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Endpoint summary
Administrative data
Description of key information
In-vitro/Chemico skin sensitisation:
DPRA (OECD 442C): negative
KeratinoSens (OECD 442D): negative
h-CLAT (OECD 442E): negative
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vitro
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 27 April 2021 to 21 October 2021
- 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 KeratinoSens™ test method)
- Version / remarks:
- adopted: June 25, 2018
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of study:
- ARE-Nrf2 luciferase KeratinoSens™ test method
- Specific details on test material used for the study:
- Name: cyclic Glucamide C12-C14
Chemical Name: anhydro-D-glucitol, 1-deoxy-1-(methylamino)-, N-[C12-14(even numbered) acryl] derivs.; Amides, C12-C14, N-(1-deoxy-D-glucitol-1-yl)-N-methyl, dehydrated
Product Name: cyclic N-dodecanoyl/tetradecanoyl-N-methylglucamine / cyclic Glucamide C12-C14
Batch No.: S148866
CAS No: not specified by the sponsor
Molecular Weight: main compounds:
359.5 g/mol (C12-derivative)
387.5 g/mol (C14-derivative)
Calculated Mean Molecular Weight: 314.35 g/mol
Density: 1.07 g/cm3
Purity: 85.90% (based on the calculated mean molecular weight)
Physical State: slightly turbid solid mass
Colour: brown
Stability: stable
Storage Conditions: room temperature
Expiry Date: 30 September 2022
Safety Precautions: The routine hygienic procedures were sufficient to assure personnel health and safety. - Details of test system:
- Keratinoses transgenic cell line [442D]
- Details on the study design:
- PREPARATION OF TEST SOLUTIONS
All test item solutions were freshly prepared immediately prior to use.
The test item was dissolved in dimethyl sulfoxide (DMSO, CAS No.: 67-68-5, purity ≥99%; AppliChem; Lot No.: 0001886811, 000192647). A stock solution of 200 mM was prepared by pre-weighing the test material into a suitable tube. A factor of 1.16 to correct for the purity of the test item was used. Vortex mixing was used to aid solubilisation.
Based on the stock solution a set of twelve master solutions in 100% solvent was prepared. The stock solution of the test item was diluted eleven times using a constant dilution factor of 1:2. Then the 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) in all test item concentrations and controls
Dose Groups
1. Negative Control: 1% (v/v) DMSO in test item exposure medium
2. Positive Control: CA: 4 µM, 8 µM, 16 µM; 32 µM; 64 µM
3. Test Item: 12 concentrations of the test item
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, 0.98 µM
Each concentration step of the test item and the positive control was assessed in three replicates in every independent run. The negative control was assessed using six replicates per 96-well plate in every independent run.
APPLICATION OF THE TEST CHEMICAL AND CONTROL SUBSTANCES
A cell suspension of 8 × 104 cells/mL in assay medium was prepared. 125 µL of the cell suspension corresponding to 1 × 104 cells were dispensed in each well, except for the blank. To determine the luciferase activity cells were seeded in white 96-well plates (flat bottom). In parallel, cells were seeded in a transparent 96-well plate (flat bottom) for the determination of the cell viability.
After seeding cells were grown for 24 h ± 1 h in assay medium at 37 °C ± 1 °C and 5% CO2. Thereafter, the assay medium was discarded and replaced by 150 µL test item exposure medium. 50 µL of the shortly before prepared 4x master concentrations were transferred to the luciferase and cell viability plates, resulting in an additional 1:4 dilution of the test item.
All plates were sealed using a sealing tape to avoid evaporation of volatile compounds and cross-contamination between wells by the test items. Treated plates were incubated for 48 h ± 1 h at 37 °C ± 1 °C and 5% CO2.
Luciferase activity
After 48 h ± 1 h of exposure, the supernatant was aspirated from the white assay plates and discarded. Cells were washed once with DPBS. Subsequently 20 µL of passive lysis buffer were added into each well and the plate was incubated for 20 min at room temperature in the absence of light.
Plates with the cell lysate were placed in the plate reader for luminescence measurement. Per well 50 µL of the luciferase substrate were injected by the injector of the plate reader. The plate reader waited for 1 sec. before assessing the luciferase activity for 2 sec. This procedure was repeated for each individual well.
LUCIFERASE ACTIVITY MEASUREMENTS
After 48 h ± 1 h of exposure, the supernatant was aspirated from the white assay plates and discarded. Cells were washed once with DPBS. Subsequently 20 µL of passive lysis buffer were added into each well and the plate was incubated for 20 min at room temperature in the absence of light.
Plates with the cell lysate were placed in the plate reader for luminescence measurement. Per well 50 µL of the luciferase substrate were injected by the injector of the plate reader. The plate reader waited for 1 sec. before assessing the luciferase activity for 2 sec. This procedure was repeated for each individual well.
Cell viability
For the cell viability plate the medium was replaced with 200 µL test item exposure medium. 27 µL MTT solution were added directly to each individual well. The plate was covered with a sealing tape and incubated for 4 h at 37 °C ± 1 °C and 5% CO2. Afterwards the medium was removed and replaced by 200 µL 10% SDS solution per well. The plate was covered with sealing tape and incubated in the incubator at 37 °C ± 1 °C and 5% CO2 overnight (experiment 1 and 2). After the incubation period the plate was shaken for 10 min and the OD was measured at λ = 600 nm.
