Potassium propionate

Endpoint summary

Description of key information

-study conducted according to OECD TG 442D (adopted 2018), transgenic keratinocytes constitutively expressing an ARE-reporter gene were incubated with Potassium Propionate at concentrations of 2000, 1000, 500, 250, 125, 63, 31, 16, 7.8, 3.9, 2.0, 0.98 and 0 µM (solvent control) for 48 h at 37°C, luminescence and cell viability were measured, the test item did not induce the luciferase activity in the transgenic KeratinoSens™ cell line in at least two independent experiment runs, the test item can be considered as non-sensitiser. 

- QSAR prediction using DEREK NEXUS, the model predicts the skin sensitizing properties by comparison of similar structural fragments from substances with experimental data. The underlying training set includes data from 685 compounds (595 sensitizers and 90 non-sensitizers). The structural fragment was identified but does not fire an alert. The target substance lies within the applicability domain of the model; its structural features are predicted to be non-sensitising.

- QSAR prediction using VEGA HUB and CAESAR 2.1.6 model, the CAESAR model for skin sensitization was developed using Adaptive Fuzzy Partition (AFP), AFP was used to develop classification models implementing a fuzzy partition algorithm. 8 descriptors from Dragon software (nN; GNar; MDDD; X2v; EEig10r; GGI8; nCconj; O-058) were used. The underlying training set is publicly available (Gerberich, 2005), comprising of 167 curated and reviewed test results of Local Lymph Node Assays. The target substance lies within the applicability domain of the model; its structural features are predicted to be non-sensitizing.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vitro

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2021-02-02 to 2021-03-31

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:

2018

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of study:

ARE-Nrf2 luciferase KeratinoSens™ test method

Details of test system:

Keratinoses transgenic cell line [442D]

Details on the study design:

442D

PREPARATION OF TEST SOLUTIONS
- Preparation of the test chemical stock solution: In the main experiments the test item was dissolved in Milli-Q water at 200 mM (clear colorless solution).
- Preparation of the test chemical serial dilutions: From this stock 11 spike solutions in Milli-Q water were prepared (2-fold dilution series). The stock and spike solutions were diluted 25-fold with exposure medium. These solutions were diluted 4-fold with exposure medium in the assay resulting in final test concentrations of 2000, 1000, 500, 250, 125, 63, 31, 16, 7.8, 3.9, 2.0 and 0.98 µM (final concentration Milli-Q water of 1%).
- Preparation of the positive controls: The positive control used in the case of KeratinoSensTM is Ethylene dimethacrylate glycol (EDMG, Sigma, Zwijndrecht, The Netherlands), for which a 2-fold dilution series ranging from 0.78 to 25 mM were prepared in DMSO and diluted, so that the final concentration of the positive control ranges from 7.8 to 250 µM (final concentration DMSO of 1%).
- Preparation of the solvent, vehicle and negative controls: The vehicle control was 1% DMSO in exposure medium for the positive control and 1% Milli-Q water in exposure medium for the test item. Eighteen wells were tested per plate per vehicle control.
All formulations formed a clear solution.

DOSE RANGE FINDING ASSAY:
- Highest concentration used: 2000 µM
- Solubility in solvents
- Solubility in incubation medium
- Cytotoxicity assessment performed: MTT assay: For the KeratinoSensTM cell viability assay, medium was replaced after the 48 hour exposure time with fresh DMEM Glutamax containing MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Thiazolyl blue tetrazolium bromide; CAS No. 298-93-1; Sigma, Zwijndrecht, The Netherlands) and cells were incubated for 3 - 4 hours at 37°C ± 1.0°C in the presence of 5% CO2. The MTT medium was then removed and cells were lysed overnight by adding 10% SDS solution (Sigma, Zwijndrecht, The Netherlands) to each well. After shaking, the absorption was measured at 570 nm with the TECAN Infinite® M200 Pro Plate Reader.


