Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01 December 1997 - 09 January 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Ace Animals, Boyertown, PA, USA- Weight at study initiation: 2.2 - 2.6 kg- Housing: Individually in suspended wire cages- Diet (e.g. ad libitum): Purina Rabbit Chow (Diet no. 5321)- Acclimation period: At least 5 daysENVIRONMENTAL CONDITIONS- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL- Amount(s) applied (volume or weight with unit): 0.5 ml/rabbit
Duration of treatment / exposure:
4 hours
Observation period:
14 days
Number of animals:
3
Details on study design:
TEST SITE- Area of exposure: 2.5 x 2.5 cm- Type of wrap if used: PlasticREMOVAL OF TEST SUBSTANCE- Washing (if done): Gentle washing with distilled water at the end of the exposure period, before scoring for dermal reactions- Time after start of exposure: 4 hoursSCORING SYSTEM: Numerical Draize technique
Irritation parameter:
other: Erythema and eschar formation, mean score
Basis:
animal: 1, 2 and 3
Time point:
other: 24 hours
Score:
2.33
Max. score:
4
Irritation parameter:
other: Erythema and eschar formation, mean score
Basis:
animal: 1, 2 and 3
Time point:
other: 72 hours
Score:
2
Max. score:
4
Irritation parameter:
edema score
Remarks:
mean value
Basis:
animal: 1, 2 and 3
Time point:
other: 24 hours
Score:
1.67
Max. score:
4
Irritation parameter:
edema score
Basis:
animal: 1, 2 and 3
Time point:
other: 72 hours
Score:
1.33
Max. score:
4
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Score:
3.67
Irritant / corrosive response data:
Erythema scores, very slight to well defined at 1 hour following patch removal, ranged from absent to severe through Day 1 and cleared by Day 14.One animal had poor hair regrowth on Day 7, which cleared by Day 14. Edema scores generally ranged from absent to slight through Day 7 and cleared by Day 14, with the exception of a score 3 (moderate) in one animal at 24 hours.
Table 1: Bodyweights (BW)
Rabbit N° 1 2 3
Pretest BW (kg) 2.2 2.6 2.2
Terminal BW 2.5 2.5 2.6

Table 2: Erythema and eschar formation
Rabbit N° 1 2 3 Mean
Time after patch removal       Score
1 h 1 1 2  
24 h 1 2 4 2.33
48 h 2 2 4  
72 h 0 2 4 2.00
7 d 0 2 4  
14 d 0 0 0  
Table 3: Edema
Rabbit N° 1 2 3 Mean
Time after patch removal       Score
1 h 0 0 2  
24 h 0 3 2 1.67
48 h 0 2 2  
72 h 0 2 2 1.33
7 d 0 1 2  
14 d 0 0 0  
Sum of mean scores       7.33
PDII       3.67
Table 4: Systemic observations
Rabbit N° 1 2 3
Time after patch removal      
1 h A A A
24 h A A A
48 h A A A
72 h A A A
7 d A A A
14 d A D A
A: normal; D: diarrhea
Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the test substance was considered to be irritating but not corrosive to skin.
Executive summary:

A study was performed to assess the skin irritation potential of the test substance to the skin of New Zealand White rabbits according to OECD Guideline 404.

0.5 mL of test substance was applied to the clipped skin area on the back of each animal under a 25 x 25 mm gauze pad. The pad was allowed to remain in contact with the skin for 4 h. Animals were scored for irritation reactions after 1, 24, 48 and 72 hours then 7 and 14 days.

The general health of the animals was monitored at each observation point (24, 48, 72 h, and 7 and 14 days). Bodyweights were recorded pre-test and at termination. Scoring was done according to the Draize methodology.

Erythema scores, very slight to well defined at 1 hour following patch removal, ranged from absent to severe through Day 1 and cleared by Day 14. One animal had poor hair regrowth on Day 7, which cleared by Day 14. Edema scores generally ranged from absent to slight through Day 7 and cleared by Day 14, with the exception of a score 3 (moderate) in one animal at 24 hours. The primary dermal skin irritation index was equivalent to 3.67.

Under the test conditions, the test substance was considered to be irritating but not corrosive to skin.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
06 April 1992 - 12 November 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS- source: Froxfield (U.K.) Ltd., Petersfield, Hampshire, England- Age at study initiation: approximately 11 to 14 weeks of age- Weight at study initiation: range of 2.6 to 3.0 kg- Housing: individually- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: yesENVIRONMENTAL CONDITIONS- Temperature (°C): approximately 19°C- Humidity (%): at 30-70%- Air changes (per hr): approximately 19 air changes per hour- Photoperiod (hrs dark / hrs light): 12 hours of artificial light in each 24 hours period
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL- Amount(s) applied (volume or weight with unit): 0.5 ml
Duration of treatment / exposure:
4 hours
Observation period:
4 days
Number of animals:
3 animals
Details on study design:
TEST SITE- Area of exposure: dorso-lumbar region, application under a 25 mm x 25 mm gauze pad- Type of wrap if used: covered with "Elastoplast" elastic adhesiveREMOVAL OF TEST SUBSTANCE- Washing (if done): Washing with warm water (30 - 40°C) (dried with absorbent paper)- Time after start of exposure: 4 hours post-exposure
Irritation parameter:
erythema score
Basis:
mean
Score:
0
Irritation parameter:
edema score
Basis:
mean
Score:
0
Irritant / corrosive response data:
No dermal response to the test substance was observed in any animal throughout the observation period.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.

