Registration Dossier

Administrative data

Description of key information

Skin sensitisation studies have been conducted on three substances in the MDI category. Buehler tests were conducted on EC 406-530-2 and EC 406-690-3, a local lymph node assay (LLNA) was conducted with EC 445-760-8 and a Guinea pig maximisation test was conducted with EC 406-690-3.

For the substance EC 406-530-2 there were no positive challenge results at 25 % w/w in corn oil in the Buehler test. In the Buehler test conducted with EC 406-690-3, in the first challenge a minimal response was observed in 9 animals (red spots) and the result was considered inconclusive, therefore, a second challenge was performed where no positive results were observed. In the Guinea pig maximisation test conducted with EC 406-690-3, no responses were seen at the challenge concentration. In the LLNA study conducted with EC 445-760-8, the maximum stimulation index observed was 1.21, and therefore the test item does not induce contact hypersensitivity.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to
Guideline:
other: Annex V (Buehler)
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Species:
guinea pig
Strain:
other: Himalayan albino
Sex:
not specified
Route:
other: Topical
Vehicle:
corn oil
Concentration / amount:
50% (w/w)
Day(s)/duration:
Not specified
Adequacy of induction:
not specified
Route:
other: Not reported
Vehicle:
corn oil
Concentration / amount:
25% w/w
Day(s)/duration:
Not specified
Adequacy of challenge:
not specified
No. of animals per dose:
Number of animals in test group: 20
Number of animals in negative control group: 10
Challenge controls:
Concentration of test material and vehicle used for each challenge: 25% (w/w) in corn oil
Positive control substance(s):
not specified
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
25 %
No. with + reactions:
0
Total no. in group:
20
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
20 %
No. with + reactions:
0
Total no. in group:
20
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25 %
No. with + reactions:
1
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
20 %
No. with + reactions:
1
Total no. in group:
10
Reading:
other: Not specified
Group:
positive control
Dose level:
Not specified
Remarks on result:
other: Positive control not specified

Maximum concentration not causing irritating effects in preliminary test: 50 %

Signs of irritation during induction: Three test group animals showed slight erythema after the last topical induction application.

Evidence of sensitisation of each challenge concentration: 0

Interpretation of results:
GHS criteria not met
Conclusions:
The test item exhibited no positive results in the challenge tests at a concentration of 25 % w/w in corn oil. Therefore, the test item is not classified for skin sensitisation.
Executive summary:

The test item was assessed for skin sensitisation at 50 % w/w suspension in corn oil at induction, and 25 % w/w suspension in corn for each challenge, following the Buehler method. Three test group animals showed slight erythema after the last topical induction application. However, no positive reactions were observed in the test item group at either assessment during the challenge. The test item is therefore not classified for skin sensitisation.

The study is a GLP compliant, guideline study and is suitable for assessment of this endpoint with restrictions.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to
Guideline:
other: Annex V
Version / remarks:
Modified Buehler test
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Species:
guinea pig
Strain:
other: Himalayan albino
Sex:
not specified
Route:
other: epicutaneous
Vehicle:
corn oil
Concentration / amount:
50% (w/w) suspension
Adequacy of induction:
other: Maximum concentration not causing irritating effects in preliminary test
No.:
#1
Route:
other: epicutaneous
Vehicle:
corn oil
Concentration / amount:
25% (w/w) suspension
Day(s)/duration:
Day 29
No.:
#2
Route:
other: epicutaneous
Vehicle:
corn oil
Concentration / amount:
5, 10 and 25% (w/w) suspensions on each animal
Day(s)/duration:
Day 36
No. of animals per dose:
Number of animals in test group: 20
Number of animals in negative control group: 10
Details on study design:
The use of 9 induction exposures is considered to be more rigorous than the Annex V method (see Buehler, Arch Dermat, 1965, vol. 91) and is therefore acceptable.
Positive control substance(s):
not specified
Positive control results:
Not reported
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
25%
No. with + reactions:
5
Total no. in group:
20
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
25%
No. with + reactions:
9
Total no. in group:
20
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
5%
No. with + reactions:
0
Total no. in group:
20
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
10%
No. with + reactions:
0
Total no. in group:
20
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
5%
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
10%
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
5%
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
5%
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
10
Reading:
other: Not specified
Group:
positive control
Dose level:
Not specified
Remarks on result:
other: Positive control not specified

Signs of irritation during induction: 4/20 animals showed grade 1 erythema after the last induction exposure.

Evidence of sensitisation of each challenge concentration: 0 at all concentrations

Other observations: At first challenge, red spots were noted in 9 test animals. This minimal response is considered inconclusive evidence of sensitisation. A second challenge was therefore performed and no skin responses were seen. The overall conclusion is that the substance is not a skin sensitiser.

Interpretation of results:
GHS criteria not met
Conclusions:
At first challenge, red spots were noted in 9 test animals. This minimal response is considered inconclusive evidence of sensitisation. A second challenge was therefore performed and no skin responses were seen.
Executive summary:

The test item was assessed for skin sensitisation using Himalayan albino guinea pigs following EU Annex V guidelines. A modified Buehler study was conducted with 9 induction exposures administered every 2 or 3 days. At induction, 20 test animals received the test item in a 50% w/w suspension in corn oil and 10 test animals were designated as the negative control. The challenge exposure of 25% w/w suspension in corn oil was administered to the test group and negative control on Day 29. Red spots were noted in 9 test animals, which was considered inconclusive evidence of sensitisation. A second challenge was therefore performed with 5, 10 and 25 % w/w suspensions in corn oil administered to the test group and negative control on Day 36, in which no skin responses were seen. The overall conclusion is that the substance is not a skin sensitiser.

