2,4,6-trinitrobenzene-1,3,5-triamine

Endpoint summary

Description of key information

- Not sensitising (OECD 406, GLP, K, rel. 2)

- No alerts for skin sensitisation (OECD QSAR Toolbox profilers, rel.2)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

purity of test substance; acclimation period, details on test animals/environmental conditions, detailed test procedure and results not reported

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

yes

Remarks:

purity of test substance; acclimation period, details on test animals/environmental conditions, detailed test procedure and results not reported

Principles of method if other than guideline:

Not applicable

GLP compliance:

no

Remarks:

pre-GLP

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

At the time of study completion (1976), the LLNA was not available.

Species:

guinea pig

Strain:

Hartley

Sex:

male

Details on test animals and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 300-400 g
- Housing: Animals were housed individually
- Diet: Commercial laboratory ration supplemented on alternate days with fresh lettuce or cabbage, ad libitum

Route:

intradermal

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1%

Concentration / amount:

0.1%
1st injection of 0.05 mL; other 9 injections of 0.1 mL (10 injections)

Day(s)/duration:

2 weeks

No.:

#1

Route:

intradermal

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1%

Concentration / amount:

0.05 mL

Day(s)/duration:

24 hours

No. of animals per dose:

10 animals

Details on study design:

PRE-TREATMENT: Before each injection, the test site was clipped free of hair with electric small-animal clippers.

INDUCTION EXPOSURE
Test substance was administered in a series of ten "sensitising" injections into the lower back and flanks of the guinea pigs. Injections were made randomly over the test area every other day using tuberculin syringe. The volume of the first injection was 0.05 mL; the other nine injections were each 0.1 mL. Twenty-four hours after each injection, the resulting reaction was scored for redness, height, and diameter. Redness and height were scored as described by Draize method; diameters of reactions were measured in millimeters using micrometer calipers.

CHALLENGE EXPOSURE
Two weeks after administration of the tenth sensitising injection, the lower back and flanks of each experimental guinea pig were clipped free of hair, and a challenge injection of 0.05 mL was administered. Each animal's reactions were graded 24 hours later and compared with those from the sensitizing injections.

Challenge controls:

None

Positive control substance(s):

not specified

Positive control results:

None

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1%

No. with + reactions:

0

Clinical observations:

None

Remarks on result:

no indication of skin sensitisation

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

0.1%

No. with + reactions:

0

Clinical observations:

None

Remarks on result:

no indication of skin sensitisation

Group:

positive control

Remarks on result:

not measured/tested

None

Interpretation of results:

GHS criteria not met

Conclusions:

Under the test conditions, the test substance is not classified as skin sensitiser, therefore it is not classified according to the annex I of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

Executive summary:

In a skin sensitisation study, the test substance was administered to group of male Hartley guinea pigs as induction and challenge phase. Test substance was diluted to a concentration of 0.1% with a 1% solution of carboxymethylcellulose. The control group received the 1% solution or of carboxymethylcellulose alone.

 

Induction phase: Test substance was administered in a series of ten "sensitising" injections into the lower back and flanks of the guinea pigs. The volume of the first injection was 0.05 mL; the other nine injections were each 0.1mL. Twenty-four hours after each injection, the resulting reaction was scored for redness, height, and diameter.

 

Challenge phase: Two weeks after administration of the tenth sensitising injection, the lower back and flanks of each experimental guinea pig were clipped free of hair, and a challenge injection of 0.05 mL was administered. Each animal's reactions were graded 24 hours later and compared with those from the sensitizing injections.

 

No skin sensitization reactions were observed in the treated animals.

 

Under the test conditions, the test substance is not classified as skin sensitiser, therefore it is not classified according to the annex I of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

Reference 2

Endpoint:

skin sensitisation, other

Remarks:

OECD QSAR Toolbox profilers

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

15 september 2017

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 adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
- OECD QSAR Toolbox v4.1

2. MODEL (incl. version number)
- Structural alerts for protein binding of OECD QSAR Toolbox v4.1:
Protein binding by OASIS
Protein binding by OECD
Protein binding potency
Protein binding potency Cys (DPRA 13%)
Protein binding potency Lys (DPRA 13%)
Protein binding alerts for skin sensitisation by OASIS
Protein binding potency h-CLAT

