2-phenylethanol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non guideline, GLP animal experimental study, available as published report, fully adequate for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Materials and methods

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Phenylethyl alcohol

IUPAC Name:

Phenylethyl alcohol

Radiolabelling:

yes

Remarks:

14-C-2-phenylethanol

Test animals

Species:

human

Sex:

male

Details on test animals or test system and environmental conditions:

TEST HUMAN
- Subject: normal healthy males volunteers
- Age: 37 and 27 years
- Housing: Institute of Clinical Pharmacology for 12 hrs preceding administration of 14C-2-phenylethanol and for 5 days after.
- Fasting period: 12 hrs prior to administration of the dose

Administration / exposure

Route of administration:

dermal

Details on exposure:

TEST SITE
- Area of exposure: The dose was transferred to an area of 100cm2 marked on the skin of the upper chest, excluding the nipples.
- % coverage: 100%
- Type of wrap if used: After 1 hr the area of treated skin was occluded with a light gauze dressing held in place with an adhesive strapping

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At 6 hrs after administration the dressing was removed and retained. The treated area was wiped with cotton wool swabs moistened with ethanol.
- Time after start of exposure:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Nominal dose level: 0.1 mg/cm2; solution of 14C-2-phenylethanol (10 mg) in ethanol (1 ml)

Duration and frequency of treatment / exposure:

6 hr

Doses / concentrations

Remarks:

Doses / Concentrations:
Nominal dose level: 0.1 mg/cm2 in ethanolic solution

No. of animals per sex per dose / concentration:

2 male human volonteers

Details on dosing and sampling:

Dosage
The subjects were fasted for 12 hr prior to administration of the dose. A solution of 10 mg of 14C-2-phenylethanol in 1 ml of ethanol. was used to prepare each dose. The dose was transferred to an area of 100 cm2 marked on the skin of the upper chest (nipples excluded).
After 1 hr the treated area was occluded with a light gauze dressing held in place with Sleek adhesive strapping (Smith and Nephew Ltd., Hull, U.K.). The treated area was wiped with cotton wool swab and then washed with cotton wool swabs moistened with ethanol. These dose washing were retained for analysis. A portion of 2x5 cm was stripped with 5 successive applications of adhesive tape and the strips retained for analysis.

Sample Collection
25 ml of blood samples were taken from an antecubital vein by venepuncture into heparinised tubes before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 and 120 hr after dosing.
Urine was collected during 0-3, 3-6, 6-12, 12-24, 24-48, 48-72, 72-96 and 96-120 hr after dosing. Faeces were collected at 24-hr intervals for 5 days.

Preparation samples and measurement of radioactivity.
Faeces samples were homogenised by maceration with methanol and radioactivity was measured in the methanol extracts and insoluble residues. Dose washing and dressing were extracted with ethanol and twice with methanol. Urine samples, plasma and other liquid were mixed with scintillation cocktail MI 31 (Packard Instrument Company), for measurement of radioactivity.
Faeces and blood samples were combusted in oxygen and the products were measured for radioactivity. The recoveries for the sample oxidisers exceeded 95%. Measurements were corrected for oxidiser efficiency.
Radioactivity was measured with a Philips Automatic Scintillation Analyser with automatic standard quench correction

Results and discussion

Main ADME results

Type:

excretion

Results:

A mean of 7.55% dose was excreted in the urine

Toxicokinetic / pharmacokinetic studies

Details on absorption:

During 5 days after topical application of the radioactive compound, a mean of 7.55 dose was absorbed through the skin and excreted in the urine. The excretion data indicate that any absorption of 14C-2-phenylethanol from the skin took place during the first 4 hr after the dose application during which time most of the dose was probably lost by evaporation.

