Registration Dossier

Administrative data

Description of key information

Skin Irritation
Three studies are provided. In both the key and supporting studies, no signs of dermal irritation were observed.
Eye Irritation
One study is provided. In the key study, no signs of ocular irritation were observed.

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:
data not available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in accordance with generally accepted scientific principles, with incomplete reporting or methodological deficiencies. This reference does not provide a full report with regard to the methods used in this study. However, as most basic key information is reported, the study can be judged as scientifically acceptable.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
other: FHSA 16 CFR 1500.41
Principles of method if other than guideline:
no data
GLP compliance:
not specified
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS:
- Source, Age at study initiation, Weight at study initiation, Housing, Diet, Water, Acclimation period: data not available

ENVIRONMENTAL CONDITIONS:
- Temperature, Humidity, Air changes, Photoperiod: data not available

IN-LIFE DATES: data not available
Type of coverage:
occlusive
Preparation of test site:
other: one intact and one abraded skin site
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
undiluted / 0.5 g
Duration of treatment / exposure:
24 hours
Observation period:
72 hours; the sites were evaluated 24 and 72 hours after the initial exposure.
Number of animals:
6
Details on study design:
TEST SITE:
- Area of exposure: ca. 2.5 cm²
- % coverage: data not available
- Type of wrap if used: data not available

REMOVAL OF TEST SUBSTANCE:
- Washing: yes (the test sites were wiped)
- Time after start of exposure: 24 hours

SCORING SYSTEM: according to Draize:

Erythema and eschar formation:

No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) or eschar formation (injuries in depth) preventing erythema reading 4

Oedema formation:

No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (edges raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) 4
Irritation parameter:
primary dermal irritation index (PDII)
Score:
0
Reversibility:
no data
Irritant / corrosive response data:
There were no signs of dermal irritation.

There were no signs of dermal irritation.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test material was not irritating under the conditions of this test and is not classified in accordance with EU criteria.
Executive summary:

In a primary dermal irritation study that broadly followed the FHSA 16 CFR 1500.41 guideline, six New Zealand White rabbits were dermally exposed to 0.5 g of the test material on one intact and one abraded skin site. Test sites were covered with an occlusive dressing for 24 hours and the animals were observed for the following 72 hours. Irritation was scored by the method of Draize 24 and 72 hours after the initial exposure.

There were no signs of dermal irritation and the Primary Dermal Irritation Index = 0.0.

Under the conditions of this study, the test material is not a dermal irritant and does not require classification in accordance with EU criteria.

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:
8 November 1990 - 11 November 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
Reference:
Composition 0
Composition 0
Qualifier:
according to
Guideline:
other: FHSA 16 CFR 1500.42
Deviations:
no
GLP compliance:
not specified
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Housing: Individually housed in suspended stainless steel caging with mesh floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum tap water supplied by automatic watering system
- Acclimation period: 5, 7 or 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68 - 73 °C

IN-LIFE DATES: From: To: 8 November 1990 - 11 November 1990
Vehicle:
unchanged (no vehicle)
Controls:
other: the right eye of each rabbit remained untreated and served as control
Amount / concentration applied:
undiluted
Amount applied: 0.1 g
Duration of treatment / exposure:
The upper and lower lids were gently held together for 1 second post-installation to prevent loss of the test material.

Three of the treated eyes were rinsed 30 seconds post-installation.
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
6; 3 male, 3 female
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): three of the treated eyes were rinsed with saline.
- Time after start of exposure: 30 seconds post-exposure.

- Scoring system: according to the method of Draize. Ocular lesions were evaluated at 24, 48 and 72 hours post installation. Fluorescein was used at the 24 hour evaluation.

Draize Scale for Scoring Ocular Irritation. Eye scores further classified by system of Kay and Calandra.

1. CONJUNCTIVAE

(A) Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Vessels normal............................................................................................................................................0
Vessels definitely injected above normal................................................................................................1
More diffuse, deeper crimson red, individual vessels not easily discernible....................................2
Diffuse beefy red.........................................................................................................................................3

(B) Chemosis
No swelling..................................................................................................................................................0
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 half closed to completely closed...............................................................................4

(C) Discharge
No discharge...............................................................................................................................................0
Any amount different from normal (does not include small amounts observed in inner
canthus of normal animals)......................................................................................................................1
Discharge with moistening of the lids and hairs just adjacent to lids...............................................2
Discharge with moistening of the lids and hairs a considerable area around the eye...................3

THE TOTAL SCORE = (A + B + C) x 2 MAXIMUM TOTAL = 20

2. IRIS

(D) Values
Normal.........................................................................................................................................................0
Folds above normal, congestion, swelling, circumcorneal injection (any or all
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

THE TOTAL SCORE = D x 5 MAXIMUM TOTAL = 10

3. CORNEA

(E) Degree of Opacity (most dense area used)
No opacity...................................................................................................................................................0
Scattered or diffuse areas, details of iris clearly visible......................................................................1
Easily discernible translucent areas, details of iris slightly obscured..............................................2
Opalescent areas, no details of iris visible, size of pupil barely discernible....................................3
Opaque, iris not discernible through the opacity................................................................................4

(F) Area of Cornea Involved
One quarter (or less) but not zero..........................................................................................................1
Greater than one quarter but less than half...........................................................................................2
Greater than half but less than three quarters......................................................................................3
Greater than three quarters, up to whole area.......................................................................................4

