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Description of key information

Skin sensitisation: Not sensitising based on read across from Orange flower ether, which was up to 100% not skin sensitising in a Buehler test (OECD TG 406).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 June 2005 - 13 July 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Information from a reliable, Buehler test is available being performed before the change in the Reach regulation, preferring the in vitro tests. The information is used for read across to Oxaspirane-819.
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
1992, Buehler
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Version / remarks:
2003
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
This study is available and is sufficient to determine the skin sensitizing potential of the substance.
Species:
guinea pig
Strain:
Hartley
Remarks:
Albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Elm Hill Breeding Laboratories, Chelmsford, MA
- Females nulliparous and non-pregnant: yes
- Age at study initiation: young adults
- Weight at study initiation:357 – 455 g
- Housing: in suspended stainless steel caging with mesh floors which confirm to the size recommendations of the Guide for the Care and Use of Laboratory Animals DHEW. Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet: Pelleted Purina Guinea Pig Chow #5025
- Water: filtered tap water, ad libitum
- Acclimation period: 12 to 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23
- Humidity (%): 40 - 66
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:
0.4 mL
Day(s)/duration:
6 hours
Adequacy of induction:
highest technically applicable concentration used
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: mineral oil
Concentration / amount:
0.4 mL of a 50% w/w mixture
Day(s)/duration:
6 hours
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
- Preliminary irritation study: 4
- Test group: 20
- Control group: 10
Details on study design:
RANGE FINDING TESTS:
A group of 4 animals was used to determine the highest non-irritating concentration (HNIC) of the test substance. The fur was removed by clipping the dorsal area and flanks of each animal. This area was divided in four test sites (two sites on each side of the midline) on each animal. The test substance was applied neat (100%) and also diluted with mineral oil to yield w/w concentrations of 75%, 50% and 25%. Each concentration was applied (0.4 mL) to a test site using an occlusive 25 mm Hilltop Chamber. The sites were wrapped with non-allergic Durapore adhesive tape. After 6 hours of exposure, the chambers were removed and the test sites were cleansed of any residual test substance. Approximately 24 hours after application, each site was evaluated for local reactions (erythema). From these results, the HNIC selected for the challenge phase was a 50% w/w mixture in mineral oil.

MAIN STUDY
A. PREPARATION AND SELECTION OF ANIMALS
Prior to initiation, the fur of a group of animals was removed by clipping the dorsal area and flanks. Animals were weighed and the skin checked to make sure no pre-existing skin irritation was present.

B. INDUCTION EXPOSURE
3 times each week for 3 weeks, 0.4 mL of the undiluted test substance was applied to the left side of each animal using an occlusive 25 mm Hilltop Chamber. The chambers were secured in place and wrapped with non-allergic Durapore adhesive tape to avoid dislocation of the chambers and to minimize loss of the test substance. After an exposure period of 6 hours, the chambers were removed and the test sites were cleansed of any residual test substance. Approximately 24 and 48 hours after each induction application, readings were made of local reactions (erythema).

C. CHALLENGE EXPOSURE
28 days after the first induction dose, 0.4 mL of a 50% w/w mixture of the test substance in mineral oil (HNIC) was applied to a naïve site on the right side of each animals as a challenge dose, under the same occlusive conditions as the induction exposure. Following the 6 hour exposure period, the chambers were removed and the test site were cleansed of residual test substance. These sites were evaluated for sensitization response at approximately 24 and 48 hours after the challenged.
Challenge controls:
10 animals were maintained under identical environmental conditions and treated with the HNIC of the test substance only.
Positive control substance(s):
yes
Remarks:
75% w/w alpha-Hexylcinnamaldehyde in mineral oil
Positive control results:
4 of 9 positive control animals exhibited signs of sensitization response 24 and 48 hours after challenge. Very faint erythema (0.5) was noted for 4 other sites after challenge.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50% w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
very faint erythema (0.5) was observed in 5 animals
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50% w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Irriation persisted in one animal
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50% w/w
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
very faint erythema (0.5) was noted in 6 animals
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50% w/w
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
75%
No. with + reactions:
4
Total no. in group:
9
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
75%
No. with + reactions:
4
Total no. in group:
9
Remarks on result:
positive indication of skin sensitisation
Interpretation of results:
other: Not a skin sensitiser.
Remarks:
according to EU CLP EC No. 1272/2008 and its amendments)
Conclusions:
The substance is not a skin sensitiser In a Buehler test (OECD 406 and GLP).
Executive summary:

