Reaction mass of (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl rel-acetate and rel-(1aR,4aR,8aR)-2,4a,8,8-tetramethyl-1,1a,4,4a,5,6,7,8-octahydrocyclopropa[d]naphthalene and rel-(3R,3aS,7S,8aS)-3,6,8,8-tetramethyl-2,3,4,7,8,8a-hexahydro-1H-3a,7-methanoazulene

Endpoint summary

Description of key information

Skin sensitisation: Sensitising 1B based on read across from Cedryl Acetate 'mono' which was tested in an LLNA (OECD TG 429)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

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

Adequacy of study:

key study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across information.

Justification for type of information:

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

Reason / purpose for cross-reference:

read-across source

Key result

Parameter:

EC3

Remarks:

%

Value:

33.1

Remarks on result:

other: read-across from Cedryl Acetate (mono)

Parameter:

SI

Value:

1.3

Remarks on result:

other: 10%

Parameter:

SI

Value:

1.9

Remarks on result:

other: 25%

Parameter:

SI

Value:

5.3

Remarks on result:

other: 50%

Interpretation of results:

other: Skin sensitiser Category 1B

Remarks:

according to Regulation (EC) No. 1272/2008 and its amendments.

Conclusions:

The SI values calculated for the substance concentrations 10, 25 and 50% were 1.3, 1.9 and 5.3, respectively. These results show that the test substance could elicit a SI ≥ 3. The EC3 is calculated to be 33.1%. The substance is a skin sensitiser (Category 1B), based on the results of the source substance.

Reference 2

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 March, 2016 - 20 April, 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

This information is used for read across to Cedryl Acetate EOA

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

July 2010

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

May 2008

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2600 (Skin Sensitisation)

Version / remarks:

March 2003

Deviations:

no

GLP compliance:

yes

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

CBA:J

Sex:

female

Details on test animals and environmental conditions:

Female CBA/J strain mice were supplied by Janvier, Le Genest-Saint-Isle, France. On receipt the animals were randomly allocated to cages. The animals were nulliparous and non pregnant. After an acc limatisation period of at least five days the animals were selected at random and given a tail mark with marker pen. At the start of the study the animals were in the weight range of 19.8 to 23.5 g, and were eight to ten weeks old.
Animals were group housed in labeled Makrolon cages containing sterilised sawdust as bedding mater ial. Paper and shelters were supplied as cage-enrichment. Free access to tap water and food (pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany)) was allowed throughout t he study.
The temperature and relative humidity were controlled to remain within target ranges of 18 to 24°C and 40 to 70 %, respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least 10 changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light and twelve hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Vehicle:

acetone/olive oil (4:1 v/v)

Concentration:

Undiluted test item or the test item at concentrations of 10%, 25 % or 50 % v/v in vehicle.

No. of animals per dose:

Groups of five mice were treated

Details on study design:

Weight of evidence analysis:
In the interest of animal welfare and to minimize any testing likely to produce severe responses in animals, a weight of evidence analysis was performed prior to the start of this study. All available information was evaluated (e.g. existing human and animal data, literature, item data supplied by the Sponsor, analysis of structure activity relationships (SAR), physicochemical properties and reactivity (pH, buffering capacity)). It was concluded by the Study Director that no severe effects were to be expected.

Preliminary Screening Test:
A pre-screen test was conducted in order to select the highest test item concentration to be used in the main study. In principle, this highest concentration should cause no systemic toxicity, may give well-defined irritation as the most pronounced response (maximum grade 2 (see section 7.8) and/or an increase in ear thickness < 25%) and/or is the highest possible concentration that can technically be applied.
Two test item concentrations were tested; a 50% and 100% concentration. The highest concentration was the maximum concentration as required in the test guidelines.
The test system, procedures and techniques were identical to those used in the main study except that the assessment of lymph node proliferation and necropsy were not performed. Two young adult animals per concentration were selected. Each animal was treated with one concentration on three consecutive days. Animals were group housed in labeled Makrolon cages. Ear thickness measurements were conducted using a digital thickness gauge prior to dosing on Days 1 and 3, and on Day 6.
Animals were sacrificed after the final observation.

