Registration Dossier

Administrative data

Description of key information

Both skin and eye irritation in vivo studies have been completed with no irritation potential noted. 

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:
27 April 1999 - 30 April 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: done under GLP and OECD method
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
July 1992
Qualifier:
according to
Guideline:
other: EEC Directive 92/69/EEC, Annex V, Test 84, July 1992.
GLP compliance:
yes
Remarks:
OECD Principles of Good Laboratory Practice, Statutory Instrument No. 654, 1997, ISBN 0-11- 064105-1.
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, England
- Age at study initiation: 3 months
- Weight at study initiation: 2.41 - 2.75 kg
- Housing: The animals were housed individually in stainless steel cages (dimensions
77.2 x 70.1 x 48 cm) with a Noryl moulded dual level interior and perforated floor beneath which was an absorbent paper lined tray.
- Water and Diet: Each cage was supplied with an automatic watering valve (domestic mains) and a food hopper. Each animal was also offered a supplement of hay or organically grown cabbage ca. twice weekly.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19°C - 21°C
- Humidity (%): 58%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycles
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Remarks:
Applied topically under water moistened gauze patches (2.5 cm x 2.5 cm)
Controls:
other: contralateral zone of same animal
Amount / concentration applied:
500 mg
Duration of treatment / exposure:
4hr
Observation period:
1hr, 24hr, 48hr and 72hr after dressing removed
Number of animals:
3
Details on study design:
All the animals were checked for viability early in the morning and again as late as possible on each day.
All the animals were examined for reaction to treatment. The onset, intensity and duration of any signs were recorded.
On the day prior to test material application, the hair was clipped from an area (approximately 8 cmx 8 cm) across the dorsal trunk of each rabbit. Care was taken to avoid abrading the skin.
On the following day, the dorsal trunk of each rabbit was wetted and treated with test material applied topically under water moistened gauze patches (2.5 cm x 2.5 cm).
Each patch was then covered with semi-occlusive tape (Micropore, 3M Medical Surgical Division, USA) and elastic bandage (Smith and Nephew, Hull, England) wrapped round the torso of the rabbit.
After a contact period of 4 hours, the patch was removed and the skin wiped with sterile water. The test site was delineated
Other effects:
There was no sign of dermal effects or define the dermal effects noted.

 

Animal

 

Body Weight at Dosing (kg)

Time after Patch Removal/Reaction Score

Erythema

Oedema

1h

24h

48h

72h

1h

24h

48h

72h

1

3.63

0

0

0

0

0

0

0

0

2

3.73

0

0

0

0

0

0

0

0

3

3.68

0

0

0

0

0

0

0

0

Acute Skin Irritation Test in Rabbits Scoring System

 

 

Ervthema and Eschar Formation

No erythema     .........................................................................................o

Very sligh terythema (barely perceptible}..................................................................1

Well defined erythema.............................................................................. 2

Moderate to severe erythema .......................................................................3

Severe erythema (beet redness} to slight eschar formation (injuries in depth)

preventing grading of erythema................................................................4

Oedema Formation

No oedema       ............................................................................................ o

Very slght oedema (barely perceptible}................................................ .........................1

Slight oedema (edges of area well defined by definite raising)......................................2

Moderate oedema (raised approximately 1mm}.............................................3

Severe oedema (raised more than 1mm and extending beyond the area

of exposure}............................................................................................4

Conclusions:
Under the conditions of the study, L-744,341 is considered to be non irritating to rabbit skin.

Executive summary:
The acute dermal irritation potential of the test material was investigated in New Zealand White rabbits. No oedema or erythema was noted in any animal at any of the observation periods. There were no additional observations noted.
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:
03 May 1999 - 07 May 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to OECD and in accordance with GLP. The study material is well characterized
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to
Guideline:
other: EEC Directive 92/69/EEC, Annex V, Test 85, July 1992
GLP compliance:
yes
Remarks:
OECD Principles of Good Laboratory Practice, Statutory Instrument No. 654, 1997, ISBN 0-11- 064105-1
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, England
- Age at study initiation: 3 months
- Weight at study initiation: 2.37-2.71 kg
- Housing: individually in stainless steel cages (dimensions 77.2 x 70.1 x 48 cm) with a Noryl moulded dual level interior and perforated floor beneath which was an absorbent paper lined tray
- Diet: Teklad Diet supplied by Harlan UK was available ad libitum. Each animal was also offered a supplement of hay or organically grown cabbage ca. twice weekly
- Water: Domestic mains quality water was available ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19°C - 21°C
- Humidity (%): 57%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Vehicle:
unchanged (no vehicle)
Controls:
other: other: left eye of each animal was untreated
Amount / concentration applied:
Amount instilled (weight equivalent of 0.1 ml)
0.0365 g - Animal 1
0.0365 g - Animal 2
0.0363 g - Animal3
Duration of treatment / exposure:
0.0365 g of test material was placed into the right eye of three rabbits by gently pulling the lower eye lid away from the eyeball to form a sac into which the test material was dropped. The lids were then gently held together for 1-2 seconds. The left eye was left untreated to serve as the control.
Observation period (in vivo):
One rabbit was treated first and observed for signs of severe irritation for up to 24 hours. As none were noted, the remaining 2 rabbits were treated in the same way
The eyes were examined using a hand held magnifier and pen torch 1, 24, 48 and 72 hours after instillation of the test material.
Number of animals or in vitro replicates:
3 female rabbits
Details on study design:
Both eyes of each rabbit were examined prior to dosing and no ocular defects were detected.
All the animals were examined for reaction to treatment. The onset, intensity and duration of any signs were recorded.
The eyes were examined using a hand held magnifier and pen torch 1, 24, 48 and 72 hours after instillation of the test material.

