Decan-4-olide

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

From 2002-04-26 to 2002-09-20

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study conducted similarly to OECD test guideline No. 406 although not mentioned in the report. γ-Caprolactone, as aliphatic γ-lactone, is considered adequate for read-across purpose (see §"Toxicokinetics").

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes (incl. QA statement)

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

At the time of study completion (2002), the LLNA OECD test method was not adopted.

Species:

guinea pig

Strain:

Hartley

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Japan SLC, Inc.
- Age at study initiation: 5 weeks old
- Weight at study initiation: 297 to 328 g (preliminary study), 276 to 345 g (main study)
- Housing: 5 amimals / cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/-2
- Humidity (%): 50+/-10
- Air changes (per hr): 17 times/hr
- Photoperiod (hrs dark / hrs light): 12 hr/12 hr

IN-LIFE DATES: From: 2002-05-07 To: 2002-06-13

Route:

intradermal and epicutaneous

Vehicle:

physiological saline

Concentration / amount:

Intradermal induction: 3.08% (Act. 3%).
Epicutaneous induction: undiluted (Act. 97.4%).
Challenge: undiluted (Act. 97.4%), 51.33% (Act. 50%), 30.80% (Act. 30%), 10.27% (Act. 10%), 5.13% (Act. 5%), 3.08% (Act.3%).

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Concentration / amount:

Intradermal induction: 3.08% (Act. 3%).
Epicutaneous induction: undiluted (Act. 97.4%).
Challenge: undiluted (Act. 97.4%), 51.33% (Act. 50%), 30.80% (Act. 30%), 10.27% (Act. 10%), 5.13% (Act. 5%), 3.08% (Act.3%).

No. of animals per dose:

5 females for intradermal treatment in preliminary study.
5 females for epicutaneous (occlusive) treatment in preliminary study.
10 females for treatment group in main study.
10 females for control group in main study.

Details on study design:

PRELIMINARY STUDY
A. Topical application
Irritation assessment following 24h occlusive exposure to test material at 97.4, 50, 30, 10, 5 and 3% (Act.%); skin assessment 3, 24 and 48h after
removal of test substance.
Result: No skin irritation was observed in any concentration tested.

B. Intradermal
0.1 mL of test substance at 10, 5, 3, 1, 0.5, 0.3% (w/w) solution applied intradermally in physiological saline. Assessments was made 24, 48 and 72h post‐administration.
Result: necrosis was observed by 10 and 5% solution. Clear or slight erythema was observed by 3% solution, and this continued up to 72 hr. Slight erythema was observed by 1% solution, but disappeared within 72 hr. No skin reactions were observed by 0.5, 0.3 and 0% solutions.

MAIN STUDY
A. INDUCTION EXPOSURE
Day 0: Treatment group:
− Injection 1: 1:1 mixture (v/v) FCA/physiological saline
− Injection 2: 3% gamma-caprolactone in physiological saline
− Injection 3: 3% gamma-caprolactone in a 1:1 mixture (v/v) FCA/physiological saline
Control group:
- Injection 1: 1:1 mixture (v/v) FCA/physiological saline
- Injection 2: physiological saline
- Injection 3: 1:1 mixture (v/v) FCA/physiological saline

Day 7: Treatment group:
Region, free of fur, was treated topically with a 2 x 4 cm patch of Lint cloth, fully loaded with an undiluted of gamma-caprolactone (Act. 97.4%). Patch was covered by an occlusive bandage and left in place for 48 hours. Due to the non irritant potential of this substance, 10% SLS (Sodium Lauryl Sulfate) in vaseline was topically applied on Day 6 and wiped off on Day 7.
Control group:
Only vehicle (water for injection) was applied.


B. CHALLENGE EXPOSURE
Day 21: Flank of all animals, including controls, treated topically with 0.05 mL of undiluted (97.4%), 50%, 30%, 10%, 5%, 3% (w/w, Act.% in water for injection) test substance for 24h under an occlusive patch.

GRADING SYSTEM
Dermal reactions graded for erythema and edema according to grading scale by Draize:


No erythema: 0
Slight erythema: 1
Clear erythema: 2
Moderate to Severe erythema: 3
Severe erythema with scab: 4


No edema: 0
Slight edema: 1
Clear edema: 2
Moderate edema: 3
Severe edema: 4

Challenge controls:

Historical control: 2,4-dinitrochlorobenzene

Positive control substance(s):

yes

Remarks:

Historical control: 2,4-dinitrochlorobenzene

Positive control results:

Sponsor confirmed that the sensitivity and reliability of the experimental technique used by the laboratory is regularly assessed using known sensitizer.

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

97.4% to 3% in challenge

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 97.4% to 3% in challenge. No with. + reactions: 0.0. Total no. in groups: 10.0.

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

0

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 10.0.

