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

Endpoint summary

Description of key information

Skin

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

Eye

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

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

2002

Deviations:

no

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)

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

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.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.11

Max. score:

4

Reversibility:

fully reversible within: 48 hours

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.

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

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.

Reference 2

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

2002

Deviations:

no

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)

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

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.

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

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.22

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

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.

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

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.

Reference 2

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

A dermal irritation study was conducted in accordance with the standardised guidelines OECD 404 and EU Method B.4 under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997). 

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.

Eye Irritation

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 study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997). 

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.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to skin and eye irritation or corrosion.