Details on distribution in tissues:

Concentrations of radioactivity in plasma and whole-blood
0.25, 0.5, 0.75 and 1 hr after application, the mean concentration of radioactivity in plasma were 3.5, 5.9, 9.5 and 12.0 ng/ml, respectively reaching the pick level of 13.8 ng/ml at 1.5 hr. After 2 hrs the concentration declined to 11.7 ng/ml and after 4 hr declined to 3.1 ng/ml. Mean concentrations of radioactivity in plasma were below the limit of accurate measurements (3.0 ng/ml) at 6 hr and later sampling times. Mean concentrations of radioactivity in whole-blood were below the limit of accurate measurement 57-15 ng/ml.

Details on excretion:

Excretion of radioactivity
During 5 days after topical application of the 14C-2-phenylethanol, a mean of 7.55% dose measured as the total detected in urine and faeces was absorbed through the skin. Radioactivity was below the limit of accurate measurement in the faeces at all sampling times and in the urine at all times after 48 hr. Most of radioactivity was excreted in urine during 12 hr after application (mean of 33.34, 2.44, 1.61% dose being detected in urine collected during 0-3, 3-6, 6-12 hr, respectively. Means of 2.60 and 0.64% dose were detected in the gauze dressing and the 6-hr treated skin washing respectively. A total mean of 10.79% dose was recovered from urine dressing and treated skin washings.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Detection components in urine
The major metabolite detected (4.1% dose) was similar to the glutamine conjugate of phenylacetic acid. The second metabolite (2.7% dose was a glucuronide or ethereal sulphate conjugate which on acid-hydrolysis (but not on enzymic- hydrolysis) yielded a compound chromatographically similar to phenylacetic acid. The initial stage of the biotransformation seemed to appear similar to those observed in rats. In the rat, phenylacetic acid was detoxified by conjugation with glycine and in humans with L-glutamine. In humans phenylacetic acid is further biotransformed and conjugated to a second unidentified metabolite.

Applicant's summary and conclusion

Conclusions:

Phenyl ethyl alcohol was rapidly absorbed from the skin and eliminated from the urine during a 6-hr exposure. During 5 days after topical application of the 14C-2-phenylethanol, a mean of 7.55% dose measured as the total detected in urine and faeces was absorbed through the skin. The major metabolite was similar to the glutamine conjugate of phenylacetic acid and the second was a glucoronide or ethereal sulphate conjugate which on acid-hydrolysis yielded a compound chromatographically similar to phenylacetic acid. Results indicated that most of the dose (ca. 90%) was lost from the surface of the skin due to evaporation.

Executive summary:

In this study, the adsorption and disposition of Phenyl ethyl alcohol was investigated in 2 male human volunteers after topical application of the 14C-2-phenylethanol at a nominal dose level of 0.1 mg/cm2 in ethanolic solution. After an exposure period of 6 hr the dose was washed from the area of application. Radioactivity was detected in the urine only during 48 hr after application. The test substance was rapidly absorbed and excreted during the first 4 hr reaching the peak of 13.8% ng/ml at 1.5 hrs. During 5 days after topical application of the 14C-2-phenylethanol, a mean of 7.55% dose measured as the total detected in urine and faeces was absorbed through the skin.

Radioactivity was below the limit of accurate measurement in the faeces at all sampling times and in the urine at all times after 48 hr. Most of radioactivity was excreted in urine during 12 hr after application (mean of 3.34, 2.44, 1.61% dose being detected in urine collected during 0-3, 3-6, 6-12 hr, respectively. Means of 2.60 and 0.64% dose were detected in the gauze dressing and the 6-hr treated skin washing respectively. A total mean of 10.79% dose was recovered from urine dressing and treated skin washings. The major metabolite detected was identical to phenylacetylglutamine (dose 4.1%) and the second (dose 2.7%) was present in urine as a conjugate (glucoronide or ethereal sulphate). The subjects did not experience any adverse effects or reaction due to the test material or vehicle. These results indicated that most of the dose (ca. 90%) was lost from the surface of the skin due to evaporation.