Oxacycloheptadecan-2-one

Endpoint summary

Description of key information

Oxacycloheptadecan-2 -one is not sensitizing to skin.

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:

experimental study

Adequacy of study:

key study

Study period:

26 August 2009 - 08 September 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

24 April 2002

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

Commission Regulation No. 440/2008

GLP compliance:

yes (incl. QA statement)

Type of study:

mouse local lymph node assay (LLNA)

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature in the dark
- Stability under test conditions: stable
- Solubility and stability of the test substance in the solvent/vehicle: soluble in acetone/olive oil 4:1

Species:

mouse

Strain:

CBA/Ca

Remarks:

(CBA/CaOlaHsd)

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 15-23 g
- Housing: individuall in suspended solid-floor polypropylene cages furnished with softwood woodflakes
- Diet (e.g. ad libitum): 2014 Teklad Global Rodent diet, Harlan Teklad, Blackthorn, Bicester, Oxon, UK, ad libitum
- Water (e.g. ad libitum): mains tap water, ad libitum
- Acclimation period: at least 5 days
- Indication of any skin lesions: none

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 (target)
- Humidity (%): 30-70 (target)
- Air changes (per hr): ca. 15
- Photoperiod (hrs dark / hrs light): 12/12
- IN-LIFE DATES: From: 26 August 2009 To: 8 September 2009

Vehicle:

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

Concentration:

50% w/w in the prelimianry study
50%, 25% and 10% w/w in the main study

No. of animals per dose:

Preminary study: 1
Main study: 4 females/dose

Details on study design:

PRE-SCREEN TESTS:
- Irritation: no excessive local irritation
- Systemic toxicity: there were no signs of systemic toxicity during 6 days post-administration

MAIN STUDY

ANIMAL ASSIGNMENT AND TREATMENT
- Criteria used to consider a positive response: The proliferation response of lymph node cells was expressed as the number of radioactive disintegrations per minute per lymph node and as the ratio of 3HTdR incorporation into lymph node cells of test nodes relative to that recorded for the control nodes (Stimulation Index).
The test material is regarded as a sensitizer if at least one concentration of the test material results in a threefold or greater increase in 3HTdR incorporation compared to control values. Any test material feiling to produce a threefold or greater increase in 3HTdR incorporation will be classified as a non-sensitizer.

TREATMENT PREPARATION AND ADMINISTRATION: The test mateial was freshly prepared as a solution in acetone/olive oil 4:1. The mice were treated by daily application of 25 µL of the test material at a concentration of 50%, 25% and 10% of the test material to the dorsal surface of each ear for three consecutive days. The test material forulation was administered using an automatic micropipette and spread over the dorsal surface of the ear using the tip of the pipette.
A further group of four mice received the vehicle alone in the same manner.

Positive control substance(s):

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

Statistics:

Not applied.

Positive control results:

Hexyl cinamic aldehyde produced SI of 8.34 at 15% (v/v) in acetone/olive oil (project number 0039/1080, study dates 24 April 2009-30 April 2009).

Key result

Parameter:

SI

Value:

1.34

Test group / Remarks:

10% cyclohexadecanone

Key result

Parameter:

SI

Value:

1.92

Test group / Remarks:

25% cyclohexadecanone

Key result

Parameter:

SI

Value:

2.56

Test group / Remarks:

50%

Cellular proliferation data / Observations:

CELLULAR PROLIFERATION DATA:
DPM:
Vehicle 15727.81
10% cyclohexadecanone: 20996.87
25% cyclohexadecanone: 30196.62
50% cyclohexadecanone: 40312.02

DETAILS ON STIMULATION INDEX CALCULATION
DPM/Node:
Vehicle: 1965.98
10% cyclohexadecanone: 2624.61
25% cyclohexadecanone: 3774.58
50% cyclohexadecanone: 5039.00

CLINICAL OBSERVATIONS:
There were no clinical signs noted.

BODY WEIGHTS
There were no mortalities.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the reliable OECD 429 guideline study performed with 50%, 25% and 10% test substance in acetone/olive oil (4:1 v/v), oxacyclohexadecan-2-one is not sensitizing to skin.

Executive summary:

In the GLP-compliant OECD 429 guideline study, oxacyclohexadecan-2 -one at concentrations 10%, 25% and 50% was found to be not sensitizing to skin . The Stimulation Indices were 1.34, 1.92 and 2.56 for 10%, 25% and 50% solutions, respectively. No mortalities occurred and no clinical signs were noted. The potisive control hexyl cinnamic aldehyde produced a Stimulation Index 8.34 at 15% in acetone/olive oil (4:1 v/v). Based on these results, classification of oxacyclohexadecan-2-one for skin sensitization is not warranted.

