4-methoxybenzyl alcohol

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1958

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Objective of study:

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test:
- Short description of test conditions: The test substance was administered to rabbits by stomach tube as suspension in water. Different metabolites were determined in urine. Mercapturic acids were determined by the modification of the method of Stekol (1936) described by Bray et al. (1956), and by a modification of the method of Grunert & Phillips (1951) for glutathione in blood. Mercapturic acid were determined by an EEL photoelectric colorimeter. The method of Bray et al. (1952) was used for determination of glycine conjugates.
- Parameters analysed / observed: mercapturic acids, glycine conjugates

GLP compliance:

no

Radiolabelling:

no

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

no details

Route of administration:

oral: gavage

Vehicle:

water

Duration and frequency of treatment / exposure:

single dose

Dose / conc.:

250 mg/kg bw (total dose)

Dose / conc.:

550 mg/kg bw (total dose)

Remarks:

Additional study with 6 rabbits.

No. of animals per sex per dose / concentration:

250.0 mg/kg: not specified
550.0 mg/kg: 6 rabbits

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Method type for identification/separation: EEL photoelectric colorimeter, paper chromatography

Type:

metabolism

Results:

2% mercapturic acid, 19% glycine conjugate, 49% copper-reducing material (as glucuronic acid) and 53% glucosiduronic acid, benzoic acid, hippuric acid

Type:

excretion

Results:

via urine

Details on excretion:

Metabolited were excreted via urine.

Metabolites identified:

yes

Details on metabolites:

Mercapturic acid, 19% glycine conjugate, 49% copper-reducing material (as glucuronic acid) and 53% glucosiduronic acid were found in urine. An additional study with 550 mg of anisyl alcohol given orally to 6 rabbits resulted in the urinary excretion of 15% of the dose as substituted benzoic acid and 5% of the dose as substituted hippuric acid.

Conclusions:

The test item is excreted via urine as mercapturic acid, glycine conjugate, copper-reducing material (as glucuronic acid) and glucosiduronic acid. Additionally, urinary excretion as substituted benzoic acid and as substituted hippuric acid was determined.

Executive summary:

Bray et al. (1958) investigated metabolites after a single dose of test substance in rabbits. Rabbits were orally exposed to 250 mg/kg bw and 550 mg/kg bw with the test substance. As a result 2% mercapturic acid, 19% glycine conjugate, 49% copper-reducing material (as glucuronic acid) and 53% glucosiduronic acid were detected in urine. An additional study with 550 mg of the test item given orally to 6 rabbits resulted in the urinary excretion of 15% of the dose as substituted benzoic acid and 5% of the dose as substituted hippuric acid.

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1972

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: The test substance were incubated with rat caecal extracts to investigate the metabolism of benzyl alcohol derivates.
- Short description of test conditions: The test substances (5-10 mg) in medium (10 mL) were incubated anaerobically at 37° for approx. 46 h with and without rat caecal extracts (1 mL). Afterwards, ether extraction was performed. Rf values and colour reactions were determined by thin-layer chromatography. Retention times of the compounds were determined by gas chromatography wiht a flame ionization detector. A GC-MS system was used for identification of metabolites.

GLP compliance:

no

Radiolabelling:

no

Remarks:

0.5 - 1 mg/mL

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: caecal rat extracts
- Method type for identification: GC-MS

Type:

metabolism

Results:

anisic acid

Metabolites identified:

yes

Details on metabolites:

anisic acid

Conclusions:

Metabolites identified after incubation of the test item with rat caecal extracts were anisic acid as well as the unchanged test substance.

Executive summary:

The test substance were incubated with rat caecal extracts to investigate the metabolism of benzyl alcohol derivates. Metabolites were identified by GC-MS. Both, the unchanged test substance as well as the metabolite anisic acid was identified.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Remarks:

Article in Japanese. Only the abstract and tables are available in english.

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

Sulfotransferase activities were examined in mouse liver and olfactory fractions.

GLP compliance:

no

Type:

metabolism

Results:

Sulfotransferase activity towards the test item is minimal in mouse liver and olfactory cytosolic fractions.

Metabolites identified:

not specified

Conclusions:

Sulfotransferase activity towards the test item is minimal in mouse liver and olfactory cytosolic fractions.

Executive summary:

Sulfotransferase activity towards the test item is minimal in mouse liver and olfactory cytosolic fractions.

Reference 4

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

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Details on test animals or test system and environmental conditions:

not applicable

Details on exposure:

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. 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.

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.

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 5

Endpoint:

dermal absorption, other

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

supporting study

Study period:

1995

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Qualifier:

no guideline followed

Principles of method if other than guideline:

Potts and Guy fitted an equation to the experimental permeation coefficients (Kp) of a variety of molecular structures through human skin. This equation was based on molecular weight (MW) and the octanolwater partition coefficient (log P).
To identify a mathematical model predictive of the mostly unexplored skin penetration of fragrance chemicals, the Potts-Guy equation was tested here by correlating the published, measured Kp for 20 such compounds with predicted Kp values.

GLP compliance:

no

Key result

Parameter:

rate

Absorption:

0.002 cm/h

Conclusions:

In this publication an experimental permeability coefficient (Kp) of 1.65E-3 cm/h available from literature is indicated.

Executive summary:

In this study the validity of the Pott-Guy algorithm was tested. Therefore, a experimental permeability coefficient determined with human skin under steady state conditions from aqueous solution is available from literature and indicated in this study. The Kp value of the test item is 1.65E-3 cm/h.

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 to yellowish liquid at room temperature with a molecular weight of 138.16 g/mol. The substance is soluble in water (37.2 g/L at 20 °C). The log Pow was determined to be 1.05. The test substance has a low vapour pressure of 0.53 Pa at 20 °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 Pow 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.

 

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 1.05, 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 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 substance showed no higher toxicity compared to the parent compound.

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.

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.