Registration Dossier

Administrative data

Description of key information

Based on the findings of the study, repeated 2-week instillation of Diovan eye drops (5%) two or four times daily into the left and right eye of albino rabbits resulted in no local or systemic intolerance reactions.

Ophthalmological and ophthalmopathological examination of the eyes revealed no changes which are considered to be related to the instillation of the test substance CGP 48933.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin corrosion: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available
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 regulatio
n 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.
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Jun - Nov 2001
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
The objective of the study is to obtain information on the local eye irritation and the systemic toxicity of Diovan eye drops (5%) when administered two or four times daily for 14 days into the conjunctiva! sac of albino rabbits. Four groups of 4 male and 4 female rabbits each were used.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was performed in compliance with:
'Good Laboratory Practice' Regulations of the EC enacted in Germany in the 'Chemikaliengesetz' [Chemicals Act], current edition;
United States Food and Drug Administration Good Laboratory Practice Regulations, 21 Code of Federal Regulations, Part 58, current edition.
The following regulations were considered:
'OECD Principles of Good Laboratory Practice' (as revised in 1997) ENV/MC/CHEM (98) 17, January 21st, 1998;
Japanese Guidelines for Non-clinical Studies of Drugs Manual 1995; Guidelines for Toxicity Studies of Drugs. Japanese Ministry of Health and Welfare.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
32 purebred New Zealand white rabbits ( 1 6 males and 1 6 females) were used for this experiment. Before start of study a thorough examination was given to a pool of 36 animals. Animals were judged to be healthy on the basis of general observations (physical/auditory, ophthalmoscopic- and laboratory examinations). Thereof 32 animals with parameters in the normal range were inserted in this study.
Diet
ALTROMIN 2023 (supplier: ALTROMIN GmbH, D-32791 Lage/Lippe; see Appendix 3:
Composition of the diet) served as food. This food was offered ad libitum. Food
residue was removed and weighed.
Samples of the food are analysed for contaminants based on EPA/USA 1 by AUA2
twice a year (see Appendix 3: Limitation for contaminants in the diet). Certificates
of analysis of the composition and for contaminants were provided by the manufacturer
and are included in the raw data.
Drinking water
Tap water of drinking water quality was offered ad libitum.
Samples of drinking water are taken twice a year by the Wasserbeschaffungsverband
Harburg, D-21220 Seevetal, and are analysed according to the 'Deutsche Trinkwasserverordnung,
Bundesgesetzblatt, Jahrgang 1990' [German Regulations on
drinking water, public notice of the law, 1990] (see Appendix 3: Limitation for
contaminants in the drinking water).
In addition, drinking water samples taken at LPT are analysed by LUFA-ITL3 once a
year for means of bacteriological investigations according to the 'Deutsche Trinkwasserverordnung,
Bundesgesetzblatt, Jahrgang 1990, Anlage 4'
Type of coverage:
other: instillation into the conjunctiva! sac of the left and right eyes
Preparation of test site:
other: Then the lower lids of the eyes were carefully pulled away from the eyeball and the test or control substance was instilled into the conjunctiva! sac.
Vehicle:
other: Diovan eye drops vehicle
Controls:
yes, concurrent vehicle
yes, concurrent negative control
Amount / concentration applied:
Group 1 (negative control)
- right eye: 0.9% NaCl solution
- left eye: 0.9% NaCl solution
1 drop each eye,
4 times a day for 2 weeks, at 2-hours intervals
Group 2 (vehicle control)
- right eye: vehicle
- left eye: vehicle
1 drop each eye,
4 times a day for 2 weeks, at 2-hours intervals
Group 3
- right eye:
- left eye:
Diovan eye drops (5%)
Diovan eye drops (5%)
1 drop each eye,
2 times a day for 2 weeks, at a 6-hours interval
Group 4
- right eye:
- left eye:
Diovan eye drops (5%)
Diovan eye drops (5%)
1 drop each eye,
4 times a day for 2 weeks, at 2-hours
intervals
1 drop ~ 25 μI/instillation/eye
The test formulation was very viscous and hardly droppable.
For instillation of the eye drops the following pipettes were used:
CP 100 ( 10-100 μI) for Mic roman M 100 (GILSON)
Duration of treatment / exposure:
Treatment for 2 weeks
1 drop is cca 25ul
Observation period:
3 adaptation weeks
14 test days
Number of animals:
32 purebred New Zealand white rabbits ( 1 6 males and 1 6 females) were used for
this experiment. Before start of study a thorough examination was given to a pool
of 36 animals. Animals were judged to be healthy on the basis of general observations
(physical/auditory, ophthalmoscopic- and laboratory examinations). Thereof 32
animals with parameters in the normal range were inserted in this study.
Details on study design:
The animals were allocated to the 4 groups by randomisation:
Treatment for 2 weeks
right eye left eye No and sex of animals
____________________________________________________________________________________
0.9% NaCl solution 0.9% NaCl solution 4M, 4F
1 drop per instillation, 1 drop per instillation,
4 times/day, at 2-h intervals 4 times/day, at 2-h intervals
_____________________________________________________________________________________
Vehicle Vehicle 4M, 4F
1 drop per instillation, 1 drop per instillation,
4 times/day, at 2-h intervals 4 times/day, at 2-h intervals
____________________________________________________________________________________
Diovan eye drops (5%) Diovan eye drops (5%) 4M, 4F
1 drop per instillation, 1 drop per instillation,
2 times/day, at a 6-h interval 2 times/day, at a 6-h interval
____________________________________________________________________________________
Diovan eye drops (5%) Diovan eye drops (5%) 4M, 4F
1 drop per instillation, 1 drop per instillation,
4 times/day, at 2-h intervals 4 times/day, at 2-h intervals
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritation parameter:
overall irritation score
Basis:
animal #1
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Remarks on result:
not measured/tested

