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EC number: 289-108-9 | CAS number: 86014-62-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
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- Flash point
- Auto flammability
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- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
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- Endpoint summary
- Stability
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- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
OECD 442C DPRA (2017): Negative
OECD 442D KSA (2017): Negative
In accordance with the integrated testing strategy for skin sensitisation, no further studies require being conducted and the endpoint can be considered negative (not sensitising).
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in chemico
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 11 May 2017 to 06 December 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Study conducted in accordance with international guidelines and in accordance with GLP. All guideline validity criteria were met.
- 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:
- direct peptide reactivity assay (DPRA)
- Details on the study design:
- Skin sensitisation (In chemico test system) - Details on study design:
The study was conducted to quantify the reactivity of the test article (Reaction mass of Ammonium mono(2-ethylhexyl)phosphate, Ammonium bis(2-ethylhexyl)phosphate and 2-ethylhexyl diphosphate ammonium salts) towards model synthetic peptides containing either lysine or cysteine.
The test article and positive control was dissolved in purified water and acetonitrile, respectively at a concentration of 100 mM.
The test solutions were incubated at 1:10 and 1:50 ratios with the cysteine and lysine peptides, respectively, for 24±2 hours in glass autosampler vials, protected from light and set at 25 °C.
The remaining concentration of cysteine- or lysine-containing peptides following the 24 hour incubation period was measured by high performance liquid chromatography (HPLC) with gradient elution and UV detection at 220 nm.
The mean percent cysteine and percent lysine depletion value was calculated.
Negative depletion was considered as “0” when calculating the mean. By using the cysteine 1:10/lysine 1:50 prediction model below, the threshold of 6.38 % average peptide depletion was used to support the discrimination between skin sensitisers and non-sensitisers in the framework of an IATA.
0% ≤ mean % depletion ≤6.38% = No or minimal reactivity/ Negative for sensitisation
6.38% < mean % depletion ≤22.62% Low reactivity/ Positive for sensitisation
22.62% < mean % depletion ≤42.47% = Moderate reactivity/ Positive for sensitisation
42.47% < mean % depletion ≤100% = High reactivity/ Positive for sensitisation - Positive control results:
- Mean PPD = 55.84 %
High reactivity (Positive result) - Key result
- Run / experiment:
- other: other: Lysine mean test item PPD
- Parameter:
- other: Peptide Percent Depletion
- Value:
- 0.55
- Vehicle controls validity:
- not examined
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Run / experiment:
- other: other: Cysteine mean test item PPD
- Parameter:
- other: Peptide Percent Depletion
- Value:
- 11.27
- Vehicle controls validity:
- not examined
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Other effects / acceptance of results:
- OTHER EFFECTS:
- Visible damage on test system: n/a
DEMONSTRATION OF TECHNICAL PROFICIENCY: Yes
The following criteria should be met for a run to be considered valid: a) the standard calibration curve should have an r2 >0.99 (actual >0.9935), b) the mean percent peptide depletion value of the three replicates for the positive control cinnamic aldehyde should be between 60.8 % and 100 % for the cysteine peptide (actual = 73.11 %) and between 40.2 % and 69.0 % for the lysine peptide (actual = 55.84 %) and the maximum standard deviation (SD) for the positive control replicates should be <14.9 % for the percent cysteine depletion (actual = 0.4 %) and <11.6 % for the percent lysine depletion (actual = 2.5 %) and c) the mean peptide concentration of reference controls A should be 0.50 ± 0.05 mM (actual = 0.53 and 0.46 mM for cysteine and lyseien standards, respectively)and the coefficient of variation (CV) of peptide peak areas for the nine reference controls B and C in acetonitrile should be <15.0 % (actual = 1.92 %).
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- Based on the condition of the study, the test article was considered to be negative in the Direct Peptide Reactivity Assay according to EU CLP and UN GHS.
- Executive summary:
OECD 442C (2017) - The in chemico study was conducted to quantify the reactivity of the test item towards model synthetic peptides containing either lysine or cysteine. The test item and positive control were dissolved in purified water and acetonitrile, respectively at a concentration of 100 mM. The test solutions were incubated at 1:10 and 1:50 ratios with the cysteine and lysine peptides, respectively, for 24 ± 2 hours in glass autosampler vials, protected from light and set at 25 °C. The remaining concentration of cysteine- or lysine-containing peptides following the 24 hour incubation period was measured by high performance liquid chromatography (HPLC) with gradient elution and UV detection at 220 nm.
The mean percent cysteine and percent lysine depletion values were calculated and determined to be 11.27 and 0.55 %, respectively. Based on the condition of the study, the test article was considered to be negative in the Direct Peptide Reactivity Assay, according to EU CLP and UN GHS.
