Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Additional information:

As an initial approach, a quantitative structure-activity relationship (QSAR) system for the estimation of the skin sensitization potency for the main constituent 4,8,11-Dodecatrienal, that incorporates skin metabolism and considers the potential of parent chemicals and/or their activated metabolites to react with skin proteins, was used. The QSAR programs TIMES-SS predicted the substance including its simulated skin metabolites to be a strong skin sensitizer. However, the substance did not fulfill the criteria for the applicability domain of the QSAR model (out of domain for the mechanistic domain). In addition, the QSAR Toolbox Version 4.2 indicated that the substance is a Schiff Base former and has a protein binding potency for cystein (DPRA above 21%).

The skin sensitizing potential of the main constituent 4,8,11-Dodecatrienal was further experimentally assessed using the radioactive Murine Local Lymph Node Assay (LLNA) according to OECD 429 and GLP. Groups of 5 female CBA/CaOlaHsd mice each were treated with 2.5%, 10% and 25% (w/w) preparations of 4,8,11-Dodecatrienal in ethanol or with the vehicle alone. Each test animal was treated with 25 μL per ear of the appropriate test-substance preparation or the vehicle alone, applied to the dorsal surfaces of both ears on three consecutive days. Three days after the last application, 20 μCi 3H-thymidine in 250 μL sterile saline were injected into the tail vein of the mice. About 5 hours after the 3H-thymidine injection, the mice were sacrificed, and the auricular lymph nodes were removed. Lymph node response was evaluated measuring 3H-thymidine incorporation (indicator of cell proliferation). Cell count and weight of each animal’s pooled lymph nodes were also determined. In addition, a 0.8 cm diameter sample was punched out of the apical part of each ear, and for each animal, the weight of the pooled punches was determined to obtain an indication of possible skin irritation.

No signs of systemic toxicity were noticed in all animals during general observation. When applied as 25% preparation in ethanol, 4,8,11-Dodecatrienal induced a biologically relevant (increase to 3-fold or above of control value = stimulation index (SI)3), statistically significant and concentration-dependent increase of 3H-thymidine incorporation into the cells from the auricular lymph nodes. The increase of the 10% test-substance preparation was statistically significant but failed to reach the cut-off value.

Concomitantly, the 25% test-substance preparation induced a biologically relevant (increase to 1.5-fold or above of control value = stimulation index (SI)1.5) and statistically significant response in the auricular lymph node cell counts. The SI of the 10% test-substance preparation lies at the border of biological relevance and was statistically significant.

In addition, statistically significant increases in lymph node weights were noted at the 25% and 10% concentration.

The test-substance concentrations did not cause relevant increases in ear weights (SI1.25), demonstrating the absence of excessive ear skin irritation. However, statistically significant and considerably increased ear weight (mean SI 1.23) was noted at the 25% concentration. In addition, moderate scaling of the ear skin was observed in all animals and slight incrustation in one animal at the 25% concentration on study day 5 (post-mortem observation).

Nevertheless, the concentration of 25% has to be considered to indicate a skin sensitization potential because of lymph node responses clearly exceeding the respective cutoff values in the absence of sufficiently strong ear skin irritation.

Thus, it is concluded that 4,8,11-Dodecatrienal exhibits a skin sensitizing potential in the Murine Local Lymph Node Assay under the test conditions chosen. The threshold concentration for sensitization induction was >10% <25% for 3H-thymidine incorporation. The EC 3 (estimated concentration that leads to the SI of 3.0) was calculated by linear regression from the results of these concentrations to be 13.6%. The EC 1.5 (estimated concentration that leads to the SI of 1.5) for cell count was calculated by linear regression from the results of all concentrations to be 10.0%.

 

The skin sensitizing potential of the constituent Cyclododecadien-1-one was assessed in an analogous approach using the LLNA acc. to OECD 429 and GLP. The test item Cyclododecadien-1-one was not a skin sensitiser when applied at concentrations of 2%, 5% and 10% (w/w) in DMF under the test conditions of this study (BASF 2016; 58V0306/15X087).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The present data on skin sensitization of the main constituent 4,8,11-Dodecatrienal do fulfill the criteria laid down in regulation (EU) 1272/2008 for a classification with "Skin sensitization" (category 1B). However, skin sensitization data for the constituent 4,8-Cyclododecadien-1-one do not fulfill the criteria laid down in regulation (EU) 1272/2008. Thus, based on the current data for the main component 4,8,11-Dodecatrienal (representing 50% to 80% of the reaction mass) a classification of the registered substance with "Skin sensitization" (category 1B) is warranted.