Reference 2

Endpoint:

skin sensitisation: in vivo (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 oxacyclohexadecan-2-one and the target chemical oxacycloheptadecan-2-one are structural homologues of each other, with the only difference between the two being one additional carbon atom in the cyclic aliphatic chain (C15 and C16, respectively). Considering a very long aliphatic chain in both substances, the presence of additional carbon atom (CH2 moiety) in oxacycloheptadecan-2-one is not expected to influence its toxicological properties in comparison to oxacyclohexadecan-2-one. Therefore read-across from oxacyclohexadecan-2-one to oxacycloheptadecan-2-one 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 oxacyclohexadecan-2-one and the target chemical oxacycloheptadecan-2-one are structural homologues of each other, with the only difference between the two being one additional carbon atom in the cyclic aliphatic chain (C15 and C16, respectively). Considering a very long aliphatic chain in both substances, the presence of additional carbon atom (CH2 moiety) in oxacycloheptadecan-2-one is not expected to influence its toxicological properties in comparison to oxacyclohexadecan-2-one. This is confirmed by the available data on both substances (see data matrix) which confirm nearly identical physico-chemical and (eco)toxicological properties for all endpoints. There are no additional functional groups present in oxacyclohexadecan-2-one 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 oxacyclohexadecan-2-one to oxacycloheptadecan-2-one is considered to be justified.

4. DATA MATRIX (data on oxacyclohexadecan-2-one taken from its dissiminated REACH dossier available on the ECHA website):

Substance Oxacycloheptadecan-2-one Oxacyclohexadecan-2-one
Molecular formula C16H30O2 C15H28O2
Molecular weight 254.4 240.38 g/mol
Melting point 35 °C 34.6 °C
Boiling point 265-275 °C 325 °C
Water solubility 0.103 mg/L 0.34 mg/L
Log Pow 7.3 5.79
Vapour pressure <= 0.053 Pa at 25 °C 0.085 Pa at 25 °C
Acute oral toxicity LD50 > 5000 mg/kg bw LD50 > 5000 mg/kg bw
Acute dermal toxicity LD50 > 5000 mg/kg bw LD50 > 5000 mg/kg bw
Skin irritation Read-across Not irritating
Eye irritation Not irritating Not irritating
Skin sensitization Read-across Not sensitizing
Repeated dose toxicity NOAEL > 1000 mg/kg bw/day NOAEL > 1000 mg/kg bw/day
Reproductive toxicity NOAEL > 1000 mg/kg bw/day NOAEL > 1000 mg/kg bw/day
Developmental toxicity NOAEL > 1000 mg/kg bw/day NOAEL > 1000 mg/kg bw/day
Toxicity to fish 96-h LC50 > solubility limit EC50 > solubility limit
Toxicity to daphnia Read-across 48-h EC50 > 0.17 mg/L
Toxicity to algae 72-h ErC50 > 0.004 mg/L 72h ErC50 > 0.47 mg, 72h ErC10 = 0.42 mg/L

Reason / purpose for cross-reference:

read-across source

Positive control results:

Hexyl cinamic aldehyde produced SI of 8.34 at 15% (v/v) in acetone/olive oil (project number 0039/1080, study dates 24 April 2009-30 April 2009).

Key result

Parameter:

SI

Value:

1.34

Test group / Remarks:

10% cyclohexadecanone

Key result

Parameter:

SI

Value:

1.92

Test group / Remarks:

25% cyclohexadecanone

Key result

Parameter:

SI

Value:

2.56

Test group / Remarks:

50%

Cellular proliferation data / Observations:

CELLULAR PROLIFERATION DATA:
DPM:
Vehicle 15727.81
10% cyclohexadecanone: 20996.87
25% cyclohexadecanone: 30196.62
50% cyclohexadecanone: 40312.02

DETAILS ON STIMULATION INDEX CALCULATION
DPM/Node:
Vehicle: 1965.98
10% cyclohexadecanone: 2624.61
25% cyclohexadecanone: 3774.58
50% cyclohexadecanone: 5039.00

CLINICAL OBSERVATIONS:
There were no clinical signs noted.

BODY WEIGHTS
There were no mortalities.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the reliable OECD 429 guideline study performed with 50%, 25% and 10% read-across substance oxacyclohexadecan-2-one in acetone/olive oil (4:1 v/v), cyclohexanone is not sensitizing to skin. These results can be read across to oxacycloheptadecan-2-one.

Executive summary:

In the GLP-compliant OECD 429 guideline study, an analogue read-across substance oxacyclohexadecan-2-one at concentrations 10%, 25% and 50% was found to be not sensitizing to skin . The Stimulation Indices were 1.34, 1.92 and 2.56 for 10%, 25% and 50% solutions, respectively. No mortalities occurred and no clinical signs were noted. The potisive control hexyl cinnamic aldehyde produced a Stimulation Index 8.34 at 15% in acetone/olive oil (4:1 v/v). Based on these results, classification of oxacyclohexadecan-2one for skin sensitization is not warranted. These results can be read across to oxacycloheptadecan-2-one.

