N-[[3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]carbamoyl]-2,6-difluorobenzamide

Endpoint summary

Description of key information

Skin irritation: Not irritating, New Zealand White rabbits, OECD 404, EPA OPPTS 870.2500, EU Method B.4, Japan MAFF Primary Dermal Irritation Study, Stebbins & Brooks 1999.

Eye irritation: Not irritating, New Zealand White rabbits, OECD 405, EPA OPPTS 870.2400, EU Method B.5, Japan MAFF Primary Eye Irritation Study, Stebbins & Brooks 1999.

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:

16 August 1999 - 20 August 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japan MAFF Primary Dermal Irritation Study, 1985

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.2 - 2.4 kg
- Diet: 5 ounces of pelleted rodent feed per day.
- Water: Municipal water was provided ad libitum
- Acclimation period: for at least two weeks prior to study start.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 ± 3 °C
- Humidity (%):40 – 60 %
- Air changes (per hr): 12-15 times/hour.
- Photoperiod (hrs dark / hrs light): 12-hour light/dark photocycle, lights on at 6:00 a.m. and off at 6:00 p.m.

IN-LIFE DATES: From: 01/05/1999 To: 20/08/1999

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

other: 0.5 % methylcellulose

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 g (neat test material)

VEHICLE
- Amount applied: 0.7 mL
- Concentration: 0.5 % methylcellulose

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

Three rabbits, two males and one female.

Details on study design:

TEST SITE
- Area of exposure: An area approximately 10 cm x 10 cm of the back of each rabbit.
- Type of wrap if use: The test site was covered with a gauze patch (approximately 6 cm²) with cotton backing. The gauze patch was held in place with an elastic rabbit jacket.

REMOVAL OF TEST SUBSTANCE
- Washing: The back of each rabbit was wiped with a damp disposable towel to remove any residual test substance.
- Time after start of exposure: 4 hours.

SCORING SYSTEM
The application sites were graded for erythema and oedema within thirty minutes, and 24, 48 and 72 hours after test material removal.

BODY WEIGHTS
Animals were weighed on the day of treatment, and at study termination.

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

99A3936

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

99A3937

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

99A3938

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

99A3936

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

99A3937

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

99A3938

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

There was no irritation observed in any of the three rabbits, see Table 2.

Other effects:

No systemic toxicity was observed.
No effect on body weight was observed.

Table 2: Individual Irritation Scores

Observation Time – Time After Removal	Animal Number	Erythema	Edema
Within 40 minutes	99A3936	0	0
	99A3937	0	0
	99A3938	0	0
24 hours	99A3936	0	0
	99A3937	0	0
	99A3938	0	0
48 hours	99A3936	0	0
	99A3937	0	0
	99A3938	0	0
72 hours	99A3936	0	0
	99A3937	0	0
	99A3938	0	0

 

Table 3: Individual Body Weights

Animal Number	Body Weight (kg)
	Test Day 1	Test Day 2
99A3936	2.389	2.445
99A3937	2.348	2.397
99A3938	2.185	2.197

 

Note: Animals 99A3936 and 99A3937 were males, 99A3938 was female.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the test, application of the test material resulted in no irritation in any of the rabbits, and had no effect on body weights.

Executive summary:

The acute dermal irritation potential of the test material was determined in a GLP study conducted in accordance with the standardised guidelines OECD 404, EPA OPPTS 870.2500, EU Method B.4, and Japan MAFF Primary Dermal Irritation Study, 1985.

Aliquots of 0.5 g of the neat test material, moistened with 0.7 mL of 0.5 % methylcellulose, were applied for four hours to the intact skin on the back of three New Zealand White rabbits.

Under the conditions of the test, application of the test material resulted in no irritation in any of the rabbits, and had no effect on body weights.

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

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 August 1999 - 27 August 1999

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

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japan MAFF Primary Eye Irritation Study, 1985.

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.6 - 2.7 kg
- Diet: 5 ounces of pelleted rodent feed per day.
- Water: Municipal water was provided ad libitum.
- Acclimation period: for at least two weeks prior to study start.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 ± 3 °C
- Humidity (%):40 – 60 %
- Air changes (per hr): 12-15 times/hour.
- Photoperiod (hrs dark / hrs light): 12-hour light/dark photocycle, lights on at 6:00 a.m. and off at 6:00 p.m.

IN-LIFE DATES: From: 01/05/1999 To: 27/08/1999

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.1 g (in powdered form).

Duration of treatment / exposure:

Single application

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

Three rabbits.

Details on study design:

APPLICATION
- Method: A 0.1 gram aliquot of XDE-007 in powder form was instilled into the conjunctival sac of the right eye of one male and two female rabbits. The eyelid of each rabbit was held closed for approximately one second after dosing.
- Control: The left eye remained untreated and served as a control.

REMOVAL OF TEST SUBSTANCE
- Washing: The eyes of all rabbits remained unwashed post-treatment. See Table 1 for scoring system.

SCORING SYSTEM: Both eyes of the rabbits were examined at approximately 1, 24, 48 and 72 hours post-instillation for conjunctival redness and chemosis, discharge, corneal opacity and reddening of the iris.

