Ethyl phenylacetate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Expert Statement

Type of information:

other: Expert Statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Statement, no study available

Data source

Reference

Reference Type:

other: Expert Statement

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl phenylacetate

EC Number:

202-993-8

EC Name:

Ethyl phenylacetate

Cas Number:

101-97-3

Molecular formula:

C10H12O2

IUPAC Name:

ethyl phenylacetate

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Duration and frequency of treatment / exposure:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, a high water solubility of more than 100 mg/L enables the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water. Ethyl phenylacetate has a water solubility of 1.2 g/L, therefore favouring absorption, and the moderate log Pow value is favourable for passive diffusion. Taken together, the physiochemical properties indicate that ethyl phenylacetate might become bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity studies. These results did not lead to classification of the substance, but at least mortality was observed in doses above 2200 mg/kg bw.

Due to the low vapour pressure of ethyl phenylacetate it is unlikely that the substance will be available as a vapour, but if it is the case absorption via inhalation route is possible due to the water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Dermal uptake is favoured for substances with a molecular weight < 100 g/mol and log Pow values between 1 and 4. The log Pow of ethyl phenylacetate is 2.36 and therefore lies in the range between -1 and 4. The molecular weight of the substances is above 100 g/mol, but <500 g/mol and therefore still small enough to be absorbed by skin. In addition, the substances must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is anticipated to be moderate to high if water solubility is between 100 – 10000 mg/L. Ethyl phenylacetate has a water solubility of 1200 mg/L, therefore supporting dermal absorption. Mortality occurred in the acute dermal toxicity study conducted on rabbits, confirming this assumption.

Details on distribution in tissues:

As mentioned above, the physicochemical properties of ethyl phenylacetate favour systemic absorption following oral and dermal uptake.
Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. In general, the smaller the molecule, the wider the distribution. Taken into account the log Pow and the water solubility, accumulation of ethyl phenylacetate is unlikely. The available study data revealed no indications of the substance to cross the blood-brain barrier.

Details on excretion:

The metabolites of ethyl phenylacetate are most likely excreted via urine due to their small molecular weight and their good water solubility.

Metabolite characterisation studies

Details on metabolites:

Metabolism mainly occurs in liver especially following oral intake.
Ethyl phenylacetate may be cleaved into the benzeneacetic acid and ethanol catalyzed by esterases. Afterwards, benzeneacetic acid could be glucuronised or sulfononated by the glucuronyltransferase or sulfotransferase, respectively, to enhance the hydrophilicity and to facilitate the elimination.
Ethanol is metabolized by alcohol dehydrogenase to acetaldehyde, which is further metabolized to acetate by aldehyde dehydrogenase. Acetate is broken down into water and carbon dioxide via the citric acid cycle.

Applicant's summary and conclusion

Conclusions:

Bioaccumulation of the test substanceis not considered critical based on expert statement.

Executive summary:

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the oral and dermal route is expected. This assumption is further supported by the results of the oral and dermal acute toxicity studies, revealing some effects at very high doses. Absorption via inhalation route is unlikely, but can not be excluded. Bioaccumulation of ethyl phenylacetate or its breakdown products will not occur. After enzymatic conversion the metabolites will be mainly excreted via urine.