Methoxycarbonyloxycyclooct-4-ene

Endpoint summary

Description of key information

Skin sensitisation: skin sensitiser (1B) based on testing in OECD TG 406.

Respiratory sensitisation: the substance is not a respiratory sensitiser in absence of human data.

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

For Violiff three studies are available in which the sensitisation potential of the substance were evaluated: a Buehler test (positive), a LLNA (EC3 > 30%) and a HRIPT test (NOEC > 2%). To derive an EC3 the information from the analogue Liffarome (Cas no: 67633-96-9) is included. Information from structure-activity relationships is also included.

Violiff Buehler test

The substance was tested in a Buehler test (OECD TG 406) at a concentration of 3% in the topical induction phase based on the irritancy seen at higher concentrations during a range-finding test. The concentration for the challenge phase was 1%. At the first reading (24 h after the challenge) slightly patchy erythema was observed in 7 animals and slight or confluent or moderate patchy erythema was observed in 3 animals. At the second reading (48 h after the challenge) slightly patchy erythema was observed in 7 animals and slight or confluent or moderate patchy erythema was observed in 1 animal. The clinical observations resulted in a 15.7% sensitised animals which exceeds the threshold of 15%. Based on these results, the substance is a skin sensitiser (1B).

Violiff LLNA study

The substance was tested in an LLNA test (OECD TG 429). The test substance was diluted in diethyl phthalate/ethanol in a 3:1 ratio at concentrations of 0, 7,5, 15 and 30%. As a positive control, a 35% solution of hexylcinnamaldehyde was used. The mice treated with the test substance did not show any clinical signs, nor increased ear thickness or changed lymph nodes. The mean DPM of the control group was 216 (± 40). Exposure to the substance at 7.5, 15 and 30% (w/v) resulted in mean DPM values of 158 (± 26), 340 (±59) and 255 (± 44) respectively correlating with stimulation indices of 0. 73, 1.57, and 1.18, respectively. The SI appeared not to be ≥ 3 when tested up to 30% and therefore no EC3 could be calculated. Based on these results, the substance is not a skin sensitizer up to 30%.

Violiff HRIPT

The substance was tested in a Repeated Insult Patch Test with 53 human volunteers. Volunteers were exposed dermally to the substance (primary/activation phase) in a series of nine applications for 3 weeks. After a resting period of two weeks, a challenge application was applied to virgin skin. All applications were done with 0.2 ml of the test material at 2% in diluent 85 -209 at the back area (exposure area not indicated), for 24 hours in a semi-occlusive way. Skin reactions were monitored throughout the study.

None of the volunteers showed any dermal reaction, neither in the induction phase, nor during challenge. It can be concluded that the substance did not show skin sensitisation at 2% in the human volunteers tested.

Liffarome - analogue of Violiff - LLNA

The skin sensitisation potential of this analogue has been tested according to OECD TG 429 and GLP principles. At 10, 30 and 100% the substance showed SI values of 0.78, 1.70 and 3.90, respectively. Reliable negative and positive controls were included. All animals appeared normal for the duration of the study. These results show that the test substance could elicit a SI ≥ 3. An EC3 has been derived resulted in an EC3 of 71%. A NOEC of 30% is derived. Based on the results, the substance was considered to be a skin sensitiser.

Structure-activity relation

The substance does not contain structural alerts for skin sensitisation when using the OECD Toolbox (3.1.0.21) and protein profilers. The functional carbonate group has some reactivity but this reactivity is not sufficient to cause skin sensitisation. The sole double bond in the ring structure on its own would be insufficiently reactive too. On the other hand some unsaturated fatty acid type of substances were shown to present skin sensitisation reactivity (Kreiling et al. 2008 and Yamashita et al. 2015). Though this reactivity was questioned because it may be an irritant reaction (Kreiling et al., 2008), Yamashita et al. (2015) concluded that some unsaturated fatty acids can indeed cause a skin sensitisation reactions. Beside this information for fatty acids, for Violiff there is also a structural analogue Liffarome present with LLNA information. Violiff and Liffarome have a hydrocarbon backbone, with one unsaturated bond and a carbonate as a functional group. In Violiff this hydrocarbon backbone is cyclic while in Liffarome this is a straight alkyl chain. Liffarome has an EC3 of 71%. Because of the similarity in chemical structure, Violiff being a skin sensitiser but with an EC3 > 30%, the LLNA EC3 of Liffarome will be used for Violiff. 

Conclusion

The positive results of Violiff in the Buehler test, the supporting positive skin sensitisation information from the analogue Liffarome, which has an EC3 of 71%, the LLNA of Violiff will be used in which a NOEC of 30% was seen. This NOEC will be forwarded to the risk characterisation. 

References

Liffarome: ECHA dissemination, https://echa.europa.eu/nl/registration-dossier/-/registered-dossier/19877

Kreiling, R., Hollnagel, H.M., Eigler, D., Lee, M.S., Griem, P., Dreezen, B., Kleber, M., Albrecht, A., Garcia, C., Wendel, A., 2008, Comparison of the skin sensitizing potential of unsaturated compounds as assessed by the using local lymph node assay (LLNA) and the guinea pig maximization test (GPMT), Food and Chem. Toxicol, 46, 1896-1904.

Yashimata, K., Shinoda, S., Hagiwara, S., Miyazaki, H., Itagaki, H., 2015, Unsaturated fatty acids show clear elicitation responses in a modified local lymph node assay with an elicitation phase, and test positive in the direct peptide reactivity assay, J. Toxicol. Sci., 6, 843-853.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

The substance is not a respiratory sensitiser in absence of human data indicating such effects. In addition, the respiratory sensitisation is assessed using the integrated evaluation strategy for respiratory sensitisation data in the ECHA guidance (R7A, Fig. 7.3-4, 2017).

1)    The substance is a skin sensitiser;

2)    The substance does not belong to the di-isocyanates;

3)    the substance has no structural alerts or is structurally related to chemicals causing respiratory sensitisation as presented in Table R.7.3-1 in the ECHA guidance of 2008 or those provided in the following document: http://ec.europa.eu/health/scientific_committees/docs/annex6_respiratory.pdf. Therefore, the substance is not considered to be a respiratory sensitiser.

Justification for classification or non-classification

The substance has to be classified as skin sensitisation category 1B and shall be labelled with H317: May cause an allergic skin reaction according to EU CLP (EC no. 1272/2008 and its amendments).