Main Test:
Test Item Administration:
Groups of five mice were treated with the undiluted test item or the test item at concentrations of 50 %, 25 % or 10 % v/v in acetone/olive oil 4:1. The vehicle was selected on the basis of maximizing the solubility using the test substance data provided by the Sponsor and trial preparation results performed at WIL Research Europe. The vehicle was chosen from the vehicles specified in the test guideline: Acetone/Olive oil (4:1 v/v), N,N-dimethylformamide, methylethylketone, propylene glycol and dimethylsulfoxide. There was no information available regarding the solubility or stability in vehicle. No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement. The preliminary screening test suggested that the test item would not produce systemic toxicity or excessive local irritation at the highest suitable concentration. The dorsal surface of both ears was topically treated (25 μL/ear) with the test substance, at approximately the same time on each day.
A further group of five mice received the vehicle alone in the same manner.
The positive control animals were similarly treated to the test animals except that 25 μl of the positive control item, α Hexylcinnamaldehyde, technical grade, at a concentration of 5, 10 and 25 % v/v in acetone/olive oil 4:1 was applied to the dorsal surface of each ear. The positive control group served as common control with another study according to the summary of positive control data for the local lymph node assay.

Induction - Days 1, 2 and 3
The dorsal surface of both ears was topically treated (25 μL/ear) with the test substance, at approximately the same time on each day. The concentrations were stirred with a magnetic stirrer immediately prior to dosing.

3H-Methyl Thymidine Administration
Five days following the first topical application of the test item, each animal was injected via the tail vein with 0.25 mL of sterile phosphate buffered saline (PBS) (Merck, Darmstadt, Germany) containing 20 μCi of 3H-methyl thymidine (PerkinElmer Life and Analytical Sciences, Boston, MA, US).

Terminal Procedures - Day 6
Termination: After five hours, all animals were killed by intraperitoneal injection (0.2 mL/animal) of Euthasol® 20% (AST Farma BV, Oudewater, The Netherlands). The draining (auricular) lymph node of each ear was excised. The relative size of the nodes (as compared to normal) was estimated by visual examination and abnormalities of the nodes and surrounding area were recorded. The nodes were pooled for each animal in approximately 3 mL PBS.

Preparation of Single Cell Suspension: Following excision of the nodes, a single cell suspension of lymph node cells (LNC) was prepared in PBS by gentle separation through stainless steel gauze (diameter: 125 μm). LNC were washed twice with an excess of PBS by centrifugation at 200g for 10 minutes at 4ºC. To precipitate the DNA, the LNC were exposed to 5% trichloroacetic acid (TCA) (Merck, Darmstadt, Germany) and then stored in the refrigerator until the next day.

Determination of 3HTdR Incorporation: Precipitates were recovered by centrifugation, resuspended in 1 mL TCA and transferred to 10 mL of Ultima Gold cocktail (PerkinElmer Life and Analytical Sciences, Boston, MA, US) as the scintillation fluid. Radioactivity measurements were performed using a Packard scintillation counter (2800TR). Counting time was to a statistical precision of ± 0.2% or a maximum of 5 minutes whichever came first. The scintillation counter was programmed to automatically subtract back ground and convert Counts Per Minute (CPM) to Disintegrations Per Minute (DPM).

Observations
Mortality/Viability Twice daily.

Clinical Observations: Once daily on Days 1-6 (on Days 1-3 between 3 and 4 hours after dosing). Any signs of toxicity or signs of ill health during the test were recorded.

Bodyweights: The bodyweight of each mouse was recorded on Day 1 (prior to dosing) and on Day 6 (prior to termination).

Irritation: Once daily on Days 1-6 (on Days 1-3 within 1 hour after dosing) according to the numerical scoring system (see any other information on materials and methods incl. tables). In addition, a description of all other (local) effects was recorded.

Positive control substance(s):

hexyl cinnamic aldehyde (CAS No 101-86-0)

Statistics:

Not performed.

Positive control results:

The positive control item, α-Hexylcinnamaldehyde, technical grade gave a Stimulation Index of 4.4 when tested at a concentration of 25 % v/v in acetone/olive oil 4:1.

