1,5-dinitronaphthalene

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation, other

Remarks:

Not Applicable (Q)SAR - structural analysis only

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

03 Oct 2017

Reliability:

1 (reliable without restriction)

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:

The (Q)SARs models used in this assessment have been evaluated by the Joint Research Centre (JRC) and the scientific validity of each software established according to five principles recommended by OECD and ECHA for regulatory purposes (Annex XI of the REACH).
At present, a summary of appropriate information on the (Q)SAR models, based on the topics listed below, is not available in a specific reporting format.
• • Endpoint, algorithm
• • Domain of applicability
• • Measures related to goodness-of-fit
• • Robustness
• • Predictivity and mechanism

However, the adequacy and reliability of each (Q)SAR prediction was checked for each endpoint following the procedures outlined in REACH Annex XI (1.3) in terms of suitability of the model (reliability, relevance for the purpose), applicability of the model to the substance of interest and adequacy of the predicted endpoint for classification and labelling.

See attached justification for further information.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

(Q)SAR analysis using valid models - no guideline required.

GLP compliance:

no

Justification for non-LLNA method:

(Q)SAR analysis using valid models. No animals used.

Test material

Test material information

Constituent 1

Reference substance name:

1,5-dinitronaphthalene

EC Number:

210-095-2

EC Name:

1,5-dinitronaphthalene

Cas Number:

605-71-0

Molecular formula:

C10H6N2O4

IUPAC Name:

1,5-dinitronaphthalene

Test material form:

other: In SIlico

Details on test material:

In silico test item

Specific details on test material used for the study:

Not applicable - (Q)SAR analysis

In vivo test system

Test animals

Species:

other: (Q)SAR analysis

Strain:

other: (Q)SAR analysis

Sex:

not specified

Details on test animals and environmental conditions:

Not Applicable (Q)SAR - structural analysis only

Results and discussion

Positive control results:

Not Applicable (Q)SAR - structural analysis only, no tissue dependance

In vitro / in chemico

Results

Key result

Run / experiment:

other: (Q)SAR - structural analysis

Parameter:

other: (Q)SAR - structural analysis

Vehicle controls validity:

other: Not aplicable: (Q)SAR

Negative controls validity:

other: Not aplicable: (Q)SAR

Positive controls validity:

other: Not aplicable: (Q)SAR

Remarks on result:

positive indication of skin sensitisation

Remarks:

Despite the lack of animal testing data for this endpoint, the weight of evidence approach suggests classification of 1,5-dinotronapthalene as a skin sensitiser category 1B.

Any other information on results incl. tables

The skin sensitisation potential of a substance is related to its intrinsic ability to react with proteins and consequently to form covalently linked conjugates that should be recognised by the human immune system (ECHA, 2016a). This property is largely dependent on the electrophilic reactivity of the chemical. To take into account this aspect, various types of electrophile-nucleophile reactions of skin sensitisation comprise the domain of applicability used by some (Q)SAR models. Accordingly, the first screening for skin sensitisation of 1,5-dinitronapthalene was performed using specific endpoints and protein binding profilers in the OECD Toolbox, such as OASIS v 1.3, OASIS v1.4 and OECD. None of these endpoints triggered alerts for electrophile-nucleophile type reactions, including the “reactivity mode of action” endpoint in Toxtree.

Further qualitative (Q)SAR predictions were performed in the models incorporating training sets of experimentally in vivo tested molecules. The “CAESAR skin sensitisation” model in VEGA(Q)SAR software predicted that 1,5-dinitronapthalene has skin sensitiser potential with good reliability (Applicability Domain Index, AD=0.93) for the prediction. The model predicts this endpoint based on grouping of similar molecules with positive data in the murine local lymph node assay (LLNA). Other in vivo skin sensitisation models available in the Danish (Q)SAR database –allergic contact dermatitis in guinea pig and human gave a “POS_IN” result from specific endpoints of CASE Ultra, and SciQSAR.

The (Q)SAR data generated with specific models to estimate in vivo skin sensitisation effects gave strong evidence that 1,5-dinitronapthalene has a skin sensitisation potential. This property seems to be related to a moderate electrophilic reactivity profile of this molecule as suggested by the results obtained in the OECD Toolbox model “Direct Peptide Reactivity Assay”- DPRA. The DPRA is a standardised OECD test (TG 442C) to provide information on the molecular initiation events of skin sensitisers using synthetic heptapeptides containing cysteine and lysine amino acids. The estimated result revealed that 1,5-dinitonapthelene can bind to both these amino acids with DPRA potency of 13% in both cases.

