Registration Dossier

Administrative data

Description of key information

The primary skin irritation/corrosion of Lithium cryolite in the rabbit (4-hour semi-occlusive application) was investigated in a study performed according to the OECD Testing Guideline No.404 and under GLP.

Three rabbits were exposed to 0.5 grams of Lithium cryolite, moistened with water by application onto clipped skin for 4 hours using a semi-occlusive dressing. Skin reactions were assessed 1, 24, 48 and 72 hours after exposure.

No skin irritation was caused by 4 hours exposure to Lithium cryolite.

 

The acute eye irritation/corrosion of Lithium cryolite in the rabbit was investigated in a study performed according to the OECD Testing Guideline No.405 and under GLP.

Single samples of approximately 67 mg of Lithium cryolite (a volume of approximately 0.1 mL) were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours and 7 and/or 14 days after instillation.

Instillation of the test substance resulted in effects on the iris and conjunctivae.

Iridial irritation grade 1 was observed and resolved within 24 hours for two animals and within 48 hours in the remaining animal. The irritation of the conjunctivae consisted of redness, chemosis and discharge. The irritation had completely resolved within 7 days in one animal and within 14 days in the other animals

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

For each of the three animals the average scores for three consecutive days (24, 48 and 72h) were calculated separately for the cornea, iris and conjonctiva . The mean scores of the three animals were below the values in CLP for corneal opacity and iritis. For conjonctival redness and oedema, only one animal showed mean values above the values in CLP for classification category 2.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 03 September 2013 (Start of in-life phase) to 09 December 2013 (GLP compliance statement and Quality assurance statement)
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:
not specified
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
not specified
Qualifier:
according to
Guideline:
other: Food and Agricultural Materials Inspection Centre (FAMIC), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions
Deviations:
not specified
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Source: Charles River France, L’Arbresle Cedex, France
- Age at study initiation: between 12 and 24 weeks old
- Weight at study initiation: body weights were at least 1.5 kg
At least prior to dosing, it was ensured that the animals were healthy and that the skin to be treated was intact and free from any abnormality.
- Housing: Animals were individually housed in labeled cages with perforated floors (Ebeco, Germany, dimensions 67 x 62 x 55 cm) and shelters (Ebeco, Germany, dimensions 40 x 32 x 23 cm).
- Diet : Pelleted diet for rabbits (Global Diet 2030 from Harlan Teklad®, Mucedola, Milanese, Italy) approximately 100 grams per day. Hay (TecniLab-BMI BV, Someren, The Netherlands) and wooden sticks (Swedish aspen wood, Bioservices, Uden, The Netherlands) were available during the study period.
- Water : Free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.
- End of treatment: After the final observation, the animals were sacrificed by intra-venous injection of Euthasol® 20% (AST Farma BV, Oudewater, The Netherlands).

ENVIRONMENTAL CONDITIONS
- Temperature : 18-24°C
- Humidity : 40-70 %
- Air changes : approximately 15 room air changes/hour
- Photoperiod : 12-hour light/12-hour dark cycle

IN-LIFE DATES: From: 03 September 2013 To: 20 September 2013.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
Amount(s) applied : Each animal was treated by dermal application of 0.5 grams of the test substance which was moistened with 0.3 mL of the vehicle (i.e. water).

VEHICLE
The powdery test substance was moistened with water (Elix, Millipore S.A.S., Molsheim, France), immediately before application, to ensure close contact with the animal's skin.
No corrections were made for the purity/composition of the test substance, since the guidelines requires a fixed amount that has to be applied.
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
3 males : The study was performed in a stepwise manner and was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner 14 days later, after considering the degree of skin irritation observed in the first animal.
Details on study design:
TEST SITE
Approximately 24 hours before treatment, the dorsal fur was clipped with electric clippers, exposing an area of approximately 150 square centimeters (10x15 cm). To facilitate scoring, treated skin areas were re-clipped at least 3 hours before the observations.
The test item was applied to the skin of one flank, using a metalline patch of 2x3 cm. The patch was mounted on Micropore tape, which was wrapped around the abdomen and secured with Coban elastic bandage.