APPLICATION OF THE TEST CHEMICAL AND CONTROL SUBSTANCES
- Number of replicates: 3
- Number of repetitions: 2
- Test chemical concentrations: 0, 0.98, 2.0, 3.9, 7.8, 16, 31, 63, 125, 250, 500, 1000, 2000 µM
- Application procedure: The medium was removed and replaced with fresh exposure medium (150 μL culture medium containing serum but without Geneticin) to which 50 μL of the 25-fold diluted test chemical and control items were added. Three wells per plate were left empty (no cells and no treatment) to assess background values. The treated plates were covered with foil and then incubated for about 48 hours ± 1 h at 37±1.0°C in the presence of 5% CO2.
- Exposure time: 48 h
- Study evaluation and decision criteria used:
The following parameters are calculated in the KeratinoSens™ test method:
• The maximal average fold induction of luciferase activity (Imax) value observed at any concentration of the tested chemical and positive control
• The EC1.5 value representing the concentration for which induction of luciferase activity is above the 1.5-fold threshold (i.e. 50% enhanced luciferase activity) was obtained
• The IC50 and IC30 concentration values for 50% and 30% reduction of cellular viability.

A KeratinoSens™ prediction is considered positive if the following 4 conditions are all met in 2 of 2 or in the same 2 of 3 repetitions, otherwise the KeratinoSens™ prediction is considered negative:
1. The Imax is equal or higher than (≥) 1.5-fold and statistically significantly different as compared to the vehicle (negative) control (as determined by a two-tailed, unpaired Student’s t-test)
2. The cellular viability is higher than (>) 70% at the lowest concentration with induction of luciferase activity ≥ 1.5-fold (i.e. at the EC1.5 determining concentration)
3. The EC1.5 value is less than (<) 1000 μM (or < 200 µg/mL for test chemicals with no defined MW)
4. There is an apparent overall dose-response for luciferase induction
Negative results obtained with concentrations <1000 µM or 200 µg/mL and which do not reach cytotoxicity (< 70% viability) at the maximal tested concentration should be considered as inconclusive.

- Description on study acceptance criteria: The KeratinoSens™ test is considered acceptable if it meets the following criteria:
a) The luciferase activity induction obtained with the positive control, Ethylene dimethacrylate glycol, should be statistically significant equal or above the threshold of 1.5 in at least one of the tested concentrations (from 7.8 to 250 µM).
b) The EC1.5 should be within two standard deviations of the historical mean. Moreover, the induction for Ethylene dimethacrylate glycol at 250 μM should be higher than 2-fold. If the latter criterion is not fulfilled, the dose-response of Ethylene dimethacrylate glycol should be carefully checked, and tests may be accepted only if there is a clear dose-response with increasing luciferase activity induction at increasing concentrations for the positive control.
c) Finally, the average coefficient of variation of the luminescence reading for the vehicle (negative) control DMSO and Milli-Q water should be below 20% in each repetition which consists of 18 wells tested. If the variability is higher, results should be discarded. If the variability is higher, a maximum of three of the eighteen wells may be excluded based on the Dixon’s Q-test. If the variability is still higher, the results should be discarded.

SEEDING AND INCUBATION
- Seeding conditions (passage number and seeding density): passage no.: 2-4 not more than 25; 10.000 cells/well
- Incubation conditions: All incubations, were carried out in a controlled environment, in which optimal conditions were a humid atmosphere of 80 - 100% (actual range 40 - 95 %), containing 5.0 ± 0.5% CO2 in air in the dark at 37.0 ± 1.0°C (actual range 35.2 - 37.2°C). Temperature and humidity were continuously monitored throughout the experiment. The CO2 percentage was monitored once on each working day.
- Washing conditions: not specified
- Precipitation noted: no

