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Toxicological information

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: Open epicutaneous test of Klecak 1977
Principles of method if other than guideline:
Method: other: Open epicutaneous test of Klecak 1977
GLP compliance:
not specified
Type of study:
open epicutaneous test
Justification for non-LLNA method:
A reliable guinea pig test is available from a time before the LLNA-OECD-TG was adopted. The information is sufficient to evaluate the sensitising potential of the test substance. Hence, a LLNA was not conducted.

Test material

Constituent 1
Chemical structure
Reference substance name:
4-methyl-m-phenylene diisocyanate
EC Number:
209-544-5
EC Name:
4-methyl-m-phenylene diisocyanate
Cas Number:
584-84-9
Molecular formula:
C9H6N2O2
IUPAC Name:
2,4-diisocyanato-1-methylbenzene
Details on test material:
- Name of test material (as cited in study report): 2,4-TDI (CAS No.584-84-9). 97% minimum

In vivo test system

Test animals

Species:
guinea pig
Strain:
Hartley
Sex:
not specified

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
epicutaneous, open
Vehicle:
other: n-butyl ether
Concentration / amount:
0, 0.025, 0.5, 0.1, 0.2, 0.4 % TDI
Challengeopen allclose all
Route:
epicutaneous, open
Vehicle:
other: n-butyl ether
Concentration / amount:
0, 0.025, 0.5, 0.1, 0.2, 0.4 % TDI
No. of animals per dose:
5-8 young adults
Details on study design:
Hair on dorsum clipped 24 h before test.
Induction by two epicutaneous applications of 25 ul TDI at 8, 20 or 40%.
Five days later, challenge by 25 ul of 0, 0.025, 0.5, 0.1, 0.2, 0.4 % TDI
Additionally at lower doses, induction by two epicutaneous applications of 25 ul TDI at 4, or 8%.
Five days later, challenge by 25 ul of 0, 0.006, 0.012, 0.025, 0.05, 0.1 % TDI
Some animals rechallenges on day 9 after first challenge.

Results and discussion

In vivo (non-LLNA)

Results
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
5
Total no. in group:
5
Clinical observations:
Score = 1 for (very slight ) erythema.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 0. No with. + reactions: 5.0. Total no. in groups: 5.0. Clinical observations: Score = 1 for (very slight ) erythema. .

Any other information on results incl. tables

The solvent controls did not produce any significant reactions although scored = 1 for very slight eryrthema. No oedema was recorded in controls.

Five days after the animals were induced with either 8, 20, or 40% TDI, they were challenged with the vehicle and dilute TDI solution (Table).  The vehicle application did not produce any significant reactions at challenge.  On the other hand, 0.025 to 0.4% TDI produced mean scores of 2.0 to 4.2 in all three TDI groups .  While the sensitization reaction was overall dependent on the concentrations used at challenge and at induction, sensitisation occurred with all TDI exposures and there was no apparent threshold for elicitation at challenge (within the range tested).  Fourteen days after induction, the 8, 20, and 40% groups were rechallenged and the 0% group was challenged (Table).  Control animals did not respond with dermal hypersensitivity reactions when challenged with applications of n-butyl ether or TDI.  For the TDI-induction groups, 100% of the animals had dermal reactions when challenged with 0.1 to 0.4% TDI.  An apparent dose response was evident with respect to both induction and challenge concentrations: however, the response was more dependent on the challenge application.

Dermal sensitization of animals induced with 2,4-Toluene diisocyanate (TDI)

Inductions

application                    Challenge concentration (%)

concentration               

(%)                  0.0       0.025   0.05     0.1       0.2       0.4                              

                                               

                                    Mean scores 24 hr after Day 5 challenge

8                      0.0       2.4       2.0       2.8       2.8       3.4

20                    0.0       2.0       1.6       2.8       3.2       3.4

40                    0.0       2.4       2.0       3.4       4.0       4.2      

                                    Mean scores 24 hr after Day 14 challenge

0                      0.0       0.5       0.9       0.6       0.0       0.4

8                      0.0       1.6       1.8       2.4       3.6       3.2      

20                    0.0       1.6       2.0       2.8       4.6       4.2      

40                    0.0       2.0       2.2       2.6       4.2       4.0      

The five guinea pigs (Camm Breeding Labs) which received induction application of either 0, 8, 20 or 40% TDI were challenged with 25 µl of TDI.

Maximum score in this system is 8.0.        

   When the 4 and 8% TDI groups were challenged with n-butyl ether, no animals showed skin reactions indicative of sensitization.  In the 4.0% group, increased skin reactions, indicative of sensitization, were seen at TDI concentrations of 0.025, 0.05, and 0.1%, where three to five animals had individual positive skin reactions consistent with sensitization.  Since the 0.006 and 0.012 challenge concentrations did not elicit a dermal sensitization response, these levels are apparently below the threshold for elicitation.  For the 8% induction group, all challenge levels elicited some degree of sensitization.  Seven of eight guinea pigs exhibited positive skin scores at 0.025% TDI, and the higher challenge levels elicited dermal hypersensitivity in all guinea pigs.  It should be mentioned, however, that only one individual in the 8% test concentration responded with a skin reaction when challenged with 0.006 and 0.012% TDI.  In addition, the results in the 4 ad 8% groups demonstrated that the sensitization reaction was overall dependent with respect to concentrations used at challenge and at induction.                 

Dermal sensitization of animals induced with 2,4-Toluene diisocyanate (TDI)

Inductions

application                    Challenge concentration (%)

concentration               

(%)                  0.0       0.006   0.012   0.025   0.05     0.1                              

                                               

                                    Mean scores 24 hr after Day 5 challenge

4.0                   1.0       1.0       0.9       1.6       1.4       1.6

8.0                   1.0       1.1       1.1       2.1       2.4       3.3

                                   

The eight guinea pigs (Hilltop Lab Animals) which received induction doses of either 4 or 8% TDI were challenged with 25 µl of TDI.

Maximum score in this system is 8.0. 

Besides demonstrating that the sensitization response was dependent on the concentrations used at challenge and induction, the second group of experiments demonstrated no observed effect levels for elicitation at challenge.  When animals were induced with 4% TDI, the 0.006 and 0.012% TDI challenge levels did not elicit dermal sensitization.  One extremely sensitive animal proved an exception in the 8% TDI group.

In conclusion, the results demonstrated that TDI produced sensitization at dilute induction applications and that the severity of the dermal response was dependent on the concentration administered at both induction and challenge.  Related to these graded responses, no observed effect levels at challenge were determined below which the challenge concentration did not elicit a dermal hypersensitivity reaction.  For the 4% TDI induction group, the no observed effect was seen with a dermal challenge application of 3µg, and a minimum effect was seen with 6.25 µg.

                          

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information
Conclusions:
. The study demonstrated that dilute concentrations of TDI can induce sensitization in guinea pigs in a dose-dependent fashion and that challenge
reactions could be measured in a dose-responsive manner.
Classification: sensitizing

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