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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vitro
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
04-May-2018 to 11-May-2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to other study
Reference
Endpoint:
skin sensitisation: in chemico
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
19-April-2018 to 27-April-2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 442C (In Chemico Skin Sensitisation: Direct Peptide Reactivity Assay (DPRA))
Version / remarks:
2015
GLP compliance:
yes
Type of study:
direct peptide reactivity assay (DPRA)
Justification for non-LLNA method:
In vitro study
Specific details on test material used for the study:
- Purity test date: 40% Active in water, ~90% purity of active material
Details on the study design:
Test items were incubated for 24hrs (±2hrs) at 25 ±2.5°C in solution at 100 mM in combination with either Cysteine or Lysine containing peptides and then run on an HPLC system (20-minute run-time) using gradient elution and UV detection at 220 nm to measure peptide concentration. Test items were compared to reference controls (i.e., cinnamic aldehyde in HPLC Grade Acetonitrile) containing the test item solvent in combination with either Cysteine or Lysine peptide in order to determine the relative percent peptide depletion. Relative percent peptide depletion values were used in a prediction model that assigns test items to one of four reactivity classes.

Prior to the main test, the test item was assessed for solubility and was found to be soluble in HPLC grade water at 100mM.
Positive control results:
The positive control in the Cysteine run (orange highlight) marginally missed the acceptance criterion (54.211 % depletion, range = 60.8 to 100). However, this was accepted as valid for use as the peptide had been depleted significantly by the PC (> 50%) and also the test item was highly reactive and depleted both peptides substantially (51.813% overall). Therefore, the data was considered valid for use and there was no impact upon the outcome of the study. All other acceptance criteria for all controls and the test item were met in both runs.
Key result
Run / experiment:
other: Run 1 (cysteine) and Run 2 (Lysine)
Parameter:
other: Mean % Cysteine and Lysine peptide depletion
Value:
51.813
Vehicle controls validity:
not examined
Negative controls validity:
valid
Positive controls validity:
other: Accept/Pass
Remarks:
According to Study Director
Remarks on result:
positive indication of skin sensitisation
Remarks:
Sensitiser with High Reactivity
Other effects / acceptance of results:
The test item produced 51.813% mean Cysteine and Lysine peptide depletion, therefore, using the Cysteine 1: 10 / Lysine 1 :50 prediction model, the test item was classified as a Sensitiser with High Reactivity. A single HPLC analysis for both the Cysteine and the Lysine peptide was considered sufficient for the test item as the result was unequivocal. A minimal level of co­elution was observed for this test item for the Cysteine peptide (in the absence of peptide the test item produced a peak at 220 nm wavelength with a similar retention time to that of the peptide). Although the co-eluted peak had a small area, it was nevertheless subtracted from the peak areas observed for each of the test item replicates.

Summary of Acceptance Criteria

Criterion

Run 1 (Cys)

Run 2 (Lys)

Outcome

Std Curve r2>0.99

0.990

0.995

Pass

PC 60.8% to 100% depletion Cys

54.211

N/A

Accept/Pass

PC 40.2% to 69.0% depletion Lys

N/A

51.871

Pass

SD Cys Depletion PC <14.9%

12.427

N/A

Pass

SD Lys Depletion PC <11.6%

N/A

1.324

Pass

RefA Mean Cone 0.50 ± 0.05mM

0.535

0.488

Pass

Peak Area CV RefB <15.0%

0.581

4.374

Pass

Peak Area CV RefC <15.0%

0.415

0.919

Pass

SD Cys Depletion Test Item <14.9%

1.271

N/A

Pass

SD Lys Depletion Test Item <11.6%

N/A

0.054

Pass

RefC Mean Cone 0.50 ± 0.05mM

0.531

0.511

Pass

Cys = Cysteine, Lys = Lysine, SD = Standard Deviation, CV= Coefficient of Variation, PC = Positive Control, RefA= control samples that are peptide plus acetonitrile, prepared to ensure peptide concentration is within specific limits, RefB= control samples that are peptide plus acetonitrile, prepared to ensure peptide stability throughout the run is within specific limits, RefC= control samples that are peptide plus acetonitrile and test item solvent, prepared as a control to assess percent peptide depletion.

