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Description of key information

The ADME fate of a group of food 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). Cinnamyl acetate was included in this group. In its assessment report, the JECFA states that cinnamyl acetate has been shown to be rapidly absorbed from the gut, metabolized and excreted primarily in the urine and to a minor extent in the faeces.

Absorption

No studies are available in the REACH registration dossier 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 cinnamyl acetate, as further explained below in the section on metabolism. The test 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 acetic acid and cinnamyl alcohol, 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).

Cinnamyl acetate has a vapour pressure of 16 Pa, a log Kow of 2.7 and a water solubility of 313 mg/L. Based on these physicochemical properties, the dermal absorption of the substance can be anticipated to be high.

Inhalation absorption

The main physicochemical 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 physicochemical properties of cinnamyl acetatete (Vapour pressure 16 Pa, log Kow 2.7 and water solubility 313 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 cinnamyl acetate is determined by the substance's tendency to undergo enzymatic hydrolysis, giving rise to the formation of acetic acid and cinnamyl alcohol.

Primary metabolic step: enzymatic hydrolysis of cinnamyl acetate

The primary metabolites formed upon the ezymatic hydrolysis of the substance are acetic acid and cinnamyl alcohol. The further metabolism and excretion of both primary metabolites will be further discussed below.

Absorption, metabolism and excretion of acetic acid

Acetic acid, under physiological conditions present as acetate, is an endogenous substance in humans. Conjugated to Co-enzyme A, it plays a central role in the citric acid cycle and hence is a key entity in the cellular energy management. In the citric acid cycle, the acetate is consumed and converted into CO2.

Absorption, metabolism and excretion of cinnamyl alcohol

The metabolic fate of cinnamyl alcohol has also been addressed by the Joint Expert Committee on Food Additives (WHO, 2001). Furthermore, the substance is also thoroughly discussed in the WHO Food Additives Series 46 Report: “Cinnamyl alcohol and related substances” (WHO, 2001b).

The reports states that cinnamyl alcohol is readily oxidized to cinnamic acid. 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.

Hence, the urinary metabolites observed upon administration of cinnamyl alcohol are mainly those derived from cinnamic acid. The JECFA refers to experimental data by Nutley (1990). Oral administration of cinnamyl alcohol to Fischer 344 rats resulted in a recovery of 83% of the dose in the urine within 24 hours, mainly as the glycine conjugate of benzoic acid (hippuric acid). Additionally, excretion in the faeces accounted for ca. 6%.

Overall, the substance is expected to be absorbed via the oral, dermal and inhalation route, but will not bioaccumulate in the organism. In stead, 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. 55thReport of the Joint FAO/WHO Expert Committee on Food Additivies. WHO, Geneva, 2001. International Programme on Chemical Safety.

WHO (2001b). WHO Food Additives Series 46 – Cinnamyl alcohol and related substances. Dr. A. Mattia and Prof. G.I. Sipes.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Physicochemical parameters used for the toxicokinetics assessment:

- Vapour pressure: 0.16 hPa at 20°C

- Water solubility of 313 mg/L at 20.0°C

- log Kow of 2.7 at 35°C.