6-Amino-5-chloro-2-cyclopyrimidine-4-carboxylic acid

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 March - 01 June 2007

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 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted 12 May 1981

Deviations:

no

GLP compliance:

yes

Test type:

traditional method

Limit test:

yes

Test material

Test material information

1

Reference substance name:

6-amino-5-chloro-2-cyclopropylpyrimidine-4-carboxylic acid

EC Number:

617-769-9

Cas Number:

858956-08-8

Molecular formula:

C8H8ClN3O2

IUPAC Name:

6-amino-5-chloro-2-cyclopropylpyrimidine-4-carboxylic acid

Test animals

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina, USA
- Age at study initiation: approximately 8 weeks (males and females)
- Weight at study initiation: 249 - 270 g (males), 181 - 197 g (females)
- Housing: individually in stainless steel, wire-mesh cages suspended above cage boards
- Diet: PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002, ad libitum
- Water: ad libitum
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26
- Humidity (%): 30 - 70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

3.5 µm

Geometric standard deviation (GSD):

1.9

Remark on MMAD/GSD:

Particle size distribution:
2.2 - 2.5 % of aerosols: less than 1 µm MMAD
37 - 49 % of aerosols: less than 3 µm MMAD
86 - 87 % of aerosols: less than 10 µm MMAD

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass (cylindrical) exposure chamber
- Exposure chamber volume: 36 L
- Method of holding animals in test chamber: Animals were individually restrained in perforated stainless steel cylinders with conical nose pieces. The restrainers were inserted into a polymethylmethacrylate faceplate attached to the exposure chamber so that the nose of each animal extended into the exposure chamber.
- Source and rate of air: house air
- Method of conditioning air: The chamber atmosphere was generated by suspension of the test substance in air with a Fluid Energy Processing model 00 Jet-O-Mizer.
- System of generating particulates/aerosols: The test substance was metered into the jetmill with a K-Tron model T-20 Twin Screw volumetric feeder. Filtered, high-pressure air, metered into the jetmill, carried the resulting atmosphere through a 1-L glass cyclone and into the exposure chamber. Chamber concentrations of test substance were controlled by varying the test substance feed rate to the jetmill.
- Method of particle size determination: Sierra® series 210 cyclone preseparator/cascade impactor and Sierra® series 110 constant flow air sampler
- Treatment of exhaust air: The test atmosphere was exhausted through a high-capacity canister filter prior to discharge into the fume hood.
- Temperature, humidity, airflow range, oxygen concentration: 20-22°C, 45-49%, 20 L/min (34 air changes/h), 21%

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetric analysis. The known volumes of chamber atmosphere were drawn from the sampling port through a 25 mm filter cassette containing a pre-weighed glass fiber (Type A/E) filter. The filters were weighed on a Cahn model C-30 Microbalance®. The atmospheric concentration of the test substance was calculated from the difference between the pre- and post-sampling filter weights divided by the volume of chamber atmosphere sampled. High performance liquid chromatography (HPLC) analysis was used to determine the percentage of active ingredient on the gravimetric filters. HPLC analysis showed that the mean DPX-MAT28 content on the filters was 90% of the collected mean gravimetric mass (8.6 g vs. 9.6 g). The average recovery of DPX-MAT28 active ingredient was 98%.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle: air

TEST ATMOSPHERE
- Particle size distribution: 2.2 - 2.5 % of aerosols: less than 1 µm MMAD, 37 - 49 % of aerosols: less than 3 µm MMAD, 86 - 87 % of aerosols: less than 10 µm MMAD
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 3.5 μm ± 1.9

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Air samples were collected at 3 separate locations (faceplate) and at the reference port. All samples (faceplate) were within 20% of the overall mean and were homogenously distributed. Difference between faceplate measurements and reference port was <1%.

Duration of exposure:

4 h

Concentrations:

5.4 ± 0.9 mg/L (mean ± standard deviation)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily for clinical signs and mortality, body weight at days 0, 1, 2, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight other: gross pathology examination included observation of the nasal passages

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.4 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortalities were observed.

Clinical signs:

other:

Body weight:

One day following exposure to the test substance, a slight, reduction in mean body weight was observed in males, but not in females. By post-exposure day 2, all rats gained body weight.

Gross pathology:

Animals sacrificed at the end of the post-treatment observation period showed no evidence of gross lesions.

Applicant's summary and conclusion

Interpretation of results:

other: CLP/EU GHS criteria are not met, no classification required according to Regulation (EC) No 1272/2008.

Conclusions:

In this acute inhalation toxicity study in rats a LC50 value of > 5.4 mg/L air was determined.