4-methoxybenzyl alcohol

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-methoxybenzyl alcohol

EC Number:

203-273-6

EC Name:

4-methoxybenzyl alcohol

Cas Number:

105-13-5

Molecular formula:

C8H10O2

IUPAC Name:

(4-methoxyphenyl)methanol

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Doses / concentrations

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

Results and discussion

Toxicokinetic / pharmacokinetic studies

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. 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 4-methoxybenzyl alcohol (molecular weight: 138.2 g/mol, water solubility: 37.2 g/L, log Pow: 1.05) absorption by passive diffusion through the epithelial barrier of the intestine is likely. This assumption is confirmed by the results of the repeated dose toxicity study and the corresponding dose range finding study. In those studies systemic effects were detected after treatment with 800 mg/kg bw/day for 2 weeks and developmental toxicity was induced in pups through oral treatment of the parental animals with 400 mg/kg bw /day.

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. 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 by the observed skin sensitization of the test item indicating dermal absorption. Additionally, signs of systemic toxicity were observed in rats treated with the target substance. The target substance is irritating to skin which may enhance the skin penetration.

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 1.05, 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:

Metabolites of 4-methoxybenzyl alcohol were determined in the urine of rabbits treated orally with the substance. 4-methoxybenzyl alcohol was excreted as ester-type glucosiduronic acid (50% of dose), 4-methoxyhippuric acid and 4-methoxybenzoic acid suggesting that glucoronidation but also conjugation with glycine occurred.

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.

Metabolite characterisation studies

Details on metabolites:

Biotransformation of 4-methoxybenzyl alcohol 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. Primary alcohols as 4-methoxybenzyl alcohol are preferably oxidized by the alcohol dehydrogenase (ADH) to the corresponding aldehyde. In a further step, the aldehyde dehydrogenase catalysed the oxidation of the intermediary formed aldehyde to the corresponding acid. Based on the results of the genotoxicity assays, it can be assumed that 4-methoxybenzyl alcohol is not enzymatically activated (toxified) during the metabolism as the metabolic activated substances showed no higher toxicity compared to the parent compound substance.
The alcohol or the metabolized acid could be glucuronised or sulfonated by the glucuronosyltransferase or sulfotransferase, respectively, to enhance the hydrophilicity and to facilitate the elimination. Glucuronidation could be the predominately Phase II reaction as sulfotransferase activity toward 4-methoxybenzyl alcohol was determined to be minimal in mouse liver.

Applicant's summary and conclusion

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.