Ophthalmological examination

No test substance-related changes of the eye and the optic region were observed for any of the tested groups.

The animals did not show any changes to conjunctivae, cornea, anterior chamber, iris, lens or fundus. Miosis, mydriasis or ptosis were not observed. The fluorescein test revealed no test substance-related changes in any of the rabbits.

Ophthalmopathology

The histopathological examination did not reveal any test substance-related morphological changes of the eyes, eyelids and eye-adnexa of all animals examined. There were no differences between the test substance-treated and the control animals.

Systemic tolerance

Behaviour, external appearance, faeces, mortality

Diovan eye drops vehicle administered 4 times/day or Diovan eye drops (5%) administered 2 or 4 times/day did not influence the behaviour and external appearance in any of the animals. None of the rabbits died prematurely.

Body weight

No test substance-related influence was observed on the body weight for any of the tested groups.

Food and drinking water consumption

No test substance-related influence was observed on food consumption for any of the tested groups.

The visual appraisal of the drinking water consumption revealed no differences between the negative control and the animals treated with Diovan eye drops vehicle 4 times/day or Diovan eye drops (5%) 2 or 4 times/day.

Haematology

Treatment with Diovan eye drops vehicle 4 times/day or Diovan eye drops (5%) 2 or 4 times/day did not cause any test substance-related changes to the haematological parameters.

No influence was observed for the differential blood count, the haematocrit value, haemoglobin content, number of erythrocytes, leucocytes, reticulocytes and platelets, the thromboplastin and activated partial thromboplastin time, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC).

Clinical biochemistry

Treatment with Diovan eye drops vehicle 4 times/day or Diovan eye drops (5%) 2 or 4 times/day did not cause any test substance-related changes to the clinicobiochemical parameters.

No influence was observed on the plasma or serum levels of bilirubin (total), cholesterol (total), creatinine, glucose, phosphate (inorganic), protein (total), triglycerides, urea (in blood), calcium, chloride, potassium and sodium.