Dermal reactions observed after application of UVECRYL P115:

(* Approximately 30 minutes after removal of the dressing)

    Rabbit number & sex

E = Erythema    

O = Oedema

          Day
 1*  2  3
288 - male  E / O 0 / 0  0 / 0 0 / 0  0 / 0 
 289 - male E / O 0 / 0 0 / 0  0 / 0  0 / 0 
 290 - male E / O 0 / 0 0 / 0 0 / 0  0 / 0
Conclusions:
Under the test conditions, the test substance was considered non-irritating to skin.
Executive summary:

A study was performed to assess the skin irritation potential of the test substance to the skin of New Zealand White rabbits according to EU Method B.4.

0.5 mL of test substance was applied to the shaved skin area on the back of each animal under a 25 mm x 25 mm gauze pad. The pad was applied and allowed to remain in contact with the skin for 4 h. Animals were scored for irritation reactions on day 1 (approximately 30 min after removal of the dressing), 2, 3 and 4 days.

A single 4 h semi-occluded application of the test substance to the intact skin of three male rabbits did not produced dermal response throughout the observation period.

Under the test conditions, the application of the test substance to intact rabbit skin for 4 h elicited no dermal reactions.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
06 June 1997 - 04 February 1998
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Qualifier:
according to
Guideline:
other: Code of Federal Regulations, Title 16, Section 1500.41
Deviations:
yes
Remarks:
The deviations are not thought to have affected the integrity or validity of the study.
Principles of method if other than guideline:
The upper value for humidity recorded was 74%. This exceeded the expected high of 70% stated in the protocol. The upper value for temperature was 27°C. This exceeded the expected high of 22°C stated in the protocol.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS- Age at study initiation: 12 to 15 weeks of age- Weight at study initiation: range of 2.7 to 3.4 kg- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitumENVIRONMENTAL CONDITIONS- Temperature (°C): 17.5 to 27°C- Humidity (%): 44 to 74%- Air changes (per hr): approximately 19 air changes per hour- Photoperiod (hrs dark / hrs light): 12 hours of artificial light in each 24 hours period
Type of coverage:
occlusive
Preparation of test site:
other: one intact and one abraded skin site on each animal
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
24 hours
Observation period:
Examination of the treated skin was made on Day 2 (approximately 60 minutes after removal of the dressings) and on Day 4 (equivalent to 24 and 72 hours after exposure).
Number of animals:
6 animals
Details on study design:
TEST SITE- Area of exposure: 25 mm x 25mm- Type of wrap if used: The treatment sites were covered with "Elastoplast" elastic adhesive dressing backed with "Sleek" water proof strapping.REMOVAL OF TEST SUBSTANCE- Washing (if done): at the end of the exposure period, the occlusive dressing and gauze pads were removed and the treatment sites were washed with warm water (30° to 40°C) to remove any residual test substance.- Time after start of exposure: 24 hours
Irritation parameter:
primary dermal irritation index (PDII)
Score:
4.1
Irritant / corrosive response data:
At the 24 hours reading, well-defined moderate to severe erythema with very slight to moderate oedema was seen at the intact and abraded sites in all animals. By the 72 hours reading, well-defined erythema with or without very light to moderate oedema was observed.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.

Dermal reactions:

 Rabbit no. & sex     E = erythema / O= Oedema     24 hours     72 hours
 Intact Abraded  Intact  Abraded 
 2201 Female E / O  2 / 3 2 / 3  2 / 3  2 / 3 
 2202 Female E / O  2 / 3 2 / 2  2 / 3  2 / 2 
 2203 Female E / O 2 / 2 3 / 2  2 / 1  2 / 1
 2204 Female  E / O 2 / 2 2 / 2  2 / 2  2 / 1 
2205 Female   E / O 2 / 2  2 / 1  2 / 2  2 / 1 
 2206 Female  E / O 2 / 2  2 / 3  2 / 2  2 / 2 

Primary Irritation Index = 4.1.

Conclusions:
Under the test conditions, the test substance was considered to be moderately irritating to the skin. The Primary Irritation Index (PII) was calculated to be 4.1.
Executive summary:

The skin irritation potential of the test substance was determined using an in vivo method described in Code of Federal Regulations, Title16, Section 1500.41.