LUCIFERASE ACTIVITY MEASUREMENTS
- Choice of luminometer with demonstration of appropriate luminescence measurements based on control test: cell lysates were placed in the TECAN Infinite® M200 Pro Plate Reader to assess the quantity of luciferase (integration time two seconds).
- Plate used: 96-well plates
- Lysate preparation: The Steady-Glo Luciferase Assay Buffer (10 mL) and Steady-Glo Luciferase Assay Substrate (lyophilized) from Promega (Leiden, The Netherlands) were mixed together. The assay plates were removed from the incubator and the medium is removed. Then 200 µL of the Steady-Glo Luciferase substrate solution (prior to addition 1:1 mixed with exposure medium) was added to each well. The plates were shaken for at least 5 minutes at room temperature. Plates with the cell lysates were placed in the TECAN Infinite® M200 Pro Plate Reader to assess the quantity of luciferase (integration time two seconds).


DATA EVALUATION
- Cytotoxicity assessment: MTT assay
- Prediction model used: According to OECD guideline 442D

Vehicle / solvent control:

other: DMSO and MiliQ water

Positive control:

EGDMA (120 M) [442D]

Key result

Group:

test chemical

Run / experiment:

run/experiment 2

Parameter:

EC 1.5 [442D]

Remarks:

No luminescence activity induction compared to the vehicle control was observed at any of the test concentrations after treatment with the test item. The Imax was 1.10 and therefore no EC1.5 could be calculated.

Cell viability:

>70%; 101 - 117%

Vehicle controls validity:

valid

Negative controls validity:

not examined

Positive controls validity:

valid

Remarks on result:

other: • No luminescence activity induction compared to the vehicle control was observed at any of the test concentrations after treatment with the test item. The Imax was 1.10 and therefore no EC1.5 could be calculated.

Key result

Group:

test chemical

Run / experiment:

run/experiment 1

Parameter:

EC 1.5 [442D]

Remarks:

No luminescence activity induction compared to the vehicle control was observed at any of the test concentrations after treatment with the test item. The Imax was 1.07 and therefore no EC1.5 could be calculated.

Cell viability:

> 70%; 94 - 112%

Vehicle controls validity:

valid

Negative controls validity:

not examined

Positive controls validity:

valid

Remarks on result:

other: No luminescence activity induction compared to the vehicle control was observed at any of the test concentrations after treatment with the test item. The Imax was 1.07 and therefore no EC1.5 could be calculated.

Outcome of the prediction model:

negative [in vitro/in chemico]

Other effects / acceptance of results:

OTHER EFFECTS:
- Visible damage on test system: No

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: please refer to Any other information on results incl. tables
- Acceptance criteria met for positive control: please refer to Any other information on results incl. tables

Table 1          
Overview Luminescence Induction and Cell Viability of PU-2020-912 in Experiment 1 and 2

Concentration (µM)	0.98	2.0	3.9	7.8	16	31	63	125	250	500	1000	2000
Exp 1 luminescence	0.97	0.96	0.93	1.01	1.04	1.04	1.07	0.94	0.92	0.83	0.74	0.65
Exp 1 viability (%)	112	103	102	100	100	98	95	94	94	97	104	109
Exp 2 luminescence	1.06	1.04	1.02	1.08	1.06	1.10	1.05	1.03	0.93	0.90	0.67	0.64
Exp 2 viability (%)	117	111	109	107	101	102	101	105	102	107	113	113

Table 2: Overview Luminescence Induction and Cell Viability Positive Control EDMG in Experiment 1 and 2

Concentration (µM)	7.8	16	31	63	125	250
Exp 1 luminescence	1.03	1.09	1.41	1.73^***	2.28^***	3.05^***
Exp 1 viability (%)	116	115	118	119	122	120
Exp 2 luminescence	1.13	1.24	1.39	1.55^***	1.71^***	2.11^***
Exp 2 viability (%)	104	97	98	98	99	90

^*** p<0.001 Student’s t test

Table 3: Overview EC_1.5, I_max, IC₃₀ and IC₅₀ Values

	EC1.5 (µM)	Imax	IC30 (µM)	IC50 (µM)
Test item Experiment 1	NA	1.07	NA	NA
Test item Experiment 2	NA	1.10	NA	NA
Pos Control Experiment 1	40	3.05	NA	NA
Pos Control Experiment 2	53	2.11	NA	NA

