2-Chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

01 - 13 Apr 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The in vivo test is performed according to Novartis internal Tiered Testing Strategy as a regular set of tests for all substances during the development of the project. (TRD Development Manual Chapter C.26 requirements.)
The Novartis Pharma Data Set (NPDS) has been put in place many years before the REACh regulation was released and we have, since then, systematically acquired data for all substances (RM, IM, DS, reagents, etc.) on behalf of TRD and PCS, for internal and external classification purposes.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

adopted in 2017

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

adopted in 2012

Test guideline 3

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

adopted in 2008

Test guideline 4

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Version / remarks:

adopted in 1998

Test guideline 5

Qualifier:

according to guideline

Guideline:

other: JMAFF Guidelines

Version / remarks:

adopted in 2000

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Cas Number:

1211443-61-6

Molecular formula:

C14 H17 Cl N4 O

IUPAC Name:

2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River France, L’Arbresle, France
- Age at study initiation: approx. 32 - 33 weeks
- Weight at study initiation: 4230 - 4478 g
- Housing: individual, in labeled cages with perforated floors (Ebeco, Germany, dimensions 67 x 62 x 55 cm), animals were provided with shelters (Ebeco, Germany, dimensions 40 x 32 x 23 cm) and wooden sticks (Swedish aspen wood, Bioservices, Uden, The Netherlands) except when interrupted by study procedures/activities
- Diet: Pelleted diet for rabbits (Global Diet 2030 Teklad®, Mucedola, Milanese, Italy) once daily throughout the study and in addition hay (TecniLab-BMI BV, Someren, The Netherlands) was available during the study period
- Water: Municipal tap-water, ad libitum (analyses were performed)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24 (mean = 20)
- Humidity (%): 40 to 70 (mean = 61 - 62)
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount applied: approx. 81.8 mg; approx. 0.1 mL

Duration of treatment / exposure:

1 h

Observation period (in vivo):

14 days
Reading timepoints: 1, 24, 48 and 72 h and for 1 animal (sentinel) 7 days after instillation of the test substance

Number of animals or in vitro replicates:

3 males

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: Yes, the treated eye was rinsed with approximately 50 mL tepid tap water
- Time after start of exposure: after the 1 h observation

SCORING SYSTEM: Draize method

TOOL USED TO ASSESS SCORE: Fluorescein for evidence of corneal damage

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

iris score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Results 3

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0.9

Max. score:

3

Reversibility:

fully reversible within: 72 h

Remarks on result:

no indication of irritation

Results 4

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

of 3 animals

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

The corneal injury consisted epithelial damage and slight dulling of the normal luster of the cornea. The corneal injury resolved within 24 h in one animal and within 72 h in the other two animal, in the third animal no corneal injury was noted.The irritation of the conjunctivae consisted of redness, chemosis and discharge and completely resolved within 7 days in one animal and within 72 h in the other two animals. No iridial irritation was observed. There was no evidence of ocular corrosion.

Other effects:

- Clinical observations/ mortaliity: No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Any other information on results incl. tables

Table 1: Individual Eye Irritation Scores

Animal No.	Time after dosing	Cornea			Iris	Conjunctivae			Comments
		Opacity	Area	Fluor area (%) (b)		Redness	Chemosis	Discharge
1 (a)	1 h	0	1	-	0	2	1	2	c, d
	24 h	0	0	0	0	2	1	1	-
	48 h	0	0	-	0	1	0	0	-
	72 h	0	0	-	0	0	0	0	-
	7 days	0	0	-	0	0	0	0	-
	Mean (24, 48, 72 h)	0.0	-	-	0.0	1.0	0.3	-	-
2	1 h	0	1	-	0	2	1	1	c, d
	24 h	0	0	15	0	2	1	1	d
	48 h	0	0	-	0	1	0	0	-
	72 h	0	0	0	0	0	0	0	-
	Mean (24, 48, 72 h)	0	-	-	0.0	1.0	0.3	-	-
3	1 h	0	0	-	0	2	1	1	c
	24 h	0	0	0	0	1	1	1	-
	48 h	0	0	-	0	1	0	0	-
	72 h	0	0	-	0	0	0	0	-
	Mean (24, 48, 72 h)	0.0	-	-	0.0	0.7	0.3	-	-
Mean (24, 48, 72 h) of 3 animals		0.0	-	-	0.0	0.9	0.3	-	-

a = sentinel

b = green staining after fluorescein treatment (percentage of total corneal area)

c = remnants of the test substance in the eye

d = slight dulling of the normal luster of the cornea

Applicant's summary and conclusion

Interpretation of results:

other: CLP/ EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008

Conclusions:

CLP: not classified

An in vivo eye irritation study according to OECD Guideline 405 in rabbits was performed with the test substance. The observed effects on the cornea and conjunctivae were reversible within the observation period.