Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1R,4S)-, compd. with rel-(.alpha.R,.beta.S)-.alpha.-(2,4-difluorophenyl)-5-fluoro-.beta.-methyl-.alpha.-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol (1:1)

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 3 to 24 June 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study run to a method comparable with current guidelines and to GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

188416- 34-4

IUPAC Name:

188416- 34-4

Constituent 2

Reference substance name:

(2RS,3SR)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1R)-10- camphorsulphonate

IUPAC Name:

(2RS,3SR)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1R)-10- camphorsulphonate

Constituent 3

Reference substance name:

2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methanesulfonate

EC Number:

917-473-2

Cas Number:

188416-34-4

Molecular formula:

C16H14F3N5O . C10H16O4S

IUPAC Name:

2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methanesulfonate

Details on test material:

- Analytical purity: 96.5%
- Lot/batch No.: 5ABK-003

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Harlan Interfauna UK Ltd, Huntingdon, Cambridgeshire, England
- Age at study initiation: Approximately 13 weeks of age
- Weight at study initiation: 3.2 kg
- Housing: Housed individually in metal cages with perforated floors
- Diet (e.g. ad libitum): A standard laboratory diet SDS Stanrab (P) Rabbit Diet
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Approximately 19℃
- Humidity (%): 30-70%
- Air changes (per hr): Approximately 19 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours of artificial light in each 24 hours period.

Test system

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Approximately 84 mg
- Concentration (if solution):

Duration of treatment / exposure:

Single instillation without washing

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

1

Details on study design:

Due to the low pH of the test material (pH 1.98), one animal was treated in advance of others to ensure that if a severe response was produced, no further animals would be exposed. As a result of the severity of ocular reactions observed, no further animals were treated.
Approximately 84 mg of the test substance, the weight occupying a volume of 0.1 ml, it was placed into the lower everted lid of one eye of each animal. The eyelids were then gently held together for one second before releasing.
The contralateral eye remained untreated.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

other: Mean of 24, 48 and 72 hours

Score:

3.33

Max. score:

4

Reversibility:

fully reversible within: 14 days

Results 2

Irritation parameter:

iris score

Basis:

animal #1

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

0

Remarks on result:

other: No reactions

Results 3

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

animal #1

Time point:

other: Mean of 24, 48 and 72 hours

Score:

2.67

Max. score:

3

Reversibility:

fully reversible within: 21 days

Remarks on result:

other: Blanching of nictating membrane

Results 4

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

other: Mean of 24, 48 and 72 hours

Score:

2

Max. score:

2

Reversibility:

fully reversible within: 21 days

Irritant / corrosive response data:

Examination of the eye was made after 1 hour and 1, 2, 3, 4, 7, 14 and 21 days after instillation.
The numerical values given to the ocular reactions elicited by this substance are shown below. No iridial inflammation was observed. Corneal opacification (Grade 4) was noted within one hour of dosing.
A diffuse beefy red colouration of the conjunctivae was seen, accompanied by blanching of the nictating membrane and swelling with partial eversion of the eyelids. These responses gradually ameliorated and the eye was normal 21 days after instillation.

Any other information on results incl. tables

There were no signs of toxicity or ill health in any rabbit during the observation period.

Rabbit number and sex	Region of eye			One hour	Day after instillation
					1	2	3	4	7	14	21
2885 ♂	Cornea	Density		4	4	3	3	3	1	0	0
		Area		1	1	1	1	1	1	0	0
	Iris			0	0	0	0	0	0	0	0
	Conjunctiva		Redness	2a	2a	3a	3a	3a	2	2	0
			Chemosis	2	2	2	2	2	2	1	0

Pilot animal

A Blanching of nictating membrane

 

Applicant's summary and conclusion

Interpretation of results:

moderately irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Instillation of the substance into the rabbit eye elicited corneal opacification and moderate conjuntival irritation.