N,N'-methylenedistearamide

Endpoint summary

Description of key information

- The weight of evidence of the assessed QSAR models suggested N,N'-methylendistearamide to be not a skin sensitizer.

- In a guinea pig maximisation test performed similar to OECD 406, the substance was considered to be non-sensitising to the skin.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation, other

Remarks:

QSAR model

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2018

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:

MODEL
Skin sensitisation potential was performed with QSAR models TOPKAT 4.5 and CAESAR (VEGA 1.1.4), with expert system Derek 5.0.2 and Toxtree 2.6.13. The assessment with OECD QSAR Toolbox v4.1 was based on the profiler.

SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
- CAS number: 109-23-9
- EC number: 203-657-3
- Smiles: O=C(NCNC(=O)CCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCC
- InChI: 1S/C37H74N2O2/c1-3-5-7-9-11-13-15-17-19-21-23-25-27-29-31-33-36(40)38-35-39-37(41)34-32-30-28-26-24-22-20-18-16-14-12-10-8-6-4-2/h3-35H2,1-2H3,(H,38,40)(H,39,41)

SCIENTIFIC VALIDITY OF THE (Q)SAR MODELs
See attached QPRFs
- Defined endpoint: Skin Sensitisation (None vs Sensitiser)

ADEQUACY OF THE RESULT
In accordance with Chapter R.7a: Endpoint specific guidance, suitable (Q)SAR predictions may reliably indicate the skin sensitisation potential or the absence thereof of a substance. Although these models have been demonstrated to be reasonable for predicting skin sensitisers correctly but they are limited in predicting non-sensitisers correctly. Therefore, the results of the (Q)SAR predictions are considered together with a published GPMT test.

Qualifier:

no guideline available

Principles of method if other than guideline:

- Models used: Skin sensitisation potential was performed with QSAR models TOPKAT 4.5 and CAESAR (VEGA 1.1.4), with expert system Derek 5.0.2 and Toxtree 2.6.13. The assessment with OECD QSAR Toolbox v4.1 was based on the profiler.

GLP compliance:

no

Remarks:

Not applicable

Key result

Run / experiment:

other: Weight of evidence of the assessed models

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

no indication of skin sensitisation

Run / experiment:

other: TOPKAT

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: negative

Remarks:

Reliability (model statistics): Mod (probability: 0.02)

Run / experiment:

other: CAESAR (VEGA)

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: positive

Remarks:

Reliability (model statistics): Low (AD index: 0)

Run / experiment:

other: DEREK

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: alert for formaldehyde donor

Remarks:

Reliability (model statistics): Plausible (equivocal or above)

Run / experiment:

other: Toxtree

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: no alert

Remarks:

Reliability (model statistics): Restricted on 5 skin protein binding principles

Run / experiment:

other: Danish (Q)SAR Database_CASE Ultra

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: inconclusive

Remarks:

Reliability (model statistics): Outside applicability domain

Run / experiment:

other: Danish (Q)SAR Database_Leadscope

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: negative

Remarks:

Reliability (model statistics): In applicability domain

Run / experiment:

other: Danish (Q)SAR Database_SciQSAR

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: negative

Remarks:

Reliability (model statistics): In applicability domain

Run / experiment:

other: OECD QSAR Toolbox_Protein binding alerts for skin sensitization by OASIS

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: no alert

Remarks:

Reliability (model statistics): Restricted on 11 mechanistic domains

Run / experiment:

other: OECD QSAR Toolbox_Protein binding alerts for skin sensitization according to GHS

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: no alert

Remarks:

Reliability (model statistics): The absence of a protein binding alert should not be taken as an absence of toxicity

Run / experiment:

other: OECD QSAR Toolbox_Metabolites: Protein binding alerts for skin sensitization by OASIS

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: no alert

Remarks:

Reliability (model statistics): Restricted on 11 mechanistic domains

Run / experiment:

other: OECD QSAR Toolbox_Metabolites_Protein binding alerts for skin sensitization according to GHS

Parameter:

other: Prediction result

Vehicle controls validity:

not applicable

Negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

other: no alert

Remarks:

Reliability (model statistics): The absence of a protein binding alert should not be taken as an absence of toxicity

 PREDICTION OF MODELS AND RELIABILITY

TOPKAT

- TOPKAT predicted the substance to be non-sensitiser.

- Moderate reliability was assessed for the prediction due to uncertainty related with low structural similarity of the four structural analogues. However, all other statistics (concordance, accuracy, probability, best split, etc.) were in line to support the prediction result.

 

CEASAR

- CAESAR of Vega predicted the substance to be sensitiser with low reliability (ADI: 0) and indicated that the query structure is outside applicability domain of the model.

