4'-methoxyacetophenone

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:

2018

Report date:

2018

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:

4'-methoxyacetophenone

EC Number:

202-815-9

EC Name:

4'-methoxyacetophenone

Cas Number:

100-06-1

Molecular formula:

C9H10O2

IUPAC Name:

1-(4-methoxyphenyl)ethanone

Specific details on test material used for the study:

not applicable

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. The good water solubility of 1737 mg/L enables the substance to readily dissolve in the gastrointestinal fluids. In combination with the low molecular weight of less than 200 g/mol the molecules can pass through aqueous pores or can also be carried through the epithelial barrier by the bulk passage of water. The moderate log Pow value (between -1 and 4) is also favourable for passive diffusion. Taken together, the physiochemical properties indicate that the substance becomes bioavailable following the oral route. This assumption is confirmed by the results of the oral toxicity study, where mortality occurred.
Due to the low volatility (vapour pressure <0.5 kPa) of the 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 water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.
Dermal absorption may also take place, favoured by the water solubility and the log Pow value, and also by the size of the molecule, even though the test results did not indicate this: No mortality occurred in an acute dermal toxicity study and no indications of a skin sensitising potential were revealed. The dermal permeability constant Kp was calculated to be 0.00348 cm/hr (Dermwin v.2.02). The test substance was found to be irritant to skin, indicating that dermal uptake might be facilitated by damaging the skin.

Details on distribution in tissues:

The physicochemical properties of the substance favour systemic absorption following oral, inhalative and dermal uptake. The systemic absorption and distribution within the body is also demonstrated by the decreased viability index of PND 4 and decreased body weights on PND 13 of the F1 pups in the OECD 422 study.
Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After being absorbed into the body, the substance is most likely distributed into the interior part of cells due to its very slightly lipophilic properties (log Pow 1.79) and in turn the intracellular concentration may be slightly higher than extracellular concentration particularly in adipose tissues.
The log Pow of the test substance indicates no bioaccumulation potential as 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 and its metabolites is via urine as substances with a molecular weight below 300 g/mol are prone to this pathway.

Metabolite characterisation studies

Metabolites identified:

yes

Remarks:

predicted yb QSAR Toolbox v4.2

Details on metabolites:

The in vitro rat liver metabolic simulator of QSAR toolbox v4.2 predicted formaldehyde, 1-(4-Hydroxyphenyl)ethanone, 1-(4-Methoxyphenyl)ethanol and formic acid as metabolites. Formaldehyde and will be further oxidized into formate and eventually to carbon dioxide. 1-(4-Hydroxyphenyl)ethanone and 1-(4-Methoxyphenyl)ethanol may further undergo conjugation reactions to facilitate excretion via urine.

Applicant's summary and conclusion

Conclusions:

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

Executive summary:

Based on physicochemical characteristics absorption by the oral and dermal route takes place. This assumption is supported by the results of the oral acute toxicity study, revealing mortality at <2000 mg/kg bw. Absorption via inhalation route is unlikely, but may also take place. Bioaccumulation of the substance is not expected.After being absorbed into the body,4’-methoxyacetophenone ismost likely distributed into the interior part of cells due to its very slightly lipophilic properties (log Pow 1.79) and in turn the intracellular concentration may be slightly higher than extracellular concentration particularly in adipose tissues. A metabolic activation to more toxic metabolites is not to be expected. Predicted metabolites formed in the liver and upon skin contact are presented above (QSAR tollbox v4.2). In general, phase I and II metabolism reactions will render the molecule more polar to faciliate excretion via urine.