Six rabbits (New Zealand White) were administered a dermal dose of 0.5 ml of the test substance to one intact and one abraded skin site and observed for three days. A single occlusive application of the test substance to intact and abraded rabbit skin for 24 h elicited well-defined moderate to severe dermal irritation.

Under the test conditions, the test substance was considered to be moderately irritating to the skin. The Primary Irritation Index (PII) was calculated to be 4.1.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
10 January 2006 - 01 February 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK- Age at study initiation: 12-20 weeks- Weight at study initiation: 2.0-3.5 kg- Housing: Individually housed in suspended cages- Diet (e.g. ad libitum): Certified Rabbit Diet (Code 5322) supplied by BCM IPS Limited, London, UK; ad libitum- Water (e.g. ad libitum): Mains drinking water; ad libitum- Acclimation period: 5 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 17-23 °C- Humidity (%): 30-70 %- Air changes (per h): 15/h- Photoperiod (h dark / h light): 12 h dark / 12 h light
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
3 min, 1 or 4 hours
Observation period:
14 days
Number of animals:
Three
Details on study design:
TEST SITE- Area of exposure: 2.5 X 2.5 cm2- Type of wrap if used: Trunk of the rabbit was wrapped in an elasticated corset to prevent the animal interfering with the patches REMOVAL OF TEST SUBSTANCE- Washing (if done): Residual test material was removed by gentle swabbing with cotton wool soaked in distilled water- Time after start of exposure: 3 min, 1 or 4 hoursSCORING SYSTEM: Draize scoring system
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
24/48 h
Score:
2
Max. score:
8
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
Exposure period: 3 min- No evidence of skin irritationExposure period: 1 h- Very slight erythema was noted at the treated skin site at 24 and 48-h- Very slight oedema was noted at the treated skin site at 24-h- Treated skin site appeared normal at the 72-hExposure period: 4 h- Very slight to well-defined erythema was noted at all treated skin sites one hour after patch removal- Well-defined erythema was noted at all treated skin sites at the 24-h observation with very slight to well-defined erythema at the 48-h observation and very slight erythema at the 72-h observation- Very slight oedema was noted at all treated skin sites one hour after patch removal and at the 24 and 48-h observations- Slight desquamation was noted at one treated skin site with moderate desquamation at the remaining two treated skin sites at the 7-d observation- Two treated skin sites appeared normal at the 14-d observation

Table 1: Individual skin reactions following 4 -h exposure

Skin reaction Observation time Individual Scores - Rabbit Number and Sex Total
Male 17 Male 124 Male 131  
Erythema/Eschar formation 1 h 1 2 2 5
24 h 2 2 2 6
48 h 1 1 2 4
72 h 1 1 1 3
7 d 0 D 0 D* 0 D* 0
14 d - 0 0 0
Oedema formation 1 h 1 1 1 3
24 h 1 1 1 3
48 h 1 1 1 3
72 h 0 0 0 0
7 d 0 0 0 0
14 d - 0 0 0
Sum of 24 and 72 h Readings (S) 12
Primary Irritation Index (S/6) 2

D = Slight desquamation D* = Moderate desquamation

Table 2: Individual skin reactions following 1-hour and 3-minute exposures

Skin Reaction  Observation Time  Individual Scores -Rabbit Number and Sex 
17 Male 
1-Hour Exposure  3-Minute Exposure 
Erythema/Eschar Formation 1 Hour  0 0
24 Hours  1 0
48 Hours  1 0
72 Hours  0 0
7 Days  0 0
Oedema Formation 1 Hour  0 0
24 Hours  1 0
48 Hours  0 0
72 Hours  0 0
7 Days  0 0
Conclusions:
Under the test conditions, the primary skin irritation score of the test substance was calculated to be 2.0.
Executive summary:

A study was performed to assess the skin irritation potential of the test substance to the skin of New Zealand White rabbits according to GLP compliant OECD Guideline 404 and EU Method B.4. 0.5 mL of the test substance was applied to the clipped skin area on the back of each animal under a 2.5 cm X 2.5 cm cotton gauze patch. On one rabbit, patches were applied at three different sites and one patch was removed at each of the three time points: 3 min, 1 and 4 hours after application. On two additional rabbits, only one patch was applied and allowed to remain in contact with the skin for 4 hours. Animals were scored for irritation reactions at 1, 24, 48 and 72 h post-application and observed for reversibility on Days 7 and 14. A single 4 h, semi-occluded application of the test substance to the intact skin of three rabbits produced well-defined erythema and very slight oedema. Slight or moderate desquamation was also noted. Two treated skin sites appeared normal on day 14. 3 min and 1 h semi-occluded applications of the test substance to the intact skin of one rabbit produced no corrosive effects. All irritation reactions were observed to be completely reversible within 14 days. Under the test conditions, the primary skin irritation score of the test substance was calculated to be 2.0 (Sanders, 2006).

