Ethyl cinnamate

Endpoint summary

Description of key information

Absorption

No studies are available that address the absorption of the test substance via the oral, dermal or inhalation route. Nevertheless, some preliminary predictions can be made from its physico-chemical properties.

Oral absorption

Oral absorption can occur along the entire length of the gastro-intestinal tract. However, it should be kept in mind that substances can undergo chemical changes in the gastro-intestinal fluids prior to absorption. This is of particular relevance for ethyl cinnamate, as further explained below in the section on metabolism. The test substance will undergo enzymatic hydrolysis of its ester moiety under the influence of gastro-intestinal esterase enzymes. This hydrolysis process gives rise to the formation of ethanol and cinnamic acid, both of which can subsequently be absorbed from the gastro-intestinal tract.

Dermal absorption

In order for a substance to cross the stratum corneum, the substance should be sufficiently lipophilic (= sufficient solubility in fat). On the other hand, partitioning from the stratum corneum into the epidermis requires sufficient hydrophilicity (= sufficient solubility in water). Hence, the likelyhood of dermal absorption is determined by the substance's log Kow and water solubility values.

According to Nielsen et al. (2010), dermal absorption is likely for a substance if it has the following properties:

- a vapour pressure < 100 Pa

- a log Kow between 1 and 4

- a water solubility in the range of 1 - 100 mg/L (moderate absorption), or 100 - 10000 mg/L (high absorption).

The test item has a vapour pressure of 6 Pa, a log Kow of 3.01 and a water solubility of 171 mg/L. Based on these physico-chemical properties, dermal absorption of the substance can be anticipated to be high.

Inhalation absorption

The main physico-chemical parameters determining the extent to which a liquid substance may be absorbed by the inhalation route are the vapour pressure, the log Kow and the water solubility.

Nielsen et al. (2010) gives the following criteria:

- Highly volatile substances are considered those substances that have a vapour pressure exceeding 25000 Pa (or boiling point < 50°C), whereas a vapour pressure < 500 Pa (or boiling point > 150C°) indicates a low volatility.

 - Log Kow > 0 indicates the potential for direct absorption across the respiratory tract epithelum. Substances with a log Kow value between 0 and 4 are sufficiently lipophilic to allow crossing the alveolar and capillary membranes, and hence are likely to be absorbed as well.

 - Sufficient water solubility increases the potential for inhalation absorption. Nevertheless, very hydrophilic substances may be retained within the mucus, and transported out of the respiratory tract by clearance mechanisms.

 

Based on the physico-chemical properties of the substance (vapour pressure 6 Pa, log Kow 3.01 and water solubility 171 mg/L), it can be concluded that absorption of the substance following exposure via the inhalation route is likely. The substance has a low volatility, limiting exposure via the inhalation route.

 

Metabolism and Excretion

As mentioned above, the metabolism of the substance is determined by the substance's tendency to undergo enzymatic hydrolysis, giving rise to the formation of ethanol and cinnamic acid.

Primary metabolic step: enzymatic hydrolysis

The metabolic fate of group of flood flavouring agents related to cinnamyl alcohol has been addressed by the Joint Expert Committee on Food Additives in the framework of the safety evaluation of certain food additives and contaminants by the World Health Organisation (WHO, 2001). The substance was included as one of the cinnamate esters in this group. In its assessment report, the JECFA states that esters of cinnamic acid have been shown to be hydrolysed rapidly to the corresponding acid and alcohol.

The primary metabolites formed upon the ezymatic hydrolysis of the test item are ethanol and cinnamic acid. The further metabolism and excretion of both primary metabolites will be further discussed below.

Absorption, metabolism and excretion of ethanol

The metabolism of ethanol has been studied in great detail due to its presence in alcoholic beverages. The main (though not only) metabolic pathway for ethanol is conversion to acetaldehyde by means of alcohol dehydrogenase, and subsequent conversion into acetate by means of aldehyde dehydrogenase. The acetate is further broken down into CO₂and water.

Absorption, metabolism and excretion of cinnamic acid

The metabolic fate of cinnamic acid has also been addressed by the Joint Expert Committee on Food Additives (WHO, 2001). Cinnamic acid has been shown to be rapidly absorbed from the gut. Cinnamic acid, like most carboxylic acids, is subsequently converted to its acyl coenzyme A ester. The thus formed cinnamoyl CoA can undergo conjugation with glycine, or can be first oxidized to yield benzoyl CoA by beta-oxidation. Benzoyl CoA can then in turn be conjugated with glycine to the corresponding hippurate, or can be hydrolyzed to the free benzoic acid; of which the further metabolic fate has been discussed above.

Overall, the substance is expected to be absorbed via the oral, dermal and inhalation route, but will not bioaccumulate in the organism. Instead, it is expected to be metabolized and excreted quickly.

References:

Nielsen E, Ostergaard G, Larsen JC (2010). Toxicological Risk Assessment of Chemicals; A Practical Guide. Published by: Informa Healthcare. ISBN-13: 9780849372650.

