2H-Pyran, 2-[4'-[difluoro(3,4,5-trifluorophenoxy)methyl]-3',5'-difluoro[1,1'-biphenyl]-4-yl]-5-ethyltetrahydro-

Endpoint summary

Description of key information

Skin irritation

No signs of skin irritation were seen in a study according to OECD TG 404 in rabbits (reference 7.3.1 -1).

Eye irritation

No signs of eye irritation were seen in a study according to OECD TG 405 in rabbits (reference 7.3.2 -1).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005-12-22 to 2006-04-13

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

2002-04-24

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

92/69/EC

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Kißlegg
- Age at study initiation: Approx. 15 weeks
- Weight at study initiation: 2.94 kg
- Housing: separately
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: more than 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 20
- Humidity (%): 57 to 59
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

other: Aqua pro injectione

Remarks:

some drops

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied: 0.5 g of the test material mixed with several drops of Aqua pr injectione to ensure good skin contact. Single application

Duration of treatment / exposure:

4 hours

Observation period:

The rabbits were examined for skin alterations, behaviour and general condition 1 hour after removal of the patches, after 24, 48 and 72 hours, and then daily up to experimental day 8.

Number of animals:

3 females

Details on study design:

TEST SITE
- Area of exposure: left side of animal's back
- Type of wrap: self-adhesive fabric (Fixomull stretch, Beiersdorf)

REMOVAL OF TEST SUBSTANCE
- Washing: Yes
- Time after start of exposure: 4 hours

OBSERVATION TIME POINTS
1 hour, 24, 48, 72 hours and then daily up to experimental day 8 after patch removal

SCORING SYSTEM:
- Method of calculation: Draize scheme

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

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

Irritant / corrosive response data:

No skin irritating potential could be detected.

Other effects:

- Other adverse local effects: none
- Other adverse systemic effects: No signs of clinical toxicity were detected. All animals survived the observation period. Body weight development of the treated rabbits was inconspicuous.

Preliminary test:

The test material was screened for its irritating potential using hen's egg test on the chorioallantoic membrane (HET-CAM). In this model the cumulative irritation score of the test item was 0.00.

Interpretation of results:

GHS criteria not met

Conclusions:

The test item is considered to be not irritating to skin.

Executive summary:

The skin irritation potential of the test item was investigated according to OECD Guideline 404 under GLP conditions. An amount of 0.5 g of the test material was mixed with several drops of Aqua pro injectione to ensure good skin contact. The initial test with one animal and the confirmatory test with two further animals showed no signs of irritation at the treated areas following single application to the intact dorsal skin of rabbits for 4 hours under semiocclusive conditions. No signs of clinical toxicity were detected. All animals survived the observation period. Body weight development of the treated rabbits was inconspicuous. Under the conditions of the present study no signs of irritation were seen.

Reference 2

Endpoint:

skin irritation: 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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2007-09-10 to 2007-10-02

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

2002-04-24

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2004/73/EC

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Kißlegg
- Age at study initiation: Approx. 24 weeks
- Weight at study initiation: 4.63 kg
- Housing: separately
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: more than 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 20
- Humidity (%): 45 to 75
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied: 0.1 g

Duration of treatment / exposure:

Information regarding rinsing after instillation not provided.

Observation period (in vivo):

For the test of primary eye irritation, the test material was applied into the conjunctival sac of rabbits. The first examination followed. The rabbits were examined for skin alterations, behaviour and general condition 1 hour after removal of the patches, after 24, 48 and 72 hours, and then daily up to experimental day 8.

Number of animals or in vitro replicates:

3 females

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: none

SCORING SYSTEM: DRAIZE scoring system

TOOL USED TO ASSESS SCORE: ophthalmoscope

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

No signs of irritation were observed at the cornea or iris. All animals showed redness of the conjunctivae (score 1) one hour after instillation of the test material.

Other effects:

- Lesions and clinical observations: none

Preliminary test

Prior to testing, the test material was screened for its irritating potential using hen's egg test on the chorioallantoic membrane (HET-CAM). The cumulative irritation sore was 0.

Interpretation of results:

GHS criteria not met

Conclusions:

The test item is not considered to be irritating to eye.

Executive summary:

The test item was tested for its eye irritating properties. Prior to testing, the test material was screened for its irritating potential using hen's egg test on the chorioallantoic membrane (HET-CAM). In the main study on eye irritation, 0.1 g of the test material was grounded in a mortar using a pestle and instilled into the conjunctival sac of the left eye of each animal by gently pulling the lid away from the eyeball to form a cup into which the test material was placed. The right eye remained untreated and served as control. After instillation, the eyelids were closed for 1 second. The test for primary eye irritation was performed initially with one animal and followed by the confirmatory test with two further animals. For the test of primary eye irritation, the test material was applied into the conjunctival sac of rabbits. The first examination of the eyes followed 1 hour after instillation. The other examinations of the eyes were performed daily for a further 7 days. No signs of irritation were observed at the cornea or iris. All animals showed redness of the conjunctivae (score 1) one hour after instillation of the test material. No relevant eye irritating potential could be detected.

Reference 2

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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

In a primary dermal irritation study, young adult New Zealand White rabbits (3 females) were dermally exposed to 0.5 g of moistened test item for 4 hours under semiocclusive conditions. Animals then were observed 1, 24, 48 and 72 hours, as well as 7 days after treatment. No erythema and no edema irritation were observed within the course of the observation period. The animal's individual mean scores (considering readings at 24, 48, and 72 hours after patch removal) for erythema and oedema were 0.00, 0.00, 0.00 and 0.00, 0.00, 0.00 respectively based on the DRAIZE scheme indicating no irritant potential. In this study, the test item is not irritating to skin (reference 7.3.1 -1).

Eye irritation

In a primary eye irritation study 0.1 g of the test item was instilled into the conjunctival sac of the left eye of young adult New Zealand White rabbits (3 females). Animals then were observed 1, 24, 48 and 72 hours, as well as 7 days after treatment. No signs of irritation were observed at the cornea or iris within the course of the observation period. The animal's individual mean scores (cosidering readings at 24, 48, and 72 hours after instillation) for cornea, iris, conjunctivae, and chemosis score were each 0.00 based on the DRAIZE scheme indicating no irritant potential. In this study, the test item is not an eye irritant (reference 7.3.2 -1)

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The available data for skin irritation and eye irritation are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on this data, the substance is not considered to be classified for skin and eye irritation under Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) 2019/521.