Phenethyl isobutyrate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2016-11-23

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:

2016

Report date:

2016

Materials and methods

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phenethyl isobutyrate

EC Number:

203-116-1

EC Name:

Phenethyl isobutyrate

Cas Number:

103-48-0

Molecular formula:

C12H16O2

IUPAC Name:

2-phenylethyl 2-methylpropanoate

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 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

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol. Moderate water solubility of 160 mg/L enables the substance to partly dissolve in the gastrointestinal fluids and thus it may be considered that direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water takes place. However, the moderate log Pow value of 3.5, which is favourable for passive diffusion, would be the more important property here regarding absorption. Therefore, it can be concluded that Phenylethyl Isobutyrate likely becomes bioavailable following the oral route, as indicated by its physic chemical properties. This assumption is confirmed by the results of the acute oral toxicity study as well as the combined repeated dose toxicity study (OECD 422). In the acute toxicity study, considerable clinical signs, as well as mortalities were observed following administration (leading to LD50 values of >5000 mg/kg bw).

Due to the low vapour pressure of 45 Pa of Phenylethyl Isobutyrate it is unlikely that the substance will be available as a vapour. However, it this case, absorption via inhalation route would be possible due to the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Dermal absorption can also take place, favoured by the log Pow value, and also by the small molecular weight of the substance. Indeed, clinical effects and mortality at the limit dose of 5000 mg/kg bw were reported (please refer to IUCLID section 7.2.3).

Details on distribution in tissues:

As mentioned above, the physicochemical properties of Phenylethyl Isobutyrate make systemic bioavailability very likely following oral, inhalative and dermal uptake.
After being absorbed into the body, Phenylethyl Isobutyrate is likely distributed into cells and intracellular concentrations may be higher than extracellular concentrations due to its slightly lipophilic properties (log Pow 3.5). This applies especially for fatty tissues.
Phenylethyl Isobutyrate is unlikely to have a bio-accumulative potential, because it is not highly lipophilic (log Pow is not greater than 4) and there are no other physic-chemical properties indicating bio-accumulating properties. As a combined repeated dose toxicity study (OECD 422) in rats 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. Furthermore, it is stated in literature that the breakdown products are readily metabolized and excreted.

Details on excretion:

Phenylethyl Isobutyrate will not be excreted in its non-hydrolysed form. One degradation product, phenylethyl alcohol, is excreted in the urine as conjugate with glycine or glucuronic acid (JECFA, 2003). The other hydrolysis product, isobutyric acid, is rapidly metabolised, integrated in endogenous pathways and thus in main parts excreted as CO2 in the breath (DiVincenzo & Hamilton, 1979). The assumption of rapid excretion is supported by findings of the acute oral toxicity study as well as the combined repeated dose study (OECD 422). In both studies surviving animals recovered rapidly when treatment was determined.

Metabolite characterisation studies

Details on metabolites:

Based on its structure, Phenylethyl Isobutyrate may be considered to possibly undergo hydrolysis in contact with aqueous fluids into the corresponding carboxylic acid (isobutyric acid) and phenylethyl alcohol. This process is also highly likely catalyzed by carboxylesterases, (Mutschler, 2001). Hydroxyl group and carboxylic acid are typical functional groups of substrates for phase II enzymes such as UGTs (UDP-glucuronosyltransferase) and GSTs (glutathione-S-transferases) (Marquat & Schäfer, 2004). Conjugated phenylethyl alcohol with glucuronic acid as well as with glycine was already demonstrated in the urine of rabbits (JECFA, 2003). Isobutyric acid, however, is conjugated with Co-enzyme-A and, following β-oxidation, integration into endogenous citric acid cycle is considered (BG Chemie, 1997). Summarizing, the substance and its hydrolytic cleavage products are considered to be readily metabolized and, with this, detoxified. This consideration is supported by findings of in vitro genotoxicity studies applying a metabolizing system (mammalian S9 mix). In both the bacterial reverse mutation assay and the in vitro micronucleus assay the substance showed no cytotoxicity when incubated together with S9. However, substantial cytotoxicity was observed when the substance was applied without metabolizing system in both assays. This is further supported by an HPRT assay, where cytotoxicity was observed irrespective of S9 application or not.

Applicant's summary and conclusion

Conclusions:

Bioaccumulation of the substance is not to be excpected after continuous exposure based on expert statement.

Executive summary:

Based on physicochemical characteristics, particularly molecular weight 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 effects at very high doses (5000 mg/kg bw), as well as the combined repeated dose study (OECD 422). Bioaccumulation of Phenylethyl Isobutyrate or its breakdown products phenylethyl alcohol or isobutyric acid will not occur. Enzymatic hydrolysis of Phenylethyl Isobutyrate is supposed to be complete. Phenylethyl alcohol is conjugated with glucuronic acid or glutathione and excreted via urine. Isobutyric acid is metabolised, incorporated in endogenous pathways and excreted as CO2 in the breath.