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Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2000-07-24 to 2000-08-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
(1992)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
(1996)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
A skin sensitization test according to OECD 406 has already excisted since 2000 and is sufficient for evaluation of the skin sensitisation potential of the test substance.
Species:
guinea pig
Strain:
other: Himalayan
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS: 
- Strain: Himalayan (SPF quality)
- Source: RCC Ltd., Biotechnology & Animal Breeding Division, Füllinsdorf  (Switzerland)
- Sex: female
- Age: approx. 7 weeks
- Weight at study initiation: 447 +/- 33 g
- Controls: 5 females (472 +/- 31 g); treatment: vehicle
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15 times/hour
- Photoperiod (hrs dark / hrs light): 12 hours
- Diet: Free access Maintenance Diet for Guinea Pigs (Altromin)
- Water: Free access to tap water
Route:
intradermal and epicutaneous
Vehicle:
other: corn oil
Concentration / amount:
1st application: Induction 0.5 % intracutaneous
2nd application: Induction 100 % occlusive epicutaneous
3rd application: Challenge 2 % occlusive epicutaneous
Route:
epicutaneous, occlusive
Vehicle:
other: corn oil
Concentration / amount:
1st application: Induction 0.5 % intracutaneous
2nd application: Induction 100 % occlusive epicutaneous
3rd application: Challenge 2 % occlusive epicutaneous
No. of animals per dose:
5 females control group
10 females test group
Details on study design:
ADMINISTRATION/EXPOSURE 
- Preparation of test substance for induction: Within 4 hours prior to  treatment, homogeneous preparation with vehicle
- Induction schedule:    
Day 1: Injections   
Day 3: Assessment for dermal irritation   
Day 8: 48 hours occlusive patch with 0.5 ml of 100 % test substance on  clipped injection sites (control animals: vehicle)   
Day 10: Removal of patch and residual test substance, assessment for  dermal irritation
- Injection details: 0.1 ml each at 6 positions in clipped scapular  region:   
2 x Freund's Complete Adjuvant (FCA) / water for injection (50:50)   
2 x test substance 0.5 % in vehicle   
2 x test substance 1.0 % in vehicle / FCA (50:50)   pairwise administration of each solution / suspension, symmetrical to  midline and from cranial 
to caudal   
controls: vehicle instead of test substance
- Challenge schedule:    
Day 22: Two 24 hours occlusive patches (each 0.15 ml) with     (a) 2 % test substance and     (b) vehicle alone on one clipped flank   
Day 23: Removal of patches and residual test substance   
Days 24 and 25: Assessment for challenge reaction 24 and 48 hours after  patch removal
- Rechallenge: no
- Positive control: alpha-hexylcinnamic aldehyde (tech. 85 %) (not more  than 6 months previously)
EXAMINATIONS
- Grading system:    
Irritation: Draize scores (0 / 1 / 2 / 3 / 4 each for erythema + eschar  and for edema)  
Challenge:    
0 = no visible change   
1 = discrete or patchy erythema  
2 = moderate and confluent erythema   
3 = moderate erythema and swelling   
4 = intense erythema and swelling   Animals with scores > 0 and with more severe or more persistent skin  reaction than the control = sensitized  
Evaluation of sensitization rate (% animals sensitized) according to  93/21/EEC
- Pilot study: Range finding: mild to moderate (for induction) and  non-irritant (for challenge) concentrations   
Concentration series 100 %, 50 %, 20 %, 10 %, 5 %, 2 %, 1 % and so on  as far down as necessary   
A) Intracuteaneous: 2 successive series of 4 concentrations each, 2  concentrations per animal, duplicate 0.1 ml injections per concentration  in 
clipped scapular region, assessment 24 and 48 hours after treatment  
B) Epicutaneous: 3 animals with 2 concentrations per animal, 0.5 ml per  concentration in 24 hours occlusive patch on clipped flank, assessment 24   and 48 hours after exposure
Challenge controls:
 0.15 ml vehicle alone on one clipped flank   
Positive control substance(s):
no
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
2 %
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 2 %. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
2 %
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 2 %. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
2 %
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
no symptoms of systemic toxicity
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 2 % . No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: no symptoms of systemic toxicity.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
2 %
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
no symptoms of systemic toxicity
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 2 %. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: no symptoms of systemic toxicity.

RESULTS OF PILOT STUDY: 
  A) Intracutaneous: Erythema of grades 2-4 at 0.5 and 1 %;  necroses of  3-12 mm at 2-100 %
  B) Epicutaneous: Erythema of grades 1-2 at 5-100 %, no edema
RESULTS OF TEST
- Sensitization reaction:
  Skin reactions of grade 2 in 10/10 animals both 24 and 48 hours after  removal of challenge patch. Additionally eschar formation in 10/10  animals at 48 hours reading. No skin reactions were evident in the  control animals. 
- Clinical signs: No mortality occurred and no symptoms of systemic  toxicity were observed in the animals of the main study.
- Other: Mean body weight gain 101 g in test group, 119 g in control  group = same range

Conclusions:
The skin reactions observed in response to the 2 % test substance concentration in all experimental animals in the challenge phase were considered indicative of sensitation, based in the absence of any response in the control animals. The results indicate a sensitisation rate of 100 %.
Executive summary:

The skin sensitizing properties of 2,2,4 -/2,4,4 -trimethylhexane-1,6 -diisocyanate were conducted in a guinea pig maximation test

according to OECD 406. Ten female guinea pigs were intradermally injected with a 0.5 % concentration of 2,2,4 -/2,4,4 -trimethylhexane-1,6 -diisocyanate (in corn oil) and epidermally exposed to a 100 % concentration of test substance. Five control animals were similary treated, but with vehicle alone. Two weeks after the epidermal application all animals were challenged with 2 % test substance and the vehicle. The skin reactions observed in response to the 2 % test substance concentration in all experimental animals in the challenge phase were considered indicative of sensitation, based in the absence of any response in the control animals. The results indicate a sensitisation rate of 100 %.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Migrated from Short description of key information:


The skin reactions observed in response to the 2 % test substance concentration in all experimental animals in the challenge phase were considered indicative of sensitization. There was no response in the control animals. The results indicate a sensitization rate of 100 %.


Justification for selection of skin sensitization endpoint:


key study

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

Based on the fact that isocyanates are well known to cause sensitizing effects in the respiratory tract, the substance 2,2,4(or 2,4,4)-trimethylhexane-1,6 -diisocyanate is also regarded as sensitizing to the respiratory tract.

Justification for classification or non-classification

According to the criteria of EC Directive 67/548/EEC and EC Regulation 1272/2008 and subsequent regulations on classification, labelling and packaging of substances and mixtures and based on the results of the studies for 2,2,4(or 2,4,4)-trimethylhexane-1,6-diisocyanate, the test substance is classified for respiratory sensitization category 1, H334, and for skin sensitization category 1, H317.