Isopropenyl acetate

Endpoint summary

Additional information

Isopropenyl acetate is hydrolytically unstable and it reacts with humidity and with water under formation of isopropenyl alcohol and acetic acid. As the resulting isopropenyl alcohol as an enol is not stable under normal conditions it will tautomerize to form the respective ketone acetone. It can be assumed that in aqueous environment of biological systems similar reactions occur. The hydrolysis will be catalyzed at lower pHs like in the stomach. Thus it can be assumed that after oral uptake resorption of at least the resulting metabolites will occur. Both metabolites are well known.

 Isopropenyl acetate is hydrolysed by hydrolytic enzymes like carboxylesterases to acetic acid and acetone, producing protons in the process. The presence of carboxylesterases capable of hydrolysing isopropenyl acetate has been demonstrated in the epithelial tissues of the nose, oral cavity, and respiratory tract, as well as the skin, blood and liver of several species including man. Carboxylesterases present in tissues lining the major portals of entry following inhalation, oral and dermal exposure, lead to pre-systemic hydrolysis of isopropenyl acetate at these sites, reducing systemic exposure to intact isopropenyl acetate to a degree in proportion with enzyme activity, i. e. where enzyme activity is highest, systemic exposure will be lowest and visa-versa. Conversely, the presence of carboxylesterases at a portal of entry can increase local concentrations of isopropenyl acetate metabolites by increasing the air-tissue flux of vinyl acetate.

In humans, acetone as a hydrolysis product is formed endogenously under fasting conditions. Under conditions where glucose stores are depleted acetone provides a means of supplying substates to tissues that are incapable of metabolizing fatty acids. .

Exogenous acetone is readily absorbed via inhalation, ingestion, and dermal exposures. After uptake, acetone is distributed throughout the body, particularly in organs with high water content. The respective metabolic pathways are dependent on the site of metabolism and on the concentration of acetone.The metabolites are transformed to glucose and other substrates of metabolism that produce carbon dioxide.In the first metabolic step acetone is oxidized to acetol by acetone monooxygenase. In one pathway, acetol is converted to methylglyoxal, which is metabolized to glucose through a lactate intermediate. The conversion of acetone on this pathway is catalyzed by acetone monooxygenase and acetol monooxygenase to form methylglyoxal. The conversion of methylglyoxal to lactate is catalyzed by glyoxylase I/ II and glutathione-S-transferase. This pathway is primarily a hepatic pathway. In another pathway, the acetol intermediate is converted to L-1,2-propanediol by an extrahepatic mechanism. The metabolism of acetone by the 1,2-propanediol pathway to lactate is catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase. 1,2-Propanediol can be converted to form glucose through a series of intermediates including lactate.

These pathways metabolism are concentration-dependant. At lower concentrations, acetone is metabolized in the liver through the methylglyoxal pathway similar to biological conditions of fasting. so that at low plasma concentrations acetone serves as a gluconeogenic substrate. At higher concentrations an alternate pathway predominates and mediates the conversion of acetone to 1,2-propanediol.

Acetone excretion is also dose-related. Exposure to low levels of acetone lead to small losses through expiration. Acetone appears in the urine only when exposure concentrations exceed approximately 15 ppm.

Acetic acid is a naturally occurring metabolite and is beeing transformed to the activated form Acetyl-Coenzyme A (Acetyl-CoA) by the enzymeacyl-CoA synthetase.The corresponding Acetyl-CoA is present in different metabolic pathways and enters the citric acid cyle of organisms where it is degraded to form water and carbon dioxide.

Metabolism Acetone.pdf / 1.16 MB (application/pdf)

US EPA: TOXICOLOGICAL REVIEW OF ACETONE (CAS No. 67-64-1) In Support of Summary Information on the Integrated Risk Information System (IRIS) May 2003

 

In humans, acetone is formed endogenously under conditions of uncontrolled diabetes or with high fat/low carbohydrate diets. Under conditions where glucose stores are depleted acetone provides a means of supplying glucose to tissues that are incapable of metabolizing fatty acids. Acetic acid is a naturally occurring metabolite and is beeing transformed to the activated form Acetyl-Coenzyme A (Acetyl-CoA) by the enzymeacyl-CoA synthetase. The correspondingAcetyl-CoA it is present in different metabolic pathways and enters the citric acid cyle of organisms where it is degraded to form water and carbon dioxide.

Exogenous acetone is readily absorbed via inhalation, ingestion, and dermal exposures. After uptake, acetone is broadly distributed throughout the body, particularly in organs with high water content. The principal metabolic pathways are dependent on the site of metabolism and on the concentration of acetone. The metabolites are incorporated into glucose and other substrates of intermediary metabolism that ultimately produce CO2. In the first metabolic step, common to all potential pathways, acetone is oxidized to acetol by acetone monooxygenase. In the first pathway, acetol is converted to methylglyoxal, which in turn is metabolized to glucose through a lactate intermediate. The conversion of acetone via the methylglyoxal pathway is mediated by acetone monooxygenase and acetol monooxygenase to form methylglyoxal. The conversion of methylglyoxal to lactate is mediated by glyoxylase I and II and glutathione-S-transferase. This pathway is primarily a hepatic pathway. In the second pathway, the acetol intermediate is converted to L-1,2-propanediol by an extrahepatic mechanism that has not been fully characterized. The metabolism of acetone via the 1,2-propanediol pathway to lactate is mediated by alcohol dehydrogenase and aldehyde dehydrogenase. Gluconeogenesis may proceed through the formation of an active form of acetate. 1,2-Propanediol may be converted to glucose through a series of intermediates including lactate.

The pathways for acetone metabolism are concentration-dependant. At lower concentrations, acetone is metabolized in the liver through the methylglyoxal pathway similar to biological conditions of fasting or exertion where the acetone is formed from fatty acids to produce glucose. Thus, at low plasma concentrations acetone serves as a gluconeogenic substrate. At higher concentrations an alternate pathway predominates and mediates the conversion of acetone to 1,2-propanediol. Although some studies indicate that 1,2-propanediol serves as an intermediate in the production of glucose, it is conceivable that the conversion from acetone to the diol diverts acetone from gluconeogenesis and facilitates the loss of acetone via urine.