 

Area of Eye

Animal/BodyWeight(kg)/Time After Instillation

1

2

3

3.83

3.56

3.83

1h

24h

48h

72h

1h

24h

48h

72h

1h

24h

48h

72h

 

Cornea:

 

 

0

 

 

0

 

 

0

 

 

0

 

 

0

 

 

0

 

 

0

 

 

0

 

 

0

 

 

0

 

 

0

 

 

0

Degree/Opacity

Area/Opacity

0

0

0

0

0

0

0

0

0

0

0

0

Iris

0

0

0

0

0

0

0

0

0

0

0

0

Conjunctivae:

 

 

 

 

 

 

 

 

 

 

 

 

Redness

0

0

0

0

0

0

0

0

0

0

0

0

Chemosis

0

0

0

0

0

0

0

0

0

0

0

0

Discharge

0

0

0

0

0

0

0

0

0

0

0

0

h= hours

Acute Eye Irritation Test in Rabbits Scoring System

CORNEA

 

Opacity:          Degree of Density (area most dense taken for reading)

 

No ulceration or opacity.········································································0

Scattered or diffuse areas of opacity (other than slight dulling of normal

lustre) details of iris clearly visible...............................................1

Easily discernible translucent area, details of iris slightly obscured..............................2

Nacreous area, no details or iris visible, size of pupil barely discernible··············· ··3

Opaque cornea, iris not discernible through the opacity.............................................4

 

Area of Opacity

 

A quarter (or less) but not more...........................................................1

Between a quarter and a half...............................................................2

Between half and three quarters  ·····-··········-·············----······---3

Between three quarters and the whole surface ....................................4

 

  IRIS

 

Normal ............. ................................................................................................0

Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia, or injection, any of these or combination of any thereof,

iris still reacting to light (sluggish reaction is positive)...............................................1

No reaction to light, haemorrhage, gross destruction (any or all of these)..................2

 

CONJUNCTIVAE

 

Redness:           (refers to palpebral and bulbar conjunctivae, cornea and iris)

 

Bloodvessels normal ··--··-······-·-·-···-···-·········-·········-·--·····O

Some blood vessels definitely hyperaemic (injected)·····-····-·-······1

Diffuse,crimson colour, individual vessels not easily discernible··-·-·2

Diffuse beefy red ··-·--··-····-····-······--·-··········-········-·-·······3

Chemosis:     lids and/or nictitating membranes

 

No swelling            -··········-··················--···················O

Any swelling above normal (includes nictitating membrane).......1

Obvious swelling with partial eversion of lids·-······-····-·-····2

Swelling with lids about half closed···-·-··..······-·-·-············3

Swelling with lids more than half closed-····-··-·-----····-··-··--4

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
Under the conditions of the study, it is considered that the test substance is not irritating to the rabbit eye.
No responses were noted in any animal during any of the observation periods.
Executive summary:

One group of three female rabbits was treated with the weight equivalent of

0.1ml of the test material instilled into the conjunctival sac of one eye. The treated eye was then examined for evidence of irritation 1,24, 48 and 72 hours after instillation.

No responses were noted in any animal during any of the observation periods.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Both skin and eye irritation in vivo studies have been completed with no irritation potential noted. Therefore, no potential for corrosivity.


Justification for selection of skin irritation / corrosion endpoint:
The acute dermal irritation potential of the test material was investigated in New Zealand White rabbits. No oedema or erythema was noted in any
animal at any of the observation periods. There were no additional observations noted.

Justification for selection of eye irritation endpoint:
One group of three female rabbits was treated with the weight equivalent of
0.1ml of the test material instilled into the conjunctival sac of one eye. The treated eye was then examined for evidence of irritation 1,24, 48 and 72
hours after instillation. No responses were noted in any animal during any of the observation periods.

Justification for classification or non-classification

Both skin and eye irritation in vivo studies have been completed with no irritation potential noted.