Registration Dossier

Administrative data

Description of key information

Skin sensitisation (OECD 442C): positive (RA CAS 10023-48-0)

Skin sensitisation (OECD 442D): positive (RA CAS 10023-48-0)

WoE conclusion from in vitro skin sensitisation battery: skin sensitising

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in chemico
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Key result
Parameter:
other: mean peptide depletion [%]
Run / experiment:
cysteine run
Value:
52.81
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks:
74.90
Remarks on result:
positive indication of skin sensitisation
Remarks:
Source: CAS 10023-48-0, 7.4.1-1
Key result
Parameter:
other: mean peptide depletion [%]
Run / experiment:
lysine run
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
not determinable
Remarks:
Source: CAS 10023-48-0, 7.4.1-1 / In the lysine run co-elution of the test substance and the lysine peptide due to a shift of the lysine peptide peak was observed.
Interpretation of results:
other: skin sensitising potential based on the key event "protein reactivity"
Conclusions:
Under the conditions of this study, the test substance showed reactivity towards selected proteins. The result does not allow for the non-classification or classification as skin sensitiser of the test substance and therefore further evaluation and/or data generation is required.
Based on the analogue approach, the same results were expected for the target substance.
Endpoint:
skin sensitisation: in vitro
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Key result
Parameter:
other: luciferase activity
Run / experiment:
Experiment 1
Value:
3.76
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Source: CAS 10023-48-0, 7.4.1-2
Key result
Parameter:
other: cell viability [%]
Run / experiment:
Experiment 1
Value:
79.6
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Source: CAS 10023-48-0, 7.4.1-2
Key result
Parameter:
other: EC1.5 [µM]
Run / experiment:
Experiment 1
Value:
810.73
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Source: CAS 10023-48-0, 7.4.1-2
Key result
Parameter:
other: luciferase activity
Run / experiment:
Experiment 2
Value:
2.75
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Source: CAS 10023-48-0, 7.4.1-2
Key result
Parameter:
other: cell viability [%]
Run / experiment:
Experiment 2
Value:
66
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Source: CAS 10023-48-0, 7.4.1-2
Key result
Parameter:
other: EC1.5 [µM]
Run / experiment:
Experiment 2
Value:
268.21
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Source: CAS 10023-48-0, 7.4.1-2
Interpretation of results:
other: skin sensitising potential based on the key event “inflammatory response in keratinocytes”
Conclusions:
Under the conditions of the test, the test substance has a keratinocyte activating potential. The result does not allow for the non-classification or classification as skin sensitiser of the test substance and therefore further evaluation and/or data generation is required.
Based on the analogue approach, same results were expected for the target substance.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Justification for read-across

There are no reliable data available regarding skin sensitisation for 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-1,3-thiazol-3-ium chloride (CAS 532-40-1). Read-across from an appropriate substance 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium (CAS 10023-48-0) is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5. in order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VII, 8.3. Common functional groups, structural similarities and comparable toxicological properties (according to the joint consideration in Annex VI to CLP) of the source and target substance are the basis of read-across. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

In chemico/in vitro

CAS 10023-48-0

The skin sensitising potential of the source substance substance (CAS 10023-48-0) was assessed in a Direct Peptide Reactivity Assay performed according to OECD guideline 442C and in compliance with GLP (reference 7.4.1-1). Test item solutions were incubated with the cysteine and lysine peptide solutions in glass vials using defined ratios of peptide to test item (1:10 cysteine peptide, 1:50 lysine peptide). The reaction solutions were left in the dark at 25 ± 2.5 °C for 24 ± 2 h before running the HPLC analysis. Reference controls, co-elution controls as well as the positive control were set up in parallel. The mean depletion of the cysteine peptide was 52.81%. Using the prediction model defined in the guideline, the test substance is allocated to the reactivity class “moderate reactivity”. In the lysine run a co-elution of the test substance with the lysine peptide peak was observed. However, all validity criteria were fulfilled, and this shift was not considered having an influence on the quality or validity of the overall results. The positive control showed high reactivity towards the synthetic peptides as the mean depletion of both peptides was 64.92%.

Under the conditions of the test, the test substance showed reactivity towards the cysteine peptide. The result does not allow for the non-classification or classification as skin sensitiser of the test substance and therefore further evaluation and/or data generation is required.

 

The activation of keratinocytes of the source substance (CAS 10023-48-0) was investigated in an ARE-Nrf2 Luciferase Test in the transgenic KeratinoSens™ cell line performed according to OECD guideline 442D and in compliance with GLP (reference 7.4.1-2). Cells were incubated with test substance concentrations of 0.98, 1.95, 3.91, 7.81, 15.63, 31.25, 61.5, 125, 250, 500, 1000, 2000 µM for 48 h at 37°C. After exposure cells were lysed and luciferase activity was assessed by luminescence measurement. The study was conducted in two independent experiments. In the first experiment a max luciferase activity (Imax) induction of 3.76 was determined at a test substance concentration of 2000 µM. The corresponding cell viability was 79.6%. In the second experiment a max luciferase activity (Imax) induction of 2.75 was determined at a test substance concentration of 2000 µM. The corresponding cell viability was 66.0%. Therefore in both experiments the luciferase activity induction was >1.5. The lowest tested concentration with a significant luciferase induction >1.5 (1.70) was found to be 500 µM. The corresponding cell viability was >70% (71.9%). The EC1.5 was 810.73 µM and 268.21 µM in Experiment 1 and 2, respectively. Under the conditions of the test, the test substance has a keratinocyte activating potential.

Conclusion

A weight of evidence approach was applied to the available data on skins sensitisation. The positive results of validated in chemico/in vitro tests covering 2 key events in the molecular initiating event leading to skin sensitisation. Therefore the test substance is considered to show a skin sensitising potential.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-1,3-thiazol-3-ium chloride (CAS 532-40-1), data will be generated from information on reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

 

The available data on the relevant read-across substance 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium (CAS 10023-48-0) meets the criteria for classification for Skin Sensitisation, Category 1 (H317). Therefore, applying the RA-A approach, the target substance 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-1,3-thiazol-3-ium chloride (CAS 532-40-1) is also considered to meet the criteria for classification for Skin Sensitisation, Category 1 (H317) according to Regulation (EC) No 1272/2008 (CLP).