Interpretation of results:
GHS criteria not met
Conclusions:
OECD 442C covers the first key event for skin sensitisation of protein binding; these results alone cannot be used to conclude if skin sensitisation has occurred. The OECD Series on Testing & Assessment No. 256 prediction model entails that two concordant results obtained from methods addressing different steps of the first three key events of the adverse outcome pathway determine the final classification. The study summarized above for OECD 442C (direct peptide reactivity assay (DPRA)) reports the registered substance is a sensitiser with high reactivity. OECD 442D (Key event #2) and OECD 442E (Key event #3), summarized elsewhere within this IUCLID dossier, are negative for skin sensitization. As the “2 out of 3 – Sens ITS” prediction model generally achieved accuracies slightly exceeding those of the murine local lymph node assay (LLNA) when compared to human data, the overall prediction for the registered substance is non-sensitizing.
Executive summary:

The skin sensitisation of the registered substance was assessed using OECD 442C (in chemico direct peptide reactivity assay). After a 24-hour incubation with both cysteine and lysine containing peptides, the percent peptide depletion was measured by high performance liquid chromatography. The Cysteine peptide 1:10 / lysine peptide 1:50 prediction model was used. The final mean % peptide depletion observed suing this model was 51.813%. Therefore, the registered substance was classified as a sensitiser with high reactivity.

 

OECD 442C covers the first key event for skin sensitisation of protein binding; these results alone cannot be used to conclude if skin sensitisation has occurred. The OECD Series on Testing & Assessment No. 256 prediction model entails that two concordant results obtained from methods addressing different steps of the first three key events of the adverse outcome pathway determine the final classification. The study summarized above for OECD 442C (direct peptide reactivity assay (DPRA)) reports the registered substance is a sensitiser with high reactivity. OECD 442D (Key event #2) and OECD 442E (Key event #3), summarized elsewhere within this IUCLID dossier, are negative for skin sensitization. As the “2 out of 3 – Sens ITS” prediction model generally achieved accuracies slightly exceeding those of the murine local lymph node assay (LLNA) when compared to human data, the overall prediction for the registered substance is non-sensitizing.

Reason / purpose for cross-reference:
reference to other study
Reference
Endpoint:
skin sensitisation: in vitro
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2018-04-20 to 2018-05-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
other: OECD Test Guideline 442E: Human Cell Line Activation Test (h-CLAT)
Version / remarks:
2017
Principles of method if other than guideline:
Skin sensitisers have been reported to induce the expression of cell membrane markers associated with Dendritic Cell (DC) activation. The h-CLAT method is an in vitro assay that quantifies these changes in cell surface marker expression (i.e., CD86 and CD54) on a human monocytic leukaemia cell line, THP-1 cells (a cell line that mimics DCs), following 24-hour exposure to the test item. The changes of surface marker expression are measured by flow cytometry following cell staining with fluorochrome-tagged antibodies. Cytotoxicity measurement is also conducted concurrently to assess whether upregulation of surface maker expression occurs at sub-cytotoxic concentrations. The relative fluorescence intensity of surface markers compared to the solvent/vehicle control are calculated and used in the prediction model, to support the discrimination between sensitisers and non-sensitisers.
GLP compliance:
yes (incl. QA statement)
Type of study:
activation of dendritic cells
Justification for non-LLNA method:
OECD Test Guideline 442E: 'in vitro skin sensitisation assays addressing the key event on activation of dendritic cells on the adverse outcome pathway for skin sensitisation' was adopted 25-June-2018.
Specific details on test material used for the study:
- Purity test date: 40% Active in Water, ~90% purity of active material
Details on the study design:
Prior to the CV75 determination, the test item was assessed for solubility and was found to be soluble in complete RPMI culture medium at 500 mg/mL.

