4,6-Dichloro-5-fluoropyrimidine

Endpoint summary

Description of key information

Acute oral toxicity study (TG 423): LD50 >30 < 50 mg/kg/bw

Acute dermal toxicity study (TG 402): LD50 >=304 <= 365 mg/kg/bw

 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001-08-09 to 2002-08-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

22 March 1996

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

HsdCpb:WU

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, District of Paderborn
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: males approx. 10 weeks and females approx. 9 weeks
- Weight at study initiation: males: 242-266 g; females: 172-188 g
- Fasting period before study: not reported
- Housing: grouped, conventionally in polycarbonate cages; the bedding consisted of low-dust wood granules type BK 8/15 (supplier: Ssniff, Spezialdiäten GmbH, Soest/Westphalia).
- Diet (e.g. ad libitum): ad libitum, "NAFAG Ò No. 9441 W 10" (manufacturer: Eberle Nafag AG, Gossau)
- Water (e.g. ad libitum): ad libitum, tap water
- Acclimation period: 5 days

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

Route of administration:

oral: gavage

Vehicle:

other: The test substance was formulated in demineralized water with the aid of 2 % Cremophor EL before administration.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200, 20 and 2.5 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw


CLASS METHOD (if applicable) acute toxic class
- Rationale for the selection of the starting dose: as required by the test guideline

Doses:

2000, 200 and 25 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weights of the rats are recorded on day 1 before administration and then weekly.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Classification is based on cut-off values as indicated in the OECD guideline.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 30 - < 50 mg/kg bw

Based on:

test mat.

Mortality:

All animals of the 2000 mg/kg bw and the 200 mg/kg bw group died within 5 to 50 min and 20 min to 2 h, respectively.

Clinical signs:

irregular respiration

observations of tremors

salivation

other:

Body weight:

other body weight observations

Remarks:

The body weight and the body weight development of males and females were not affected by the treatment.

Gross pathology:

In animals that died during the observation period the following changes were detected:
Dark-red discoloration of liver
Slightly collapsed lung
Pale discoloration of kidneys
Pale discoloration of spleen
No gross pathologic changes were observed in animals sacrificed at the end of the study period.

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

In the present study conducted according to OECD test guideline 423 (1996) three animals were administered a single dose of either 2000, 200 or 25 mg/kg bw of the test substance and observed for further 14 days. All animals of the 2000 mg/kg bw and the 200 mg/kg bw groups died at least within 2h. None of the animals of the 25 mg/kg bw group died, thus the LD50 value was determined at > 30 < 50 mg/kg bw.

Executive summary:

In an acute oral toxicity study according to OECD guideline 423, adopted 22 March 1996, 6 female, fasted, 9 weeks old Wistar strain rats and 3 male, fasted, 10 weeks old Wistar strain rats were given a single oral dose of 4,6-dichlor-5-fluorpyrimidinbe in demineralized water containing 2% Cremophor by gavage at a dose of 2000, 200 (females) and 25 mg/kg bw (males and females) and observed for 14 days.

6/6 animals of the 2000 and 200 mg/kg bw groups died 50 min and 2h after dosing, respectively. Clinical signs shown by the animals found dead included decreased, uncoordinated gait, labored breathing, increased salivation, narrowed palpebral fissures, and temporary tremor,. lateral position, temporary convulsions, reddened skin, increased motility, and tachypnea.

A dose of 25 mg/kg body weight was tolerated by male and female rats without mortalities and clinical signs.

The body weight and the body weight development of males and females were not affected by the treatment.

In animals that died during the observation period the following changes were detected:

Dark-red discoloration of liver

Slightly collapsed lung

Pale discoloration of kidneys

Pale discoloration of spleen

No gross pathologic changes were observed in animals sacrificed at the end of the study period.

Oral LD50 (rat, combined) > 30< 50 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

>= 30 - <= 50 mg/kg bw

Quality of whole database:

guideline study, reliability and validity high

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

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

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

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

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.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

365 mg/kg bw

Based on:

test mat.

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.

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”.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

>= 304 - <= 365 mg/kg bw

Quality of whole database:

guideline study, reliability and validity high

Justification for classification or non-classification

Based on the presented results 4,6-Dichloro-5-fluorpyrimidine needs to be classified according to Regulation (EU) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling (GHS) as 'fatal if swallowed' Category 2 and 'toxic in contact with skin' Category 3 with regard to oral and dermal acute toxicity, respectively.