Registration Dossier

Administrative data

Description of key information

Skin sensitisation (OECD TG 429, modified LLNA (OECD TG 429): non-sensitising.

Respiratory sensitisation: In absence of skin sensitisation the substance is also not a respiratory sensitiser.

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 from a guideline study
Justification for type of information:
For assessment of the skin sensitising potential of Orivone, read-across is used from p-tert-butylcyclohexanone. In the file attached and in the endpoint summary the full read-across is documented.
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Key result
Parameter:
SI
Value:
1
Remarks on result:
other: 0%
Remarks:
vehicle control
Key result
Parameter:
SI
Value:
1.03
Remarks on result:
other: 2%
Key result
Parameter:
SI
Value:
1.12
Remarks on result:
other: 10%
Key result
Parameter:
SI
Value:
1.24
Remarks on result:
other: 50%
Interpretation of results:
other: Not skin sensitising
Remarks:
according to EU CLP (EC1272/2008 and its amendments)
Conclusions:
The substance is not a skin sensitiser based on read across from para-tert-butyl cyclohexanol.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

No information on the skin sensitising properties of Orivone are available. Therefore LLNA information from 4-tBCH (CAS #98-53-3, para-tert-butyl cyclohexanol) is used for read-across to Orivone. In this section the available data on 4-tBCH is summarized followed by the read-across justification.

Skin sensitisation of 4 -tBCH: modified LLNA (IMDS)

The skin sensitisation potential of the test substance has been tested using a modified Local Lymph Node Assay (Integrated Model for the Differentiation of Skin reactions (IMDS)) according to OECD TG 429 and GLP principles. The modifications in the LLNA method refer to the measurement of cell proliferation by cell counting instead of radioactive labeling. The 50% is the maximum attainable concentration because the substance is a solid. The application of the test substance at concentrations of 2, 10 and 50% in a vehicle of acetone and olive oil (4:1 v/v) for three consecutive days did not result in an increased cell count above the (test system specific) positive level. In addition the positive level of ear swelling has not been exceeded in any dose group indicating the absence of irritating potential. No effects on body weight were observed. Based on the results, the substance was not considered to be a skin sensitiser.

Assessing the skin sensitisation potential of Orivone (CAS# 16587-71-6) using read-across from p-tert-butylcyclohexanone(CAS# 98-53-3)

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

Orivone (CAS# 16587-71-6) has a cyclohexanone backbone substituted with a (1,1)dimethyl-propyl moiety on thepara-position. For this substance no data on skin sensitising properties are available. In accordance with Article 13 of REACH,lacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, SARs, grouping and read-across. For assessing the skin sensitising potential of Orivone the analogue read-across approach is selected because forp-tert-butylcyclohexanone (source), which shows high structural similarity to Orivone, data is available.

Hypothesis:Orivone (target) has the same skin sensitising potential compared top-tert-butylcyclohexanone (source).

Available information: For Orivone no data on skin sensitising properties are available. For the structurally related substancep-tert-butylcyclohexanone a well conducted modified LLNA (IMDS method), according to OECDTG429 and GLP, is available. In this study no skin sensitisation was observed for p-tert-butyl-cyclohexanone concentrations up to 50%, the highest dose that could be tested, due to the substance being a (low melting point) solid.The study was assigned with reliability 1.

2. Target and Source chemical

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

3. Purity / Impurities

The reported purity of the Orivone andp-tert-butylcyclohexanoneis > 98%. For Orivone the major impurity identified iscis‐4‐(2‐methylbutan‐2‐yl)cyclohexanol. The functional group is an alcohol, present at 1.6 % (relative peak area) and has no skin sensitising (reactive) features. Thisimpurity therefore does not influence the read-across.

4. Analogue justification

According to REACH Annex XI an analogue approach and structural alert information can be used to replace testing when information from different sources provides sufficient evidence to conclude that this substance has or does not have a particular dangerous property. The result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation.The current read-across is based on structural similarity of Orivone (target) andp-tert-butylcyclohexanone (source).

