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Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983-05-04 to 1983-06-03
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions: Purity of test substance not reported

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
A skin sensitization test according to OECD 406 has already excisted since 1983 and is sufficient for evaluation of the skin sensitisation potential of the test substance.

Test material

Constituent 1
Chemical structure
Reference substance name:
3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate
EC Number:
223-861-6
EC Name:
3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate
Cas Number:
4098-71-9
Molecular formula:
C12H18N2O2
IUPAC Name:
5-isocyanato-1-(isocyanatomethyl)-1,3,3-trimethylcyclohexane
Details on test material:
Isophorone diisocyanate of Hüls AG, purity not reported

In vivo test system

Test animals

Species:
guinea pig
Strain:
Pirbright-Hartley
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS: 
- Strain: Dunkin-Hartley, Pirbright White, Hoe: DHPK (SPF - LAC.) /Boe.
- Sex: no data
- Source: Lippische Versuchstierzucht Hagemann, Extertal (Germany)
- Weight at study initiation: mean 350 g
- Controls: 20 animals, concurrent vehicle
- 2 Animals per cage in Makrolon III cages
- Sniff Bedding from fir-, spruce-, pine wood, dried; cleared from dust and sterilised
- diet: ssniff G (Ssniff, soest)
- water ad libitum
- Acclimation period: approx. 7 days

ENVIRONMENTAL CONDITIONS:
- room temperature: 21°C (+/- 2°C)
- humidity: 45-55%
- light: 12h/day

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
other: Paraffin oil (DAB 6)
Route:
intradermal
Concentration / amount:
1st application: Induction 10 % intracutaneous in paraffin
10 % intracutaneous in FCA which was diluted 1:1 with Oleum rachaidis prior to mixing with the test item

control group 1:1 FCA in aqua dest
paraffin
Adequacy of induction:
not specified
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:

2nd application: Induction undiluted occlusive epicutaneous

Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
other: Paraffin oil (DAB 6)
No.:
#3
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:

3rd application: Challenge undiluted occlusive epicutaneous
No. of animals per dose:
20 test / 20 control
Details on study design:
ADMINISTRATION/EXPOSURE 
- Induction schedule:    
Day 0: Injection   
- Injection details: pairwise injections of 0.05 ml each on shoulders:  
2 x test substance 10 % in vehicle (paraffin)    (control: vehicle)   
2 x test substance 10 % in 50:50 mixture of Freund's Complete Adjuvant (FCA) / oleum arachidis   (control: vehicle instead of test substance)   
2 x FCA / distilled water (50:50)   (control: FCA undiluted) - Days 7-9: 48 hours closed patch treatment of injection sites (0.5 ml;  control: vehicle)
- Challenge schedule:    
Days 21-22: 24 hour closed patch treatment with test substance (left  flank) / vehicle (right flank)   
Days 22-23: Readings at patch removal and 24 hours later
- Concentrations used for challenge: 100 % (0.5 ml)
- Rechallenge: no - Positive control: none

EXAMINATIONS
- Grading system:   
0 = no skin reaction   
0.5 = slight and spotted erythema   
1 = slight and regular, or moderate and spotted erythema   
2 = moderate erythema    
3 = severe erythema or edema

- Pilot study: range finding (skin irritation)   Test substance undiluted; 75 %; 50 % in vehicle tested in 2 animals per  concentration   
Single dermal treatment with 0.5 ml, probably (not reported) 24 hour  occlusive patch  
Observation period 4 days after test substance administration
Challenge controls:
Treatment: vehicle and test item
Positive control substance(s):
no

Results and discussion

Positive control results:
no positive control

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
undiluted
No. with + reactions:
17
Total no. in group:
20
Clinical observations:
RESULTS OF PILOT STUDY: no irritation at any concentration
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: undiluted. No with. + reactions: 17.0. Total no. in groups: 20.0. Clinical observations: RESULTS OF PILOT STUDY: no irritation at any concentration .
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
vehicle
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
RESULTS OF PILOT STUDY: no irritation at any concentration
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: vehicle. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: RESULTS OF PILOT STUDY: no irritation at any concentration .
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
undiluted
No. with + reactions:
16
Total no. in group:
20
Clinical observations:
RESULTS OF PILOT STUDY: no irritation at any concentration
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: undiluted. No with. + reactions: 16.0. Total no. in groups: 20.0. Clinical observations: RESULTS OF PILOT STUDY: no irritation at any concentration .
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
RESULTS OF PILOT STUDY: no irritation at any concentration
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: vehicle. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: RESULTS OF PILOT STUDY: no irritation at any concentration .
Group:
positive control
Remarks on result:
other: no positive control tested in this study
Remarks:
validation tests not reported

Applicant's summary and conclusion

Conclusions:
Under the conditions of this guinea pig maximization test, the test item 3-Isocyanatomethyl-3,3,3-trimetylcyclohexylisocyanate exhibited the potential to produce dermal sensitization in guinea pigs.
Executive summary:

The clear liquid test item 3 -isocyanatomethyl-3,5,5 -trimethylcyclohexyl isocyanate; IPDI ( CAS# 4098 -71 -9 / EC# 223 -861 -6) was tested in a Guinea pig maximization test (Magnussen and Kligmann) according to OECD 406 for its sensitizing properties.

20 Dunkin-Hartley, Pirbright White guinea pigs with a mean body weight of 350 g were used in this study for both, for the test item group as well as for the control group. Prior to the main study a pilot range finding study in order to assess skin irritation by the test item was conducted. The test item was tested undiluted; 75 % and  50 % in the vehicle paraffin in 2 animals per concentration.

The induction was conducted on day 0 intradermal and after 7 days epicutane:

Day 0: Pairwise injections of 0.05 ml each on shoulders:  

-         2 x test substance 10 % in vehicle (paraffin) (control: vehicle)   

-         2 x test substance 10 % in 50:50 mixture of  FCA / oleum arachidis

(control: vehicle instead of test substance)   

-         2 x FCA / distilled water (50:50)   (control: FCA undiluted)       

Day 7: 48 hours closed patch treatment of injection sites (0.5 ml undiluted test item; control: vehicle)

The challenge was conducted after 21 -22 days for 24 hour by closed patch treatment of the undiluted the test item (0.5 mL; left flank) / vehicle (right flank) and readings were conducted at patch removal and 24 hours later.

 

Grading system:   

- 0 = no skin reaction   

- 0.5 = slight and spotted erythema   

- 1 = slight and regular, or moderate and spotted erythema   

- 2 = moderate erythema    

- 3 = severe erythema or edema

 

The test item showed no indication of primary irritation in the range finding study in concentrations up to 100%.

24 hours after the challenge, 17 out of 20 animals were positive having an overall mean score of 1.15 (max.3). After 48 hours 16 out of 20 animals were positive having an overall mean score of 0.85 (max.3). 24 and 48 hours after the challenge 19 out of 20 animals showed a positive reaction. In the control group 0 out of 20 animals were positive at 24 and at 48 hours after the challenge.

Under the conditions of this guinea pig maximization test, the test item 3 -Isocyanatomethyl-3,3,3 -trimetylcyclohexylisocyanate exhibited the potential to produce dermal sensitization in guinea pigs. These results characterize the test substance as a dermal sensitizer under the conditions of this study.

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