Registration Dossier

Administrative data

Description of key information

Skin irritation: non-irritating, OECD 404, RCC Research & Consulting Company Ltd. 1998
Eye irritation: non-irritating, OECD 405, RCC Ltd Toxicology Division 2000

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:
1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP.
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: Recognised animal supplier
- Age at study initiation: 15 weeks
- Weight at study initiation: 2809 - 3039 g
- Housing: Individually in stainless steel cages with an automatic cleaning system equipped with feed hoppers, drinking water bowls, with wood and haysticks for gnawing.
- Diet (e.g. ad libitum): Certified pellet diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod: 12 hour light / 12 hour dark

IN-LIFE DATES: From: 13/10/98 To: 22/10/98
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5ml
Duration of treatment / exposure:
4 hours
Observation period:
3 days
Number of animals:
3 animals (1 male; 2 females)
Details on study design:
TEST SITE
- Area of exposure: dorsal area
- % coverage: 6 sq. cm (2.5 cm x 2.5 cm)
- Type of wrap if used: semi-occlusive

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

SCORING SYSTEM: The skin reaction was assessed according to the numerical scoring system listed in the EEC Commission Directive 92/69/EEC, July 31, 1992 at approximately 1, 24, 48 and 72 hours after the removal of the dressing, gauze patch and test article.
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 1, 24, 48, 72 h
Score:
0
Max. score:
8
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24, 48, 72h
Score:
0
Max. score:
4
Remarks on result:
other: mean of all 3 organisms
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 48, 72h
Score:
0
Max. score:
4
Remarks on result:
other: mean of all 3 organisms
Irritant / corrosive response data:
Local signs (mean values from 24 to 72 hours) consisted of grade 0.00 erythema and grade 0.00 edema. No signs of irritation were observed. No irreversible alterations of the treated skin were observed nor were corrosive effects evident on the skin.
Other effects:
No staining by the test article of the treated skin was observed. No clinical signs of systemic toxicity were observed in the animals during the test and observation period, and no mortality occurred.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study the test material is considered to be not irritating to the skin.
Executive summary:

The study was performed EU Method B.4 and OECD 404 guideline in accordance with GLP to assess the irritancy potential of the test material to the skin of the New Zealand White rabbit. A dose of 0.5 ml test substance (undiluted), was applied to the intact clipped dorsal skin site under a semi-occlusive dressing for 4 hours. The patch was then removed and the application site was washed to remove residual test material. Skin observations were made 1, 24, 48 and 72 hours after patch removal. A single 4-hour, semi-occluded application of the test material to the intact skin produced no irritation effects. The test material produced a primary irritation index (PII) of 0 and is considered to be non-irritating to skin. No clinical signs of systemic toxicity were observed in the animals during the test and observation period, and no mortality occurred.

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:
2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP.
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
inspected November 1998; signature: March 1999
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Recognised animal supplier
- Age at study initiation: 12-14 weeks
- Weight at study initiation: 3.0 kg
- Housing: Individually in stainless steel cages equipped with feed hoppers, drinking water bowls, with autoclaved wood and haysticks for gnawing.
- Diet (e.g. ad libitum): certified pelleted diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 5-6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5-23.5
- Humidity (%): 49-71
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 h dark / 12 h light

IN-LIFE DATES: From: 17/08/2000 To: 31/08/2000
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
Duration of treatment / exposure:
Treated eyes were not rinsed after instillation. Occular reaction was assessed at 1, 24, 48 and 72 hours, as well as 7 days after application.
Observation period (in vivo):
Occular reaction was assessed at 1, 24, 48 and 72 hours, as well as 7 days after application.
Number of animals or in vitro replicates:
3 (1 male; 2 females)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): none
- Time after start of exposure: not applicable

SCORING SYSTEM: The ocular reaction was assessed according to the numerical scoring system listed in the EEC Commission Directive 92/69/EEC, July 31, 1992 at approximately 1, 24, 48 and 72 hours, as well as 7 days after application.

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 luster),
details of iris clearly visible ................................................................................................... 1
Easily discernible translucent area, details of iris slightly obscured ............................. 2
Nacreous area, no details of iris visible, size of pupil barely discernible ...................... 3
Opaque cornea, iris not discernible through the opacity ................................................ 4

IRIS
Normal ...................................................................................................................................... 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperemia, or
injection, any of these or combination of any thereof, iris still reacting to light
(sluggish reaction is positive) ................................................................................................ 1
No reaction to light, hemorrhage, gross destruction (any or all of these) ..................... 2

CONJUNCTIVAE
Redness (refers to most severe reading of palpebral and bulbar conjunctivae when compared with
control eye)
Blood vessels normal ............................................................................................................... 0
Some blood vessels definitely hyperemic (injected) ........................................................... 1
Diffuse, crimson color, individual vessels not easily discernible ..................................... 2
Diffuse beefy red ...................................................................................................................... 3

Chemosis: lids and/or nictitating membranes
No swelling .................................................................................................................................. 0
Any swelling above normal (including nictitating membranes) .......................................... 1
Obvious swelling with partial eversion of lids ....................................................................... 2
Swelling with lids about half-closed ........................................................................................ 3
Swelling with lids more than half-closed ................................................................................ 4