- Endpoint:
- skin sensitisation: in vitro
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 02 June 2017 to 16 April 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Study conducted in accordance with international guidelines and in accordance with GLP. All guideline validity criteria were met.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 442D (In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of study:
- activation of keratinocytes
- Details on the study design:
- Skin sensitisation (In vitro test system) - Details on study design:
Treatment plate preparation
The cells were 80-90 % confluent. On the day prior to treatment, cells were harvested and distributed into 96-well plates (10000 cells/well) and incubated at 37 ± 1 °C, 5 % (v/v) CO2, for 24 ± 1 hours.
For each repetition, three replicates were used for the luciferase activity measurements and one parallel replicate used for the cell viability assay.
Treatment
At the end of the 24-hour incubation period, the medium was removed and replaced with fresh culture medium (containing serum but without Geneticin) to which test article and control formulations were added.
One well per plate was left empty (no cells and no treatment) to assess background values.
Each plate was sealed and incubated at 37 ± 1 °C, 5 % (v/v) CO2 in air, in a humidified environment for 48 ± 1 hours.
For each test article and positive control, one experiment was needed to derive a prediction (positive or negative), consisting of at two independent repetitions each containing three replicates of each concentration.
Each independent repetition was performed on a different day with fresh stock solutions of chemicals and independently harvested cells. The cells came from the same passage.
Cytotoxicity assessment
After the 48-hour exposure period, the medium was replaced with fresh medium containing MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide).The plate was sealed and incubated for 4 hours at 37 ± 1 °C, 5 % (v/v) CO2.
The MTT medium was removed and SDS (at 10% w/v) added per well. The plate was sealed and placed into an incubator at 37 ± 1 °C, 5 % (v/v) CO2 in air and left overnight.
After the overnight incubation, the plate was shaken to ensure homogeneity of the solution in the wells and then absorption read at 600 nm using a SpectraMax M2e.
Luciferase activity measurements
After the 48-hour exposure period, the cells were washed with phosphate buffered saline and lysis buffer for luminescence readings was added to each well. The plates were then incubated for 20 minutes at 25 ± 2 °C, loaded into the luminescence plate reader and read using the following parameters: 100 µL injection (Luciferase assay substrate), 15 second delay, 7 second luminescence integration time. - Positive control results:
- Luciferase activity induction obtained with the positive control was statistically significant above the threshold of 1.5 at concentrations of 16, 32 and 64 µM in Experiments 1 and 2.
The EC1.5 values for the positive control were 15.42 and 10.35 µM in Experiments 1 and 2, respectively.
The average induction in the three replicates for the positive control at 64 µM was 4.32 in both experiments. - Key result
- Run / experiment:
- other: other: Two experimental runs with Imax (fold increase) of 4.27 (statistically signifiant) and 1.52 (not statistically significant)
- Parameter:
- other:
- Remarks:
- ARE-Nrf2 Luciferase induction
- Value:
- 1.52
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Other effects / acceptance of results:
- Luciferase activity induction obtained with the positive control was statistically significant above the threshold of 1.5 at concentrations of 16, 32 and 64 µM in Experiments 1 and 2.
The EC1.5 values for the positive control were 15.42 and 10.35 µM in Experiments 1 and 2, respectively.
The average induction in the three replicates for the positive control at 64 µM was 4.32 in both experiments.
The average coefficient of variation of the luminescence reading for the negative control (DMSO) was 10.02 % and 16.20 % in Experiments 1, and 2, respectively. - Interpretation of results:
- GHS criteria not met
- Conclusions:
- Based on the condition of this study, the test article was considered to be negative in the ARE-Nrf2 Luciferase Test according to EU CLP and UN GHS.
- Executive summary:
In an OECD 442D 2017: the test item potential was investigated at concentration range of 0.2 to 400 μg/mL. Aliquots of 50 μL of each of the final concentrations were transferred to each of three luciferase plates and a single viability plate. Each plate was sealed using a plate sealer and then incubated at 37±1°C, 5% (v/v) CO2 in air, in a humidified environment for 48±1 hours.
After the 48-hour exposure period, the medium in the viability plate was replaced with fresh medium containing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The plate was sealed and incubated for 4 hours at 37±1°C, 5% (v/v) CO2. The MTT medium was then removed and SDS (at 10% w/v) added per well. The plate was sealed and placed into an incubator at 37±1°C, 5% (v/v) CO2 in air and left overnight. After the overnight incubation, the plate was shaken to ensure homogeneity of the solution in the wells and then absorption read at 600 nm using a SpectraMax M2e. After the 48-hour exposure period, the cells in the luciferase plates were washed with phosphate buffered saline and lysis buffer for luminescence readings was added to each well. The plates were then incubated for 20 minutes at 25±2°C, loaded into the luminescence plate reader and read.