NA = Not applicable

 

Table 4: Historical Control Data for the KeratinoSens^TM Studies

	Positive control
	EC1.5 (µM)	Imax
Range (mean ± 2x SD)	-3.0 – 120	-5.65 – 12.15
Mean	58.5	3.25
SD	30.7	4.45
n	503	503

SD = Standard deviation

n = Number of observations

 

 

 

 

Interpretation of results:

GHS criteria not met

Conclusions:

The test item showed no toxicity (no IC30 and IC50 value) and no biologically relevant induction of the luciferase activity (no EC1.5 value) was measured at any of the test concentrations in both experiments. The maximum luciferase activity induction (Imax) was 1.07 -fold and 1.10-fold in experiment 1 and 2 respectively. the test item is classified as negative in the KeratinoSensTM assay since negative results (<1.5-fold induction) were observed at test concentrations up to 2000 µM.

Executive summary:

In this study conducted according to OECD test guideline 442d (adopted 2018) transgenic keratinocytes constitutively expressing an ARE-reporter gene were incubated with Potassium Propionate at concentrations of 2000, 1000, 500, 250, 125, 63, 31, 16, 7.8, 3.9, 2.0, 0.98 and 0 µM (solvent control) for 48 h at 37°C. Afterwards the test substance containing medium was removed and the cells lysed and luminescence subsequently measured with a plate reader for 2.000 ms. Beside the luminescence the cell viability was measured using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium  bromide) assay method. The KeratinoSens™ assay is considered to provide positive results if the following conditions are all met in two of two independent experimental repetitions:

- the  I max   is  higher  than  (>)  1.5  fold  and  statistically  significant  different  as  compared  to  the solvent (negative) control (as determined by a two-tailed, unpaired Student’s T-test);

- the  cellular  viability  is  higher  than  (>)  70%  at  the  lowest  concentration  with  induction  of luciferase activity above 1.5 fold (i.e. at the EC 1.5  determining concentration);

- the EC 1.5  value is less than (<) 1000 µM (or < 200  µg/mL for test chemicals with no defined MW);

- there  is  an  apparent  overall  dose-response  for  luciferase  induction.

 

In the first experiment, a max luciferase activity (Imax) induction of not more than 1.07 was determined at any of test item concentrations. The corresponding cell viability was between 94 – 112%. There was no concentration with a significant luciferase induction >1.5. The calculated EC1.5 was < 1000 μM (40 μM).

 

In the second experiment, a max luciferase activity (Imax) induction of not more than 1.10 was determined at any of the test item concentrations. The corresponding cell viability was between 101 – 117%. There was no concentration with a significant luciferase induction >1.5. The calculated EC1.5 was < 1000 μM (53 μM).

No dose response for luciferase activity induction was observed for each individual run as well as for an overall luciferase activity induction.

The EC_1.5 of the positive control was within two standard deviations of the historical mean (40 µM and 53 µM in experiment 1 and 2, respectively). A dose response was observed and the induction at 250 µM was higher than 2-fold (3.05-fold and 2.11-fold in experiment 1 and 2, respectively).

Finally, the average coefficient of variation of the luminescence reading for the vehicle (negative) control DMSO (4.0% and 11% in experiment 1 and 2, respectively) and for Milli-Q water (6.3% and 6.6% in experiment 1 and 2, respectively) was below 20%.

 

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. However, the data generated with this method may be not sufficient to conclude definitely on the absence of skin sensitisation potential of chemicals and should be considered in the context of integrated approach such as IATA.

