3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indenyl propionate

Endpoint summary

Description of key information

Cyclaprop is not sensitising based on read across from Cyclobutanate which was tested in a GPMT test according to OECD TG 406.

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Cyclaprop is not sensitising based on read across from Cyclobutanate. At first the skin sensitisation information of Cyclobutanate will be presented and thereafter the read across justification

Cyclobutanate and its skin sensitising properties

This Guinea Pig Maximisation Test (GPMT) was performed according to OECD guideline 406. The sensitising potential of Cyclobutanate was determined. Intradermal induction was performed with 5% Cyclobutanate in arachis oil BP, epicutaneous induction with 100% test material and epicutaneous challenge with concentrations of 100 and 75%. After induction injection discrete/patchy moderate and confluent erythema was noted at the intradermal induction sites of test and control group animals. Discrete or patchy erythema was also noted after topical induction of test group animals on the induction sites. Bleeding from intradermal injection sites was noted in 9 test group animals after 1 hour. The control animals showed discrete or patchy erythema at topical induction site. At challenge, 8 and 0 out of 20 test group animals (100% Cyclobutanate) showed a positive skin reaction at the 24 and 48 hour reading, respectively. For the control group, this was 1 and 0 out of 10, respectively. In the 75% Cyclobutanate group, 6 and 0 out of 20 animals responded positive after 24 and 48 hours, respectively. In the control group 2 and 0 positive skin reactions were observed, respectively. Under the conditions of this study, a positive skin reaction was seen in 8 out of 20 guinea pigs 24 hours after challenge. These reactions were not considered sensitising, as they were not apparent after 48 hours (sensitisation rate: 0%). Based on these results, Cyclobutanate is not a skin sensitiser.

Cyclaprop (Cas no 68912-13-0) and its absence of sensitising properties are based on read across from Cyclobutanate (Cas no 113889-23-9)

Introduction and hypothesis for the read across

Cyclaprop has a tricyclodecenyl fused ring backbone structure to which a propyl ester is attached. For this substance no experimental skin sensitisation data is available. In accordance with Article 13 of REACH where is presented that lacking information can be generated by means other than experimental testing such as in vitro tests, SARs, grouping and read-across, the data gap of Cyclaprop is filled by using read across from the analogue Cyclobutanate.

Hypothesis: Cyclaprop is not a skin sensitiser based on the negative sensitisation results of the analogue Cyclobutanate, which has one methyl group extra in the alkyl chain of the ester.

Available information: Cyclobutanate is negative in a well conducted guinea pig maximisation test (OECD TG 406, Klimisch 1)

Target and Source chemical(s)

The information on substance target and the analogue information from Cyclaprop and Cyclobutanate are presented in the data matrix. Also, relevant physico-chemical properties are listed there.

Purity / Impurities:

Cyclaprop is a reaction masses containing a mixture of two very similar isomers (5-yl and 6-yl). The impurities are all below 1%.

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 backbone and a common functional group. 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, which is presented below.

Analogue selection: For Cyclaprop the analogue Cyclobutanate is selected based on similarity in chemical structure and for Cyclobutanate skin sensitisation information is available.

Structural similarities and differences: Cyclaprop (target) and Cyclobutanate (source) both have a tricyclodecenyl fused ring structure with an unsaturated bond in the outside ring, which can be on the 5yl or 6 yl -position. On the other side of the ring an ester bond is attached with a short alkyl chain. The alkyl chain of Cyclaprop is a propyl chain while the source Cyclobutanate has a butyl chain. The protrusive effect of the one additional carbon atom in the structure of Cyclobutanate is discussed in the reactivity paragraph.

Dermal absorption: Cyclaprop and Cyclobutanate are both liquids and have similar molecular weight. Also, the physico-chemical properties such as log Kow (4.4 and 4.48, respectively) indicate that these substances will be absorbed by the skin to a similar extent.

Skin sensitisation reactivity: For skin sensitisation protein binding has to take place with a chemical to be able to form a hapten. The most important sensitisation mechanism is chemical electrophilicity. Generally carboxylic esters without any other electrophilic substituted structural alerts in their neighbourhood will not have sufficient electrophilic properties to cause skin sensitisation. The butyric ester group compared to the propyl ester group is expected to be similarly insensitive to sensitisation, because the protrusive effect of the one additional CH group of the source chemical towards the ester bond, which may favour sensitisation, is expected to be minimal. Other skin sensitisation mechanisms such as the formation of radicals are unknown for simple carboxylic esters, which have no other substituents than CH groups in their neighbourhood. The OECD QSAR Toolbox further supports the reasoning for absence of protein binding for both esters (data not shown).

Other human health endpoint related to reactivity: Cyclaprop and Cyclobutanate are both not skin or eye irritants further supporting limited reactivity.

Remaining uncertainties: There are no other remaining uncertainties other than those already addressed above.

Conclusions for skin sensitisation 

For Cyclaprop no skin sensitisation information is available but for Cyclobutanate such information is available and this can be used to fill the data gap of Cyclaprop. 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. This documentation is presented in the current document. For Cyclobutanate reliable data are available from a guinea pig maximization test (OECD TG 406), showing absence of skin sensitisation potential. This information can be used for read-across to Cyclaprop.

Final conclusion: Cyclaprop is not a skin sensitiser.

Data matrix: Information on Cyclaprop and Cyclobutanate for assessment of skin sensitisation

Common names	Cyclaprop	Cyclobutanate
	Target	Source
Chemical structures
Cas no 5-yl Cas no of the generic	- 68912-13-0	1361017-07 -3 113889-23-9
EC number	272-805-7	441-420-8
Empirical formula	C13H18O2	C14H20O2
REACH registration	Registered	Registered
Molecular weight	206	220
Physico-chemical data
Physical state	liquid	liquid
Melting point (°C)	< -20	< -20
Boiling point (°C)	263	275
Water solubility (mg/l)	57	11.5
Log Kow	4.4 (HPLC, OECD TG 117)	4.48 (Shake-flask, OECD TG 107)
Human health
Skin sensitisation	RA Cyclobutanate	Not sensitising (OECD 406)
Skin irritation	Not irritating (OECD 404)	Not irritating (OECD 404)
Eye irritation	Not irritating (OECD 405)	Not irritating (OECD 405)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

The respiratory sensitization potential of Cyclaprop is assessed using the integrated evaluation strategy for respiratory sensitization data in the ECHA guidance (R7A, Fig. 7.3-4, 2017).
1) The substance does not have skin sensitizing properties;

2) Then the substance is not considered a respiratory sensitiser.
Therefore, Cyclaptop is not considered a respiratory sensitiser.

Justification for classification or non-classification

Based on the information presented the substance does not need to be classified for skin and respiratory sensistisation according to EU CLP (EC 1272/2008 and its amendments).