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Smiles code : Nc1c(c(N)c(c(N)c1[N+]([O-])=O)[N+]([O-])=O)[N+]([O-])=O
CAS Number: 3058-38-6

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached document

5. APPLICABILITY DOMAIN
See attached document

6. ADEQUACY OF THE RESULT
See attached document

Qualifier:

no guideline required

Principles of method if other than guideline:

- Software tool(s) used including version: OECD QSAR Toolbox v4.1
- Model(s) used: Structural alerts for protein binding
- Model description: see field 'Justification for type of information'
- Justification of QSAR prediction: see field 'Justification for type of information'

Remarks on result:

other: QSAR prediction

Remarks:

See 'Any other information on results incl. tables'

Table: Results for skin sensitisation profilers of TATB using the OECD QSAR Toolbox 4.1

Profiler	Result
Protein binding by OASIS	No alert found
Protein binding by OECD	No alert found
Protein binding potency	Not possible to classify according to these rules (GSH)
Protein binding potency Cys (DPRA 13%)	DPRA less than 9% (DPRA 13%)
Protein binding Lys (DPRA 13%)	DPRA less than 9% (DPRA 13%)
Protein binding alerts for skin sensitisation according to GHS	No alert found
Protein binding alerts for skin sensitisation by OASIS	No alert found
Protein binding Potency h-CLAT	No alert found
Respiratory sensitisation	No alert found

 

Interpretation of results:

GHS criteria not met

Conclusions:

No protein binding and Skin Sensitisation-relevant structural alerts were triggered for TATB. Since no structural analogues with known experimental data were identified, no read-across exercise could be performed.

Executive summary:

The key objective of this work was to perform a read-across and QSAR analyses to predict the skin sensitisation potential of TATB using OECD QSAR Toolbox v4.1

This report provides a summary of how the QSAR results were derived using OECD QSAR Toolbox profilers. Please refer to the tool directly to get further information on each of these profilers.

TATB was screened through the 9 Skin Sensitisation profilers (listed in Table 2) incorporated into the OECD QSAR Toolbox v4.1 to identify its protein binding potential. In KREATiS’ opinion, profiling can be considered as an initial screening approach to get a general idea about the Skin Sensitisation potential of TATB on the basis of the triggered structural alerts. 

 

Based on structural similarity, a category was defined to identify structural analogues of TATB, however none of them had any experimental data available therefore no read-across was performed.

 

Autoxidation, Dissociation, Hydrolysis and Skin Metabolism simulators incorporated into this toolbox were also applied, however no potential metabolites for TATB were identified.

Conclusion: No protein binding (first event of the AOP) and Skin Sensitisation-relevant structural alerts were triggered for TATB. Since no structural analogues with known experimental data were identified, no read-across exercise could be performed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

A key study was identified (Newell 1976). In this dermal sensitisation study performed similarly to the OECD guiideline No. 406, the test substance was administered to group of male Hartley guinea pigs as induction and challenge phase. Test substance was diluted to a concentration of 0.1% with a 1% solution of carboxymethylcellulose.

Test substance was administered in a series of ten induction injections (1st 0.05, then 0.1 mL) into the lower back and flanks of the guinea pigs. Twenty-four hours after each injection, the resulting reaction was scored for redness, height, and diameter.

Two weeks after administration of the tenth sensitising injection, the lower back and flanks of each experimental guinea pig were clipped free of hair, and a challenge injection of 0.05 mL was administered. Each animal's reactions were graded 24 hours later and compared with those from the sensitizing injections.

No skin sensitization reactions and no clinical signs were observed in the treated animals.

Under the test conditions, the test substance is not a skin sensitiser.

Moreover, the registered substance was screened through the 9 Skin Sensitisation profilers incorporated into the OECD QSAR Toolbox v4.1 to identify its protein binding potential and the conclusion was that No protein binding and Skin Sensitisation-relevant structural alerts were triggered.

Considering both the results of the in vivo study and the predictions from the OECD QSAR Toolbox v4.1, it is concluded that the test substance is not a skin sensitiser.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Based on the available data no additional self-classification is proposed according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

No data was available for respiratory sensitisation. However, this substance is not a skin sensitizer, therefore according to Figure R.7.3 -2 of the Chapter R.7 (V 4.1 - October 2015) the chemical is not considered as a respiratory sensitizer.