DATA EVALUATION
For each test item two independent repetitions using separately prepared test item solutions and independently harvested cells are necessary to derive a prediction. Each independent run consisted of three replicates for every concentration step of the test item and the positive control. In case of discordant results a third independent run is performed.
For every concentration showing >1.5 fold luciferase activity induction, statistical significance (p <0.05) was calculated using a two-tailed Student’s t-test comparing the luminescence values for the three replicated samples with the luminescence values in the solvent (negative) control wells.
The lowest concentration with >1.5 fold luciferase activity induction was the value determining the EC1.5 value. It was checked in each case whether this value was below the IC30 value, indicating that there was less than 30% reduction on cellular viability at the EC1.5 determining concentration
Prediction Model
A KeratinoSens™ prediction is considered positive if the following conditions will be met in at least two independently prepared test repetitions:
- Imax is >1.5 fold increased and statistically significant (p <0.05) compared to the negative control
- cell viability is >70% at the lowest concentration with an induction of luciferase activity >1.5
- EC1.5 value is <1000 µM
- an apparent overall dose-response for luciferase induction
If in a given repetition, all of the three first conditions are met but a clear dose-response for the luciferase induction cannot be observed, the result of that repetition is considered as inconclusive and further testing may be required.
In addition, a negative result obtained with test items at a maximal test concentration < 1000 µM and which do not reach cytotoxicity (< 70% viability) at the maximal tested concentration is considered as inconclusive.
A negative result for test items with a log KOW > 7 has to be interpreted with care due to the applicability of the test method. - Vehicle / solvent control:
- DMSO
- Negative control:
- not applicable
- Positive control:
- cinnamic aldehyde [442D]
- Positive control results:
- valid
- Key result
- Group:
- test chemical
- Run / experiment:
- run/experiment 1
- Parameter:
- EC 1.5 [442D]
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- no significant luciferase induction > 1.5 was found in the tested concentration range. Therefore, no EC1.5 value could be calculated.
- Key result
- Group:
- test chemical
- Run / experiment:
- run/experiment 2
- Parameter:
- EC 1.5 [442D]
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- no significant luciferase induction > 1.5 was found in the tested concentration range. Therefore, no EC1.5 value could be calculated.
- Outcome of the prediction model:
- negative [in vitro/in chemico]
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- In this study under the given conditions the test item did not induce the luciferase activity in the transgenic KeratinoSens™ cell line in at least two independent experiment runs. Therefore, the test item can be considered as non-sensitiser.
- Executive summary:
The in vitro KeratinoSens™ assay enables detection of the sensitising potential of a test item by addressing the second molecular key event of the adverse outcome pathway (AOP), namely activation of keratinocytes, by quantifying the luciferase activity in the transgenic cell line KeratinoSens™. The luciferase activity, assessed by luminescence measurement, compared to the respective solvent controls is used to support discrimination between skin sensitisers and non-sensitisers.
In the present study cyclic Glucamide C12-C14 was dissolved in DMSO.
Based on a calculated molecular weight of 314.35 g/mol a stock solution of 200 mM was prepared.
Based on the stock solution a set of twelve master solutions in 100% solvent was prepared by serial dilution using a constant dilution factor of 1:2. These master solutions were diluted 1:100 in cell culture medium. 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, 0.98 µM
Cells were incubated with the test item for 48 h at 37°C. After exposure cells were lysed and luciferase activity was assessed by luminescence measurement.
In the first experiment, no significant luciferase induction > 1.5 was found in the tested concentration range. Therefore, no EC1.5 value could be calculated.
In the second experiment, no significant luciferase induction > 1.5 was found in the tested concentration range. Therefore, no EC1.5 value could be calculated.
No dose response for luciferase activity induction was observed for each individual run as well as for an overall luciferase activity induction.
Under the condition of this study the test item is therefore considered as non-sensitiser.
The controls confirmed the validity of the study
- Endpoint:
- skin sensitisation: in vitro
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 01 July 2021 to 14 October 2021
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 442E (In Vitro Skin Sensitisation assays addressing the key event on activation of dendritic cells on the Adverse Outcome Pathway for skin sensitisation)
- Version / remarks:
- 23rd July 2018
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Human Cell Line Activation Test (h-CLAT) for Skin Sensitisation, DB-ALM Protocol n°158, July 1st, 2015
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, München, Germany
- Type of study:
- activation of dendritic cells
- Specific details on test material used for the study:
Batch No.: S148866
CAS No.: not specified by the sponsor
Molecular Weight: main compounds: 359.5 g/mol (C12-derivative)
387.5 g/mol (C14-derivative)
Density: 1.07 g/cm3
Purity: 100% (UVCB)
Physical State: slightly turbid solid mass
Colour: brown
Log KOW: not specified by the sponsor
Stability: stable
Storage Conditions: room temperature
Expiry Date: 30 September 2022
Safety Precautions: The routine hygienic procedures were sufficient to assure
personnel health and safety.- Details on the study design:
- The in vitro human cell line activation test (h-CLAT) enables detection of the sensitising potential of a test
item by addressing the third molecular key event of the adverse outcome pathway (AOP), namely
dendritic cell activation, by quantifying the expression of the cell surface markers CD54 and CD86 in
the human monocytic cell line THP-1. The expression of the cell surface markers compared to the
respective solvent controls is used to support discrimination between skin sensitisers and
