3,7-dimethylocta-1,3,6-triene

Endpoint summary

Description of key information

Skin sensitisation (OECD TG 429) with read across substance Myrcene: not sensitising, EC3 > 50% which is the highest non-irritating dose.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: read-across information from an analogue is used

Justification for type of information:

The read across justification is presented in the Endpoint summary, the accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Key result

Parameter:

EC3

Value:

> 50

Interpretation of results:

other: Not a skin sensitiser

Remarks:

according the EU CLP (EC1272/2008 and its amendments)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

For Ocimene a HRIPT study is available but is insufficient to fulfil the REACH requirement. Some detail is presented after the LLNA executive summary of the analogue Myrcene.

In silico: Myrcene and also Ocimene are suspected prehaptens in view of the terpenoid structure. In view of the clear negative result in the LLNA up to the maximum concentration of 50%) the substance is not considered a skin sensitiser.

Diagnostic patch testing: In addition, Myrcene was tested during diagnostic patch testing in which only 1 out of 1511 patients reacted positively further supporting the absence of skin sensitisation (SCCS, 2012: http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_102.pdf)

Skin sensitisation of Myrcene: LLNA

The skin sensitisation potential of the test substance has been tested using the Local Lymph Node Assay (LLNA) according to OECD TG 429 and GLP principles. Test concentrations were determined in a preliminary test (including 10, 25, 50 and 100%). Since the test item was irritating to the skin at the concentration of 100%, the highest tested concentration retained for the main test was 50%. The application of the test substance at concentrations of 2.5, 5, 10, 25 and 50% in a vehicle of acetone and olive oil (4:1 v/v) for three consecutive days did not result in an increase in isotope incorporation which was greater than 3-fold. No clinical effects or mortality were observed. Based on the results, the substance was not considered to be a skin sensitizer.

A HRIPT study in which Ocimene is tested at 0.5% is available (IFF, 1965). In this study 0/41 subjects revealed a reaction when exposed to 0.5% of test material. This information is considered insufficient to fulfil the REACH requirements. Therefore LLNA information from Myrcene (CAS #123 -35 -3) is used for read-across to Ocimene. In this section the available data on Myrcene is summarized followed by the read-across justification.

Assessing the skin sensitisation potential of Ocimene (CAS #13877-91-3) using read-across from Myrcene (CAS #123-35-3)

1. Introduction and hypothesis for the analogue approach for skin sensitisation

Ocimene (CAS #13877-91-3), a multi-constituent of E (CAS #3779-61-1) and Z (CAS #3338-55-4) isomer, has a poly-unsaturated alkene backbone consisting of 8 carbon atoms containing 3 double bonds and methyl substituents on the 3^thand 7^thposition. For Ocimene no data on skin sensitising potential is available. Therefore, additional information is used in accordance with Article 13 of REACH where it is said thatlacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such asin vitrotests, QSARs, grouping and read-across. For Ocimene, read-across will be applied using skin sensitising data on Myrcene (Source), which is a structurally similar substance to Ocimene and of identical in elemental composition. Therefore, information on Myrcene can be used to determine the skin sensitisation potential of Ocimene (see data matrix).

Hypothesis:Ocimene (target) has a similar skin sensitisation potential comparedto Myrcene (source).Available information:For Ocimene a HRIPT test with 0.5 % (v/v) is available. In this study no skin sensitisation was observed, but the endpoint requirements cannot be fulfilled with this information. For the analogue Myrcene a well conducted LLNA assay is available, performed according to OECD 429 and GLP up to the maximum concentration of 50%. At 100% the skin irritation was too severe to be tested. The study was assigned reliability 1.

2.Target and source chemical

Chemical structures of the target and source substance are shown in the data matrix.

3. Purity / Impurities

Ocimene is a multi-constituent consisting of E (66%,CAS #3779-61-1) and Z (29%,CAS #3338-55-4) isomers and an impurity, 1-methylidene-4-(prop-1-en-2-yl)cyclohexane(CAS499-97-8), is present at 1.5 % in this substance. Myrcene is a mono-constituent and a close isomer of Ocimene. It is not expected that the impurities of the source and target chemicals affect the read-across justification.