Reference 2

Endpoint:

skin sensitisation, other

Remarks:

QSAR prediction VEGA (CAESAR 2.1.6)

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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
VEGA 1.5.1
2. MODEL (incl. version number)
CAESAR 2.1.6
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O=C([O-])CC
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Skin Sensitisation
- Unambiguous algorithm: Adaptive Fuzzy Partition (AFP) model, consisting of eight descriptors (which is an extension of the original model, which was only based on seven descriptors (Chaudry, 2010).
- Defined domain of applicability: The applicability domain of predictions is assessed using an Applicability Domain Index (ADI) as implemented in VEGA that has values from 0 (worst case) to 1 (best case). The ADI is calculated by grouping several other indices, each one taking into account a particular issue of the applicability domain. Most of the indices are based on the calculation of the most similar compounds found in the training and test set of the model, calculated by a similarity index that consider molecule's fingerprint and structural aspects (count of atoms, rings and relevant fragments).
- Appropriate measures of goodness-of-fit and robustness and predictivity:
Accuracy: Training %: 93; Test %: 90
Precision: Training %: 95; Test %: 94
Sensitivity (class S): Training %: 96; Test %: 100
Specificity (class NC):Training %: 79; Test %: 75
F-measure:Training %: 96; Test %: 97
The statistics used in the table are derived as follows:
True positive (TP) = number of sensitisers correctly predicted
False positive (FP) = number of non sensitisers predicted as sensitisers
True negative (TN) = number of non sensitisers correctly predicted
False negative (FN) = number of sensitisers predicted as non sensitisers
Accuracy = (TN+TP)/(TN+FN+FP + TP)
Precision = TP/(TP+FP)
Sensitivity (true positive rate) = TP/TP+FN
Specificity (true negative rate) = TN/TN+FP
F-measure = 2/(1/precision)+(1/sensitivity)
- Mechanistic interpretation:

5. APPLICABILITY DOMAIN
- Descriptor domain: This model was derived from 8 descriptors from Dragon software (nN; GNar; MDDD; X2v; EEig10r; GGI8; nCconj; O-058).
- Similarity with analogues in the training set: The underlying training set is publicly available (Gerberich, 2005), comprising of 167 curated and reviewed test results of Local Lymph Node Assays.

6. ADEQUACY OF THE RESULT
The reliability of the prediction is assigned as moderate; the substance might be outside the applicability domain. Three out of six structurally similar chemicals presented with the prediction are known skin sensitisers. Although for each of those three compounds, the responsible structural alerts have been identified and the differences to the target molecules have been explained, the robustness of the prediction is reduced due to the insufficient availability of structurally similar surrogate substances.

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Software tool(s) used including version: VEGA 1.5.1
- Model(s) used: CAESAR 2.1.6
- Model description: see field 'Justification for non-standard information'
- Justification of QSAR prediction: see field 'Justification for type of information'

GLP compliance:

no

Key result

Group:

test chemical

Run / experiment:

other: QSAR prediction CAESAR

Parameter:

other: Not applicable for in silico prediction with the global CAESAR model

Remarks on result:

other: The substance was predicted to be a NON-Sensitizer, however there were contrasting results from similar molecules. Thus, the prediction is of moderate reliability

Interpretation of results:

study cannot be used for classification

Conclusions:

In this study under the given conditions the test item was predicted to be a NON-Sensitizer. However, the data generated with this prediction may be not sufficient to conclude definitely 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 skin sensitizing potential of Potassium Propionate was determined by QSAR estimation using VEGA HUB1.5.1 (CAESAR 2.1.6). The prediction is built on Adaptive Fuzzy Partition (AFP) model, consisting of eight descriptors (which is an extension of the original model, which was only based on seven descriptors (Chaudry, 2010). The applicability domain of predictions is assessed using an Applicability Domain Index (ADI) as implemented in VEGA that has values from 0 (worst case) to 1 (best case). The ADI is calculated by grouping several other indices, each one taking into account a particular issue of the applicability domain. Most of the indices are based on the calculation of the most similar compounds found in the training and test set of the model, calculated by a similarity index that consider molecule's fingerprint and structural aspects (count of atoms, rings and relevant fragments). The reliability of the prediction is assigned as moderate; the substance might be outside the applicability domain. Three out of six structurally similar chemicals presented with the prediction are known skin sensitizers. Although for each of those three compounds, the responsible structural alerts have been identified and the differences to the target molecules have been explained, the robustness of the prediction is reduced due to the insufficient availability of structurally similar surrogate substances.

