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Diss Factsheets

Administrative data

Description of key information

Cyclopentadecanone is not sensitizing to skin.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12 February 2001 - 16 March 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
Official Journal of the European Union No. L 248, p. 206 - 211 of September 30, 1996
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was performed in 2001, i.e. before LLNA was officially considered as a preferred testing method.
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: stable
Species:
guinea pig
Strain:
Dunkin-Hartley
Remarks:
Crl:(HA)BR
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, D-97320 Sulzfeld
- Microbiological status of animals, when known: SPF
- Age at study initiation: approximately 18 days at the start of acclimatization
- Weight at study initiation: 271.2 ± 18.3 g (n = 30)
- Housing: The animals were housed under semi-barrier conditions up to 5 to a cage (Makroion® T ype 4)
- Diet (e.g. ad libitum): ALTROMIN 1322, standard diet for guinea pigs, ad libitum (ALTROMIN, D-32791 Lage/Lippe)
- Water (e.g. ad libitum): tap water, ad libitum (municipal supply), Makrolon® b ottles, changed daily
- Acclimation period: 13 days before administration (main study)
- Indication of any skin lesions: none

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24
- Humidity (%): 30 - 60 %%, with a short falling below to 20 %
- Photoperiod (hrs dark / hrs light): 12/12
- IN-LIFE DATES: From: 19 February 2001 To: 16 March 2001 (main study)
Route:
intradermal
Vehicle:
arachis oil
Concentration / amount:
5%
Day(s)/duration:
Day 0
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol/diethylphthalate (1:1 v/v)
Concentration / amount:
25% (w/v), 0.5 mL per flank
Day(s)/duration:
7
Adequacy of induction:
non-irritant substance, but skin pre-treated with 10% SDS
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol/diethylphthalate (1:1 v/v)
Concentration / amount:
25%; 0.5 mL per flank
Day(s)/duration:
21
Adequacy of challenge:
not specified
No. of animals per dose:
20/dose group, 10/control group
Details on study design:
RANGE FINDING TESTS:
Intracutaneous tolerance test:
Twenty four hours after preparation of the animals 4 pairs of the following intracutaneous injections of 0.1 ml volume were given to both animals in the shoulder region so that one of each pair lies on each side of the midline in cranial to caudal sequence.
Injection 1: 5 % (w/v) solution of the test item in AO
Injection 2: 3 % (w/v) solution of the test item in AO
Injection 3: 2 % (w/v) solution of the test item in AO
Injection 4: 1 % (w/v) solution of the test item in AO

Epicutaneous tolerance test:
Twenty four hours after preparation of the animals two layers of filter paper (2 x 4 cm) were loaded with 0.5 ml of the test item formulations and applied to the test areas.
Area 1 (left flank): 25 % (w/v) solution of the test item in ED
Area 2 (left shoulder): 10 % (w/v) solution of the test item in ED
Area 3 (right shoulder): 5 % (w/v) solution of the test item in ED
Area 4 (right flank): 1 % (w/v) solution of the test item in ED
The papers were covered with film and held in contact with the skin by occlusive dressing (Lohmann GmbH & Co., Neuwied). After 24 hours the patches were removed and the administration areas were rinsed with ED.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 1 intradermal, 1 epicutaneous
- Exposure period: 48 hours for epicutaneous induction
- Test groups: 20 animals/group
- Control group: 10 animals/group
- Site:
Intradermal:
Three pairs of intracutaneous injections of 0.1 ml volume were given to each animal in the shoulder region so that one of each pair lay on each side of the midline in cranial to caudal sequence.
Dose group:
Injection 1: mixture of water for injections and Freund' s Complete Adjuvant (FCA) (1:1, v/v)
Injection 2: 5 % (w/v) solution of the test item in arachis oil
Injection 3: 5 % (w/v) Suspension of the test item in FCA/water (1:1, v/v)
Control group:
Injection 1: mixture of water and FCA (1:1, v/v)
Injection 2: arachis oil
Injection 3: 50 % mixture (w/v) of arachis oil in a mixture of water and FCA (1:1, v/v)

Epicutaneous:
Dose group:
Two layers of filter paper (2 x 4 cm) were loaded with 0.5 ml of the 25 % (w/v) solution of the test item in ED. One patch each was then placed on the skin of both sides of the body.
Control group:
Two layers of filter paper (2 x 4 cm) were soaked with 0.5 ml of ED. One patch each was then placed an the skin of both sides of the body.
In both groups the papers were covered with film and held in contact with the skin by occlusive dressing (Lohmann GmbH & Co., Neuwied). After 48 hours the patches were removed and the administration areas were rinsed with ED.