 

DEREK

- DEREK triggered for the substance an alert described as formaldehyde donor. The reasoning level of the prediction was plausible.

- According to DEREK, the substance was identified as a pre/pro-hapten producing an electrophile with Schiff base forming potential. In addition, the alert by DEREK demonstrated moderate predictive performance as described in validation comments. There were no compounds activating this alert in (2) Gerberick and (3) Contact Dermatitis databases. Only the (1) Cronin and Basketter database showed 5 compounds which activate this alert, of which 4 were reported as positive. In the section EC3 Result for Derek EC3 model, only one structural similar compound (methenamine,similarity 8.8%) was reported to be a weak sensitiser. Therefore, this one structural analogue was insufficient to calculate the EC3 value for the substance.

 

Danish (Q)SAR database

- According to the Danish (Q)SAR database, with respect to allergic contact dermatitis in guinea pig and human, Leadscope and SciQSAR predicted negative results for the substance within applicability domain of the models. The CASE Ultra fragment‐based statistical model predicted inconclusive skin sensitisation for the substance. However, in this model the substance was outside applicability domain.

- Few ADME data from Danish (Q)SAR database for the substance could be considered. In the record on skin absorption, EPI DERMWIN predicted for the substance the dermal absorption of 1.57 × 10-8mg/cm2/event (where default event duration is 0.58 h). In addition, based on the prediction for possible metabolism by Battery of models in Danish (Q)SAR database, the substance as substrate for CYP2C9 and CYP2D6 was negative.

Toxtree

- Toxtree identified no alert for the substance in respect to skin sensitisation reactivity domains.

 

QSAR Toolbox

- The protein binding alerts for skin sensitisation by OASIS and according to GHS in OECD QSAR Toolbox profiler triggered no alerts for the substance.

- The autoxidation and neutral hydrolysis simulators of OECD QSAR Toolbox generated no metabolites/transformation products for the substance. However, the skin metabolism simulator gave 3 metabolites for the substance. None of them were profiled for protein binding alerts for skin sensitisation by OASIS or according to GHS.

Interpretation of results:

GHS criteria not met

Conclusions:

The weight of evidence of the assessed models suggested N,N'-methylendistearamide to be not a skin sensitizer.

Executive summary:

The prediction of N,N'-methylendistearamide skin sensitisation potential was performed with QSAR models TOPKAT 4.5 and CAESAR (VEGA 1.1.4), with expert system Derek 5.0.2 and Toxtree 2.6.13. The assessment with OECD QSAR Toolbox v4.1 was based on the profiler.

TOPKAT predicted N,N'-methylendistearamide to be non-sensitizer. CAESAR of Vega predicted N,N'-methylendistearamide to be sensitizer with low reliability (ADI: 0) and indicated that the query structure is outside applicability domain of the model. DEREK triggered for N,N'-methylendistearamide an alert described as formaldehyde donor.

The weight of evidence of the assessed models suggested N,N'-methylendistearamide to be not a skin sensitizer.

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

No clear description of methods, however a reference is made to the original GPMT procedure (Magnusson and Kligman, procedure similar to OECD TG 406)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

Test was performed according to Magnusson and Kligman (1969), which is also the basis for OECD TG 406

Principles of method if other than guideline:

No clear description of methods, however a reference is made to two well described standard procedure (Magnusson and Kligman, GPMT procedure similar to OECD TG 406; Goodwin and Johnson, SIAT test). All non-sensitizers were identified using the GPMT procedure.

MAGNUSSON AND KLIGMAN
Bibliographic source: J Invest Dermatol. 1969 Mar;52(3):268-76.
Name of the method: guinea pig maximization test (GPMT)
Principle of the method:
- Induction procedure: Injections are given intradermally with and without complete Freund's
Adjuvant (The final concentration of the allergen is 5% by weight provided that it can be well tolerated locally and generally) to Albino guinea pigs weighing 300-500 Grams. A row of 3 injections,
six in all, are made on each side as follows: (1) 0.1 ml of the adjuvant without the test agent, (2) 0.1 ml of test agent without adjuvant and (3) 0.1 ml of the test substance emulsified in complete adjuvant. One week later the test agent is applied topically over the injection site (The test agent in petrolatum is spread over a 2 x 4 cm patch of Whatman No. 3MM filter paper in a thick even layer or, if liquid, to saturation. The patch is covered by an overlapping impermeable, plastic adhesive tape. This in turn is firmly secured by elastic adhesive bandage (6.4 cm in width), wound around the torso of the animal. This dressing is left in place for 48 hours) .
- Challenge procedure: The animals are challenged by patch test two weeks later. The test agent is applied on a 2 x 2 cm piece of filter paper in the same fashion as for topical induction. The patch is sealed to the flank for 24 hours under a 4 cm strip.