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
25 August 1999 - 25 February 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
Himalayan
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Boehringer Ingelheim Pharma KG- Age at study initiation: Young adult animals- Housing: single housing- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): tap water ad libitum- Acclimation period: acclimatization for at least 1 weekENVIRONMENTAL CONDITIONS- Temperature (°C): range of 20 - 24°C- Humidity (%): range of 30 - 70%- Photoperiod (hrs dark / hrs light): 12h/ 12h
Type of coverage:
semiocclusive
Preparation of test site:
other: intact untreated skin
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated skin sites of the same animal
Amount / concentration applied:
0.5 ml of unchanged liquid test substance
Duration of treatment / exposure:
4 hours
Observation period:
14 days (readings at 1 hour, 24 hours, 48 hours, 72 hours, 7 days and 14 days)
Number of animals:
3 animals
Details on study design:
TEST SITE- Area of exposure: 2.5 cm x 2.5 cm- Type of wrap if used: The test substance was covered with a test patch (Idealbinde, Pfaelzische Verbandstoff-Fabrik, Kaiserslautern) and Fixomull (R) stretch (adhesive fleece), Beiersdorf AGREMOVAL OF TEST SUBSTANCE- Washing (if done): Removed at the end of the exposure period with Lutrol (R) and Lutrol (R)/water (1:1).Lutrol (R) E400 - Polyethyleneglycol DAB, BASF Aktiengesellschaft
Irritation parameter:
erythema score
Basis:
mean
Score:
2
Reversibility:
not reversible
Remarks:
in all animals within 14 days
Irritation parameter:
edema score
Basis:
mean
Score:
0.3
Reversibility:
fully reversible within: 24 h
Irritant / corrosive response data:
The average score (24 to 72 hours) for irritation was calculated to be 2.0 for erythema and 0.3 for edema.

Tabulation of irritant response data for each individual animal at each observation time as well as calculation of the means.

 Readings  Animal  Erythema  Edema  Symptoms (exposure period : 4 hours)
 1 hour        01  2 24 
 02  2  
 03  2  
 24 hours        01  2 15, 16, 24 
 02 15, 16 
 03 15 
 48 hours        01  2 15, 24 
 02  2 15 
 03 15 
 72 hours        01  2 15, 24 
 02  2
 03  2  
 7 days         01  2  15, 24
 02  2
 03
 14 days        01  2 S, 15 
 02  2 S
 03  1
 Mean        01  2.0 0.7   
 02  2.0 0.3   
 03  2.0 0.0   
 Mean    2.0 0.3   

S: scaling

15: Erythema extending beyond the area of exposure

16: Edema extending beyond the area of exposure

24: Petechiae

Conclusions:
Under the test conditions, the test substance was considered to be irritating to skin.
Executive summary:

A study was conducted to evaluate the skin irritancy potential of the test substance using the in vivo acute dermal irritation/ corrosion assay in rabbits.

The average score (24 to 72 h) for irritation was calculated to be 2.0 for erythema and 0.3 for edema. The skin findings were not reversible in all animals within 14 days after removal of the patches. Symptoms observed and described in the respective observation table in detail together with the average score for irritation indicate an irritant property of the test substance to the skin.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28 November 1997 - 09 January 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS- Source: Ace Animals, Boyertown, PA, USA- Weight at study initiation: 2.1 - 2.3 kg- Housing: Individually in suspended metal cages- Diet (e.g. ad libitum): Purina Rabbit Chow (Diet no. 5321)- Acclimation period: At least 5 daysENVIRONMENTAL CONDITIONS- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: The contralateral eye remained untreated.
Amount / concentration applied:
A 0.1 ml amount of the test substance was placed into the conjunctival sac of the lower everted lid of one eye of each animal.
Duration of treatment / exposure:
The eyelids were then gently held together for one second before releasing.
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE- Washing (if done): NoneSCORING SYSTEM: Draize scaleTOOL USED TO ASSESS SCORE: hand-slit lamp
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 1 h
Score:
36
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 24 h
Score:
41
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 48 h
Score:
36
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 72 h
Score:
22
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 7 d
Score:
0
Irritant / corrosive response data:
Corneal opacity and conjunctival irritation, noted in 3/3 eyes, cleared by Day 7. Iritis, noted in 3/3 eyes, cleared by Day 3.
Other effects:
One instance of diarrhea was the only abnormal physical sign noted during the observation period.

