Octahydro-4,7-methano-1H-inden-5-yl acetate

Endpoint summary

Description of key information

Skin sensitisation: The substance is not considered a skin sensitiser based on information from Mysore acetate, supported with information from Cyclobutanate, which were tested in a GPMT tests (OECD TG 406).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vitro

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The substance has not been tested up to 100%

Justification for type of information:

The information is used for read across to Cyclacet Dihydro.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.6 (Skin Sensitisation)

Deviations:

no

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

The test was performed in a time that the GPMT method was the key method for regulatory use.

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male/female

Details on test animals and environmental conditions:

Guinea pigs (Pirbright white, Bor: DHPW (SPF) were retrieved from Frima Winkelmann, Versuchstierzucht, Gartenstr. 27, W-4799-Borchen. They were acclimised for at least 5 days.
Housing: collective housing up to a maximum of
5 animals per cage (Macrolon type IV)
Illumination: artificial lighting (120 lux) from 7.00 a.m. - 7.00 p.m.
Temperature: 22 ± 3° C
Relative humidity:
Measurement: 30 - 70 % with thermohygrometer twice daily

Route:

intradermal and epicutaneous

Vehicle:

arachis oil

Concentration / amount:

Intradermal induction: 2.5%
Epicutaneous induction: 50%
Epicutaneous challenge: 50%

Day(s)/duration:

21

Adequacy of induction:

non-irritant substance, but skin pre-treated with 10% SDS

No.:

#20

Route:

epicutaneous, occlusive

Vehicle:

arachis oil

Concentration / amount:

50% of the substance

Day(s)/duration:

2

Adequacy of challenge:

highest non-irritant concentration

No. of animals per dose:

Test group: 20 males
Control group: 10 males

Details on study design:

RANGE FINDING TESTS:
Intradermal: two guinea pigs injected with 1% and 5% test substance in arachis oil BP. Highest concentration at which only mild to moderate skin irritation was observed and which was well tolerated systemically is selected for the main study: 5%.
Epicutaneous induction: two guinea pigs treated with 100%, 75%, 50% and 25% test material in arachis oil BP (48 hours). Highest concentration at which only mild to moderate skin irritation was observed is selected for the main study: 100%.
Epicutaneous challenge: two guinea pigs treated with 100%, 75%, 50% and 25% test material in arachis oil BP (24 hours). Highest non-irritating concentration and one lower were selected for the main study: 100% and 75%.

MAIN STUDY
A. INDUCTION EXPOSURE
According to guideline:
- No. of exposures: 2 (intradermal and epicutaneous)
- Exposure period: 48 hours (epicutaneous)
- Test group: induction with cyclobutanate
- Control group: test material omitted (intradermal and epicutaneous)
- Site: Shoulder
- Concentrations:
Intradermal: 5% in arachis oil BP (one of three injections)
Epicutaneous: 100%

B. CHALLENGE EXPOSURE
According to guideline:
- No. of exposures: 1
- Day of challenge: 21
- Exposure period: 24 hours
- Site: Flank
- Concentrations: 100% on right flank, 75% on left flank
- Evaluation (hr after challenge): 24 and 48 hours

Challenge controls:

Not induced (only vehicle)

Positive control substance(s):

yes

Remarks:

2,4 dinitrochlorobenzene (strong sensitizer) and benzocaine (moderate sensitizer) is tested periodically. The last test with an acceptable level of response to each of these substances was performed in October, 1991.

Vehicle:

other: Vaseline and Arachis oil

Concentration:

Induction: 2.5% intradermal and 50% epicutaneously

No. of animals per dose:

Control group: 20 animals
Test group: 20 animals

Details on study design:

First stage:
First stage - an area of 4 x 6 cm over the shoulders was clipped short with electric clippers
and cleaned with 70 % (v/v) ethanol. Three pairs of intradermal injections were then made symmetrically in two rows on either side of the spine:
Test group:
1. 0.1 ml FCA 50 % (w/w) diluted in water
2. 0.1 ml test article diluted in peanut butter oil (final concentration: 5 %)
3. 0.1 ml test article emulsified in FCA/water (final concentration: 5 %)
Control group:
1. 0.1 ml FCA 50 % (w/w) diluted in water
2. 0.1 ml vehicle (undiluted)
3. 0.1 ml vehicle 50 % (w/w) emulsified with FCA

Second stage - 7 days after the injections the dermal application was initiated. Because the
test article was non-irritating at the highest concentration tested, the area was clipped and
pretreated with 10 % sodium lauryl sulfate (SLS) in petrolatum 24 hours before. Based on the
results of the pilot study the test article concentration was 100 %. The test article was spread
in a thick layer [to saturation] over a 4 x 5 cm patch (filier paper). The lauer was firmly
secured over the previous injection sites by an occlusive dressing for 48 h. Control animals
received a patch loaded with the vehicle alone.

