(2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Oct 1988 - May 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: EPA/FIFRA Guideline, Section 40 CFR 158.135, 85-2 and Section 40 CFR 795, Subpart D

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

(2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane

EC Number:

406-850-2

EC Name:

(2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane

Cas Number:

133855-98-8

Molecular formula:

C17 H13 Cl F N3 O

IUPAC Name:

1-{[(2R,3R)-3-(2-chlorophenyl)-2-(4-fluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, Ch-4414 Fuellinsdorf/Switzerland
- Age at study initiation: not specified
- Weight at study initiation: about 200-250 g
- Housing:groups of 2-3
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

occlusive

Vehicle:

methylcellulose

Duration of exposure:

max 10 h. (0.5, 1, 2, 4, 10 h)

Doses:

- 3 mg/kg bw
- 30 mg/kg bw

No. of animals per group:

4

Control animals:

no

Details on study design:

DOSE PREPARATION
- Method for preparation of dose suspensions: Preparation of two stock solutions. Respective aliquots were based on the intended dose levels of 3.0 mg/kg and 30.0 mg/kg. Assuming a rat body weight of 250 g, these quantities would correspond to 0.75 mg/15 cm² rat skin and 7.5 mg/15 cm² rat skin, respectively.
- Method of storage: Stock solutions stored at -20 degrees celsius

APPLICATION OF DOSE: about 800 µl per rat

TEST SITE
- Preparation of test site: shaved
- Area of exposure: back
- Treated area: 15 cm²
- Type of cover / wrap if used: occlusive (except for rats exposed to 0.5 h. They had no gauze or bandage)
- Time intervals for shavings or clipplings: adminsitration of test substance once

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: not specified

REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: after max 10 h
- Washing procedures and type of cleansing agent: yes, soap-solution and water
- Time after start of exposure: max 10 h
- Duration of recovery: 0.5, 1, 2, 4, 10, and 72 h after termination of the treatment

SAMPLE COLLECTION
- Collection of blood: yes
- Collection of urine and faeces: yes
- Collection of expired air: no
- Analysis of organs: yes; treated skin, liver, kidney, GIT (with contents), and residual carcass.

ANALYSIS
- Method type(s) for identification: Liquid scintillation counting, TLC,
- Liquid scintillation counting results (cpm) converted to dpm as follows: not applicable

Results and discussion

Signs and symptoms of toxicity:

no effects

Dermal irritation:

no effects

Absorption in different matrices:

At the low dose level, only small amounts of radioactivity were absorbed. Total absorbed radioactivity was similar at all time intervals and ranged from 5.82 % to 9.44%. The significant difference (0.01

Total excreted radioactivity up to 10 hours ranged from <0.01% (1 hour) to 0.21 % (10 hours). After 72 hours, total excreted radioactivity amounted to 3.17%. The increase was mainly due to an increase in fecal excretion (2.25 %) as compared to the amount of urinary excretion (0.84%) and cage-wash (0.08%).
The major part of the fecal radioactivity was excreted within the first 38 hours after the 10 hours dermal exposure period.
Except for 72 hours, the amount of radioactivity totally absorbed reflected mainly the amount of radioactivity remaining in the treated skin after skinwash and ranged from 4.80 % (4 hours) to 7.12 % (10 hours). After 72 hours, radioactivity in the treated skin was reduced to 2.02 %.
In liver, kidney, gastro—intestinal tract (with contents) and blood, only small amounts of radioactivity were found, ranging from (0.01% to 0.36 %. Only the residual carcass showed somewhat higher levels, ranging from 0.32 % to 1.51 %.

At a ten times higher dose level, total absorbed radioactivity ranged from 9.57 % to 20.06 % at all time intervals. As compared to the low dose level, only about 2 times higher amounts were absorbed from 2 to 72 hours. The significant difference (0.002

Total excreted radioactivity up to 10 hours ranged from <0.01 % (0.5 hours) to 0.13 % (10 hours). After 72 hours, totaT excreted radioactivity amounted to 5.76 %. Again, the increase was mainly due to an increase in fecal excretion (4.25 %) as compared to urinary excretion (1.22 %) and cage-wash (0.29 %).
The major part of fecal radioactivity was excreted within 38 hours after the 10 hours dermal exposure period, although still a sign1ficant amount (1.53 %) was excreted from 48 to 72 hours (Table 15).
Except for 72 hours, the amount of radioactivity totally absorbed reflected mainly the amount of radioactivity remaining in the treated skin after skinwash, ranging from 7.26 % to 18.21 %. From 10 hours to 72 hours, radioactivity in the treated skin was reduced from 16.08 % to 5.10 %. In liver, kidney, gastro-intestinal tract (with contents) and blood, only small amounts of radioactivity were found, ranging from (0.01 % to 0.79 %. Only the residual carcass showed somewhat higher levels, ranging from 1.09 %
to 2.34% .
In conclusion, at both dose levels only small amounts of radioactivity were absorbed during 10 hours of dermal exposure. The increased amount of radioactivity excreted and the simultaneously decrease of radioactivity in the treated skin from 10 to 72 hours, indicated that the test substance was further absorbed and eliminated after 10 hours of dermal exposure.

Total recovery:

Total mean recoveries for both dose levels at all time intervals ranged from 96.55% to 106.19%. The complete recoveries indicate that - except for the quantity absorbed - other routes of loss could be excluded.

Percutaneous absorption

Percutaneous absorption 1

Time point:

72 h

Dose:

3 mg/kg bw

Parameter:

percentage

Absorption:

>= 0.014 - <= 4.519 other: µg/g

Remarks on result:

other: Radioactivity level in plasma, blood, treated skin, liver, kidney, GIT, and residual carcass.

Percutaneous absorption 2

Time point:

72 h

Dose:

30 mg/kg bw

Parameter:

percentage

Absorption:

>= 0.12 - <= 129.64 other: µg/g

Remarks on result:

other: Radioactivity level in plasma, blood, treated skin, liver, kidney, GIT, and residual carcass.

Any other information on results incl. tables

In conclusion, at the dose level of 3.0 mg/kg, highest residual radioactivity levels were found at 10 hours of dermal exposure in treated skin, liver and gastro-intestinal tract. After 72 hours, except for blood, all radioactivity levels decreased. Accordingly, significant amounts of radioactivity were excreted via urine and feces from 10 to 72 hours.

In conclusion, at the dose level of 30.0 mg/kg, except for the 2-fold reduction of radioactivity levels in treated skin and residual carcass, all levels were higher at 72 hours as compared to 10 hours, indicating that elimination of radioactivity was not compIete at the last time interval. Accordingly, significant amounts of radioactivity were still excreted in urine and feces from 48 to 72 hours. Taking into account the about 5 times higher LOQ-values at the high dose at about 10 times higher dose levels, except for treated skin and gastro-intestinal tract with contents, maximal residual radioactivity levels in organs/tissues increased 6 to 14 times. In the blood, only a twofold increase was found.