Decan-4-olide

Skin sensitisation

Administrative data

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").

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

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.

Test material

Test material information

Constituent 1

Reference substance name:

Hexan-4-olide

EC Number:

211-778-8

EC Name:

Hexan-4-olide

Cas Number:

695-06-7

IUPAC Name:

5-ethyldihydrofuran-2(3H)-one

Test material form:

liquid

Details on test material:

- Name of test material (as cited in study report): gamma-caprolactone
- Physical state: transparent liquid without color
- Storage condition of test material: room temperature in the dark

In vivo test system

Test animals

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

Study design: in vivo (non-LLNA)

Induction

Induction 1

Route:

intradermal and epicutaneous

Vehicle:

physiological saline

Induction 2

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%).

Challenge

Challenge 1

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Challenge 2

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

Results and discussion

Positive control results:

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

In vivo (non-LLNA)

Results

Results 1

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.

Results 2

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.

Results 3

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.

Results 4

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.

Any other information on results incl. tables

none

Applicant's summary and conclusion

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).