non-sensitisers. - Positive control results:
- The positive control (DNCB) led to an upregulation of the expression of CD54 and CD86 in both
experiments. The threshold of 150% for CD86 (150% experiment 1; 266% experiment 2) and
200% for CD54 (388% experiment 1; 356% experiment 2) were clearly exceeded. - Key result
- Group:
- test chemical
- Run / experiment:
- run/experiment 2
- Parameter:
- other: RFI CD54>200
- Value:
- 0
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- All CD54 was not upregulated above the threshold of 200%
- Key result
- Group:
- test chemical
- Run / experiment:
- run/experiment 2
- Parameter:
- other: RFI CD86>150
- Value:
- 0
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- All CD86 was not upregulated above the threshold of 150%
- Key result
- Group:
- test chemical
- Run / experiment:
- run/experiment 1
- Parameter:
- other: RFI CD86>150
- Value:
- 0
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- All CD86 was not upregulated above the threshold of 150%
- Key result
- Group:
- test chemical
- Run / experiment:
- run/experiment 1
- Parameter:
- other: RFI CD54 > 200
- Value:
- 1
- Cell viability:
- 12.3
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: RFI=205 at Concentration: 62.47 µg/mL (Cell viability 12.3). At other dose levels, CD54 was not upregulated above the threshold of 200%
- Outcome of the prediction model:
- negative [in vitro/in chemico]
- Other effects / acceptance of results:
- Acceptance criteria:
The test meets acceptance criteria if:
• the cell viability of the solvent controls is >90%,
• the cell viability of at least four tested doses of the test item in each run is >50%,
• the RFI values of the positive control (DNCB) is ≥150% for CD86 and ≥200% for CD54 at a cell viability of >50%,
• the RFI values of the solvent control is not ≥150% for CD86 and not ≥200% for CD54,
• the MFI ratio of CD86 and CD54 to isotype IgG1 control for the medium and DMSO control, is >105%.
The test mets the acceptance criteria. - Interpretation of results:
- GHS criteria not met
- Conclusions:
- In this study under the given conditions the test item did not upregulate the expression of the cell surface marker in two independent experiment runs. Therefore, the test item is considered as non-sensitiser.
The data generated with this method may be not sufficient to conclude on the absence of skin sensitisation potential of chemicals and should be considered in the context of integrated approach such as IATA. - Executive summary:
The in vitro human cell line activation test (h-CLAT) enables detection of the sensitising potential of a test item by addressing the third molecular key event of the adverse outcome pathway (AOP), namely dendritic cell activation, by quantifying the expression of the cell surface markers CD54 and CD86 in the human monocytic cell line THP-1. The expression of the cell surface markers compared to the respective solvent controls is used to support discrimination between skin sensitisers and non-sensitisers.
In the present study cyclic Glucamide C12-C14 was dissolved in DMSO. For the dose finding assay stock solutions with concentrations ranging from 500.00 mg/mL to 3.91 mg/mL were prepared by a serial dilution of 1:2. Cells were incubated with the test item for 24 h at 37°C. After exposure cells were stained with propidium iodide and cell viability was measured by FACS analysis.
A CV75 of 52.06 ± 3.00 µg/mL was derived in the dose finding assay
Based on the CV75, the main experiment was performed covering the following concentration steps:
62.47, 52.06, 43.38, 36.15, 30.12, 25.10, 20.92 and 17.43 µg/mL
In all experiments no precipitation or turbidity of the test item was observed for all concentration steps when mixing the test item stock solutions with cell culture medium.
Cells were incubated with the test item for 24 h at 37°C. After exposure cells were stained and cell surface markers CD54 and CD86 were measured by FACS analysis. Cell viability was assessed in parallel using propidium iodide staining.
Severe cytotoxic effects were observed for the cells treated with the test item. Relative cell viability at the highest test item concentration was reduced to 6.4% (CD86), 12.3% (CD54) and 7.7% (isotype IgG1 control) in the first experiment and to 28.1% (CD86), 27.7% (CD54) and 33.1% (isotype IgG1 control) in the second experiment.
The expression of the cell surface marker CD86 was not upregulated above the threshold of 150% in any of the experiments. The expression of cell surface marker CD54 was upregulated above the threshold of 200% in first experiment at the highest test item concentration. As viability was <50% (12.3%) at the highest test item concentration, the concentration was excluded from further evaluation. In the second experiment, the expression of cell surface marker CD54 was not upregulated above the threshold of 200%. Therefore, the test item can be considered as non-sensitiser.
The controls confirmed the validity of the study for all experiments.
- Endpoint:
- skin sensitisation: in chemico
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2021-06-04 to 2021-07-29
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 442C (In Chemico Skin Sensitisation: Direct Peptide Reactivity Assay (DPRA))
- Qualifier:
- according to guideline
- Guideline:
- other: Direct Peptide Reactivity Assay (DPRA) for Skin Sensitization Testing, DB-ALM Protocol n°154, January 12, 2013
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, München, Germany
- Type of study:
- other: (in chemico) reactivity against synthetic peptides with a thiol or amino group
- Specific details on test material used for the study:
- Name: cyclic Glucamide C12-C14
Chemical Name: anhydro-D-glucitol, 1-deoxy-1-(methylamino)-, N-[C12-14(even numbered) acryl] derivs.; Amides, C12-C14, N-(1-deoxy-D-glucitol-1-yl)-N-methyl, dehydrated
Product Name: cyclic N-dodecanoyl/tetradecanoyl-N-methylglucamine / cyclic Glucamide C12-C14
Batch No.: S148866
CAS No: not specified by the sponsor
Molecular Weight: main compounds:
359.5 g/mol (C12-derivative)
387.5 g/mol (C14-derivative)
Calculated Mean Molecular Weight: 314.35 g/mol
Density: 1.07 g/cm3
Purity: 85.90% (based on the calculated mean molecular weight)
Physical State: slightly turbid solid mass
Colour: brown
Stability: stable
Storage Conditions: room temperature
Expiry Date: 30 September 2022
Safety Precautions: The routine hygienic procedures were sufficient to assure personnel health and safety. - 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.