THP-1 cells (human monocytic leukaemia cell line) were pre-cultured for 72hrs. Following this, the cells were dosed with the test item over an 8 dose range and incubated for 24 ±0.5hrs. The cells were then washed and stained with propidium iodide which allows for discrimination of live/dead cells by flow cytometry using the Merck Guava easyCyte 6HT-2L flow cytometer. The dose of test item that yields 75% cell viability (CV75) was calculated and taken forward for the next stage of testing. This dose finding assay was carried out over two independent runs.

THP-1 cells were pre-cultured for either 48 or 72hrs. Once the CV75 was determined, a narrower dilution series based around the CV75 value was produced for the test item. This dilution range was used to dose the cells again for 24 ±0.5hrs. The cells were then washed and stained with propidium iodide and also with antibodies that detect CD54 and CD86 expression as well as a negative control antibody. This allowed for discrimination of live/dead cells and also changes in CD54 and CD86 marker expression by flow cytometry using the Merck Guava easyCyte 6HT-2L flow cytometer.

Positive control for CV75: 2,4-dinitrochlorobenzene (DNCB)
Positive control for CD54 and CD86 Expression: nickel sulphate
Run / experiment:
other: Run 1 - max dose 481.08 µg/ml
Parameter:
other: RFI of CD54
Value:
102
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Average cell viability 87.44%
Run / experiment:
other: Run 1 - max dose 481.08 µg/ml
Parameter:
other: RFI of CD86
Value:
84
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Average cell viability 87.44%
Run / experiment:
other: Run 3 - max dose 481.08 µg/ml
Parameter:
other: RFI of CD54
Value:
91
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Average cell viability 93.58%
Run / experiment:
other: Run 3 - max dose 481.08 µg/ml
Parameter:
other: RFI of CD86
Value:
78
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Average cell viability 93.58%
Other effects / acceptance of results:
The CV75 value derived from two independent experiments was as follows:
Rep 1: 401.1 µg/mL
Rep 2: 400.7 µg/mL
Average C75: 400.9 µg/mL
Acceptance criteria for all controls and the test item were met in both runs for the CV75 determination. The CV75 dose informs the dosing range selected for the CD54/86 expression assay. The top dose for the CD54/86 expression assay (main test) is 1.2 x CV75 which was equal to 481.08 µg/mL.

Acceptance criteria for all controls and the test item were considered acceptable in 2 out of 3 runs for the measurement of CD54 and CD86 expression. In Run 1 the positive control CD86 RFI value was borderline (RFI = 147, range 150 or above) and was just below the threshold but this was accepted as valid due to the low RFI values in the test item. All other criteria for the positive control were met in this run. The positive control in Run 2 failed for CD86 expression (RFI = 110). In Run 3 the viability at the top concentration was > 90% but was borderline. Therefore, as Runs 1 and 2 yielded < 90% viability at this concentration and all three runs gave a negative response for the test item this was accepted. RFI values for the test item in Run 3 were all <100, therefore a drop in viability of 3.59% is very unlikely to lead to a significant change in RFI based upon the available data.

The expression of CD54 as measured by the RFI did not cross the threshold (RFI ≥200) at any of the doses tested in Runs 1 and 3. Likewise, the expression of CD86 as measured by the RFI did not cross the threshold (RFI ≥150) at any of the doses tested.

Acceptance Criteria: CV75 Determination

Criterion

Run 1

Run 2

Outcome

Cell viability must be≥75% at the lowest dose

96.64

96.67

Pass

The highest test item concentration should produce cytotoxicity (< 90% cell viability) unless 5 mg/mL in medium, 1 mg/mL in DMSO or the highest soluble concentration is used as the maximal test concentration of a test item.

