Cyclopentadecanone

Endpoint summary

Description of key information

Cyclopentadecanone is not irritating to skin and eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin corrosion: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

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

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 February 2001-16 February 2001

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

Official Journal of the European Union No. L 383 A, p. 124 - 127 of December 29, 1992

Deviations:

yes

Remarks:

Observation period 72 hours, occlusive dressing

GLP compliance:

yes (incl. QA statement)

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
- Solubility and stability of the test substance in the solvent/vehicle: unsoluble in water

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test item was administered as the original substance alter crushing with a pestle and mortar to a fine dust moistened using a mixture of ethanol*/diethylphthalate* 1:1 (v/v) (as ED abbreviated in the following text) or as solutions with fixed concentrations in this mixture.

Species:

rabbit

Strain:

New Zealand White

Remarks:

Crl:NZW

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, D-97320 Sulzfeld, Germany
- Weight at study initiation: 2720, 2465, 2615 and 2626 g (average 2607 g)
- Housing: Cages of stainless steel with bottom grid of oval steel and with tub for faeces, dimensions of the cages: 50 x 55 x 40 cm
- Diet (e.g. ad libitum): ALTROMIN 2123, standard diet for rabbits ad libitum (ALTROMEN, D-32791 Lage/Lippe)
- Water (e.g. ad libitum): tap water, ad libitum (municipal supply), Makrolon® b ottles, changed daily
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5-22.5
- Humidity (%): 30-40
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: February 12, 2001 To: February 16, 2001

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

other: ethanol / diethylphthalate 1:1 (v/v)

Controls:

yes, concurrent no treatment

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g crushed material moistened using a mixture of ethanol/diethylphthalate or 0.5 mL of a 50, 25 and 10% (w/v) solution in a mixture of ethanol/diethylphthalate (1:1 v/v)
- Concentration (if solution): solid material, 50, 25 and 10%

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5 mL

Duration of treatment / exposure:

4 hours

Observation period:

60 minutes, 24, 48 and 72 hours post patch removal

Number of animals:

4 (four different concentrations were applied to the trunk of each of the four animals)

Details on study design:

TEST SITE
- Area of exposure: approx. 2 x 3 cm
- % coverage: 100
- Type of wrap if used: occlusive dressing (Lohmann GmbH & Co., Neuwied)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with a mixture of ethanol/diethylphthalate 1:1 (v/v)
- Time after start of exposure: 4 hours

OBSERVATION TIME POINTS
(indicate if minutes, hours or days) 60 minuts, 24, 48 and 72 hours

SCORING SYSTEM: Draize

Irritation parameter:

erythema score

Remarks:

pure test substance, 50%, 25% and 10% solutions

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no skin effects were observed

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Remarks:

pure test suibstance, 50%, 25% and 10% solutions

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no skin reactions were noted

Irritant / corrosive response data:

All skin areas, treated with the moistened original test item or with solutions of the test item in three concentrations (50, 25 and 10 %) and also the control skin areas (untreated and treated with ethanol/diethylphthalate), did not show any alterations at any observation time.

Other effects:

No animal died during the course of investigation and no clinical signs were observed.
Necropsy was not carried out, because no clinical signs were observed.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the reliable guildeine study with 4 rabbits, the test substance cyclohexadecanone was not irritating to rabbit skin.

Executive summary:

In the GLP-compliant study performed according to the EU B.4 method the test substance cyclohexadecanone was not irritating to rabbit skin, when administered as a pure substance and 10%, 25% and 50% solution in ethanol/diethylphthalate (1:1) v/v for 4 hours to 4 rabbits under occlusive dressing. Animals were observed for 60 minutes, 24, 48 and 72 hours. No skin reactions were noted in any animal at any time point. Based on the results of the study, the test substance cyclohexadecanone is considered to be not irritating to skin.

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

12 February 2001-16 February 2001

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 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.

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 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. This is confirmed by the data matrix that shows comparable properties for both substances across all endpoints. There are no additional functional groups present in cyclohexadecanone which may influence its skin irritating 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 file 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

Irritation parameter:

erythema score

Remarks:

pure test substance, 50%, 25% and 10% solutions

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no skin effects were observed

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Remarks:

pure test suibstance, 50%, 25% and 10% solutions

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no skin reactions were noted

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the reliable guildeine study with 4 rabbits with a read-across analogue cyclohexadecanone, the test substance was not irritating to rabbit skin. These results can be read across to cyclopentadecanone.

Executive summary:

In the GLP-compliant study performed according to the EU B.4 method the analogue substance cyclohexadecanone was not irritating to rabbit skin, when administered as a pure substance and 10%, 25% and 50% solution in ethanol/diethylphthalate (1:1) v/v for 4 hours to 4 rabbits under occlusive dressing. Animals were observed for 60 minutes, 24, 48 and 72 hours. No skin reactions were noted in any animal at any time point. Based on the results of the study, the test substance cyclohexadecanone is considered to be not irritating to skin. These results can be read across to cyclopentadecanone.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

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

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

May 12, 1981

Deviations:

yes

Remarks:

Observation period 72 hours

Qualifier:

according to guideline

Guideline:

other: EWG Directive 84/449/EWG, Amtsblatt der Europaeischen Gemeinschaften L 251, Jahrgang 27, 19.9.84 B.5 . Akute Toxizitaet - Augenreizung / 109

GLP compliance:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 6002

Species:

rabbit

Strain:

New Zealand White

Remarks:

KFM (SPF-quality)

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH 4414 Fuellinsdorf, Switzerland
- Age at study initiation: 15-16 weeks
- Weight at study initiation: 2.4-2.8 kg
- Housing: individually in stainless steel cages equipped with an automatic cleaning and drinking system (Dipl. Ing. W. Ehret GmbH).
- Diet (e.g. ad libitum): pelleted standard Kliba 341, batch 14/B6 rabbit maintenance diet ("Kliba", Klingentalmuehle AG, 4303 Keiseraugst, Switzerland), ad libitum
- Water (e.g. ad libitum): community tap water from Itingen, ad libitum
- Acclimation period: three days under laboratory conditions after veterinary examination

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: April 14, 1986 To: April 17, 1986

Vehicle:

not specified

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g
- Concentration (if solution): 100% (pure substance) or 30% dilution

Duration of treatment / exposure:

Single instillation

Observation period (in vivo):

1, 24, 48 and 72 hours post-administration

Number of animals or in vitro replicates:

3 (2 males, 1 female)

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not performed

SCORING SYSTEM: Draize

Irritation parameter:

cornea opacity score

Remarks:

100% pure substance

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no corneal effects observed in any animal at any time point

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Remarks:

100% pure substance

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: no effects on iris observed in any animal at any time point

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

100% pure substance

Basis:

mean

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 h

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Remarks:

100% pure substance

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 24 hours post-instillation

Remarks on result:

probability of weak irritation

Irritation parameter:

cornea opacity score

Remarks:

30% dilution

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no corneal effects noted in any animal at any time point

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Remarks:

30% dilution

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: no iris effects observed in any animal at any time point

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

30% dilution

Basis:

mean

Time point:

24/48/72 h

Score:

0.11

Max. score:

3

Reversibility:

fully reversible within: 48 hours post-instillation

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effects observed in any animal at any time point

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

100% pure substance:
After 1 hour, erythema (general, severe in one animal) and ventral edema (slight in one animal) of the conjunctiva was observed in all three rabbits. Severe discharge and erythema of the sclera (slight in one animal) were observed in all animals. Furthermore, test article remains, partly white mass, were observed in one out of three animals.
After 24 hours, conjunctival and scleral erythema were observed in all animals.
After 48 and 72 hours, no abnormal changes were noted in any animal.

30% dilution:
After 1 hour, ventral conjunctival erythema was observed in 2 out of 3 animals. Furthermore, test article remains, ventral erythema of the sclera and slight discharge were observed in 1 out of 3 animals.
After 24 hours, slight, hardly perceptible erythema of conjunctivae and ventral erythema of the sclera, as well as test article remains were noted in one out of three animals.
After 48 and 72 hours, no abnormal changes were noted in any animal.

Other effects:

- Lesions and clinical observations: in the area of application no discoloration of the cornea and conjunctivae was observed which could be related to the color to the test article.
- Other observations: the body weight gain of all rabbits was similar. Due to the results obtained, no macroscopic organ examination was indicated.

Interpretation of results:

GHS criteria not met

Conclusions:

In the reliable guideline study with rabbits, cyclopentadecanone administered as a pure substance and at 30% dilution was not irritating to rabbit eyes.

Executive summary:

In a reliable study performed according to OECD Guideline 405, 0.1 g cyclopentadecanone was instilled into eyes of three rabbits either as a pure substance or at 30% dilution. The average scores over 24, 48 ad 72 hours in case of pure substance were 0 for corneal opacity, 0 for iritis, 0.33 for conjunctival erythema and 0 for chemosis. In case of 30% dilution, the average scores over 24, 48 and 72 hours were 0 for corneal opacity, 0 for iritis, 0.11 for conjunctival erythema and 0 for chemosis. All observed effects were fully reversible within max. 48 hours. Based on these results, classification of cyclopentadecanone for eye irritation is not required.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

For skin irritation, an in vivo study with New Zealand White rabbits, performed according to the EU Method B.4, was available for a structural analogue of cyclopentadecanone, cyclohexadecanone. 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. The test substance cyclohexadecanone was not irritating to rabbit skin, when administered as a pure substance and 10%, 25% and 50% solution in ethanol/diethylphthalate (1:1) v/v for 4 hours to 4 rabbits under occlusive dressing. Animals were observed for 60 minutes, 24, 48 and 72 hours. No skin reactions were noted in any animal at any time point. Based on this cyclohexadecanone and respectively its structural analogue cyclopentadecanone are considered to be not irritating to skin.

In an in vivo eye irritation study performed with cyclopentadecanone, performed according to OECD guideline 405, erythema and ventral edema of the conjunctiva were observed in all three rabbits one hour post-instillation. Severe discharge and erythema of the sclera (slight in one animal) were observed in all animals. Furthermore, test article remains, partly white mass, were observed in one out of three animals.

After 24 hours, conjunctival and scleral erythema were observed in all animals. After 48 and 72 hours, no abnormal changes were noted in any animal. Based on this, cyclopentadecanone was considered to be not irritating to rabbit eyes.

Justification for classification or non-classification

Based on the results of an in vivo skin irritation study with a structural analogue of cyclopentadecanone, cyclohexadecanone, and an in vivo eye irritation study with cyclopentadecanone, classification for skin and eye irritation is not warranted according to Regulation (EC) 1272/2008.