The target substance lies within the applicability domain of the model; its structural features are predicted to be non-sensitizing. However, three out of six training set substances exhibit contradictory results, thus, the robustness of the prediction is reduced due to the insufficient availability of structurally similar surrogate substances. In this prediction Potassium Propionate is not a dermal sensitizer.

Based on these results Potassium Propionate is not considered a dermal sensitizer.

Reference 3

Endpoint:

skin sensitisation, other

Remarks:

QSAR prediction

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Justification for type of information:

1. SOFTWARE
Derek Nexus: 6.1.0
2. MODEL (incl. version number)
Nexus: 2.3.0
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Smiles: CCC([O-])=O.[K+]
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: skin sensitisation
- Unambiguous algorithm: The software is a rule-based expert system based on a proprietary data set that has been assessed in a fragmentation approach for the presence of potential toxicophores (2D SARs). Also, substructures of known non-sensitizers as well as physicochemical have been identified and added to the underlying algorithm. The model has been trained with data from several testing methodologies, including primarily OECD guideline-compliant animal tests (Buehler test, Guinea Pig Maximization Test, Local Lymph Note Assay), human data (e.g. human maximization test and human repeat insult patch tests), regulatory information (GHS Classification) and chemical properties (e.g. assessment of structural alerts). The underlying training set includes data from 685 compounds (595 sensitizers and 90 non-sensitizers) (Langton, 2020).
- Defined domain of applicability: The prediction is built on a Nearest Neighbour Model, where the nearest neighbours are taken from a reference set of compounds that fire the same alert as the query compound. The nearest neighbour compounds are selected from over 650 compounds in the Lhasa EC3 dataset.
Firstly, the query compound is processed in Derek to determine whether a skin sensitisation alert is fired.
Secondly, those compounds from the Lhasa EC3 dataset which fire the same skin sensitisation alert as the query compound are identified. Because they fire the same alert, these compounds are believed to cause skin sensitisation through the same mechanism as the query compound.
Thirdly, the compounds in the Lhasa EC3 dataset are assessed using an in-house structural fingerprinting technique. They are then evaluated for their similarity to the query compound using the Tanimoto score. Up to 10 nearest neighbours are highlighted and are used to make the EC3 prediction, based on a weighted average. If less than 3 nearest neighbours are found, no prediction is made.
- Appropriate measures of goodness-of-fit and robustness and predictivity: The model has been designed not to under-predict, as this may bring about exposure to a chemical that is a sensitiser. The model correctly or over-predicts the compounds to be within the appropriate ECETOC category 79% of the time, and to be within the GHS category 89% of the time. Proprietary of Lhasa Ltd.
- Mechanistic interpretation: Those compounds from the Lhasa EC3 dataset which fire the same skin sensitisation alert as the query compound are identified. Because they fire the same alert, these compounds are believed to cause skin sensitisation through the same mechanism as the query compound.

5. APPLICABILITY DOMAIN
- Descriptor domain: structural fragments
- Similarity with analogues in the training set: The underlying training set includes data from 685 compounds (595 sensitizers and 90 non-sensitizers). The structural fragment was identified but does not fire an alert.


6. ADEQUACY OF THE RESULT
The target substance lies within the applicability domain of the model; its structural features are predicted to be non-sensitising. The sensitivity of the model lies between 73 and 76 %, as determined in separate assessments, and is therefore not unsimilar to in vivo data.

