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Description of key information

Not a skin sensitizer (WOE approach)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

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Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1985
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted similarly to an old version of the OECD test guideline No. 406 (1981) with deviations: concentrations not specified, individual animals weights at beginning and end of the test not reported; grading system not described; individual animal data not reported
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
adopted in 1981
Deviations:
yes
Remarks:
individual animals weights at beginning and end of the test not reported; grading system not described; no data on individual animal
Principles of method if other than guideline:
Not applicable
GLP compliance:
not specified
Type of study:
open epicutaneous test
Justification for non-LLNA method:
At the time of study completion (1985), the LLNA OECD test method was not adopted.
Species:
guinea pig
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 300-450 g
Route:
epicutaneous, open
Vehicle:
other: suitable vehicle
Concentration / amount:
minimal irritating concentration, maximal non-irritant concentration and 2 lower non-irritating concentrations
Route:
epicutaneous, open
Vehicle:
other: suitable vehicle
Concentration / amount:
minimal irritating concentration, maximal non-irritant concentration and 2 lower non-irritating concentrations
No. of animals per dose:
10 in control and at least 6 per dose in treatment group
Details on study design:
RANGE FINDING TESTS:
- One day before the induction procedure, 6-8 guinea pigs, subsequently used for the experimental group, were applied with test material (0.025 mL) at different concentrations (e.g. 1, 3, 10, 30 and 100 % depending on the solubility) and observed for erythema and oedema at 24 h. This pre-testing phase allows establishing the minimal irritating and the maximal nonirritating concentration i.e. the lowest concentration causing skin irritation and the highest concentration not causing macroscopic skin reactions, respectively.

MAIN STUDY
A. INDUCTION EXPOSURE: Epicutaneous, open
- On Day 1, 0.1 mL of the test material was applied on clipped flank skin (8 cm²) of guinea pigs. The applications were repeated daily for 3 weeks or 5 times weekly during 4 weeks. The application sites were evaluated 24 h after application or at the end of each week.

B. CHALLENGE EXPOSURE: TOPICAL
- All guinea pigs of control and treatment groups were tested on Days 21 and 35 on the contralateral flanks (2 cm²) with the test material (0.025 mL) at the minimal irritating and some lower non-irritating concentrations. The application sites were evaluated 24, 48 and 72 h after application.
Challenge controls:
- During challenge phase, all guinea pigs of control group were tested similarly to treatment group.
Positive control substance(s):
no
Positive control results:
Not applicable
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
maximum non-irritating concentration
No. with + reactions:
0
Total no. in group:
6
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: maximum non-irritating concentration. No with. + reactions: 0.0. Total no. in groups: 6.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
maximum non-irritating concentration
No. with + reactions:
0
Total no. in group:
6
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: maximum non-irritating concentration. No with. + reactions: 0.0. Total no. in groups: 6.0.
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:
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.
Group:
positive control
Remarks on result:
not measured/tested

γ-Undecalactone was reported to be negative in the Open Epicutaneous Test (OET).

Interpretation of results:
GHS criteria not met
Conclusions:
Under these test conditions, γ-Undecalactone was reported to be negative in the Open Epicutaneous Test (OET) therefore it is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
Executive summary:

An Open Epicutaneous Test (OET) was performed similarly to an old version of the OECD test guideline No. 406 (1981). One day before the induction procedure, 6-8 guinea pigs were applied with γ-Undecalactone (0.025 mL) at different concentrations (e.g. 1, 3, 10, 30 and 100 % depending on the solubility) and observed for erythema and oedema at 24 h. On Day 1, 0.1 mL of γ-Undecalactone was applied on the clipped flank skin (8 cm²) of at least 6 guinea pigs. The applications were repeated daily for 3 weeks or 5 times weekly during 4 weeks. The application sites were evaluated 24 h after application or at the end of each week. Negative or vehicle control was also included in the study. During challenge phase, all guinea pigs of control and treatment groups were tested on Days 21 and 35 on the contralateral flanks (2 cm²) with the test material (0.025 mL) at the minimal irritating and some lower non-irritating concentrations. The application sites were evaluated 24, 48 and 72 h after application.

Under these test conditions, γ-Undecalactone showed negative results in the Open Epicutaneous Test (OET) therefore it is not classified according to the Regulation (EC) No. 1272 /2008 (CLP) and to the GHS.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
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: see 'Remark'
Remarks:
GLP study conducted similarly to OECD test guideline No. 406 although not mentioned in the report. γ-Caprolactone, as a linear saturated 4-hydroxycarboxylic acid derived-lactones, is considered adequate for read-across purpose (see §"Toxicokinetics").
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
At the time the study order was signed, the LLNA OECD test method was not already 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%).
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Concentration / amount:
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 group
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 group
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.
Group:
positive control
Remarks on result:
other: Historical control

none

Interpretation of results:
GHS criteria not met
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 both the sensitivity and the 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 Regulation EC No. 1272/2008 (CLP) and to the GHS.

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

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

An Open Epicutaneous Test (OET) was conducted on γ-Undecalactone (Klecak, 1985, rel.4). Under the test conditions, the substance is 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.

To confirm the absence of skin sensitization potential, a weight of evidence approach was built using data from another linear saturated 4-hydroxycarboxylic acid derived-lactones, γ-Caprolactone (see §”Toxicokinetics” for read-across justification).

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 undiluted γ-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.

γ-Caprolactone can be considered as a worst-case regarding the dermal absorption by comparison with γ-Undecalactone. This is based on its lower molecular weight together with its partition coefficient and water solubility which are more in favour of dermal absorption if sensitisation would have been observed.

Based on the available data on both substances, γ-Undecalactone is not considered to be a skin sensitizer.

This absence of sensitising potential is also confirmed by a human maximisation study, in which γ-Undecalactone (2%) was applied to a panel of 25 male and female healthy adult volunteers (Kligman, 1971).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Harmonized classification:

γ-Undecalactone has no harmonized classification according to the Regulation (EC) No. 1272/2008 (CLP).

Self classification:

Based on the available data no additional self-classification is proposed regarding skin sensitization according to the Annex I of Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

No data was available for respiratory sensitization.