TOOL USED TO ASSESS SCORE: Eye examinations were made with a Varta Cliptrix diagnostic-lamp
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 1 hour
Score:
1.67
Max. score:
13
Reversibility:
fully reversible
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 hours
Score:
0.67
Max. score:
13
Reversibility:
fully reversible
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 48 hours
Score:
0.33
Max. score:
13
Reversibility:
fully reversible
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 72 hours
Score:
0
Max. score:
13
Reversibility:
fully reversible
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 7 days
Score:
0
Max. score:
13
Reversibility:
fully reversible
Irritant / corrosive response data:
No corneal or iridal effect was observed in the treated eyes of all animals. Some definitely hyperemic blood vessels of the conjunctivae/nictitating membrane were noted in all animals at the 1-hour reading before diminishing to be clear at 24 (one animal), 48 (one animal) or 72 hours (one animal). Slight swelling of the conjunctivae/nictitating membrane was seen in two animals at the 1-hour reading.
Other effects:
Slight redness of the sclera was observed in two animals at the 1-hour reading and persisted in one animal through 24 hours. Slight watery discharge was noted in one animal at the 1-hour reading. All eye reactions were clear within 72 hours after treatment.

Table 1. Individual eye irritation scores

Animal Evaluation interval Corneal Opacity Iris Conjunctivae Cumulative Sclera
Redness Chemosis Score Mean
1 1 hour 0 0 1 1 2 1.67 1
2 0 0 1 1 2 1
3 0 0 1 0 1 0
1 24 hours 0 0 0 0 0 0.67 0
2 0 0 1 0 1 1
3 0 0 1 0 1 0
1 48 hours 0 0 0 0 0 0.33 0
2 0 0 1 0 1 0
3 0 0 0 0 1 0
1 72 hours 0 0 0 0 0 0 0
2 0 0 0 0 0 0
3 0 0 0 0 0 0
1 7 days 0 0 0 0 0 0 0
2 0 0 0 0 0 0
3 0 0 0 0 0 0
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study the test material is not considered to be irritating to the eye.
Executive summary:

The study was performed to the requirements of OECD 405 and EU Method B.5 in accordance with GLP to assess the irritancy potential of the test material to the eye following a single application in the New Zealand White rabbit. A volume of 0.1 ml of the test material was placed into the conjunctival sac of the left eye of all test animals. The right eye remained untreated and was used for control purposes. The treated eyes were not rinsed after instillation. Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48,72 hours and 7 days following treatment. No corneal or iridal effect was observed in the treated eyes of all animals. Some definitely hyperemic blood vessels of the conjunctivae/nictitating membrane were noted in all animals at the 1-hour reading before diminishing to be clear at 24 (one animal), 48 (one animal) or 72 hours (one animal). Slight swelling of the conjunctivae/nictitating membrane was seen in two animals at the 1-hour reading. All treated eyes appeared normal at the 72h observation. Under the conditions of this study the test material is not considered to be irritating to the eye.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion:

The study was performed EU Method B.4 and OECD 404 guideline in accordance with GLP to assess the irritancy potential of the test material to the skin of the New Zealand White rabbit. A dose of 0.5 ml test substance (undiluted), was applied to the intact clipped dorsal skin site under a semi-occlusive dressing for 4 hours. The patch was then removed and the application site was washed to remove residual test material. Skin observations were made 1, 24, 48 and 72 hours after patch removal. A single 4-hour, semi-occluded application of the test material to the intact skin produced no irritation effects. The test material produced a primary irritation index (PII) of 0 and is considered to be non-irritating to skin. No clinical signs of systemic toxicity were observed in the animals during the test and observation period, and no mortality occurred.

 

Eye irritation/corrosion:

The study was performed to the requirements of OECD 405 and EU Method B.5 in accordance with GLP to assess the irritancy potential of the test material to the eye following a single application in the New Zealand White rabbit. A volume of 0.1 ml of the test material was placed into the conjunctival sac of the left eye of all test animals. The right eye remained untreated and was used for control purposes. The treated eyes were not rinsed after instillation. Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48,72 hours and 7 days following treatment. No corneal or iridal effect was observed in the treated eyes of all animals. Some definitely hyperemic blood vessels of the conjunctivae/nictitating membrane were noted in all animals at the 1-hour reading before diminishing to be clear at 24 (one animal), 48 (one animal) or 72 hours (one animal). Slight swelling of the conjunctivae/nictitating membrane was seen in two animals at the 1-hour reading. Mean irritation scores after 24, 48 and 72 hours were: Animal #1: Opacity = 0; Iris = 0; Redness: 0; Chemosis: 0 (N=3), Animal #2: Opacity = 0; Iris = 0; Redness: 0.67; Chemosis: 0 (N=3) and Animal #3: Opacity = 0; Iris = 0; Redness: 0.33; Chemosis: 0 (N=3). All treated eyes appeared normal at the 72h observation. Under the conditions of this study the test material is not considered to be irritating to the eye.


Justification for selection of skin irritation / corrosion endpoint:
One in vivo GLP study (Klimisch 1).

Justification for selection of eye irritation endpoint:
One in vivo GLP study (Klimisch 1) with individual scoring tables presented.

Justification for classification or non-classification

The substance does not meet classification criteria under EU Directive 67/548/EEC for dermal irritation.

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for dermal irritation.

 

The substance does not meet classification criteria under EU Directive 67/548/EEC for eye irritation.

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for eye irritation.

For skin irritation, the weight of evidence indicates that the substance is not irritating to the skin (mean erythmea and odema scores = 0); 4 -hour application; clipped skin, semi-occlusive dressing).

For eye irritation, the weight of evidence indicates that the substance can produce a mild transient redness to the eye but which is not sufficient for classification and all effects fully reverse within 72 hours. No corneal or iritis or chemosis effects have been observed.