5-fluoro-2-methoxypyrimidin-4(3H)-one

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

other information

Study period:

09 June 2005 to 18 June 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

2002

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Version / remarks:

2004

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

473-810-9

EC Name:

-

Cas Number:

1480-96-2

Molecular formula:

Hill formula: C5H5FN2O2 CAS formula: C5H5FN2O2

IUPAC Name:

5-fluoro-2-methoxy-3,4-dihydropyrimidin-4-one

Test material form:

solid: particulate/powder

Details on test material:

- Appearance: white powder
- Storage conditions of test material: at room temperature, protected from humidity and under nitrogen gas

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Age at study initiation: The animals were 2 to 4 months old on the day of treatment
- Weight at study initiation: The animals had a mean body weight ± standard deviation of 2.9 ± 0.1 kg
- Housing: The animals were housed individually in polystyrene cages (48.2 x 58 x 36.5 cm). Each cage was equipped with a food container and a water bottle.
- Diet: ad libitum access to pelleted diet
- Water: Drinking water filtered by an FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature: 18 ± 3 °C
- Humidity: 30 to 70 % (relative)
- Air changes: Approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod: 12 hours of light / 12 hours of darkness

IN-LIFE DATES: Not reported

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

100 mg

Duration of treatment / exposure:

As possible irritant effects were anticipated, the test material was first administered to a single animal; it was then evaluated on two other animals.
A single dose of the test material was introduced into the conjunctival sac of the left eye after gently pulling the lower lid away from the eyeball. The lower and upper eyelids were held together for about one second to avoid any loss of test material.

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 males

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Irrigation was not performed.

SCORING SYSTEM: The day before treatment, the eyes of each animal were examined in order to check the absence of any signs of ocular irritation, ocular defects or pre-existing corneal injury. The eyes were examined approximately 1, 24, 48 and 72 hours after administration. Conjunctival reactions, iritis and corneal opacification were evaluated daily for each animal. Any other lesions observed were noted. The numerical scale is presented in Table 1.

TOOL USED TO ASSESS SCORE: For the evaluation of corneal opacification (presence or absence, affected area), the eyes were examined under a UV lamp after instillation of one or two drops of 0.5 % sodium fluorescein solution (a clear fluorescence is visible in the areas of opacification). This evaluation was performed on day 2 and repeated thereafter whenever necessary.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Time point:

24/48/72 h

Score:

0.44

Max. score:

3

Reversibility:

fully reversible within: 72 hours

Results 2

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.22

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Results 3

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Results 4

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritant / corrosive response data:

A very slight chemosis was noted in all three animals on day 1; it persisted up to day 3 in one of them. A moderate redness of the conjunctiva was observed in all the animals on day 1. A slight redness of the conjunctivae was noted on day 2 in all three animals; it persisted on day 3 in one of them. No other ocular reactions were noted during the study.
Mean scores calculated for each animal over 24, 48 and 72 hours were 0.7, 0.0 and 0.0 for chemosis, 0.3, 0.7 and 0.3 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity.

Any other information on results incl. tables

Table 2: Summary of Individual Results

Rabbit Number	Ocular Reaction	Time point (h)				Mean irritation score*	Interpretation
		1	24	48	72
113	Chemosis	1	1	1	0	0.7	Negative
	Redness	2	1	0	0	0.3	Negative
	Discharge	0	0	0	0	0.0
	Iris	0	0	0	0	0.0	Negative
	Corneal opacity	0	0	0	0	0.0	Negative
	Other	Su	*	*	*
	Fluorescein	/	U	/	/
479	Chemosis	1	0	0	0	0.0	Negative
	Redness	2	1	1	0	0.7	Negative
	Discharge	0	0	0	0	0.0
	Iris	0	0	0	0	0.0	Negative
	Corneal opacity	0	0	0	0	0.0	Negative
	Other	Su	*	*	*
	Fluorescein	/	U	/	/
480	Chemosis	1	0	0	0	0.0	Negative
	Redness	2	1	0	0	0.3	Negative
	Discharge	0	0	0	0	0.0
	Iris	0	0	0	0	0.0	Negative
	Corneal opacity	0	0	0	0	0.0	Negative
	Other	Su	*	*	*
	Fluorescein	/	U	/	/

*Mean of 24, 48 and 72 h scores

* = none

Su = residual test material

U = fluorescein applied

/ = fluorescein not used

Applicant's summary and conclusion

Interpretation of results:

other: Not classified in accordance with EU criteria

Conclusions:

Under the conditions of this study, the test material was determined to be not irritating to the eyes.

Executive summary:

The potential of the test material to cause eye irritation was investigated in accordance with the standardised guidelines OECD 405 and EU Method B.5 under GLP conditions.

The test material was first administered to a single male New Zealand White rabbit. Since the test material was not severely irritating on the first animal treated, it was then evaluated in two other animals. A single dose of 100 mg of the test material in its original form was introduced into the left conjunctival sac. The right eye was not treated and served as control. The eyes were not rinsed after administration of the test material. Ocular reactions were observed approximately 1, 24, 48 and 72 hours after the administration. Mean scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal.

A very slight chemosis was noted in all three animals on day 1 and it persisted up to day 3 in one of them. A moderate redness of the conjunctiva was observed in all the animals on day 1. A slight redness of the conjunctivae was noted on day 2 in all three animals; it persisted on day 3 in one of them. No other ocular reactions were noted during the study. Mean scores calculated for each animal over 24, 48 and 72 hours were 0.7, 0.0 and 0.0 for chemosis, 0.3, 0.7 and 0.3 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity.

Under the conditions of this study, the test material was determined to be not irritating to the eyes.