95.77 (5 mg/mL medium used)

97.12 (5 mg/mL medium used)

Pass

CV75= dose of test item that yields 75% cell viability

Acceptance Criteria: Measurement of CD54 and CD86 Expression

Criterion

Run 1

(Pass)

Run 2

(Fail)

Run 3

(Pass)

Outcome

Cell viabilities of medium and solvent controls should be higher than 90%

97.29

97.42

97.01

Pass

In the solvent control, RFI values of both CD86 and CD54 should not exceed the positive criteria (CD86 RFI≥150% and CD54 RFI≥200%) compared to the medium control

N/A

(No solvent control)

N/A

(No solvent control)

N/A

(No solvent control)

N/A

For both medium and solvent controls, the MFI ratio of both CD86 and CD54 to isotype control should be >105%

CD54: 183.76%

CD86: 160.89%

CD54: 169.21%

CD86: 147.76%

CD54: 127.42%

CD86: 120.37%

Pass

In the positive control (Nickel Sulphate), RFI values of both CD86 and CD54 should meet the positive criteria (CD86 RFI≥150 and CD54 RFI≥200) and cell viability should be greater than 50%

CD54 RFI: 240

CD86 RFI: 147

CD54 Via: 88.72%

CD86 Via:

89.19%

CD54 RFI: 351

CD86 RFI: 110

CD54 Via: 86.55%

CD86 Via:

86.73%

CD54 RFI: 448

CD86 RFI: 153

CD54 Via: 90.33%

CD86 Via:

90.77%

Run:

1. Accept

2. Fail

3. Pass

For each test item, the cell viability should be greater than 50% in at least four tested concentrations in each run

8/8

8/8

8/8

Pass

Negative results are acceptable only for test items exhibiting a cell viability of less than 90% at the highest concentration tested, unless 5 mg/mL in medium, 1 mg/mL in DMSO or the highest soluble concentration is used as the maximal test concentration of a test item.

87.44

89.92

93.58

Run:

1. Pass

2. Pass

3. Accept

RFI= Relative Fluorescence Intensity, MFI= Mean Fluorescence Intensity, DMSO= Dimethyl Sulphoxide

Interpretation of results:
study cannot be used for classification
Conclusions:
OECD 442E covers the third key event for skin sensitisation of dendritic cell activation; these results alone cannot be used to conclude if skin sensitisation has occurred. The OECD Series on Testing & Assessment No. 256 prediction model entails that two concordant results obtained from methods addressing different steps of the first three key events of the adverse outcome pathway determine the final classification. The study summarized above for OECD 442E (dendritic cell activation) reports the registered substance is negative for sensitisation. OECD 442C (Key event #1) was positive for skin sensitisation and OECD 422D (Key event #2) was negative for skin sensitisation; summarized elsewhere within this IUCLID dossier. As the “2 out of 3 – Sens ITS” prediction model generally achieved accuracies slightly exceeding those of the murine local lymph node assay (LLNA) when compared to human data, the overall prediction for the registered substance is non-sensitizing.
Executive summary:

The skin sensitisation of the registered substance was assessed using OECD 442E (in vitro dendritic cell activation assay). After a 24-hour incubation with the test item the expression of cell surface markers CD54 and CD86 on THP-1 cells was measured by flow cytometry. For registered substance the dose that gave 75% cell viability was found to be 400.9 µg/ml. The threshold for sensitisation for CD54 or CD86 was not crossed at any of the test item concentrations and therefore, the registered substance was classified as negative for skin sensitisation.

 