- Frequency of applications: 1 intradermal (3 injections), 1 epicutaneous
- Duration: 48 hours for epicutaneous application
- Concentrations: 5% in arachis oil for intradermal induction, 25% in ethanol/diethylphthalate (1:1 v/v)

B. CHALLENGE EXPOSURE
- No. of exposures: one
- Day(s) of challenge: 21
- Exposure period: 24 hours
- Test groups: 20 animals
- Control group: 10 animals
- Site: right flank
- Concentrations: 25% in ethanol/diethylphthalate (1:1 v/v)
- Evaluation (hr after challenge): 24 and 48 hours after patch removal
Challenge controls:
Strips of gauze patch were loaded with 0.5 ml of the 25 % (w/v) solution of the test item in ethanol/diethylphthalate (1:1 v/v) and applied to the right flank of all animals. Other strips of gauze patch were soaked with 0.5 ml of ethanol/diethylphthalate (1:1 v/v) and applied to the left flank of all animals.
Positive control substance(s):
yes
Remarks:
Benzocaine at the same experimental conditions.
Positive control results:
The following dosing scheme was used:
Intracutaneous induction day 0: 2% benzocaine aqueous solution
Epicutaneous induction day 7: 25 % suspension in liquid paraffin
Challenge day 21: 10 % suspension in liquid paraffin
The epicutaneous administration of the 10 % suspension of Benzocaine in liquid paraffin caused a slight to moderate erythema (grade 1-2) in all animals of the dose group on day 23. In 9 of 10 animals these irritating signs were also observed on day 24.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25% in ethanol/diethylphthalate (1:1 v/v)
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:
25% in ethanol/diethylphthalate (1:1 v/v)
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25% in ethanol/diethylphthalate (1:1)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
25% in ethanol/diethylphthalate (1:1 v/v)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
10% benzocaine in liquid paraffin
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
The epicutaneous administration of the 10 % suspension of Benzocaine in liquid paraffin caused a slight to moderate erythema (grade 1-2) in all animals of the dose group on day 23.
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
10% benzocaine in liquid paraffin
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
Slight to moderate erythema was observed in 9 animals on day 24
Remarks on result:
positive indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Conclusions:
In the study performed according to OECD guideline 406 (guinea pig maximization test), the test substance cyclohexadecanone was not sensitizing to skin.
Executive summary:

In a reliable study, performed according to OECD guideline 406 (guinea pig maximization test) the test substance cyclohexadecanone was not sensitizing following intradermal induction with 5% in arachis oil and epicutaneous induction with 25% in ethanol/diethylphthalate (1:1 v/v). No skin reactions were observed in any of 20 test animals following epicutaneous challenge with 25% test substance in ethanol/diethylphthalate (1:1 v/v). Positive control benzocaine produced satisfactory positive response (10/10 animals exibiting slight to moderate erythema following challenge with 10% in liquid paraffin). Based on the results of the study, cyclohexadecanone is not considered to be sensitizing to skin.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across source chemical cyclohexadecanone and the target chemical cyclopentadecanone are structural homologues of each other, with the only difference between the two being one additional carbon atom in the cyclic aliphatic chain (C16 and C16, respectively). Considering a very long aliphatic chain in both substances, the presence of additional carbon atom (CH2 moiety) in cyclohexadecanone is not expected to influence its toxicological properties in comparison to cyclopentadecanone. Therefore read-across from cyclohexadecanone to cyclopentadecanone is considered to be justified.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both substances are mono-constituent substances of high purity (details on purity are provided in the confidential sections of the robust study summaries) and do not contain toxicologically relevant impurities which could influence their toxicological behavior.

3. ANALOGUE APPROACH JUSTIFICATION
The read-across source chemical cyclohexadecanone and the target chemical cyclopentadecanone are structural homologues of each other, with the only difference between the two being one additional carbon atom in the cyclic aliphatic chain (C16 and C16, respectively). Considering a very long aliphatic chain in both substances, the presence of additional carbon atom (CH2 moiety) in cyclohexadecanone is not expected to influence its toxicological properties in comparison to cyclopentadecanone. This is confirmed by the data matrix which shows comparable properties of both substances across all endpoints. There are no additional functional groups present in cyclohexadecanone which may influence its binding to skin proteins and subsequently its skin sensitizing properties. Both substances have comparable physico-chemical properties, i.e. high log Pow (> 4) and poor water solubility (< 1 mg/L), thus their ability to penetrate the skin is expected to be comparable. Therefore read-across from cyclohexadecanone to cyclopentadecanone is considered to be justified.

