Tranexamic acid

Endpoint summary

Description of key information

Tranexamic acid was negative in the DPRA and was classified in the “no or minimal reactivity class” when using the Cysteine 1:10 / Lysine 1:50 prediction model.

Tranexamic Acid is classified as negative (no activation of the antioxidant/electrophile responsive element (ARE)-dependent pathway in keratinocytes).

DEREK NEXUS version 6.1.1 did not yield any alerts for skin sensitization of Tranexamic acid. Additionally, the query structure does not contain any unclassified or misclassified features and is consequently predicted to be a non-sensitizer.

Based on the concordant negative results of the 2o3 DA test methods, as described in OECD TG 497, the overall 2o3 prediction is considered negative and Tranexamic acid is concluded to be a non-sensitizer.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation, other

Remarks:

Assessment of the Skin Sensitization potential of Tranexamic acid

Type of information:

not specified

Remarks:

Using the "2 out of 3" (2o3) defined approach mentioned in OECD TG 497 to determine whether the substance causes skin sensitization. The DPRA and the KeratinoSensTM assay, were used as the individual information sources.

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 497

Type of study:

other: "2 out of 3" (2o3) defined approach mentioned in OECD TG 497

Remarks on result:

not measured/tested

Remarks:

No data were available that would preclude performance of the studies to determine the potential for skin sensitization. Therefore the DPRA (Charles River project no 203298595), and the KeratinoSensTM assay (Charles River project no 203298606) were performed and used as the individual information sources for the 2o3 DA. The DEREK nexus prediction (Charles River project no 203298607) was performed to provide supporting information on skin sensitization.

Outcome of the prediction model:

negative [in vitro/in chemico]

Type of Evidence / Source Name - Reference	Relevance	Reliability	Prediction model assay	Prediction model 2o3 DA (Annex 1)
OECD TG 442C	Study appropriate for investigation of Key event 1 and the 2o3 DA.	Klimisch score 1	Negative	Negative (nonborderline)
OECD TG 442D	Study appropriate for investigation of Key event 2 and the 2o3 DA.	Klimisch score 1	Negative	Negative (nonborderline)
Derek Nexus prediction	Supporting information on skin sensitisation.	Klimisch score 2	Negative	-

A valid DPRA was performed in accordance with OECD TG 442C and in accordance with GLP principles. The substance was dissolved in Milli-Q water at 100 mM and formed a clear solution (as judged by visual inspection). Upon preparation as well as after incubation of the test item with synthetic peptides containing either cysteine (SPCC) or lysine (SPCL) no precipitate or phase separation was observed. In the cysteine reactivity assay the test item showed 2.3% SPCC depletion while in the lysine reactivity assay the test item showed 0.5% SPCL depletion. The mean of the SPCC and SPCL depletion was 1.4% and as a result the test item was considered to be negative in the DPRA and classified in the “no or minimal reactivity class” when using the Cysteine 1:10 / Lysine 1:50 prediction model.

These values resulted in a negative outcome (non-borderline) according to the adapted prediction model for use within the 2o3 DA as described in OECD TG 497 (refer to Annex 1, Figure 1.1)

A valid KeratinoSensTM assay was performed according to OECD 442D and in accordance with GLP principles. The test item was dissolved in dimethyl sulfoxide at 200 mM. From this stock, 11 spike solutions in DMSO were prepared. The stock and spike solutions were diluted 100-fold in the assay resulting in test concentrations of 0.98 – 2000 μM (2-fold dilution series). The highest test concentration was the highest dose required in the current guideline. No precipitate was observed at any dose level tested. Two independent experiments were performed. Both experiments passed the acceptance criteria. Overall it was concluded that the test conditions were adequate and that the test system functioned properly. 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 1.18-fold and 1.32-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.

These values resulted in a negative outcome (non-borderline) according to the adapted prediction model for use within the 2o3 DA as described in OECD TG 497 (refer to Annex 1, Figure 1.2)

Derek Nexus version 6.1.1 yielded no alert for skin sensitization of Tranexamic acid and predicted the substance to be a non-sensitizer. The structure did not contain misclassified or unclassified features.

Interpretation of results:

GHS criteria not met

Conclusions:

In conclusion, based on the concordant negative results of the 2o3 DA test methods, as described in OECD TG 497, the overall 2o3 prediction is considered negative and Tranexamic acid is concluded to be a non-sensitizer. Therefore, Tranexamic acid does not need to be classified for skin sensitization according to Regulation (EC) No 1272/2008 (CLP).

Reference 2

Endpoint:

skin sensitisation, other

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Qualifier:

no guideline followed

Interpretation of results:

study cannot be used for classification

Conclusions:

DEREK NEXUS version 6.1.1 did not yield any alerts for skin sensitization of Tranexamic
acid. Additionally, the query structure does not contain any unclassified or misclassified
features and is consequently predicted to be a non-sensitizer.
Tranexamic acid is predicted to be not sensitizing to the skin.

Reference 3

Endpoint:

skin sensitisation: in vitro

Type of information:

experimental study

Adequacy of study:

key study

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)

GLP compliance:

yes

Type of study:

ARE-Nrf2 luciferase KeratinoSens™ test method

Details of test system:

Keratinoses transgenic cell line [442D]

Vehicle / solvent control:

DMSO

Positive control:

EGDMA (120 M) [442D]

Group:

test chemical

Run / experiment:

run/experiment 1

Parameter:

Imax [442D]

Value:

1.18 %

Group:

test chemical

Run / experiment:

run/experiment 2

Parameter:

Imax [442D]

Value:

1.32 %

Interpretation of results:

GHS criteria not met

Conclusions:

In conclusion, Tranexamic Acid is classified as negative (no activation of the antioxidant/electrophile responsive element (ARE)-dependent pathway in keratinocytes) under the experimental conditions described in this report.

Reference 4

Endpoint:

skin sensitisation: in chemico

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 442C (In Chemico Skin Sensitisation: Direct Peptide Reactivity Assay (DPRA))

GLP compliance:

yes

Type of study:

direct peptide reactivity assay (DPRA)

Details of test system:

cysteine peptide, (Ac-RFAACAA-COOH)

lysine peptide (Ac-RFAAKAACOOH)

Vehicle / solvent:

water

Positive control:

cinnamic aldehyde

Group:

test chemical

Run / experiment:

mean

Parameter:

mean lysine depletion

Value:

0.5 %

Group:

test chemical

Run / experiment:

mean

Parameter:

mean cystein depletion

Value:

2.3 %

Outcome of the prediction model:

no or minimal reactivity [in chemico]

Interpretation of results:

GHS criteria not met

Conclusions:

In conclusion, this DPRA test is valid. Tranexamic acid was negative in the DPRA and was
classified in the “no or minimal reactivity class” when using the Cysteine 1:10 / Lysine 1:50
prediction model.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Justification for classification or non-classification

Tranexamic acid does not need to be classified for skin sensitization according to Regulation (EC) No 1272/2008 (CLP).