Reaction mass of (((1,3-phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-methylacrylate) and (1,3-phenylenebis(oxy))bis(propane-3,1-diyl) bis(2-methylacrylate) and 3-(3-(2-(2-(methacryloyloxy)ethoxy)ethoxy)phenoxy)propyl methacrylaterate

Endpoint summary

Description of key information

Computational profiling was conducted on each of the three main contituents of DiBrORMA. All three components were expected to have dermal sensitization potential based on the results of the profiling workflow.

Additionally, literature sources indicate that high molecular weight methacrylates are most often weak dermal sensitizers (Kimber et al., 2019).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation, other

Type of information:

other: See 'Remarks'

Remarks:

Review article from a literature source.

Adequacy of study:

weight of evidence

Study period:

2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

DiBrORMA is a UVCB substance that contains a mixture of three main structures with methacrylate functional groups. Since the DPRA, h-CLAT and Keratinosens assays have not been validated for use with multiconstituent substances, alternative data sources were compiled to determine the skin sensitization potential of a multiconstituent substance while avoiding unecessary animal testing. Methacrylates and acrylates are generally well-documented to have skin sensitization potential.

DiBrORMA is a brominated methacrylate monomer and based on the chemical class it is expected to be a skin sensitizer. While methacrylates are sensitizers, they are not usually considered potent skin sensitizers (Kimber et al., 2019). In addition, some high molecular weight methacrylates (i.e., isodecyl
methacrylate and dodecyl methacrylate) are not skin sensitizers in the local lymph node assay. The average molecular weight of DiBrORMA (530 g/mol) is higher than the molecular weights of the compounds evaluated by Kimber et al., (226 and 254 g/mol, respectively). Since DiBrORMA contains methacrylate functional groups with sensitization potential but has a relatively high molecular weight, the weight of evidence suggests that a GHS Category 1B skin sensitization classification would be most appropriate.

Qualifier:

no guideline available

Principles of method if other than guideline:

Review article published in Regulatory Toxicology and Pharmacology.

Type of study:

other: Review article

Key result

Remarks on result:

other: See 'Remarks'

Remarks:

Positive indication of weak dermal sensitization potential for high molecular weight methacrylates.

Interpretation of results:

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

Conclusions:

DiBrORMA contains methacrylate functional groups with sensitization potential but has a relatively high molecular weight. The weight of evidence suggests that a GHS Category 1B skin sensitization classification is most appropriate.

Executive summary:

DiBrORMA is a UVCB substance that contains a mixture of three main structures with methacrylate functional groups.  Since the DPRA, h-CLAT and Keratinosens assays have not been validated for use with UVCB substances, alternative data sources were compiled to determine the skin sensitization potential of multiconstituents while avoiding unecessary animal testing.  Methacrylates and acrylates are generally well-documented to have skin sensitization potential.

DiBrORMA is a brominated methacrylate monomer and based on the chemical class it is expected to be a skin sensitizer. While methacrylates are sensitizers, they are not usually considered potent skin sensitizers (Kimber et al., 2019).  In addition, some high molecular weight methacrylates (i.e., isodecyl

methacrylate and dodecyl methacrylate) are not skin sensitizers in the local lymph node assay. The average molecular weight of DiBrORMA (530 g/mol) is  higher than the molecular weights of the compounds evaluated by Kimber et al., (226 and 254 g/mol, respectively). Since DiBrORMA contains methacrylate functional groups with sensitization potential but has a relatively high molecular weight, the weight of evidence suggests that a GHS Category 1B skin sensitization classification is most appropriate.

Reference 2

Endpoint:

skin sensitisation, other

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE : OECD QSAR Toolbox Version 4.4.1

2. MODEL: Automated workflow for Skin Sensitization Defined Approaches

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL : 3 main components of the UVCB:

CC(=C)C(=O)OCCCOc1cc(OCCCOC(=O)C(=C)C)c(Br)cc1Br.
CC(=C)C(=O)OCCCOc1cc(OCCOCCOC(=O)C(=C)C)c(Br)cc1Br.
CC(=C)C(=O)OCCOCCOc1cc(OCCOCCOC(=O)C(=C)C)c(Br)cc1Br.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: EC3, Skin sensitisation;
- Unambiguous algorithm: See attached documentation .pdf providing more detail around the automated workflow within OECD QSAR Toolbox version 4.4.1.
- Defined domain of applicability: 1/3 of the components of the UVCB substance have log Kow values that fall within the applicability
domain of the skin sensitization category profiler. The average log Kow was 5.22 for DiBrOE2MA, 5.36
for DiBrORMA, and 4.77 for DiBrE4RMA. The active descriptor range of the category is 3.09-4.94.
All the components fall within the applicability domain of the following profilers:
Protein binding alerts for skin sensitization by OASIS (Primary Grouping)
Protein binding alerts for skin sensitization by OASIS (Subcategorization)
- Appropriate measures of goodness-of-fit and robustness and predictivity: Substances with structural alerts for protein binding have been shown to have skin sensitization potential. The components of
the uvcb substance each have structural alerts for protein binding.
- Mechanistic interpretation: The components of the UVCB substance each have structural alerts for protein binding. Structures containing methacrylate functional groups are well-documented skin sensitizers.

See attached documentation .pdf providing more detail around the automated workflow within OECD QSAR Toolbox version 4.4.1.

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
- Descriptor domain: - Active descriptor(s) range:- log Kow: from 3.09 to 4.94
- Mechanistic domain: Methacrylate functional groups are identified as potential protein binders within the mechanistic framework of the automated workflow.
- Similarity with analogues in the training set: Other structures containing acrylate and methacrylate functional groups were present in the category assembles by the AW to determine the final prediction. Analogs had similar MWs and log Kow values.

6. ADEQUACY OF THE RESULT

The skin sensitization potential of this UVCB substance was evaluated with skin sensitization and protein binding structural alert profilers using OECD QSAR Toolbox version 4.4.1 Additionally, the constituents and estimated metabolites were evaluated using a category approach to determine if
structural analogs of the constituents are dermal sensitizers. Based on the structural alerts for the constituents of the mixture and the structural analogs with positive sensitization data, the multiconstituent target is predicted to be a GHS Category 1 skin sensitizer

Qualifier:

no guideline available

Principles of method if other than guideline:

- Software tool(s) used including version: OECD QSAR Toolbox v. 4.4.1
- Justification of QSAR prediction: see field 'Justification for type of information'

GLP compliance:

no

Specific details on test material used for the study:

NA: Calculation method.

Key result

Parameter:

other: See 'Remarks'

Remarks:

Computational Profiling

Remarks on result:

positive indication of skin sensitisation based on QSAR/QSPR prediction

Interpretation of results:

Category 1 (skin sensitising) based on GHS criteria

Conclusions:

Based on the computational profiling conducted with the main components of the UVCB substance, DiBrORMA is expected to be a GHS Category 1 skin sensitizer.

Executive summary:

The skin sensitization potential of this UVCB substance was evaluated with skin sensitization and protein binding structural alert profilers using OECD QSAR Toolbox version 4.4.1 Additionally, the constituents and estimated metabolites were evaluated using a category approach to determine if structural analogs of the constituents are dermal sensitizers. Based on the structural alerts for the constituents of the mixture and the structural analogs with positive sensitization data, the UVCB target is predicted to be a GHS Category 1 skin sensitizer.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Justification for classification or non-classification

DiBrORMA contains methacrylate functional groups with sensitization potential but has a relatively high molecular weight. The weight of evidence suggests that a GHS Category 1B skin sensitization classification is most appropriate.