GOODWIN AND JOHNSON
Bibliographic source: Curr Probl Dermatol. 1985;14:201-7.
Name of the method: Single injection adjuvant test (SIAT)
Principle of the method: the procedure involves a single injection of the test substance in Freund’s complete adjuvant followed 12 days later by challenge using a 6-hour occlude patch.

GLP compliance:

no

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

Test was conducted before the LLNA method became a standard procedure for in vivo skin sensitisation

Specific details on test material used for the study:

- Name as cited in the report: methylene distearamide

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 300-500 Grams (according to Magnusson and Kligman, 1969)

Route:

intradermal and epicutaneous

Vehicle:

not specified

Route:

epicutaneous, occlusive

Vehicle:

not specified

Concentration / amount:

Not specified

Day(s)/duration:

1 day

Details on study design:

METHODS AS DECRIBED IN MAGNUSSON AND KLIGMAN, 1969
- Induction procedure: Injections are given intradermally with and without complete Freund's Adjuvant (The final concentration of the allergen is 5% by weight provided that it can be well tolerated locally and generally) to Albino guinea pigs weighing 300-500 Grams. A row of 3 injections, six in all, are made on each side as follows: (1) 0.1 ml of the adjuvant without the test agent, (2) 0.1 ml of test agent without adjuvant and (3) 0.1 ml of the test substance emulsified in complete adjuvant. One week later the test agent is applied topically over the injection site (The test agent in petrolatum is spread over a 2 x 4 cm patch of Whatman No. 3MM filter paper in a thick even layer or, if liquid, to saturation. The patch is covered by an overlapping impermeable, plastic adhesive tape. This in turn is firmly secured by elastic adhesive bandage (6.4 cm in width), wound around the torso of the animal. This dressing is left in place for 48 hours) .
- Challenge procedure: The animals are challenged by patch test two weeks later. The test agent is applied on a 2 x 2 cm piece of filter paper in the same fashion as for topical induction. The patch is sealed to the flank for 24 hours under a 4 cm strip.

Key result

Reading:

other: not specified

Group:

test chemical

Dose level:

not specified

Remarks on result:

no indication of skin sensitisation

Reading:

other: not specified

Group:

negative control

Remarks on result:

not measured/tested

Reading:

other: not specified

Group:

positive control

Remarks on result:

not measured/tested

From the scores obtained in the GPMT, chemicals may be classified qualitatively into one of four groups, i.e. non, weak, moderate or strong sensitisers. The substance under evaluation in this dossier was classified as non sensitiser.

Interpretation of results:

study cannot be used for classification

Conclusions:

In this study performed similar to OECD 406, the substance was considered to be non-sensitising.

Executive summary:

The sensitising potential of the test substance was assessed in a guinea pig maximisation test (GPMT test) performed similar to OECD 406. During the induction procedure the test animals were given a row of 3 injections on each side (six in total) as follows: (1) 0.1 ml of the adjuvant without the test agent, (2) 0.1 ml of test agent without adjuvant and (3) 0.1 ml of the test substance emulsified in complete adjuvant. One week later the test agent is applied topically over the injection site under occlusive conditions for 48 hours. The animals were challenged by patch test two weeks later. The test agent was applied on a 2 x 2 cm piece of filter paper in the same fashion as for topical induction. The patch was sealed to the flank for 24 hours under a 4 cm strip.

In this study, the substance was considered to be non-sensitising.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

In a weight of evidence approach using various (Q)SAR Models, the prediction of the skin sensitisation potential of the substance was performed with QSAR models TOPKAT 4.5 and CAESAR (VEGA 1.1.4), with expert system Derek 5.0.2 and Toxtree 2.6.13. The assessment with OECD QSAR Toolbox v4.1 was based on the profiler. Of the prediction results, 8/11 indicated no risk/potential for skin sensitisation. One result (CAESAR (VEGA)) was positive, however the reliability of this model was low (AD index:0). Only DEREK suggests a plausible formaldehyde donor alert via pre/pro-hapten action mechanism. However, the simulated skin metabolites by OECD QSAR Toolbox were exempted from protein binding alerts for skin sensitization by OASIS and according to GHS. Moreover, the substance was not activated by CYP2C9 and CYP2D6 enzymes in the Danish (Q)SAR database. The weight of evidence of the assessed models suggested the substance to be not a skin sensitiser. These results are evaluated in a weight of evidence approach utilizing published results from a GPMT study.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the available data on skin sensitisation, classification is not warranted according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.