p-methoxybenzyl acetate

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

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

p-methoxybenzyl acetate

EC Number:

203-185-8

EC Name:

p-methoxybenzyl acetate

Cas Number:

104-21-2

Molecular formula:

C10H12O3

IUPAC Name:

4-methoxybenzyl acetate

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:

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. The moderate water solubility of 616 mg/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the low molecular weight of less than 200 g/mol the test substance can pass through aqueous pores or can be carried through the epithelial barrier by the bulk passage of water. The moderate log Pow value is also favourable for passive diffusion. Taken together, the physiochemical properties indicate that the test substance becomes bioavailable following the oral route. This assumption is confirmed by the results of the repeated dose toxicity studies. In those studies systemic effects were detected after treatment with 800 mg/kg bw/day for 2 weeks and developmental toxicity was induced in pups through oral treatment of the parental animals with 400 mg/kg bw /day.
Due to the relatively low vapour pressure of the test substance it is unlikely that the substance will be available as a vapour to a large extend, but if it is the case absorption via inhalation route might be possible due to the moderate 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. The occurrence of dermal absorption is also likely as the substance was found to be sensitising to skin and therefore it has to pass into the lower parts of the epidermis and into the dermis to induce inflammatory/ immune cell responses.

Details on distribution in tissues:

As mentioned above, the physicochemical properties of the test substance favour systemic absorption following oral, inhalative and dermal uptake. The systemic absorption and distribution within the body is also demonstrated by changes detected in the kidneys of male rats and especially by the developmental toxicity observed in pups after repeated oral application in parental rats.
Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After being absorbed into the body, the test substance is most likely distributed into the interior part of cells due to its very slightly lipophilic properties (log Pow 1.9) and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues.
The logPow of the test substance indicates no bioaccumulation potential. It is below 3 and the most likely uptake mechanism into cells is passive diffusion, therefore the test substance is not considered to be bioaccumulative.

Details on excretion:

The test substance will be excreted most likely in its metabolised form.
The likely excretion pathway of the test substance is via urine. As substances with a molecular weight below 300 g/mol are prone for this pathway and the substance’s molecular weight is 180 g/mol.

Metabolite characterisation studies

Details on metabolites:

The genotoxicity studies indicated no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic activation systems. Generally it is likely that common protein interaction such as cytochrome P450 oxidases interaction during Phase I metabolism introduce a reactive or polar group in the test substance. Those might be further processed into polar compounds during the metabolism in Phase II.

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.