Propyl acetate

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 acute toxicity studies, revealing some effects at very high doses (above 2000 mg/kg bw resp. at very high vapour concentrations). Bioaccumulation of n-propyl acetate or its breakdown products will not occur. Enzymatic hydrolysis of n-propyl acetate  is rapid. Propan-1-ol is oxidized to propionaldehyde and propionic acid and degraded via the tricarboxylic acid cycle. The second degradation product, acetic acid, is a common ingredient in food and a metabolite in animal tissues. It is used in the biosynthesis of various structural and functional molecules and can also be degraded via the tricarboxylic acid cycle.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

N-propyl acetate is a colourless liquid at room temperature with a molecular weight of 102.1317 g/mol. The substance is soluble in water (18.9 g/L). The log Pow value was determined to be 1.4. N-propyl acetate has a vapour pressure of 33 hPa at 20 °C.

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, the relatively high water solubility 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 of n-propyl acetate is favourable for passive diffusion. Taken together, the physiochemical properties indicate n-propyl acetate 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 (leading to LD50 values of >2000 mg/kg bw).

Furthermore acetic esters with shorter alkyl chains, like propyl acetate, are known to be absorbed by the dermal route as these esters easily penetrate the skin (CIR 2010).

Absorption through mucous membranes does also take place, therefore uptake via inhalation is possible as well.

 

Distribution

The physicochemical properties of propyl acetate favour systemic absorption following oral, inhalative and dermal uptake. After uptake in the body n-propyl acetate and its metabolites are distributed via the bloodstream. As mentioned above, the physicochemical properties of propyl acetate 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. After being absorbed into the body, propyl acetate and also its hydrolysis product propan-1-ol are most likely distributed into the interior part of cells due to their slightly lipophilic properties (log Pow 1.4 and 1.6, respectively) and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues.

Propyl acetate does not have an accumulative potential, as it is reported that acetic esters are in general rapidly hydrolysed by carboxylesterases into acetic acid and the respective aliphatic alcohol. The enzyme mediated hydrolysis occurs in the respiratory tract, blood and other body fluids and in most body tissues.

Based on the results of the subchronic repeated dose toxicity studies (respiratory route) conducted with the breakdown product propan-1-ol and the structural analogue butyl acetate the substance is classified as STOT SE Cat. 3. Clinical signs were reduced activity, less movement and slower response to external stimuli (tapping on the chamber wall). Therefore the substance has distributed to the CNS.

Further signs of target organ toxicity or other indications for an accumulation of the substance or its breakdown products in any organ or tissue were not observed. There is no evidence for an accumulative property of the substance.

 

Metabolism

As mentioned above, alkyl acetates are generally hydrolysed by carboxylesterases into the respective alcohol and acetic acid. The enzymes are present on the skin, respiratory tract, blood and gastrointestinal tract (Dahl et al., 1987, please refer to IUCLID section 7.1.1). Primary acetates like propyl acetate are metabolised more rapidly than secondary or tertiary ones. In rats the blood levels of propyl acetate and propyl alcohol after inhalation exposure to propyl acetate clearly demonstrated that hydrolysis is rapid as 5 min after exposure to propyl acetate vapour the concentration of propylalcohol exceeded the concentration of the ester by far (Pacific Northwest National Laboratory; Poet, 2004). Furthermore, propyl alcohol levels started to decrease after 15 min indicating that further metabolisation steps follow immediately.

Respiratory bioavailability experiments in rats with n-propyl acetate demonstrated the rapid hydrolysis of this acetate ester to its corresponding alcohol both in vivo and in vitro (Poet 2004, Corley et al. 2000, Dahl et al. 1987; please refer to IUCLID section 7.1.1). Blood levels of propyl alcohol were between 2.5 and 5-fold greater than propyl acetate within the 90-minute exposure interval.

In an effort to understand the respiratory bioavailability of aliphatic alcohols and esters, a whole-body plethysmograph was installed in a gas uptake chamber. The chamber is charged with 2000-ppm propyl acetate and the chamber concentration decay curve is followed by gas chromatography. In addition, venous blood samples are taken at 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, and 90 minutes. The presence of propyl alcohol following propyl acetate inhalation exposure clearly demonstrates that propyl alcohol was the major metabolite of propyl acetate metabolism. The formation of the alcohol following inhalation exposure to propyl acetate demonstrates that in vivo exposures to propyl acetate will lead to appreciable blood levels of n-propyl alcohol within 15 minutes of exposure (Poet et al. 2004, please refer to IUCLID section 7.1.1).

Groups of 3 to 4 male F-344 rats were individually exposed for 2 hr to target vapor concentrations of 200 or 2000 ppm n-propyl acetate in a closed, recirculating gas uptake exposure chamber (Corley et al. 2000, please refer to IUCLID section 7.1.1). Clearances of n-propyl acetate from the gas uptake chamber over time followed a log-linear (first-order) process which was independent of concentration over a concentration range of 200-2000 ppm; 67 -89% were cleared within 2 hrs (Corley et al. 2000).