Other factors not covered by the (Q)SAR models, such as hydrophobicity extrapolated by the Log P, were also considered in the evaluation. Specifically, the Log P of 2.8 estimated in DEREK Nexus for 1,5-dinitronapthalene is within the range of values that facilitate penetration into the human skin (EC, 2003).

Assessment of the quality of predictions: The skin sensitisation prediction in VEGA(Q)SAR was inside the applicability domain of the model and the overall assessment gave an AD index close to 1 (i.e., 0.903). The skin sensitisation prediction in the Consensus model available in the Danish QSAR database gave a result “POS_IN” which is an indication that the tested molecule was inside the applicability domain of this model.

General follow-up procedure: Despite the lack of animal testing data for this endpoint, the weight of evidence approach suggests classification of 1,5-dinotronapthalene as a skin sensitiser category 1B.

Applicant's summary and conclusion

Interpretation of results:

Category 1B (indication of skin sensitising potential) based on GHS criteria

Conclusions:

The (Q)SAR data generated with specific models to estimate in vivo skin sensitisation effects gave strong evidence that 1,5-dinitronapthalene has a skin sensitisation potential. This property seems to be related to a moderate electrophilic reactivity profile of this molecule as suggested by the results obtained in the OECD Toolbox model “Direct Peptide Reactivity Assay”- DPRA. The DPRA is a standardised OECD test (TG 442C) to provide information on the molecular initiation events of skin sensitisers using synthetic heptapeptides containing cysteine and lysine amino acids. The estimated result revealed that 1,5-dinitonapthelene can bind to both these amino acids with DPRA potency of 13% in both cases.
Other factors not covered by the (Q)SAR models, such as hydrophobicity extrapolated by the Log P, were also considered in the evaluation. Specifically, the Log P of 2.8 estimated in DEREK Nexus for 1,5-dinitronapthalene is within the range of values that facilitate penetration into the human skin (EC, 2003).
Assessment of the quality of predictions: The skin sensitisation prediction in VEGA(Q)SAR was inside the applicability domain of the model and the overall assessment gave an AD index close to 1 (i.e., 0.903). The skin sensitisation prediction in the Consensus model available in the Danish QSAR database gave a result “POS_IN” which is an indication that the tested molecule was inside the applicability domain of this model.
General follow-up procedure: Despite the lack of animal testing data for this endpoint, the weight of evidence approach suggests classification of 1,5-dinotronapthalene as a skin sensitiser category 1B.

Executive summary:

The (Q)SAR data generated with specific models to estimate in vivo skin sensitisation effects gave strong evidence that 1,5-dinitronapthalene has a skin sensitisation potential. This property seems to be related to a moderate electrophilic reactivity profile of this molecule as suggested by the results obtained in the OECD Toolbox model “Direct Peptide Reactivity Assay”- DPRA. The DPRA is a standardised OECD test (TG 442C) to provide information on the molecular initiation events of skin sensitisers using synthetic heptapeptides containing cysteine and lysine amino acids. The estimated result revealed that 1,5-dinitonapthelene can bind to both these amino acids with DPRA potency of 13% in both cases.

Other factors not covered by the (Q)SAR models, such as hydrophobicity extrapolated by the Log P, were also considered in the evaluation. Specifically, the Log P of 2.8 estimated in DEREK Nexus for 1,5-dinitronapthalene is within the range of values that facilitate penetration into the human skin (EC, 2003).

Assessment of the quality of predictions: The skin sensitisation prediction in VEGA(Q)SAR was inside the applicability domain of the model and the overall assessment gave an AD index close to 1 (i.e., 0.903). The skin sensitisation prediction in the Consensus model available in the Danish QSAR database gave a result “POS_IN” which is an indication that the tested molecule was inside the applicability domain of this model.

General follow-up procedure: Despite the lack of animal testing data for this endpoint, the weight of evidence approach suggests classification of 1,5-dinotronapthalene as a skin sensitiser category 1B.