- Positive control results:
- The 100 mM stock solution of the positive control (cinnamic aldehyde) showed high reactivity towards the synthetic peptides. The mean depletion of both peptides was 65.65%.
- Key result
- Group:
- test chemical
- Run / experiment:
- other: cysteine run (Test Item (100mM))
- Parameter:
- cysteine depletion
- Value:
- 2.89
- At concentration:
- 100 mM
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Group:
- test chemical
- Run / experiment:
- other: cysteine run (Test Item (maximum solubility))
- Parameter:
- cysteine depletion
- Value:
- 5.54
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Group:
- test chemical
- Run / experiment:
- other: lysine run (Test Item (100 mM))
- Parameter:
- other: mean peptide depletion [%]
- Value:
- 2.26
- At concentration:
- 100 mM
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Group:
- test chemical
- Run / experiment:
- other: lysine run (Test Item (maximum solubility))
- Parameter:
- other: mean peptide depletion [%]
- Value:
- 1.69
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Other effects / acceptance of results:
- Acceptance Criteria
The run meets the acceptance criteria if:
- the standard calibration curve has a r² > 0.99,
- the mean percent peptide depletion (PPD) value of the three replicates for the positive control is
between 60.8% and 100% for the cysteine peptide and the maximum standard deviation (SD) for the
positive control replicates is < 14.9%,
- the mean percent peptide depletion (PPD) value of the three replicates for the positive control is
between 40.2% and 69.0% for the lysine peptide and the maximum SD for the positive control
replicates is < 11.6%,
- the mean peptide concentration of the three reference controls A replicates is 0.50 ± 0.05 mM,
- the coefficient of variation (CV) of peptide peak areas for the six reference control B replicates and three reference control C replicates in acetonitrile is < 15.0%.
The results of the test item meet the acceptance criteria if:
- the maximum standard deviation (SD) for the test chemical replicates is < 14.9% for the cysteine
percent depletion (PPD),
- the maximum standard deviation (SD) for the test chemical replicates is < 11.6% for the lysine
percent depletion (PPD),
- the mean peptide concentration of the three reference controls C replicates in the appropriate solvent is 0.50 ± 0.05 mM.
Both peptide runs and the test item results met the acceptance criteria of the test. - Interpretation of results:
- GHS criteria not met
- Conclusions:
- In this study under the given conditions the 100 mM test item solution showed minimal reactivity towards both peptides. The test item is considered as “non-sensitiser”.
In this study under the given conditions the maximum solubility solution of the test item showed minimal reactivity towards both peptides. Due to the observed turbidity the prediction model does not apply and a prediction cannot be made for the maximum solubility solution of the test item.
The data generated with this method may be not sufficient to conclude on the absence of skin sensitisation potential of chemicals and should be considered in the context of integrated approach such as IATA. - Executive summary:
In the present study cyclic Glucamide C12-C14 was dissolved in isopropanol, based on the results of the pre-experiments.
Based on a molecular weight of314.35 g/mola 100 mM stock solution was prepared and additionally the neat test item was tested to its maximum solubility. The test item solutions were testedby 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.
For the 100 mM stock solution and the maximum solubility solution of the test item no turbidity or precipitation was observed when diluted with the cysteine peptide solution.After the 24 h±2 h incubation period but prior to the HPLC analysis samples were inspected for precipitation, turbidity or phase separation. No precipitation, turbidity or phase separation was observed for the samples of the100 mM stock solution of thetest item. Slight turbidity was observed for the samples of themaximum solubility solution of thetest item (excluding the co-elution control). Samples were not centrifuged prior to the HPLC analysis.
For the 100 mM stock solution and the maximum solubility solution of the test item no turbidity or precipitation was observed when diluted with the lysine peptide solution.After the 24 h±2 h incubation period but prior to the HPLC analysis samples were inspected for precipitation, turbidity or phase separation. No precipitation, turbidity or phase separation was observed for the samples of the test item. Slight turbidity was observed for the samples of the positive control (excluding the co-elution control). Samples were not centrifuged prior to the HPLC analysis.Since the acceptance criteria for the depletion range of the positive control were fulfilled, the observed turbidity was regarded as not relevant.
For the 100 mMstock solution of the test item, no co-elution of test item with the peptide peaks was observed. Sensitising potential of the test item was predicted from the mean peptide depletion of both analysed peptides (cysteine and lysine) by comparing the peptide concentration of the test item treated samples to the corresponding reference control C (RC Cisopropanol).
The 100 mM stock solution of the test item showed minimal reactivity towards the synthetic peptides. The mean depletion of both peptides was£ 6.38% (2.58%).Based on the prediction model 1 the test item can be considered as non-sensitiser.
For themaximum solubility stock solution of thetest item,turbidity in the cysteine experiment was observed. Since it cannot be determined if the precipitate resulted from the test item or the peptide, the given peak areas and corresponding peptide values can only be considered as an estimation of the peptide depletion.