Positive control substance(s):

other: 2,4 dinitrobenzen or benzocaine were tested are regularly

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

50%

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

none

Remarks on result:

no indication of skin sensitisation

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

50%

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

none

Remarks on result:

no indication of skin sensitisation

Interpretation of results:

other: not sensitising

Remarks:

according to the EU CLP Regulation 1272/2008 and its amendments

Conclusions:

Under the conditions of this study, no skin reactions were seen in 20 guinea pigs 24 and 48 hours after challenge. Based on these results, Mysore acetate does not need to be classified as sensitising.

Executive summary:

The skin sensitisation potential of the substance was tested in the Guinea Pig Maximisation Test (GPMT) according to OECD guideline 406 and GLP. Intradermal induction was performed with 5% in arachis oil , epicutaneous induction with 50% substance and also the challent3 with 50% substance.

After a preliminary study with 2 animals, intradermal and epicutaneous application at 50% did not show irritation (The test material was supplied in 50% vaseline to the lab and therefore higher concentrations could not be applied). All concentrations are presented as % Mysore acetate).

After induction injection and epicutaneous application no irritation was seen. Therefore the application sites were pretreated with SDS. At challenge with 50% Mysore acetate no reaction were seen.

Therefore Mysore acetate is not considered not a skin sensitiser. Though the test concentration were not up to 100%, SLS has been applied to enhance penetration and therefore it can be assumed that the substance has reached the cells that initiate the skin sensitisation. The expected skin penetration is further supported by the molecular weight (< 200) and the predicted log Kow of 3.5.

Reference 3

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Remarks:

The information is based on in vivo information of an analogue.

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: The information is retrieved from read across

Justification for type of information:

The executive summary of the read across is presented below. The full reasoning is presented in the Endpoint summary. The accompanying files are attached in the present study record.
Cyclacet Dihydro has the same skin sensitisation potential as Mysore acetate in view of high similarity in structure: backbone and functional group, resulting in the same absence of skin sensitisation. The information is supported with data from Cyclobutanate.
Structural similarities and differences: Cyclacet Dihydro, the target, and the source chemical Mysore acetate have identical structural features consisting of a tricyclodecane fused ring structure and an acetic ester attached to this fused ring system. The difference is that Cyclacet Dihydro has the acetic ester attached to the bridged hexyl-ring, while Mysore acetate has it attached to the pentyl-ring. Cyclobutanate has a butyl tail instead of an ethyl tail attached to the ester bond. It also has a double bond in the pentyl-ring; both features are not affecting the skin sensitisation.
Toxico-kinetics: Skin absorption. For skin sensitisation skin absorption is a parameter to consider. The molecular weights, appearance, physico-chemical properties of both substances all indicate a similar bioavailability. Cyclobutanate has the same appearance, and a somewhat lower water solubility which can be expected because of the butyl- versus the ethyl chain. Its physic-chemical properties are still within the range of some dermal absorption.
Toxico-dynamic-reactivity: Cyclacet Dihydro and Mysore acetate will have the same reactivity because they have almost the same structure. The spot of attachment on the ring system is not expected to have any influence on the protein reactivity which is a key parameter for inducing skin sensitisation. For Cyclobutanate it can be argued that the butyl-chain compared to the ethyl-chain will not present additional reactivity to the ester. Also the sole double bond in the pentyl-ring of Cyclobutanate is non-reactive. When running the OECD Toolbox all three structures do not indicate protein binding potential (Data not shown). There are no anticipated alerts for pre-or prohaptens either (e.g. double bonds with methyl groups and ether bonds).
Uncertainty: There is no uncertainty in the prediction based on the same backbone and functional group of Cyclacet Dihydro and Mysore acetate and supported by Cyclobutanate.

Reason / purpose for cross-reference:

read-across source

Justification for non-LLNA method:

The information is based on read across from Mysore acetate.