OECD 442E covers the third key event for skin sensitisation of dendritic cell activation; these results alone cannot be used to conclude if skin sensitisation has occurred. The OECD Series on Testing & Assessment No. 256 prediction model entails that two concordant results obtained from methods addressing different steps of the first three key events of the adverse outcome pathway determine the final classification. The study summarized above for OECD 442E (dendritic cell activation) reports the registered substance is negative for sensitisation. OECD 442C (Key event #1) was positive for skin sensitisation and OECD 442D (Key event #2) was negative for skin sensitisation; summarized elsewhere within this IUCLID dossier. As the “2 out of 3 – Sens ITS” prediction model generally achieved accuracies slightly exceeding those of the murine local lymph node assay (LLNA) when compared to human data, the overall prediction for the registered substance is non-sensitizing.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 442D (In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method)
Version / remarks:
2015
GLP compliance:
yes (incl. QA statement)
Type of study:
activation of keratinocytes
Justification for non-LLNA method:
Skin sensitisers have been reported to induce genes that are regulated by the antioxidant response element (ARE). The KeratinoSens™ test is a method for which validation studies have been completed followed by an independent peer review conducted by the European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM). The KeratinoSens™ test method was considered scientifically valid to be used as part of an IATA (Integrated Approach to Testing and Assessment), to support the discrimination between skin sensitisers and non-sensitisers for the purpose of hazard classification and labelling. The method cannot be used on its own, neither to sub-categorise skin sensitisers into subcategories 1A and 1B as defined by the UN GHS, for authorities implementing these two optional subcategories, nor to predict potency for safety assessment decisions. However, depending on the regulatory framework a positive result may be used on its own to classify a chemical into UN GHS category 1.

Test material

1
Chemical structure
Reference substance name:
Octan-1-ol, reaction products with diphosphorus pentaoxide, potassium salts
EC Number:
807-789-8
Cas Number:
111062-42-1
Molecular formula:
C8-H18-O.K.O5-P2
IUPAC Name:
Octan-1-ol, reaction products with diphosphorus pentaoxide, potassium salts
Specific details on test material used for the study:
Purity: 40% active in water, ~90% purity of active material

In vitro test system

Details on the study design:
Method of administration of test item:
- Per plate, a single application of 12 concentrations of the test item was applied in cell culture medium (dilution factor of 2) with a final concentration of DMSO of 1 %. The top concentration was previously determined by solubility testing.

Method of administration of reference items:
- Per plate, a single application of 5 concentrations of the positive control was applied in cell culture medium (dilution factor of 2) with a final concentration of DMSO of 1% and a single application of culture medium with 1% DMSO was applied as the negative control (6 wells per plate). One well per plate was left empty (no cells).

Exposure times of test items and reference items:
- Cells were incubated with the test or reference item for 48 ± 2h prior to endpoint measurements.
- After 48h exposure of cells with 12 concentrations of Agent 447C (chemical name: 1-octanol, reaction products with phosphorus oxide (P2O5), potassium salts), Luciferase measurements and MTT viability testing were performed.

Number of repetitions:
- Three repetitions (runs) were performed. Each repetition consisted of 3 x 96-well plates for luminescence (n=9 overall) and 2 x 96-well plates for MTT (n=6 overall). The validity of each repetition was assessed according to the following acceptance criteria:
(1) The positive control (cinnamic aldehyde) produces positive results, i.e. the luciferase gene induction produced by this control is above the threshold of 1.5 in at least one of the tested concentrations and this induction is statistically significant compared to the solvent (negative) control (p<0.05).
(2) The I(MAX) and the EC(1.5) for cinnamic aldehyde is calculated and meet either or both of the following targets:
(a) Average induction in the three replicates for cinnamic aldehyde at 32 μM is within the XCellR8 historical range (currently 1.6 and 3)
(b) EC(1.5) value for cinnamic aldehyde is within the XCellR8 historical range (currently 6 μM and 39 μM).

At least one of these criteria must be met, otherwise the run is discarded unless there is sufficient reason not to do this as determined by the Study Director. If only one criterion is met, it is recommended to check the dose-response curve of cinnamic aldehyde in order to decide on acceptability.

(3) CV% of blank values < 20%

Results and discussion

Positive control results:
Criteria 1: Positive Control (Cinnamic aldehyde) induction ≥ 1.5-fold in at least one concentration.
Result: PASS; Positive 16-128 μM

Criteria 2: Average induction of Positive Control at 32μM is [1.6-3.0]
Result: FAIL, 3.994 μM
Note: All other acceptance criteria were met, and there was a dose-dependent increase of induction with the Positive Control therefore, the results are considered as valid.