Key result

Parameter:

EC3

Remarks:

%

Value:

33.1

Parameter:

SI

Value:

1.3

Remarks on result:

other: 10%

Parameter:

SI

Value:

1.9

Remarks on result:

other: 25%

Parameter:

SI

Value:

5.3

Remarks on result:

other: 50%

Parameter:

other: NOEC %

Value:

25

Cellular proliferation data / Observations:

CELLULAR PROLIFERATION DATA

DETAILS ON STIMULATION INDEX CALCULATION
The SI values calculated for the test item concentrations 10, 25 and 50% were 1.3, 1.9 and 5.3, respectively.

EC3 CALCULATION
These results indicate that the test item elicits a SI ≥ 3. The data showed a dose-response and an EC3 value (the estimated test item concentration that will give a SI =3) of 33.1% was calculated.

CLINICAL OBSERVATIONS/BODY WEIGHTS:
No mortality occurred and no clinical signs of systemic toxicity were observed in the animals of the main study. Body weights and body weight gain of experimental animals remained in the same range as controls over the study period.

Pre-screen test:

Very slight to well-defined erythema was noted for the pre-screen animals. Variations in ear thickness during the observation period were less than 25% from Day 1 pre-dose values. The animals treated at 100% showed piloerection and erythema between the ears. No signs of systemic toxicity were noted for the animals treated at 50%. Based on the tolerability of the test item, the highest test item concentration selected for the main study was a 50% concentration.

Interpretation of results:

other: Skin sensitiser Category 1B

Remarks:

according to Regulation (EC) No. 1272/2008 and its amendments.

Conclusions:

The SI values calculated for the substance concentrations 10, 25 and 50% were 1.3, 1.9 and 5.3, respectively. These results show that the test substance could elicit a SI ≥ 3. An EC3 has been derived resulted in an EC3 of 33.1%. A NOEC of 25% is derived. Based on these results the substance should be classified as skin sensitizer (Category 1B) in accordance with the criteria outlined in Annex I of the CLP Regulation (1272/2008/EC).

Executive summary:

The skin sensitisation potential of the substance has been tested according to OECD TG 429: Local Lymph Node Assay" method and GLP principles. At 10, 25 and 50% the substance showed SI values of 1.3, 1.9 and 5.3, respectively. Reliable negative and positive controls were included. All auricular lymph nodes of the experimental animals treated at 10% and 25% and control groups were considered normal in size. Most auricular lymph nodes of the animals treated at 50% were considered enlarged. No macroscopic abnormalities of the surrounding area were noted for any of the animals. These results show that the test substance could elicit a SI ≥ 3. An EC3 has been derived resulted in an EC3 of 33.1%. A NOEC of 25% is derived. The substance was considered to be a sensitiser and should be classified as skin sensitizer (Category 1B) and labeled as H317: May cause an allergic skin reaction according to Regulation (EC) No. 1272/2008 and GHS.

Reference 3

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

08 June 2011 - 15 June 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The LLNA was performed before the REACH regulation came into force requesting in vitro skin sensitisation information first (October, 2016). This information is used for read across to Cedryl Acetate EOA

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

22 July 2010

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

2004

Deviations:

no

GLP compliance:

yes

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

CBA:J

Sex:

female

Details on test animals and environmental conditions:

Female CBA/J strain mice were supplied by Jackson Laboratories, Bar Harbor, ME 04609. On receipt the animals were randomly allocated to cages. The animals were nulliparous and non pregnant. After an acclimatisation period of six days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail. At the start of the study the animals were in the weight range of 18 to 25 g, and were eight to twelve weeks old.

The animals were group housed per cage. Free access to tap water and food (Harlan Teklad Certified Rodent Chow 2016C) was allowed throughout the study.
The temperature and relative humidity were controlled to remain within target ranges of 24 to 28°C and 16 to 69 %, respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The lighting was controlled by a time switch to give twelve hours continuous light (06.00 to 18.00) and twelve hours darkness.

Vehicle:

other: 3:1 Diethyl Phthalate:Ethanol (3:1 DEP:EtOH)

Concentration:

Test item concentrations of 2.5%, 5%, 10%, 25% or 50% v/v in vehicle.

No. of animals per dose:

Groups of five mice were treated

Details on study design:

Justification for route and dose levels:
The dermal route was selected as this is the route required for this model of hypersensitivity.
In general, the doses have been selected so that the highest concentration maximizes exposure while avoiding systemic toxicity and excessive local irritation. Doses were selected based on known reported uses of the material.
The frequency of dosing is the convention for this type of study.