Analogue selection:Based on database searches (RIFM database and OECD QSAR Toolbox using similarity with a Tanimoto coefficient of 80% and expert judgement, the substancep-tert-butyl-cyclohexanone(CAS# 98-53-3) was identified as potential candidate. This molecule has one methyl group less in the alkyl tail compared to Orivone. Other hits were notpara-substituted or contained a different functional group and were therefore not considered for read-across of skin sensitisation.

Structural similarities:Both Orivone andp-tert-butylcyclohexanonehave a cyclohexanone backbone with an alkyl chain substituted on thepara-position. For Orivone the alkyl tail is a(1,1)dimethyl-propyl moiety, which is different forp-tert-butylcyclohexanone, which has atertiary-butyl structure substituted on this position. The one additional methyl group in the tail of Orivone does not significantly change the reactivity of the molecule.

Toxico-kinetic reasoning: Orivone andp-tert-butylcyclohexanonehave a similar molecular weight and Log Kow, which are both in the favourable range for dermal absorption. These parameters indicate that the substances will be absorbed by the skin to a similar extent.

Toxico-dynamic reasoning:The additional methyl group in the tail of Orivone, does not significantly affect the reactivity of the molecule. Therefore, both substances are expected to be equally reactive to skin proteins.

Uncertainty of the prediction:There are no remaining uncertainties considering the reactivity and dermal absorption between Orivone andp-tert-butylcyclohexanone.Though Orivone is a liquid andp-tert-butylcyclohexanoneis a solid and therefore tested up to 50%, this does not affect the read-across becausethere are no skin sensitisation structural features that indicate skin sensitisation as shown in the OECD Toolbox (data not shown). Both substance are not expected to oxidise in air, the functional ketone group may be reduced to an alcohol during which process no skin sensitisation features will occur. Therefore there is high certainty that Orivone is not a skin sensitiser up to 100%.

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

For p-tert-butylcyclohexanone a well conducted LLNA study, performed according to OECD TG 429 and GLP is available. No sensitising properties were observed. Based on the obtained results for p-tert-butylcyclohexanone and consequently for Orivone the latter is not considered to be sensitising to the skin.

Final conclusion on hazard to be used for &L and risk characterization:Orivone is not a skin sensitiser.

 

Data matrix: Relevant information on Orivone and p-tert-butylcyclohexanone for assessment of skin sensitising properties.

Source/target

Target

Source

Common names

Orivone

p-tert-butylcyclohexanone

Chemical structures

 

 

CAS No.

16587-71-6

98-53-3

EINECS

240-642-0

202-678-5

Tanimoto

1

0.83

Empirical formula

C11H20O

C10H20O

Molecular weight

168.28

154.251

Physical state

Liquid

Low melting point solid

Melting point °C

< -20 (IFF measured)

48 (measured) (EPISuite database match)

Boiling point °C

246.8 (IFF measured)

210.92 (estimated)

Vapour pressure Pa

4.2 at 24°C (IFF measured)

23.1 (estimated)

Water solubility mg/L

370.8 at 24°C (IFF measured)

590 at 20°C(measured) (ECHA dissemination site)

Log Kow

3.9 at 25°C(measured)

3.4 (estimated EPIsuite)

2.91 (estimated EPIsuite)

Human health

 

 

Skin sensitisation

Read across from p-tert-butyl cyclohexanone

Not sensitising

(OECDTG429, modified LLNA (IMDS))

 

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The substance is not a respiratory sensitizer because there are no human data that indicate respiratory sensitisation. In addition the potential for respiratory sensitisation of the substance is assessed using the integrated evaluation strategy for respiratory sensitisation data in the ECHA guidance (R7A, Fig. 7.3-2). The substance is not a skin sensitizer and therefore not a respiratory sensitiser either.

Justification for classification or non-classification

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