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EC number: 202-956-6 | CAS number: 101-58-6
- Life Cycle description
- Uses advised against
- Endpoint summary
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- Density
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- Short-term toxicity to fish
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Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in chemico
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Experimental Starting Date 16 Jun. 2020, Experimental Completion Date 19 Jun. 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2020
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 442C (In Chemico Skin Sensitisation: Direct Peptide Reactivity Assay (DPRA))
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of study:
- other: Peptide Reactivity Assay (DPRA)
Test material
- Reference substance name:
- Bis(4-(1,1,3,3-tetramethylbutyl)phenyl) ether
- EC Number:
- 202-956-6
- EC Name:
- Bis(4-(1,1,3,3-tetramethylbutyl)phenyl) ether
- Cas Number:
- 101-58-6
- Molecular formula:
- C28H42O
- IUPAC Name:
- 1-(2,4,4-trimethylpentan-2-yl)-4-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]benzene
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- Purity: 90.2 % Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)ether
In chemico test system
- Details on the study design:
- The OECD AOP (The adverse outcome pathway for skin sensitisation) is initiated by key event 1 (Covalent interaction with skin proteins), which is followed sequentially by three key events (KE): (KE2) keratinocyte activation, (KE3) dendritic cell activation, and (KE4) proliferation of antigen-specific T cells. However, none of the assays addressing the different KEs is currently accepted as stand-alone test method and may not be sufficient to conclude on the presence or absence of skin sensitisation potential of chemicals. But supports the discrimination between skin sensitisers and non sensitisers in combination with other complementary data.
The direct peptide reactivity assay (DPRA) addresses the molecular initiating event (KE1) of the AOP. It is an in chemico assay to quantify the depletion of synthetic model peptides caused by known amounts of the test item measured by HPLC.
This study is performed in order to evaluate the reactivity of Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)ether towards cysteine and lysine containing peptides. The peptide depletion compared to the solvent controls is calculated and leads to a DPRA prediction (reactive/positive or non-reactive/negative) that could be used to support the discrimination between skin sensitisers and non-sensitisers. Additionally, an assignment to one of four reactivity classes could be made in order to possibly support a potency assessment.
The DPRA is part of a tiered strategy for the evaluation of the skin sensitization potential. Thus, all data generated with the present Test Guideline OECD 442C and EU-Method B.59 should be used in the context of an integrated approach to testing and assessment (IATA).
The test item was incubated for 24 h at 25 °C together with Cys- and Lys-peptides, respectively. The peptide concentration after the incubation period was measured using HPLC-UV.
Three replicates were prepared using 1:10 and 1:50 molar ratio of the test item with the Cys- and Lys-peptides, respectively. Triplicate samples of the solvent without test item were incubated and measured simultaneously.
Results and discussion
- Positive control results:
- One valid experiment was performed.
Experiment 1 was valid for both peptide assays. In the Lys-peptide assay, the percent mean area ratio 220/258 nm for the positive control was slightly out of the range 90-110%. The mean area ratio is an indicator for peak purity and sign for co-elution. As the chromatogram of the co-elution control shows no sign of co-elution this might be due to really small peaks at 258 nm. The mean area ratio is no acceptance criterion and has no influence on the result of the test item peptide depletion or the result of the study.
In vitro / in chemico
Results
- Run / experiment:
- other: One valid experiment was performed. Experiment 1 was valid for both peptide assays. In the Lys-peptide assay, the percent mean area ratio 220/258 nm for the positive control was slightly out of the range 90-110%.
- Parameter:
- other: reactivity towards the Cys- and Lys-peptides.
- Value:
- 0
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
Applicant's summary and conclusion
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The test item is not soluable neither in the media used for the h-CLAT nor in the one for the LuSens. Therefore it is not possible to perform the studies according tom OECD 422E and OECD 422D.
The test item is soluable in Isopropanol so it is possible to perform the Direct Peptide Reactivity Assay: DPRA according to OECD 422C.
The DPRA prediction is “negative” according to the Cysteine 1:10/Lysine 1:50 prediction model. Thus, under the experimental conditions reported, the test item Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)ether shows no reactivity towards the two model synthetic peptides.
This assignment supports the discrimination between skin sensitisers and non-sensitisers in the framework of an integrated approach (IATA).
For sensitising potency assessment within an IATA, the test item Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)ether could be assigned to the reactivity class that covers no or minimal reactivity under the conditions of this study.
As the calculated peptide depletion is minimal (i.e. much smaller than the limit required for a positive classification) the classification as “negative” is reasonable despite the slight precipitation.
As the result is unambiguos there is no reason to perform a further study with animals. - Executive summary:
This in chemico study was performed in order to evaluate the reactivity of the test item Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)ether towards cysteine (Cys-) and lysine (Lys-) containing peptides.
The calculated peptide depletion could be used to support the discrimination between skin sensitisers and non-sensitisers. The DPRA is part of a tiered strategy for the evaluation of skin sensitisation potential in the context of an integrated approach to testing and assessment (IATA).
The test item was incubated for 24 h at 25 °C together with Cys- and Lys-peptides, respectively. The peptide concentration after the incubation period was measured using HPLC-UV.
Three replicates were prepared using 1:10 and 1:50 molar ratio of the test item with the Cys- and Lys-peptides, respectively. Triplicate samples of the solvent without test item were incubated and measured simultaneously.
One valid experiment was performed.
Experiment 1 was valid for both peptide assays. In the Lys-peptide assay, the percent mean area ratio 220/258 nm for the positive control was slightly out of the range 90-110%. The mean area ratio is an indicator for peak purity and sign for co-elution. As the chromatogram of the co-elution control shows no sign of co-elution this might be due to really small peaks at 258 nm. The mean area ratio is no acceptance criterion and has no influence on the result of the test item peptide depletion or the result of the study.
The test item “Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)ether” shows no reactivity towards the Cys- and Lys-peptides.
Therefore, the DPRA prediction is “negative” with “no or minimal” reactivity.
According to the guideline OECD 442C, in samples with observed precipitation or phase separation the peptide depletion may be underestimated and a conclusion on the lack of reactivity cannot be drawn with sufficient confidence in case of a negative result and it should be interpreted with due care.
In the test item replicates of the Cys- and Lys-peptide assay, slight precipitation was observed immidiatelly upon addition of the test item and after the incubation period.
As the calculated peptide depletion is minimal (i.e. much smaller than the limit required for a positive classification) the classification as “negative” is reasonable despite the slight precipitation.
The peptide depletion values after incubation are shown in Table 3a:
Table 3a Results
Cys-peptide
depletion [%]Lys-peptide
depletion [%]Mean peptide
depletion [%]Experiment 1
0.00
0.00
0.00
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