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Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Evaluation of toxicokinietcs based on literature data
Adequacy of study:
key study
Study period:
NA
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Details on absorption:
ORAL
Ethyl propionate possesses the phys/chem properties that favor absorption from the GI tract but bioavailability of the parent molecule would be limited because of hydrolysis in the GI tract. As a result, the toxicokinetics of ethyl propionate is largely determined by its rate of hydrolysis in the GI tract and the distribution, metabolism, and elimination of the corresponding alcohol and carboxylic acid hydrolysis products.
According to the ECHA Guidelines (2014) molecules with molecular weights of less than 500 g/mole are small enough to be candidates for absorption by passive diffusion from the GI tract. The molecular weight of ethyl propionate is 102.1 g/mole which would favor its absorption from the GI tract. In addition, ethyl propionate is water soluble (19 g/L) and has an octanol-water partition coefficient (log Pow) of 1.31. This combination of aqueous and lipid solubility also generally favors absorption by the oral route.
However, ethyl propionate is expected to be readily hydrolyzed in the GI tract which would effectively reduce the availability of parent for absorption. Finally, any intact ethyl propionate that is absorbed would be almost immediately hydrolyzed by esterases in blood. Rapid hydrolysis of isoamyl-3-(2’-furyl) propionate (CAS 7779-67-1) and allyl phenylacetate (CAS 1797-74-6), also small esters, was reported for whole blood preparations. Both esters underwent 98% hydrolysis in guinea pig blood within 1 minute (Pelling, 1980). Further support comes from the in vivo portion of the Pelling study in which guinea-pigs were administered these two esters through a bolus intraduodenal injection and blood levels of intact ester monitored. No intact ester was detected in the blood.
Based on this, the biological effects from ingestion of ethyl propionate would be predicted to result from exposure to the ethanol and the propionic acid formed from the hydrolysis of ethyl propionate.
Based on the available information, it is reasonable to assume that 100% of the ethyl propionate, or its hydrolysis products, will gain systemic circulation by the oral route of administration.
Although the test item can be expected to be well absorbed by the oral route, in the absence of experimental absorption data, default values are used in the derivation of DNELs according to REACH guidance R.8 page 19. For oral absorption this is 50%.

DERMAL
Based on the phys/chem properties, ethyl propionate is likely to be absorbed after dermal application. According to the ECHA Guidelines (2014) molecules with molecular weights of less than 500 g/mole are capable of migration through the skin into systemic circulation. In addition, both water and lipid solubility influences the potential for dermal penetration. These factors have been used in various models for predicting dermal penetration.
The US EPA model (2007) is one of the most widely applied. It utilizes molecular weight and partition coefficient to predict the dermal permeability coefficient according to the following;
log(Kp) = 0.71 log Pow – 0.0061 MW – 2.72

where Kp is expressed in cm/h

The log Pow is 1.31 and the molecular weight is 102.1 g/mol. The resulting dermal permeability coefficient, (Log Kp) is -2.4 cm/hr (Kp = 0.004 cm/hr).
This permeability coefficient can be used to estimate the amount of ethyl propionate absorbed when applied to the skin. The following equation utilizes the dermal permeability coefficient (Kp), the concentration of test substance in water (Cw), the surface area of exposed skin (SA) the exposure time (ET) and a liter to cm3 conversion factor (CF1) to calculate the absorbed dose rate (ADR).