Main Test
Test Item Administration
Groups of five mice were treated with the test item at concentrations of 2.5%, 5%, 10%, 25% or 50% v/v in vehicle. No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement. The mice were treated by daily application of 25 µL of the appropriate concentration of the test item to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). Approximately 24 ± 2.5 hours separated each application of test substance. A further group of five mice received the vehicle alone in the same manner.

The positive control animals were similarly treated to the test animals except that 25 µL of the positive control item, α Hexylcinnamaldehyde, at a concentration of 5%, 15% or 35% v/v in 3:1 Diethyl Phthalate:Ethanol (3:1 DEP:EtOH) was applied to the dorsal surface of each ear.

3H-Methyl Thymidine Administration
Five days following the first topical application of the test item, vehicle control or positive control item (Day 6) all mice were injected i.v. with 250 µL of sterile saline containing 3H methyl thymidine (3HTdR:1mCi/ml, specific activity 5 Ci/mmol, Moravek Biochemicals, Inc.) giving a total of 20 µCi to each mouse.

Observations
Mortality/morbidity: Daily on days 1 to 6.
Clinical Observations: Observations were performed prior to dose administration and following dose administration. Clinical observations were performed once daily on Days 4-6. particular attention was given to the application sites. Any significant alterations to the application sites, and the general appearance of the pinnae, including build up of test article, was recorded.

Bodyweights: The bodyweight of each mouse was recorded on Day 1 (prior to dosing) and Day 6 (prior to termination).

Dermal irritation: Animals were examined daily for signs of erythema and edema. Irritation was scored and recorded using the Draize scoring system. Scoring was performed prior to dosing on Days 1-3.

Terminal Procedures
Termination: Five hours following the administration of 3HTdR all mice were killed by carbon dioxide asphyxiation. At removal, the number of nodes collected per animal was recorded, and the nodes were examined for size/appearance and the data recorded. Any unexpected observations were noted in study records.

Preparation of Single Cell Suspension: A single cell suspension was prepared from the lymph nodes of each individual mouse (un-pooled). Celle were washed twice with PBS and precipitated with 5% trichloroacetic acid (TCA) overnoght at 2-8°C.

Determination of 3HTdR Incorporation: The pellets were recovered by centrifugation and resuspended in 1 mL of TCA and transferred to a vial containing scintillation fluid. An additional 1 mL of TCA was used to rinse the tube, and it was also transferred to the scintillation fluid. Incorporation of 3H-thymidine was measured in a β-scintillation counter.

Positive control substance(s):

hexyl cinnamic aldehyde (CAS No 101-86-0)

Statistics:

All data was collected manually except for the data generated by the scintillation counter (Beckman LS 6000 SC). SYSTAT version 0.01, developed by SPSS, Inc was used for statistical analysis.

Positive control results:

The positive control item, α-Hexylcinnamaldehyde, gave a Stimulation Index of greater than 3 when tested at a concentration of 15 and 30 % v/v in 3:1 Diethyl Phthalate:Ethanol (3:1 DEP:EtOH).

Key result

Parameter:

EC3

Remarks:

%

Value:

31.4

Parameter:

SI

Value:

1.5

Remarks on result:

other: 2.5%

Parameter:

SI

Value:

0.9

Remarks on result:

other: 5%

Parameter:

SI

Value:

2

Remarks on result:

other: 10%

Parameter:

SI

Value:

2.1

Remarks on result:

other: 25%

Parameter:

SI

Value:

5.6

Remarks on result:

other: 50%

Parameter:

other: NOAEL

Remarks:

%

Value:

25

Cellular proliferation data / Observations:

CELLULAR PROLIFERATION DATA

DETAILS ON STIMULATION INDEX CALCULATION
The following SI values were derived at 2.5, 5, 10, 25 and 50%: 1.5, 0.9, 2.0, 2.1 and 5.6, respectively.

EC3 CALCULATION
Based on the results the EC3 is 31.4%.

CLINICAL OBSERVATIONS:
There was no mortality and all animals appeared normal throughout the study.
No erythema or edema was noted in any of the mice in the vehicle group, positive groups or in those treated with test substance concentrations. The ears of the mice treated with 35% HCA appeared wet on Days 2 through 4. There were no other findings.

