2-phenylethanol

Endpoint summary

Description of key information

Pharmacokinetic of Phenyl ethyl alcohol following different routes was investigated in human and animals. After a single dermal doses of 14C- 2 phenylethanol to female CD rats at dose level of 0.14 and 0.7 ml/kg, means of 80.7% and 39%, respectively, were recovered from urine and faeces. The major metabolite is phenylacetic acid which is eliminated in urine as glycine and glucoronic acid conjugates.

Key value for chemical safety assessment

Absorption rate - dermal (%):

39

Additional information

Five studies investigated the toxicokinetic fate of Phenyl ethyl alcohol. The studies were conducted in human, rats, rabbits by different routes exposure.

In the study conducted by Huntingdon Research Centre (1987) 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 6hr of exposure period the dose was washed from the area of application. The results of the study showed that 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 hr. 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 phenylacetyl glutamine (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.

 

In a second study conducted by Huntingdon Research Centre (1987), the absorption, distribution and disposition of radioactive Phenyl ethyl alcohol was studied in male Long-Evans rats after single and repeated dermal application of the 14C-compound at dose level of 0.14 ml/kg.

Excretion and plasma concentrations data indicated that Phenyl ethyl alcohol is rapidly absorbed from the skin and rapidly eliminated in the urine after a single or repeated dermal application of 14C compound at dosage level of 0.14 and 0.7 ml/kg. After a single dermal doses of 14C- 2 phenylethanol to female CD rats at dose level of 0.14 and 0.7 ml/kg, means of 80.7% and 39.0% of the cumulative dose were recovered from urine and faeces, respectively. After 5 repeated dermal doses of 14C- 2 phenylethanol to female CD rats at dose level of 0.14 ml/kg, means of 68.6 and 1.1% of the cumulative dose were recovered from urine and faeces, respectively, during 216 hrs after the first dose. After 5 repeated dermal doses of 14C- 2 phenylethanol to female CD rats at dose level of 0.7 ml/kg, means of 40.2 and 0.6% of the cumulative dose were recovered from urine and faeces, respectively, during 216 hr after the first dose. The test substance was partially was lost in the dressing and due to evaporation. Radioactivity compound was detected in the bladder, Harderian gland, at the application site. Lower levels were found in the small intestine content, kidney, faecal contents, liver, blood, lung, uterus and nasal mucosa, intestine contents, liver, blood, lung, jawbone, ovary, uterus, eye and fur and mammary tissue. Radioactivity was detected in the foetuses of pregnant rats sacrificed at peak plasma concentration after 10 doses at both dose levels. The major metabolite corresponded to phenaceturic acid and accounted for about 80% of the urinary radioactivity. Some urinary radioactivity corresponded to hippuric acid and phenylacetic acid. Very little amount corresponded to Phenyl ethyl alcohol.

 

The absorption and disposition of Phenyl ethyl alcohol was investigated also in female New Zealand White rabbits after topical application of the 14 C- compound at dose level of 0.14 and 0.7 ml/kg (Huntingdon Research Centre, 1987). Excretion data, plasma concentration data and metabolic data indicated that Phenyl ethyl alcohol was rapidly and extensively absorbed, biotransformated and eliminated. Approximately half the dose was recovered at both dose levels, mainly from the urine. Most of the remaining dose was lost probably due to evaporation. The initial stage in the biotransformation of Phenyl ethyl alcohol in rabbits was similar to that in humans and rats in which the alcohol was oxided to phenylacetic acid. The biotransformation of phenylacetic acid in the rabbit followed the same pathway as that in the rat where the acid was conjugated with glycine forming phenaceturic acid rather than that in humans where the acid was conjugated with L-glutamine. In rabbit as in rats, traces of hippuric acid and conjugated Phenyl ethyl alcohol were detected.

