Dipraseodymium tricarbonate

Endpoint summary

Description of key information

SKIN IRRITATION
Six read across studies are provided on a Weight of Evidence basis for the three analogous test materials Praseodymium III, IV oxide, Dilanthanum tricarbonate and Dineodymium tricarbonate.
Four in vivo studies are supplied, two each for Praseodymium III, IV oxide and Dilanthanum tricarbonate. A further two in vitro studies are provided for Dineodymium tricarbonate.
All six results were negative, showing no irritation or corrosion.
EYE IRRITATION
Two studies are provided on the substance to be registered (one in vivo and one in vitro); both results were negative. Therefore the test material was determined to be non-irritating.  

Key value for chemical safety assessment

Skin irritation / corrosion

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:

11 February 2013 - 21 February 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted to GLP 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.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Strain: Hsdlf:NZW
- Age at study initiation: 12 - 20 weeks
- Weight at study initiation: 2.38 or 2.44 kg
- Housing: The animals were individually housed in suspended cages.
- Diet: ad libitum
- Water: Free access to mains drinking water.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23 °C
- Humidity (%): 30 to 70 %
- Air changes (per hr): At least 15 per hour.
- Photoperiod (hrs dark / hrs light): The lighting was controlled by a time switch to give twelve hours continuous light (0600 to 1800) and twelve hours darkness.

IN-LIFE DATES: From: 11 February 2013 To: 21 February 2013

Vehicle:

unchanged (no vehicle)

Controls:

other: The left eye of each animal remained untreated and was used for control purposes.

Amount / concentration applied:

A volume of 0.1 mL of the test material, which was found to weigh approximately 86 mg (as measured by gently compacting the required volume into an adapted syringe).

Duration of treatment / exposure:

The upper and lower eyelids were held together for about one second immediately after treatment, to prevent loss of the test material, and then released. The eye was not rinsed.

Observation period (in vivo):

The observation period was 72 hours. There was no ocular irritation in either animal at the 48 hour observation; therefore no further observation was required after the 72 hour observation.

Number of animals or in vitro replicates:

Initially, one animal was treated; after consideration of the ocular response, a second animal was treated.

Details on study design:

Immediately after administration of the test material, an assessment of the initial pain reaction was made against as 6 point scale.

SCORING SYSTEM: Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment, according to the Draize numerical evaluation.
Individual bodyweights were recorded on Day 0 (the day of dosing) and at the end of the observation period. Any clinical signs of toxicity, if present, were also recorded.

Draize Scale for Scoring Ocular Irritation

1. CONJUNCTIVAE

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

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

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

2. IRIS

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

3. CORNEA

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

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


TOOL USED TO ASSESS SCORE: Any additional ocular effects were also noted. Examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: mean score at 24, 48 and 72 hours

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

mean

Time point:

other: mean score at 24, 48 and 72 hours

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: mean score at 24, 48 and 72 hours

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: mean score at 24, 48 and 72 hours

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

other: discharge score

Basis:

mean

Time point:

other: mean score at 24, 48 and 72 hours

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Irritant / corrosive response data:

Individual scores for ocular irritation are given in Table 1.
No corneal effects were noted during the study. Iridial inflammation (Grade 1) was noted in both treated eyes one hour after treatment.
Moderate conjunctival irritation (Grade 2 redness, Grade 2 chemosis and Grade 1 discharge) was noted in both treated eyes one hour after treatment. Minimal conjunctival irritation (Grade 1 redness and Grade 1 chemosis) was noted in both treated eyes at the 24 hour observation.
Both treated eyes appeared normal at the 48 hour observation and the study was terminated after the 72 hour observation.

Other effects:

BODYWEIGHT
One animal showed expected gain in bodyweight and one animal showed no gain in bodyweight during the study.

Table 1 Individual Scores for Ocular Irritation

Rabbit Number and Sex	72957 Male				72986 Male
	IPR = 2				IPR = 2
Time After Treatment	1 hour	24 hours	48 hours	72 hours	1 hour	24 hours	48 hours	72 hours
Cornea Degree Area	0 0	0 0	0 0	0 0	0 0	0 0	0 0	0 0
Iris	1	0	0	0	1	0	0	0
Redness	2	1	0	0	2	1	0	0
Chemosis	2	1	0	0	2	1	0	0
Discharge	1	0	0	0	1	0	0	0

 IPR = Initial pain reaction; a score of 2 indicates slight initial pain. The rabbit blinks and tries to open the eye but reflex closes it.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the test material requires no classification in accordance with EU criteria.

Executive summary:

The irritancy potential of the test material was assessed in vivo in accordance with the standardised guidelines OECD 405 and EU Method B.5.

A single application of 0.1 mL of the test material (which was found to weigh approximately 86 mg) was sequentially administered to the right eye of two New Zealand White rabbits. The treated eyes were not irrigated; the left eye remained untreated and served as the control. The animals were observed for ocular effects 1, 24, 48 and 72 hours after administration of the test material.