THE TOTAL SCORE = (E x F) x 5 MAXIMUM TOTAL = 80

MAXIMUM TOTAL SCORE POSSIBLE = 110
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0.11
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Unwashed
Irritation parameter:
iris score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0.11
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Unwashed
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0.56
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Unwashed
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0.44
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Unwashed
Irritation parameter:
other: discharge
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Unwashed
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: n/a
Remarks on result:
other: Washed
Irritation parameter:
iris score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: n/a
Remarks on result:
other: Washed
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0.56
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Washed
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0.22
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Washed
Irritation parameter:
other: discharge
Basis:
mean
Remarks:
of 3 animals
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0.11
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Washed
Irritant / corrosive response data:
All treated eyes exhibited conjunctival irritation 24 hours post installation. With the exception of one washed eye, this had cleared 48 hours after installation. The remaining eye was free of irritation by 72 hours.
Other effects:
All animals appeared active and healthy. No signs of gross toxicity, adverse pharmacologic effects or abnormal behaviour were observed.

Table 1: Individual Results

Time Point (hours)

Rabbit Number

Cornea

Iris

Conjunctivae

Chemosis

Discharge

 

 

24

7758

7759

7760

7761

7762

7763

1*

0

0

0

0

0

0

0

1

0

0

0

2

1

2

2

1

1

2

1

1

1

1

0

2

1

3

1

0

0

 

 

48

7758

7759

7760

7761

7762

7763

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

 

 

72

7758

7759

7760

7761

7762

7763

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Rabbits 7761, 7762 and 7763 had the treated eye rinsed with 30 cc of saline solution 30 seconds post-installation.

*The area affected by the corneal opacity was judged to be one quarter (or less) but not zero and the area of the cornea involved was therefore given a score of 1.

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test material produced minor irritation effects to both the unwashed and washed eyes, all of which were reversible withing 72 hours. No classification is required under the conditions of this study.
Executive summary:

A primary eye irritation study was conducted in accordance with FHSA guideline16 CFR 1500.42.

0.1 g of the test material was instilled into the left eye of six New Zealand white rabbits, with three of the treated eyes being rinsed after 30 seconds with saline. The animals were observed for three days and the eyes examined at 24, 48 and 72 hours. Irritation was scored according to the method of Draize.

 

The test material produced minor irritation effects to both the unwashed and washed eyes, all of which were reversible withing 72 hours. No classification is required under the conditions of this study in accordance with EU criteria. 

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

Respiratory irritation

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

Additional information

Skin Irritation

The key study is a primary dermal irritation study that broadly followed the FHSA 16 CFR 1500.41 guideline. Six New Zealand White rabbits were dermally exposed to 0.5 g of the test material on one intact and one abraded skin site. Test sites were covered with an occlusive dressing for 24 hours and the animals were observed for the following 72 hours. Irritation was scored by the method of Draize 24 and 72 hours after the initial exposure.

There were no signs of dermal irritation and the Primary Dermal Irritation Index = 0.0.

Under the conditions of this study, the test material is not a dermal irritant and does not require classification.

 

Supporting information is provided in the form of two studies conducted on the analogous substance Neodymium fluoride. Both substances have a similar toxicological profile. The studies were both awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch (1997). The reports are being used in a read-across capacity as the results are considered to be representative of the registered material.

The first supporting study was conducted in accordance with the standardised guideline OECD 404.

Six male New Zealand White rabbits were dermally exposed to 0.5 g of the test material moistened with 0.06 mL of water to form a paste. Test sites were covered with a semi-occlusive dressing for 4 hours, followed by observation of the animals for 72 hours. Irritation was evaluated based on erythema and oedema reactions observed 24, 48 and 72 hours after the end of application.

No skin reactions were observed during the study. The mean score for the readings at 24, 48 and 72 hours for both erythema and oedema was equal to 0.

Under the conditions of this study, the test material is not classified.

In the second supporting study, the primary skin irritation potential of the test material was investigated in accordance with the FHSA guideline 16 CFR 1500.41.

0.5 g of the test material was applied to both an intact and abraded site on each of six New Zealand White rabbits. The sites were occluded for 24 hours. The patches were then removed and the test sites wiped to prevent further exposure. Evaluation occurred 24 and 72 hours after exposure.

With the exception of one intact site with very slight erythema at 24 hours, all sites were clear of irritation during the test period.

Under the conditions of this study, the test material is not irritating to skin and requires no classification.

 

Eye Irritation

The key study is a primary eye irritation study conducted in accordance with FHSA guideline16 CFR 1500.42.

0.1 g of the test material was instilled into the left eye of six New Zealand white rabbits, with three of the treated eyes being rinsed after 30 seconds with saline. The animals were observed for three days and the eyes examined at 24, 48 and 72 hours. Irritation was scored according to the method of Draize.

The test material produced minor irritation effects to both the unwashed and washed eyes, all of which were reversible withing 72 hours. No classification is required under the conditions of this study in accordance with EU criteria.


Justification for selection of skin irritation / corrosion endpoint:
The key study was conducted in accordance with generally accepted scientific principles, though the reference does not provide a full report with regard to the methods used in this study. However, as most basic key information is reported, the study can be judged as scientifically acceptable. The method used broadly followed the FHSA 16 CFR 1500.41 guideline and was awarded a reliability score of 2 in accordance with the criteria of Klimisch (1997).

Justification for selection of eye irritation endpoint:
The key study was conducted in accordance with the standardised guideline FHSA 16 CFR 1500.42. It was well reported and adhered to sound scientific principles. It was awarded a reliability score of 1 in accordance with the criteria of Klimisch (1997).

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008, the test material does not require classification for irritation or corrosion to either the skin or eye.