Readily hydrolysis was demonstrated also in vitro in respiratory tract tissues of test animals. A series esters of straight chain aliphatic alcohol (methanol, ethanol, propanol, butanol, pentanol, hexanol and octanol) were tested as substrates for carboxyesterases in nasal, lung and liver tissues from male F344 rats, male New Zealand White rabbits, and male Syrian hamsters (Dahl et al. 1987). The hydrolysis rate was 56 +- 4 nmol carboxylic acid formed/ mg S-9 protein/ min in the rat.

In a publication the enzymatic hydrolysis of several aliphatic esters with alkyl residues from one to seven carbon atoms was compared (Arndt & Krisch, 1973). Therefore, carboxylesterases were extracted from rat liver microsomes. As a result, the velocity of the enzymatic reaction was found to increase for alkyl residues from one to three carbon atoms, therefore reaching a maximum for propyl acetate. Longer alkyl residues like butyl acetate were more slowly hydrolysed.

In another in vitro study the differences in substrate specificity of two rat liver carboxylesterase isoenzymes, E1 and EA, was examined. As a result it could be demonstrated that esterase E1 has a higher affinity to acetate esters with alkyl groups of C1-C3. The esterase EA prefers alkyl groups from C3 onwards instead (Arndt et al., 1978, please refer to IUCLID section 7.1.1).

 

One hydrolysis product of n-propyl acetate, propan-1-ol will be oxidised by alcohol dehydrogenases (ADH), more specifically by the Class I isozymes, into propionaldehyde and further metabolised into propionic acid. In chronic exposure the NADPH-dependent microsomal ethanol oxidizing system (MEOS) involving cytochrome P450 may also take part in the oxidation step. Propionic acid was reported to be conjugated with coenzyme A (CoA). This conjugation product is carboxylated to methylmalonyl-CoA, and further converted to succinyl-CoA. Succinyl-CoA enters the tricarboxylic cycle to be metabolized to carbon dioxide and water (European Chemicals Bureau (ECB), EU Risk assessment Report Propan-1-ol, 2008).

 

The other hydrolysis product, acetic acid, and acetate occur in plant and animal tissues and are present in food. Besides that, acetates are produced to considerably amounts during digestion and metabolism of foods (Select Committee on GRAS Substances (SCOGS), 1977). The various metabolic pathways of acetic acid are well known (Draft Assessment Report (DAR), 2008): All possible pathways have the formation of ketone bodies in common. The degradation products were shown to be used in the formation of cholesterol and in fatty acid-, carbohydrate- and glycogensynthesis. Furthermore acetic acid is used in the acetylation of amines and biosynthesis of proteins. After reaction with co-enzyme A acetic acid forms acetyl-CoA which can enter the tricarboxylic acid cycle. As a conclusion, acetates and acetic acids are normal metabolites in the human body. They have a low acute toxicity and the only remarkable effects are the local effects on skin and mucous membranes (irritation, corrosion) (The MAK-Collection, 2011).

 

Excretion

N-propyl acetate will not be excreted in its unhydrolysed form. The first degradation product, propanol, and its metabolism and excretion are well known (see above). The second degradation product, acetic acid, is a common ingredient in food and a metabolite in animal tissues. Its metabolisation and excretion are well known as well.

PBPK modelling

Smith JN et al. (2020) developed a PBPK model for the propyl metabolic series in rats and humans for application to risk assessment. The model predicts rapid clearance of propyl acetate, higher levels of propanol from propyl acetate inhalation compared to propanol inhalation in rats but not humans, and low concentrations of propionic acid in blood following exposures to propyl acetate or propanol. Regulators can use this model for risk assessment of propyl compounds by linking internal dosimetries under various scenarios of exposure to propyl compounds.

 

References:

CIR Cosmetic Ingredient Review (2010). Report of the 116th CIR Expert Panel Meeting (August 30- 31,2010).

 

Draft Assessment Report (DAR) (2008). Acetic acid - Initial risk assessment provided by the rapporteur Member State Germany.

 

European Chemicals Bureau (ECB) (2008). EU Risk assessment Report Propan-1-ol. Part II Human Health.

 

Pacific Northwest National Laboratory (2004). Poet, T: Respiratory Bioavailability of a Series of Acetate Esters and Alcohols in Rats. Unpublished Report  No. 43863. Cited in OECD SIDS Dossier for N-propyl acetate. May 2009.

 

Select Committee on GRAS Substances (SCOGS) (1977). SCOGS Opinion: Acetic Acid; Sodium Acetate; Sodium Diacetate. Retrieved from U.S. Food and Drug Administration, GRAS Substances (SCOGS) Database, SCOGS Report Number 82: http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/ucm255100.htm

Smith JN et al. (2020): Linking internal dosimetries of the propyl metabolic series in rats and humans using physiologically based pharmacokinetic (PBPK) modeling. Regulatory Toxicology and Pharmacology 110 (2020) 104507

 

The MAK-Collection (2011). Part I: MAK Value Documentations, Vol. 26. Acetic Acid. DFG. Deutsche Forschungsgesellschaft.