Benzyl propionate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

Type of information:

other: Expert Statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Details on test animals or test system and environmental conditions:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Remarks:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Details on absorption:

The likelihood of systemic absorption through the walls of the intestinal tract, into the skin and after inhalation depends on several physicochemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Kow need to be considered.

The smaller the molecule the more easily it may be taken after oral administration. Molecular weights below 500 are favourable for absorption. Additionally, moderate log Pow values (between -1 and 4) are favourable for absorption by passive diffusion. An adequate hydrophilicity of the substance should be given to dissolve into the gastrointestinal fluid and thus get in contact with the mucosal surface. Based on the physicochemical properties of substance (molecular weight: 164.2 g/mol, water solubility: 742 mg/L, log Pow: 2.4) absorption by passive diffusion through the epithelial barrier of the intestine is likely. This assumption is confirmed by the results of the oral acute toxicity study indicating systemic effects in test item treated rats such as lethargy, pilorection, tremors and chromodacryorrhea. Additionally, clinical signs (salivation) were detected after repeated treatment of rats via oral route with a test item concentration of 500 mg/kg bw/day in an OECD 422 study.

After dermal application, the compound must first penetrate into the stratum corneum which is the greatest barrier function against hydrophilic compounds. However, the substances must be sufficiently soluble in water to partition from the stratum corneum into the viable epidermis. If the water solubility is between 100 – 10000 mg/L absorption is anticipated to be moderate to high. Furthermore, dermal uptake is favoured for substances possessing a log Pow value between 1 and 4, particular if water solubility is high. Taken into account the log Pow values and water solubility of the test substance, dermal uptake into the stratum corneum followed by transfer into the viable epidermis is likely.

Considering the relatively low vapour pressure (< 0.5 kPa) and the resulting low volatility, exposure as vapour is very limited. However, absorption via inhalation is possible as absorption following ingestion did also occur. Liquids are able to readily dissolve into the mucus lining the respiratory tracts. Based on the log Pow value greater than 0, the substance have the potential to be absorbed directly across the respiratory tract epithelium.

Details on distribution in tissues:

As mentioned above, the physicochemical properties and toxicological data revealed that small amounts of the test substance can become systemically available following oral and dermal exposure. Additionally, absorption can be expected after exposure via inhalation. Once absorbed, the distribution of the test substance via blood stream can be assumed. In general, the smaller the molecule, the wider the distribution. Since the log Pow value is 2.4, distribution into cells is likely. Furthermore, accumulation within the body is not expected as the log Pow value is well below 4.

Details on excretion:

Due to the enhanced hydrophilicity, the conjugated metabolites are favorable for urinary excretion. Additionally, the test substance itself is most likely excreted via urine due to their small molecular weight (below 300 g/mol) and their water solubility.

Details on metabolites:

Biotransformation of benzylpropionate mainly occurs in the liver especially following oral intake. Biotransformation of a substance aimed to increase the hydrophilicity of lipophilic substances by Phase I (functionalization) and Phase II (conjugation) enzymes. benzylpropionate contains an ester group which will be primary hydrolytically cleaved by esterase in liver to propanoic acid and the corresponding alcohol benzyl alcohol. The formed acid and the corresponding alcohol could be glucuronised by the glucuronosyltransferase to enhance the hydrophilicity and to facilitate the elimination.
Formation of toxic metabolites is unlikely which is supported by the results of genotoxicity pre- and main experiments. It can be assumed that benzlpropionate is not enzymatically activated (toxified) during metabolism as the metabolic activated substance did not show higher cytotoxicity than the parent compound.

Conclusions:

Bioaccumulation of the test substanceis not considered critical based on expert statement.

Executive summary:

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 oral repeated dose study revealing some systemic effects. Bioaccumulation of the test substance is not to be expected after continuous exposure. Phase I and II metabolism within liver cells is likely and excretion will presumably occur after renal passage via urine.

Reference 2

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Penetration through excised human epidermis was measured using glass chamber followed by gas chromatography.

GLP compliance:

no

Radiolabelling:

no

Details on test animals or test system and environmental conditions:

Not applicable.

Details on in vitro test system (if applicable):

SKIN PREPARATION
- Source of skin: Human skin was excised from a cadaver during autopsy, kept at -20°C and thawed prior to examination.
- Type of skin: lower abdominal skin
- Preparative technique: Subcutaneous tissue was removed using Cooper's scissors. Epidermis was separated from dermis by a modification of Baumberger's method. Full thickness skin was placed dermis side down on a metal plate heated to 60°C, for a period of 10 minutes. The epidermis was separated from the dermis using forceps.

PRINCIPLES OF ASSAY
- Glass chamber: The upper surface of the epidermis was fixed to the lowest part of the glass tube, using adhesive. The glass tube was then placed inside one arm of the U-shaped glass Chamber. The glass tube was withdrawn from the other side of the U-shaped glass Chamber, and approximately 5 ml of saline was poured into the Chamber until it came into complete contact with the bottom of the epidermis. The glass tube was then replaced into the Chamber.

- Application of test samples: 0.2 mL of each test sample was applied to the top of the epidermis attached to the glass tube by using a micropipette. In order to avoid evaporation of the test sample, the mouth of the glass tube was covered with Parafilm (American Can Company).
The Chamber was kept in a thermostatically controlied cabinet (HAM-40 type, Seiwa Riko Company) at 21°C and 55% relative humidity for 72 hours.