Table 1: Ocular findings and systemic observations    
Animal no. Item Tissue Reading 1 h 24 h 48 h 72 h 7 d
1 A Cornea Opacity 2 2 2 2 0
B   Area 2 2 2 1 0
  1. Total = (AxB)x5   20 20 20 10 0
C Iris   0 1 1 0 0
  2. Total = Cx5   0 5 5 0 0
D Conjunctiva Redness 2 2 2 1 0
E   Chemosis 3 3 2 2 0
F   Discharge 2 2 2 2 0
3. Total = (D+E+F)x2   14 14 12 10 0
Total = 1+2+3   34 39 37 20 0
Systemic observations   A A A A A
Pretest bodyweight 2.2 kg          
Animal no. Item Tissue Reading 1 h 24 h 48 h 72 h 7 d
2 A Cornea Opacity 2 2 2 2 0
B   Area 2 2 2 1 0
  1. Total = (AxB)x5   20 20 20 10 0
C Iris   1 1 0 0 0
  2. Total = Cx5   5 5 0 0 0
D Conjunctiva Redness 2 2 1 1 0
E   Chemosis 2 2 2 2 0
F   Discharge 2 2 2 0 0
  3. Total = (D+E+F)x2   12 12 10 6 0
Total = 1+2+3   37 37 30 16 0
Systemic observations   A A A D A
Pretest bodyweight 2.3 kg          
Animal no. Item Tissue Reading 1 h 24 h 48 h 72 h 7 d
3 A Cornea Opacity 2 2 2 2 0
B   Area 2 3 3 2 0
  1. Total = (AxB)x5   20 30 30 20 0
C Iris   1 1 0 0 0
  2. Total = Cx5   5 5 0 0 0
D Conjunctiva Redness 2 2 1 1 0
E   Chemosis 2 2 2 2 0
F   Discharge 2 2 2 2 0
3. Total = (D+E+F)x2   12 12 10 10 0
Total = 1+2+3   37 47 40 30 0
Systemic observations   A A A A A
Pretest bodyweight 2.1 kg          
Mean scores   36 41 36 22 0
A: normal; D: diarrhea
Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Executive summary:

A study was performed to assess the eye irritancy potential of the test substance in New Zealand White rabbits according to OECD Guideline 405.

A single ocular dose of 0.1 mL of test substance was applied into the lower everted lid of one eye of each animal. The eyelids were then gently held together for one second before releasing. Examination of the eyes was made 1, 24, 48 and 72 hours post dose, then on Day 7. SCoring was conducted according to the method of Draize. The general health of the animals was monitored at each observation time. Bodyweights were recorded pretest.

Corneal opacity and conjunctival irritation, noted in 3/3 eyes, cleared by Day 7. Iritis, noted in 3/3 eyes, cleared by Day 3. One instance of diarrhea was the only abnormal physical sign noted during the observation period.

Under the test conditions, the test substance was considered to be irritating but not corrosive to eyes.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
13 December 1993 - 24 February 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: 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:Froxfield (U.K.) Ltd., Petersfield, Hampshire, England- Age at study initiation: approximately 13 to 15 weeks of age- Weight at study initiation: range of 2.9 to 3.5 kg- Housing: individually- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: yesENVIRONMENTAL CONDITIONS- Temperature (°C): approximately 19°C- Humidity (%): relative humidity at 30-70%- Air changes (per hr): approximately 19 air changes per hour- Photoperiod (hrs dark / hrs light): 12 hours of artificial light in each 24 hours period
Vehicle:
unchanged (no vehicle)
Controls:
other: The contralateral eye remained untreated.
Amount / concentration applied:
A 0.1 ml amount of the test substance was placed into the lower everted lid of one eye of each animal.
Duration of treatment / exposure:
The eyelids were then gently held together for one second before releasing.
Observation period (in vivo):
14 days after instillation
Number of animals or in vitro replicates:
3 animals
Details on study design:
TOOL USED TO ASSESS SCORE: handheld light
Irritant / corrosive response data:
Corneal opacities developed in all three animals. Stripping of the corneal epithelial cells was seen in all three animals.Iridial inflammation was seen on one occasion only in two animals.A crimson colouration of the conjunctivae was seen in all three animals, accompanied by swelling with partial eversion of the eyelids.The eyes were normal 7 or 14 days after instillation.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.

Ocular reactions observed after instillation of P115:

(* - pilot animal; a - stripping of corneal epithelial cells; D - Dulling)

 Rabbit number and sex     Region of eye           One hour                    Day after instillation
 1 14 
          2765 female *     Cornea aD  a1
    Iris  0
    Conjunctiva  Redness  2
 Chemosis  2
          2773 female     Cornea  aD  
    Iris  0  
    Conjunctiva  Redness  2 1  
 Chemosis  2  
          2775 female     Cornea  aD  
    Iris  0  
    Conjunctiva  Redness  2 1 0  
 Chemosis  2  
Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the test substance was considered to slightly irritating.
Executive summary:

A study was performed to assess the eye irritancy potential of the test substance to the eye of New Zealand White rabbits according to EU Method B.5.