Themaximum solubilitystock solution of the test item showed minimal reactivity towards the synthetic peptides. The mean depletion of both peptides was£ 6.38% (3.61%).
According to the evaluation criteria in the guideline, if a precipitation or phase separation is observed after the incubation period, 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. Due to the observed turbidity in the cysteine experiment no prediction can be madefor themaximum solubility stock solution of thetest item.
The 100 mM stock solution of the positive control (cinnamic aldehyde) showed high reactivity towards the synthetic peptides. The mean depletion of bothpeptides was 65.65%.
Referenceopen allclose all
Cytotoxicity
Table 1: Results of the Cytotoxicity Measurement
| Concentration [µM] | Cell Viability [%] | |||
Experiment 1 | Experiment 2 | Mean | SD | ||
Solvent Control | - | 100 | 100 | 100 | 0.0 |
Positive Control | 4.00 | 123.1 | 85.1 | 104.1 | 26.9 |
8.00 | 113.8 | 83.1 | 98.5 | 21.7 | |
16.00 | 128.8 | 90.5 | 109.7 | 27.1 | |
32.00 | 140.2 | 88.7 | 114.4 | 36.4 | |
64.00 | 145.4 | 84.0 | 114.7 | 43.4 | |
Test Item | 0.98 | 108.4 | 98.0 | 103.2 | 7.4 |
1.95 | 110.8 | 107.1 | 109.0 | 2.6 | |
3.91 | 108.4 | 104.3 | 106.3 | 2.9 | |
7.81 | 101.0 | 100.7 | 100.8 | 0.2 | |
15.63 | 109.0 | 97.0 | 103.0 | 8.5 | |
31.25 | 105.7 | 79.8 | 92.7 | 18.3 | |
62.50 | 0.7 | 36.7 | 18.7 | 25.5 | |
125.00 | 0.8 | 18.0 | 9.4 | 12.1 | |
250.00 | 0.9 | 4.7 | 2.8 | 2.7 | |
500.00 | 0.5 | 0.6 | 0.5 | 0.1 | |
1000.00 | 0.8 | 0.6 | 0.7 | 0.1 | |
2000.00 | 0.9 | 0.7 | 0.8 | 0.1 |
Luciferase Activity Experiment 1
Table 2: Induction of Luciferase Activity Experiment 1
Experiment 1 | Concentration [µM] | Fold Induction | Significance | ||||
Rep. 1 | Rep. 2 | Rep. 3 | Mean | SD | |||
Solvent Control | - | 1.00 | 1.00 | 1.00 | 1.00 | 0.00 |
|
Positive Control | 4.00 | 1.50 | 0.95 | 1.25 | 1.23 | 0.27 |
|
8.00 | 1.28 | 1.24 | 1.32 | 1.28 | 0.04 |
| |
16.00 | 1.43 | 1.41 | 1.39 | 1.41 | 0.02 |
| |
32.00 | 1.63 | 1.73 | 1.81 | 1.72 | 0.09 | * | |
64.00 | 1.99 | 2.33 | 1.83 | 2.05 | 0.25 | * | |
Test Item | 0.98 | 1.01 | 1.19 | 1.17 | 1.12 | 0.10 |
|
1.95 | 1.08 | 1.36 | 1.24 | 1.23 | 0.14 |
| |
3.91 | 1.05 | 1.44 | 1.19 | 1.23 | 0.20 |
| |
7.81 | 1.09 | 1.34 | 1.36 | 1.26 | 0.15 |
| |
15.63 | 1.15 | 1.51 | 1.05 | 1.24 | 0.24 |
| |
31.25 | 1.15 | 1.52 | 1.40 | 1.36 | 0.19 |
| |
62.50 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
125.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
250.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
500.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
1000.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
2000.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
|
* = significant induction according to Student’s t-test, p<0.05
Luciferase Activity Experiment 2
Table 3: Induction of Luciferase Activity Experiment 2
Experiment 2 | Concentration [µM] | Fold Induction | Significance | ||||
Rep. 1 | Rep. 2 | Rep. 3 | Mean | SD | |||
Solvent Control | - | 1.00 | 1.00 | 1.00 | 1.00 | 0.00 |
|
Positive Control | 4.00 | 1.42 | 1.35 | 0.99 | 1.25 | 0.23 |
|
8.00 | 1.57 | 1.43 | 1.30 | 1.43 | 0.14 |
| |
16.00 | 1.28 | 1.42 | 1.75 | 1.49 | 0.24 |
| |
32.00 | 1.58 | 1.86 | 2.09 | 1.85 | 0.26 | * | |
64.00 | 7.50 | 6.04 | 6.41 | 6.65 | 0.76 | * | |
Test Item | 0.98 | 0.93 | 0.81 | 0.96 | 0.90 | 0.08 |
|
1.95 | 0.90 | 0.91 | 0.96 | 0.92 | 0.03 |
| |
3.91 | 1.02 | 1.09 | 1.00 | 1.04 | 0.04 |
| |
7.81 | 1.03 | 0.93 | 1.06 | 1.00 | 0.07 |
| |
15.63 | 1.24 | 1.23 | 1.72 | 1.39 | 0.28 |
| |
31.25 | 1.31 | 1.46 | 1.39 | 1.39 | 0.07 |
| |
62.50 | 0.03 | 0.02 | 0.10 | 0.05 | 0.04 |
| |
125.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