The study is a GLP compliant guideline experimental study acceptable with restrictions for assessment of this endpoint.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to
Guideline:
other: Annex V
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Species:
guinea pig
Strain:
other: Himalayan spotted
Sex:
not specified
Route:
intradermal and epicutaneous
Vehicle:
petrolatum
Concentration / amount:
Intradermal: 1% w/w in ethanol
Topical: 15% w/w in vaseline
Adequacy of induction:
other: Maximum concentration not causing irritating effects in preliminary test: 10% (topical) and <1% (intradermal)
No.:
#1
Route:
other: epicutaneous
Vehicle:
petrolatum
Concentration / amount:
Topical: 0% w/w in vaseline
Topical: 10% w/w in vaseline
No. of animals per dose:
Number of animals in test group: 20
Number of animals in negative control group: 10
Positive control substance(s):
not specified
Positive control results:
Not reported
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
10%
No. with + reactions:
0
Total no. in group:
20
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
0%
No. with + reactions:
0
Total no. in group:
20
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
10%
No. with + reactions:
0
Total no. in group:
20
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
0%
No. with + reactions:
0
Total no. in group:
20
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
10%
No. with + reactions:
0
Total no. in group:
20
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
0%
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
10%
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
0%
No. with + reactions:
0
Total no. in group:
20
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Reading:
other: Not specified
Group:
positive control
Dose level:
Not specified
Remarks on result:
other: Positive control not specified

Signs of irritation during induction: Very slight erythema (grade 1) was recorded in 2 test animals 24 hours after topical application.

Evidence of sensitisation of each challenge concentration: None

Other observations: One control died during the study.

Interpretation of results:
GHS criteria not met
Conclusions:
No skin responses were seen at the challenge concentration.
Executive summary:

The test item was assessed for skin sensitisation using Himalayan spotted guinea pigs in a maximisation test following EU Annex V guidelines. At induction, 20 test animals received 1% test item w/w in ethanol intradermally and 15% test item w/w in vaseline topically and 10 test animals were designated as the negative control. The challenge exposure of 10% test item w/w in vaseline was administered topically to the test group and negative control. No skin responses were seen at the challenge concentration. The overall conclusion is that the substance is not a skin sensitiser.

The study is a GLP compliant, guideline experimental study and is acceptable with restrictions for assessment of this endpoint.

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
GLP compliance:
yes
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA:J
Sex:
not specified
Vehicle:
dimethylformamide
Concentration:
0.25, 0.5, 1, 2.5 and 5%
The vehicle alone is administered to a control group
No. of animals per dose:
4
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Positive control results:
Not reported
Parameter:
SI
Value:
>= 1.17 - <= 1.21
Test group / Remarks:
0.25%
Remarks on result:
other: Range for all concentrations tested
Parameter:
SI
Value:
>= 1.17 - <= 1.21
Test group / Remarks:
0.5%
Remarks on result:
other: Range for all concentrations tested
Parameter:
SI
Value:
>= 1.17 - <= 1.21
Test group / Remarks:
1%
Remarks on result:
other: Range for all concentrations tested
Parameter:
SI
Value:
>= 1.17 - <= 1.21
Test group / Remarks:
2.5%
Remarks on result:
other: Range for all concentrations tested
Parameter:
SI
Value:
>= 1.17 - <= 1.21
Test group / Remarks:
5%
Remarks on result:
other: Range for all concentrations tested
Cellular proliferation data / Observations:
CLINICAL OBSERVATIONS:
Mortality and clinical signs: No mortality and no clinical signs were observed during the study.
Local irritation: No well-defined skin reaction is observed in the animals in the treated groups. A slight increase in ear thickness is noted in the animals that received the substance at a concentration of 5%, showing a slight irritating potential of the substance at this concentration.
Sensitizing potential: No lymphoproliferation was observed in the treated groups.
Under the experimental conditions of the test, the substance does not induce contact hypersensitivity.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the experimental conditions of the test, the substance does not induce contact hypersensitivity in an OECD 429 guideline study.
Executive summary:

The test item was assessed for skin sensitisation at 0.25, 0.5, 1, 2.5 and 5 % w/w suspensions in DMF alongside a control and positive reference substance in an OECD 429 guideline study. No mortality and no clinical signs were observed during the study and no well-defined skin reaction was observed in the animals in the treated groups. A slight increase in ear thickness was noted in the animals that received the substance at a concentration of 5%, showing a slight irritating potential of the substance at this concentration. However, no lymphoproliferation was observed in the treated groups and therefore under the experimental conditions of the test, the substance does not induce contact hypersensitivity.

 

The study is a GLP compliant, guideline experimental study and is acceptable with restrictions for assessment of this endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Skin sensitisation studies have been conducted on three substances in the MDI category. Buehler tests were conducted on EC 406-530-2 and EC 406-690-3, a local lymph node assay (LLNA) was conducted with EC 445-760-8 and a Guinea pig maximisation test was conducted with EC 406-690-3. 

For the substance EC 406-530-2 there were no positive challenge results at 25 % w/w in corn oil in the Buehler test. In the Buehler test conducted with EC 406-690-3, in the first challenge a minimal response was observed in 9 animals (red spots) and the result was considered inconclusive; a second challenge was performed where no positive results were observed. For the substance 406-690-3 in the Guinea pig maximisation test, no responses were seen at the challenge concentration. In the LLNA study conducted with EC 445-760-8, the maximum stimulation index observed was 1.21, and therefore the test item does not induce contact hypersensitivity. Based on the available data, no sensitisation classification is required for the MDI category substances.

Justification for classification or non-classification

No sensitisation classification is required for MDI category members based on studies with category members indicating that they are non sensitisers. During substance identity analysis conducted with samples of the substances registered under REACH it was confirmed that no residual diisocyanate is present in the MDI substances and therefore residual diisocyanate will not contribute to the classification of the substances.