3-phenylpropan-1-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from similar mixture/product

Adequacy of study:

key study

Study period:

01/02/2021 - 15/02/2021

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

The present expert opinion is based on the well-accepted hypothesis that substances of structural and constitutional similarity also have similar toxicological and toxicokinetic properties. The analysis is further based on the strong dependence of the toxicokinetic behavior on the physicochemical properties of the compounds. Supporting information in form of acute oral and dermal toxicity results is also used. While there is very limited experimental data available on the toxicokinetic behavior of 3-phenylpropan-1 itself, the compound belongs to the large family of
cinnamyl alcohol derivatives, some representatives of which have been studied extensively. Cinnamyl alcohol and a shorter alkyl-chain saturated phenyl alkyl alcohol were selected as source compounds.

As mentioned above, the toxicokinetc profile of a compound is strongly related to the physicochemical properties of that compound. In particular, the aqueous solubility, partition coefficients, molecular weight, pKa and vapor pressure are key factors determining the uptake, the distribution and overall fate of a substance in an organism. Consequently, the following parameters need to be considered when evaluating the toxicokinetics of 3-phenylpropan-1-ol:
Physical state: liquid (at 20°C and 1 atm);
Boiling point: 236-238°C at 1 atm;
Vapor pressure: 25 Pa at 20°C, 35 Pa at 25°C and 143 Pa at 50°C (OECD TG 104)
Water solubility: 7,80 g/L at 20 °C (OECD TG 105);
Octanol-water partition coefficient: 1.6 (at 35°C, OECD TG 117)
Molecular weight: 136.19 g/mol

Purity and impurities
The source and target compounds can be considered to be of similar purity, as these compounds can be obtained with similar purity at similar cost/effort. Neither the source nor the target compounds contained impurities relevant to the classification.

Structural similarity
The source and target compounds can be considered structurally rather similar, as they are all phenyl-alkyl primary alcohols. Source 1 differs from target by a -CH2- group in the alkyl chain, while Source 2 has the same number of carbons in the chain but introduces an unsaturated function in form of a double bond. The molecular weight of all compounds considered is very close to each other.

Physicochemical similarity
Most of the physicochemical properties of the source and target compounds are close to each other. All of the substances are polar water-soluble liquids at relevant temperatures. The aqueous solubility of the target compound falls in-between the source compounds.

Toxicokinetic data/assessments
The toxicokinetic behavior of Source 1 and Source 2 were based on in vivo assessments. The results agree with each other and with other data available on the wider cinnamyl alcohol derivate group of compounds. Namely, these compounds are readily absorbed and become bioavailable, followed by rapid metabolism and fast and complete excretion primarily via urine.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-phenylpropan-1-ol

EC Number:

204-587-6

EC Name:

3-phenylpropan-1-ol

Cas Number:

122-97-4

Molecular formula:

C9H12O

IUPAC Name:

3-phenylpropan-1-ol

Test material form:

liquid

Radiolabelling:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

The target compound is likely to become easily bioavailable after entrance through oral or dermal route. Absorption via inhalation route is also possible. The absorption via dermal route is supported by the classification as corrosive to skin.

Main ADME results 2

Type:

distribution

Results:

Rapid uptake and high bioavailability support the distribution of 3-phenylpropan-1- ol throughout the systemic circulation, as it will be transported by aqueous body-fluids.

Main ADME results 3

Type:

metabolism

Results:

The compounds are metabolized to the respective carboxylic acids, followed by fast and complete excretion primarily in urine.

Main ADME results 4

Type:

excretion

Results:

After metabolism yielding primarily benzoic acid, the metabolites of 3- phenylpropan-1-ol will be rapidly and completely excreted, primarily in urine in form of hippuric acid.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The absorption benefits from the low molecular weight and high aqueous solubility. The low logKow value indicates suitability for passive diffusion. Therefore, the target compound is likely to become easily bioavailable after entrance through oral or dermal route. Absorption via inhalation route is also possible. The bioavailability is supported by acute oral toxicity test results of 2500 < LD50 < 5000 mg/kg bw. For a clear dose dependence to occur at this range, the bioavailability must be significant. The absorption via dermal route is supported by the classification of the target compound as corrosive to skin.

Details on distribution in tissues:

Rapid uptake and high bioavailability support the distribution of 3-phenylpropan-1-ol throughout the systemic circulation, as it will be transported by aqueous body-fluids. There is no accumulation potential for either the target compound or any of its metabolites.

Details on excretion:

After metabolism yielding primarily benzoic acid, the metabolites of 3-phenylpropan-1-ol will be rapidly and completely excreted, primarily in urine in form of hippuric acid.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The aromatic primary alcohols (and aldehydes) in the cinnamyl alcohol group are readily oxidized to the respective carboxylic acids - 3-phenylpropanoic acid in case of 3-phenylpropan-1-ol in the mitochondrial beta oxidation pathway In animals, most carboxylic acids, such as cinnamic acid, are converted to acyl coenzyme A esters. The metabolic end product of several steps of conjugation and oxidation are hippuric acid or benzoic acid, which get excreted rapidly7 as conjugates or free acids.

Applicant's summary and conclusion

Conclusions:

The structural similarities between the source and the target substances, the general agreement of the dependence of the toxicokinetic behavior on the physico-chemical properties and the support of acute toxicity tests support the read-across hypothesis and the analysis. Adequate, reliable and available scientific information indicates that the source and target substances have similar toxicokinetic profiles. These, relatively small polar organic molecules undergo rapid absorption either via oral, dermal or inhalation route, making them readily bioavailable. The compounds are metabolized to the respective carboxylic acids, followed by fast and complete excretion primarily in urine. There is no potential for bioaccumulation, neither for the target compound nor for any of the metabolites.

Executive summary:

The structural similarities between the source and the target substances, the general agreement of the dependence of the toxicokinetic behavior on the physico-chemical properties and the support of acute toxicity tests support the read-across hypothesis and the analysis. Adequate, reliable and available scientific information indicates that the source and target substances have similar toxicokinetic profiles. These, relatively small polar organic molecules undergo rapid absorption either via oral, dermal or inhalation route, making them readily bioavailable. The compounds are metabolized to the respective carboxylic acids, followed by fast and complete excretion primarily in urine. There is no potential for bioaccumulation, neither for the target compound nor for any of the metabolites.