- Measurements of penetration: Seventy-two hours after application of each test sample, the glass tube was removed. The saline from the U-shaped Chamber was poured into a test tube. The U-shaped Chamber and the bottom of the epidermis attached to the glass tube were both washed 3 times with saline which was also poured into the same test tube. The final volume in the test tube of both the original saline and that used for washing was approximately 10 mL. This saline was then poured into a 100 mL flask. 10 mL of saturated salt water and 25 mL of ether were added to the flask and mixed vigorously. The Compound was extracted in ether. Furthermore, an additional 25 mL of ether was added to the water fraction remaining after extraction, in order to insure complete extraction. The resultant 50 mL of ether, after the two extractions, was dehydrated by adding approximately 2 grams of anhydrous Na2SO4. In order to remove the anhydrous Na2SO4, the ether fraction was filtered with filter paper (Toyo Filter Paper No. 2) and then condensed to 1 mL of ether by using a Kderna-Danish condenser. 2 µL of the condensed sample was injected into a Shimazu GC-6A gas Chromatograph. The peak area on the gas chromatograms was compared with that of a Standard sample, in which the concentration of the material tested was known.

Absorption in different matrices:

- Skin preparation (in vitro test system): 0.392% (+/- 0.036%) of the test amount penetrated human epidermis

Conclusions:

As a result, 0.392% of the test amount penetrated human epidermis skin.

Executive summary:

Penetration through excised human epidermis skin of the test item was examined using a glass chamber system. An appropriate amount of test sample was applied for 72 hours to the top of the epidermis attached to the glass tube. The amount of the compound was determined by gas chromatography. As a result, 0.392% of the test amount penetrated human epidermis skin.

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 oral repeated dose study revealing some systemic effects. Bioaccumulation of the test substance is not to be expected after continuous exposure. Phase I and II metabolism within liver cells is likely and excretion will presumably occur after renal passage via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic Assessment

The test substance is a colourless liquid at 1013.25 hPa with a molecular weight of 164.2 g/mol. The water solubility of the test item was determined to be 742 mg/L at 20°C. The log Pow was determined to be 2.4 at 35°C. The test substance has a low vapour pressure of 0.12 hPa at 25 °C.

 

Absorption

The likelihood of systemic absorption through the walls of the intestinal tract, into the skin and after inhalation depends on several physicochemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Kow need to be considered.

 

The smaller the molecule the more easily it may be taken after oral administration. Molecular weights below 500 are favourable for absorption. Additionally, moderate log Pow values (between -1 and 4) are favourable for absorption by passive diffusion. An adequate hydrophilicity of the substance should be given to dissolve into the gastrointestinal fluid and thus get in contact with the mucosal surface. Based on the physicochemical properties of substance (molecular weight: 164.2 g/mol, water solubility: 742 mg/L, log Pow: 2.4) absorption by passive diffusion through the epithelial barrier of the intestine is likely. This assumption is confirmed by the results of the oral acute toxicity study indicating systemic effects in test item treated rats such as lethargy, pilorection, tremors and chromodacryorrhea. Additionally, clinical signs (salivation) were detected after repeated treatment of rats via oral route with a test item concentration of 500 mg/kg bw/day in an OECD 422 study.

 

After dermal application, the compound must first penetrate into the stratum corneum which is the greatest barrier function against hydrophilic compounds. However, the substances must be sufficiently soluble in water to partition from the stratum corneum into the viable epidermis. If the water solubility is between 100 – 10,000 mg/L absorption is anticipated to be moderate to high. Furthermore, dermal uptake is favoured for substances possessing a log Pow value between 1 and 4, particular if water solubility is high. Taken into account the log Pow values and water solubility of the test substance, dermal uptake into the stratum corneum followed by transfer into the viable epidermis is likely.

This assumption is supported a study measuring the penetration through excised human epidermis using glass chamber followed by gas chromatography. As a result, 0.392% of the test amount penetrated human epidermis skin.

 

Considering the relatively low vapour pressure (< 0.5 kPa) and the resulting low volatility, exposure as vapour is very limited. However, absorption via inhalation is possible as absorption following ingestion did also occur. Liquids are able to readily dissolve into the mucus lining the respiratory tracts. Based on the log Pow value greater than 0, the substance have the potential to be absorbed directly across the respiratory tract epithelium.

 

Distribution

As mentioned above, the physicochemical properties and toxicological data revealed that small amounts of the test substance can become systemically available following oral and dermal exposure. Additionally, absorption can be expected after exposure via inhalation. Once absorbed, the distribution of the test substance via blood stream can be assumed. In general, the smaller the molecule, the wider the distribution. Since the log Pow value is 2.4, distribution into cells is likely. Furthermore, accumulation within the body is not expected as the log Pow value is well below 4.

 

Metabolism and excretion

Biotransformation of benzylpropionate mainly occurs in the liver especially following oral intake. Biotransformation of a substance aimed to increase the hydrophilicity of lipophilic substances by Phase I (functionalization) and Phase II (conjugation) enzymes. benzylpropionate contains an ester group which will be primary hydrolytically cleaved by esterase in liver to propanoic acid and the corresponding alcohol benzyl alcohol. The formed acid and the corresponding alcohol could be glucuronised by the glucuronosyltransferase to enhance the hydrophilicity and to facilitate the elimination.

Formation of toxic metabolites is unlikely which is supported by the results of genotoxicity pre- and main experiments. It can be assumed that benzlpropionate is not enzymatically activated (toxified) during metabolism as the metabolic activated substance did not show higher cytotoxicity than the parent compound.

 

Due to the enhanced hydrophilicity, the conjugated metabolites are favorable for urinary excretion. Additionally, the test substance itself is most likely excreted via urine due to their small molecular weight (below 300 g/mol) and their water solubility.