ADR = Cw x SA x ET x Kp x CF1

Solubilization of the test substance is necessary for dermal penetration, even if the substance is applied as a solid. For this calculation, the limit of solubility in water is used. The maximum solubility of ethyl propionate in water is 19 g/L at 20°C at pH 4.5. Skin pH is 6.5, however it is reasonable to use the solubility number generated at pH 4.5 as a wost case scenario.. For the surface area 1 cm2 is used to generate a flux value that can be applied across a variety of applications with different surface area values.
For ethyl propionate the ADR is 0.076 mg/cm2/hr or 76 µg/cm2/hr. Thus, dermal exposure to ethyl propionate would be expected to result in systemic exposure. Ethyl propionate has been classified as a skin irritant and this might facilitate dermal penetration. However, once the parent ethyl propionate crosses the stratum cornea, the esterases present in epidermal cells (Jewell et al., 2007) would be expected to hydrolyze the parent to its corresponding alcohol and carboxylic acid.
Based on the available information it is reasonable to apply the rate of dermal absorption, 76 µg/cm2/hr, calculated by the flux model described above to estimate systemic exposures from dermal application of ethyl propionate.
Since there was no mortality from ethyl propionate in the dermal acute toxicity assay conducted, and no significant clinical observations, it is not possible to corroborate this conclusion with information generated from in vivo studies.
Although the test item can be expected to be absorbed by the dermal route, in the absence of experimental absorption data, default values are used in the derivation of DNELs according to REACH guidance R.8 page 19. For dermal absorption this is 50%.

INHALATION
Ethyl propionate is a liquid at room temperature with reasonable volatility. The vapor pressure of ethyl propionate is high (48 hPa at 20°C). If ethyl propionate were inhaled, absorption across the respiratory epithelium would be likely rapid based on its partition coefficient and small molecular weight. It is also reasonable to expect significant hydrolysis by esterases in the respiratory epithelium (Olson et al., 1993) which would generate ethanol and propionic acid as described for the oral and dermal routes of administration.
There are no reliable key studies available on the inhalational toxicity of ethyl propionate although an LT50 value of 32 minutes was calculated following the whole body exposure of rats to a near saturated vapour of ethyl propionate. Clinical signs and necropsy findings were localized to the respiratory system.
Although the test item can be expected to be absorbed by the inhalation route, in the absence of experimental absorption data, default values are used in the derivation of DNELs according to REACH guidance R.8 page 19. For inhalation absorption this is 100%.
Details on distribution in tissues:
The distribution of ethyl propionate has not been characterized. The systemic effects noted after dermal dosing are minimal and not specific enough to determine a distribution of absorbed ethyl propionate. However, as noted, by all routes of exposure, significant hydrolysis of ethyl propionate is expected forming ethanol and propionic acid. Both materials are expected to freely distribute systemically and enter intermediary metabolism in all tissues. Therefore, the distribution of ethanol and propionic acid would be proportional to organ blood flow. After administration by the oral route, the hydrolysis products would enter hepatic portal circulation resulting in distribution primary to the liver. Dermal absorption would result in general systemic exposure. By inhalation the distribution would also be expected to be more general as absorption by the lungs would result in distribution systemically via cardiac output.
Since the hydrolysis products of ethyl propionate enter into intermediary metabolism it is unlikely that either would bioaccumulate.
Details on excretion:
The excretion kinetics of ethyl propionate are dependent on the hydrolysis of the ester and the metabolic fate of the ethanol and propionic acid. For ethanol, the majority of the dose is expected to be metabolized and incorporated into endogenous metabolic pathways. The propionic acid may be excreted in urine, either as the free acid or conjugated with glucuronic acid. It may also be broken down and utilized nutritionally.
Details on metabolites:
The test item is expected to be rapidly and completly hydrolyzed to ethanol and propionic acid either before, or immediately after absorption by all routes of exposure. Both of these hydrolysis products become substrates for intermediary metabolism.

Ethanol (CAS 64-17-5): Ethanol is oxidized by alcohol and aldehyde dehydrogenases to eventually form acetyl CoA which joins the citric acid cycle / natural carbon pool to be converted into CO2, fatty acids, ketone bodies and cholesterol (Cederbaum, 2012).

Propionic acid (CAS 79-09-4): This straight chain carboxylic acid with three carbon units is a substrate for endogenous metabolism via the production of propionate CoA which is converted to malonate semialdehyde by hydroxy isobutyryl CoA deacylase and then transaminated to ß-alanine (Rendina and Coon, 1957 and Vagelos and Earl, 1959). It is suggested that these conversions may also be available to gut microflora, which would reduce systemic exposure to propionic acid.