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

97.4 to 3% in challenge

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 97.4 to 3% in challenge. No with. + reactions: 0.0. Total no. in groups: 10.0.

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

0

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 10.0.

none

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material, γ-Caprolactone, is not classified as skin sensitiser under the test conditions .

Executive summary:

In a dermal sensitisation study performed according to Japanese guideline for medicines (similar to OECD test guideline No. 406) and in compliance with GLP, γ-Caprolactone was tested in female Hartley guinea-pigs using the Guinea-Pig Maximisation Test method (10 treated animals + 10 controls).

The preliminary study determined the concentration to be used for the induction and challenge phases of the main study.

In study Day 0, induction was performed by intradermally injecting 0.1 mL of each 1:1 mixture (v/v) FCA/physiological saline, 3% γ-Caprolactone in physiological saline, and 3% γ-caprolactone in a 1:1 mixture (v/v) FCA/physiological saline. In study Day 7, undiluted of γ-Caprolactone (Act. 97.4%) was patched for 48 hr occlusively. In the absence of irritant potential of this substance, 10% SLS (Sodium Lauryl Sulfate) in vaseline was topically applied on Day 6 and wiped off on Day 7. In study Day 21, challenge was performed by treated topically with 0.05 mL of undiluted (97.4%), 50%, 30%, 10%, 5%, 3% (w/w, Act.% in water for injection) test substance for 24h under an occlusive condition.

In this study, no skin reaction was observed in test group and control group.

Sponsor confirmed that the sensitivity and reliability of the experimental technique used by the laboratory is regularly assessed using known sensitizer.

Based on the overall sensitisation rate, γ-Caprolactone is not classified as skin sensitiser according to the Directive 67/548/EEC and the Regulation EC No. 1272/2008 (CLP).

This study is considered as acceptable and satisfies the requirement for skin sensitisation endpoint.

γ-Caprolactone, as aliphatic γ-lactone, is considered adequate for read-across purpose (see §"Toxicokinetics).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

No animal studies were available to evaluate the skin sensitization potential of γ-Decalactone. Therefore, to confirm the absence of this potential, a weight of evidence approach was built using data from two others aliphatic γ-lactone: γ-Caprolactone, (6 carbon atoms) and γ-Undecalactone (11 carbon atoms) (see §”Toxicokinetics” for read-across justification).

An Open Epicutaneous Test (OET) was conducted onγ-Undecalactone (Klecak, 1985, rel.4). Under the test conditions, the substance was not a skin sensitizer. Although conducted similarly to the OECD test guideline No. 406 (1981), the study protocol and results were poorly reported in the publication, decreasing the reliability of the study. Moreover, the concentrations used were not clearly stated. However, some of the concentrations used for induction and challenge being specified to be “the minimal irritating and the maximal non-irritating concentrations” (i.e. those recommended in current guideline), the result was considered appropriate for hazard assessment purpose.

γ-Caprolactone was tested in a Guinea-Pig Maximisation Test performed similarly to the OECD test guideline No. 406 and in compliance with GLP (Ooyama, 2002, rel.2). The highest concentration to cause mild-to-moderate skin irritation selected for intradermal induction was 3%, whereas undilutedγ-Caprolactone was used for epicutanuous induction on day 7. In the absence of irritant potential of the substance, 10% SLS (Sodium Lauryl Sulfate) in vaseline was topically applied on Day 6 and wiped off on Day 7. On study Day 21, challenge was performed by topical application of undiluted (97.4%), 50%, 30%, 10%, 5%, 3% (w/w, Act.% in water for injection) test substance for 24h under an occlusive condition. In this study, no skin sensitisation was observed in test group and control group.

Based on these read-across data, γ-Decalactone is not considered to be a skin sensitizer.

This absence of sensitising potential is also confirmed by a human maximisation test, in which γ-Decalactone (unknown %) was applied to a panel of 25 male and female healthy adult volunteers (Kligman, 1975).

Migrated from Short description of key information:
Not sensitising: OET and GPMT tests on γ-Undecalactone and γ-Caprolactone, respectively (WoE)

Justification for selection of skin sensitisation endpoint:
No animal studies were available to evaluate the skin sensitization potential of γ-Decalactone. Therefore, a weight of evidence approach was considered using data from γ-Caprolactone (6 carbon atoms) and γ-Undecalactone (11 carbon atoms) in a read-across approach (see §”Toxicokinetics” for read-across justification).

Respiratory sensitisation

Endpoint conclusion

Additional information:

Migrated from Short description of key information:
No data available

Justification for classification or non-classification

Harmonized classification:

γ-Decalactone has no harmonized classification according to the Regulation (EC) No. 1272/2008 including ATP2.

Self classification:

Based on the available data no additional self-classification is proposed according to the Regulation (EC) No. 1272/2008 (CLP) and the Directive 67/548/EEC.

No data was available for respiratory sensitisation.