The substance was tested in a Buehler test (OECDTG 406, Rel. 1). The undiluted test substance was topically applied to 20 Hartley Guinea pigs, 2 times each week for a 3 week induction period. 28 days after the first induction dose, a challenge of the test substance at the highest non-irritating concentration (50% w/w in mineral oil) was applied to a naïve site on each animals. A naïve control groups (10 animals) received the challenge alone. Approximately 24 and 48 hours after each induction and challenge dose, the animals were scored for erythema. No sensitizing effects were observed in both the test animals and controls animals. The validity of these results was confirmed by a historical positive control validation study with alpha-Hexylcinnamaldehyde 75% w/w in mineral oil. Based on the results of this study the test substance is not considered to be a skin sensitizer.

Endpoint:
skin sensitisation: in vivo (non-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 information is derived from read across, the read across rationale is presented in the Endpoint summary and the accompanying files are also attached there.
Reason / purpose for cross-reference:
read-across source
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50% w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
very faint erythema (0.5) was observed in 5 animals
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50% w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Irriation persisted in one animal
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50% w/w
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
very faint erythema (0.5) was noted in 6 animals
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50% w/w
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
75%
No. with + reactions:
4
Total no. in group:
9
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
75%
No. with + reactions:
4
Total no. in group:
9
Remarks on result:
positive indication of skin sensitisation
Interpretation of results:
other: Not a skin sensitser
Remarks:
According to EU CLP (EC No. 1272/2008 and its amendments).
Conclusions:
The test substance is considered not a skin sensitiser, based on read across from Orange flower ether, which is tested in an OECD TG 406, Buehler test.
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:
no adverse effect observed (not sensitising)
Additional information:

Skin sensitisation potential of Oxaspirane is derived from Orange flower ether using read across. First the executive summary of Orange flower ether is presened below followed by the read-across rationale.

Orange flower ether and its skin sensitisation potential

The substance was tested in a Buehler test (OECDTG 406, Rel. 1). The undiluted test substance was topically applied to 20 Hartley Guinea pigs, 2 times each week for a 3 week induction period. 28 days after the first induction dose, a challenge of the test substance at the highest non-irritating concentration (50% w/w in mineral oil) was applied to a naïve site on each animals. A naïve control groups (10 animals) received the challenge alone. Approximately 24 and 48 hours after each induction and challenge dose, the animals were scored for erythema. No sensitizing effects were observed in both the test animals and controls animals. The validity of these results was confirmed by a historical positive control validation study with alpha-Hexylcinnamaldehyde 75% w/w in mineral oil. Based on the results of this study the test substance is not considered to be a skin sensitizer.

The skin sensitizing potential of Oxaspirane-819 using read across from Orange flower ether (CAS 14576-08-0)

 

Introduction and hypothesis for the analogue approach

Oxaspirane-819 consists of 3 main constituents. All three have a 2 hexyl rings touching each other at one spot. One ring contains an ether bond. All constituents have a double bond and a methyl group opposite the ether bond. The two major constituents have an internal double bond conjugated with the methyl group, while the minor one has an external double bond. For Oxaspirane-819 there are no experimental skin sensitisation data. In accordance with Article 13 of REACH, lacking information can generated by other means i.e. applying alternative methods such as QSARs, grouping and read-across. For assessing the skin sensitisation of Oxaspirane-819 the analogue approach is selected because for a related analogue, Orang Flower Ether skin sensitisation information is available which can be used for read across.