BODY WEIGHTS
On day 1 there were statistically significant differences in the mean body weights for the groups treated with 5 and 25% Longifolene and 5 and 35% HCA when compared to the vehicle control group (p < 0.01, p < 0.001, p < 0.01, and p < 0.01, respectively). On Day 6 there were statistically significant differences in the mean body weights for the groups treated with 5% Longifolene and 5% HCA when compared to the vehicle control group (p < 0.05 and p < 0.01, respectively). However, when the mean body weight changes were compared, the only statistically significant difference that was observed was an increase for the group treated with 25% Longifoline when compared to the vehicle group (p < 0.001 ). None of these differences were biologically relevant. Therefore, administration of the test article or positive control did not appear to exert any overt toxicity.

Interpretation of results:

other: Skin sensitiser Category 1B

Remarks:

according to Regulation (EC) No. 1272/2008 and its amendments.

Conclusions:

The SI values calculated for the substance concentrations 2.5, 5, 10, 25 and 50 % were 1.5, 0.9, 2.0, 2.1 and 5.6, respectively. These results show that the test substance could elicit a SI ≥ 3. An EC3 value of 31.4% v/v was calculated. A NOEC of 25% is derived. The test isubstance was considered to be a sensitiser under the conditions of the test.

Executive summary:

The skin sensitisation potential of the substance has been tested according to OECD TG 429 test guideline and GLP principles. At 2.5, 5, 10, 25 and 50% the substance showed SI values of 1.5, 0.9, 2.0, 2.1 and 5.6, respectively. Reliable negative and positive controls were included. These results show that the test substance could elicit a SI ≥ 3. An EC3 value of 31.4% w/v was calculated. A NOEC of 25% is derived. Based on the results, the substance was considered to be a sensitiser.

Reference 4

Endpoint:

skin sensitisation: in vitro

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Skin sensitisation is assessed based on read-across from Cedryl Acetate 'mono' and Longifolene Coeur. The executive summary of the source information is presented below followed by the read-across rationale.

Cedryl Acetate 'mono'

Cedryl Acetate 'mono' skin sesnitisation potential has been tested according to OECD TG 429: Local Lymph Node Assay" method and GLP principles. At 10, 25 and 50% the substance showed SI values of 1.3, 1.9 and 5.3, respectively. Reliable negative and positive controls were included. All auricular lymph nodes of the experimental animals treated at 10% and 25% and control groups were considered normal in size. Most auricular lymph nodes of the animals treated at 50% were considered enlarged. No macroscopic abnormalities of the surrounding area were noted for any of the animals. These results show that the test substance could elicit a SI ≥ 3. An EC3 has been derived resulted in an EC3 of 33.1%. A NOEC of 25% is derived. based on the results, the substance was considered to be a sensitiser.

Longifolene Coeur

Longifolene Coeur skin sensitisation potential has been tested according to OECD TG 429 test guideline and GLP principles. At 2.5, 5, 10, 25 and 50% the substance showed SI values of 1.5, 0.9, 2.0, 2.1 and 5.6, respectively. Reliable negative and positive controls were included. These results show that the test substance could elicit a SI ≥ 3. An EC3 value of 31.4% w/v was calculated. A NOEC of 25% is derived. Based on the results, the substance was considered to be a sensitiser.

Skin sensitizing potential of Cedryl Acetate EOA based on read across from data available for Cedryl Acetate ‘mono’ (CAS #77-54-3) and Longifolene Coeur (CAS #475-20-7)

 

Introduction and hypothesis for the analogue approach

Cedryl Acetate EOA consists of one major, two minor constituents and a number of impurities, all containing a hydrocarbon fused-ring system. Half of the constituents have an acetate attached to this ring the other half does not have this ester group. Most constituents have a double bond with a methyl group attached. The constituents are sub-grouped into two main types: Cedryl Acetate 'type and Longifolene Coeur-type (hydrocarbon-fused-ring-type).

For Cedryl Acetate EOA there are no data on skin sensitization data available.In accordance with Article 13 of REACH, lacking information can be by other means than experimental testing applying alternative methods such as QSARs, grouping and read-across.For assessing the skin sensitising properties of Cedryl Acetate EOA, the analogue approach is selected because for one of Cedryl Acetate EOA’s key constituents, Cedryl Acetate ‘mono’ skin sensitisation information is available. For the hydrocarbon constituents the analogue Longifolene Coeur can be used for which also skin sensitization data is available.

