1-phenylethyl acetate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
The toxicokinetics of the substance were assessed by literature available on benzyl acetate, a structurally similar substance to 1-phenylethyl acetate, which is expected to follow the same metabolic pathway as the test substance. The available data indicated that initially, the substance undergoes rapid hydrolysis in the body and undergoes several enzyme dependent steps to eventually form hippuric acid. Several investigations within two of the three studies demonstrated that the metabolic pathway (the CoA conjugation pathway) can become saturated, affecting the rate and quantity at which metabolites are formed and also the dependence on the availability of glycine (this was not demonstrated in the NTP (1986) study). Excretion of benzyl acetate was found to be rapid, and was complete by 72 hours with negligible amounts retained in the body.
Short description of key information on absorption rate: 
Low level absorption of the benzyl acetate occurs through human skin in vitro. Human skin in less permeable to benzyl acetate than rat skin. The information available indicates that some low level systemic exposure to the test substance will occur, however testing dermally in animal models is likely to overestimate systemic exposure.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

17.8

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetics

Three studies were submitted as a weight of evidence to address the toxicokinetics of 1-phenylethyl acetate, both of which were performed on benzyl acetate. Benzyl acetate is structurally very similar to 1-phenylethyl acetate and is expected to follow the same metabolic pathway.

The focus of Yuan et al (1995), was to provide a rudimentary map of the metabolic pathway of benzyl acetate using both in vivo and in vitro techniques and to determine whether the route (oral gavage vs. oral feed) influenced the rate of metabolism. The study was reported to a high standard, and performed in line with good scientific principles, as such a reliability score of 2 was considered suitable, in accordance with Klimisch (1997). From the in vivo and in vitro tests, benzyl acetate and benzyl alcohol were found to undergo rapid hydrolysis in the blood to form benzoic acid. The proposed metabolic pathway model of benzoic acid was a first-order input and a first order elimination mechanism for hippuric acid. The elimination rate of benzoic acid was found to be greater than the formation rate hippuric acid. Hippuric acid was detected at later time points therefore a simultaneous zero-order formation mechanism was proposed.

Chidgey and Caldwell (1986), also investigated the influence of different dosing techniques by varying the dose size and the vehicle. This study too was reported to a high standard, and performed in line with good scientific principles, as such a reliability score of 2 was also assigned. Under the conditions of the test, the levels of metabolites in the plasma were found to be affected by dose size, test substance and time after dosing indicating the potential for the metabolic pathway to become saturated with high doses. In urine the proportion of administered 14C converted to hippuric, benzoic and benzylmercapturic acids were not significantly influenced by the size of the dose. The dose vehicle had no effect upon the metabolic pattern of benzyl acetate. Excretion of the test substance was found to be rapid, and was considered complete by 72 hours less than 1 % was found to be retained by the carcass after 72 hours.

NTP (1986), also investigated whether the size, route and number of doses benzyl acetate affected the rate of absorption and metabolism in rats and mice. Rats were dosed singly either orally, intravenously or dermally and repeatedly via oral gavage. Mice were dosed singly either orally or intravenously and repeatedly via oral gavage. The study was reported to a good level in two publications and was performed in line with good scientific principles with only minor deficiencies affect the quality of the data presented. In line with the principles for assessing data quality, in accordance with Klimisch (1997), the study was assigned a reliability score of 2. Under the conditions of the test, absorption of benzyl acetate was found to be rapid and almost complete via the gastro-intestinal tract (considerably slower via dermal absorption) and metabolism was also found to be rapid and complete, with almost the entirety of the radioactive dose recovered in urine as the major metabolite hippuric acid. No radioactivity was observed in any of the tissues analysed after 24 hours post-dosing. No radioactivity was found to be retained in the tissues, and the level of recovery of the test substance in the urine indicated that benzyl acetate will not accumulate in the body.

Dermal absorption

The key study, Garnett et al (1994), performed a comparison of the rate of absorption of the test substance benzyl acetate in both rat and human skin in vitro using diffusion cells. Absorption was measured up to 72 hours in both tissues and compared. The method was comparable to the OECD guideline 428, however extra evaluations were performed comparing inter-species differences. The study was well reported and performed in line with good scientific principles. The study was therefore assigned a reliability score 2 in accordance with Klimisch (1997). The study was performed on the substance benzyl acetate, which is structurally similar to 1-phenylethyl acetate (the only difference being, a methyl group present on the carbon chain of 1-phenylethyl acetate) and considered to be representative of the effects. Under the conditions of the test, low level absorption of the test substance, benzyl acetate through human skin was demonstrated (17.8 ± 3.3 %) indicating that some low level systemic exposure may occur in humans. The study did demonstrate that human skin in less permeable than rat skin, with the absorption through rat skin reaching 55.8 ± 5.0 %.