Reference 3

Endpoint:

skin sensitisation, other

Remarks:

Human patch test

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1972

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: As there is no proof of proper induction, the absence of sensitisation in human volunteers is not sufficient to conclude that the test substance does not have sensitising properties.

Qualifier:

equivalent or similar to guideline

Guideline:

other: repeated insult method as approved by the Food and Drug Administration

Version / remarks:

(Draize Technique)

GLP compliance:

no

Type of study:

patch test

Justification for non-LLNA method:

The reported data are based on a historical data set.

Route:

epicutaneous, occlusive

Vehicle:

other: dimethyl phtalate

Concentration / amount:

2% solution/ 0.5mL

Day(s)/duration:

appr. 3 weeks, new patches were applied for 10 times

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

other: dimethyl phtalate

Concentration / amount:

2% solution/ 0.5mL

Day(s)/duration:

7 days

Adequacy of challenge:

not specified

No. of animals per dose:

54 human volunteers (43 females, 11 males)

Details on study design:

The test substance was tested as 2.0% solution in dimethyl phtalate. The test substance was applied repeatedly to the skin of healthy volunteers in a closed patch test with 0.5ml of the solution per patch. The patches were applied to the area to be tested in a definite fixed sequence, identical at each testing. The patches were secured by means of overlying strips of impervious adhesive tape which were then further occluded with additional overlying strips of similar tape. The patches were allowed to remain in situ for 48 hours and were then removed, at which time readings were recorded. Following the removal of these tests, identical, similarly prepared patches were then applied to the next area in the identical sequence with the identical occlusive precautions. Only after first exposure the patcehs were removed after 24 hours to assess skin effects, and over the weekend patches were not removed for 72 hours. Total number of patches applied was 10. Initial (and third, etc.) site: inner surface of right deltoid area; Second (and fourth, etc.) site: inner surface of left deltoid area. After the last patch was removed, no patches were applied for 10 days (incubation period). After this period, the individuals were challenged by similar patch application, except that tests were applied in duplicate (one patch for each deltoid). These patches were removed after 48 hours and after 48, and 72 hours and after 1 week readings were recorded. During this period, the exposed skin was protected by a loosely applied cover of plain sterile gauze.
Prior to the application of each test series, including the challenge tests, the application site was cleansed with an ether-acetone mixture.

Positive control substance(s):

not specified

Key result

Hours after challenge:

48

Group:

test chemical

Dose level:

2%

No. with + reactions:

0

Total no. in group:

54

Clinical observations:

None

Remarks on result:

no indication of skin sensitisation

No skin reactions were observed at 48 and 72 hours, or one week after start of the challenge.

Interpretation of results:

study cannot be used for classification

Conclusions:

A human patch test was conducted with 54 volunteers who were exposed repeatedly during three weeks to patches with 0.5mL GIV 2-2701 (hexadecanolide) as 2% solution in dimethyl phtalate. Ten days after removal of final patch, the volunteers were challenged by application of two patches with test substance in the same ocncentration. No skin reaction ndicating sensitisation were observed in any of the volunteers at 48 and 72 hours, or one week after start of the challenge. No skin effects were seen at any time point of the study. Based on this data, it cannot be concluded whether proper sensitisation took place. Therefore no conclusions can be drawn on skin senstising potential of GIV 2-2701 based on these data.

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:

no adverse effect observed (not sensitising)

Additional information:

In the GLP-compliant OECD 429 guideline study, an analogue read-across substance oxacyclohexadecan-2-one at concentrations 10%, 25% and 50% was found to be not sensitizing to skin. The read-across source chemical oxacyclohexadecan-2-one and the target chemical oxacycloheptadecan-2-one are structural homologues of each other, with the only difference between the two being one additional carbon atom in the cyclic aliphatic chain (C15 and C16, respectively). Considering a very long aliphatic chain in both substances, the presence of additional carbon atom (CH2 moiety) in oxacycloheptadecan-2-one is not expected to influence its toxicological properties in comparison to oxacyclohexadecan-2-one. Therefore read-across from oxacyclohexadecan-2-one to oxacycloheptadecanone is considered to be justified.

The Stimulation Indices were 1.34, 1.92 and 2.56 for 10%, 25% and 50% solutions, respectively. No mortalities occurred and no clinical signs were noted. The potisive control hexyl cinnamic aldehyde produced a Stimulation Index 8.34 at 15% in acetone/olive oil (4:1 v/v). Based on these results, classification of oxacyclohexadecan-2one for skin sensitization is not warranted. These results can be read across to oxacycloheptadecan-2-one.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

No study on respiratory sensitization is available for oxacycloheptadecan-2-one. 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 oxacycloheptadecan-2-one, oxacyclohexadecan-2-one, no classification for skin sensitization is warranted according to Regulation (EC) 1272/2008.