Ethyl benzoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2015-06-09

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:

2015

Report date:

2015

Materials and methods

Principles of method if other than guideline:

Expert statement

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl benzoate

EC Number:

202-284-3

EC Name:

Ethyl benzoate

Cas Number:

93-89-0

Molecular formula:

C9H10O2

IUPAC Name:

ethyl benzoate

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Doses / concentrations

Remarks:

Doses / Concentrations:
not applicable

No. of animals per sex per dose / concentration:

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

Preliminary studies:

not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, the relatively high water solubility of 720 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. The moderate log Pow value of ethyl benzoate is favourable for passive diffusion. Taken together, the physiochemical properties indicate that ethyl benzoate becomes 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 (leading to LD50 values of >2000 mg/kg bw).

Due to the low vapour pressure of ethyl benzoate 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 absorption will also take place, favoured by the water solubility and the log Pow value, and also by the size of the molecule. Indeed, some clinical effects (diarrhoe in rabbits, salivation, tremor, muscular incoordination at a very high dose of 10000 mg/kg bw in cats) and mortality at doses over 2000 mg/kg bw in rabbits were reported (please refer to IUCLID section 7.2.3).

Details on distribution in tissues:

The physicochemical properties of ethyl benzoate favour systemic absorption following oral, inhalative and dermal uptake.
After being absorbed into the body, ethyl benzoate is most likely distributed into the interior part of cells due to its slightly lipophilic properties (log Pow 2.59) and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues.
Ethyl benzoate does not have an accumulative potential, as it is reported that benzoate esters are in general rapidly hydrolysed by carboxylesterases into benzoic acid and aliphatic alcohols. The enzyme mediated hydrolysis occurs in the blood, other body fluids and most body tissues, but predominantly carboxylesterases are found in hepatocytes (JECFA, 2002). As a chronic feeding study in rats conducted on benzoic acid did not reveal any signs of target organ toxicity or other indications for an accumulation in any organ or tissue, there is also no evidence for an accumulative property of this compound. Besides that, it is stated in literature that the breakdown products are further metabolized and excreted.

Details on excretion:

Ethyl benzoate will not be excreted in its unhydrolized form. The first degradation product, ethanol, and its metabolism and excretion are well known.
The second hydrolysis product, benzoic acid, is metabolised by conjugation to hippuric acid and renally excreted.

Metabolite characterisation studies

Details on metabolites:

As mentioned above, benzoate esters are generally hydrolysed by carboxylesterases into benzoic acid and aliphatic alcohols. This enzymatic reaction follows a first order kinetic. Ethyl benzoate was shown to have the longest half-life time of all alkyl benzoate esters. The experimentally determined half-life time for ethyl benzoate was 3.5 h (Nielsen & Bundgaard, 1987). Metabolism of ethyl benzoate is considered to be complete, and the metabolites are not supposed to be more toxic than the parent compound. This assumption is supported by the results obtained in the in vitro genetic toxicity tests conducted on ethyl benzoate and methyl benzoate in the presence of metabolic activation.

After hydrolysis of ethyl benzoate the resulting aliphatic alcohol (ethanol) is oxidized to a more polar metabolite (acetaldehyde) and further metabolized in the tricarboxylic acid cycle (JECFA, 2002). Benzoic acid is undergoing phase II reactions, and, after mainly being conjugated to hippuric acid, rapidly excreted via urine (IPCS & IOMC, 2000; Abdo et al., 1985).

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Taken together, ethyl benzoates becomes bioavailable but will be metabolized and excreted completely and rapid.

Applicant's summary and conclusion

Conclusions:

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the dermal, oral and inhalation 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 (above 2000 mg/kg bw). Bioaccumulation of ethyl benzoate or its breakdown products ethanol or benzoic acid will not occur. Enzymatic hydrolysis of ethyl benzoate is supposed to be complete. Ethanol is oxidized to acetaldehyde and degraded via the tricarboxylic acid cycle. Benzoic acid is conjugated to hippuric acid and excreted via urine.