Methyl phenylacetate

Endpoint summary

Description of key information

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 methyl phenylacetate or its breakdown products methanol or benzeneacetic acid will not occur. After enzymatic conversion the metabolites will be mainly renally excreted.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Methyl phenylacetate is a colourless liquid at room temperature with a molecular weight of150.1745 g/mol.The substance is soluble in water (923 mg/L at 25 °C). The log Pow of methyl phenylacetate was determined to be 1.91. Methyl phenylacetate has a vapour pressure of 75 Pa at 20 °C.

 

Absorption

 

Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, the relatively high water solubility of 923 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 is favourable for passive diffusion. Taken together, the physiochemical properties indicate that methyl phenylacetate 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 in doses from 2560 mg/kg bw onwards.

 

Due to the low vapour pressure of methyl phenylacetate 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 uptake is favoured for substances with a molecular weight < 100 g/mol and log Pow values between 1 and 4. Dermal absorption will therefore take place, favoured by the water solubility and the log Pow value.The log Pow is 1.91 and therefore lies in the range between -1 and 4, although it is <2 and therefore not in the optimal range. The molecular weight of the substance is above 100 g/mol, but still small enough to penetrate skin. Indeed, mortality was observed in the acute dermal toxicity study with rabbits, leading to an LD50 of 2400 mg/kg bw.

 

Distribution

 

As mentioned above, the physicochemical properties of methyl phenylacetate favour systemic absorption following oral, inhalative and dermal uptake.

Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. In general, the smaller the molecule, the wider the distribution. Taken into account the log Pow and the water solubility, accumulation of methyl phenylacetate is unlikely. The available study data revealed no indications of the substance to cross the blood-brain barrier.

 

Metabolism

 

Based on the results received from in vitro Chromosome Aberration test and HPRT test it can be assumed that the structural analogue ethyl phenylacetate is detoxified during the metabolism as the parent compound showed higher cytotoxicity compared to the metabolically modified substance. Due to their structural similarity the same is anticipated for methyl phenylacetate. Metabolism mainly occurs in liver especially following oral intake.

Methyl phenylacetate may be cleaved into the benzeneacetic acid and methanol catalyzed by esterases. Afterwards, benzeneacetic acid could be glucuronised or sulfononated by the glucuronosyltransferase or sulfotransferase, respectively, to enhance the hydrophilicity and to facilitate the elimination.

Methanol is slowly converted to formaldehyde by alcohol dehydrogenase, then rapidly to formic acid by formaldehyde dehydrogenase in the liver. Formic acid also occurs as endogenous metabolic intermediate. Some of the formic acid is oxidized via the tetrahydrofolate system to form carbon dioxide which is exhaled; the rest is eliminated unchanged with the urine.

 

Excretion

 

The metabolites of methyl phenylacetate are most likely excreted via urine due to their small molecular weight (below 300 g/mol) and their good water solubility.