, biotransformations are effected w ...
of cinnamaldehyde. The minor route of biotransformation is the
S-glutathionylation S-Glutathionylation is the posttranslational modification of protein cysteine residues by the addition of glutathione, the most abundant and important low-molecular-mass thiol within most cell types. Protein S-glutathionylation is involved in * o ...
. The major route, however, is the conversion of cinnamaldehyde into
cinnamic acid Cinnamic acid is an organic compound with the formula C6H5-CH=CH- COOH. It is a white crystalline compound that is slightly soluble in water, and freely soluble in many organic solvents. Classified as an unsaturated carboxylic acid, it occurs n ...
by the enzyme
aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have b ...
. Next, the cinnamic acid is transformed into cinnamoyl CoA which is again converted to either cinnamoylglycine by N-acyl transferase or to benzoyl CoA through
β-oxidation In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, ...
, the latter being the major route. Intermediate metabolites in the β-oxidation pathway can be converted to 3-hydroxy-3-phenylpropionic acid and
acetophenone Acetophenone is the organic compound with the formula C6H5C(O)CH3. It is the simplest aromatic ketone. This colorless, viscous liquid is a precursor to useful resins and fragrances. Production Acetophenone is formed as a byproduct of the cumene p ...
, which can be excreted via the urine. However, the conversions of these intermediate metabolites are minor routes. Finally, the benzoyl CoA is conjugated with
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
under formation of
hippuric acid Hippuric acid ( Gr. ''hippos'', horse, ''ouron'', urine) is a carboxylic acid and organic compound. It is found in urine and is formed from the combination of benzoic acid and glycine. Levels of hippuric acid rise with the consumption of phenoli ...
or it is hydrolyzed generating free
benzoic acid Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. It is the simplest aromatic carboxylic acid. The name is derived from gum benzoin, wh ...
. This can be excreted via the urine directly or after
glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosid ...
. Hippuric acid, which is the major metabolite, is also excreted via the urine. ::


Toxicity

Since cinnamyl acetate is used as both a fragrance material and a food flavouring ingredient, dermal and oral exposure are considered to be the major routes of absorption. The dermal systematic exposure of cinnamyl acetate via cosmetic products is estimated to be 0.0115 mg/kg body weight/day. Several experiments using animals were conducted in the past to assess the toxicity of cinnamyl acetate. In one experiment, the oral toxicity was tested in rats. The rats received oral doses of cinnamyl acetate and the LD50 was found to be 3.3 g/kg. During the experiment, symptoms as slow respiration and coarse tremors were observed for high doses. Other experiments showed LD50 values of 4.750 g/kg for oral administration in mice and guinea pigs. Also, the LD50 value for intraperitoneal administration was investigated and found to be 1.200 g/kg. Furthermore, studies on the dermal toxicity were performed. Experiments on rabbits resulted in an LD50 of more than 5.0 g/kg, but no clinical effects were observed. Moreover, the level of skin irritation in swines was tested via a 48-h patch test. In this study, 0.05 g of cinnamyl acetate was applied and no irritation was observed. Another two experiments examined the skin irritation caused by 0.1 mL cinnamyl acetate on guinea pigs and rabbits via a direct application on the skin (open application). Mild to moderate irritation was observed in these experiments. A
NOAEL The no-observed-adverse-effect level (NOAEL) denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effec ...
for oral administration of 275 mg/kg body weight/day was determined from toxicological data by the
EFSA The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...
Panel on Additives and Products or Substances used in Animal Feed (FEEDAP). Besides these experiments on animals, some human studies were executed. A 48-h closed patch test on five healthy, male volunteers was performed using 5% cinnamyl acetate in
petrolatum Petroleum jelly, petrolatum, white petrolatum, soft paraffin, or multi-hydrocarbon, CAS number 8009-03-8, is a semi-solid mixture of hydrocarbons (with carbon numbers mainly higher than 25), originally promoted as a topical ointment for its he ...
. In this study, no irritation was observed. Mild irritation was observed in another 48-h patch test on fifty male volunteers using 32% cinnamyl acetate in
acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscib ...
. Finally, a human study on skin sensitization was executed on 25 healthy, male volunteers. In this experiment a maximization test (48-h patch) was done using 5% cinnamyl acetate in petrolatum. Skin sensitization reactions were not observed. Moreover, standard Draize tests were used to assess the dermal toxicity in humans, guinea pigs and rabbits. This resulted in mild skin irritation for doses of 16 mg per 48 hours for humans and for doses of 100 mg per 24 hours for guinea pigs. Moderate skin irritation was observed for rabbits exposed to doses of 100 mg per 24 hours. Lastly, the potential of cinnamyl acetate to cause sister chromatid exchanges was tested using Chinese Hamster Ovary Cells. This was done because it was found that another component of plant essence and cinnamyl derivative,
cinnamaldehyde Cinnamaldehyde is an organic compound with the formula(C9H8O) C6H5CH=CHCHO. Occurring naturally as predominantly the ''trans'' (''E'') isomer, it gives cinnamon its flavor and odor. It is a phenylpropanoid that is naturally synthesized by the shik ...
, increased the frequency of sister chromatid exchanges induced by
mitomycin C Mitomycin C is a mitomycin that is used as a chemotherapeutic agent by virtue of its antitumour activity. Medical uses It is given intravenously to treat upper gastro-intestinal cancers (e.g. esophageal carcinoma), anal cancers, and breast c ...
. However, the result of this test proved that cinnamyl acetate does not cause sister chromatid exchange due to the absence of an alpha-beta unsaturated
carbonyl group In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...
.


Effects on animals

Cinnamyl acetate is found in the leaf oils of the ''
Cinnamomum osmophloeum ''Cinnamomum osmophloeum'', commonly known as pseudocinnamomum or indigenous cinnamon, is a medium-sized evergreen tree in the genus ''Cinnamomum''. It is native to broad-leaved forests of central and northern Taiwan. Cinnamaldehyde, an essentia ...
'' tree, which grows in central and northern Taiwan. It is found that these oils have antibacterial, antimildew, antitermite, antimite, antifungal and anti-inflammatory activities. Furthermore, the oils show mosquito larvicidal activity against ''
Aedes aegypti ''Aedes aegypti'', the yellow fever mosquito, is a mosquito that can spread dengue fever, chikungunya, Zika fever, Mayaro and yellow fever viruses, and other disease agents. The mosquito can be recognized by black and white markings on its legs ...
'' and ''
Aedes albopictus ''Aedes albopictus'' (''Stegomyia albopicta''), from the mosquito (Culicidae) family, also known as the (Asian) tiger mosquito or forest mosquito, is a mosquito native to the tropical and subtropical areas of Southeast Asia. In the past few ce ...
'' larvae. However, cinnamyl acetate serves only a minor role in these activities. Moreover, cinnamyl acetate has a repellent effect on ''
Anopheles gambiae The ''Anopheles gambiae'' complex consists of at least seven morphologically indistinguishable species of mosquitoes in the genus ''Anopheles''. The complex was recognised in the 1960s and includes the most important vectors of malaria in sub- ...
'', and is therefore useful to protect against these insects.


References

{{Reflist, 32em Food additives Methyl esters Cinnamomum Acetate esters