Registration Dossier

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
year of publication: 1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: sufficiently documented literature data
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Percutaneous absorption of 14C-labelled 2-chlorobenzaldehyde in rats. Metabolism and toxicokinetics.
Author:
Rietveld EC, Hoet RMA, Seutter-Berlage F, van Rossum JM
Year:
1988
Bibliographic source:
European Journal of Drug Metabolism and Pharmacokinetics 13: 231-240

Materials and methods

Principles of method if other than guideline:
percutaneous absorption
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 2-chlorobenzaldehyde
- Radiochemical purity (if radiolabelling): at least 98%
- Specific activity (if radiolabelling): 20 mCi/mmol; reduced to 0.275 mCi/mmol by addition of pure unlabelled material
- Locations of the label (if radiolabelling): carbonyl-group
Radiolabelling:
yes
Remarks:
2-Chloro(carbonyl-14C)benzaldehyde

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: TNO, Zeist (The Netherlands)
- Age at study initiation: about 6 weeks
- Individual metabolism cages: yes
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least three days prior to experiments rats were housed in individual glass metabolism cages
- Air was drawn through the metabolism cage (volume 24 l) at a rate of 400 ml/min; pressure inside the cage was somewhat lower than outside
- polyethylene catheters (I.D. 0.4 mmmm; O.D. 0.8 mm) were placed into the femoral artery and the jugular vein and led subcutaneously to the nuchal area where they went out of the body

Administration / exposure

Type of coverage:
other: non-occluding glass cup
Vehicle:
unchanged (no vehicle)
Duration of exposure:
72 hours
Doses:
75 µl/kg (1.83 mCi/ml)
No. of animals per group:
8
Control animals:
no
Details on study design:
Preparation of dose:
- radiolabelled substance was pipetted undiluted in the cup, which was closed immediatly afterwards with a glass cover using the cyanoacrylate adhesive

TEST SITE
- Preparation of test site: shaved, 16 hours before application
- Area of exposure: right dorsal skin,
- Type of cover: with a glass cup (I.D. 16 mm, O.D. 24 mm, height: 10 mm) which was fixed to the skin with cyanoacrylate adhesive; the cup was glued in such a way that no contact between the glass or the adhesive with the treated skin was possible.


SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes: glass cup

REMOVAL OF TEST SUBSTANCE
- Washing procedures and type of cleansing agent: the glass was rinsed with methanol
- exposed skin was widely excised, cut into small pieces and solubilized bevor counting of radioactivity


SAMPLE COLLECTION
- Collection of blood: from femural artery
- Collection of urine and faeces: urine was colleted for 72 hours after the administration; faeces was collected at daily intervals


ANALYSIS
- radioactivity was measured by liquid scintillation counting (for details see below)

Results and discussion

Signs and symptoms of toxicity:
not specified
Dermal irritation:
no effects
Absorption in different matrices:
Plasma radioactivity increases slowly after percutaneous application. Peak-plasma concentrations of 4000-6000 dpm/g (approximately 0.1 % of dose) were reached 10-15 hours post dosing. Plasma-radioactivity declined slowly, the calcualted half-life ranged between 20 and 40 h.


Total recovery:
- Total recovery: 102.7% +/- 9.12
- Recovery of applied dose acceptable: yes
- Results adjusted for incomplete recovery of the applied dose: no
Percutaneous absorption
Dose:
75 µl/kg bw
Parameter:
percentage
Absorption:
ca. 85 %
Remarks on result:
other: 72 hours
Remarks:
calculated as difference between applied dose and residual dose on the skin survace and glass-cup

Any other information on results incl. tables

Percent of administered radioactivity after percutaneous application (values are means +/- SD)

   Skin (n=8)
 Dose (µl/kg)  75
 Urine  
   0 -12 h  21.1 +/- 14.62
  12 -24 h  24.3 +/- 6.33
  24 -48 h  22.7 +/- 6.65
  48 -72 h  13.0 +/- 6.25
 Total Urine  81.1 +/- 13.98
 Faeces Total  3.1 +/- 1.25
 14CO2 Total (Exhaled)  1.1 +/- 0.48
 Glasscup  11.7 +/- 8.27
 On Skin  4.1 +/- 5.15
 In Skin  1.6 +/- 1.27
 Recovery  102.7 +/- 9.12

Applicant's summary and conclusion

Conclusions:
The test substance was almost entirely absorbed into the rat-skin within 72 hours, although the percutaneous absorption process was slow. The total absorbed dose was mainly excreted via urine. There was no evidence of storage in the skin or skin toxicity after cutaneous application of the test item.
Executive summary:

Rats were exposed to 14C-radiolabelled 2-chlorobenzaldehyde via percutaneous application (75 µl/kg). After dermal application of the test item in a glass-cup a slow skin penetration was observed as indicated by plasma radioactivity levels. The slow increase in plasma radioactivty was followed by a slow decline of radioactivity in plasma over a 3-day period. Percutaneous absorption was nearly complete (about 85%), as could be calculated from the difference between the applied dose and the residual dose. The test item was mainly eliminated via urine (about 81% of the administered dose), radioactivity in faeces and exhaled air were below 5% of the administered dose. There was no evidence of skin toxicity or storage in the skin after test substance application.

This well performed study was judged to be reliable with restriction (RL2) and has been selected as key study.