Registration Dossier

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets generally accepted scientific principles

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
No guidelines exist for this kind of study. The study was performed considering parts of the OECD guideline No. 427, Percutaneous Absorption: in vivo method, 2004.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
2,4-TDI
- Name of test material (as cited in study report): 2,4-TDI
- Supplier: Sigma-Aldrich
- Analytical purity: 99.7%
- Batch No.: 6124X
- Stability under test conditions: stability was guaranteed under the storage conditions until 04 May 2009
- Homogeneity: homogeneous by visual inspection and due to the high purity

2,6-TDI
- Name of test material (as cited in study report): 2,6-TDI
- Supplier: Sigma-Aldrich
- Analytical purity: 99.8%
- Batch No.: 1284332
- Stability under test conditions: stability was guaranteed under the storage conditions until 31 Aug 2007
- Homogeneity: homogeneous by visual inspection and due to the high purity
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Chales River Laboratories, Sulzfeld, Germany
- Age at study initiation: 10 - 12 weeks
- Weight at study initiation: ca. 300 g
- Fasting period before study: no
- Housing: Macrolon cages type III
- Individual metabolism cages: no
- Diet: Provimi Kliba SA, Kaiseraugust, Switzerland, ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Photoperiod: natural day/night rhythm with additional artificial light as required during working hours

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
1 min (skin sample), 1 h, 2 h, 4 h, 8 h
Doses:
300 µl/kg which corresponds to 360 mg/kg
No. of animals per group:
2 animals per exposure period (1 h, 2 h, 4 h, 8 h);
1 animal was sacrificed without exposur (untreated control)
1 animal for skin preparation (2 skin samples were prepared) and 1 min exposure of the preparated skin
= 10 animals in total
Control animals:
yes
Remarks:
Negative control: untreated skin sites (2) of one animal; Positive control: 10 µl of the undiluted mixture of 2,6-TDI and 2,4-TDI (1:1, v:v) directly given into the reagent
Details on study design:
DOSE PREPARATION
undiluted 2,6-TDI and 2,4-TDI (1:1, v:v)

APPLICATION OF DOSE:
10 µl/cm2 (100µl/10 cm2)

TEST SITE
- Preparation of test site: clipping and cleaning with acetone at least 24 h before treatment
- Area of exposure: 10 cm2, difined by a rubber ring and spacer
- Type of cover / wrap used: a permeable (gauze) dressing containing a chorcoal filter and the whole was further protected by a semi-occlusive adhesive bandage

SAMPLE PREPARATION
- Preparation details: animals were sacrificed, skin samples were prepared, the skin samples were transferred into the reagent (consisting of Dibutylamine in toluene). It was guaranteed that samples remained submersed in the reagent
- Storage procedure: after reaction time of 15 min samples were stored at 4°C

ANALYSIS
The amount of free isocyanates on the skin was determined by chemical analysis

Results and discussion

Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined

Any other information on results incl. tables

- Analytical results of 2,6- and 2,4 -TDI on rat skin are shown in table 1. The negative control (0µl/10cm2) showed no background detection of isocyanate reactivity in untreated skin.

- Positive control (1:1 mixture of 2,6 -TDI and 2,4 -TDI) resulted in values of 40 and 100 mg/100 µl. Therefore the nominal ratio of 1:1 varied from the experimental ratio of 4:10 (due to preparation of stock solution or calibration of analytical equipment)

Table 1: Analytical results of 2,6 -TDI and 2,4 -TDI on rat skin after different exposure periods

Nominal dose [µl/10 cm2] Positive control 0 0 100 100 100 100 100 100 100 100 100 100
Exposure time [min] - - - 1 1 60 60 120 120 240 240 480 480
Animal no. - 1 1 2 2 3 4 5 6 7 8 9 10
2,6-TDI [mg/sample] 40 <1 <1 12 12 18 8 8 10 6 4 2 3
2,4-TDI [mg/sample] 100 <1 <1 57 59 56 24 24 29 21 14 14 18

Applicant's summary and conclusion