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Diss Factsheets

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 Apr 1984 - 11 Jan 1985
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:
1985
Report date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 427 (Skin Absorption: In Vivo Method)
Version / remarks:
adopted 2004
Deviations:
yes
Remarks:
i.a., small group size and thus, no interim sacrifice at end of exposure, acclimation period belong guideline recommendation, exposure period above guideline recommendation
Principles of method if other than guideline:
No guideline mentioned in the study report, however, the test conduct is in principle compliant to the OECD test guideline 427.
GLP compliance:
yes
Remarks:
with following deviations: No standard operating procedure available for receiving rodents In the Radiation Building during the course of this study; Dosing solutions not analyzed for for purity and stability of the test chemical.

Test material

Constituent 1
Chemical structure
Reference substance name:
2,6-dibromo-4-cyanophenyl octanoate
EC Number:
216-885-3
EC Name:
2,6-dibromo-4-cyanophenyl octanoate
Cas Number:
1689-99-2
Molecular formula:
C15H17Br2NO2
IUPAC Name:
2,6-dibromo-4-cyanophenyl octanoate
Radiolabelling:
yes
Remarks:
14C ring radiolabel

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hilltop Lab Animals, Inc., Scottdale, Pennsylvania, USA
- Age at study initiation: 7 - 9 weeks
- Weight at study initiation: 265 - 286 g
- Fasting period before study: no
- Housing: during acclimation, rats were housed in groups of three in shoe-box cages with Ab-sorb-dri bedding (Garfield, New-Jersey), after application, rats were housed individually.
- Individual metabolism cages: Roth-type metabolism cages designed for the separate collection of urine, feces and expired gases.
- Diet: basic diet of Agway, Pro-Lab, certified pelleted rodent chow (RMH 3000; Agway Inc., St. Marys, Ohio), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2 To: 6 Apr 1984

Administration / exposure

Type of coverage:
occlusive
Vehicle:
acetone
Remarks:
only for the applied dose of 1037 µg/25 cm2 corresponding to 46.9 µCi; for the remaining doses, water was used as vehicle.
Duration of exposure:
48 h
Doses:
67, 137 and 1037 µg/25 cm2, equivalent to 3, 6.2 and 46.9 µCi, respectively
No. of animals per group:
3 µCi:1 animal
6.2 µCi : 1 animal
46.9 µCi: 2 animals
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: The test substance radiolabelled with 14C was received in 4.2 mL toluene. Two 1 mL aliquots of the toluene solution were evaporated to dryness. One was dissolved in 2.6 mL acetone and the other suspended In 2.6 mL water. The water solution was sonicated before dosing.

APPLICATION OF DOSE:
For the rats receiving the highest dose of radiolabelled test material in acetone, the dose was applied to the 25 cm2 skin application area in two 0.5 mL aliquots. For the rats receiving the lower doses of radiolabelled test material in water, each dose was applied in 3 to 4 aliquots.

VEHICLE
- Justification for use and choice of vehicle: chosen as appropriate
- Amounts applied: 1 mL

TEST SITE
- Preparation of test site: one day before the experiment, the hair at the test side was clipped, a neoprene rubber template was glued in place and rats were surgically implanted with an indwelling cannula in the right external jugular vein under Metofane anesthesia (for blood withdrawal).
- Area of exposure: 25 cm²
- Type of cover / wrap if used: polyethylene wrap
- Time intervals for shavings or clippings: on the day before the experiment

SITE PROTECTION:
To prevent oral ingestion, the polyethylene wrap used to cover the application area, was secured with Elastikon tape.

REMOVAL OF TEST SUBSTANCE
- Washing procedures and type of cleansing agent: 1:1 mixture of acetone and water
- Time after start of exposure: 48 h
The washings and polyethylene wrap were stirred continuously for approximately 6 h in 1 L of methanol and 1 mL samples were removed for radiometrlc analyses.