The maximal fold increase (Imax) was 4.27 in Experiment 1 and was statistically significant. However, the viability at the lowest concentration with > 1.5-fold induction (50 mg/mL) was only 12.9%. Therefore this was considered to be a false positive result.
In Experiment 2, the Imax was 1.52, but was not statistically significant, therefore this was considered a negative result.
It was concluded that under the condition of the study, the test item was considered to be negative in the ARE-Nrf2 Luciferase Test according to EU CLP and UN GHS.
Referenceopen allclose all
Table 1 Lysine Depletion Summary
Substance |
Replicate Peptide Peak Areas |
Reference Control C |
PPD |
Mean PPD |
SD |
Test Article |
38.717 |
38.38 |
-0.88 |
0.55 |
0.9 |
38.588 |
-0.54 |
||||
37.749 |
1.64 |
||||
Positive Control |
16.192 |
35.78 |
54.75 |
55.84 |
2.5 |
16.414 |
54.13 |
||||
14.792 |
58.66 |
Table 2 Cysteine Depletion Summary
Substance |
Replicate Peptide Peak Areas |
Reference Control C |
PPD |
Mean PPD |
SD |
Test Article |
23.579 |
26.115 |
9.71 |
11.27 |
1.5 |
23.126 |
11.45 |
||||
22.809 |
12.66 |
||||
Positive Control |
7.243 |
26.748 |
72.92 |
73.11 |
0.4 |
7.059 |
73.61 |
||||
7.277 |
72.79 |
Table 1 Luminescence Readings for Experiment 1
Substance |
Concentration (µg/mL) |
||||||||||||
0.20 |
0.39 |
0.78 |
1.56 |
3.13 |
6.25 |
12.5 |
25 |
50 |
100 |
200 |
400 |
||
Test Article |
Plate 1 |
1595543 |
1949671 |
2150748 |
1977587 |
1939608 |
1503695 |
1466992 |
1411049 |
7414562 |
-4 |
-1334 |
-891 |
Plate 2 |
1425323 |
2405398 |
2444141 |
2252869 |
1967323 |
1588885 |
1382291 |
1761253 |
8290327 |
1672 |
-913 |
-615 |
|
Plate 3 |
1875925 |
1876982 |
2098413 |
2115341 |
2253219 |
1562467 |
1647061 |
1685263 |
8939677 |
506 |
-1112 |
-773 |
|
Mean Fold Induction |
0.85 |
1.08 |
1.16 |
1.10 |
1.07 |
0.81 |
0.78 |
0.84 |
4.27 |
0.00 |
0.00 |
0.00 |
Substance |
Individual Values |
||||||
Negative Control |
Plate 1 |
1964652 |
2133206 |
1808828 |
1981876 |
2009225 |
1725812 |
Plate 2 |
1854369 |
1817851 |
2077112 |
1941072 |
2001819 |
1929047 |
|
Plate 3 |
1564894 |
1808335 |
1860888 |
2489171 |
1886345 |
1816473 |
Substance |
Concentration (µM) |
|||||
4 |
8 |
16 |
32 |
64 |
||
Positive Control |
Plate 1 |
2214660 |
2247164 |
2805564 |
3624814 |
9044607 |
Plate 2 |
2171338 |
2723033 |
3029193 |
3895171 |
7591194 |
|
Plate 3 |
2571740 |
2779511 |
2904452 |
4639515 |
8310327 |
|
Mean Fold Induction |
1.20 |
1.34 |
1.51 |
2.11 |
4.32 |
Table 2 Luminescence Readings for Experiment 2
Substance |
Concentration (µg/mL) |
||||||||||||
0.20 |
0.39 |
0.78 |
1.56 |
3.13 |
6.25 |
12.5 |
25 |
50 |
100 |
200 |
400 |
||
Test Article |
Plate 1 |
681637 |
813061 |
836969 |
814404 |
760686 |
693972 |
611022 |
671329 |
3249179 |
186 |
-432 |
-310 |
Plate 2 |
916614 |
977708 |
927934 |
999602 |
940968 |
885310 |
852727 |
1137502 |
105122 |
-633 |
-644 |
-366 |
|
Plate 3 |
1126957 |
1091203 |
1013303 |
932404 |
895338 |
795742 |
807759 |
823055 |
608566 |
-380 |
-436 |
-302 |
|
Mean Fold Induction |
0.92 |
0.98 |
0.95 |
0.94 |
0.89 |
0.81 |
0.77 |
0.89 |
1.52 |
0.00 |
0.00 |
0.00 |
Substance |
Individual Values |
||||||
Negative Control |
Plate 1 |
745443 |
820675 |
821712 |
1047885 |
813494 |
770470 |
Plate 2 |
938363 |
983923 |
1365594 |
1092872 |
862394 |
946182 |
|
Plate 3 |
1126957 |
1091203 |
1013303 |
932404 |
895338 |
795742 |
Substance |
Concentration (µM) |
|||||
4 |
8 |
16 |
32 |
64 |
||
Positive Control |
Plate 1 |
929885 |
1092452 |
1512082 |
2284728 |
3861519 |
Plate 2 |
1272749 |
1734957 |
1807804 |
2041535 |
4905376 |
|
Plate 3 |
1207810 |
1344946 |
1610995 |
2376396 |
3804812 |
|
Mean Fold Induction |
1.16 |
1.42 |
1.69 |
2.32 |
4.32 |
Table 3 MTT-Absorbance Readings
Substance |