250.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
500.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
1000.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
2000.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
|
* = significant induction according to Student’s t-test, p<0.05
Luciferase Activity - Overall Induction
Table 4: Induction of Luciferase Activity – Overall Induction
Overall Induction | Concentration [µM] | Fold Induction | Significance | |||
Experiment 1 | Experiment 2 | Mean | SD | |||
Solvent Control | - | 1.00 | 1.00 | 1.00 | 0.00 |
|
Positive Control | 4.00 | 1.23 | 1.25 | 1.24 | 0.01 |
|
8.00 | 1.28 | 1.43 | 1.36 | 0.10 |
| |
16.00 | 1.41 | 1.49 | 1.45 | 0.05 |
| |
32.00 | 1.72 | 1.85 | 1.79 | 0.09 | * | |
64.00 | 2.05 | 6.65 | 4.35 | 3.25 |
| |
Test Item | 0.98 | 1.12 | 0.90 | 1.01 | 0.16 |
|
1.95 | 1.23 | 0.92 | 1.07 | 0.21 |
| |
3.91 | 1.23 | 1.04 | 1.13 | 0.14 |
| |
7.81 | 1.26 | 1.00 | 1.13 | 0.18 |
| |
15.63 | 1.24 | 1.39 | 1.32 | 0.11 |
| |
31.25 | 1.36 | 1.39 | 1.37 | 0.02 |
| |
62.50 | 0.00 | 0.05 | 0.03 | 0.03 |
| |
125.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
250.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
500.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
1000.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| |
2000.00 | 0.00 | 0.00 | 0.00 | 0.00 |
|
* = significant induction according to Student’s t-test, p<0.05
Additional Parameters
Table 5: Additional Parameters
Parameter | Experiment 1 | Experiment 2 | Mean | SD |
EC1.5 | n.a. | n.a. | n.a. | n.a. |
Imax | 1.36 | 1.39 | 1.38 | 0.03 |
IC30 | 41.87 | 38.37 | 40.12 | 2.48 |
IC50 | 47.83 | 52.88 | 50.35 | 3.57 |
n.a.=not applicable
Results of the Cell Batch Activation Test (Batch 11)
Sample | Concentration | CD86 | CD54 | Activated | Pass /Fail | ||||
Cell Viability [%] | RFI | Threshold OECD TG 442E | Cell Viability [%] | RFI | Threshold OECD TG 442E | yes/no | |||
DNCB | 4 µg/mL | 86 | 265 | >150 | 87 | 393 | >200 | yes | pass |
NiSO4 | 100 µg/mL | 83 | 219 | >150 | 79 | 711 | >200 | yes | pass |
LA | 1000 µg/mL | 91 | 88 | ≤150 | 92 | 111 | ≤200 | no | pass |
Results of the Cell Batch Activation Test (Batch 12)
Sample | Concentration | CD86 | CD54 | Activated | Pass /Fail | ||||
Cell Viability [%] | RFI | Threshold OECD TG 442E | Cell Viability [%] | RFI | Threshold OECD TG 442E | yes/no | |||
DNCB | 4 µg/mL | 89 | 349 | >150 | 88 | 386 | >200 | yes | pass |
NiSO4 | 100 µg/mL | 97 | 244 | >150 | 89 | 1007 | >200 | yes | pass |
LA | 1000 µg/mL | 88 | 125 | ≤150 | 94 | 181 | ≤200 | no | pass |
Results of the Dose Finding Assay
Sample | Experiment 1 | Experiment 2 | |||
Concentration applied [µg/mL] | Cell Viability [%] | Concentration applied [µg/mL] | Cell Viability [%] | ||
Medium Control | -- | -- | 93.38 | -- | 92.83 |
Solvent Control | DMSO | -- | 93.97 | -- | 94.25 |
cyclic Glucamide C12-C14 | C8 | 7.81 | 93.07 | 7.81 | 88.70 |
C7 | 15.63 | 93.39 | 15.63 | 91.77 | |
C6 | 31.25 | 91.75 | 31.25 | 89.70 | |
C5 | 62.50 | 70.65 | 62.50 | 67.96 | |
C4 | 125.00 | 2.30 | 125.00 | 2.70 | |
C3 | 250.00 | 2.53 | 250.00 | 2.53 | |
C2 | 500.00 | 1.27 | 500.00 | 1.64 | |
C1 | 1000.00 | 3.78 | 1000.00 | 4.44 | |
Calculated CV75 [µg/mL] | 54.18 | 49.93 | |||
Mean CV75 [µg/mL] | 52.06 | ||||
SD CV 75 [µg/mL] | 3.00 |
CD54 and CD86 Expression Experiment 1
Sample | Conc. | Cell Viability [%] | Mean Fluorescence Intensity | corrected Mean Fluorescence Intensity | Relative Flourescence Intensity (RFI) | Ratio [%] Isotype IgG1 to: | |||||||
CD86 | CD54 | Isotype IgG1 | CD86 | CD54 | Isotype IgG1 | CD86 | CD54 | CD86 | CD54 | CD86 | CD54 | ||
