L-Valine, N-(1-oxopentyl)-N-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-, phenylmethyl ester

Endpoint summary

Description of key information

Skin irritation: CLP: not classified

Eye irritation CLP: not classified

According to the EC classification criteria PBS 859 DS is classified as nonirritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6.6.1994 - 27.6.1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

other: Chbb:HM (SPF)

Details on test animals or test system and environmental conditions:

Rabbits Chbb:HM (SPF) from Dr. K. Thomae GmbH, Biberach (FRG) were used. Animals were utilized only if they were judged healthy on the basis of general
observations and body weight (performed predose).
Animals were assigned to the study using computer-generated random numbers.
Animal identification was by an individual number written with a waterproof marker on the ear.
The animals were acclimatized to laboratory conditions for 7 days. The initial age (at dosing) was 148 to 169 days. The initial weight range (at dosing) was 2309 to
2346 g.
Husbandry
The animals were housed individually in stainless steel cages in an air-conditioned room. The temperature was 20 ± 3 °c, and the relative humidity 30 to 70 %.
Artificial light was provided from 6 a.m. to 6 p.m.
Pelleted standard diet NAFAG No. 814 was freely available (NAFAG, 9202 Gossau, Switzerland). The diet is analyzed for composition and contaminants by
the manufacturer and analytical results are archived by the Animal Supply Office CIBA-GEIGY (batches are given in the raw data).
Tap water was freely available. The water is analyzed periodically by Industrielle Werke Basel (Basel City water supply plant) for compliance with Swiss drinking
water specifications.

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

other:

Controls:

other: not required, the untreated skin sites of each animal served as control

Amount / concentration applied:

Application volume: 0.5 g / animal
Amount of test article applied: 0.5 g / patch

Duration of treatment / exposure:

4 h

Observation period:

7 d
reading time points: 1, 24, 48 and 72 h and 7 d

Number of animals:

3

Details on study design:

The study was conducted according to the OECD guideline 404 (adopted l 7-Jul-92).
The rabbit is one of the recommended species for irritation testing.
The animals were observed for 7 days after dosing to see if there were any latent toxic effects.
Selection of dose levels was based on OECD guideline.
PBS 859 DS, batch P.Op. 1 / 94, was administered topically under occlusion for 4 hours to groups of 3 rabbits (russian) Chbb:HM (SPF)

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Other effects:

Spotts of slight erythema reactions were observed in two of 3 animals 24 and 48 hrs. after removing the bandages. In one animal the slight erythema reaction covered the whole application area when assessed 72 hrs. after removing the bandage. At the end of the observation period, scaling was observed in the two animals showing erythema reactions at the beginning of the observation period. No edema formation was observed during the whole observation period.

Mortality: No mortality was observed.

Clinical Signs: No systemic clinical signs were observed

Body Weight: No compound related effect was observed.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
The reactions observed are clearly lower than the criteria defined for the risk phrase of skin irritation of the EEC

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

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 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.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6.6.1994 - 1.7.1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

other: Chbb:HM (SPF)

Details on test animals or tissues and environmental conditions:

Rabbits Chbb:HM (SPF) from Dr. K. Thomae GmbH, Biberach (FRO) were used. Animals were utilized only if they were judged healthy on the basis of general
observations and body weight (performed predose).
Animals were assigned to the study using computer-generated random numbers.
Animal identification was by an individual number written with a waterproof marker on the ear.
The animals were acclimatized to laboratory conditions for 8 days. The initial age (at dosing) was 179 to 193 days. The initial weight range (at dosing) was 2145 to
2252 g.
Husbandry
The animals were housed individually in stainless steel cages in an air-conditioned room. The temperature was 20 ± 3 °c, and the relative humidity 30 to 70 %.
Artificial light was provided from 6 a.m. to 6 p.m.
Pelleted standard diet NAFAG No. 814 was freely available (NAFAG, 9202 Gossau, Switzerland). The diet is analyzed for composition and contaminants by the manufacturer and analytical results are archived by the Animal Supply Office CIBA-GEIGY (batches are given in the raw data).
Tap water was freely available. The water is analyzed periodically by lndustrielle Werke Basel (Basel City water supply plant) for compliance with Swiss drinking
water specifications.

Vehicle:

unchanged (no vehicle)

Controls:

other: not required, the untreated eye of each animal served as control

Amount / concentration applied:

Application volume: approx. 0.1 g / animal
0.07 g was the maximal amount which could be put into the conjunctiva! sac
The Test Artice! was administered into the conjunctiva! sac of one eye. The contralateral eye was used as control.

Duration of treatment / exposure:

single application

Observation period (in vivo):

72 h
reading time points: 1, 24, 48 and 72 h

Number of animals or in vitro replicates:

3

Details on study design:

Three animals of a pool were selected based on a primary eye examination (24 hrs. before dosing).
0.1 g of the test article was prepared for the application into the conjunctiva! sac of the first animal. 0.07 g was the maximal amount which could be put into the
conjunctiva! sac. After the first assessment of eye reactions in the first animal, the same amount (0.07 g) of compound was then applied to two additional animals.
This stepwize procedure was used to omitt unexpected severe eye reactions in a whole group of 3 animals.
The lids were gently hold together for a second to prevent loss of material.
The test article was administered once.
The administration was performed between 10:00 a.m. and 12:00 a.m ..

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

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

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 24 h

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 48h

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 48h

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

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

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

Remarks on result:

no indication of irritation

Other effects:

One and 24 h after application of the test article to the rabbit eyes, only a slight redness of the conjunctivae was observed. The redness was reversible in all animals by 48 h after application of the test article. No other effects were observed. Therefore, the test was finished after 3 days of observation.

Mortality: No mortality was observed.

Clinical Signs: No clinical signs were observed.

Body Weight: No significant compound related effect was observed.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
According to the EC classification criteria PBS 859 DS is classified as nonirritant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The reactions observed are clearly lower than the criteria defined for the risk phrase of skin and eye irritation of the EEC.