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Diss Factsheets

Administrative data

Description of key information

In chemico/ in vitro testing battery (OECD TG 442 c, d, and e) according to OECD guidelines and under GLP. The DPRA yielded indication for skin sensitization. According to the evaluation criteria in the OECD guideline, a second run should be considered, which has not been carried out. A KeratinoSens assay was negative. An h-CLAT assay yielded indication for skin sensitization in its first run. The second run was negative. Its overall result was equivocal.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in chemico
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 2017 - 22 december 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 442C (In Chemico Skin Sensitisation: Direct Peptide Reactivity Assay (DPRA))
Version / remarks:
February 4, 2015
GLP compliance:
yes (incl. QA statement)
Type of study:
direct peptide reactivity assay (DPRA)
Details on the study design:
The in chemico direct peptide reactivity assay (DPRA) enables detection of the sensitising potential of a test item by quantifying the reactivity of test chemicals towards synthetic peptides containing either lysine or cysteine.
In the present study N-(1,3-Dimethylbutylidene)-3-(triethoxysilyl)propylamine was dissolved in acetonitrile, based on the results of the pre-experiments.
Based on a molecular weight of 303.51 g/mol a 100 mM stock solution was prepared. The test item solutions were tested by incubating the samples with the peptides containing either cysteine or lysine for 24 ± 2 h at 25 ± 2.5 °C. Subsequently samples were analysed by HPLC.
All test item solutions were freshly prepared immediately prior to use.
Key result
Parameter:
other: Depletion of the synthetic cysteine peptide (%)
Value:
15.25
Vehicle controls validity:
valid
Positive controls validity:
valid
Remarks on result:
positive indication of skin sensitisation
Remarks:
According to the evaluation criteria in the guideline, for test items with a cysteine peptide depletion between 9% and 17% a second run should be considered. This has not been carried out and, therefore, no definite prediction could be made.
Other effects / acceptance of results:
Turbidity in the lysine experiment was observed. Therefore, the given peak areas and corresponding lysine peptide values can only be considered as an estimation of the peptide depletion and cannot be used for evaluation.
Sensitising potential of the test item was predicted from the mean peptide depletion of the cysteine peptide by comparing the peptide concentration of the test item treated samples to the corresponding reference control C (RC Cacetonitrile).
The 100 mM stock solution of the test item showed low reactivity towards the synthetic peptides. The mean depletion of the cysteine peptide was > 13.89% (15.25%). Based on the prediction model 2 the test item can be considered as sensitiser.
See attachment for data tables.
Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Endpoint:
skin sensitisation: in vitro
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 July 2017 - 20 March 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
other: 442e
Version / remarks:
adopted 09 October 2017
GLP compliance:
yes (incl. QA statement)
Type of study:
activation of dendritic cells
Details on the study design:
The test item was freshly prepared immediately prior to use. The test item was soluble in tetrahydrofuran (THF) at a concentration of 500 mg/mL.
Stock solutions were prepared by diluting the highest soluble concentration seven times with a constant dilution factor of 1:2.
The working stock solutions were prepared by diluting each stock solution 250 times with cell culture medium.
Phase separation was observed in the dose finding assay when diluted 1:250 in cell culture medium. Sonication was used to aid solubilisation. No precipitation, turbidity or phase separation was observed in the main experiment when diluted 1:250 in cell culture medium.
The working stock solutions were applied to the cells by adding equal volumes of each solution to prepared cells, resulting in a further 1:2 dilution of the working solutions. The solvent was present at a constant volume ratio of 0.2% (v/v) in all cultures, i.e. in all concentrations of the test item and the solvent control.
A medium control, a solvent control, and a positive control were set up in parallel in order to confirm the validity of the test.
Medium Control
A medium control was included in the test.
Solvent Controls
Solvent controls were included in the test. The solvent controls were set up depending on the appropriate solvent.
Since the test item was solubilized in THF, a THF control served as solvent control for the test item.
Since the positive control was solubilized in DMSO, a DMSO control was included and served as solvent control for the positive control.
The solvent controls were diluted according to the procedure described for the test item in chapter 10.7.1, resulting in a final concentration of 0.2% (v/v) for THF.
Positive Control
2,4-dinitrochlorobenzene (DNCB) at a final concentration of 4 μg/mL (alternatively at the concentration of the CV75) was tested concurrently with the test item. DNCB was dissolved in DMSO and diluted according to the procedure described for the test item in chapter 10.7.1, resulting in a final DMSO concentration of 0.2% (v/v).
Key result
Run / experiment:
other: first
Parameter:
other: CD86 (% upregulation)
Value:
193
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: upregulation above the threshold of 150% was observed at a concentration of 593.09 μg/mL
Key result
Run / experiment:
other: second
Parameter:
other: CD86 (% upregulation)
Value:
150
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of skin sensitisation
Other effects / acceptance of results:
Relative cell viability at the highest test item concentration was reduced to 82.9% (CD86), 83.9% (CD54) and 82.8% (isotype IgG1 control) in the first experiment and to 82.4% (CD86), 82.7% (CD54) and 81.1% (isotype IgG1 control) in the second experiment.
The expression of the cell surface marker CD86 was upregulated to 193% in the first experiment but not the second. The upregulation above the threshold of 150% was observed at a concentration of 593.09 μg/mL. The expression of the cell surface marker CD54 was not upregulated above the threshold of 200% in any of the experiments. Due to the equivocal outcome of these two experiments, no prediction could be made.
See attachment for data tables.
Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
CD86 upregulation above the threshold of 150%, indicating potency for skin sensitization, was observed at a concentration of 593.09 μg/mL during the first run.
Endpoint:
skin sensitisation: in vitro
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 July 2017 - 18 May 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 442D (In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method)
Version / remarks:
adopted: February 04, 2015
GLP compliance:
yes (incl. QA statement)
Type of study:
activation of keratinocytes
Details on the study design:
Test item.
All test item solutions were freshly prepared immediately prior to use.
The test item was dissolved in Tetrahydrofuran (THF, CAS No.: 67-68-5, purity ≥99%, Merck, Lot No.: I864407/ Sigma, Lot No.: STBH3251). A stock solution of 200 mM was prepared by pre-weighing the test material into a glass vial. A correction factor of 1.17 was applied to correct for the purity of the test item.
Based on the stock solution a set of twelve master solutions in 100% solvent was prepared. Therefore, the stock solution of the test item was diluted eleven times using a constant dilution factor of 1:2. Then, the twelve 100x concentrated master solutions were further diluted 1:25 in cell culture medium resulting in a 4% share of the solvent.
These 4x concentrated test item solutions were finally diluted 1:4 when incubated with the cells. Based on this procedure the final concentration of the solvent was 1% (v/v) for all test item concentrations as well as the solvent control.
The following concentration range was tested in the assay:
2000, 1000, 500, 250, 125, 62.5, 31.25, 15.63, 7.81, 3.91, 1.95 and 0.98 μM