Medium Control | - | 94.0 | 92.8 | 92.9 | 1672 | 713 | 364 | 1308 | 349 | 88 | 90 | 459 | 196 |
Solvent Control | 0.20% | 93.9 | 93.8 | 93.6 | 1828 | 728 | 340 | 1488 | 388 | 100 | 100 | 538 | 214 |
DNCB | 4.00 | 76.2 | 74.8 | 75.1 | 2598 | 1869 | 364 | 2234 | 1505 | 150 | 388 | 714 | 513 |
cyclic Glucamide C12-C14 | 62.47 | 6.4 | 12.3 | 7.7 | 691 | 1117 | 320 | 371 | 797 | 25 | 205 | 216 | 349 |
52.06 | 51.4 | 49.2 | 58.4 | 696 | 986 | 337 | 359 | 649 | 24 | 167 | 207 | 293 | |
43.38 | 65.2 | 67.2 | 67.9 | 1027 | 1007 | 352 | 675 | 655 | 45 | 169 | 292 | 286 | |
36.15 | 84.6 | 82.7 | 84.1 | 1312 | 912 | 341 | 971 | 571 | 65 | 147 | 385 | 267 | |
30.13 | 90.1 | 90.3 | 90.4 | 1298 | 743 | 329 | 969 | 414 | 65 | 107 | 395 | 226 | |
25.11 | 89.6 | 91.2 | 91.5 | 1324 | 689 | 320 | 1004 | 369 | 67 | 95 | 414 | 215 | |
20.92 | 91.1 | 92.4 | 93.1 | 1441 | 662 | 314 | 1127 | 348 | 76 | 90 | 459 | 211 | |
17.43 | 91.3 | 92.3 | 91.5 | 1317 | 663 | 350 | 967 | 313 | 65 | 81 | 376 | 189 |
CD54 and CD86 Expression Experiment 2
Sample | Conc. | Cell Viability [%] | Mean Fluorescence Intensity | corrected Mean Fluorescence Intensity | Relative Flourescence Intensity (RFI) | Ratio [%] Isotype IgG1 to: | |||||||
CD86 | CD54 | Isotype IgG1 | CD86 | CD54 | Isotype IgG1 | CD86 | CD54 | CD86 | CD54 | C86 | CD54 | ||
Medium Control | - | 96.3 | 93.9 | 93.4 | 1933 | 622 | 474 | 1459 | 148 | 104 | 73 | 408 | 131 |
Solvent Control | 0.20% | 94.0 | 93.1 | 92.2 | 1838 | 639 | 436 | 1402 | 203 | 100 | 100 | 422 | 147 |
DNCB | 4.0 | 82.4 | 85.5 | 85.6 | 4219 | 1214 | 491 | 3728 | 723 | 266 | 356 | 859 | 247 |
cyclic Glucamide C12-C14 | 62.47 | 28.1 | 27.7 | 33.1 | 714 | 790 | 440 | 274 | 350 | 20 | 172 | 162 | 180 |
52.06 | 47.8 | 51.3 | 52.9 | 963 | 789 | 401 | 562 | 388 | 40 | 191 | 240 | 197 | |
43.38 | 70.8 | 70.2 | 73.8 | 1241 | 742 | 401 | 840 | 341 | 60 | 168 | 309 | 185 | |
36.15 | 84.4 | 84.5 | 86.4 | 1439 | 681 | 398 | 1041 | 283 | 74 | 139 | 362 | 171 | |
30.13 | 88.9 | 91.5 | 86.7 | 1317 | 603 | 391 | 926 | 212 | 66 | 104 | 337 | 154 | |
25.11 | 91.2 | 90.9 | 92.1 | 1468 | 556 | 383 | 1085 | 173 | 77 | 85 | 383 | 145 | |
20.92 | 90.2 | 93.6 | 91.2 | 1449 | 594 | 378 | 1071 | 216 | 76 | 106 | 383 | 157 | |
17.43 | 91.7 | 90.6 | 91.5 | 1535 | 586 | 391 | 1144 | 195 | 82 | 96 | 393 | 150 |
Acceptance Criteria
Acceptance Criterion | range | Experiment 1 | pass/fail | Experiment 2 | pass/fail | ||||
cell viability medium and solvent control [%] | >90 | 92.8 | - | 94.0 | pass | 92.2 | - | 96.3 | pass |
number of test dosed with viability >50% CD86 | ≥4 | 7 | pass | 6 | pass | ||||
number of test dosed with viability >50% CD54 | ≥4 | 6 | pass | 7 | pass | ||||
number of test dosed with viability >50% IgG1 | ≥4 | 7 | pass | 7 | pass | ||||
RFI of positive control of CD86 | ≥150 | 150 | pass | 266 | pass | ||||
RFI of positive control of CD54 | ≥200 | 388 | pass | 356 | pass | ||||
RFI of solvent control of CD86 | <150 | 114 | pass | 96 | pass | ||||
RFI of solvent control of CD54 | <200 | 111 | pass | 137 | pass | ||||
MFI ratio CD86/IgG1 for medium control [%] | >105 | 459 | pass | 408 | pass | ||||
MFI ratio CD86/IgG1 for solvent control [%] | >105 | 538 | pass | 422 | pass | ||||
MFI ratio CD54/IgG1 for medium control [%] | >105 | 196 | pass | 131 | pass | ||||
MFI ratio CD54/IgG1 for solvent control [%] | >105 | 214 | pass | 147 | pass | ||||
Historical Data
Criterion | mean | SD | N |
cell viability solvent controls [%] | 96.3 | 1.5 | 1566 |
number of test doses with viability >50% | - | - | 4058 |
RFI of positive control of CD86 | 354.4 | 122.7 | 261 |
RFI of positive control of CD54 | 434.5 | 254.7 | 261 |
RFI of solvent control of CD86 | 111.0 | 31.2 | 261 |
