N-((3R,4R)-1-benzyl-4-alkylpiperidin-3-yl)-2-halogeno-N-alkyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 03 to 16 January 2008

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:

2008

Report date:

2008

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Details on test material:

Purity: 94.2%
Batch No.: E010005747 or 902/690550/A/1/1

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Harlan Netherlands BV
- Age at study initiation: 13 weeks (male), 12-13 weeks (females)
- Weight at study initiation: No.67: 2991g, No.68: 2538g, No.69: 2690g
- Housing: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks and haysticks were provided for gnawing.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23 °C
- Humidity (%): 30-70 %
- Air changes (per hr): Air-conditioned with 10-15 air change her hour
- Photoperiod (hrs dark / hrs light): automatically controlled lighte cycle of 12 hrs dark/12 hrs light

IN-LIFE DATES: From: 03 January 2008 To: 16 January 2008

Test system

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g per animal
- Concentration (if solution):

VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:

Duration of treatment / exposure:

Single instillation, eye unwashed

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

One male, two females

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:

SCORING SYSTEM: Commission Directive 2004/73/EC, April 29, 2004

TOOL USED TO ASSESS SCORE: Varta Cliptrix diagnostic-lamp
The eyes of each animal were examined approximately 1, 24, 48, 72 hours, as well as 7 days after administration.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

1

Reversibility:

fully reversible within: 24 hours

Results 2

Irritation parameter:

iris score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

0

Results 3

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

ca. 0.89

Max. score:

2

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Two animals were reversible with 72 hours and one reversible within 7 days.

Results 4

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

ca. 0.22

Max. score:

2

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: Two animals were reversible with 24 hours and one reversible within 72 hours.

Irritant / corrosive response data:

The mean score was calculated across 3 scoring times (24, 48 and 72 hours after instillation) for each animal for corneal opacity, iris, redness and chemosis of the conjunctivae, separately. The individual mean scores for corneal opacity and iris were 0.00 for all the animals. The individual mean scores for the conjunctivae were 0.67, 1.33 and 0.67 for reddening and 0.00, 0.67 and 0.00 for chemosis, respectively.
A very slight opacity affecting the whole was observed in both females 1 hour after instillation.
A moderate reddening of the conjunctivae was noted in all animals at the same observation time point and persisted as slight up to the 48- and 72- hour reading, respectively. Additionally, a slightly to obvious swelling of the conjunctivae with partial eversion of lids was observed in all animals at the 1- hour observation and persisted as slight up to the 48- hour evaluation in the first treated female.
A slight to moderate reddening of the sclera was present in the three animals 1 hour after treatment and persisted as slight up to the 24- and 72- hour reading, respectively.
Slight to moderate ocular discharge was present in all animals 1 hour after instillation.
No abnormal findings were observed in the treated eye of any animal 72 hours of 7 days after treatment.
No corrosion of the cornea was observed at any of the reading times.

Any other information on results incl. tables

No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred.

 

No staining produced by the test item of the treated eye was observed.

 

Brown test item remnants were evident in the eye or conjunctival sac of all animals 1 hour after instillation and persisted up to the 24- or 48- hour reading in both females.

 

The body weights of all rabbits were considered to be within the normal range of variability.

Body weight in grams
Animal No.	Sex	First Day of Acclimatization	Day of Treatment	Last Day of Observation
67	male	2700	2991	3238
68	female	2419	2538	2784
69	female	2284	2690	2966

Eye Irritation Scores- Individual Values

Animal Number	Sex	Evaluation Interval	Corneal Opacity	Area of Corneal Opacity	Iris	Conjunctivae		Sclera
						Redness	Chemosis
67 68 69	M F F	1 hour	0 1 1	0 4 4	0 0 0	2 2 2	1 2 1	2 2 1
67 68 69	M F F	24 hours	0 0 0	0 0 0	0 0 0	1 2 1	0 1 0	1 1 1
67 68 69	M F F	48 hours	0 0 0	0 0 0	0 0 0	1 1 1	0 1 0	0 1 0
67 68 69	M F F	72 hours	0 0 0	0 0 0	0 0 0	0 1 0	0 0 0	0 1 0
67 68 69	M F F	7 days	0 0 0	0 0 0	0 0 0	0 0 0	0 0 0	0 0 0

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test substance is considered to be not irritating to the rabbit eye.