4,6-Dichloro-5-fluoropyrimidine

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005-04-05 to 2005-08-01

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

23 February 1987

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

1

Reference substance name:

-

EC Number:

446-560-3

EC Name:

-

Cas Number:

213265-83-9

Molecular formula:

C4HCl2FN2

IUPAC Name:

4,6-dichloro-5-fluoropyrimidine

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan/Winkelmann GmbH, 33178 Borchen, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 9-13 weeks
- Weight at study initiation: males: 203-255 g; females: 207-232 g
- Fasting period before study:
- Housing: The animals were caged individually in polycarbonate cages on low dust wood granulate bedding (J. Rettenmaier & Sohne, 73494 Rosenberg, Germany).
- Diet (e.g. ad libitum): The animals received the standard diet "Provimi Kliba 3883.0.15 Maus/Ratte Haltung, Kaiseraugst Switzerland", ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 5
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: between 1.0 and 20.0 cm²
- % coverage: approx. 10%
- Type of wrap if used: For each dose and animal the required amount of the pure liquid test substance was weighed and applied as uniformly and thinly as possible to the test area, covered with a gauze-layer (6.0 cm x 5.0 cm = 30.0 cm²) of a ,,Cutiplast® steril" coated with air-tight ,,Leukoflex®". The gauze strip was placed on the rat's back and secured in place using ,,Peha®-Haft" cohesive stretch tape (8 cm x 23 cm) and additionally covered with a "Lomir biomedical Inc rat jacket", which was connected with a
safety pin to the stretch tape to ensure that the animals could not ingest the test
substance.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After 24 h the dressings were removed and the area was rinsed with tepid water using soap and gently patting the area dry.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): between 20.5 and 75.0 mg/cm²

Duration of exposure:

24 h

Doses:

160, 400, 1000, 4000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 21 days
- Frequency of observations and weighing: Clinical signs and mortality rates were determined several times on the day of application and subsequently at least once daily for an observation period of at least 21 days. The weight gain of the animals was checked weekly until the end of the study.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

The LD50 value was calculated with the aid of a software program according to Spearman, Karber (D.J. Finney; Statistical method in biological assay, 2nd Edition, Griffin, London, 524-530; 1971). The algorithm was taken from L. Sachs (Angewandte Statistik, 6th Edition 1984, pp. 178 ff.). Where calculation of the LD50 using the software program was not possible or meaningful, an assessment was made based on the applied dose and dose-response curve, respectively.

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

365 mg/kg bw

Based on:

test mat.

Effect levels 2

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

304 mg/kg bw

Based on:

test mat.

Mortality:

All animals of the 1000 and 4000 mg/kg bw treatment group died within 2 days. In the 400 mg/kg bw dose group 3 males and 4 females died after 2 to 3 days. None of the animals of dose group 160 mg/kg bw died.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

There were no toxicological effects on body weight or body weight development in the surviving males and females.

Gross pathology:

Gross Pathology Findings
4000 mg/kg bw.:
stomach: fluid, gas-filled.
1000 mg/kg bw.:
stomach: consistency-changes light colored, partly reddening.
400 mg/kg bw.:
stomach: partly reddening, hemorrhagic watery fluid; lung: pale discolorations;
skin: black to blue discolorations of the treatment area, scars on the treatment area.
160 mg/kg bw.:
skin: scars on the treatment area.

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Based on the present investigations, HEC 5725-DCF-Pyrimidine is to be regarded to have the following LD50 values:
LD50 rat, male : 365 mg/kg body weight (235-567 mg/kg)
rat, female : 304 mg/kg body weight (212-435 mg/kg)
So it is regarded as low toxic after dermal application.

Executive summary:

In an acute dermal toxicity study according to OECD test guideline 402 (1987), groups of young adult males and female Wistar rats (5/sex) were dermally exposed to 4,6-dichlor-5-fluorpyrimidine (100 % a.i) for 24 hours to 10 % of body surface area at doses of 160, 400, 1000 and 4000 mg/kg bw.  Animals then were observed for 21 days.

Dermal LD50 Males =365 mg/kg bw

                        Females = 304 mg/kg bw

4,6-dichlor-5-fluorpyrimidine is of low Toxicity based on the LD50 value for female Wistar rats. Animals of both high dose groups (1000 and 4000 mg/kg bw) died within 2 days. In all dose groups clinical signs related to treatment were observed corresponding to the findings during necropsy.

 Based on the results the substance needs to be classified according to Regulation (EU) 1272/2008 (CLP) and the Globally Harmonized System for Calssification and Labelling of Chemicals (GHS) as acute toxic via the dermal route Castegory 3 “Toxic in contact to skin”.