1-[(4-chlorophenyl)methyl]-1-cyclopentyl-3-phenylurea

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1982-02-03

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Objective of study:

absorption

distribution

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

See "Overall remarks" for more information

GLP compliance:

no

Remarks:

Older study, predates mandatory GLP

Test material

Test material information

Constituent 1

Reference substance name:

1-[(4-chlorophenyl)methyl]-1-cyclopentyl-3-phenylurea

EC Number:

266-096-3

EC Name:

1-[(4-chlorophenyl)methyl]-1-cyclopentyl-3-phenylurea

Cas Number:

66063-05-6

Molecular formula:

C19H21ClN2O

IUPAC Name:

1-[(4-chlorophenyl)methyl]-1-cyclopentyl-3-phenylurea

Radiolabelling:

yes

Test animals

Species:

other: rat and mouse

Strain:

other: rat: Fisher, and mouse: CD-1 (males only)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation:
Rats: ca. 150g (male) and ca. 125 g (female).
Mice (only males): ca. 25 g.
- Diet: ad libitum.
- Water: ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature: 24±2°C
- Fasting period: 16 hr

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: N,N-dimethylformamide in polyethylene glycol 400 (1:9 v/v)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Phenyl labeled 14C-pencycuron or carbonyl labeled 14C-pencycuron dissolved in 0.5 ml of N,N-dimethylformamide was diluted with 4.5 ml of polyethylene glycol 400 and a 5 ml of mixture solution per kilogram body weight (200 µCi/kg).

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Dose / conc.:

40 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

3/sex/dose/time point

Control animals:

no

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution)
- Tissues and body fluids sampled:
* Rats: liver, kidney, heart, lung, brain, spleen, pancreas, adrenal, thymus, right femoral muscle, abdominal fat and sexual organs (male: testis, female: uterus and ovary), and blood.
* Mice: blood cell, plasma, liver, kidney, lung, heart, brain, spleen, pancreas, adrenal, gall-bladder, muscle, adipose and testis.

- Time and frequency of sampling:
* Rats: 1, 3, 8, 24, 48, 72 and 144 or 168 hr after the oral administration.
* Mice: 2, 8, 24 and 72 hr after the oral administration.

- Analysis of tissues:
*Rats:
Blood was collected in a 10 ml glass centrifuge tube containing heparin and centrifuged at 2,000 xg for 5 min for separation of plasma and blood cell. The precipitate was washed with 0.9% sodium chloride centrifugally and the washing supernatant was combined with plasma. The total radiocarbon in tissues and blood preparations was analyzed by LSC after the combustion with a sample oxidizer of 100 to 500 mg homogenized tissue sample in triplicate. Digestive organs of stomach, small intestine and large intestine were collected from each animal.

Each digestive organs in rats were homogenized in a Waring blender with five volume of methanol. The methanol extracts after concentration were analyzed directly by Isc and remaining organs samples were analyzed by LSC after oxygen combustion.

*Mice:
The total radiocarbon in tissues of male mice were analyzed by LSC after the combustion with a sample oxidizer of 50 to 400 mg homogenized tissue samples in triplicate.

Results and discussion

Main ADME results

Type:

distribution

Results:

In rats, excluding the gastro-intestinal tract, concentration of radiolabel at any time-point was highest in the liver. As mice, in contrast to rats, do have a gall-bladder this organ was also included. It
showed by far the highest concentration.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

In male rats administered [14C-phenyl]pencycuron, total radiolabel in tissues and organs, excluding the gastro-intestinal tract, peaked three hours after administration at 1.8% of the administered radiolabel. Thereafter, it steadily declined to 0.09% seven days after administration. No such data were presented for other treated groups. No remarkable differences in distribution of radiolabel in male rats were found between administration 14C-phenyl- and 14C-carbonyl labelled pencycuron. For female rats only results of administration of 14C-carbonyl-labelled pencycuron were presented. Both in male and female rats the concentration of radiolabel in tissues and organs, excluding the gastro-intestinal tract, peaked between 3 to 8 hours after administration. Thereafter levels steadily declined. In rats, excluding the gastro-intestinal tract, concentration of radiolabel at any time-point was highest in the liver. For example, three days after administration, concentration of radioactivity in the liver was ca. 1.3 mg eq./kg, while in the other tissue, excluding the gastro-intestinal tract, concentrations were at least 2 times lower. Male mice showed similar patterns after oral administration of 14C-phenyl-labelled pencycuron. As mice, in contrast to rats, do have a gall-bladder this organ was also included. It showed by far the highest concentration of all tissues, with a residual peak 8 h after administration when it was ca. 85 times higher than in the liver.

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Conclusions:

Administration of carbonyl labeled 14C-pencycuron observed the excretion patterns approximately similar to those obtained with phenyl labeled chemical. Significant difference in the residual concentration of radiocarbon was not observed between male and female rats. No accumulation of 14C-pencycuron in the specific tissues of rat and mouse were presumed.

Executive summary:

Male and female rats and male mice were administered orally with phenyl labeled ¹⁴C-pencycuron [1-(p chlorobenzyl)-1-cyclopentyl-3-phenyl urea] at the dosage level of 40 mg/Kg and the absorption, the distribution and the residue levels in the tissues and organs studied. The administered ¹⁴C-pencycuron was readily absorbed and distributed into various tissues. The radiocarbon in tissues was found shortly after the administration; liver, kidney, lung, adrenal and adipose contain large amount of radiocarbon, while brain, muscle and testis might contain less amount of radiocarbon. The half lives of animal body were in order of 13-27 hr (rat) and 6-16 hr (mouse). In addition, administration of carbonyl labeled ¹⁴C-pencycuron observed the excretion patterns approximately similar to those obtained with phenyl labeled chemical. Significant difference in the residual concentration of radiocarbon was not observed between male and female rats. No accumulation of ¹⁴C-pencycuron in the specific tissues of rat and mouse were presumed. The high residue concentration observed in the gall-bladder of mouse was suggested to be due to active biliary excretion.