SAMPLE COLLECTION
- Collection of blood: yes, 0.1 - 0.2 mL, 30 min and 1, 2, 4, 8, 12, 24, 32 and 48 h following dosing and 30 min and 1, 2, 4, 8, 12, 24, 32 and 48 h post-washing
- Collection of urine and feces: yes, daily during exposure and daily for 48 h post-washing.
- Collection of expired air: yes, expired volatiles were trapped in acetonitrile and collected at 8, 24 and 48 hours post-application and at 8 h post-washing. Expired CO2 was collected in ethanolamine/2-methoxyethanol traps (3:7 v/v) at 8, 24 and 48 hours post-dose application and following the same schedule following the skin wash.
- Cage wash: yes, each cage was washed daily with a 1:1 mixture of acetone and water.
- Terminal procedure: 96 h post-application, rats were anesthetized with Metofane and exsanguinated via the abdominal aorta
- Analysis of organs: skin from the dosing area (solubilized in 200 mL of 10N NaOH), remaining carcass (solubilized in 2 L of 10N NaOH).

SAMPLE PREPARATION
- Storage procedure: The stock sample was stored at ca. 4 °C.
- Preparation details: Samples of plasma, blood cells, cage and skin washings, acetonitrile (trapping solution) and urine were counted directly in Aquasol-II. Aliquots (1 mL) of the trapping solution from the C02 traps were analyzed using a dioxane-based scintillator. Triplicate samples of NaOH solubillzation mixtures were diluted 10-fold with deionized water and aliquots (1 mL) of these dilutions were counted in Dimilume-30.

ANALYSIS
- Method types for identification: Liquid scintillation counting (LSC)
- Validation of analytical procedure: Standards for radioactivity determination were prepared by diluting weighed 0.1 mL samples of each dosing solution 100 fold in methanol. 0.1 mL of this dilution was counted according to standard operating procedures. The measured amounts of radioactivity in the dosing solutions were 46.9 µci (1037 µg) in the acetone vehicle and 6.2 µci (137 µg) and 3.0 µci (67 µg) in the two water vehicle suspensions. The amounts of radioactivity differed between solvents because of unequal solubility of the radiolabelled chemical.
- Limits of detection and quantification: not reported

The pharmacokinetic behavior of the test substance was evaluated using the BASIC computer program, ESTRIP. Terminal half-life (t 1/2) was calculated as follows:

t1/2 (h) = (0.693)/k

k = rate constant for terminal exponential phase

Results and discussion

Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Absorption in different matrices:
All percentages of recovery reported below are over the total exposure and recovery period, for details, please refer to Attachment 1.

- Skin (washed): 6.61 and 6.95% (acetone vehicle), 10.46 and 8.02% (water vehicle)
- Carcass: 8.41 and 5.31% (acetone vehicle), 6.07 and 13.46% (water vehicle)
- Urine: 17.14 and 23.7% (acetone vehicle), 17.19 and 9.65% (water vehicle)
- Cage wash + cage wipe: 4.44 and 3.95% (acetone vehicle), 5.09 and 6.51% (water vehicle)
- Feces: 3.38 and 5.92% (acetone vehicle), 2.7 and 7.14% (water vehicle)
- Expired air: < 0.2%
- Dosing rod and template: 4.76 and 2.2 % (acetone vehicle), 5.4 and 4.62% (water vehicle)
- Skin washings and polyethylene wrap: 46.4 and 40.42% (acetone vehicle), 51.43 and 46.05% (water vehicle)

- total percentage of radioactivity recovered from wrapping, washing fluid, dosing rod and template: 42.62 and 51.16% (acetone vehicle), 50.67 and 56.83% (water vehicle)
- total percentage of radioactivity recovered in urine, feces, expired air, carcass and skin: 40.01 and 45.86% (acetone vehicle), 41.61 and 45.07% (water vehicle)

- Blood: For blood, a pharmacokinetic investigation was conducted. The nanogram equivalents of the radiolabeled test substance were measured in plasma during exposure and up to 48 h after the end of administration. During exposure, the radioactivity values for the test substance applied in acetone were maximal for the 12 to 24 h period (3781.0 ng/g) in one animal and 24 to 32 h for the other animal (3836.6 ng/g) and declined for subsequent samples. With the water
vehicle, the radioactivity in plasma during exposure was at a maximum for the 24 to 32 h sample with one animal and at a plateau during the 12 to 24 h and 24 to 32 h sample periods with the second animal. Radioactivity in the plasma after washing the dosing solution from the skin decreased slowly and similarly for all animals dosed with the radiolabelled test substance. Radioactivity in red blood cells was negligible and was not tabulated.