WHO (2001). WHO Technical Report Series 901 – Evaluation of certain food additives and contaminants. 55^thReport of the Joint FAO/WHO Expert Committee on Food Additivies. WHO, Geneva, 2001. International Programme on Chemical Safety.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Absorption

No studies are available that address the absorption of the test substance via the oral, dermal or inhalation route. Nevertheless, some preliminary predictions can be made from its physico-chemical

properties.

Oral absorption

Oral absorption can occur along the entire length of the gastro-intestinal tract. However, it should be kept in mind that substances can undergo chemical changes in the gastro-intestinal fluids prior to

absorption. This is of particular relevance for ethyl cinnamate, as further explained below in the section on metabolism. The substance will undergo an enzymatic hydrolysis of its ester moiety under the

influence of gastro-intestinal esterase enzymes. This hydrolysis process gives rise to the formation of ethanol and cinnamic acid, both of which can subsequently be absorbed from the gastro-intestinal tract.

Dermal absorption

A number of physico-chemical factors determine the extent to which a substance may be absorbed by the dermal route. In order for a substance to cross the stratum corneum, the substance should

be sufficiently lipophilic (= sufficient solubility in fat). On the other hand, partitioning from the stratum corneum into the epidermis requires sufficient hydrophilicity (= sufficient solubility in water). Hence, the likelyhood of dermal absorption is determined by the substance's log Kow and water solubility values.

According to Nielsen et al. (2010), dermal absorption is likely for a substance if it has the following properties:

- a vapour pressure < 100 Pa

- a log Kow between 1 and 4

- a water solubility in the range of 1 - 100 mg/L (moderate absorption), or 100 - 10000 mg/L (high absorption).

The test item has a vapour pressure of 6 Pa, a log Kow of 3.01 and a water solubility of 171 mg/L.

Based on these physico-chemical properties, it can be concluded that the dermal absorption of the substance can be anticipated to be high, i.e. the substance is sufficiently soluble in both fat and water to allow for dermal uptake. The volatility of the substance is low, an evaporation from the skin is limited.

Inhalation absorption

The main physico-chemical parameters determining the extent to which a liquid substance may be absorbed by the inhalation route are the vapour pressure, the log Kow and the water solubility.

Nielsen et al. (2010) gives the following criteria:

- Highly volatile substances are considered those substances that have a vapour pressure exceeding 25000 Pa (or boiling point < 50°C), whereas a vapour pressure < 500 Pa (or boiling point > 150°C)

indicates a low volatility.

- Log Kow > 0 indicates the potential for direct absorption across the respiratory tract epithelium.

Substances with a log Kow value between 0 and 4 are sufficiently lipophilic to allow crossing the alveolar and capillary membranes, and hence are likely to be absorbed as well.

- A sufficient water solubility increases the potential for inhalation absorption. Nevertheless, very hydrophilic substances may be retained within the mucus, and transported out of the respiratory tract

by clearance mechanisms.

Based on the physico-chemical properties of the substance (Log Kow 3.01 and water solubility 171 mg/L), it can be concluded that absorption of the substance following exposure via the inhalation route is likely.

However, the low vapour pressure (6 Pa) and high boiling point (272°C) will mitigate the likelihood of exposure via the inhalation route.

Metabolism and Excretion

As mentioned above, the metabolism of ethyl cinnamate is determined by the substance's tendency to undergo enzymatic hydrolysis to form a carboxylic acid and its corresponding alcohol.

Primary metabolic step: enzymatic hydrolysis

The enzymatic hydrolysys giving rise to the formation of cinnamic acid and ethanol in the gastrointestinal tract and further metabolization after absorption mostly in the liver.

Further metabolism and excretion of the primary metabolites

The primary metabolites formed upon the ezymatic hydrolysis of the substance are ethanol and cinnamic acid.

The metabolism of ethanol has been studied in great detail due to its presence in alcoholic beverages. The main (though not only) metabolic pathway for ethanol is conversion to acetaldehyde by means of alcohol dehydrogenase, and subsequent conversion into acetate by means of aldehyde dehydrogenase. The acetate is further broken down into CO2 and water.

In animals, most carboxylic acids, such as cinnamic acid, are converted to acyl coenzyme A esters. Cinnamoyl coenzyme A undergoes either glycine conjugation catalysed by a glycine N-acyl transferase or beta-oxidation, eventually leading to the formation of benzoyl coenzyme A. This is in turn either conjugated with glycine, yielding hippuric acid, or hydrolysed to yield free benzoic acid, which is then excreted (WHO).

References

Nielsen E, Ostergaard G, Larsen JC (2010). Toxicological Risk Assessment of Chemicals; A Practical

Guide. Published by: Informa Healthcare. ISBN-13: 9780849372650.

WHO Food Additives Series 46: Cinnamyl Alcohol and Related Substances. http://www.inchem.org/

documents/jecfa/jecmono/v46je07.htm. Accessed online on Nov. 3, 2017.