4,6-Dichloro-5-fluoropyrimidine

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001-07-29 to 2003-07-14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

17 July 1992

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2600 (Skin Sensitisation)

Version / remarks:

August 1998

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

A valid GPMT conducted according to guideline is available, which is reliable without restrictions and adequate for classification and labelling purposes. Potency estimation is not mandatory when existing guideline and GLP conforming data are available, which were conducted before the new annex of the REACH Regulation entered into force. For this reason and for reasons of animal welfare no additional LLNA was conducted.

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

In vivo test system

Test animals

Species:

guinea pig

Strain:

Hartley

Remarks:

Crl: HA for the main study and HsdPoc:DH for the rasnge finding study

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratory Animal Breeders in 88353 Kißlegg and Harlan Winkelmann GmbH Laboratory Animal Breeders in 33176 Borchen
- Females (if applicable) nulliparous and non-pregnant: yes
- Microbiological status of animals, when known:
- Age at study initiation: 4 weeks
- Weight at study initiation: 272-377 g
- Housing: the animals were conventionally kept in type IV Makrolon® cages, in groups of five during the adaptation period and in groups of two or three per cage throughout the study period. Low-dust wood shavings supplied by Ssniff Spezialdiaten GmbH, Soest, were used as bedding.
- Diet (e.g. ad libitum): ad libitum, "PROVIMI KLIBA 3420 - Maintenance Diet for Guinea Pigs" supplied by PROVOMI KLIBA AG
- Water (e.g. ad libitum): ad libitum, tap water
- Acclimation period: 5 days
- Indication of any skin lesions: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 40- 60
- Air changes (per hr):10
- Photoperiod (hrs dark / hrs light):12/12

Study design: in vivo (non-LLNA)

No. of animals per dose:

20 animals for the main study and treatment groups and 10 animals for the control and the range-finding experiments

Details on study design:

RANGE FINDING TESTS:

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: two, epicutaneous and intradermal
- Exposure period: 48 h for epicutaneous
- Test groups:
Epicutaneous:
Test item group: 0.5 ml 1% HEC 5725-DCF-PYRIMIDINE
intradermal:
Injection site: medial/bilateral 0.5% HEC 5725-DCF-PYRIMIDINE formulated in polyethylene glycol 400
Injection site: caudal/bilateral 0.5% HEC 5725-DCF-PYRIMIDINE formulated at equal parts in polyethylene
glycol 400 and complete Freund's adjuvant
- Control group:
Epicutaneous: 0.5 ml polyethylene glycol 400
Intradermal: Injection site: cranial/bilateral complete Freund's adjuvant (DIFCO LAB.) diluted 1:1 with sterile physicological saline solution
- Site: Dorsal
- Frequency of applications: Epicutaneous once one week prior to intradermal injection.
Intradermal once 21 days before challenge
- Duration: Epicutaneous 48 h
- Concentrations: Intradermal 0.5%; Epicutaneous: 1%

B. CHALLENGE EXPOSURE
- No. of exposures: One
- Day(s) of challenge: 22nd
- Exposure period: 24 h
- Test groups: 1% test item in polyethylene glycol
- Control group: 1% test item in polyethylene glycol
- Site: the 1% test item
formulation was placed on the right flank (caudal) of the animals of the test item group and the control group and held securely in place on the skin with a ORABAND® self-adhesive tape for 24 hours.
- Concentrations: 1%
- Evaluation (hr after challenge): 21 h

Results and discussion

Positive control results:

alpha-Hexylzimtaldehyd formulated in sterile physicological saline solution

In vivo (non-LLNA)

Results

Results 1

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

positive control

Dose level:

5% induction and 12% challenge

Remarks on result:

other: total number of animals was not reported: 100% dermal reaction to positive control

Results 2

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

1%

No. with + reactions:

0

Total no. in group:

10

Results 3

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

1%

No. with + reactions:

0

Total no. in group:

10

Results 4

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

1%

No. with + reactions:

18

Total no. in group:

20

Clinical observations:

Appearance and behaviour of the test item group were not different from the control group.

Results 5

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

1%

No. with + reactions:

20

Total no. in group:

20

Clinical observations:

Appearance and behaviour of the test item group were not different from the control group.

Applicant's summary and conclusion

Interpretation of results:

Category 1A (indication of significant skin sensitising potential) based on GHS criteria

Conclusions:

After the intradermal induction the animals in the test item group showed strong effects up to encrustation at the injection sites of the first induction.
The challenge with the 1% test item formulation led to skin effects (grade 1-3) in 20
of 20 animals (100%) in the test item group and no skin effects were seen in the
control group animals. In summary, by comparing the results in the treatment group and in the control group under the conditions of the maximization test and with respect to the evaluation criteria the test item therefore exhibits a skin sensitization potential.

Executive summary:

In a dermal sensitization study according to OECD test guideline 406 (1992) with 4,6-dichlor-5-fluorpyrimidine (100 % a.i).] in polyethylene glycol, young adult Hartley guinea pigs(20/treatment group) were tested using the method of Magnusson and Kligman. After the intradermal induction the animals in the test item group showed strong effects up to encrustation at the injection sites of the first induction. The challenge with the 1% test item formulation led to skin effects (grade 1-3) in 20 of 20 animals (100%) in the test item group and no skin effects were seen in the control group animals.

Based on the results 4,6-dichlor-5-fluorpyrimidine is classified according to Regulation (EU) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) as skin sensitizer Category 1A (May cause an allergic skin reaction).