Benzyl propionate

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:

Benzyl propionate

EC Number:

204-559-3

EC Name:

Benzyl propionate

Cas Number:

122-63-4

Molecular formula:

C10H12O2

IUPAC Name:

benzyl propanoate

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Duration and frequency of treatment / exposure:

not applicable

Doses / concentrations

Remarks:

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:

The likelihood of systemic absorption through the walls of the intestinal tract, into the skin and after inhalation depends on several physicochemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Kow need to be considered.

The smaller the molecule the more easily it may be taken after oral administration. Molecular weights below 500 are favourable for absorption. Additionally, moderate log Pow values (between -1 and 4) are favourable for absorption by passive diffusion. An adequate hydrophilicity of the substance should be given to dissolve into the gastrointestinal fluid and thus get in contact with the mucosal surface. Based on the physicochemical properties of substance (molecular weight: 164.2 g/mol, water solubility: 742 mg/L, log Pow: 2.4) absorption by passive diffusion through the epithelial barrier of the intestine is likely. This assumption is confirmed by the results of the oral acute toxicity study indicating systemic effects in test item treated rats such as lethargy, pilorection, tremors and chromodacryorrhea. Additionally, clinical signs (salivation) were detected after repeated treatment of rats via oral route with a test item concentration of 500 mg/kg bw/day in an OECD 422 study.

After dermal application, the compound must first penetrate into the stratum corneum which is the greatest barrier function against hydrophilic compounds. However, the substances must be sufficiently soluble in water to partition from the stratum corneum into the viable epidermis. If the water solubility is between 100 – 10000 mg/L absorption is anticipated to be moderate to high. Furthermore, dermal uptake is favoured for substances possessing a log Pow value between 1 and 4, particular if water solubility is high. Taken into account the log Pow values and water solubility of the test substance, dermal uptake into the stratum corneum followed by transfer into the viable epidermis is likely.

Considering the relatively low vapour pressure (< 0.5 kPa) and the resulting low volatility, exposure as vapour is very limited. However, absorption via inhalation is possible as absorption following ingestion did also occur. Liquids are able to readily dissolve into the mucus lining the respiratory tracts. Based on the log Pow value greater than 0, the substance have the potential to be absorbed directly across the respiratory tract epithelium.

Details on distribution in tissues:

As mentioned above, the physicochemical properties and toxicological data revealed that small amounts of the test substance can become systemically available following oral and dermal exposure. Additionally, absorption can be expected after exposure via inhalation. Once absorbed, the distribution of the test substance via blood stream can be assumed. In general, the smaller the molecule, the wider the distribution. Since the log Pow value is 2.4, distribution into cells is likely. Furthermore, accumulation within the body is not expected as the log Pow value is well below 4.

Details on excretion:

Due to the enhanced hydrophilicity, the conjugated metabolites are favorable for urinary excretion. Additionally, the test substance itself is most likely excreted via urine due to their small molecular weight (below 300 g/mol) and their water solubility.

Metabolite characterisation studies

Details on metabolites:

Biotransformation of benzylpropionate mainly occurs in the liver especially following oral intake. Biotransformation of a substance aimed to increase the hydrophilicity of lipophilic substances by Phase I (functionalization) and Phase II (conjugation) enzymes. benzylpropionate contains an ester group which will be primary hydrolytically cleaved by esterase in liver to propanoic acid and the corresponding alcohol benzyl alcohol. The formed acid and the corresponding alcohol could be glucuronised by the glucuronosyltransferase to enhance the hydrophilicity and to facilitate the elimination.
Formation of toxic metabolites is unlikely which is supported by the results of genotoxicity pre- and main experiments. It can be assumed that benzlpropionate is not enzymatically activated (toxified) during metabolism as the metabolic activated substance did not show higher cytotoxicity than the parent compound.

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 dermal, oral and inhalation route is expected. This assumption is further supported by the results of the oral repeated dose study revealing some systemic effects. Bioaccumulation of the test substance is not to be expected after continuous exposure. Phase I and II metabolism within liver cells is likely and excretion will presumably occur after renal passage via urine.