Benzene, (1-methylethyl)-, oxidized, polyphenyl residues

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study is comparable to OECD Guideline 417 with acceptable restrictions (different routes of exposure but only one dose level studied; partly limited documentation, e.g. fasting period; expiration not measured as a possible route of elimination [minor restriction, no main route of elimination])

Data source

Reference

Reference Type:

publication

Title:

Disposition of phenol in rat after oral, dermal, intravenous, and intratracheal administration

Author:

Hughes MF, Hall LL

Year:

1995

Bibliographic source:

Xenobiotica 25: 873-883

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

[only one (low) dose tested]

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Phenol

EC Number:

203-632-7

EC Name:

Phenol

Cas Number:

108-95-2

Molecular formula:

C6H6O

IUPAC Name:

phenol

Details on test material:

Uniformly 14C-ring labelled phenol (specific activity 100 µCi/µmol)
Radiochemical purity > 98% determined by radiochromatography
Source: Moravek Biochemicals (Brea, CA, USA)
No further data

Radiolabelling:

yes

Remarks:

14C-phenol

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, NC, USA)
- Age at study initiation: 96 +- 2 days old
- Weight at study initiation: 168 to 189 g
- Fasting period before study: no data
- Housing: after dosing rats were housed in metabolism cages
- Individual metabolism cages: yes
- Diet & water ad libitum
- Acclimation period: The animals were placed in metabolism cages 24 h before dosing


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-27
- Humidity (%): 40-60
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

other: oral, dermal, intratracheal and intravenous

Vehicle:

other: see details on exposure

Details on exposure:

Rats used for dermal exposure were anaesthetized 24 h before treatment and hair on the dorsal skin surface removed with an electric clipper; animals received then a collar (for acclimatization). Animals were dosed with 0.033 mg 14C-phenol/kg bw via oral, dermal, intratracheal or intravenous routes.
- Oral: via gavage, phenol in 1 ml Emulphor/ethanoJ/water (1/1/3)
- i.v.: rats placed in a nose cone bag and administered phenol in 0.2 ml Emulphor/ethanol/water (1/1/3) via the tail vein
- intratracheal: rats anaesthetized with halothane and administered phenol in 0.2 ml Emulphor/ethanol/water (1/1/3), followed by a bolus of air (0.2 ml) to ensure
consistent delivery to the lung
- dermal: rats anaesthetized by ether and phenol applied on a marked skin area of 2.57 cm²; plastic blister glued over the treated skin with cyanoacrylate adhesive

Duration and frequency of treatment / exposure:

single application, duration 72 h (study terminated, animals sacrificed)

Doses / concentrations

Remarks:

Doses / Concentrations:
0.033 mg/kg bw in all experiments

No. of animals per sex per dose / concentration:

3-4 females

Control animals:

no

Positive control reference chemical:

no

Details on study design:

After dosing rats returned to the metabolism cages; urine collected at 4, 8, 12, 24, 48 and 72 h and faeces at 24, 48 and 72 h; samples weighed after collection and stored at - 70°C until analysed. Urine (0,1 ml) analysed for radioactivity in the scintillation counter. Faeces air-dried, weighed, pulverized, and 200-300 mg of the pulverized faeces combusted in the oxidizer and also analysed for radioactivity. Aliquots of the 4 and 8-h urine were directly analysed by HPLC methods (metabolites measured).
At 72 h post-exposure, the orally, intravenously, and intratracheally treated animals sacrificed (cardiac puncture) and tissues removed [liver, kidney, trachea, Iung, skin, muscle (vastus lateralis), epididymal fat, stomach, small intestine, large intestine (including caecum) and the contents of the last three tissues]. Tissues weighed, combusted and analysed for radioactivity; carcasses homogenized, combusted and also analysed for radioactivity.

Dermally treated animals anaesthetized and a piece of untreated skin removed (dorsal side); plastic blister cut with a razor blade and the treated skin washed with 3x1 ml of soap/water mixture, followed by 1x 1 ml water and dried; wash samples analysed for radioactivity; the treated skin was then removed from the animal and rat sacrificed (cardiac puncture), tissues collected as described above. Radioactivity detected in the skin washes and treated skin added to the recovered dose; radioactivity in blisters 2.5% (not in recovered dose).

Details on dosing and sampling:

see study design

Statistics:

No data

Results and discussion

Preliminary studies:

No data

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Data on excretion profile suggested rapid and extensive absorption after oral, intratracheal and dermal application. Slightly reduced absorption rates were detected after dermal application: ca. 80% of the applied dose.

Details on distribution in tissues:

Phenol was distributed throughout the body. At termination (post exposure duration 72 h) only 1-5% of the recovered dose remained in the body by the four routes.