All results were within the normal limits of the negative control. The serum protein electrophoresis revealed no test substance-related changes. The activity of the alanine aminotransferase (ALAT /GPT), the aspartate aminotransferase

(ASAT/GOT), the alkaline phosphatase (aP) and the lactate dehydrogenase (LDH) was not increased.

All relative organ weights were compared statistically. No test substance-related differences were observed from the negative control for animals treated with Diovan eye drops vehicle 4 times/day or Diovan eye drops (5%) 2 or 4 times/day.

Histopathology

The histopathological examination did not reveal any test substance-related morphological changes in any ot the organs examined.

Bone marrow evaluation

No test substance-related changes were noted on the myeloid : erythroid ratio.

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the findings of the study, repeated 2-week instillation of Diovan eye drops (5%) two or four times daily into the left and right eye of albino rabbits resulted in no local or systemic intolerance reactions.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available
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 regulatio
n 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.
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Aug 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
no guideline followed
Principles of method if other than guideline:
The rum of this ex-periment was to obtain information on the local tolerance of rabbits (pigmented Himalayan) to CGP 48933 (ex tempore), batch no. 800291, during short-term administration into the conjunctival sac of the right eye. The rabbits were also examined for their systemic reactions. As control animals, further rabbits were used which were treated \\oith 0.9% sodium chloride solution, batch no. 914425, abbreviated to 'Control'.
The present paper reports on the results of an experiment m which either a 0.5% solution or a 2.0% solution of CGP 43933 was instilled into the conjunctival sac of the right eye of rabbits for a period of 5 days. The solutions were prepared according to the sponsor's instructions and administered at a volume of 50 pi/animal .either 4 times/day at intervals of 90 minutes or 8 times/day at intervals of 45 minutes.
The study was performed in compliance \\oith the principles of 'Good Laboratory Practice' regulations (cf Management Statement, QAU Statement and the 'enclosure' for details).
GLP compliance:
yes
Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
12 male and 12 female pure-bred pigmented Himalayan rabbits aged approximately 4 months were used for this experiment (breeder: CHR.F. LEUSCHNER & Co., D-2355 Löhndorf).
Initial body weight at the start of treatment was 2.1 to 2.4 kg (males) and 2.2 to 2.6 kg (females). Animals were identified by ear tattoo and cage number.
Each rabbit received a continuous number from the breeding station Löhndorf.

Food, water and accommodation
ALTROMIN 2023 served as food. Periodic analyses of the food for contaminants are carried out at least tv.ice a year by the Landv:irtschaftliche Untersuchungs- und Forschungsanstalt · Kiel, Gutenbergstral3e 75 - 77, D-2300 Kiel 1. This food was offered ad lib. Food residue was removed and weighed.
All analyses are performed based on EPA/USA, Proposed Health Effects Test Standards for Toxic Substances Control Act Test Rules, Federal Register, 44, 27334 - 27375, May 1979_ The results were \\ithin the admissible limits.
Tap water was also given unrestrictedly (in drinking bottles). Samples of the water are analysed regularly (twice a year) by Medizinisches Zentral-Laboratorium, Lauenburger Str. 65, D-2054 Geesthacht.
Vehicle:
other: (100 mM Na2HPO4 + 50 mM 0.9% NaCl solution + 10 N NaOH
Controls:
yes, concurrent negative control
Amount / concentration applied:
Group 2:
50 ul CGP 48933 (ex tempore) (0.5% solution) referred to in this report as 0.5% CGP 48933
4 instillations/animal/day at intervals of 90 minutes
Group 3:
50 ul CGP 48933 (ex tempore) (2.0% solution), referred to in this report as 2% CGP 48933
4 instillations/animal/day at intervals of 90 minutes
Group 4:
50 ul CGP 48933 (ex tempore) (2.0% solution), referred to in this report as 2% CGP 48933
8 instillations/animal/day at intervals of 45 minutes