Hypothesis: Oxaspirane-819 has the same skin sensitisation potential as Orange flower ether.

Available information: Orange flower ether was negative up to 100% in a Buehler test (OECD TG 406, Rel. 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 skin sensitisation.

Purity / Impurities

The purity and impurities of the target chemical do not indicate skin sensitizing potential. Orange flower ether does not contain any impurities that are considered to impact the assessment of 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. 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:Orange flower ether was selected as an analogue because it shares a similar backbone and functional group with Oxaspirane-819 and it has reliable skin sensitisation information.

Structural similarities and differences: Oxaspirane-819‘s constituents and Orange flower ether contain a hydrocarbon backbone with at least one hexyl ring. This contains a double bond to which a methyl group is attached. Both substances have an ether bond too. The difference is that in Oxaspirane-819 part of the hydrocarbon backbone is an additional hexyl ring, while Orange flower ether has the other carbons external of the hexyl ring. Another difference is that Oxaspirane-819 has the ether bond in the ring, while Orange flower ether has it outside the ring. These differences are not considered to influence the skin sensitisation potential.

Dermal absorption: Oxaspirane-819 and Orange flower ether have a similar dermal absorption based on a very similar molecular weight and log Kow.

Skin sensitisation reactivity:The reactivity of Oxaspirane-819 and Orange flower ether both have ether as a functional group and therefore are expected to have the same reactivity.

Information on other endpoints: Oxaspirane-819 and Orange flower ether have the same skin and eye irritation potential supporting the similarity in reactivity.

Uncertainty of the prediction: There are no other uncertainties, which are not already covered above.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in Table 2.

Conclusions for hazard and risk assessment

For Oxaspirane-819 experimental skin sensitisation information is not available and therefore Orange flower ether information is used for read across.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, which is presented in the current document. For Orange flower ether is tested up to 100% in a Buehler test (OECD TG 406, Rel. 2) and was negative. This result can be used also for Oxaspirane-819.

Final conclusion on hazard and risk assessment: Oxaspriane-819 is not a skin sensitizer.

 

Data matrix to support the read across for skin sensitisation to Oxaspirane-819 from Orange flower ether

Common names

Oxaspirane-819

 

Orange flower ether

 

Target

 

Source

Constituent

1 and 2

3

 

Constituent name

4-methyl-1-oxaspiro[5.5]undec-4-ene

4-methylidene-1- oxaspiro[5.5]undecane

 

4-(1-methoxy-1-methylethyl)-1-methylcyclohexene

Chemical structures

Typical concentration (%)

30-50 and 25-45

15-35

 

CAS no

62062-89-9

62062-84-4

14576-08-0

Smiles:

CC2=CC1(CCCCC1)OCC2

C=C2CC1(CCCCC1)OCC2

COC©©C1CCC©=CC1

EC no

944-753-1

 

238-620-0

REACH registration

2018

 

Registered

Empirical formula

C11H18O

C11H18O

C11H20O

Molecular weight

166

166

168

Physico-chemical data

 

 

 

Water solubility, mg/l

24.95* (6300, measured)

21.38*

22.61*(83, measured)

Log Kow

3.99* (4.3, measured)

4.07* (4.4, measured)

4.03* (4.5, measured)

pKa

4.47

4.47

4.76

Human health

 

 

 

Skin irritation

Skin irritant Cat 2

(OECD TG 439)

 

Skin irritant Cat 2

(OECD TG 439)

Eye irritation

Not an eye irritant

(OECD TG 438)

 

Not an eye irritant

(OECD TG 405)

Skin sensitisation

Not a skin sensitiser

(Read across)

 

Not a skin sensitiser

(OECD TG 406, Buehler)

* Episuite v4.11

Justification for classification or non-classification

Based on the results, the substance does not need to be classified and labelled for skin sensitisation in accordance with Regulation (EC) No. 1272/2008 and its amendments.