REMOVAL OF TEST SUBSTANCE
Four hours after the application, the dressing was removed and the skin cleaned of residual test substance using tap water.

OBSERVATION AND SCORING SYSTEM:
Mortality/Viability : observation twice daily.
Toxicity : observation at least once daily.
Body Weight : observation the day of treatment (prior to application) and after the final observation.
Necropsy : No necropsy was performed according to protocol.
Irritation : The skin reactions were assessed at approximately 1, 24, 48 and 72 hours after the removal of the dressings and test substance. The irritation scores and a description of all other (local) effects were recorded. Adjacent areas of the untreated skin of each animal served as controls.
The irritation was assessed according to the following numerical scoring system. At each observation, the highest scores given were recorded:

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) *.......................................................................................... 4
*. Where signs of necrosis or corrosion (injuries in depth) prevent erythema scoring, the
maximum grade for erythema (= 4) is given.

Oedema formation:
No oedema ............................................................................................................................ 0
Very slight oedema (barely perceptible) ................................................................................. 1
Slight oedema (edges of area well-defined by definite raising) ............................................... 2
Moderate oedema (raised approximately 1 millimeter) ........................................................... 3
Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure) 4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
all the 3 animals showed the same score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Remarks:
first reading at 1h
Irritation parameter:
edema score
Basis:
mean
Remarks:
all the 3 animals showed the same score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Remarks:
first reading at 1h
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Irritant / corrosive response data:
Irritation:
No skin irritation was caused by 4 hours exposure to Lithium cryolite.
Corrosion:
There was no evidence of a corrosive effect on the skin.
Coloration / Remnants:
No staining of the treated skin by the test substance was observed and no test substance remnants were seen.
Toxicity / Mortality :
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.
Other effects:
No histopathology was performed.

Deviations:

- protocol deviations : Deviations from the minimum and maximum level of daily mean relative humidity occurred.

Evaluation: Laboratory historical data do not indicate an effect of the deviations.

The study integrity was not adversely affected by the deviations.

- standard operating procedures deviations : Any deviations from standard operating procedures were evaluated and filed in the study file. There were no deviations from standard operating procedures that affected the integrity of the study.

Interpretation of results:
GHS criteria not met
Conclusions:
Lithium cryolite does not have to be classified for skin irritation according to the CLP and the UN GHS.
Executive summary:

The primary skin irritation/corrosion of Lithium cryolite in the rabbit (4-hour semi-occlusive application) was investigated in a study performed according to the OECD Testing Guideline No.404 and under GLP.

Three rabbits were exposed to 0.5 grams of Lithium cryolite, moistened with water by application onto clipped skin for 4 hours using a semi-occlusive dressing. Skin reactions were assessed 1, 24, 48 and 72 hours after exposure.

No skin irritation was caused by 4 hours exposure to Lithium cryolite.

Based on these results Lithium cryolite does not have to be classified for skin irritation according to the CLP and the UN GHS.

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

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 09 September 2013 (Start of in-life phase) to 19 December 2013 (GLP compliance statement)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
deviations from the maximum level of daily mean relative humidity : see additional data in results' section
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
not specified
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
not specified
Qualifier:
according to
Guideline:
other: Food and Agricultural Materials Inspection Centre (FAMIC), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions.
Deviations:
not specified
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River France, L’Arbresle Cedex, France
- Age at study initiation: between 12 and 24 weeks old
- Weight at study initiation: body weights were at least 1.5 kg
- Housing: Animals were individually housed in labeled cages with perforated floors (Ebeco, Germany, dimensions 67 x 62 x 55 cm) and shelters (Ebeco, Germany, dimensions 40 x 32 x 23 cm).
- Diet : Pelleted diet for rabbits (Global Diet 2030 from Harlan Teklad®, Mucedola, Milanese, Italy) approximately 100 grams per day. Hay (TecniLab-BMI BV, Someren, The Netherlands) and wooden sticks (Swedish aspen wood, Bioservices, Uden, The Netherlands) were available during the study period.
- Water : Free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): maintained from 18 to 24°C
- Humidity (%): from 40 to 70 %
- Air changes (per hr): approximately 15 room air changes / hour.
- Photoperiod (hrs dark / hrs light): 12-hour light / 12-hour dark.

