p-fluorophenyl 4-piperidyl ketone hydrochloride

Eye irritation

Administrative data

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2004-01-27 to 2004-09-23

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Only a study summary was available for review which provided limited details on the test substance and methodology; however, sufficient information was provided to deem the study reliable with restrictions.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The ocular irritancy potential of the test material was assessed using the Rabbit Enucleated Eye Test (REET). This method involved the application of the test material onto the cornea of the enucleated eye.

GLP compliance:

no

Remarks:

This study was conducted in facility operating to GLP within the UK national GLP monitoring programme, but the study report has not been audited by the QA Unit. No formal claim of GLP compliance is made for this study.

Test material

Test material information

Constituent 1

Reference substance name:

p-fluorophenyl 4-piperidyl ketone hydrochloride

EC Number:

247-070-0

EC Name:

p-fluorophenyl 4-piperidyl ketone hydrochloride

Cas Number:

25519-78-2

Molecular formula:

C12H14FNO.ClH

IUPAC Name:

4-(4-fluorobenzoyl)piperidine hydrochloride

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

- Name of test material (as cited in study report): T 1047
- Substance type: no data
- Physical state: no data
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other: no data

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: not applicable
- Housing: not applicable
- Diet (e.g. ad libitum): not applicable
- Water (e.g. ad libitum): not applicable
- Acclimation period: not applicable

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 32 +/- 1.5
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: not applicable

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: yes, 0.9 % sodium chloride

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL (approx. 52 mg)
- Concentration (if solution): undiluted

VEHICLE
- Amount(s) applied (volume or weight with unit): not applicable
- Concentration (if solution): not applicable
- Lot/batch no. (if required): not applicable
- Purity: not applicable

Duration of treatment / exposure:

single application

Observation period (in vivo):

- corneal opacity and corneal epithelium condition: 60, 120, 180 and 240 min
- fluorescein uptake: 240 min
- corneal swelling: 60, 120 and 240 min

Number of animals or in vitro replicates:

Three enucleated eyes were treated with the test substance, two enucleated eyes were treated as control.

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no
- Time after start of exposure: not applicable

SCORING SYSTEM:
- Method for Evaluation of Ocular Irritation by Slit-Lamp Biomicroscopic Examination (McDonald - Shadduck Score System)

- The scoring scheme measures the severity of corneal cloudiness and the area of the cornea involved. Severity of corneal cloudiness is graded as follows:
0 = Normal cornea. Appears with the slit-lamp as having a bright grey line on the epithelial surface and a bright grey appearance of the stroma.
1 = Some loss of transparency. Only the anterior half of the stroma is involved as observed with an optical section of the slit-lamp. The underlying structures are clearly visible with diffuse illumination, although some cloudiness can be readily apparent with diffuse illumination.
2 = Moderate loss of transparency. In addition to involving the anterior stroma, the cloudiness extends all the way to the endothelium. The stroma has lost its marble-like appearance and is homogeneously white. With diffuse, illumination, underlying structures are clearly visible.
3 = Involvement of the entire thickness of the stroma. With optical section, the endothelial surface is still visible. However, with diffuse illumination the underlying structures are just visible.
4 = Involvement of the entire thickness of the stroma. With the optical section cannot clearly visualise the endothelium. With diffuse illumination, the underlying structures cannot be seen.

The surface of the cornea relative to the area of cloudiness is divided into five grades from 0 to 4:
0 = Normal cornea with no area of cloudiness
1 = 1 to 25% area of stromal cloudiness 2 = 26 to 50% area of stromal cloudiness
3 = 51 to 75% area of stromal cloudiness
4 = 76 to 100% area of stromal cloudiness

FLUORESCEIN
- The use of fluorescein is a valuable aid in defining epithelial damage for fluorescein staining. The area can be judged as a 0 to 4 scale using the same terminology as for corneal cloudiness.

The intensity of fluorescein staining can be divided into a 0 to 4 scale:
0 = Absence of fluorescein staining
1 = Slight fluorescein staining confined to a small focus. With diffuse illumination the underlying structures are clearly visible, although there is some loss of detail.
2 = Moderate fluorescein staining confined to a small focus. With diffuse illumination the underlying structures are clearly visible, although there is some loss of detail.
3 = Marked fluorescein staining. Staining may involve a larger portion of the cornea. With diffuse illumination underlying structures are barely visible but are not completely obliterated.
4 = Extreme fluorescein staining. With diffuse illumination the underlying structures cannot be seen.

REFERENCE
Hackett R B and McDonald T O, Eye Irritation. In: Advances in Modern Toxicology: Dermatoxicology. 4th ed. (F Marzulli and H Maibach, eds) Hemisphere Publishing Corporation, Washington DC, 1991, pp 749-815

TOOL USED TO ASSESS SCORE:
- hand-slit lamp / biomicroscope / fluorescein

Results and discussion

In vitro

Results

Results 1

Irritation parameter:

cornea opacity score

Remarks:

cloudiness and area

Run / experiment:

mean, 60, 120, 180 and 240 min

Value:

0

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not examined

Results 2

Irritation parameter:

fluorescein retention score

Run / experiment:

mean, 240 min

Value:

0

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not examined

Results 3

Irritation parameter:

other: corneal swelling (%)

Run / experiment:

mean, 60 min

Value:

16.9

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not applicable

Results 4

Irritation parameter:

other: corneal swelling (%)

Run / experiment:

mean, 120 min

Value:

24.9

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not examined

Results 5

Irritation parameter:

other: croneal swelling (%)

Run / experiment:

mean, 240 min

Value:

34.4

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not examined

Other effects / acceptance of results:

Corneal epithelium condition:
- Sloughing was observed in one animal at 60 and 120 min and in all 3 animals at 180 and 240 min.
- The control eyes were normal at all time points.

Applicant's summary and conclusion

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

The test substance was considered to have the potential to cause severe ocular irritancy in vivo.