2-tert-pentylcyclohexyl acetate

Endpoint summary

Description of key information

Skin corrosion: Not corrosive based on absence of acidic or base groups and OECD testing

Skin irritation: Not irritating based on read across from Verdox which was tested in OECD TG 404

Eye irritation: Irritant based on OECD TG 405

Respiratory irritation: Not a respiratory irritant

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

The information on skin irritation for Coniferan is retreived from the anologue Verdox, which summary will be presented first. Thereafter the eye irritation information from Coniferan will be presented. At the end the read across justification will be presented.

Skin corrosion: The substance is not considered corrosive in absence of skin irritation.

Skin irritation based on the analogue Verdox

In the skin irritation test with 7 New-Zealand rabbits, similar to OECD TG 404 but non-GLP, mean erythema and oedema scores over 24 + 48 + 72 hours were 1.7 and 1.05.In only one out of 7 animals mean erythema score over 24, 48 and 72 hours was 2.33.When applied to rabbit skin under semi-occlusive conditions for 4 hours, the test substance produced fairly distinct erythema and marginal to fairly distinct oedema, cracking and scaling. The skin effects were not fully reversible within 72 hours, after which the observation stopped. Considering their slight severity, the dermal changes are likely to be fully reversible within 14 days. Based on the average erythema and oedema scores, the substance is considered to be not irritating to skin.

Eye irritation using Coniferan

In a pre-GLP acute toxicity study similar to OECD 405, 0.1 mL neat test material was installed in the right eye of 3 albino rabbits. The left untreated eye served as control. The eyes were examined 24, 48, 72 hours and 7 days after instillation of the test substance and scored according to the Draize scale. No corneal opacity or iris congestion was observed. Redness and chemosis were observed in all animals, but the effects were reversible in all animals within 7 days. Mean 24, 48 and 72 hour redness was 1.33 in one animal and 2 in two animals. Therefore, the test substance was considered irritating to eyes.

Respiratory irritation

There are no occupational or consumer data indicating respiratory tract irritation. There are also no relevant experimental guidelines or results available that indicate respiratory irritation. The ECHA guidance presents (R7a: 7.2.12.1, 2017) that respiratory irritation maybe be indicated when the substance is a severe irritant. However, the substance is not a skin irritant, it is an eye irritant (Cat 2) not indicating severe irritation and therefore not a respiratory irritant.

Read across justification

The skin irritation of Coniferan (CAS #67874-72-0) using read across from Verdox (CAS #20298-69-5)

Introduction and hypothesis for the analogue approach

Coniferan is an acetate-ester attached to a cyclohexyl ring with a tert-pentyl- group attached at the ortho-position. For this substance no skin irritation data are available. In accordance with Article 13 of REACH, lacking information can be generated whenever possible, i.e. e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For assessing the irritating potential of Coniferan the analogue approach is selected because for a closely related analogue, Verdox, skin irritation information is available which can be used for read across.

Hypothesis: Coniferan has similar irritating potential compared to Verdox as the additional methyl group attached to the tert-butyl -group in Coniferan is not expected to influence the irritation potential.

Available information: The target chemical Verdox is tested undiluted in vivo similar to an OECD TG 404 study. The test is well conducted but pre-GLP guidelines and therefore receives a reliability of 2.

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemicals are shown in the data matrix, including physico-chemical properties and toxicological information, thought relevant for irritation, of both substances.

Purity / Impurities

It is not expected that the impurities of the source chemical affect the read-across justification. Coniferan is a multi-constituent containing two stereo isomers. The purity of Coniferan is close to 100% therefore impurities will not affect irritation. In view of Verdox being a multi-constituent also containing two stereo isomers and having a purity close to 100%, there will be no significant impurities relevant for read across.

Analogue approach 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.

In accordance with ECHA guidance (2017, RAAF) Verdox was selected as an analogue because it has only one methyl group less being the closest analogue for which information is available.

Structural similarities and differences: Coniferan as well as the structural analogue Verdox have a cyclohexyl ring, the backbone, with an acetate ester and a tert-butyl-group in ortho position attached. Coniferan has one additional methyl group attached to this tert-butyl group. This difference between the target and source chemical is not expected to influence significantly the skin irritating potential of these chemicals.

Toxico-kinetic similarities and differences: Bioavailability: Most skin irritating substances need to be absorbed through the skin to a certain extent to present irritating properties. Coniferan and Verdox are both liquids, have similar molecular weight and physico-chemical properties indicating similar absorption characteristics: molecular weight (212.33 and 198.31 g/mol), log Kow (5.4 and 4.75), water solubility (7.6 and 10 mg/L), and vapour pressure (4.24 and 9.72 Pa at 25 °C), for Coniferan and Verdox, respectively). The log Kow being > 4 present that skin absorption is not in the favourable range of log Kow 1-4 and skin absorption cannot be excluded.

Reactivity: The reactive group in both Coniferan and Verdox is the ester group which may present irritation. In view of Verdox not showing classifiable skin irritating properties also Coniferan will not present a classifiable skin irritation.

Metabolism: Although metabolism is of lesser importance for local effects compared to systemic effects some local metabolism in the skin could occur. Small chain straight alkyl esters such as this Coniferan and Verdox are likely to be metabolized by carboxylesterases in the skin into the respective: 2-methylbutan-2-yl-cyclohexanol and acetic acid and 2-tertbutyl-cylohexyl-alchol and acetic acid, respectively (Belsito et al., 2008, Yamada et al., 2013). The similarity in metabolites presents similar skin irritating properties and this means that the skin irritation information on Verdox can be used for Coniferan.

Uncertainty of the prediction: There is no remaining uncertainty, in view of similarities in structure, toxico-kinetic profile (absorption and metabolism) and reactivity between the substances. If anything, Verdox is slightly more bioavailable via the skin based on a lower log Kow and therefore the read across can be considered conservative. According to ECHA guidance (2017, RAAF) the score 5 can be applied.

Data matrix

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

Conclusions per endpoint for Hazard assessment and C&L.

Verdox is not a skin irritant in a similar to OECD 404 pre-GLP study (reliability 2). Based on these results it can be concluded that Coniferan is not skin irritating either.

Final conclusion on hazard and C&L

Coniferan is not skin irritating. Classification and labelling is not needed for this endpoint according to CLP Regulation (EC) No. 1272/2008 and its updates.

Data matrix for the read across to Coniferan from Verdox

Common names	Coniferan	Verdox
Chemical structures
CAS no	67874-72-0	20298-69-5
EC no	Registration in 2018	243-718-1 (registered)
Empirical formula	C13H24O2	C12H22O2
Physico-chemical data
Molecular weight	212.33	198.31
Physical state	Liquid	Liquid at 30°C
Melting point, °C	-20	29.8
Boiling point, °C	251.9	232
Vapour pressure, Pa	4.24 at 24°C	9.72 at 23°C
Water solubility, mg/L	7.6 at 24°C	10 at 23°C
Log Kow	5.4	4.75
Human health endpoints
Skin irritation	Read across from Verdox	Similar to OECD 404 not irritating

 

Justification for classification or non-classification

The substance does not have to be classified for Skin irritation according to EU CLP (EC No. 1272/2008 and its amendments).

The substance has to be classified as Eye irritant and shall be labelled with H319: Causes serious eye irritation according to EU CLP (EC No. 1272/2008 and its amendments).