Hypothesis:Cedryl Acetate EOA as a whole has similar skin sensitisation properties as the representatives of its two sub-groups of constituents: Cedryl Acetate ‘mono’ and Longifolene Coeur.

Available information:For Cedryl Acetate ‘mono’ an EC3 of 33.1% is derived in an LLNA (OECD TG 429, Rel. 1). For Longifolene Coeur an EC3 of 31.4% v/v is derived in an LLNA (OECD TG 429, Rel. 1).

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemical(s) are shown in the data matrix, including physico-chemical properties and available toxicologicalinformation.

Purity / Impurities

The unidentified impurities of Cedryl Acetate EOA are not considered to have a significant influence on the sensitizing 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, which is presented below.

Analogue selection:Cedryl Acetate ‘mono’ was selected because this acetate is a key constituent of Cedryl acetate EOA and is similar to the other acetates present in Cedryl Acetate EOA. Longifolene Coeur was selected as an analogue because it represents the hydrocarbon type constituents of Cedryl Acetate EOA which do not have the ester functionality.

Structural similarities and differences: Cedryl Acetate EOA components all have a hydrocarbon fused-ring system and have a double bond in the structure. Some of the constituents have an acetate group, while others are not acetylated. The constituents have methylene groups attached to its rings (double bond with a methyl group), which are prone to oxidation. Longifolene Coeur has a similar functional group a double bonded carbon attached to its ring also prone to oxidation.

Bioavailability: The dermal bioavailability will be similar between target and source because all are liquids, have low water solubility and high log Kow values (>5).

Reactivity: The reactivity of Cedryl Acetate EOA is considered similar to both Cedryl Acetate ‘mono’ and Longifolene Coeur based on the similar auto-oxidising functional groups, such as the methylene groups.

Uncertainty of the prediction: In view of the reasoning above no other uncertainties need to be addressed.

Data matrix

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

Conclusions for skin sensitisation

For Cedryl Acetate EOA no skin sensitisation information is available. Read across is used to cover this data gap. 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. The text in the present document fulfils this requirement. For Cedryl Acetate EOA read across information is used from Cedryl Acetate ‘mono’ and Longifolene Coeur for which well conducted LLNA’s are available (Reliability 1). TheEC3 values were 33.1% v/v and 31.4% v/v, respectively, resulting in beingskin sensitisers Cat. 1B. The information of these two analogues can be used for Cedryl Acetate EOA as is reasoned above and therefore this substance is skin sensitizer 1B too.

Final conclusion:Cedryl Acetate EOA has an EC3 o 31.4% and is a skin sensitiser Cat. 1B.

 

Data matrix to support the read across to Cedryl acetate EOA from Cedryl acetate and Longifolene Coeur for skin sensitisation

Common names	Cedryl Acetate EOA							Cedryl acetate	Longifolene Coeur
	Target	Target	Target	Target	Target	Target	Target	Source	Supporting source
	Cedryl Acetate type			Longifolene type
Chemical structures
Typical concentration (%)	30-45 (major)	<10	<10	15-30 (minor)	8-16 (minor)	<10	<10
CAS no				32435-95-3	22567-43-7			77-54-3	475-20-7
Einecs	944-520-4							201-036-1	207-491-2
REACH		2018						2018	2018
Molecular weight	264	264	264	204	204	204	202	264	204
Phys-Chem data*
Log Kow	5.33	5.33	5.94	6.12	5.74	5.82	6.19	5.33 (6 exp.)	5.48 (5 exp.)
Human health
Skin Sensitisation	Skin Sensitisation 1B (Read across)	Skin Sensitisation 1B (Read across))	Skin Sensitisation 1B (Read across)	Skin Sensitisation 1B (Read across)	Skin Sensitisation 1B (Read across)	Skin Sensitisation 1B (RA)	Skin Sensitisation 1B (RA)	Skin sensitisation (OECD TG 439)	Skin sensitisation (OECD TG 439)

*Physico-chemical properties are calculated with EpiSuite; RA=Read across

 

Justification for classification or non-classification

Based on the results, the substance needs to be classified as Skin sensitizer Category 1B, and shall be labelled as 'H317: May cause an allergic skin reaction', according to EU CLP (EC 1272/2008 and its amendments).