3-phenylpropan-1-ol

Endpoint summary

Link to relevant study record(s)

Reference

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, only limited number of studies available

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

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:

Generally, oral absorption is favoured for molecular weights below 500 g/mol. 3-phenylpropan-1-ol has high water solubility and may, thus, dissolve in the gastrointestinal fluids, which facilitates uptake into the systemic circulation.
The low log Pow value of 3-phenylpropan-1-ol is favourable for passive diffusion. Taken together, the physico-chemical properties indicate that 3-phenylpropan-1-ol is likely to become bioavailable following the oral route. This assumption is confirmed by the results of the acute oral toxicity study in rats. The LD50 value was determined to be greater than 2500 mg/kg bw and smaller than 5000 mg/kg bw, as deaths occurred at this high dose level and clinical signs were also observed, proving the bioavailability of the substance. Treatment related effects observed in the combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening (OECD 422) further indicate oral absorption.

Due to the low vapour pressure of 3-phenylpropan-1-ol it is unlikely that the substance will be available as a vapour, but if it is the case, absorption via inhalation route is possible due to the water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Dermal absorption will also take place, favoured by the water solubility and the moderate log Pow value, as well as by the size of the molecule. Furthermore the substance is classified as corrosive to skin, thus degrading the skin barrier. At a dosage of 5000 mg/kg bw mortality occurred, also proving bioavailability after dermal exposure. A significant absorption through the skin was experimentally evidenced in an in vitro percutaneous absorption study with human skin (Diez-Salez et al., 1993) and in an in vitro study with rat skin (López at al., 1998). In human skin, the rate of penetration Kp was determined to be 52.35 ± 4.98 cm/h (3-phenylpropan-1-ol dissolved at a concentration to 75 % of its solubility in the medium). The same concentration tested on rat skin lead to a permeability coefficient of 60.07 ± 3.52 /h, with a saturated solution a Kp of 88.97 cm/h was reached. As a conclusion, as mentioned above, dermal absorption takes place.

Details on distribution in tissues:

As mentioned above, the physico-chemical properties of 3-phenylpropan-1-ol favour systemic absorption following oral, inhalation 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, 3-phenylpropan-1-ol will most likely be present in the aqueous body fluids.
3-phenylpropan-1-ol does not have an accumulative potential, and its metabolic pathway and excretion is presented below.

Details on excretion:

As mentioned above, 3-phenylpropan-1-ol will be excreted after metabolism to benzoic acid. Benzoic acid is undergoing phase II reactions, and, after mainly being conjugated to hippuric acid, rapidly excreted via urine (Abdo et al., 1985; IPCS & IOMC, 2000). Metabolism of 3-phenylpropionic acid to benzoic acid and subsequent excretion will be rapid and complete (Belsito et al., 2011).

Details on metabolites:

3-phenylpropan-1-ol is expected to be metabolized in the mitochondrial beta oxidation pathway. The alcohol will be oxidized to 3-phenylpropionic acid, which after activation through CoA will be further metabolized by beta oxidation and dehydration to cinnamoyl-CoA. After rapid oxidation to benzoic acid, the molecule is supposed to be conjugated and excreted via urine (Belsito et al., 2011).

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 (if exposure happens) route is expected. This assumption is further supported by the results of the oral and dermal acute toxicity studies, revealing some effects at very high doses. Bioaccumulation of 3-phenylpropan-1-ol or its breakdown product benzoic acid will not occur. Benzoic acid will be conjugated, mainly to hippuric acid, and rapidly excreted via the urine.

Description of key information

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the dermal, oral and inhalation (if exposure happens) route is expected. This assumption is further supported by the results of the oral and dermal acute toxicity studies, revealing some effects at very high doses. Bioaccumulation of 3-phenylpropan-1-ol or its breakdown product benzoic acid will not occur. Benzoic acid will be conjugated, mainly to hippuric acid, and rapidly excreted via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

3-phenylpropan-1-ol is a colourless liquid at room temperature with a molecular weight of 136.19 g/mol. Its water solubility is rather high (7799 mg/L). The substance has a low log P_owvalue of 1.6 and a vapour pressure of 25 Pa at 20 °C.

 

Absorption

 

Generally, oral absorption is favoured for molecular weights below 500 g/mol. 3-phenylpropan-1-ol has high water solubility and may, thus, dissolve in the gastrointestinal fluids, which facilitates uptake into the systemic circulation.

The low log P_owvalue of 3-phenylpropan-1-ol is favourable for passive diffusion. Taken together, the physico-chemical properties indicate that 3-phenylpropan-1-ol is likely to become bioavailable following the oral route. This assumption is confirmed by the results of the acute oral toxicity study in rats. The LD₅₀value was determined to be greater than 2500 mg/kg bw and smaller than 5000 mg/kg bw, as deaths occurred at this high dose level and clinical signs were also observed, proving the bioavailability of the substance. Treatment related effects observed in the combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening (OECD 422) further indicate oral absorption.

 

Due to the low vapour pressure of 3-phenylpropan-1-ol it is unlikely that the substance will be available as a vapour, but if it is the case, absorption via inhalation route is possible due to the water solubility and the moderate log P_owvalue, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

 

Dermal absorption will also take place, favoured by the water solubility and the moderate log P_owvalue, as well as by the size of the molecule. Furthermore the substance is classified as corrosive to skin, thus degrading the skin barrier. At a dosage of 5000 mg/kg bw mortality occurred, also proving bioavailability after dermal exposure. A significant absorption through the skin was experimentally evidenced in anin vitropercutaneous absorption study with human skin (Diez-Salez et al., 1993) and in anin vitrostudy with rat skin (López at al., 1998). In human skin, the rate of penetration K_pwas determined to be 52.35±4.98 cm/h (3-phenylpropan-1-ol dissolved at a concentration to 75 % of its solubility in the medium). The same concentration tested on rat skin lead to a permeability coefficient of 60.07±3.52 /h, with a saturated solution a K_pof 88.97 cm/h was reached. As a conclusion, as mentioned above, dermal absorption takes place.

 

Distribution

 

As mentioned above, the physico-chemical properties of 3-phenylpropan-1-ol favour systemic absorption following oral,inhalationand dermal uptake.

Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After being absorbed into the body, 3-phenylpropan-1-ol will most likely be present in the aqueous body fluids.

3-phenylpropan-1-ol does not have an accumulative potential, and its metabolic pathway and excretion is presented below.

 

Metabolism

 

3-phenylpropan-1-ol is expected to be metabolized in the mitochondrial beta oxidation pathway. The alcohol will be oxidized to 3-phenylpropionic acid, which after activation through CoA will be further metabolized by beta oxidation and dehydration to cinnamoyl-CoA. After rapid oxidation to benzoic acid, the molecule is supposed to be conjugated and excreted via urine (Belsito et al., 2011).

 

Excretion

 

As mentioned above, 3-phenylpropan-1-ol will be excreted after metabolism to benzoic acid. Benzoic acid is undergoing phase II reactions, and, after mainly being conjugated to hippuric acid, rapidly excreted via urine (Abdo et al., 1985; IPCS & IOMC, 2000). Metabolism of 3-phenylpropionic acid to benzoic acid and subsequent excretion will be rapid and complete (Belsito et al., 2011).