Route:

intradermal and epicutaneous

Vehicle:

unchanged (no vehicle)

Concentration / amount:

The test item concentration was 5 and 100%, respectively containing 2.5 and 50% mysore acetate

Day(s)/duration:

7 days

Adequacy of induction:

non-irritant substance, but skin pre-treated with 10% SDS

No.:

#20

Route:

epicutaneous, semiocclusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

100% of the test item containing 50% Mysore acetate

Day(s)/duration:

2-days

Adequacy of challenge:

highest non-irritant concentration

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

100%, with 50% Mysore acetate

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

None

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

100% containing 50% Mysore acetate

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

None

Interpretation of results:

other: not a skin sensitiser

Remarks:

according to EU CLP (1272/2008 and its amendments)

Conclusions:

The substance is not considered a skin sensitiser.

Reference 4

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Remarks:

Test was carried out before the REACH regulation came into force requesting in vitro studies (October 2016).

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study with the read-across substance Cyclobutanate was conducted according to OECD guideline 406 and under GLP conditions.

Justification for type of information:

Information is used as supporting for read across to Cyclacet Dihydro.

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.6 (Skin Sensitisation)

Deviations:

no

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: David Hall Limited, Burton-on-Trent, Staffordshire, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 300-450
- Housing: Singly or in pairs, standard laboratory conditions
- Diet (e.g. ad libitum): Ad libitum (certified guinea pig diet)
- Water (e.g. ad libitum): Ad libitum (tap water)
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route:

intradermal and epicutaneous

Vehicle:

arachis oil

Concentration / amount:

Intradermal induction: 5%
Epicutaneous induction: 100%
Epicutaneous challenge: 100% and 75%

Adequacy of induction:

highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically

Route:

epicutaneous, occlusive

Vehicle:

arachis oil

Concentration / amount:

Intradermal induction: 5%
Epicutaneous induction: 100%
Epicutaneous challenge: 100% and 75%

Day(s)/duration:

2

Adequacy of challenge:

other: Maximum possible concentration applied

No. of animals per dose:

Test group: 20 males
Control group: 10 males

Details on study design:

RANGE FINDING TESTS:
Intradermal: two guinea pigs injected with 1% and 5% test substance in arachis oil BP. Highest concentration at which only mild to moderate skin irritation was observed and which was well tolerated systemically is selected for the main study: 5%.
Epicutaneous induction: two guinea pigs treated with 100%, 75%, 50% and 25% test material in arachis oil BP (48 hours). Highest concentration at which only mild to moderate skin irritation was observed is selected for the main study: 100%.
Epicutaneous challenge: two guinea pigs treated with 100%, 75%, 50% and 25% test material in arachis oil BP (24 hours). Highest non-irritating concentration and one lower were selected for the main study: 100% and 75%.

MAIN STUDY
A. INDUCTION EXPOSURE
According to guideline:
- No. of exposures: 2 (intradermal and epicutaneous)
- Exposure period: 48 hours (epicutaneous)
- Test group: induction with cyclobutanate
- Control group: test material omitted (intradermal and epicutaneous)
- Site: Shoulder
- Concentrations:
Intradermal: 5% in arachis oil BP (one of three injections)
Epicutaneous: 100%

B. CHALLENGE EXPOSURE
According to guideline:
- No. of exposures: 1
- Day of challenge: 21
- Exposure period: 24 hours
- Site: Flank
- Concentrations: 100% on right flank, 75% on left flank
- Evaluation (hr after challenge): 24 and 48 hours

Challenge controls:

Not induced (only vehicle), challenged as test group

Positive control substance(s):

yes

Remarks:

historical (2-Mercaptobenzothiazole and alpha-Hexylcinnamaldehyde)

Concentration:

Not relevant

No. of animals per dose:

Not relevant

Details on study design:

Not relevant

Statistics:

Not relevant

Positive control results:

Historically:
- 2-Mercaptobenzothiazole: sensitisation rate 100% in all 3 studies
- alpha-Hexylcinnamaldehyde: sensitisation rate of 20%, 40% and 50%

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

100%

No. with + reactions:

8

Total no. in group:

20

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100%. No with. + reactions: 8.0. Total no. in groups: 20.0.

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

100%

No. with + reactions:

1

Total no. in group:

10

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 100%. No with. + reactions: 1.0. Total no. in groups: 10.0.

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

100%

No. with + reactions:

0

Total no. in group:

20

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 20.0.

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

100%

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 10.0.