4. DATA MATRIX (data on cyclohexadecanone taken from the disseminated REACH dossier available on the ECHA website)
Substance Cyclopentadecanone Cyclohexadecanone
Molecular formula C15H28O C16H30O
Molecular weight 224.38 238.41
Melting point 61 °C 67.4 °C
Boiling point 246 °C 339-341 °C
Water solubility 0.578 mg/L <1 mg/L
Log Pow 3.3-5.9 6.4
Vapour pressure < 0.63 Pa at 25 °C. 0.008 Pa at 20 °C
Acute oral toxicity LD50 > 5000 mg/kg bw LD50 > 2000 mg/kg bw
Acute dermal toxicity LD50 > 5000 mg/kg bw LD50 > 2000 mg/kg bw
Skin irritation Read-across Not irritating
Eye irritation Not irritating Not irritating
Skin sensitization Read-across Not sensitizing
Repeated dose toxicity LOAEL = 100 mg/kg bw/day NOAEL > 1000 mg/kg bw/day
Reproductive toxicity NOAEL > 1000 mg/kg bw/day No data available
Developmental toxicity NOAEL > 1000 mg/kg bw/day No data available
Toxicity to fish 96-h LC50 0.17 mg/L 96-h NOEC 0.1 mg/L
Toxicity to daphnia 48-h EC50 0.18 mg/L 48-h NOEC 0.19 mg/L
Toxicity to algae 72-h NOEC 0.17 mg/L 72-h NOEC >= 0.18 mg/L
Reason / purpose for cross-reference:
read-across source
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25% in ethanol/diethylphthalate (1:1 v/v)
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:
25% in ethanol/diethylphthalate (1:1 v/v)
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25% in ethanol/diethylphthalate (1:1)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
25% in ethanol/diethylphthalate (1:1 v/v)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
10% benzocaine in liquid paraffin
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
The epicutaneous administration of the 10 % suspension of Benzocaine in liquid paraffin caused a slight to moderate erythema (grade 1-2) in all animals of the dose group on day 23.
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
10% benzocaine in liquid paraffin
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
Slight to moderate erythema was observed in 9 animals on day 24
Remarks on result:
positive indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Conclusions:
In the study performed according to OECD guideline 406 (guinea pig maximization test), the analogue test substance cyclohexadecanone was not sensitizing to skin. This result can be read across to cyclopentadecanone.
Executive summary:

In the reliable study, performed according to OECD guideline 406 (guinea pig maximization test) the analogue test substance cyclohexadecanone was not sensitizing following intradermal induction with 5% in arachis oil and epicutaneous induction with 25% in ethanol/diethylphthalate (1:1 v/v). No skin reactions were observed in any of 20 test animals following epicutaneous challenge with 25% test substance in ethanol/diethylphthalate (1:1 v/v). Positive control benzocaine produced satisfactory positive response (10/10 animals exibiting slight to moderate erythema following challenge with 10% in liquid paraffin). Based on the results of the study, cyclohexadecanone is not considered to be sensitizing to skin. This result can be read across to cyclopentadecanone.

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

A reliable in vivo skin sensitization study performed according to OECD guideline 406 (guinea pig maximization test)

was available with a structural analogue of cyclopentadecanone, cyclohexadenone.

The read-across source chemical cyclohexadecanone and the target chemical cyclopentadecanone are structural homologues of each other, with the only difference between the two being one additional carbon atom in the cyclic aliphatic chain (C16 and C15, respectively). Considering a very long aliphatic chain in both substances, the presence of additional carbon atom (CH2 moiety) in cyclohexadecanone is not expected to influence its toxicological properties in comparison to cyclopentadecanone. Therefore read-across from cyclohexadecanone to cyclopentadecanone is considered to be justified.

Cyclohexadecanone was not sensitizing following intradermal induction with 5% in arachis oil and epicutaneous induction with 25% in ethanol/diethylphthalate (1:1 v/v). No skin reactions were observed in any of 20 test animals following epicutaneous challenge with 25% test substance in ethanol/diethylphthalate (1:1 v/v). Positive control benzocaine produced satisfactory positive response (10/10 animals exibiting slight to moderate erythema following challenge with 10% in liquid paraffin). Based on the results of the study, cyclohexadecanone is not considered to be sensitizing to skin. This conclusion can be read across to cyclopentadecanone.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

No study on respiratory sensitization is available for cyclopentadecanone. However, considering that the substance is not sensitizing to skin and its very low volatility, the substance is not expected to be a respiratory sensitizer.

Justification for classification or non-classification

Based on the results of a reliable in vivo study with a structural analogue of cyclopentadecanone, cyclohexadecanone, no classification for skin sensitization is warranted according to Regulation (EC) 1272/2008.