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

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

02 June 2005 to 10 June 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

2002

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal 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

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system 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 2.8 ± 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

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

500 mg

Duration of treatment / exposure:

The test material was first evaluated on a single animal; the durations of exposure were 3 minutes, 1 hour and 4 hours. It was then applied for 4 hours to two additional animals.

Observation period:

72 hours

Number of animals:

3 males

Details on study design:

TEST SITE
- Area of exposure: Flank. The day before treatment, both flanks of each animal were clipped using electric clippers and the skin of each animal was examined in order to check the absence of any signs of skin irritation. Doses were applied to the anterior left flank (application for 3 minutes), the anterior right flank (application for 1 hour) or the posterior right flank (application for 4 hours) of the animals.
- Type of wrap if used: The test material was placed on a gauze pad moistened with purified water. The gauze pad was held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No washing was done, however after removal of the dressing any residual test material was wiped off by means of a dry cotton pad.
- Time after start of exposure: After the 3 minute and 1 and 4 hour exposure periods.

OBSERVATION TIME POINTS: The skin was examined approximately 1, 24, 48 and 72 hours after removal of the dressing.

SCORING SYSTEM: Dermal irritation was evaluated for each animal according to the following scale:
- Erythema and Eschar Formation
0 = No erythema
1 = Very slight erythema (barely perceptible)
2 = Well-defined erythema
3 = Moderate to severe erythema
4 = Severe erythema (beet redness) to slight eschar formation (injuries in depth)

- Oedema Formation
0 = No oedema
1 = Very slight oedema (barely perceptible)
2 = Slight oedema (edges of area well-defined by definite raising)
3 = Moderate oedema (edges raised approximately 1 mm)
4 = Severe oedema (raised more than 1 mm and extending beyond the area of exposure)

Any other lesions were noted.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.11

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Results 2

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

After the 3-minute and 1-hour exposures in one animal, no cutaneous reactions were observed.
After the 4-hour exposure in all three animals, a very slight erythema (grade 1) was noted in 2/3 animals on day 1; it persisted on day 2 in 1/3 animals. No other cutaneous reactions were recorded.
Mean scores over 24, 48 and 72 hours for each animal were 0.3, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for oedema.

Any other information on results incl. tables

Table 1: Summary of Individual Results After the 4 Hour Exposure

Rabbit Number	Dermal Irritation	Time point (h)				Mean irritation score*	Interpretation
		1	24	48	72
113	Erythema	1	1	0	0	0.3	Negative
	Oedema	0	0	0	0	0.0	Negative
	Other	-	-	-	-
479	Erythema	0	0	0	0	0.0	Negative
	Oedema	0	0	0	0	0.0	Negative
	Other	-	-	-	-
480	Erythema	1	0	0	0	0.0	Negative
	Oedema	0	0	0	0	0.0	Negative
	Other	-	-	-	-

*Mean of 24, 48 and 72 h scores

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 skin.

Executive summary:

A dermal irritation study was conducted in accordance with the standardised guidelines OECD 404 and EU Method B.4 under GLP conditions.

The test material was first applied for periods of 3 minutes, 1 hour and 4 hours to a single male New Zealand White rabbit. Since the test material was not severely irritating to the first animal, it was then applied for 4 hours to two other animals. A single dose of 500 mg of the test material in its original form was applied to the closely-clipped skin of one flank. The test material was held in contact with the skin by means of a semi-occlusive dressing. Cutaneous reactions were observed approximately 1, 24, 48 and 72 hours after removal of the dressing. The mean values of the scores for erythema and oedema were calculated for each animal.

After the 3-minute and 1-hour exposures in one animal, no cutaneous reactions were observed. After the 4-hour exposure in all three animals, a very slight erythema (grade 1) was noted in 2/3 animals on day 1; it persisted on day 2 in 1/3 animals. No other cutaneous reactions were recorded.

Mean scores over 24, 48 and 72 hours for each animal were 0.3, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for oedema.

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