Registration Dossier

Administrative data

Description of key information

The prediction of the skin sensitising potential was performed using BIOVIA Discovery Studio (TOPKAT) 4.5, VEGA NIC 1.1.4 (CAESAR), OECD QSAR Toolbox 4.1 and Toxtree 2.6.13. The absence of any alert for skin sensitising properties in Toxtree and the OECD Toolbox, the negative prediction by CAESAR and the false-positive prediction for zinc oxide may suggest that the substance is not likely to be sensitising. However there is only low confidence in these predictions as the rules and training data considered in the models are mainly based on purely organic structures. The predictions are therefore not considered conclusive, though the majority of results suggests that the substance is not sensitising.

The substance was found to be negative for skin sensitisation in a reliable murine Local Lymph Node Assay at concentrations of 25%, 10% or 5% w/w.






Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation, other
Remarks:
In silico
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
29 May 2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Qualifier:
no guideline available
Principles of method if other than guideline:
The prediction of the skin sensitising potential was performed with BIOVIA Discovery Studio (TOPKAT) 4.5, VEGA NIC 1.1.4 (CAESAR), OECD QSAR Toolbox 4.1 and Toxtree 2.6.13.
GLP compliance:
not specified
Key result
Parameter:
other: QSAR
Remarks on result:
no indication of skin sensitisation

Prediction results

 Model Prediction result   Reliability (model statistics)
TOPKAT   Positive  Low (probability: 0.78)
CAESAR (VEGA): zinc oxide  Positive  Low (AD index: 0.307)
CAESAR (VEGA): phosphite  Negative  Low (AD index: 0)
Toxtree  No alert  Restricted on 5 skin protein binding principles

OECD QSAR Toolbox

Protein binding alerts for skin sensitization by OASIS

 No alert  

Restricted on 11 mechanistic domains

OECD QSAR ToolboxProtein binding alerts for skin sensitization according to GHS

 No alert   The absence of a protein binding alert should not be taken as an absence of toxicity
Interpretation of results:
GHS criteria not met
Conclusions:
The substance is not predicted to be a skin sensitizer.
Executive summary:

The prediction of the skin sensitising potential was performed using BIOVIA Discovery Studio (TOPKAT) 4.5, VEGA NIC 1.1.4 (CAESAR), OECD QSAR Toolbox 4.1 and Toxtree 2.6.13. The absence of any alert for skin sensitising properties in Toxtree and the OECD Toolbox, the negative prediction by CAESAR and the false-positive prediction for zinc oxide may suggest that the substance is not likely to be sensitising. However there is only low confidence in these predictions as the rules and training data considered in the models are mainly based on purely organic structures. The predictions are therefore not considered conclusive, though the majority of results suggests that the substance is not sensitising.



Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04 September 2018 - 25 September 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
22 July 2010
Deviations:
yes
Remarks:
Due to the receipt of a replacement sample, the batch number and expiry date differ to those stated in the Study Plan.
GLP compliance:
yes
Type of study:
mouse local lymph node assay (LLNA)
Specific details on test material used for the study:
Batch: 1013T08961
Purity: 100%
Physical state / Appearance: White powder
Expiry Date: 29 March 2019
Storage Conditions: room temperature in the dark
Species:
mouse
Strain:
CBA/Ca
Remarks:
CBA/Ca (CBA/CaOlaHsd)
Sex:
female
Details on test animals and environmental conditions:
The animals were nulliparous and non-pregnant. Acclimatization period of at least 5 days. At the start of the study the animals were in the weight range of 15 to 23 g, and were 8 to 12 weeks old. The animals were housed in suspended solid floor polypropylene cages. Food and water was administered ad libitum. The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70%, respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.
Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
25%, 10% or 5% w/w.
No. of animals per dose:
Four mice/concentration.
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Key result
Parameter:
SI
Value:
0.96
Test group / Remarks:
5%
Key result
Parameter:
SI
Value:
0.88
Test group / Remarks:
10%
Key result
Parameter:
SI
Value:
1.49
Test group / Remarks:
25%

Preliminary test results:

The animal treated at a dose level of 50% showed no signs of systemic toxicity or visual local skin irritation but showed an increase in ear thickness of greater than 25% which was considered indicative of excessive irritation.

No signs of systemic toxicity, visual local skin irritation or irritation indicated by an equal to or greater than 25% increase in mean ear thickness were noted in the animal treated at a dose level of 25%.

Based on this information the dose levels selected for the main test were 25%, 10% and 5% w/w in acetone/olive oil 4:1.

Main test:

There were no deaths. No signs of systemic toxicity were noted in the test or control animals during the test.

Body weight change of the test animals between Day 1 and Day 6 was comparable to that observed in the corresponding control group animals over the same period.

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is not a skin sensitiser under the conditions of the study.
Executive summary:

A study was undertaken to evaluate the potential of the substance to induce delayed contact hypersensitivity using the murine Local Lymph Node Assay. Evaluation of irritation was also conducted in parallel by measurement of ear thickness. Following a preliminary screening test in which no clinical signs of toxicity were noted at a concentration of 25% w/w, this concentration was selected as the highest dose investigated in the main test of the Local Lymph Node Assay. Three groups, each of four animals, were treated with 50 μL (25 μL per ear) of the substance as a solution in acetone/olive oil 4:1 at concentrations of 25%, 10% or 5% w/w. A further group of four animals was treated with acetone/olive oil 4:1 alone. The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group indicates that the substance is not a skin sensitiser.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

(Q)SAR predictions are not applicable to metals and inorganic salts, respectively. In chemico & in vitro methods presented in OECD 442C, D & E, describe the biological mechanisms of skin sensitisation initiated by covalent binding of substances to skin proteins. However, this AOP does not cover metals (or allergens of biological origin) but only those substances that form covalent bonds with skin proteins. The OECD 429 LLNA is applicable to the testing of metal compounds/salts (but not for nickel compounds) and so can be considered to be appropriate for testing of the substance (subject to satisfactory formulation in a suitable vehicle to achieve exposure to appropriate test concentrations).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the negative findings of a reliable in vivo LLNA assay, classification of the substance is not justified.