1-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)ethyl 2-methylpropanoate

Endpoint summary

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study

Qualifier:

no guideline available

Principles of method if other than guideline:

The purpose of the study wasto determine the skin irritation potential of the test material using the SkinEthic Reconstituted Human Epidermal model (SkinEthic Labs, Nice, France) following treatment periods of 4 and 24hrs. The study consists of a test for direct redution of MTT by the test material followed by determination of skin irritation/corrosion potential. For th determination of skin irritation potential, triplicate SkinEthic tissues were treated with approx. 25mg of the test material and exposued for 4 and 24hrs. . At the end of the treatment period tissues were tested for viability using MTT conversion relative to controls.

GLP compliance:

yes (incl. QA statement)

Species:

human

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

4 and 24hrs

Irritation / corrosion parameter:

% tissue viability

Run / experiment:

at 4 hours

Value:

ca. 2.7

Remarks on result:

positive indication of irritation

Irritation / corrosion parameter:

% tissue viability

Run / experiment:

at 24 hours

Value:

ca. 2

Remarks on result:

positive indication of irritation

Other effects / acceptance of results:

The relative viability of test material treated tissues was 2.7% after 4hrs exposure and 2.0% after 24hrs exposure.

Interpretation of results:

irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

GSK1873183A was considered to be a skin irritant

Executive summary:

The purpose of the study was to determine the skin irritation potential of the test material using the SkinEthic Reconstituted Human Epidermal model (SkinEthic Labs, Nice, France) following treatment periods of 4 and 24hrs. The study consists of a test for direct redution of MTT by the test material followed by determination of skin irritation/corrosion potential. For th determination of skin irritation potential, triplicate SkinEthic tissues were treated with approx. 25mg of the test material and exposued for 4 and 24hrs. . At the end of the treatment period tissues were tested for viability using MTT conversion relative to controls. The relative mean viability of the test material treated tissues was 2.7% afetr 4hrs exposure and 2.0% after 24hrs exposure. It was considered unneccesary to proceed with tissue histology and the test material was considered to be a skin irritant (R38)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Study

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Reconstitured Human Cornea: Determination of eye irritation potential using the SkinEthic Reconstituted Human Corneal model (RHC, SkinEthic Labs, Nice, France) following treatment periods of 10 and 60 minutes. The test is based on the hypothesis that irritant materials are able to penetrate the corneal epitelial tissue and are sufficiently cytotoxic to cuase cell death.

GLP compliance:

yes (incl. QA statement)

Species:

human

Vehicle:

unchanged (no vehicle)

Irritation parameter:

other: relative mean viability

Run / experiment:

10 mins

Value:

ca. 36.8

Negative controls validity:

valid

Remarks on result:

positive indication of irritation

Irritation parameter:

other: relative mean viability

Run / experiment:

60 mins

Value:

ca. 4.4

Negative controls validity:

valid

Remarks on result:

positive indication of irritation

Other effects / acceptance of results:

RHC Model: The relative mean viability of the test material treated tissue was 36.8% after 10minutes and 4.4% after 60 minute exposure.

results are from in vitro/ ex vivo studies and time points, score and max score are not applicable endpoints

Interpretation of results:

moderately irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

GSK1873183A was considered to be irritating to eyes based upon the results of the in vitro/ex vivo studies.

Executive summary:

An in vitro test strategy was adopted to assess the potential eye irritation of GSK1873183A. In the rabbit enulceated eye test (REET), 0.1ml of test material was applied to the cornea of each of three enucleated eyes which had been maintained ata temperature of 32deg C within the superfusion chamber. A further two enucleated eyes were treated with saline solution as controls. Assessment or corneal cloudiness was made approx 60, 120, 180 and 240mins following treatment. Examination of the eye facilitated by use of a slit-lamp biomicroscope and the thickness of the cornea was measured using an ultrasonic pachymeter. In the Human Reconsititued Corneal Model (RHC) determination of eye irritation potential was assessed using the SkinEthic Reconstituted Human Corneal model (RHC, SkinEthic Labs, Nice, France) following treatment periods of 10 and 60 minutes. The test is based on the hypothesis that irritant materials are able to penetrate the corneal epitelial tissue and are sufficiently cytotoxic to cuase cell death.

The REET assay indicated that GSK1873183A is unlikely to have potential to cause severe ocular irritancy in vivo. The RHC model indicated thatthe test material is likley to be a moderate eye irritant and should be classified as R36; Irritating to eyes (GHS Category 2A)

Reference 2

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Study

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Rabbit Enucleated Eye Test: 0.1ml of test material was applied to the cornea of each of three enucleated eyes which had been maintained ata temperature of 32deg C within the superfusion chamber. A further two enucleated eyes were treated with saline solution as controls. Assessment or corneal cloudiness was made approx 60, 120, 180 and 240mins following treatment. Examination of the eye facilitated by use of a slit-lamp biomicroscope and the thickness of the cornea was measured using an ultrasonic pachymeter.

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Vehicle:

unchanged (no vehicle)

Irritation parameter:

percent corneal swelling

Run / experiment:

60 mins

Value:

ca. 7.7

Negative controls validity:

valid

Remarks on result:

no indication of irritation

Irritation parameter:

percent corneal swelling

Run / experiment:

120 mins

Value:

ca. 6.7

Negative controls validity:

valid

Remarks on result:

no indication of irritation

Irritation parameter:

percent corneal swelling

Run / experiment:

240 mins

Value:

ca. 4.8

Negative controls validity:

valid

Remarks on result:

no indication of irritation

Other effects / acceptance of results:

REET Model: Corneal swelling in control eyes was 8.6, 10.6 and 7.8% after 60, 120 and 240mins respectively. In eyes treated with 0.1% GSK1873183A corneal swelling was 7.7, 6.7 and 4.8% at the same time periods

results are from in vitro/ ex vivo studies and time points, score and max score are not applicable endpoints

Interpretation of results:

moderately irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

GSK1873183A was considered to be irritating to eyes based upon the results of the in vitro/ex vivo studies.

Executive summary:

An in vitro test strategy was adopted to assess the potential eye irritation of GSK1873183A. In the rabbit enulceated eye test (REET), 0.1ml of test material was applied to the cornea of each of three enucleated eyes which had been maintained ata temperature of 32deg C within the superfusion chamber. A further two enucleated eyes were treated with saline solution as controls. Assessment or corneal cloudiness was made approx 60, 120, 180 and 240mins following treatment. Examination of the eye facilitated by use of a slit-lamp biomicroscope and the thickness of the cornea was measured using an ultrasonic pachymeter. In the Human Reconsititued Corneal Model (RHC) determination of eye irritation potential was assessed using the SkinEthic Reconstituted Human Corneal model (RHC, SkinEthic Labs, Nice, France) following treatment periods of 10 and 60 minutes. The test is based on the hypothesis that irritant materials are able to penetrate the corneal epitelial tissue and are sufficiently cytotoxic to cuase cell death.

The REET assay indicated that GSK1873183A is unlikely to have potential to cause severe ocular irritancy in vivo. The RHC model indicated thatthe test material is likley to be a moderate eye irritant and should be classified as R36; Irritating to eyes (GHS Category 2A)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)