RFI of solvent control of CD54 | 114.5 | 43.1 | 261 |
MFI ratio IgG1/CD86 for medium control [%] | 308.5 | 153.7 | 261 |
MFI ratio IgG1/CD86 for DMSO control [%] | 352.3 | 362.9 | 261 |
MFI ratio IgG1/CD54 for medium control [%] | 179.0 | 149.7 | 261 |
MFI ratio IgG1/CD54 for DMSO control [%] | 176.6 | 54.1 | 261 |
Cysteine and Lysine Values of the Calibration Curve
Sample |
Cysteine Peptide |
Lysine Peptide |
||
Peak Area |
Peptide Concentration [mM] |
Peak Area |
Peptide Concentration [mM] |
|
STD1 |
17.0730 |
0.5340 |
15.4430 |
0.5340 |
STD2 |
8.6330 |
0.2670 |
7.8040 |
0.2670 |
STD3 |
4.3570 |
0.1335 |
3.9380 |
0.1335 |
STD4 |
2.1380 |
0.0667 |
1.9680 |
0.0667 |
STD5 |
1.0580 |
0.0334 |
1.0020 |
0.0334 |
STD6 |
0.4820 |
0.0167 |
0.5040 |
0.0167 |
STD7 |
0.0000 |
0.0000 |
0.0000 |
0.0000 |
Depletion of the Cysteine Peptide
Cysteine Peptide |
||||||
Sample |
Peak Area |
Peptide Conc. [mM] |
Peptide Depletion [%] |
Mean Peptide Depletion [%] |
SD of Peptide Depletion [%] |
CV of Peptide Depletion [%] |
Positive Control |
4.8680 |
0.1517 |
69.47 |
69.73 |
0.41 |
0.59 |
4.8600 |
0.1514 |
69.52 |
||||
4.7500 |
0.1480 |
70.21 |
||||
Test Item (100 mM) |
15.6970 |
0.4896 |
0.10 |
2.89 |
3.72 |
128.78 |
15.4840 |
0.4829 |
1.46 |
||||
14.5940 |
0.4551 |
7.12 |
||||
Test Item (maximum solubility) |
15.0150 |
0.4683 |
4.44 |
5.54 |
1.09 |
19.76 |
14.8410 |
0.4628 |
5.55 |
||||
14.6710 |
0.4575 |
6.63 |
Depletion of the Lysine Peptide
Lysine Peptide |
||||||
Sample |
Peak Area |
Peptide Conc. [mM] |
Peptide Depletion [%] |
Mean Peptide Depletion [%] |
SD of Peptide Depletion [%] |
CV of Peptide Depletion [%] |
Positive Control |
5.4140 |
0.1860 |
62.63 |
61.56 |
1.28 |
2.08 |
5.5180 |
0.1896 |
61.91 |
||||
5.7750 |
0.1984 |
60.14 |
||||
Test Item (100 mM) |
14.4100 |
0.4971 |
2.07 |
2.26 |
0.48 |
21.35 |
14.3000 |
0.4933 |
2.81 |
||||
14.4330 |
0.4979 |
1.91 |
||||
Test Item (maximum solubility) |
14.5540 |
0.5021 |
1.09 |
1.69 |
0.74 |
43.97 |
14.3440 |
0.4948 |
2.51 |
||||
14.5000 |
0.5002 |
1.45 |
Prediction Model 1
Cysteine 1:10/ Lysine 1:50 Prediction Model 1
Mean Cysteine andLysine PPD |
Reactivity Class |
DPRA Prediction² |
0.00% ≤ PPD ≤ 6.38% |
No or Minimal Reactivity |
Negative |
6.38% < PPD ≤ 22.62% |
Low Reactivity |
Positive |
22.62% < PPD ≤ 42.47% |
Moderate Reactivity |
|
42.47% < PPD ≤ 100% |
High Reactivity |
1 The numbers refer to statistically generated threshold values and are not related to the precision of the measurement.
2 DPRA predictions should be considered in the framework of an IATA.
Prediction Model 2
Cysteine 1:10 Prediction Model
Cysteine PPD |
ReactivityClass |
DPRA Prediction² |
0.00% ≤ PPD ≤ 13.89% |
No or Minimal Reactivity |
Negative |
13.89% < PPD ≤ 23.09% |
Low Reactivity |
Positive |
23.09% < PPD ≤ 98.24% |
Moderate Reactivity |
|
98.24% < PPD ≤ 100% |
High Reactivity |
Categorization of the Test Item
Prediction Model |
Prediction Model 1 |
Prediction Model 2 |
||||
Test Substance |
Mean Peptide Depletion [%] |
Reactivity Category |
Prediction |
Mean Peptide Depletion [%] |
Reactivity Category |
Prediction |
Test Item (100 mM) |
2.58 |
Minimal Reactivity |
negative |
2.89 |
Minimal Reactivity |
negative |
Test Item (maximum solubility) |
3.61 |
Minimal Reactivity |
- |
5.54 |
Minimal Reactivity |
- |
Positive Control |
65.65 |
High Reactivity |
positive |
69.73 |
Moderate Reactivity |
positive |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
In three in-chemico/vitro studies according to OECD 442 C/D/E, no skin sensitisation potential is indicated. Therefore, the resitered substance is considered as non-sensitizer and not classified for skin sensitisation.
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