Table 1 Physical/chemical properties of ethyl propionate and hydrolysis products relevant to toxicokinetics

Physicochemical endpoints

Ethyl propionate

Target

Ethanol*

Hydrolysis Product

Propionic acid*

Hydrolysis Product

CAS

105-37-3

64-17-5

79-09-4

EC

203-291-4

200-578-6

201-176-3

Molecular formula

C5H10O2

C2H6O

C3H6O2

Molecular weight

102.1

46.1

74.1

Physical state

liquid

liquid

liquid

Melting point (°C)

-73.7

-114

-21

Boiling point (°C)

99.3

78.4

141.1

Density (g/cm3)

0.89 @ 20 °C

0.79 @ 20 °C

0.99 @ 20 °C

Vapor pressure (hPa)

42.8 @ 20 °C

59.5 @ 20 °C

3.9 @ 20 °C

Water solubility (g/L)

19 @ 20° C pH 4.5

miscible

1000 @ 25° C

Partition coefficient log Kow

1.31

-0.18

0.33

*Information obtained from Pub Chem -https://pubchem.ncbi.nlm.nih.gov

Toxicokinetics

The kinetics of absorption, distribution, metabolism and excretion (ADME) of ethyl propionate have not been evaluated in vivo. As a result, this analysis of the basic toxicokinetics is a qualitative assessment based on phys/chem properties and available biological information on ethyl propionate and structurally-related analogs according to the guidance provided in the ECHA guidelines (ECHA, 2014). 

Since the target substance is a small aliphatic ester, it is subject to hydrolysis to the corresponding alcohol and carboxylic acid. For ethyl propionate these areethyl alcohol (ethanol, CAS 64-17-5) and propionic acid (CAS 79-09-4). The hydrolysis facilitates absorption, metabolism and excretion by generating smaller size molecules from the parent ester and is facilitated by esterases which are present in nearly every mammalian tissue (WHO, 1997; Jewellet al., 2010; Oslonet al.,1993).

Hydrolysis studies with artificial pancreatic juice demonstrated that compounds with similar structures such as ethyl caproate are rapidly hydrolyzed with a half-life (t½) of 3 minutes (Longlandet al.,1977). Thus, hydrolysis of ethyl propionate is predicted to result in a short residence time of intact ester in the gastrointestinal (GI) tract after ingestion. Because of the ubiquitous nature of esterases in the body, similar rates of hydrolysis would also be expected in other tissue compartments. Therefore by any route of administration, esterase-mediated hydrolysis would be likely.

Mode of Action

No mode of action for adverse effects has been developed for ethyl propionate. Studies available to date have not identified a target organ and no significant adverse effects have been noted by which a mode of action can be derived. In addition, there are no structural alerts with ethyl propionate or propionic acid products which could be used to hypothesize a mode of action. The metabolism of ethanol results in the formation reactive electrophiles such as acetaldehyde or reactive oxygen species (ROS), which can, in excess, result in adverse effects resulting from protein binding or cellular oxidative stress. This process is considered to be a key event in the development of alcohol–induced liver disease. The exposure to ethanol resulting from the use of ethyl propionate is unlikely to result in the levels these reactive species at concentrations necessary to to cause cellular injury.

Toxicodynamics

The biological effects of ethyl propionate are limited. As a result, no toxicodynamic effects have been described.

Mode of Action

No mode of action for adverse effects has been developed for ethyl propionate. Studies available to date have not identified a target organ and no significant adverse effects have been noted by which a mode of action can be derived. In addition, there are no structural alerts with ethyl propionate or propionic acid products which could be used to hypothesize a mode of action. The metabolism of ethanol results in the formation reactive electrophiles such as acetaldehyde or reactive oxygen species (ROS), which can, in excess, result in adverse effects resulting from protein binding or cellular oxidative stress. This process is considered to be a key event in the development of alcohol–induced liver disease. The exposure to ethanol resulting from the use of ethyl propionate is unlikely to result in the levels these reactive species at concentrations necessary to to cause cellular injury.

