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

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

01 June 2005 to 29 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 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

2001

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

2004

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

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:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Sprague-Dawley Rj: SD (IOPS Han)
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Approximately 8 weeks old
- Weight at study initiation: Animals had a mean body weight ± standard deviation of 195 ± 9 g (184 - 210 g)
- Fasting period before study: Animals were fasted for an overnight period of approximately 18 hours before dosing and for a further 4 hours post dose. Water was always freely available.
- Housing: The animals were housed in polycarbonate cages with stainless steel lid (48 x 27 x 20 cm). Each cage contained one to seven animals during the acclimation period and three rats of the same group during the treatment period. Each cage contained autoclaved sawdust.
- Diet: ad libitum. All the animals had free access to adapted 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: 22 ± 2 °C
- Humidity: 30 to 70 % (relative)
- Air changes: approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod: 12 hour light/12 hour dark cycles

IN-LIFE DATES: Not reported

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

0.5 %

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): The volume administered to each animal was adjusted according to body weight determined on the day of treatment.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The test material preparation was made extemporaneously under nitrogen atmosphere. The preparations were maintained under agitation during all the treatment period.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: As no information on the toxic potential of the test material was available, for animal welfare reasons, the starting dose-level of 300 mg/kg was chosen. After the first assay, as no deaths occurred, another assay was carried out on three animals at the next higher dose-level, i.e. 2000 mg/kg. After the second assay, as all animals died, the result obtained at the dose-level of 300 mg/kg were confirmed on another group of three animals.

Doses:

300 and 2000 mg/kg

No. of animals per sex per dose:

3 animals per dose group; two groups dosed at 300 mg/kg and one group dosed at 2000 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days.
- Frequency of observations and weighing: The animals were observed frequently during the hours following administration of the test material, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day. The animals were weighed individually just before administration of the test material on day 1 and then on days 8 and 15. For the animals that died, time of death was recorded individually, in terms of the number of hours or days after dosing.
- Necropsy of survivors performed: Yes. On day 15, all surviving animals were killed by carbon dioxide asphyxiation. All study animals were subjected to a macroscopic examination as soon as possible after death. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

- Dose-level of 300 mg/kg (three females then confirmation on three other females): No mortality was observed during the study.
- Dose-level of 2000 mg/kg (three females): All animals died within 2 hours of treatment.

Clinical signs:

- Dose-level of 300 mg/kg (three females then confirmation on three other females): No clinical signs were observed during the study.
- Dose-level of 2000 mg/kg (three females): Hypoactivity and tremors were observed prior to the death of the animals.

Body weight:

Dose-level of 300 mg/kg: Although the animals gained weight, the weight gain of 2/6 animals was slightly reduced during the second week of the study when compared to historical control animals. The body weight gain of the other animals was not considered to be affected by treatment with the test material.

Gross pathology:

Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.

Applicant's summary and conclusion

Interpretation of results:

other: Classified as Category 4 in accordance with EU criteria

Conclusions:

Under the conditions of this study, the LD50 of the test material in female rat lies between 300 and 2000 mg/kg bodyweight.

Executive summary:

The acute oral toxicity potential of the test material was assessed in the Sprague-Dawley rat in accordance with the standardised guidelines OECD 423 and EU Method B.1 tris under GLP conditions using the acute toxic class method.

The test material was prepared in 0.5 % methylcellulose and was administered by gavage at a dose volume of 10 mL/kg to three groups of three fasted female rats. As no information on the toxic potential of the test material was available, for animal welfare reasons the starting dose-level of 300 mg/kg was chosen. As no deaths occurred at this dose level, another assay was carried out on three animals at the next higher dose-level (2000 mg/kg). After the second assay, as all animals died, the results obtained at the dose-level of 300 mg/kg were confirmed on another group of three animals. The animals were weighed individually just before administration of the test material on day 1 and then on days 8 and 15. The animals were observed frequently during the hours following administration of the test material and daily throughout the observation period.

At 300 mg/kg (three females then confirmation on three other females) no clinical signs and no mortality were observed during the study. The body weight gain of 2/6 animals was slightly reduced during the second week of the study when compared to historical control animals. The body weight gain of the other animals was not considered to be affected by treatment with the test material.

At 2000 mg/kg (three females) all animals died within 2 hours of treatment. Hypoactivity and tremors were observed prior to the death of the animals.

At necropsy, no apparent abnormalities were observed in any animal.

Under the conditions of this study, the LD50 of the test material in female rat lies between 300 and 2000 mg/kg bodyweight.