tert.butyl amine salt of (+)-(3R, 5S)-7[4-(4-Fluorophenyl)-6-Isopropyl-2 [methyl-(methylsulfonyl amino] pyrimidin-5-yl]-3,5- dihydroxy-6(E)- heptenoic acid

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

tert.butyl amine salt of (+)-(3R, 5S)-7[4-(4-Fluorophenyl)-6-Isopropyl-2 [methyl-(methylsulfonyl amino] pyrimidin-5-yl]-3,5- dihydroxy-6(E)- heptenoic acid

Cas Number:

917805-74-4

Molecular formula:

C26H39FN4O6S

IUPAC Name:

tert.butyl amine salt of (+)-(3R, 5S)-7[4-(4-Fluorophenyl)-6-Isopropyl-2 [methyl-(methylsulfonyl amino] pyrimidin-5-yl]-3,5- dihydroxy-6(E)- heptenoic acid

Test material form:

solid: particulate/powder

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: S&K-LAP Kft., 2173 Kartal, Császár út 135, Hungary
- Age at study initiation: 11 weeks
- Weight at study initiation: 2719-2750 g
- Housing: animal was housed individually in metal cage
- Diet (e.g. ad libitum): ad libitum, Hare fattening mixed dietby YAO-TÁP Kft., Nyíregyháza (Tokaji út 22.), Hungary
- Water (e.g. ad libitum): tap water from watering bottles ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12-12

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: the contralateral eye served as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0,1 g of the test item was used for the study in pura state, in a single dose
- Concentration (if solution):

Duration of treatment / exposure:

The eyes of the test animals were not washed out after the application of the test item.

Observation period (in vivo):

7 day

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
The eyes of the test animals were not washed out after the application of the test item

SCORING SYSTEM:
Draize (1959) and OECD 405

TOOL USED TO ASSESS SCORE: hand-slit lamp

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

conjunctivae score

Basis:

animal: 1,2,3

Time point:

other: 1 h

Score:

>= 1 - <= 3

Max. score:

3

Reversibility:

fully reversible within: one week

Results 2

Irritation parameter:

conjunctivae score

Basis:

animal: 1,2

Time point:

24 h

Score:

>= 1

Max. score:

1

Reversibility:

fully reversible within: 48 hour

Results 3

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

72 h

Score:

>= 1

Max. score:

1

Reversibility:

fully reversible within: one week

Results 4

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

other: 1 h

Score:

>= 2 - <= 4

Max. score:

2

Reversibility:

fully reversible within: 24 hour

Irritant / corrosive response data:

The eyes were examined at 1, 24, 48, 72 hours then one week after the applicaiton.

One hour after treatment some hyperaemic blood vessels (score 1) were observed in two animals (No.: 00108, 00115). The vessels were diffuse and the individual vessels were not easily discernible (score 2) in animal No.: 00107. The swelling was different from normal (score 1) in all animals. The discharge moistened lids and hairs on considerable area around the treated eye (score 3) was found in two animals (No.: 00107, 00115) and the discharge was different from normal (score 1) in animal No.: 00108. However, easily discernible translucent areas of the cornea were detected and the details of iris were slightly obscured (score 2) in animal No.: 00115. The area of cornea involved was greater than three quarters, up to the whole area (score 4).

There were no effects observed in the iris during the study period.

24 hours after treatment some hyperamic blood vessels (score1) were observed in two animals (No.: 00107, 00115). The discharge was different from normal (score 1) in animal No.: 00108.

48 hours after treatment some hyperaemic blood vessels (score 1) were observed in animal No.: 00115. Animal No.: 00107 and No.: 00108 became free of symptoms.

72 hours after treatment the state of animals did not change when compared to the pervious observation.

1 week after treatment all animals were free of symptoms.

1 week after treatment the study was terminated, since no primary irritation symptoms occurred.

During the study the control eyes of animals were symptom-free.

Applicant's summary and conclusion

Interpretation of results:

other: Not irritating

Conclusions:

In conclusion, test item Rosuvastatin TBA Salt (EGIS-14660-3) applied to the rabbits' eye mucosa, caused slight to severe conjunctival and moderate corneal irritant effects, fully reversible within 1 week.

According to the EC criteria for classification and labelling requirements for dangerous substances and preparations, the test item does not have to be classified and has no obligatory labelling requirement for eye irritation.