Details on excretion:

The urinary excretion profile of radioactivity was similar in rats receiving phenol by intravenous, oral and intratracheal route; 70-85% of the recovered dose was excreted in urine 4h after administration and urinary elimination was essentially complete by 12 h; after 72 h totally 95% of the applied dose were excreted via urine and only 1-3% were excreted via faeces. After dermal exposure 75% of applied radioactivity was excreted via urine and 3% in faeces within 72 h.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Main metabolite excreted in urine was phenyl sulphate; smaller amounts were excreted as phenyl glucuronide.

Any other information on results incl. tables

Distribution

At termination (post exposure duration 72 h) only 1-5% of the recovered dose remained in the body by the four routes. The highest percentage of the recovered dose was detected in the carcass and the large intestinal contents (see Table below) in the orally, dermally, and intravenously treated animals. The lung of the intratracheally treated animals also had a higher percentage of the recovered dose than the lungs of the other animals. The percentage of recovered dose in other organs (not presented in the Table) was <0.1%.

Excretion

The urinary excretion profile of radioactivity was similar in rats receiving phenol by intravenous, oral and intratracheal route. Urinary excretion of radioactivity was extensive by 4 h post-exposure in the orally, intratracheaIly, and i.v. treated animals: 70-85% of the recovered dose was excreted in urine 4h after administration and urinary elimination was essentially complete by 12 h; after 72 h totally 95% of the applied dose were excreted via urine by intravenous, oral and intratracheal route and only 1-3% were excreted via faeces. Dermal exposure: only 40% of the recovered dose was excreted in urine by 4 h and 70% by 12 h; urinary elimination of radioactivity after dermal exposure was essentially complete by 24 h; after 72 h totally 75% of applied radioactivity was detected in urine and 3% in faeces; washing the dermal site 72 h post-exposure removed 14% of the dose, 2% of the dose were detected in the skin. In comparison to excretion via urine faecal elimination was considerably lower independent on the route of application.

Metabolites

In HPLC analysis (4 and 8 h samples) only two peaks were observed. Percentage of the recovered dose of phenol excreted in urine by rats as phenyl sulphate (peak I), and phenyl glucuronide (peak II) by 8-h post-exposure after administration by the corresponding route is shown in the Table below.

Table 1

Percentage of the recovered dose of phenol excreted in urine by rat as phenyl sulphate

(peak I) and phenyl glucuronide (peak II) 8 h after administration of 0.033 mg/kg bw
14C-labelled phenol by various routes

Exposure route	phenyl sulphate	phenyl glucuronide
Oral	63.4 +- 2.3	26.8 +- 2.7
Dermal	48.4 +- 3.3	16.2 +- 3.4
Intratracheal	68.7 +- 2.6	19.4 +- 2·1
i.v.	72.6 +- 5.0	14.3 +- 0.9
mean +- SD of 3-4 animals

Table 2

Percentage of the recovered dose in the tissues of rats 72 h after application by various routes

Tissue	Oral	Intratracheal	Dermal	i.v.
Contents large intestine	0.14	2.8	0.28	0.21
Lung	0.001	0.13	0.002	0.006
Untreated skin	0.072	0.13	0.21	0.11
Carcass	0.75	1.5	0.98	2.2
mean +- SD of 3-4 animals; other organs < 0.1%

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: rapid absorption, conjugation and excretion after oral and dermal exposure
The oral, dermal, intratracheal, and i.v. exposure to phenol results in its rapid absorption, conjugation and elimination via urine.

Executive summary:

The study is comparable to OECD Guideline 417 with acceptable restrictions (different routes of exposure but only one dose level studied; partly limited documentation, e.g. fasting period; expiration not measured [minor restriction, no main route of elimination]).

Female F344 rats (n=3 -4 per group) received 0.03 mg/kg bw 14C-labelled phenol via oral, dermal, intratracheal, or i.v. administration. Radioactivity in urine and feaces was analysed after sampling in metabolism cages; the animals were sacrificed 72 h after application and radioactivity in organs, carcass and washings determined. Rapid and complete absorption of the administered radioactivity was found after oral and intratracheal exposure: 70-85% of the recovered dose was excreted in urine 4h after administration and urinary elimination was essentially complete by 12 h, after 72 h totally 95% of the applied dose were excreted via urine and only 1 -3% were excreted via faeces. Slightly reduced absorption rates were detected after dermal application: total amount of applied radioactivity excreted via urine was 75%, 3% were measured in faeces, 14% in skin washing at 72 h, 2% in the treated skin, and 2.5% in plastic blisters. The total dermal absorption rate was ca. 80% of the applied dose. Independent on the route of exposure low amounts (1 -5% of the recovered dose) retained in the rat 72 h after application. Phenol was distributed throughout the body. At a dose level of 0.033 mg/kg bw phenol was metabolized in rats to the sulphate (main metabolite) and glucuronide conjugates after absorption from the four routes of exposure.

Conclusion: The oral, dermal, intratracheal, and i.v. exposure to phenol results in its rapid absorption, conjugation and elimination via urine.