4. Analogue justification

According to Annex XI 1.5 read-across can be used to replace testing when the similarity can be based on a common molecular structure and functional groups. When using read-across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation. The current read-across is based on structural similarity of Ocimene (target) and Myrcene (source) which are close isomers.

Analogue selection:No data were found on the individual isomers of Ocimene. Two other candidates were identified, Ocimene is an isomer of Myrcene and Dihydromyrcene (CAS #2436-90-0) is a potential source candidate based on structural similarity and length of the alkyl chain. The latter substance has two double bonds in the alkyl chain in contrast to Ocimene and Myrcene which each have 3 double bonds. Although the Tanimoto coefficient is equal for Ocimene and the two potential source substances (0.45) and the predicted toxicological profile (OECD Toolbox) are similar as well, the lack of the conjugated double bond in dihydromyrcene makes Myrcene the preferred source substance.

Structural similarities:Ocimene and Myrcene have the same alkene backbone, with 3 double bonds which can be conjugated and are branched with a methyl group on two positions. The one difference is that Ocimene (trans) has the double bond in the long alkene chain, while Myrcene has the double bond attached to the methyl group branching from the alkene chain. For both substances this results in a conjugated bond with the primary double bond (at the top of the structure, see data matrix).

Toxico-kinetic similarities and differences:Both molecules appear as liquids, share similar (predicted) log Kow values and the water solubility is expected to be similar. Therefore, skin absorption is expected to be comparable.

Toxico-dynamic aspects:Since Ocimene and Myrcene both contain a conjugated double bond, the reactivity is expected to be similar and therefore the skin sensitisation potential.

Experimental data other than skin sensitisation:The skin and eye irritation endpoints are other local endpoints for which reactivity is a key parameter. Both Ocimene and Myrcene are skin irritants indicating similar reactivity in the skin. For eye irritation there is a difference which may be due to differences in the method: in vivo versus in vitro.

Uncertainty of the prediction:There are no remaining uncertainties based on the reasoning above.

5. Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the data matrix.

6. Conclusions per endpoint for hazard and C&L

When using read across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation.

For Myrcene a well conducted LLNA study, performed according to OECD 429 and GLP is available. For none of the tested concentrations the substance induced signs of sensitisation indicating an EC3 > 50% (higher concentrations could not be tested due to skin irritation). Based on the obtained results for Myrcene and consequently for Ocimene, Ocimene is not considered to be sensitising to the skin.

Final conclusion on hazard, C&L, DNEL and risk characterization:

Ocimene is not a skin sensitiser based on read across from Myrcene for which a LLNA (OECD TG 429) is available.

According to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 and its amendments Ocimene is not classified as a skin sensitiser.

 

Data matrix for assessment of skin sensitising properties of Ocimene using read-across from Myrcene

Common name	Ocimene	Myrcene
Chemical name	(3E)-3,7-dimethylocta-1,3,6-triene, (3Z)-3,7-dimethylocta-1,3,6-triene	1,6-Octadiene, 7-methyl-3-methylene-
Chemical structures	3E                             3Z
Cas no	3779-61-1 and 3338-55-4
CAS no generic	13877-91-3	123-35-3
REACH registered	2018	Registered
EINECS	237-641-2	204-622-5
Empirical formula	C10H16	C10H16
Molecular weight	136.24	136.24
Physical state	Liquid	Liquid
Melting point	<-20 °C (IFF measured)	<-80 °C (ECH dissemination site)
Boiling point	184.1 °C (IFF measured)	165°C (ECHA dissemination site)
Vapour pressure	220.7 Pa (at 24 °C) (IFF measured)	267 Pa (ECHA dissemination site)
Water solubility	14.5 (at 24 °C) (IFF measured)	5.1 (ECHA dissemination site)
Log Kow	5.4 (at 25 °C) (IFF measured) 4.8 (Predicted value by ECOSAR)	4.8 (ECHA dissemination site) 4.9 (Predicted value by ECOSAR)
Human health
Eye irritation/ corrosion	Not irritating (OECD 438)	Irritating (OECD 405)
Skin irritation/ corrosion	Irritating (OECD 439)	Irritating (similar to OECD 439)
Skin sensitisation	Read-across	Not skin sensitising (OECD 429)

 

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The substance does not need to be classified for skin sensitisation according to EU CLP (Regulation (EC) No. 1272/2008 and its updates).