Group 1: Control
50 ul 0.9% NaCl solution (control solution)
8 instillations/animal/day at intervals of 45 minutes
Duration of treatment / exposure:
5 days
Observation period (in vivo):
5days
Number of animals or in vitro replicates:
24 (12 male and 12 female) rabbits
four groups each containing 3 male and 3 female rabbits
Details on study design:
Route of administration: into the conjunctival sac of the right eye; the left eye remained untreated
Treatment vwith 50 ul 0.5% CGP 48933/animal 4 times per day, or with 50 ul 2% CGP 48933/animal 4 or 8 times per day,
or with 50 ul 0.9% NaCl solution/animal 8 times per day into the conjunctival sac of the right eye did not cause any substancerelated intolerance reactions in the eye and the optic region during or after 5 test days.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
The study was 5-day ocular tolerance study, not only 72 as indicated in the table (due to validation).

During the 5 - day treatment, the conjunctivae of each animal were examined on a daily basis before the first and after the last instillation.

Redness (grade 1 or 2 based on BALDWIN) was detected as follows TD5 and/or 6:

Group 1: 50 ul 0.9% NaCl solution/animal, 8 instillations/day (control)

no. 2 m left untreated eye                                   grade 1       

no. 5 f left untreated eye, right treated eye        grade 1           

Group 2: 50 ul 0.5% CGP 48933/animal, 4 instillations/day

no. 2m right treated eye                                   grade 2

no. 3m left untreated eye                                   grade 1

no. 4 f left untreated eye                                   grade 1

Group 3: 50 ul 2% CGP 48933/animal, 4 instillations/day

no. 5 f left untreated eye                                   grade 1

no. 6f left untreated eye                                    grade 1

Opacity of the cornea (grade 1 based on BALDWIN) was observed animals in the treated right eye only, TD5 and/or 6:

Group 1: 50 ul 0.9% NaCl solution/animal, 8 instillations/day (control)

no. 1 m right treated eye                                   grade 1

Group 3: 50 ul 2% CGP 48933/animal, 4 instillations/day

no. 5 f right treated eye                                  grade 1

Group 4: 50 ul2% CGP 48933/animal, 8 instillations/day

no. 5 f right treated eye                                   grade 1

no. 6 f left untreated eye, right treated eye       grade 1

The fluorescein test resulted in slight staining (grade 1) in 50% of the cornea in one control animal (50 ,ul 0.9% NaCl solution/animal, 8 instillations/day) during both of the examinations on test day 5 and moderate staining (grade 2) in 50% of the cornea during the examination carried out on test day 6.

The fluorescein tests were negative in all other animals.

The iris was inconspicuous during the examinations. The anterior chamber and lens were inconspicuous in all 24 rabbits from all 4 groups at the various examination dates. The same was also true for the fundus of the eyes.

Miosis, mydriasis and/or ptosis were not observed.

Interpretation of results:
GHS criteria not met
Conclusions:
Under the present test conditions, treatment for 5 days with 50 ul 05% CGP 48933/animal, by instillation into the conjunctival sac of the right eye of rabbits - 4
times/day, or wiith 50 ul 2% CGP 48933/animal, administered 4 or 8 times/day, resulted in no local or systemic substance-related macroscopic intolerance reactions. Ophthalmological and ophthalmopathological examination of the eyes revealed no changes which are considered to be related to the instillation of the test substance CGP 48933.
Furthermore, other organs revealed no substance-related changes.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

No local or systemic intolerance reactions were noted. No test substance-related

findings were noted on mortality, clinical signs, body weight, food and water

consumption, ophthalmoscopy, haematology, clinical biochemistry or myeloid : erythroid

ratio. Gross examinations of the tissues and organs during dissection revealed

no test substance-related findings. The histopathological examination did not reveal

any test substance-related morphological changes of the eyes, eyelids, eye-adnexa

or the other organs examined.