Quinazolin-4(1H)-one

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2011-05-31 to 2011-07-12

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Version / remarks:

2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Quinazolin-4(1H)-one

EC Number:

207-735-8

EC Name:

Quinazolin-4(1H)-one

Cas Number:

491-36-1

Molecular formula:

C8H6N2O

IUPAC Name:

4-Hydroxyquinazoline

Test material form:

solid

Specific details on test material used for the study:

Batch No.: 1176335
Purity: 99.8%

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories, B.V.
- Age at study initiation: 10 – 12 weeks
- Weight at study initiation: 169.2 – 193.5 g
- Fasting period before study: overnight prior to treatment and approximately 3 - 4 hours post dose
- Housing: In groups of five in Makrolon type-4 cages with wire mesh tops and standard softwood bedding including paper enrichment
- Diet (e.g. ad libitum): Pelleted Teklad Rat-Mouse Diet 2914C, ad libitum
- Water (e.g. ad libitum): Community tap-water, ad libitum
- Acclimation Period: Five to sixteen days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour fluorescent light / 12-hour dark cycle, Music was played during the daytime light period.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 9.5, 30 or 95 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg body weight.
- Justification for choice of vehicle: A 20%:80% (weight:weight) mixture of the test item with polyethylene glycol 300 formed a beige, viscous liquid suitable for
oral gavage application.
- Lot/batch no. (if required): STBB2046019

MAXIMUM DOSE VOLUME APPLIED:

DOSAGE PREPARATION (if unusual):
The dose formulations were prepared on the day of application, shortly before each treatment. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle was added (weight:volume). The formulations were homogenized using a spatula and a magnetic stirrer.
Homogeneity of the test item in the vehicle was maintained using a magnetic stirrer until administration.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Potential dose levels for the test were 3, 9.5, 30, 95, 300, 950 and 2000 mg/kg body weight. The starting dose was 300 mg/kg body weight. Depending on survival or death of the treated animals, the dose levels were increased or decreased.

Doses:

95, 300, 950 mg/kg body weight

No. of animals per sex per dose:

2, 3, 1 animal each for 95, 300, 950 mg/kg body weight dose level

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- Viability / Mortality: Daily during acclimatization; prior to treatment, within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on test day 1 (with the clinical signs); twice daily during test days 2-15.
- Clinical Signs: Daily during acclimatization; prior to treatment, within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on test day 1; once daily during test days 2-15.
- Body Weights: On the last day of acclimatization (prior to removal of food), on test day 1 (prior to treatment), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: All animals surviving to the end of the observation period and all moribund animals were sacrificed by carbon dioxide asphyxiation. An external examination and opening of the abdominal and thoracic cavities for examination of major organs was performed. All macroscopic abnormalities were recorded. Thereafter, the animals were discarded. No organs or tissues were retained. Animals that died spontaneously during the observation period were
examined as soon as they are found dead. All animals killed in extremis for animal welfare reasons were considered in the same way as animals that die on the test.

Statistics:

The statistical program AOT425StatPgm was used for the selection of dose levels and calculation of the LD50 value.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

300 mg/kg bw

Based on:

test mat.

95% CL:

> 50.13 - < 1 220

Mortality:

All animals treated with 95 mg/kg survived until the end of the observation period. One animal treated with 300 mg/kg survived until the end of the observation period, while two animals treated with 300 mg/kg were killed in extremis on test day 1. One animal treated with 950 mg/kg was killed in extremis on test day 1.

Clinical signs:

other: No clinical signs were observed throughout acclimatization. In animals which survived treatment (animals treated with 95 or 300 mg/kg, respectively), mild clinical signs, such as slightly increased activity, slightly ruffled fur and slight tachypnea were

Gross pathology:

No macroscopic findings were recorded at necropsy of the animals that survived the scheduled observation period (animals treated with 95 or 300 mg/kg).
The stomach of all animals which were killed in extremis on test day 1 contained fluid (animals treated with 300 or 950 mg/kg). Additionally, the animal treated with 950 mg/kg was noted with light brown discolored kidneys.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The estimated median lethal dose of test item after single oral administration to female rats, observed over a period of 14 days, is:
LD50 (female rat) = 300 mg/kg body weight (the one dose with partial response), 95% PL confidence interval is 50.13 to 1220 mg/kg body weight

Executive summary:

The acute toxicity of the test item when administered by a single oral gavage to rats was assessed based on OECD 425.

Six female RccHan:WIST (SPF) rats were treated sequentially with test item by single oral gavage administration at dose levels of 95, 300 or 950 mg/kg body weight. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. Body weights were recorded on test day 1 (prior to administration) and on test days 8 and 15. All animals were necropsied and macroscopically examined.

All animals treated with 95 mg/kg survived until the end of the observation period. One animal treated with 300 mg/kg survived until the end of the observation period, while two animals treated with 300 mg/kg were killed in extremis on test day 1. One animal treated with 950 mg/kg was killed in extremis on test day 1.

No clinical signs were observed throughout acclimatization. In animals which survived treatment, mild clinical signs, such as slightly increased activity, slightly ruffled fur and slight tachypnea were observed after treatment on test day 1 and up to test day 3. No clinical signs were observed in these animals from test day 4 until the end of the observation period.

In animals which were killed in extremis after treatment on test day 1 marked clinical signs such as collapse, dragging of fore and hind limbs, moderately to markedly decreased activity, slightly to moderately ruffled fur, ptosis and/or clear lacrimation of both eyes, slight to marked tachypnea, prostration, hunched posture and moderately reduced body temperature were observed prior to sacrifice.

The body weight of the animals was within the range commonly recorded for this strain and age. Body weight development of the surviving animals was not affected by treatment with the test item.

There were no macroscopic findings at the necropsy of the animals that survived the scheduled observation period. The stomach of all animals which were killed in extremis on test day 1 contained fluid. Additionally, the animal treated with 950 mg/kg was noted with light brown discolored kidneys.

The estimated median lethal dose of test item after single oral administration to female rats, observed over a period of 14 days, is:

LD50 (female rat) = 300 mg/kg body weight (the one dose with partial response), 95% PL confidence interval is 50.13 to 1220 mg/kg body weight