A single ocular dose of 0.1 mL of test substance was applied into the eye of the rabbit (into the lower everted lid of one eye of each animal). The eyelids were then gently held together for one second before releasing. Examination of the eyes was made 1 h and 1, 2, 3, 4, 7 and 14 days after instillation.

A single instillation of the test substance into the eye of the rabbits elicited corneal opacification, iridial inflammation and well-defined conjunctival irritation. All reactions had resolved 7 or 14 days after instillation.

Under the test conditions, the application of the test substance into the eye of the rabbit elicited slight irritation.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
06 February 2006 - 14 March 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: 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: David Percival Ltd, Moston, Sandbach, Cheshire, UK- Age at study initiation: 12-20 weeks- Weight at study initiation: 2.0-3.5 kg- Housing: Individually housed in suspended cages- Diet (e.g. ad libitum): Certified Rabbit Diet (Code 5322) supplied by BCM IPS Limited, London, UK; ad libitum- Water (e.g. ad libitum): Mains drinking water; ad libitum- Acclimation period: 5 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 17-23 °C- Humidity (%): 30-70 %- Air changes (per h): 15/h- Photoperiod (h dark / h light): 12 h dark / 12 h light
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL- Amount(s) applied (volume with unit): 0.1 mL
Duration of treatment / exposure:
Single exposure
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
Three
Details on study design:
SCORING SYSTEM: Draize Scoring SystemTOOL USED TO ASSESS SCORE: Standard ophthalmoscope
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
ca. 0.47
Max. score:
4
Reversibility:
fully reversible within: 21 days
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
ca. 0.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
ca. 1.23
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
ca. 1.1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 48 hours
Score:
19
Max. score:
110
Irritant / corrosive response data:
- Average cornea opacity, iritis, conjunctival redness and conjuctival chemosis at 24, 48 and 72 hours for the three animals was observed to be 0.7/1.0+/1.7/1.3; 0.0/0.7/1.0/1.0 and 0.7/0.3/1.0/1.0, respectively- Maximum group mean score of the test material was calculated to be 19.0/110

Table 1: Individual and Mean Scores for Cornea, Iris and Conjunctivae for EU Labelling Regulations

Rabbit Number and Sex  Time After Treatment  Corneal Opacity  Iridial Inflammation  Conjunctival Redness  Conjunctival Chemosis 
20 Male  24 h 0 1 2 2
48 h 1 1 2 1
72 h 1 1 1 1
Total    2 3 5 4
Mean    0.7 1.0+  1.7 1.3
159 Male  24 h 0 1 1 1
48 h 0 1 1 1
72 h 0 0 1 1
Total    0 2 3 3
Mean    0 0.7 1 1
161 Male  24 h 1 1 1 1
48 h 1 0 1 1
72 h 0 0 1 1
Total    2 1 3 3
Mean    0.7 0.3 1 1

+ = Positive criteria

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the maximum mean eye irritation score of the test substance was calculated to be 19.0/110.
Executive summary:

A study was performed to assess the eye irritation potential of the test substance to the eyes of the New Zealand White rabbits according to GLP compliant OECD Guideline 405 and EU Method B.5.

0.1 mL of the test substance was instilled into the conjuctival sac of the right eye of each rabbit. The left eye of each animal served as a control. Without washing, eyes were scored (Draize scoring system) for irritation reactions at 1, 24, 48, 72 h and 7, 14 and 21days post-instillation.

A single application of the test substance to the non-irritated eye of three rabbits produced scattered or diffuse corneal opacity, iridial inflammation and moderate conjunctival irritation. Petechial haemorrhage of the nictitating membrane was also noted. Two treated eyes appeared normal at the 7 days observation and the remaining treated eye appeared normal at the 21 days observation. Average cornea opacity, iritis, conjunctival redness and conjuctival chemosis at 24, 48 and 72 h for the three animals was observed to be 0.7/1.0+/1.7/1.3; 0.0/0.7/1.0/1.0 and 0.7/0.3/1.0/1.0 respectively.

Under the test conditions, the maximum group mean eye irritation score of the test substance was calculated to be 19.0/110.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
23 September 1999 - 25 February 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
TEST ANIMALS- Source: Boehringer Ingelheim Pharma KG- Age at study initiation: Young adult animals- Housing: single housing- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): tap water ad libitum- Acclimation period: acclimatization for at least 1 weekENVIRONMENTAL CONDITIONS- Temperature (°C): range of 20 - 24°C- Humidity (%): range of 30 - 70%- Photoperiod (hrs dark / hrs light): 12h/ 12h
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye
Amount / concentration applied:
0.1 ml (the test substance was applied in a single dose to the conjunctival sac of the right eyelid)
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
up to 14 days (1 hour, 24 hours, 48 hours, 72 hours, 7 days and 14 days)
Number of animals or in vitro replicates:
3 animals(As the irritant potential of the test substance was unknown 1 animal was tested in a first step. As no severe findings were noted in the animal, another 2 animals were tested. The results of the 3 animals were pooled for evaluation.)
Details on study design:
Both eyes of the animal(s) were examined before application of the test material for signs of pre-existing irritation, reaction or abnormality which would prevent it from being used in the study.REMOVAL OF TEST SUBSTANCE- Washing (if done): washed out with tap water - Time after start of exposure: about 24 hours after application
Irritation parameter:
cornea opacity score
Basis:
mean
Score:
0.8
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Score:
0.4
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Score:
1.7
Max. score:
3
Irritation parameter:
chemosis score
Basis:
mean
Score:
0.6
Max. score:
4

Tabulation of irritant response data for each individual animal at each observation time as well as calculation of the means.

