2-methyl-m-phenylene diisocyanate

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

The supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Prediction is done using QSAR Toolbox version 3.4

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4

GLP compliance:

no

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2,6-Toluene diisocyanate
- Molecular formula: C9H6N2O2
- Molecular weight: 174.1584 g/mol
- Smiles notation: c1(cccc(c1C)N=C=O)N=C=O
- InChl: 1S/C9H6N2O2/c1-7-8(10-5-12)3-2-4-9(7)11-6-13/h2-4H,1H3
- Substance type: Organic
- Physical state: Liquid

Species:

guinea pig

Strain:

not specified

Sex:

female

Details on test animals and environmental conditions:

no data

Route:

intradermal

Vehicle:

other: olive oil or Freund's adjuvant

Concentration / amount:

not specified

Day(s)/duration:

not specified

Adequacy of induction:

not specified

Route:

epicutaneous, semiocclusive

Vehicle:

no data

Concentration / amount:

not specified

Day(s)/duration:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

no data

Details on study design:

no data

Challenge controls:

no data

Positive control substance(s):

not specified

Vehicle:

not specified

Concentration:

not specified

No. of animals per dose:

not specified

Details on study design:

not specified

Positive control results:

not specified

Reading:

1st reading

Group:

test chemical

Clinical observations:

sensitizing

Remarks on result:

positive indication of skin sensitisation

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" or "b" or "c") and("d" and(not "e")) ) and("f" and(not "g")) ) and "h") and("i" and(not "j")) ) and("k" and "l") )

Domain logical expression index: "a"

Referential boundary:The target chemical should be classified as Acylation AND Acylation >> Isocyanates and Isothiocyanates AND Acylation >> Isocyanates and Isothiocyanates >> Isocyanates by DNA binding by OECD

Domain logical expression index: "b"

Referential boundary:The target chemical should be classified as Acylation AND Acylation >> (Tio)carbamoylation of protein nucleophiles AND Acylation >> (Tio)carbamoylation of protein nucleophiles >> Isothiocyanates, Isocyanates AND AN2 AND AN2 >> Direct carbamoylation of protein amines AND AN2 >> Direct carbamoylation of protein amines >> Isocyanates and Diisocyanates by Protein binding by OASIS v1.4

Domain logical expression index: "c"

Referential boundary:The target chemical should be classified as Acylation AND Acylation >> Isocyanates and Related Chemicals AND Acylation >> Isocyanates and Related Chemicals >> Isocyanates by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary:The target chemical should be classified as Acylation AND Acylation >> Isocyanates and Isothiocyanates AND Acylation >> Isocyanates and Isothiocyanates >> Isocyanates by DNA binding by OECD

Domain logical expression index: "e"

Referential boundary:The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "f"

Referential boundary:The target chemical should be classified as Acylation AND Acylation >> (Tio)carbamoylation of protein nucleophiles AND Acylation >> (Tio)carbamoylation of protein nucleophiles >> Isothiocyanates, Isocyanates AND AN2 AND AN2 >> Direct carbamoylation of protein amines AND AN2 >> Direct carbamoylation of protein amines >> Isocyanates and Diisocyanates by Protein binding by OASIS v1.4

Domain logical expression index: "g"

Referential boundary:The target chemical should be classified as SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.4

Domain logical expression index: "h"

Referential boundary:The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "i"

Referential boundary:The target chemical should be classified as Isocyanate and isothiocyanate groups AND Primary aromatic amine, hydroxyl amine and its derived esters by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "j"

Referential boundary:The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.2

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.48

Interpretation of results:

sensitising

Conclusions:

The substance 2, 6-Toluene diisocyanate (CAS No: 91-08-7) is estimated to be sensitising to skin of female guinea pigs.

Executive summary:

The skin sensitization potential for 2, 6-Toluene diisocyanate (CAS No: 91-08-7) is estimated using OECD QSAR toolbox version 3.4

The test substance 2, 6-Toluene diisocyanate (CAS No: 91-08-7) is estimated to be sensitising to skin of female guinea pigs.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Skin sensitization

Skin sensitization behaviour of test compound 2, 6-Toluene diisocyanate (CAS No: 91-08-7)have been summarized below by using data from prediction model based estimation and its read across substances.

The OECD QSAR toolbox version 3.4 estimated the skin sensitization potential of test chemical e 2, 6-Toluene diisocyanate (CAS No: 91-08-7) on guinea pigs by guinea pig maximization test. According to this prediction model, the test chemical was able to induce skin sensitization in guinea pigs. Thus the test compound 2, 6-Toluene diisocyanate (CAS No: 91-08-7)is estimated to be sensitizing to skin of guinea pigs.

According to Danish (Q) SAR Database 2017, the sensitization effects were observed for target e 2, 6-Toluene diisocyanate (CAS No: 91-08-7) in guinea pig and human. Based on the QSAR prediction done using the Danish (Q)SAR Database, the skin sensitization was estimated to be skin sensitizer on guinea pig and human for 2, 6-Toluene diisocyanate (CAS No: 91-08-7). Thus it can be concluded that the substance 2, 6-Toluene diisocyanate (CAS No: 91-08-7) has positive skin sensitization effects.