Controls
A blank, solvent controls and a positive control were set up in parallel in order to confirm the validity of the test.
Solvent Controls
DMSO (AppliChem; Lot No.: 0001055932, 0001779895) at a final concentration of 1% (v/v) in test item exposure medium was used as solvent control for the positive control.
THF at a final concentration of 1% (v/v) in test item exposure medium was used as solvent control for the test item.
For each solvent control six wells were included in every testing plate. The preparation of the solvent controls was carried out analogous to the test item.
Positive Control
Cinnamic aldehyde (CA, (2E)-3-phenylprop-2-enal; CAS 104-55-2; >98%; Alfa Aesar; Lot No.: 10176010) was used as positive control. CA was dissolved in DMSO at a concentration of 6.4 mM and was further diluted four times with a constant dilution factor of 1:2 resulting in a concentration range of 0.4 – 6.4 mM. The subsequent preparation of the positive control was carried out analogous to the preparation of the test item, resulting in a final concentration range of 4 – 64 μM. The final concentration of the solvent DMSO was 1% (v/v) for all wells.
Blank
A blank well without seeded cells was included in every plate to determine the background. The well was incubated with the negative control.

Key result
Run / experiment:
other: first
Parameter:
other: luciferase induction (fold)
Remarks:
all concentrations upto 2 mM
Value:
1.5
Vehicle controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of skin sensitisation
Key result
Run / experiment:
other: second
Parameter:
other: luciferase induction (fold)
Remarks:
all concentrations upto 2 mM
Value:
1.5
Vehicle controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of skin sensitisation
Other effects / acceptance of results:
No dose response for luciferase activity was observed for each of the individual runs as well as for the average, overall luciferase activity induction. No significant luciferase induction > 1.5 was found in the tested concentration range and no EC1.5 value could be calculated. See attachment for data tables.
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on a positive DPRA and equivocal h-CLAT assay according to OECD guidelines and under GLP, 3 -Triethoxysilyl-(1,3 -dimethylbutylidene)propylamine is classified as Category 1B (indication of skin sensitising potential) according to GHS criteria.