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Registration Dossier
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EC number: 915-277-1 | CAS number: 32052-51-0
Skin sensitisation
Administrative data
- 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
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 000
- Report date:
- 2000
Materials and methods
Test guidelineopen allclose all
- 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.
Test material
- Reference substance name:
- 2,2,4(or 2,4,4)-Trimethylhexane-1,6-diisocyanate
- EC Number:
- 915-277-1
- Cas Number:
- 32052-51-0
- Molecular formula:
- C11H18N2O2
- IUPAC Name:
- 2,2,4(or 2,4,4)-Trimethylhexane-1,6-diisocyanate
- Test material form:
- other: liquid
- Details on test material:
- Vestanat TMDI = 2,2,4-/2,4,4-trimethylhexane-1,6-diisocyanate of Degussa-Hüls AG, batch 11910056, purity > 99.5 %
Constituent 1
In vivo test system
Test animals
- 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
Study design: in vivo (non-LLNA)
Inductionopen allclose all
- 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
Challengeopen allclose all
- 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
Results and discussion
In vivo (non-LLNA)
Resultsopen allclose all
- 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.
Any other information on results incl. tables
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
Applicant's summary and conclusion
- 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 %.
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