The skin sensitization study was conducted by FRANCIS J. KOSCHIER, EDWARD J. BURDEN, CINDY S. BRUNKHORST, AND MARVIN A. FRIEDMAN (1983)for similar read across substance 2, 4-Toluene diisocyanate (CAS No: -584-84-9) on guinea pigs via open epicutaneous test for test chemical. This study was designed to determine the concentration-dependent elicitation of dermal sensitization in guinea pigs treated with TDI. In this study, young adult guinea pigs received two open, epicutaneous induction applications (25 µL) of 8, 20, or 40% TDI in n-butyl ether on two separate areas. During induction at 20 and 40%concentrations, both the 24- and 48-hr readings (2.0) were much greater than those for the solvent group. Five days later, animals were challenged with 0.0, 0.025, 0.05, 0.1, 0.2, and 0.4% TDI (25 µL per concentration site). 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. All challenge applications except the 0.0% solution elicited a positive response in 75 to 100% of the animals. Fourteen days after induction, the 8, 20, and 40% groups were rechallenged and the 0% group was challenged. 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, and the severity of the skin reactions was dependent on the concentrations of the challenge and induction application. Based upon the observations the test material2, 4-Toluene diisocyanate(CAS No: -584-84-9)was considered to be sensitizing on guinea pigs.

Another skin sensitization study was carried out for same read across substance 2, 4-Toluene diisocyanate (CAS No: -584-84-9) by Kazumasa YAsuDA, Goro NozAwA, Tomoko Goto, Norihiro SASAKI and Sumiko ISHIZU (1890)on BALB/c (hairy) mice via the ear swelling test.  In this test, the mice were divided into 2 groups: group A-28 hairy mice sensitized with TDI; Group B- 28 unsensitized hairy mice, the control for group A. During induction, a solution of1%, 5% and 30%TDI in olive oil was applied on depilated skin of group A for 5 consecutive days and then left without any treatment for next 3 days. On the 4thday after the fifth sensitizing application, a solution of1% TDI in olive oil was applied on ears for challenge. The results were obtained my measurement of the ear thickness after 24 and 48 hours post-challenge.   It was observed that the ears of group A began to redden and swell drastically following the challenge. The ear thickness increased from 25.1X10 -2mm to 56.7 X 10-2. The increase rate was 126%. The ear of group B showed a slight reddening and swelling 24hr after challenge. The ear thickness increased from 24.3x10-2mm before challenge to 27.5X 10-2mm in group B receiving challenge. The increased percentage of ear thickness was 13%. At microscopic examination, tenement related pathological changes were notably observed in the thymus. As animals showed atrophy of the thymus. The weight decreased from 41.2 ±5.5 mg in group B to 22.9 ± 4.0 mg in group a being reduced by nearly half.in addition, it was observed that the weight of the spleen (140.5 ± 9.3mg) increased in group A as compared with group B (110 ± 9.7mg). As for the liver there was no special changes in gross observation, while the differences in weight between group A and group B being 1.20 ± 0.13G and 1.22 ± 0.12 g respectively, were not significant On the basis of observed effects, the test material2, 4-Toluene diisocyanate(CAS No: -584-84-9)was considered to be sensitizing on BALB/c (hairy) mice.

 

Thus the available data estimated by prediction model for target substance 2, 6-Toluene diisocyanate (CAS No: 91-08-7) as well as available data for read across substance 2, 4-Toluene diisocyanate (CAS No: -584-84-9) and applying weight of evidence approach suggests that the test chemical substance 2, 6-Toluene diisocyanate (CAS No: 91-08-7) is likely to cause skin sensitization and thus can be classified as skin sensitizer.

Migrated from Short description of key information:

The OECD QSAR toolbox version 3.4 estimated the skin sensitization potential of test chemical e 2, 6-Toluene diisocyanate (CAS No: 91-08-7) on guinea pigs by guinea pig maximization test. According to this prediction model, the test chemical was able to induce skin sensitization in guinea pigs. Thus the test compound 2, 6-Toluene diisocyanate (CAS No: 91-08-7) is estimated to be sensitizing to skin of guinea pigs.

Justification for selection of skin sensitisation endpoint:

The substance 2, 6-Toluene diisocyanate (CAS No: 91-08-7) is estimated to be sensitising to skin of female guinea pigs.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test chemical substance 2, 6-Toluene diisocyanate (CAS No: 91-08-7)and its read acrosssubstance 2, 4-Toluene diisocyanate (CAS No: -584-84-9) were observed in various studies. From the results obtained from these studies it is concluded that the chemical substance 2, 6-Toluene diisocyanate (CAS No: 91-08-7) was able to cause skin sensitization and hence can be classified as skin sensitizing.