For further details, please refer to Attachment 2.
Total recovery:
- Total recovery: The total recovery of radiochemical was similar for both vehicles with values of 88.48 and 91.17% of the applied dose for acetone and 95.74 and 98.44% of the applied dose for water.
- Recovery of applied dose acceptable: yes
Percutaneous absorptionopen allclose all
Key result
Time point:
48 h
Dose:
46.9 μci (acetone as vehicle)
Parameter:
percentage
Absorption:
>= 40 - <= 46 %
Remarks on result:
other: i.e., percentage of administered dose based on radioactivity recovery in animal tissues and excreta
Key result
Time point:
48 h
Dose:
3 and 6.2 μci (water as vehicle)
Parameter:
percentage
Absorption:
>= 41 - <= 45 %
Remarks on result:
other: i.e., percentage of administered dose based on radioactivity recovery in animal tissues and excreta
Conversion factor human vs. animal skin:
No data reported.

Any other information on results incl. tables

Radioactivity recovered from the application materials and in the fluid used to wash the skin was in the range of 42.5 to 51.5% of the administered dose of 46.9 µCi in acetone; radioactivity recovered from the application materials and in the fluid used to wash the skin was between 50 and 57% of the administered doses in water (3 and 6.2 µCi).

The half-life (t 1/2) In hours for the post-washing (elimination) phase was reported as 40.8 and 27.7 hours for the dose in acetone as vehicle and as 25.7 and 30.1 hours for the doses in water as vehicle.

For further details, please refer to Attachment 3.

Applicant's summary and conclusion

Conclusions:
The dermal absorption of the test compound was investigated in a GLP-compliant study conducted similar to OECD 427. During the study, males rats received single dermal applications of the radiolabelled test material at doses of 1037 µg/25 cm2 of skin (acetone used as vehicle, 2 rats), 137 µg/25 cm2 of skin (water as vehicle, one rat)and 67 µg/25 cm2 of skin (water as vehicle, one rat) for 48 h. These doses corresponded to 46.9, 6.2 and 3 µCi, respectively. The application volume for each dosage was 1 mL. Treatment was followed by a recovery period and the animals were finally sacrificed after 96 h post-treatment. The study is considered valid, scientifically acceptable and appropriate for the assessment of dermal absorption in the rat, despite of the low number of animals used.
The total recovery of radioactivity relative to the administered dose was 88.5% and 91.2% for the highest dose (46.9 µCi in acetone), and 95.7% and 98.4% for the lower doses (6.2 and 3 µCi in water). Thus, the choice of the vehicle had no impact on the dermal absorption. In fact, for both vehicles, the predominant route of radioactivity excretion was via the urine and the greatest relative recovery of radioactivity in the body was in the carcass and washed skin. Dermal absorption was calculated and reported as percentage of the administered dose based on recovery of radioactivity in the animal tissues and excreta. The percentage of absorbed radiolabel relative to the administered dose, over the 48-hour treatment period, was about 40 to 46% for the high dose of 46.9 µCi in acetone. The percentage of absorbed radiolabel relative to the administered dose, over the 48-hour treatment period, was about 41 to 45% for the lower doses in water (i.e., 6.2 and 3 µCi).
Radioactivity recovered from the application materials and in the fluid used to wash the skin was about 42 to 51.5% of the administered dose for 46.9 µCi in acetone, and 50.5 to 57% for the lower doses in water (i.e., 6.2 and 3 µCi).
The half-life (t 1/2) In hours for the post-washing (elimination) phase was reported to be 40.8 and 27.7 hours for the high dose of 46.9 µCi in acetone, and 25.7 and 30.1 hours for the doses in water (i.e., 6.2 and 3 µCi).