Registration Dossier

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 417
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 14C-Basisch Gelb 8511
- Physical state: solid
- Lot/batch No.: 718-1003
- Radiochemical purity (if radiolabelling): > 95%
- Storage condition of test material: at 4°C in the dark
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Boehringer Ingelheim Pharma KG
- Age at study initiation: about 8 weeks at application
- Weight at study initiation: ca. 261- 299 g
- Housing: During acclimatization and prior to the experiment in type III Macrolon cages; during experiments individually in all-glass metabolism
cages; type Metabowl (Jencons, Leighton Buzzard, UK) which were labelled with the project number and the animal number.
- Diet ad libitum
- Water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%



Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
other: acetate buffer
Duration of exposure:
8 hours
Doses:
- Nominal doses: 0.080; 0.016; 0.0032 mg/cm² corresponding to 0.80, 0.16 and 0.032 mg/animal and about 3.8, 0.7 and 0.2 mg/kg body weight
- Dose volume: 10 µl/cm²
- Rationale for dose selection: The dermal application was selected in order to simulate potential exposure scenarios. According to the relevant guidelines, experiments shall be performed using doses expected in practice. Dose levels were calculated with the following assumptions: The concentration of Basisch Gelb 8511 in paper is about 0.2 %. With paper of 80 g/m², this corresponds to 160 mg Basisch Gelb 8511/m². Assuming that the flat of both hands is in contact with paper (ca. 400 cm²) and that the dye in paper is completely available for penetration, exposure can be calculated to be 6.4 mg/400 cm², corresponding to 0.016 mg/cm² (= intermediate dose level). Using a factor of 5 upwards and downwards, 0.08 and 0.0032 mg/cm² were selected as additional dose levels.
No. of animals per group:
4
Control animals:
no
Details on study design:
In this set of experiments, animals were dosed and then placed in metabolism cages in order to collect excreta up to 72 hours. After 8 hours of exposure, the protective cover was removed and the exposed skin was washed with a mild soap solution. After 72 hours, animals were sacrificed and the following specimens/tissues were checked for remaining radioactivity: excreta, bloodcells, plasma, liver, kidneys, carcass, skin (treated (= application site) and non-treated areas (surrounding skin)). For balance estimates the cage wash and skin wash as well as the protective cover (including the silicone ring) were also checked for radioactivity.

Results and discussion

Percutaneous absorptionopen allclose all
Dose:
0.080 mg/cm²
Parameter:
percentage
Absorption:
0.4 %
Remarks on result:
other: 72 hours
Remarks:
After 8 hours of exposure, the protective cover was removed and the exposed skin was washed with a mild soap solution.
Dose:
0.016 mg/cm²
Parameter:
percentage
Absorption:
0.8 %
Remarks on result:
other: 72 hours
Remarks:
After 8 hours of exposure, the protective cover was removed and the exposed skin was washed with a mild soap solution.
Dose:
0.0032 mg/cm²
Parameter:
percentage
Absorption:
1.2 %
Remarks on result:
other: 72 hours
Remarks:
After 8 hours of exposure, the protective cover was removed and the exposed skin was washed with a mild soap solution.

Any other information on results incl. tables

- High dose:

Following a single dermal administration of14C-BASISCH GELB 8511 at a nominal dose level of 0.080 mg/cm² (0.80 mg/animal or about 3.8 mg/kg body weight), the recovery of radioactivity was between 91.83% and 95.11% of the applied radioactivity. The largest portion of radioactivity was recovered from the skin wash (85.83% of dose). In the dressing, 0.88% of the applied radioactivity was found. The application site contained 4.00% of the applied radioactivity. The penetration of radioactivity into the skin adjacent to the application site was 0.42% of the applied radioactivity. The amount of radioactivity absorbed (including excreta, cage wash, tissues/organs and carcass) was 0.39%. The absorbed radioactivity was excreted mainly via the feces. Due to the very limited skin penetration, concentrations of radioactivity in organs and tissues analyzed were very low with the remaining carcass showing the highest values being about 0.005 µg Eq/g tissue.

 

- Intermediate dose:

Following a single dermal administration of14C-BASISCH GELB 8511 at a nominal dose level of 0.016 mg/cm² (0.16 mg/animal or about 0.7 mg/kg body weight), the recovery of radioactivity was between 92.30% and 96.12% of the applied radioactivity. The largest portion of radioactivity was recovered from the skin wash (77.69% of dose). In the dressing, 2.58% of the applied radioactivity was found. The application site contained 9.20% of the applied radioactivity. The penetration of radioactivity into the skin adjacent to the application site was 0.65% of the applied radioactivity. The amount of radioactivity absorbed (including excreta, cage wash, tissues/organs and carcass) was 0.85%. The absorbed radioactivity was excreted mainly via the feces. Due to the very limited skin penetration, concentrations of radioactivity in organs and tissues analyzed were very low with the kidneys and the remaining carcass showing the highest values being about 0.002 µg Eq/g tissue.

 

- Low dose:

Following a single dermal administration of14C-BASISCH GELB 8511 at a nominal dose level of 0.0032 mg/cm² (0.032 mg/animal or about 0.2 mg/kg body weight), the recovery of radioactivity was between 90.34% and 95.21% of the applied radioactivity. The largest portion of radioactivity was recovered from the skin wash (76.85% of dose). In the dressing, 1.49% of the applied radioactivity was found. The application site contained 12.48% of the applied radioactivity. The penetration of radioactivity into the skin adjacent to the application site was 0.51% of the applied radioactivity. The amount of radioactivity absorbed (including excreta, cage wash, tissues/organs and carcass) was 1.25%. The absorbed radioactivity was excreted mainly via the feces. Due to the very limited skin penetration, concentrations of radioactivity in organs and tissues analyzed were very low with kidneys and the remaining carcass showing the highest values being about 0.001 µg Eq/g tissue.

 

A comparison of the penetration at the different dose levels shows, that the percentage of radioactivity absorbed decreased with increasing dose indicating saturation of skin penetration with increasing dose. An increase in dose by a factor of 5 resulted in 30-50% decrease in the percentage of radioactivity absorbed.

Applicant's summary and conclusion

Conclusions:
Following single dermal administration of 14C-BASISCH GELB 8511 diluted in an acetate buffer, there was very limited systemic absorption amounting to 1.25 % of the dose applied at maximum. With increasing dose the percentage of radioactivity absorbed decreased indicating saturation of skin penetration with increasing dose. Due to the limited skin penetration, concentrations of radioactivity in organs and tissues analyzed were very low with kidneys and the remaining carcass showing the highest values.
Executive summary:

The study was conducted according to OECD guideline 417 in compliance with GLP.

Mean recoveries of radioactivity from all dose groups were in the range of 90.34 - 96.12% of the total radioactivity administered. The largest portion of radioactivity was recovered from the skin wash (>76 %). Whereas 1.25 % of the applied radioactivity was absorbed at maximum at the low dose level, relative absorption decreased to about 0.85% at the intermediate dose level and to about 0.39 % at the high dose level. These.results clearly indicated saturation of penetration with increasing dose.

 

Dose level (mg/cm²)

% of radioactivity absorbed

0.080

0.39

0.016

0.85

0.0032

1.25

 

The radioactivity absorbed was excreted mainly via the feces. Due to the very limited skin penetration, concentrations of radioactivity in organs and tissues analyzed were very low.