TOOL USED TO ASSESS SCORE
Binocular loupe and a white halogen light.

BODY WEIGHT
Rabbits were weighed on the day of treatment and at study termination.

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Time point:

24/48/72 h

Score:

0.22

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

cornea opacity score

Remarks:

opacity

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritant / corrosive response data:

One hour after dosing, all rabbits had slight conjunctival redness, slight or moderate chemosis, and slight or moderate ocular discharge.
Twenty-four hours after dosing, two rabbits had slight conjunctival redness.
Forty-eight hours after dosing, the eyes of all rabbits were normal, and the study was terminated seventy-two hours after dosing.

Other effects:

There was no effect of individual body weights.

Table 2: Individual Irritation Scores

Observation Time	Animal No.	Redness	Conjunctivae Chemosis	Discharge	Corneal Opacity	Reddening of Iris
1 hour	99A3944	1	1	1	0	0
	99A3945	1	2	2	0	0
	99A3946	1	1	1	0	0
24 Hours	99A3944	0	0	0	0	0
	99A3945	1	0	0	0	0
	99A3946	1	0	0	0	0
48 Hours	99A3944	0	0	0	0	0
	99A3945	0	0	0	0	0
	99A3946	0	0	0	0	0
72 hours	99A3944	0	0	0	0	0
	99A3945	0	0	0	0	0
	99A3946	0	0	0	0	0

 

Table 3: Individual Body Weights

Animal Number	Body Weight (kg)
	Test Day 1	Test Day 2
99A3944	2.600	2.622
99A3945	2.672	2.599
99A3946	2.684	2.662

 

Note: Animals 99A3945 and 99A3946 were females, 99A3944 was male.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the test, the test material did not cause any adverse effects and is classified as not irritating.

Executive summary:

The acute eye irritation potential of the test material was determined in a GLP study performed in accordance with the standardised guidelines OECD 405, EPA OPPTS 870.2400, EU Method B.5, and Japan MAFF Primary Eye Irritation Study, 1985.

Aliquots of 0.1 g of the test material were placed into the conjunctival sac of the right eye of three New Zealand White rabbits.

One hour after dosing, all rabbits had slight conjunctival redness, slight or moderate chemosis, and slight or moderate ocular discharge. Twenty-four hours after dosing, two rabbits had slight conjunctival redness. Forty-eight hours after dosing, the eyes of all rabbits were normal, and the study was terminated seventy-two hours after dosing. Instillation of XDE-007 in the eye had no effect on body weight.

Under the conditions of the test, the test material did not cause any adverse effects and is classified as not irritating.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation

In the key study (Stebbins & Brooks, 1999) the acute dermal irritation potential of the test material was determined in a GLP study conducted in accordance with the standardised guidelines OECD 404, EPA OPPTS 870.2500, EU Method B.4, and Japan MAFF Primary Dermal Irritation Study, 1985.

Aliquots of 0.5 g of the neat test material, moistened with 0.7 mL of 0.5 % methylcellulose, were applied for four hours to the intact skin on the back of three New Zealand White rabbits.

Under the conditions of the test, application of the test material resulted in no irritation in any of the rabbits, and had no effect on body weights.

The conclusion of the key study is supported by the findings of second study (Brooks, 1997), where neither rabbit in the acute irritation study showed signs of irritation. This study was performed in accordance with generally accepted scientific principles, with incomplete reporting that did not affect the quality of the relevant results. This study was assigned a reliability score of 2, reliable with restrictions.

Eye Irritation

In the key study (Stebbins & Brooks, 1999) the acute eye irritation potential of the test material was determined in a GLP study performed in accordance with the standardised guidelines OECD 405, EPA OPPTS 870.2400, EU Method B.5, and Japan MAFF Primary Eye Irritation Study, 1985.

Aliquots of 0.1 g of the test material were placed into the conjunctival sac of the right eye of three New Zealand White rabbits.

One hour after dosing, all rabbits had slight conjunctival redness, slight or moderate chemosis, and slight or moderate ocular discharge. Twenty-four hours after dosing, two rabbits had slight conjunctival redness. Forty-eight hours after dosing, the eyes of all rabbits were normal, and the study was terminated seventy-two hours after dosing. Instillation of XDE-007 in the eye had no effect on body weight.

Under the conditions of the test, the test material did not cause any adverse effects and is classified as not irritating.

Justification for selection of skin irritation / corrosion endpoint:

Key study was conducted under GLP conditions, in accordance with standardised guidelines and is fully reported. The study was assigned a reliability score of 1, reliable without restrictions, in line with the principles of Klimisch et al (1997).

Justification for selection of eye irritation endpoint:

Only one study is available. The key study was conducted under GLP conditions, in accordance with standardised guidelines and is fully reported. The study was assigned a reliability score of 1, reliable without restrictions, in line with the principles of Klimisch et al (1997).

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I (Classification and Labelling Requirements for Hazardous Substances and Mixtures), Regulation (EC) No. 1272/2008 (CLP), the substance does not require classification with respect to either skin irritation or eye irritation.