Pyrimidine, 2-ethoxy-4,6-difluoro-

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28 September 1993 to 1 February 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-ethoxy-4,6-difluoropyrimidine

EC Number:

692-762-1

Cas Number:

166524-65-8

Molecular formula:

C6H6F2N2O

IUPAC Name:

2-ethoxy-4,6-difluoropyrimidine

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): 2-ethoxy-4,6-difluoropyrimidine (DFEP)
- Physical state: liquid
- Vapour pressure: 1.2489 mm Hg at 24 °C
- Saturated atmosphere: approximately 1643 ppm at 24 °C
- Lower flammability limit: 1.4 ± 0.3 Vol. %
- Boiling point: 165 °C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8 - 11 weeks (on arrival); 12 - 13 weeks (time of exposure)
- Weight at study initiation (group mean values): 226.1 - 257.0 g (males); 152.8 - 162.0 g (females)
- Housing: 2 per cage in stainless steel wire cages during acclimation; individually housed post exposure
- Diet: Rodent Chow, ad libitum
- Water: municipal water, ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 24 °C (during exposure)
- Humidity (%): 43 - 54 % (during exposure)
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

CHAMBERS
A stainless steel and glass 157 L Rochester-type chamber (50 cm x 50 cm x 50 cm) with pyramidal top and bottom was used for the study. Compressed air supplied to the chamber was controlled by a system designed to maintain temperature at approximately 22 °C. Airflow was maintained at approximately 30 L/min, which was sufficient to provide the normal concentration of oxygen to the animals. Rats were exposed to the test material by whole-body techniques and were housed singly to minimise crowding during the exposure period. The chamber was operated at slight negative pressure relative to the surrounding area.

GENERATION SYSTEM
The test material was vapourised using the glass J-tube method.

CHAMBER MONITORING
Airflow through each chamber was determined with a manometer. The manometer was calibrated with a gas meter prior to the start of the study. Relative humidity was determined with a hygrometer. The hygrometer was calibrated prior to the initial exposure with a Bacharach sling psychrometer. Temperature, relative humidity and airflow values were recorded every 30 minutes during the 4 hour exposure period.

NOMINAL CONCENTRATION
The nominal concentration of the vapour present in the chamber was determined as accurately as possible based on the amount of test material used and the total chamber airflow.

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

4 h

Concentrations:

127, 287, 528 and 1620 ppm

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were weighed and examined prior to exposure to the test material. All animals were observed during the exposure period and daily during the 14 day post exposure period. All surviving animals were weighed on test days 2, 4, 8, 11 and 15.
- Necropsy of survivors performed: yes. All animals that died were submitted as soon as possible for a complete necropsy examination. All surviving animals were submitted for a complete gross necropsy examination on test day 15. The rats were anaesthetised with methoxyflurane and euthanised.
- Examinations performed: Observations included an evaluation of the fur, eyes, mucous membranes and respiration. Behaviour pattern and nervous system activity were assessed by specific observation for tremors, convulsions, salivation, lacrimation and diarrhoea, as well as lethargy and other signs of altered central nervous system function. Observations and routine monitoring on weekends and holidays was limited to husbandry procedures.
Necropsy examination included examination of the eyes with a microscope slide using fluorescent illumination. Tissues were not saved and histopathologic examination was not performed.

Statistics:

The LC50 was determined by linear interpolation.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

191 ppm

Based on:

test mat.

Exp. duration:

4 h

Mortality:

All animals exposed to test atmospheres of 287 ppm and above died during or shortly after the exposure. There were no deaths as a result of exposure to 127 ppm test material.

Clinical signs:

other: Clinical observations noted during the exposures to test atmospheres of 287 ppm and above included squinted eyes and lacrimation, salivation, nasal discharge, decreased activity, lateral recumbency and laboured breathing. Clinical observations noted durin

Body weight:

The mean body weights of male and female rats exposed to 127 ppm were decreased 7 and 10 %, respectively, on the day following exposure. The mean body weights of both males and females surpassed pre-exposure values by day 11 and increased 4 % by the end of the two week post exposure period.

Gross pathology:

All animals from the 1620 and 528 ppm exposure groups had visceral congestion. Atelectasis was noted in two animals from the 287 ppm exposure group. The remaining animals from the 287 ppm exposure group, and all animals from the 127 ppm exposure group, had no treatment-related observations.

Any other information on results incl. tables

Table 1: Group Mean Body Weights (grams)

Sex	Exposure conc (ppm)	Test day
		1	2	4	8	11	15
M	127	230.5	213.3	221.1	228.6	231.6	239.7
	287	226.1	***	***	***	***	***
	528	257.0	***	***	***	***	***
	1620	252.5	***	***	***	***	***
F	127	162.0	145.7	153.3	160.1	162.2	168.0
	287	153.8	***	***	***	***	***
	528	156.3	***	***	***	***	***
	1620	152.8	***	***	***	***	***

*** all animals dead

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category II

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on linear interpolation between 127 and 287 ppm, the 4 hour LC50 value of the test material in Fischer 344 rats was determined to be 191 ppm under the conditions of this study. The test material therefore requires classification as Category 2 in accordance with EU criteria.

Executive summary:

The acute inhalation toxicity of the test material was determined in a study conducted under GLP conditions and in accordance with the standardised guideline OECD 403.

During the study, groups of 5 male and 5 female Fischer 344 rats were exposed to test atmospheres of 127, 287, 528 and 1620 ppm test material for a single 4 hour exposure period. In-life observations were made, and body weights were taken during the 14 day post-exposure period. All animals underwent a gross pathologic examination.

Under the conditions of the study, all animals exposed to test atmospheres of 287 ppm and above died during or shortly after the exposure. Clinical observations included: squinted eyes and lacrimation, salivation, nasal discharge, decreased activity, lateral recumbency and laboured breathing. There were no deaths as a result of exposure to 127 ppm test material and clinical signs were limited to squinted eyes and lacrimation in these animals; all animals appeared normal by test day 6. Mean body weights of both male and female rats exposed to 127 ppm were decreased up to 10 days following exposure. At the end of the two week observation period, the mean body weights were increased slightly when compared to pre-exposure values. Non-specific gross pathologic observations were noted in most animals that died as a result of exposure. No treatment-related observations were noted in any animal that survived exposure.

Based on linear interpolation between 127 and 287 ppm, the 4 hour LC50 value of the test material in Fischer 344 rats was determined to be 191 ppm under the conditions of this study. The test material therefore requires classification as Category 2 in accordance with EU criteria.