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Diss Factsheets

Toxicological information

Skin sensitisation

Currently viewing:

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-05-20 to 2009-07-09
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
In consideration of the available human data the results of the animal studies, namely the LLNA, seems to be over-predictive for the endpoint skin sensitisation.

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4'-Methylenediphenyl diisocyanate, oligomers
EC Number:
500-040-3
EC Name:
4,4'-Methylenediphenyl diisocyanate, oligomers
Cas Number:
25686-28-6
Molecular formula:
C14 H10 N O [C29 H20 N4 O2]n NCO, n= 0-2
IUPAC Name:
1,1'-methylenebis(4-isocyanatobenzene) homopolymer

In vivo test system

Test animals

Species:
guinea pig
Strain:
Hartley
Sex:
male/female

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
other: propylene glycol
Concentration / amount:
0.5%
Day(s)/duration:
D1
Adequacy of induction:
not specified
Route:
epicutaneous, semiocclusive
Vehicle:
other: propylene carbonate
Concentration / amount:
50%; 0.3mL
Day(s)/duration:
D8
Adequacy of induction:
not specified
Challenge
No.:
#1
Route:
epicutaneous, semiocclusive
Vehicle:
other: propylene carbonate
Concentration / amount:
20%; 0.2mL
Day(s)/duration:
D22
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
11 Dose Range-finding
10 Test Article Group
5 Vehicle Control Group
Positive control substance(s):
yes
Remarks:
1-chloro-2, 4-dinitrobenzene (DNCB)

Results and discussion

Positive control results:
The positive control animals exhibited the anticipated positive response to DNCB. DNCB at 0.05% in petrolatum caused moderate to severe reactions at 24 and 48 hours and is considered an extreme sensitizer. This periodic positive
control report (0423GC62.010) is attached as Appendix III.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Remarks on result:
positive indication of skin sensitisation

Applicant's summary and conclusion

Interpretation of results:
other: Harmonized classification as skin sensitizer category 1 (H317)
Conclusions:
The test material was evaluated in the Magnusson-Kligman guinea pig maximization model of delayed hypersensitivity. Prior to experimental initiation

of the induction, the irritation potential of the test article was determined with a dose range-finding studies (intradermal and topical) utilizing 11 naIve guinea

pigs. Based upon these results, the intradermal dose utilized was 0.5%, the topical induction dose was 50% and the challenge dose utilized was 20% in the

main study.



The main study was conducted with 10 animals for the test article group and five animals for the vehicle control group. Positive control information is

provided in a positive control study report (see Appendix III). For the intradermal induction phase (Day 1), each guinea pig received intradermal

injections (0.1 mL each) of Freund's Complete Adjuvant and either Jeffsol Propylene Carbonate-NF (vehicle control group) or the test article at a

concentration of 0.5% (test article group) with and without Freund's Complete Adjuvant for a total of six dose sites.



On Day 8, either the test article at 50% (test article group-0.3 mL) or Jeffsol Propylene Carbonate-NF (vehicle control group-0.3 mL) was spread over a 2 x 4

cm filter paper and applied to the injection site areas. Blenderm® tape was used to occlude the injection area. The dressings were removed following 48 hours of

exposure.



Two weeks after the topical induction, the hair was removed from right and left flanks. On Day 22, all test article and vehicle control group animals were

challenged with occluded patches for 24 hours on the left and right flanks. A 2 x 2 cm filter paper was saturated (0.2 mL test article) with the test article at 20%

and applied to the animal's left flank. Another 2 x 2 cm filter paper was saturated (0.2 mL) with the vehicle (Jeffsol Propylene Carbonate-NFl and

applied to the animal's right flank. The same occlusive technique was employed as for topical induction. After 24 hours, sites were unwrapped and

wiped cleaned with gauze. Twenty one hours after unwrapping, the sites were depilated. Three hours later the sites were graded for elicited skin reactions

(24-hour grade). Approximately 24 hours later the sites were graded a second time (48-hour grade).



No mortality was observed in any vehicle control or test article group animals on study. No clinical signs were observed in any vehicle control group animals on

study. Three animals were observed as slightly pale in the test article treated group on Day 15 of the study. No other clinical signs were noted in the test

article treated group during the study.



In conclusion, under the conditions of this study, an intradermal induction of the test substance at 0.5% with a topical induction at 50%, followed by a topical

challenge at 20% to guinea pigs did elicit a dermal sensitization response at 24 and 48 hours post treatment. Therefore, the test substance is considered to be a

contact sensitizer in Guinea Pigs.
Executive summary:

The test material is part of a MDI category.  Numerous animal studies are available to demonstrate the skin sensitizing potential of MDI, which is supported by clinical observations in humans. For the endpoint skin sensitization, all effects are consistent with the hypothesized MoA and direct electrophilic reactions of the NCO group on mMDI with biological nucleophiles. Reaction of NCO with a protein, marks antigen formation and the MIE of the sensitization process. Upon re-exposure via the dermal route, protein-hapten complexes are recognized by the immune system, triggering an immunological response resulting in the induction of sensitization.


All substances of the MDI category share similar chemical features namely that they a) all contain a significant amount of mMDI, and b) contain at least two NCO functional groups per molecule which is bound to an aromatic ring and this ring is connected to a second aromatic ring by a methylene group. It is the NCO value (driven by the bioaccessible groups on monomeric MDI and low molecular weight constituents (e.g. three-ring oligomer) which is responsible for chemical and physiological reactivity and subsequent toxicological profile. As reactive NCO groups are a common feature of all substances of the MDI category, it is predicted that these have a similar reactivity profile and a read across within the category is warranted (detailed information on the Mode of Action is available in Category Justification Document).


 


The current study on the test material supports category hypothesis and conclusions.