Alkylated Naphthalene

Skin sensitisation

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Administrative data

Endpoint:

skin sensitisation

Remarks:

other: QSAR

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Assessment made with accepted QSAR model (TOXTREE)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

The mechanism of toxicity for most skin sensitizers is by covalent bond formation with skin proteins. It is accepted that for a chemical to have skin sensitizing potential it must either be directly electrophilic or have the potential to be converted (via oxidation or metabolism) into an electrophile These reactions can be described in terms of nucleophilic-electrophilic reaction chemistry. Therefore, a QSAR analysis may be made via assesment of a chemical's potential mechanism of action which enables prediction of the substances nucleophilic-electrophilic reaction chemistry.

GLP compliance:

no

Type of study:

other: Expert report based on QSAR model

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

liquid: viscous

Details on test material:

Identification: Alkylated Naphthalene
Description: Clear amber slightly viscous liquid
Purity/Composition: UVCB 100%
The tri-alkylated component occurs most abundantly, therefore, for the purposes of the present modeling, the tri-alkylated structure was used as the representative chemical species.

In vivo test system

Test animals

Species:

other: The QSAR model

Results and discussion

Any other information on results incl. tables

The representative constituent of alkylated naphthalene was entered into the TOXNET program using the SMILES code for the substance.

The program made the following SMARTS evaluations for this structure (SMARTS are 2D structural descriptors) :

Nucleophilic Aromatic Substitution	No
Schiff Base Formation	No
Michael Acceptor	No
Acyl Transfer Agents	No
Nucleophilic Aliphatic Substitution	No
At least one alert for skin sensitisation?	No

 

Classification          No skin sensitization alerts identified.  

Applicant's summary and conclusion

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Evaluation of alkylated naphthalene with the TOXTREE model for skin sensitization alerts indicates the substance has no structural alerts for sensitization. The weight of the available evidence indicates the substance is not sensitizing.

Executive summary:

The sensitization potential of Alkylated Naphthalene was made using the QSAR model in the TOXTREE set of models. In order to reduce both the cost and the numbers of animals tested for skin sensitization determination, the use of quantitative structure-activity relationships (QSAR) has been encouraged and should be part of compliance testing strategies.

The mechanism of toxicity for most skin sensitizers is by covalent bond formation with skin proteins. It is accepted that for a chemical to have skin sensitizing potential it must either be directly electrophilic or have the potential to be converted (via oxidation or metabolism) into an electrophile [1]. These reactions can be described in terms of nucleophilic-electrophilic reaction chemistry. Therefore, the initial step in QSAR analysis is the assessment of a chemical's potential mechanism of action which enables placement of the substance in an appropriate reactivity domain.

 

A recently published dataset of 210 LLNA test results was used as the primary training data in order to derive the SMARTS patterns for the five mechanisms of action. The goal of Enoch et al. [2] was to create a series of SMARTS patterns capable of reproducing the expert classification recently published by Roberts et al. [3]. The SMARTS strings developed covered a number of possible reactions within each of the five electrophilic mechanisms. In addition, a range of likely oxidation and metabolism transformations were included. The SMARTS patterns correctly identified the mechanisms of action of 203 of the 208 chemicals investigated. In the majority of cases (195) only a single mechanism of action was assigned to each chemical, however for the remaining 13 chemicals two potential mechanisms were identified.

 

Having defined the initial SMARTS patterns, a second recently published series of 44 LLNA assay results with mechanisms of action assigned to them was used to validate the rules [4]. The mechanisms assigned by the SMARTS patterns were in agreement with those assigned by Roberts et al. [4] for 40 out of the 44 chemicals. In six cases more than a single possible mechanism was suggested, with three chemicals being assigned to the SN2 and acylation mechanisms and two chemicals flagging both the SN2 and Michael addition mechanisms.

 

Evaluation of alkylated naphthalene with the TOXTREE model for skin sensitization alerts indicates the substance has no structural alerts for sensitization. If a chemical fails to trigger any of the electrophilic rules coded in the SMARTS patterns, it does not necessarily mean that it will be a non-sensitizer. It should be recognized that animal-based studies do not identify all sensitizers also. Final evaluations should be based on a weight of evidence approach. For Alkylated Naphthalene it is significant, therefore, that no reports of sensitization reactions have been reported for the substance or its commercial product formulation.

 

Based on the modeling results and the history of use of the product, it is concluded that alkylated naphthalene poses acceptably low or negligible risks of sensitization effects and does not require classification.

 

References

 

[1] A.O. Aptula, G. Patlewicz, and D.W. Roberts, Skin sensitization: Reaction mechanistic applicability domains for structure–activity relationships, Chem. Res. Toxicol. 18 (2005), pp. 1420–1426.

 

[2]Enoch SJ,Madden JC,Cronin.2008. Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach.SAR QSAR Environ Research.19(5-6): 555-78. 

 

[3] D.W. Roberts, G. Patlewicz, P.S. Kern, F. Gerberick, I. Kimber, R.J. Dearman, C.A. Ryan, D.A. Basketter, and A.O. Aptula, Mechanistic applicability domain classification of a local lymph node assay dataset for skin sensitization, Chem. Res. Toxicol. 20 (2007),

pp. 1019–1030.

 

[4] D.W. Roberts, G. Patlewicz, S.D. Dimitrov, L.K. Low, A.O. Aptula, P.S. Kern,

G.D. Dimitrova, M.I.H. Comber, R.D. Phillips, J. Niemela, C. Madsen, E.B. Wedebye,

P.T. Bailey, and O.G. Mekenyan, A mechanistic evaluation of an external

validation study using reaction chemistry principles, Chem. Res. Toxicol. 20 (2007),

pp. 1321–1330.