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Description of key information

Short description of key information on bioaccumulation potential result:
Methyl acetate is rapidly hydrolysed into methanol and acetic acid after oral or inhalative exposure.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - inhalation (%):
100

Additional information

Several experimental studies on toxicokinetics are available for methyl acetate. Furthermore, the toxicokinetik behaviour of methyl acetate was assessed from substance-specific physico-chemical properties and the available toxicological studies of the substance.

Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of the substance methyl acetate was conducted based on the relevant available information.

Absorption:

Due to high-vapour pressure of methyl acetate (220 hPa at 20°C), water solubility (295 g/l) and partition coefficient (log Pow) of 0.18 indicate bioavailability of the substance at all routes.

Methyl acetate is absorbed via the lungs in animals and humans, absorption via the oral route is demonstrated. After absorption the substance undergoes hydrolysis to methanol and acetic acid.

Metabolism and Kinetics:

There are several studies available that show the hydrolysis of methyl acetate:

Ghittori et al. (1984) reported on hydrolysis of methyl acetate in blood at 37ºC (concentration: 2.18 μg/l; 7 hours later: 1.96 μg/l). The products were identified as acetic acid and methanol.

Mizunuma et al. (1992) detected hydrolysis of methyl acetate to methanol in vitro when methyl acetate was incubated with human blood (27.9 μg/ml) for 2 to 8 hours at 36°C. The velocity of the reaction was so fast that 60% of methyl acetate was converted to methanol in 2 hours, almost all of methyl acetate disappeared in 8 hours (detection limit 0.1 μg/ml). Concentrations were analysed by head-space gas chromatography, the methanol formation was further confirmed by means of gas chromatography-mass spectrometry. The capacity to hydrolyse methyl acetate was evenly distributed in cellular and noncellular fractions of blood.

After incubation of methyl acetate with carboxylic esterases from nasal mucosa of male F344 rats (S9-homogenate) a rate of hydrolysis of 15 + 3 nmol/mg S9-protein/min was determined (Dahl et al., 1987).

Cleavage of methyl acetate into methanol and acetic acid in the gastrointestinal tract takes place by esterases of the gastric mucosa. It is furthermore hydrolysed by esterases of the blood. It is roughly estimated that the half-life of methyl acetate amounts to 2 – 3 h (rat blood) and ca. 2 h (human blood).

HMR (1999) reported methyl acetate concentration less than 5 ppm (v/v; < 4.6 mg/l) in rats immediately after 6 hours inhalation exposure (2,000 ppm) on the last day of a subacute study (6 hours daily, 5 days/week) and 30, 60, 120 min. as well as 18 hours later. At each time point two male rats and two female rats were sacrified to collect blood.

Shortly after start of inhalation exposure of tracheotomized rabbits to methyl acetate in a 645 l chamber for up to 3 hours methyl acetate was found in the exhaled air in a concentration of up to 30-50% of the inhaled quantity (up to 20 mg/l). After termination of exposure no methyl acetate was detected in the exhaled air. Although there was retention of methyl acetate during inhalation, methyl acetate could not be found in the blood indicating a rapid hydrolysis (BG Chemie, 1995).

 Methyl acetate is rapidly metabolised in humans after inhalation. Methanol can serve as an indicator of metabolic degradation.

Repeated inhalation 2h-exposure of each of 2 test persons to about 200 ppm methyl acetate (165 290 ppm; approx. 610 mg/m3) respectively to methanol (160-225 ppm) 2 times per day (2h interval) over 3-4 days resulted in each of the first exposures per day to enhanced methanol concentrations in urine, which reached a maximum after each second exposure per day respectively within 4 h after second exposure (>10 mg methanol/ l urine). At each next morning the values restored to normal (< 5 mg/l) (Tada et al., 1974).

More recently Kumagai et al (1999) reported that the percentage of methyl acetate in end-exhaled air and in mixed-exhaled air of human beings increased after the start of the exposure and reached a quasi-steady-state level within a few minutes. The mean respiratory uptake for the last 5 minutes of methyl acetate respiration was 60.4%. Methanol, its metabolite, was detected in exhaled air (concentration: 1.3 ppm) at the first minute reaching a quasi-steady state level of 3 ppm at the 5th minute, and suggesting removal of the solvent by metabolism in the wall tissue of the respiratory tract.

To conclude methyl acetate is hydrolysed rapidly and completely by esterases to methanol and acetic acid in the gut and/or blood.

The main metabolite is methanol which itself is metabolised to formic acid. Methanol is rapidly and completely absorbed from the gastrointestinal tract following oral ingestion, reaching peak serum levels within 30-60 minutes, depending on the presence or absence of food in the stomach. Methanol distributes readily and uniformly to organs and tissues in direct proportion to their water content, and has a volume of distribution of 0.6-0.7 L/kg b.w. (IPCS/WHO, 1997). Methanol is rapidly and extensively metabolised in the liver, first to formaldehyde, by alcohol dehydrogenase in humans, then to formic acid or formate (depending on pH), primarily by formaldehyde dehydrogenase and finally to carbon dioxide, catalysed by formyl-tetrahydrofolic acid (THF) synthetase. Formic acid combines with THF to give 10-formyl-THF which is then converted into carbon dioxide by formyl-THF dehydrogenase. (IPCS/WHO, 1997; Cruzan, 2009). The rate of formate oxidation depends on the availability of folate, which varies amongst species. This is a key determinant in species differences in sensitivity to acute methanol toxicity. In general folate levels are lower in primates than in rodents (Johlin et al., 1987). The elimination half-life of methanol in humans is 2.5-3.0 h, although at high doses saturation of elimination results in more prolonged half-lives (Jones, 1987). In contrast, the elimination of formaldehyde is extremely rapid, with a half-life of approximately 1.5 min, in Cynomolgus monkeys (McMartin et al., 1979). Therefore interspecies differences in the metabolism were considered mainly of concern at dose levels leading to acute toxicity. Thus rat is a useful model to indicate subacute/subchronic toxic effects below sublethal dosages.

The second hydrolysis product acetic acid is almost completely absorbed from the gastrointestinal (GI) tract and is also absorbed via the lungs following inhalation. It is a weak acid and hence at the pH of body fluids will be found in both the acid and acetate forms. Acetic acid is rapidly metabolised in plasma and most tissues, with a half-life of the order of a few minutes (3-5 min, depending on dose) (Freundt, 1973, as cited by ECHA, 2012).

Acetate is readily converted to acetyl-CoA, which enters the citric acid cycle, being converted eventually to carbon dioxide (Smith et al., 2007).

Excretion:

Therefore, in blood and urine only methanol and acetic acid were found, not methyl acetate.

Almost 97 % of an oral dose of methanol is eliminated as CO2 (IPCS/WHO, 1997; Cruzan, 2009). A small amount of methanol (~2 %) is excreted unchanged in urine and expired air.

Due to convertion of acetic acid to carbon dioxide only a small amount (~0.6 %) of acetic acid is excreted unchanged, in the urine as acetate (Smith et al., 2007).