Concentration (µg/mL) |
||||||||||||
0.20 |
0.39 |
0.78 |
1.56 |
3.13 |
6.25 |
12.5 |
25 |
50 |
100 |
200 |
400 |
||
Test Article |
Experiment 1 |
0.963 |
1.254 |
1.149 |
1.145 |
1.096 |
0.991 |
0.744 |
0.612 |
0.149 |
0.001 |
0.001 |
0.003 |
Experiment 2 |
0.665 |
0.828 |
0.824 |
0.771 |
0.736 |
0.657 |
0.607 |
0.661 |
0.006 |
0.005 |
0.002 |
0.001 |
|
Mean Viability (%) |
82.33 |
104.94 |
100.14 |
96.71 |
92.44 |
83.12 |
69.32 |
66.89 |
6.78 |
0.35 |
0.16 |
0.20 |
Substance |
Individual Values |
||||||
Negative Control |
Experiment 1 |
1.023 |
1.140 |
1.218 |
1.189 |
1.173 |
1.186 |
Experiment 2 |
0.726 |
0.884 |
0.824 |
0.811 |
0.803 |
0.857 |
Substance |
Concentration (µM) |
|||||
4 |
8 |
16 |
32 |
64 |
||
Positive Control |
Experiment 1 |
1.187 |
1.362 |
1.266 |
1.295 |
1.019 |
Experiment 2 |
0.828 |
1.045 |
1.024 |
1.045 |
1.048 |
|
Mean Viability (%) |
102.01 |
122.87 |
117.44 |
120.01 |
108.20 |
Table 4. Result Summaries
Condition |
Repetition 1
|
Repetition 2 |
Imax(fold increase) |
4.27 (at 50 μg/mL) and statistically significant
|
1.52 (at 50 μg/mL), but not statistically significant
|
Cell Viability at 50 μg/mL |
12.9% |
Not applicable |
Cell viability at 25 μg/mL |
53% |
Not applicable
|
EC1.5(μg/mL) |
29.81 |
Not applicable
|
Dose Response for Luciferase Induction |
No |
No |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
- Additional information:
OECD 442C (2017) - The in-chemico study was conducted to quantify the reactivity of the test item (towards model synthetic peptides containing either lysine or cysteine. The test solutions were incubated at 1:10 and 1:50 ratios with the cysteine and lysine peptides, respectively, for 24 ± 2 hours in glass autosampler vials, protected from light and set at 25 °C.
The remaining concentration of cysteine- or lysine-containing peptides following the 24 hour incubation period was measured by high performance liquid chromatography (HPLC) with gradient elution and UV detection at 220 nm.
The mean percent cysteine and percent lysine depletion values were calculated and determined to be 11.27 and 0.55 %, respectively.
Based on the condition of the study, the test article was considered to be negative in the Direct Peptide Reactivity Assay, according to EU CLP and UN GHS.
OECD 442D (2017): the test item potential was investigated at concentration range of 0.2 to 400 μg/mL. Aliquots of 50 μL of each of the final concentrations were transferred to each of three luciferase plates and a single viability plate then incubated at 37±1°C, 5% (v/v) CO2 in air, in a humidified environment for 48±1 hours.
After the 48-hour exposure period, the medium in the viability plate was replaced with fresh medium containing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and incubated overnight. This is followed by washing cells in luciferase plates using phosphate buffered saline and lysis buffer for luminescence readings.
The maximal fold increase (Imax) was 4.27 in Experiment 1 and was statistically significant. However, the viability at the lowest concentration with > 1.5-fold induction (50 mg/mL) was only 12.9%. Therefore this was considered to be a false positive result.
In Experiment 2, the Imax was 1.52, but was not statistically significant, therefore this was considered a negative result.
It was concluded that under the condition of the study, the test item was considered to be negative in the ARE-Nrf2 Luciferase Test according to EU CLP and UN GHS.
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
The substance did not meet the classification criteria in accordance with Regulation (EC) No 1272/2008 (CLP).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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