IN-LIFE DATES: From: 09 September 2013 To: 03 December 2013.
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
The powdery test substance was instilled undiluted as delivered by the sponsor. No correction was made for the purity/composition of the test substance, since the guidelines require a fixed amount to be instilled.
Animals were treated by instillation of, on average, 67.3 mg (range 67.0 – 67.5 mg) of the test substance (a volume of approximately 0.1 mL) in the conjunctival sac of one of the eyes.

VEHICLE
not applicable
Duration of treatment / exposure:
Single instillation.
Observation period (in vivo):
21 days.
Number of animals or in vitro replicates:
3 animals.
The study was performed in a stepwise manner and was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner 10 weeks later, after considering the degree of eye irritation observed in the first animal.
Details on study design:
APPLICATION OF THE TEST SUBSTANCE:
Animals were treated by instillation of the test substance in the conjunctival sac of one of the eyes after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test substance. The other eye remained untreated and served as the reference control.

REMOVAL OF TEST SUBSTANCE
Immediately after the 1 hour observation, the treated eye was rinsed with approx 50 mL tepid tap water, using a velocity of flow which did not affect the eye, to remove any visible residual test substance. For reference control the other eye was also rinsed.

SCORING SYSTEM:
The eyes of each animal were examined approximately 1, 24, 48 and 72 hours and 7 and/or 14 days after instillation of the test substance. The irritation scores and a description of all other (local) effects were recorded.The irritation was assessed according to the following numerical scoring system. At each observation, the highest scores given were recorded:

- CORNEAL IRRITATION

Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity (may include slight dulling of normal luster) ............................................ 0
Scattered or diffuse areas of opacity, 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

Area of cornea involved:
No ulceration or opacity................................................................................................................ 0
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

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

- CONJUNCTIVAL IRRITATION

Redness (refers to palpebrae and sclera, excluding cornea and iris):
Blood vessels normal .................................................................................................................. 0
Some blood vessels definitely hyperaemic (injected).................................................................... 1
Diffuse, crimson color, individual vessels not easily discernible.................................................... 2
Diffuse beefy red.......................................................................................................................... 3

Chemosis (refers to lids and/or nictitating membranes):
No swelling ………………………………………… ........................................................................ 0
Any swelling above normal (includes 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

- Discharge:
No discharge (may include small amounts observed in inner canthus of normal animals) ........... 0
Any amount different from normal and/or lacrimation ................................................................... 1
Discharge with moistening of the lids and hairs just adjacent to lids ............................................. 2
Discharge with moistening of the lids and hairs (considerable area around the eye) ................... 3


TOOL USED TO ASSESS SCORE:
A solution of 2% fluorescein (Merck, Darmstadt, Germany) in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage.
Where standard lighting was considered inadequate for observing minor effects, eye examinations were performed using an ophthalmic examination lamp.
In cases of equivocal results when comparing the treated and untreated eyes, the illustrated guide from the Consumer Product Safety Commission, Washington, D.C. 20207 was used for additional control purposes.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: The highest individual score was 1.
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible within: 24 hours
Remarks on result:
other: The highest individual score was 1.
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible within: 24 hours
Remarks on result:
other: The highest individual score was 1.
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.3
Max. score:
3
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: The highest individual score was 3.
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.7
Max. score:
3
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: The highest individual score was 2.
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.7
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: The highest individual score was 2.
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: The highest individual score was 3.
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: The highest individual score was 2.
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: The highest individual score was 3.
Irritant / corrosive response data:
Irritation
Instillation of approximately 67 mg of Lithium cryolite (a volume of approximately 0.1 mL) into one eye of each of three rabbits resulted in effects on the iris and conjunctivae.
Iridial irritation grade 1 was observed and resolved within resolved within 24 hours for two animals and within 48 hours in the remaining animal.
The irritation of the conjunctivae consisted of redness, chemosis and discharge. The irritation had completely resolved within 7 days in one animal and within 14 days in the other animals.
No corneal opacity was observed, and treatment of the eye with 2% fluorescein 24 hours after test substance instillation revealed no corneal epithelial damage.