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

75% in arachis oil BP

No. with + reactions:

6

Total no. in group:

20

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 75% in arachis oil BP. No with. + reactions: 6.0. Total no. in groups: 20.0.

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

75% in arachis oil BP

No. with + reactions:

2

Total no. in group:

10

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 75% in arachis oil BP. No with. + reactions: 2.0. Total no. in groups: 10.0.

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

75% in arachis oil BP

No. with + reactions:

0

Total no. in group:

20

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 75% in arachis oil BP. No with. + reactions: 0.0. Total no. in groups: 20.0.

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

75% in arachis oil BP

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 75% in arachis oil BP. No with. + reactions: 0.0. Total no. in groups: 10.0.

Effects noted after induction:

- Discrete or patchy moderate and confluent erythema was noted at the intradermal induction sites of test and control group animals

- Discrete or patchy erythema noted at topical induction sites of test group animals. Bleeding from intradermal injection sites was noted in 9 test group animals after 1 hour. Control animals: discrete or patchy erythema at topical induction site

Interpretation of results:

other: not a skin sensitiser

Remarks:

according to EU CLP (1272/2008 and its amendments)tion

Conclusions:

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%).

Executive summary:

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 100 and 75% concentrations. 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. For the control group, this was 1 and 0 out of 10. In the 75% cyclobutanate group, 6 and 0 out of 20 animals responded positive. In the control group 2 and 0 positive skin reactions were observed. 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 does not need to be classified as sensitising to the skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

The skin sensitisation potential of Cyclacet Dihydro is retrieved from the key analogue Mysore acetate. In view of Mysore acetate only be tested up to 50% also Cyclobutanate is used for support which is tested up to 100% in a GPMT test (OECD TG 406). The full read across justification is presented at the end of this section. The accompanying files are attached in the study record. First the summary of the results of Mysore acetate (key) and Cyclobutanate (supporting) are presented.

Mysore acetate GPMT information

The skin sensitisation potential of the substance was tested in the Guinea Pig Maximisation Test (GPMT) according to OECD guideline 406 and GLP. Intradermal induction was performed with 5% in arachis oil , epicutaneous induction with 50% substance and also the challent3 with 50% substance.

After a preliminary study with 2 animals, intradermal and epicutaneous application at 50% did not show irritation (The test material was supplied in 50% vaseline to the lab and therefore higher concentrations could not be applied). All concentrations are presented as % Mysore acetate).

After induction injection and epicutaneous application no irritation was seen. Therefore the application sites were pretreated with SDS. At challenge with 50% Mysore acetate no reaction were seen.

Therefore Mysore acetate is not considered not a skin sensitiser. Though the test concentration were not up to 100%, SLS has been applied to enhance penetration and therefore it can be assumed that the substance has reached the cells that initiate the skin sensitisation. The expected skin penetration is further supported by the molecular weight (< 200) and the predicted log Kow of 3.5.

Cyclobutanate GPMT information

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 100 and 75% concentrations. 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. For the control group, this was 1 and 0 out of 10. In the 75% Cyclobutanate group, 6 and 0 out of 20 animals responded positive. In the control group 2 and 0 positive skin reactions were observed. 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 does not need to be classified as sensitising to the skin.

Cyclacet Dihydro (Cas no 64001-15-6)and its skin sensitisation potential derived from Mysore acetate (Cas no30772-69-1) and for support Cyclobutanate is added.

Introduction

Cyclacet Dihydro has atricyclodecane-fused ring structure to which an acetic-ester is attached (Fig. 1 and data matrix). For this substance no skin sensitisation information is available. In accordance with Article 13 of REACH, lacking information can be generated by means of applying alternative methods such as in vitro, QSARs, grouping and read-across. For Cyclacet Dihydro the skin sensitisation will be derived from Mysore acetate and are supported with data from Cyclobutanate

Hypothesis: Cyclacet Dihydro has the same skin sensitisation potential as Mysore acetate in view of high similarity in structure: backbone and functional group, resulting in the same absence of skin sensitisation. The information is supported with data from Cyclobutanate.

Available information:For Mysore acetate a GPMT test is available according to OECDTG 406 and under CLP. The substance is applied at 50%, with SLS to assure skin penetration but because the applied concentration is not 100%, it receives reliability 2. Therefore for support Cyclobutanate information is added for which also a GPMT according to OECD 406 under CLP is available and which has been tested up to 100% and receives a Reliability 1.

