2-Pyridinamine, 5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-

Endpoint summary

Description of key information

Skin irritation/corrosion
Two studies are available:
1) A skin irritation study (Beerens - Heijnen, 2010) is available which is key study. This study showed that the test substance is not irritating.
2) An in vitro skin corrosion study (Buskens, 2010) is available which is supporting study. This study showed that the test substance is not corrosive.
Eye irritation
Two studies are available:
1) An acute eye irritation study (Beerens - Heijnen, 2010) is available which is key study. This study showed that the test substance is slightly irritating.
2) An in vitro BCOP study (Verspeek-Rip, 2010) is available which is supporting study. This study showed that the test substance is not irritating.

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:

From 24 August to 02 September 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study run to a method comparable with current guidelines and to GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

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 France, L'Arbresle Cedex, France
- Age at study initiation: between 10-20 weeks old
- Weight at study initiation: 2-4 kg
- Housing: housed in labeled cages with perforated floors and shelters
- Diet (e.g. ad libitum): Pelleted diet approximately 100 grams per day, Hay was provided at least three times a week.
- Water (e.g. ad libitum): Free access to tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0ºC (actual range: 19.0-19.9ºC)
- Humidity (%): 40-70% (actual range: 49 - 87%)
- Air changes (per hr): approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day

IN-LIFE DATES: From: 2010-08-24 To: 2010-09-02

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 grams
- Concentration (if solution):

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.2 mL
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3 males

Details on study design:

TEST SITE
- Area of exposure: approximately 150 square centimeters (10x15 cm)
- % coverage:
- Type of wrap if used: Micropore tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): tap water
- Time after start of exposure: 4 hours

SCORING SYSTEM: numerical scoring system

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

0

Remarks on result:

other: The exposure period is 4 hours.

Irritation parameter:

edema score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

0

Remarks on result:

other: The exposure period is 4 hours.

Irritant / corrosive response data:

No skin irritation was caused by 4 hours exposure to the test substance.

Other effects:

No staining of the treated skin by the test substance was observed and no test substance remnants were seen.

No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Animal	476		479		480
Time after exposure	Erythema (0-4)	Oedema (0-4)	Erythema (0-4)	Oedema (0-4)	Erythema (0-4)	Oedema (0-4)
1 hour	0	0	0	0	0	0
24 hours	0	0	0	0	0	0
48 hours	0	0	0	0	0	0
72 hours	0	0	0	0	0	0

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

No skin irritation was caused by 4 hours exposure to the test substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 02 to 24 August 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study run to a method comparable with current guidelines and to GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

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 Deutschland, Kisslegg, Germany
- Age at study initiation: between 10-20 weeks old
- Weight at study initiation: 2-4 kg
- Housing: labeled cages with perforated floors and shelters
- Diet (e.g. ad libitum): pelleted diet approximately 100 grams per day, hay was provided at least three times a week
- Water (e.g. ad libitum): free access to tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0±3.0℃ (actual range: 19.2-20.3℃)
- Humidity (%): 40-70% (actual range: 46-82%)
- Air changes (per hr): approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day

IN-LIFE DATES: From: 2010-08-02 To: 2010-08-24

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 98.3 mg (range 95.3-103.8 mg) (a volume of approximately 0.1 mL)

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

3 males

Details on study design:

Immediately after the 24-hour observation, a solution of 2% fluorescein (Merck, Darmstadt, Germany) in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage. Any bright green stained area, indicating epithelial damage, was estimated as a percentage of the total corneal area.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

0

Irritation parameter:

iris score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

0

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

ca. 0.89

Max. score:

2

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: fully reversible within 72 hours in two animals and within 7 days in the other animal

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 hours

Score:

ca. 0.67

Max. score:

1

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: fully reversible within 48 hours in all of 3 animals

Irritant / corrosive response data:

Instillation of approximately 98 mg of the test substance into one eye of each of three rabbits resulted in irritation of the conjunctivae, which consisted of redness, chemosis and discharge. The irritation had completely resolved within 72 hours in two animals and within 7 days in the other animal.

No iridial irritation or corneal opacity was observed, and treatment of the eyes with 2% fluorescein 24 hours after test substance instillation revealed no corneal epithelial damage.

Other effects:

Remnants of the test substance were present in the eye of two animals on Day 1.

No symptoms of systemic toxicity were observed in the animals during test period and no mortality occurred.

Animal	Time after dosing	Cornea (0-4)	Iris (0-2)	Conjunctivae
				Redness (0-3)	Chemosis (0-4)	Discharge (0-3)
462	1 hour 24 hours 48 hours 72 hours	0 0 0 0	0 0 0 0	1 1 1 0	1 1 0 0	1 1 0 0
470	1 hour 24 hours 48 hours 72 hours 7 days	0 0 0 0 0	0 0 0 0 0	1 2 1 1 0	1 1 0 0 0	1 1 0 0 0
471	1 hour 24 hours 48 hours 72 hours 7 days	0 0 0 0 0	0 0 0 0 0	2 1 1 0 0	1 0 0 0 0	1 0 0 0 0

Interpretation of results:

slightly irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Treatment of the test substance caused reversible effects on conjunctivae of all the three rabbits.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation/corrosion

Two studies are available:

1) A primary skin irritation study was conducted according to OECD 404 using rabbits (Beerens - Heijnen, 2010). Key study.

This study showed that the test substance is not irritating.

2) An in vitro skin corrosion study was conducted according to OECD 431 using a human skin model (Buskens, 2010). Supporting study.

In the interest of animal welfare and to minimize any testing likely to produce severe responses in animals, a human skin model test was performed. This study showed that the test substance is not corrosive. Based on this, in vivo skin irritation study in rabbit was performed to establish the possible skin irritating properties of the test substance.

Eye irritation

Two studies are available:

1) An acute eye irritation study was conducted according to OECD 405 using rabbits (Beerens - Heijnen, 2010). Key study.

This study showed that the test substance is slightly irritating.

2) An in vitro BCOP study was conducted according to OECD 437 using bovine cornea (Verspeek-Rip, 2010). Supporting study.

In the interest of animal welfare and to minimize any testing likely to produce severe responses in animals, an in vitro BCOP test was performed. This study showed that the test substance is not irritating. Based on this, in vivo eye irritation study in rabbit was performed to establish the possible eye irritating properties of the test substance.

Justification for selection of skin irritation / corrosion endpoint:
Study run to a method comparable with current guidelines and to GLP

Justification for selection of eye irritation endpoint:
Study run to a method comparable with current guidelines and to GLP

Effects on eye irritation: slightly irritating

Justification for classification or non-classification

Skin irritation/corrosion: Mean scores at 24, 48 & 72 hours for erythema were < 2.3 (actual value 0) for oedema were < 2.3 (actual value 0). In addition all reactions were fully reversible within the observation period (actual value within 72 hours).

Serious eye damage/eye irritation: Mean scores at 24, 48 & 72 hours for corneal opacity were < 1 (actual value 0), for iritis were < 1 (actual value 0), for conjunctival redness were < 2 (actual value 0.89) and for conjunctival oedema were < 1 (actual value 0.67).

Therefore in accordance with Regulation (EC) No. 1272/2008 Tables 3.2.2 & 3.3.2 the substance is not classified for the skin corrosion/irritation and serious eye damage/eye irritation endpoint.