In vitro / in chemico

Resultsopen allclose all
Run / experiment:
other: Repetition 1
Parameter:
other: EC1.5
Remarks:
The EC(1.5) value is the Effective Concentration (EC) of test item that yielded an induction of luciferase activity greater than 1.5-fold over untreated controls.
Value:
1.5
Vehicle controls validity:
not specified
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Did not induce statistically significant luciferase induction >= 1 .5
Run / experiment:
other: Repetition 2
Parameter:
other: EC1.5
Remarks:
The EC(1.5) value is the Effective Concentration (EC) of test item that yielded an induction of luciferase activity greater than 1.5-fold over untreated controls.
Value:
1.5
Vehicle controls validity:
not specified
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other:
Remarks:
The test item did induce statistically significant luciferase induction >= 1.5 in repetition 2. The respective EC(1.5) value in rep 2 was calculated as 883.462 μM however the viability was less than 70% at the inducing concentration and therefore rep 2 was also considered negative.
Run / experiment:
other: Repetition 3
Parameter:
other: EC1.5
Remarks:
The EC(1.5) value is the Effective Concentration (EC) of test item that yielded an induction of luciferase activity greater than 1.5-fold over untreated controls.
Value:
1.5
Vehicle controls validity:
not specified
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Did not induce statistically significant luciferase induction >= 1.5
Other effects / acceptance of results:
Criteria 1: Positive Control (Cinnamic aldehyde) induction ≥ 1.5-fold in at least one concentration.
Result: PASS; Positive 16-128 μM

Criteria 2: Average induction of Positive Control at 32μM is [1.6-3.0]
Result: FAIL, 3.994 μM

Criteria: EC(1.5) value is [6-39μM]
Result: PASS, 9.178 μM

Criteria: CV% of blank values < 20%
Result: PASS, 19.9287 %

Note: All other acceptance criteria were met, and there was a dose-dependent increase of induction with the Positive Control therefore, the results are considered as valid.

Applicant's summary and conclusion

Interpretation of results:
study cannot be used for classification
Conclusions:
OECD 442D covers the second key event for skin sensitisation of keratinocyte activation; these results alone cannot be used to conclude if skin sensitisation has occurred. The OECD Series on Testing & Assessment No. 256 prediction model entails that two concordant results obtained from methods addressing different steps of the first three key events of the adverse outcome pathway determine the final classification. The study summarized above for OECD 442D (keratinocyte activation) reports the registered substance is negative for sensitisation. OECD 442C (Key event #1) was positive for skin sensitisation and OECD 442E (Key event #3) was negative for skin sensitisation; summarized elsewhere within this IUCLID dossier. As the “2 out of 3 – Sens ITS” prediction model generally achieved accuracies slightly exceeding those of the murine local lymph node assay (LLNA) when compared to human data, the overall prediction for the registered substance is non-sensitizing.
Executive summary:

The skin sensitisation of the registered substance was assessed using OECD 442D (in vitro keratinocyte activation assay). After 48-hour exposure of cells with 12 concentrations of the registered substance, Luciferase measurements and MTT viability testing were performed. The registered substance was classified as negative for sensitisation.

 

OECD 442D covers the second key event for skin sensitisation of keratinocyte activation; these results alone cannot be used to conclude if skin sensitisation has occurred. The OECD Series on Testing & Assessment No. 256 prediction model entails that two concordant results obtained from methods addressing different steps of the first three key events of the adverse outcome pathway determine the final classification. The study summarized above for OECD 442D (keratinocyte activation) reports the registered substance is negative for sensitisation. OECD 442C (Key event #1) was positive for skin sensitisation and OECD 442E (Key event #3) was negative for skin sensitisation; summarized elsewhere within this IUCLID dossier. As the “2 out of 3 – Sens ITS” prediction model generally achieved accuracies slightly exceeding those of the murine local lymph node assay (LLNA) when compared to human data, the overall prediction for the registered substance is non-sensitizing.

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