 

In an extensive study conducted by Huntingdon Research Centre (1986), 76 female rats were treated with a single dermal dose of Phenyl ethyl alcohol at dosage level of 0.14 and 0.7 ml/kg. Gas chromatography/ mass techniques were used to determine the concentrations of phenylacetic acid (major metabolite of phenylethanol), which is eliminated in urine as glycine and glucuronic acid conjugates. The peak plasma concentration of 520 µg/ml was reached after 4 hrs and declined rapidly to 0.29 µg/ml at 24 hr after dosing. At concentration level of 1.4 ml phenylethanol, the peak plasma concentration was 671 µg/ml at 4 hr and declined rapidly to 0.48 µg/ml at 24 hr after dosing. After application of Phenyl ethyl alcohol at levels of 1.4 ml/kg and 0.7 ml/kg, in a ratio of 2.0, the mean peak plasma phenylacetic acid concentration ratio was 1.3, the man AUC ratio was 1.6 and the mean 24 hr post-dose plasma concentration ratio was 1.7. These ratios appear to be lower than those required for linearity of response with dosage level of parent compound. The rates of phenylacetic acid concentration decline appeared similar after application of phenylethanol at each dosage level; therefore the origin of the non-linearity may be dose- dependent dermal absorption of phenylethanol or dose-dependent formation of phenylacetic acid from absorbed precursor.

 

The last study described a comparison of the pharmacokinetics of phenylacetic acid and phenylethanol in the CD-1 rat following single dose administration via dermal application, oral gavage or in the diet (Huntingdon Research Centre, 1990).

Peak plasma concentrations of unchanged Phenyl ethyl alcohol were reached within 0.5 hr, on the average, following dermal application and oral administration (gavage) of 0.43 ml/kg. Plasma concentrations of Phenyl ethyl alcohol were higher after the dermal route compared to oral administration. Phenyl ethyl alcohol is eliminated by oxidative metabolism to the correspondent acid (phenylacetic acid), which is subsequently eliminated by the following parallel processes; renal excretion of unchanged phenylacetic acid, conjugation with glycine and formation of a glucuronic acid conjugate and subsequent renal elimination. Following oral administration (gavage or ad libitum ingestion), approximately 70% of the administered dose is eliminated via the renal route as phenylacetic acid or its conjugates within 24 hr. The lower proportion eliminated in the urine following dermal application is most probably related to a lower extent of percutaneous absorption relative to the oral route. After a single dermal application of 0.43 ml phenylethanol/kg, the mean concentration of phenylacetic acid in 0-24 hr urine was 2.77 mg/ml and the mean amount of phenylacetic acid excreted was 28.5 mg. After a single oral dose of 0.43 ml phenylethanol/kg, the mean concentration of phenylacetic acid in 0-24 hr urine was 73.5 mg. After ad libitum oral administration of 0.43 ml phenylethanol/kg, the mean concentration of phenylacetic acid in 0-24 hr urine was 4.67 mg/ml and the mean amount of phenylacetic acid excreted was 42.0 mg. Following a single oral dose of 0.43 ml/kg Phenyl ethyl alcohol by gavage, plasma concentration (AUC) of phenylacetic acid were markedly higher than those observed after a similar oral dose of Phenyl ethyl alcohol ingested over 24 hr in the diet. It appears that metabolic clearance of phenylacetic acid is reduced at higher plasma concentration due to capacity- limited metabolism in an analogous manner to that described for salicylic acid, i. e. the elimination of phenylacetic following oral and dermal doses appears to be characterised by both zero-order and first-order kinetics. The differences in AUC values of phenylacetic acid following equal dose of phenyl ethyl alcohol as oral gavage or in the diet is most probably due to a slower input of Phenyl ethyl alcohol following the diet, resulting in a lower phenylacetic plasma concentration profile and higher average clearance. Following increasing dermal doses of 0.43, 0.7 and 1.4 ml/kg phenylethanol, AUCs of both unchanged drug and phenylacetic acid tended to increase proportionally with dose and the terminal half-life of phenylethanol remained at ca. 5 hr irrespective of the applied dose.

 

The results of the studies underlined that Phenyl ethyl alcohol is rapidly absorbed (within 24 hr) and excreted in maximum 5 days. Phenyl ethyl alcohol is rapidly absorbed when administrated to rats by oral route, followed by gavage and, finally by dermal route. Part of the test material administrated by dermal route can be lost due to evaporation or dressing absorption. The major metabolite is phenylacetic acid which is eliminated in urine as glycine and glucoronic acid conjugates.