3-hydroxy-p-anisaldehyde

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1974.

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 available

GLP compliance:

no

Radiolabelling:

no

Species:

rabbit

Strain:

other: albino

Sex:

male

Details on test animals or test system and environmental conditions:

- Weight range: 200-350g (250g for quantitative experiments).
- Diet: commercial pellet diet (Vestlandske Kjøpelag, Bergen) and switched to a purified diet consisting of sucrose, casein, soya oil, salts and vitamins (Scheline, 1968) 2 days before administration of the test compounds. Diet and water were given ad libitum.

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Remarks:

or water.

Details on exposure:

The test compounds were administered by stomach tube as a suspension in water for qualitative experiments, by stomach tube in a solution of propylene glycol-water (1: 1, 1ml) for quantitative experiments, and by intraperitoneal injection in a solution of propylene glycol-water (1 : 1, 0.5 ml).

Duration and frequency of treatment / exposure:

Single dose administration.

Dose / conc.:

100 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

12-19 males, same dose (see Table 1 in results).

Control animals:

no

Details on study design:

Urinary excretion was studied in rats receiving oral doses of 100mg/kg of isovanillin, and biliary excretion was studied in rats receiving intraperitoneal doses of 100mg/kg of these compounds.
The daily urine samples, after thawing and filtering, were diluted with water to 20 ml and divided into two equal portions. These were either used at once or stored at -20ºC until required.
Three procedures were used: (1) giving free and conjugated fractions, (2) giving a total fraction, (3) giving total acidic and phenolic fractions. The degree of recovery of the metabolites in comparison with that of the internal standard homoveratric acid when employing the appropriate extraction method was assessed. The various metabolites in the range 1-8 mg were added to control urines containing internal standard.

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: Urine and faeces were collected separately for 24h periods in containers maintained at <0ºC. Bile samples were collected for periods of up to 24h by inserting a thin plastic tube in the common bile duct as described previously (Scheline, 1968), except that the samples were collected at room temperature and that no food was given during the collection period. For quantitative experiments, bile collected for 5h was used, according to method (2).
- Method type(s) for identification: TLC, GLC and combined GLC-mass spectrometry.

Type:

metabolism

Results:

This study of the metabolism of vanillin and isovanillin in vivo in rats demonstrates that these aromatic aldehydes undergo two primary pathways of transformation, oxidation and reduction. The dominating pathway is the oxidative.

Type:

excretion

Results:

Rapid excretion via urine: 89% after 48h, most metabolites within the first 24h.

Details on excretion:

Most metabolites were excreted by urine within 24 h, and after 48 h, 89% of the dose of isovanillin was accounted for. Glucuronides of the aldehyde and their respective alcohol and acid derivatives are excreted in the bile (mainly during the first 3h after intraperitoneal dosing), and the conjugates are metabolized by the intestinal bacteria to toluene derivatives and decarboxylated products.

Metabolites identified:

yes

Details on metabolites:

After 48h: isovanillin (19%), isovanillyl alcohol (10%), isovanillic acid (22%), vanillic acid (11%), isovanilloylglycine (19%), catechol (7%) and 4-methylcatechol (1%). Protocatechuic acid was also formed (it could not be quantitated).

Table 1. Urinary excretion of isovanillin and metabolites in rats: urine collected for 48h after oral administration of 25mg (approx.. 100mg/kg) isovanillin/animal. Results are mean values, as % dose, ± S.D. with numbers of animals in parentheses.

 

Metabolite	Extraction method 2, TMS derivatives	Extraction method 2, diazomethane-treated	Approximate mean excretion values (%)
Isovanillin	Not determined	18.7 ± 3.5 (18)	19
Isovanillyl alcohol	11.8 ± 3.0 (17)	8.8 ± 2.2 (18)	10
Isovanillic acid	15.9 ± 2.4 (17)	27.0 ± 6.6 (19)	22
Vanillic acid	9.0 ± 3.4 (17)	12.0 ± 2.8 (19)	11
Isovanilloylglycine	Not determined.	19.0 ± 4.4 (19)	19
Catechol	6.7 ± 2.8 (12)	Not determined	7
4-methylcatechol	1.4 ± 0.6 (14)	Not determined	1
			Total = 89

 

Conclusions:

48h after oral administration, 89% of the administered test item had been excreted from urine, in the form of isovanillin (19%), isovanillyl alcohol (10%), isovanillic acid (22%), vanillic acid (11%), isovanilloylglycine (19%), catechol (7%), 4-methylcatechol (1%) and protocatechuic acid (it could not be quantitated). Therefore, the test item undergoes rapid elimination. Based on the available data, the test item shows no potential for bioaccumulation.

Executive summary:

The metabolism of orally administered isovanillin was studied in rats, following basic scientific principles (no GLP). The test item was administered to male albino rats by gavage, at a dose of 100 mg/kg bw. Urine and faeces were examined after 24h periods. Under test conditions, 89% of the administered isovanillin had been excreted from urine after 48h, in the form of isovanillin (19%), isovanillyl alcohol (10%), isovanillic acid (22%), vanillic acid (11%), isovanilloylglycine (19%), catechol (7%), 4-methylcatechol (1%) and protocatechuic acid (it could not be quantitated). Most of the metabolites were excreted during the first 24h. Therefore, the test item undergoes rapid elimination. Based on the available data, the test item shows no potential for bioaccumulation.

Description of key information

Key Study. 89% of the administered isovanillin had been excreted from urine after 48h, in the form of isovanillin (19%), isovanillyl alcohol (10%), isovanillic acid (22%), vanillic acid (11%), isovanilloylglycine (19%), catechol (7%), 4-methylcatechol (1%) and protocatechuic acid (it could not be quantitated). Most of the metabolites were excreted during the first 24h. Therefore, the test item undergoes rapid elimination. Based on the available data, the test item shows no potential for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Key Study. The metabolism of orally administered isovanillin was studied in rats, following basic scientific principles (no GLP). The test item was administered to male albino rats by gavage, at a dose of 100 mg/kg bw. Urine and faeces were examined after 24h periods. Under test conditions, 89% of the administered isovanillin had been excreted from urine after 48h, in the form of isovanillin (19%), isovanillyl alcohol (10%), isovanillic acid (22%), vanillic acid (11%), isovanilloylglycine (19%), catechol (7%), 4-methylcatechol (1%) and protocatechuic acid (it could not be quantitated). Most of the metabolites were excreted during the first 24h. Therefore, the test item undergoes rapid elimination. Based on the available data, the test item shows no potential for bioaccumulation.