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Software tool(s) used including version:
- Model(s) used:
- Model description: see field 'Justification for non-standard information', 'Attached justification' and/or 'Cross-reference'
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'Cross-reference'

GLP compliance:

no

Key result

Group:

test chemical

Run / experiment:

other: QSAR prediction

Parameter:

other: not applicable for in silico prediction

Cell viability:

N/A

Remarks on result:

no indication of skin sensitisation

Remarks:

According to the in silico prediction performed with DEREK Nexus ther are no indications for skin sensitising properties of Potassium Propionate

Interpretation of results:

study cannot be used for classification

Conclusions:

In this study under the given conditions the test item did not exhibit strutctural alerts dor skin sensitising properties. Therefore, the test item can be considered as non-sensitiser. However, the data generated with this prediction may be not sufficient to conclude definitely 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 skin sensitizing potential of Potassium Propionate was determined by QSAR estimation using DEREK NEXUS 6.1.0. The prediction is built on a Nearest Neighbour Model, where the nearest neighbours are taken from a reference set of compounds that fire the same alert as the query compound. The nearest neighbour compounds are selected from over 650 compounds in the Lhasa EC3 dataset. Firstly, the query compound is processed in Derek to determine whether a skin sensitisation alert is fired. Secondly, those compounds from the Lhasa EC3 dataset which fire the same skin sensitisation alert as the query compound are identified. Because they fire the same alert, these compounds are believed to cause skin sensitisation through the same mechanism as the query compound. Thirdly, the compounds in the Lhasa EC3 dataset are assessed using an in-house structural fingerprinting technique. They are then evaluated for their similarity to the query compound using the Tanimoto score. Up to 10 nearest neighbours are highlighted and are used to make the EC3 prediction, based on a weighted average. If less than 3 nearest neighbours are found, no prediction is made.

The target substance lies within the applicability domain of the model; its structural features are predicted to be non-sensitising. The sensitivity of the model lies between 73 and 76 %, as determined in separate assessments, and is therefore not unsimilar to in vivo data.

In this prediction Potassium Propionate is not a dermal sensitizer.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

A qualitative assessment for determining the weight for each Line of Evidence (LoE) was applied in accordance with the Guiding Principles and Key Elements for Establishing a Weight of Evidence for Chemical Assessment (OECD, 2019). Each LoE was assigned a combined weight based on its determined reliability and relevance. Results are provided in the WoE robust study summaries in the attached WoE assessment document. Each presented LoE suggests that potassium propionate is non-sensitising. Only LoE 2 was assigned a high reliability, as it was based on test data, while most LoEs were based on in silico predictions or information from public literature (Reliability moderate or low). Most LoEs were assigned a high relevance, as the predicted information were usually suitable to fulfil the information requirement for the endpoint skin sensitisation as stand-alone data. Consequently, LoEs were assigned a combined moderate to high weight.

The LoEs are split into two groups: The first four LoEs address the first three key elements of the Adverse Outcome Pathway (OECD, 2012). LoE 4 (in silico prediction with Derek Nexus) is listed twice, as it a) predicts the endpoint skin sensitization in toto and b) has been shown to suit as a replacement of the DPRA (OECD 442C) for the prediction of Key Event 1 in a Defined Approach (2 out of 3) (Macmillan, 2019), providing comparable accuracy. Although each Key Event is addressed, it is acknowledged that Key Event 3 (Dendritic cell activation) is only addressed with an in silico prediction with low reliability. However, the 2 out of 3 approach allows that in case of consistent prediction of the skin sensitisation potential based on any two Key Events, information from the third Key Event does not need to be gathered, as its outcome does not influence the overall conclusion (Bauch, 2012; Urbisch, 2015; Kolle, 2019; ECHA, 2017).

The second group addresses the endpoint skin sensitisation in toto; it consists of in silico methods largely to solely based on endpoint-specific data (guideline studies in guinea pigs and mice, and human data) and on supporting information from public literature. Independently from the AOP-driven LoEs, the outcome is consistently negative.

In conclusion, the Weight of Evidence suggests that potassium propionate is not a skin sensitizer.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the performed WoE-approach, Potassium Propionate is considered a NON-Sensitizer and does not need to be classified according to Regulation (EU) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).