Corrosion
There was no evidence of ocular corrosion.
Other effects:
Coloration / Remnants:
Remnants of the test substance were present in the eye on Day 1. No staining of (peri) ocular tissues by the test substance was observed.

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

Table 1: Individual eye irritation scores

 

Cornea

Iris

Conjunctivae

Animal

Time after dosing

Opacity

(0-4)

 Area

(0-4)

 Fluor area (%)2

(0-2)

Redness

(0-3)

 Chemosis

(0-4)

 Discharge

(0-3)

Comments

5271

1 hour

0

0

 

1

1

3

3

b

 

24 hours

0

0

0

1

3

3

2

-

 

48 hours

0

0

-

0

2

2

1

-

 

72 hours

0

0

-

0

2

1

0

-

 

7 days

0

0

-

0

1

0

0

-

 

14 days

0

0

-

0

0

0

0

-

 

 

 

 

 

 

 

 

 

 

569

1 hour

0

0

 

1

2

2

2

b

 

24 hours

0

0

0

0

2

2

2

-

 

48 hours

0

0

-

0

2

1

1

-

 

72 hours

0

0

-

0

1

0

0

-

 

7 days

0

0

-

0

1

0

0

-

 

14 days

0

0

-

0

0

0

0

-

 

 

 

 

 

 

 

 

 

 

579

1 hour

0

0

 

1

2

3

3

b

 

24 hours

0

0

0

0

2

2

1

-

 

48 hours

0

0

-

0

2

1

1

-

 

72 hours

0

0

-

0

1

1

1

-

 

7 days

0

0

-

0

0

0

0

-

1 Sentinel

2 Green staining after fluorescein treatment (percentage of total corneal area)

Comments:

b Remnants of the test substance in the eye.

Protocol deviations:

- Deviations from the maximum level of daily mean relative humidity occurred.

Evaluation: Laboratory historical data do not indicate an effect of the deviations. The study integrity was not adversely affected by the deviation.

Standard operating procedures deviations:

Any deviations from standard operating procedures were evaluated and filed in the study file. There were no deviations from standard operating procedures that affected the integrity of the study.

Interpretation of results:
GHS criteria not met
Conclusions:
Lithium cryolite does not have to be classified for eye irritation according to the CLP and the UN GHS.
Executive summary:

The acute eye irritation/corrosion of Lithium cryolite in the rabbit was investigated in a study performed according to the OECD Testing Guideline No.405 and under GLP.

Single samples of approximately 67 mg of Lithium cryolite (a volume of approximately 0.1 mL) were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours and 7 and/or 14 days after instillation.

Instillation of the test substance resulted in effects on the iris and conjunctivae.

Iridial irritation grade 1 was observed and resolved within 24 hours for two animals and within 48 hours in the remaining animal. The irritation of the conjunctivae consisted of redness, chemosis and discharge. The irritation had completely resolved within 7 days in one animal and within 14 days in the other animals

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

For each of the three animals the average scores for three consecutive days (24, 48 and 72h) were calculated separately for the cornea, iris and conjonctiva . The mean scores of the three animals were below the values in CLP for corneal opacity and iritis. For conjonctival redness and oedema, only one animal showed mean values above the values in CLP for classification category 2.

Based on these results Lithium cryolite does not have to be classified for eye irritation according to the CLP and the UN GHS.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

According to the results obtained in the test performed according to the OECD 404 test guideline, Lithium cryolite does not have to be classified for skin irritation according to the CLP and the UN GHS.

According to the results obtained in the test performed according to the OECD 405 test guideline, Lithium cryolite does not have to be classified for eye irritation according to the CLP and the UN GHS.