 Readings  Animal  Cornea op  Cornea ar  Iris  Conjunctiva red  Conjunctiva sw  Conjuntiva di Symptoms 
 1 h        01  0  
 02  0  
 03  0 Suppuration 
 24 h        01  1  
 02  1  
 03  1 Suppuration 
 48 h        01  0  
 02  1  
 03  1 Suppuration 
 72 h       01   0  
02  1 0  
03  Suppuration
 7 d        01  0 0  0  Study discontinued because the animal was free of symptoms
 02 0 0 0 1  
 03  0  1  
 14 d     02  0 0  0 Study discontinued because the animal was free of symptoms
 03  0 0 Study discontinued because the animal was free of symptoms
 Mean        01  0.3   0.0  1.3  0.7     
 02  1.0   0.3  1.7  0.0     
 03  1.0   1.0  2.0  1.0     
 Mean    0.8   0.4  1.7  0.6     
Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the test substance was considered to be slightly irritating to the eye.
Executive summary:

A study was conducted to evaluate the eye irritancy potential of the test substance using in vivo acute eye irritation assay in rabbits.

A sample of 0.1 mL was instilled into the conjuctival sac of the right eye of each rabbit. Effects were scored according to the Draize methodology after 1, 24, 48 and 72 hours, then 7 and 14 days. Calculation of the mean according to 93/21/EEC criteria of April 27th, 1993 (for calculation of the means of cornea opacity, redness and swelling of the conjunctiva only the readings of 24, 48 and 72 h were used).

The mean in vivo irritation score (24 to 71 h) for the test substance was calculated to be 0.8 for cornea opacity, 0.4 for iris, 1.7 for conjunctiva redness and 0.6 for chemosis. The findings were reversible in all animals within 7days (animal 1) or within 14 days (animals 2 and 3) after application, thus this study was terminated after 7 or 14 days. Symptom observed and described in the respective observation table in detail together with the average score for irritation indicate a slight irritant property of the test substance to the eye.

Under the test conditions, the test substance was considered to be slightly irritant to the eye.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

A study was performed to assess the skin irritation potential of amine synergist in New Zealand White rabbits according to OECD Guideline 404 and EU Method B.4. A sample of 0.5 mL was applied to the clipped skin on the back of each animal under a 2.5 x 2.5 cm cotton gauze patch. Animals were scored for irritation reactions at 1, 24, 48 and 72 h post-application and observed for reversibility on Days 7 and 14. Well-defined erythema and very slight oedema occurred. Slight or moderate desquamation was also noted. Two treated skin sites appeared normal on Day 14. Three minutes and 1 h semi-occluded applications of the test substance to the intact skin of one rabbit produced no corrosive effects. All irritation reactions were observed to be completely reversible within 14 days. The primary skin irritation score was calculated to be 2.0. The substance thereby qualifies as mildly irritating (Sanders, 2006).

A study was conducted in Himalayan rabbits to evaluate the skin irritation potential of the substance using thein vivoacute dermal irritation/ corrosion assay in rabbits (OECD Guideline 404 and EU Method B.4). The average score (24 to 72 h) for irritation was calculated to be 2.0 for erythema and 0.3 for edema. On Day 14 after removal of the patches, scaling was seen in 3 animals and erythema extending beyond the area of exposure in one. Edema was resolved within 24 h. The authors conclude that the substance gives indications of irritant properties since some effects persisted until end of the 14 day observation period (Wiemann and Hellwig, 2000).

A study was performed to assess the skin irritation potential of the test substance to the skin of New Zealand White rabbits according to OECD Guideline 404. 0.5 mL of test substance was applied to the clipped skin area on the back of each animal under a 25 x 25 mm gauze pad. The pad was allowed to remain in contact with the skin for 4 h. Animals were scored for irritation reactions after 1, 24, 48 and 72 hours then 7 and 14 days. Erythema scores, very slight to well defined at 1 hour following patch removal, ranged from absent to severe through Day 1 and cleared by Day 14. One animal had poor hair regrowth on Day 7, which cleared by Day 14. Edema scores generally ranged from absent to slight through Day 7 and cleared by Day 14, with the exception of a score 3 (moderate) in one animal at 24 hours. The primary dermal skin irritation index was equivalent to 3.67. Under the test conditions, the test substance was considered to be irritating but not corrosive to skin (Kieffer, 1998).