Target chemical and source chemical(s)

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

Purity / Impurities

The purity and impurities of the target chemical do not indicate other constituents or impurities (all< 10%) that indicated a different skin sensitisation potential.

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. 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.

In accordance with ECHA guidance (2017, RAAF) Mysore acetate is selected as the key source.Structural similarities and differences:Cyclacet Dihydro, the target, and the source chemical Mysore acetate have identical structural features consisting of a tricyclodecane fused ring structure and an acetic ester attached to this fused ring system. The difference is that Cyclacet Dihydro has the acetic ester attached to the bridged hexyl-ring, while Mysore acetate has it attached to the pentyl-ring. Cyclobutanate has a butyl tail instead of an ethyl tail attached to the ester bond. It also has a double bond in the pentyl-ring; both features are not affecting the skin sensitisation.

Toxico-kinetics:Skin absorption. For skin sensitisation skin absorption is a parameter to consider. The molecular weights, appearance, physico-chemical properties of both substances all indicate a similar bioavailability. Cyclobutanate has the same appearance, and a somewhat lower water solubility which can be expected because of the butyl- versus the ethyl chain. Its physic-chemical properties are still within the range of some dermal absorption.

Toxico-dynamic-reactivity:Cyclacet Dihydro and Mysore acetate will have the same reactivity because they have almost the same structure. The spot of attachment on the ring system is not expected to have any influence on the protein reactivity which is a key parameter for inducing skin sensitisation. For Cyclobutanate it can be argued that the butyl-chain compared to the ethyl-chain will not present additional reactivity to the ester. Also the sole double bond in the pentyl-ring of Cyclobutanate is non-reactive. When running the OECD Toolbox all three structures do not indicate protein binding potential (Data not shown). There are no anticipated alerts for pre-or prohaptens either (e.g. double bonds with methyl groups and ether bonds).

Uncertainty: There is no uncertainty in the prediction based on the same backbone and functional group of Cyclacet Dihydro and Mysore acetate and supported by Cyclobutanate. In accordance with ECHA guidance (RAAF, 2017) the read across receives score 5.

Data matrix

The Data matrix is presented in Table 1, below.

Conclusions for acute oral toxicity and classification and labelling

Skin sensitisation:The skin sensitisation of Cyclacet Dihydro is derived from read across of Mysore acetate and supported with Cyclobutanate. Mysore acetate and Cyclobutanate do not have to be classified for skin sensitisation and therefore Cyclacet Dihydro is not a skin sensitiser either.

Classification and Labelling: Cyclacet Dihydro has no skin sensitisation potential and therefore the substance does not need to be classified and labelled according to EU CLP (EC 1272/2008 and its amendments). 

 

Table 1: Data matrix presenting the characteristics of Cyclacet Dihydro, its source Mysore acetate and supporting information from Cyclobutanate to support the read across for skin sensitisation

Common names	Cyclacet Dihydro	Mysore acetate	Cyclobutanate
Chemical structures
	Target	Source	Supporting
Cas no of the main isomer	64001-15-6	30772-69-1	113889-23-9 (5-yl)
Einecs	264-598-7	-
REACH registration	REACH registered for 2018	No registration information	Elincs registration
Empirical formula	C12H18O2	C12H16O2	C14H20O2
Smiles	CC(=O)OC3CC1CC3C2CCCC12	CC(=O)OC3CCC2C1CCC(C1)C23	CCCC(=O)OC3CC1CC3C2CC=CC12
Physico-chemical data
Molecular weight	194	194	220
Physical state	liquid	liquid	Liquid
Vapour pressure Pa	2.2 (IFF measured)	3.9 (EpiSuite)	11.2 (0.323: EPiSuite)
Water solubility mg/l (measured)	89 (IFF measured)	113 (EpiSuite)	11.5
Log Kow (measured)	4.5 (HPLC)	3.8 (RIFM database)	4.48 (Shake flask)
Log Kow	3.1 (EpiSuite)	3.1 (EpiSuite)	3.8
Human health
Skin sensitisation	Read across from Mysore acetate and Cyclobutanate	Not a skin sensitiser (OECD TG 406 at 50%)	Not a skin sensitiser (OECD TG 406 at 100%)

Justification for classification or non-classification

The substances does not need to be classified for skin sensitisation based on information from two analogues tested in GPMT tests in accordance with EU CLP 1272/2008 and its amendments.