Toxicodynamics

The biological effects of ethyl propionate are limited. As a result, no toxicodynamic effects have been described.

Conclusions:
1. The test item can be assumed to be absorbable by the oral, dermal, and inhalation routes of exposure, however in the absence of experimental data, default absorption values are used in the derivation of DNELs, according to REACH guidance R.8 page 19.
2. The test item is rapidly and completely hydrolyzed to form ethanol and propionic acid.
3. Both ethanol and propionic acid are readily incorporated into intermediary metabolism.
4. There is no evidence of the formation of reactive or toxic metabolites from propionic acid and given the low potential exposure, ethanol intoxication is unlikely.
5. The test item is unlikely to bioaccumulate because of its extensive metabolism and rapid excretion.
Executive summary:

Ethyl propionate is a small aliphatic ester with a molecular weight of 102.1 g/mole. It is soluble in water (19.0 g/L at 20¿C, pH 4.4) with a partition coefficient (Log Pow) of 1.31 and a vapor pressure of 42.8 hPa at 20°C. With these physical/chemical (phys/chem) properties, oral, dermal and inhalation exposures are all potential routes of exposure.

The metabolism and excretion of a number of flavouring esters with a similar structure to ethyl propionate (such as ethyl butyrate) has been evaluated by the WHO Expert Committee on Food Additives in a review of food additives and contaminants (WHO 1997). These esters are readily hydrolyzed to ethyl alcohol (ethanol) and the corresponding aliphatic carboxylic acid. It is therefore expected that ethyl propionate will behave in the same way, giving rise to ethanol and propionic acid. Ethanol is oxidized by alcohol and aldehyde dehydrogenases to eventually form acetyl CoA which joins the natural carbon pool to be converted into CO2, fatty acids, ketone bodies and cholesterol (Cederbaum, 2012). Due to its size and water solubility propionic acid may be excreted directly in urine, conjugated with glucuronic acid and excreted in the urine, or be incorporated into intermediary metabolism and utilized nutritionallyviaamino acid metabolic pathways (Rendinaet al., 1956;Vageloset al., 1959).

The test item has limited chemical and biological reactivity and no defined mode of action for adverse effects. The oral LD50in rats is > 7,000 mg/kg and dermal LD50is > 2,000 mg/kg. The inhalational LT50following whole body exposure to a near saturated vapour was 32 minutes (Myers et al.,1992). It is not genotoxic, has no structural alerts for protein or DNA binding and no alerts for cancer. Ethyl propionate is classified as an eye and skin irritant based on in vitromodel studies. As a result, there is no basis for identifying analogs based on common systemic modes of action. Therefore, selection of analogs for read-across to predict toxicokinetics is based solely on structural similarity.

Description of key information

Ethyl propionate is a small aliphatic ester with a molecular weight of 102.1 g/mole. It is soluble in water (19.0 g/L at 20¿C, pH 4.4) with a partition coefficient (Log Pow) of 1.31 and a vapor pressure of 42 hPa at 20°C. With these physical/chemical (phys/chem) properties, oral, dermal and inhalation exposures are all potential routes of exposure.

1.       The test item can be assumed to be absorbable by the oral, dermal, and inhalation routes of exposure, however , in the absence of experimental data, default absorption values are used in the derivation of DNELs, according to REACH guidance R.8 page 19

2.       The test item is rapidly and completely hydrolyzed to form ethanol and propionic acid.  

3.       Both ethanol and propionic acid are readily incorporated into intermediary metabolism.

4.       There is no evidence of the formation of reactive or toxic metabolites from propionic acid and given the low potential exposure, ethanol intoxication is unlikely.  

5.       The test item is unlikely to bioaccumulate because of its extensive metabolism and rapid excretion.  

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information