3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione;famoxadone (ISO)

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: E91/414/EEC [Annex III, Point 7]

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: US EPA Pesticide Assessment Guidelines Subdivision F, Section 85-2

Deviations:

no

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

5-methyl-5-(4-phenoxyphenyl)-3-(phenylamino)-1,3-oxazolidine-2,4-dione

EC Number:

603-520-1

Cas Number:

131807-57-3

Molecular formula:

C22H18N2O4

IUPAC Name:

5-methyl-5-(4-phenoxyphenyl)-3-(phenylamino)-1,3-oxazolidine-2,4-dione

Test material form:

solid

Specific details on test material used for the study:

Substance name: [14C-U-phenoxyphenyl]DPX-JE874
Radiochemical purity: 98%
Specific activity: 61.8 µCi/mg

Substance name: DPX-JE874
Lot #: 352DE1 REF92
Purity: 99.6%

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

other: CRl:CD(SD)BR

Sex:

female

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

other: Acetone or deionized water

Duration of exposure:

8, 24, 48, 144 h

Doses:

10 (formulation concentrate), 0.75 (aqueous solution) mg/animal

No. of animals per group:

4

Control animals:

no

Results and discussion

Signs and symptoms of toxicity:

no effects

Remarks:

No overt pharmacological or toxicological signs were observed in the test animals which could have been attributed to the administration of [14C]test substance.

Total recovery:

An acceptable material balance (ca 87% of the dermally applied radioactivity, range 84 to 90% for all 4 sampling groups) was attained. The majority of the applied radioactivity was recovered in the back washes (>64% of the dermally applied radioactivity) at the 8 and 24 hours washing intervals, and from the washings of the bandages and protective appliances (5 to 18%). At the 24 h washing interval, only ca 5% of the applied radioactivity remained at the application site after washing. When test animals were sacrificed at the 72 and 168 h sampling intervals, only low levels of radioactivity (0.01 to 0.9%) were recovered from the second back wash and solubilised skin. Low levels of radioactivity were recovered in the excreta, surrounding skin area and remaining carcass. Negligible levels of 14C-residue were observed in the blood with values at, or close to the limit of detection. Approximately 4% of the applied radioactivity (mainly in the faeces) was recovered in the excreta, 168 h after treatment. This distribution data showed the limited in vivo dermal penetration of [14C]test substance after dermal application of DPX-MC444-11 formulation concentrate to female laboratory rats.

The overall distribution profile of the administered [14C]test substance radioactivity in this treatment group after exposure to a dilute aqueous solution of DPX-MC444-11 was similar to that observed with the undiluted concentrate formulation. An acceptable material balance (>85%) was attained. The majority of the applied radioactivity was recovered in the application site skin washes, bandages and protective appliance. Negligible levels of 14C-residue were observed in the blood with values at, or close to the limit of detection. Approximately 11% of the applied radioactivity remained at the application site after the 24 h washing interval, and was subsequently dissipated at the 72 and 168 h sacrifice intervals. Approximately 7% of the applied radioactivity was recovered in the combined excreta (mainly faeces), application skin site and remaining carcass, which further confirmed the limited dermal penetration of [14C]test substance in the diluted aqueous DPX-MC444-11 solution.

Percutaneous absorption

Percutaneous absorption 1

Key result

Time point:

8 h

Dose:

10 mg [14C]DPX-JE874 (formulation concentrate)

Parameter:

percentage

Absorption:

4.31 %

Percutaneous absorption 2

Key result

Time point:

8 h

Dose:

0.75 mg [14C]DPX-JE874 (aqueous solution)

Parameter:

percentage

Absorption:

5.37 %

Percutaneous absorption 3

Key result

Time point:

24 h

Dose:

10 mg [14C]DPX-JE874 (formulation concentrate)

Parameter:

percentage

Absorption:

5.86 %

Percutaneous absorption 4

Key result

Time point:

24 h

Dose:

0.75 mg [14C]DPX-JE874 (aqueous solution)

Parameter:

percentage

Absorption:

13.77 %

Percutaneous absorption 5

Time point:

72 h

Dose:

10 mg [14C]DPX-JE874 (formulation concentrate)

Parameter:

percentage

Absorption:

3.07 %

Percutaneous absorption 6

Time point:

72 h

Dose:

0.75 mg [14C]DPX-JE874 (aqueous solution)

Parameter:

percentage

Absorption:

9.27 %

Percutaneous absorption 7

Time point:

168 h

Dose:

10 mg [14C]DPX-JE874 (formulation concentrate)

Parameter:

percentage

Absorption:

4.93 %

Percutaneous absorption 8

Time point:

168 h

Dose:

0.75 mg [14C]DPX-JE874 (aqueous solution)

Parameter:

percentage

Absorption:

10.1 %

Applicant's summary and conclusion

Conclusions:

The maximum dermal absorption occurred within 24 hours after exposure. An approximately 2-fold difference in the percent penetration was observed in the aqueous test solution.

Executive summary:

This study was designed to investigate the in vivo dermal penetration of [14C]test substance (and/or its metabolites) in female laboratory rats, following a single dermal administration of [14C]DPX-MC444-11 formulation at two dose levels: as the undiluted emulsifiable concentrate and as an aqueous dilution of the concentrate equivalent to approximately ten times that of the field application solution.

Overall, limited dermal penetration of test substance was observed. The majority of administered radioactivity was removed at 8 h or 24 h by washing of the application site. Maximal dermal absorption occurred within 24 h after the initial application. Dermal absorption (expressed as the percent of the applied radioactivity) for the aqueous solution was approximately twice that for the formulation concentrate.

Negligible amounts (<1%) of the applied radioactivity was recovered in the urine. Faeces accounted for approximately 6% of the applied radioactivity. The majority of the applied radioactivity was removed in the skin wash.

Analysis of the skin washes, by HPLC, following 24 h exposure showed the presence of a single radioactive component with a retention time consistent with that of the test substance. Excreted radioactivity was largely eliminated as test substance in the faeces with some IN-KZ007 also present.

In conclusion, following a single dermal administration of [14C]test substance, limited dermal penetration was observed, with the majority of excreted radioactivity eliminated in the faeces. Washing the application site effectively removed the majority of applied radioactivity.