A study was performed to assess the skin irritation potential of the substance in New Zealand White rabbits according to EU Method B.4. 0.5 mL were applied to the shaved skin area on the back of each animal under a 25 x 25 mm gauze pad. The pad was allowed to remain in contact with the skin for 4 h. Animals were scored for irritation reactions on Days 1 (approximately 30 minutes after removal of the dressing), 2, 3 and 4. No dermal reactions were observed (Liggett, 1992).

The skin irritation potential of the substance was determined using anin vivomethod, as described in the Code of Federal Regulations, Title16, Section 1500.41. Six New Zealand White rabbits were administered a dermal dose of 0.5 ml to one intact and one abraded skin site under occlusive conditions for 24 hours and observed for three days. Well-defined moderate to severe dermal irritation was noted. The Primary Irritation Index (PII) was calculated to be 4.1 (Parcell, 1998). This study was disregarded because the protocol is not in line with classification and labelling requirements: exposure was 24 h rather than 4 h and abraded skin was also evaluated.

Eye irritation

A study was performed to assess the eye irritation potential of amine synergist in New Zealand White rabbits according to OECD Guideline 405 and EU Method B.5. The left eye served as a control. Without washing, eyes were scored (Draize scoring system) for irritation reactions at 1, 24, 48, 72 h and 7, 14 and 21days post-instillation. Scattered or diffuse corneal opacity, iridial inflammation and moderate conjunctival irritation were seen. Petechial haemorrhage of the nictitating membrane was also noted. Two treated eyes appeared normal at Day 7 and the remaining treated eye appeared normal at Day 21. The maximum group mean eye irritation score was calculated to be 19.0/110 (Sanders, 2006).

A further study was performed to assess the eye irritation potential of the substance in Himalayan rabbits according to OECD Guideline 405 and EU Method B.5. A sample of 0.1 mL was instilled into the conjuctival sac of the right eye of each rabbit. Effects were scored according to the Draize methodology after 1, 24, 48 and 72 hours, then 7 and 14 days. Calculation of the mean according to 93/21/EEC criteria of April 27th, 1993 (for calculation of the means of cornea opacity, redness and swelling of the conjunctiva only the readings of 24, 48 and 72 h were used). The meanin vivoirritation score (24 to 72 h) was calculated to be 0.8 for cornea opacity, 0.4 for iris, 1.7 for conjunctiva redness and 0.6 for chemosis. The findings were reversible in all animals within 7 or 14 days. Under the test conditions, the test substance was considered to be slightly irritating to the eye (Wiemann, 2000).

A study was performed to assess the eye irritation potential of the substance in New Zealand White rabbits according to EU Method B.5. A single ocular dose of 0.1 mL was applied into the lower everted lid of one eye of each animal. The eyelids were then gently held together for one second before releasing. Examination was made after 1 h and 1, 2, 3, 4, 7 and 14 days. Corneal opacification, iridial inflammation and well-defined conjunctival irritation were seen. All reactions had resolved within 7 or 14 days (Parcell, 1998).

A study was performed to assess the eye irritancy potential of the test substance in New Zealand White rabbits according to OECD Guideline 405. A single ocular dose of 0.1 mL of test substance was applied into the lower everted lid of one eye of each animal. The eyelids were then gently held together for one second before releasing. Examination of the eyes was made 1, 24, 48 and 72 hours post dose, then on Day 7. Scoring was conducted according to the method of Draize. The general health of the animals was monitored at each observation time. Bodyweights were recorded pretest. Corneal opacity and conjunctival irritation, noted in 3/3 eyes, cleared by Day 7. Iritis, noted in 3/3 eyes, cleared by Day 3. One instance of diarrhoea was the only abnormal physical sign noted during the observation period. Under the test conditions, the test substance was considered to be irritating but not corrosive to eyes (Cerven, 1998).

Justification for classification or non-classification

Amine synergist was only mildly or not irritating to skin in two of four studies. In a third study, certain effects (scaling in three animals,erythema extending beyond the area of exposure in one animal) were still seen at the end of the 14 day observation period, so that the authors concluded that the substance gave indications of irritant properties. In the fourth test, the substance was clearly irritating, with symptoms resolving by end of the 14 day observation period.Individual animal scores from the two last studies suggest that classification as Skin Irrit. 2 – H315 (Causes skin irritation) is required according to CLP (EC 1271/2008) criteria.

The substance was not irritating in one study and slightly irritating in two studies. In a last study, individual irritation scores suggest classification under CLP (EC 1271/2008) criteria. Classification of the substance as Eye Irrit. 2 - H319 (Causes serious eye irritation) according to CLP (EC 1271/2008) criteria is proposed.