The individual mean scores for corneal opacity and iritis were 0.0 for both animals. The individual mean scores for conjunctival redness and chemosis were 0.3 for both animals. Both treated eyes appeared normal at the 48 hour observation and the study was terminated after the 72 hour observation.

Under the conditions of this study, the test material requires no classification in accordance with EU criteria.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In Vivo Skin Irritation

Praseodymium III, IV Oxide

The first study was conducted in accordance with the standardised guideline FHSA 16 CFR 1500.41 and was awarded a reliability score of 2 in accordance with the criteria of Klimisch (1997).

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 rabbit, which exhibited very slight erythema without oedema at both the intact and abraded site 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.

 

The second study provided 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).

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.

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

In this study the test material is not a dermal irritant and does not require classification.

 

Dilanthanum Tricarbonate

The first dermal irritation study provided was conducted in accordance with the standardised guidelines OECD 404 and EU Method B.4. It was awarded a reliability score of 2 in accordance with the criteria of Klimisch (1997).

Three New Zealand White rabbits were dermally exposed to 0.5 g of the test material moistened with 0.5 mL of water. One animal was treated with three patches, applied sequentially. The first patch was removed after three minutes, the second after 1 hour and the third after 4 hours. The other two animals were treated for an exposure period of 4 h only. Test sites were covered with a semi-occlusive dressing for the exposure period. The animals were observed for 72 - 96 hours.

Very slight erythema was observed in one animal at the 1 hour reading after the 4 hour exposure procedure. The individual mean score at the 24, 48 and 72 hour readings for erythema/eschar and oedema for each of the three animals was 0.

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

The second primary dermal irritation study provided was conducted in accordance with the standardised Guideline of the Department of Transportation (D.O.T), Code of Federal Regulations, Title 49, Part 173. This was also awarded a reliability score of 2 in accordance with the criteria of Klimisch (1997).

Five New Zealand White rabbits were dermally exposed to 2000 mg of the test material on shaved skin. Test sites were covered with an occlusive dressing for 24 hours and the animals were observed for the following 48 hours. Irritation was scored by the method of Draize 24 and 48 hours after removal of the patch.

There were no signs of dermal irritation. Under the conditions of this study, the test material is not a dermal irritant and does not require classification in accordance with EU criteria.

In Vitro Skin Irritation

Dineodymium Tricarbonate

The corrosivity potential of the test material was investigated in vitro in accordance with the standardised guideline OECD 431. It was awarded a reliability score of 2 in accordance with the criteria of Klimisch (1997).

The Episkin reconstituted human epidermis model was exposed to the test material for 3, 60 and 240 minutes. Duplicate tissues were treated and at the end of exposure, viability was assessed based on the MTT reduction in the test material treated tissues relative to the negative control tissues. The relative mean viabilities of the test material treated models were 100.4, 107.4, and 91.4 % after 240, 60 and 3 minutes, respectively.

The test material was considered to be non-corrosive to the skin and accredited the EU risk phrase of NO label and a UN packing group Non-Corrosive.

 

A further in vitro study is provided, also awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch (1997.)

The skin irritation potential of the test material was evaluated using the EPISKIN reconstituted human epidermis model, after a treatment period of 15 minutes followed by a post-exposure incubation period of 42 hours. 

The principle of the assay was based on the measurement of cytotoxicity in reconstituted human epidermal cultures following topical exposure to the test material by means of the colourimetric MTT reduction assay. Cell viability is measured by enzymatic reduction of the yellow MTT tetrazolium salt (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) to a blue formazan salt (within the mitochondria of viable cells) in the test material treated tissues relative to the negative controls. 

The relative mean viability of the test material treated tissues was 96.1 % after the 15 minute exposure.

The test material was therefore considered to be Non-Irritant.

Eye Irritation

The potential for the test material to cause eye irritation was assessed using both in vitro and in vivo methods. The in vivo study has been provided as key in addressing this endpoint, with the in vitro data acting as supporting.

In vitro eye irritation was investigated using the SkinEthic reconstructed Human Corneal Epithelium model. The study was performed under GLP conditions and in accordance with sound scientific principles and was assigned a reliability score of 1 in accordance with the principles for assessing data quality as defined by Klimisch (1997).

Triplicate SkinEthic tissues were treated with 30 mg of the test material for 10 minutes. Triplicate tissues treated with 30 µL of Solution A served as the negative control and triplicate tissues treated with 30 µL of 2 % w/v Sodium Dodecyl Sulphate (SDS) served as the positive control. At the end of the exposure period each SkinEthic tissue was rinsed and two tissues per group taken for MTT loading. The remaining tissues were retained for possible histopathology. Following MTT loading, the reduced MTT was extracted from the tissues. After extraction the absorbency of triplicate aliquots of the extracted MTT solution for each SkinEthic tissue was measured. The optical density was measured at 540 nm (OD540). Data are presented in the form of percentage viability (MTT conversion relative to negative controls).

Under the conditions of this study, the relative mean viability was 77.6 %. The test material was therefore considered to be a Non-Irritant (NI) and therefore requires no classification in accordance with EU criteria.

 

In vivo eye irritation was determined under GLP conditions and in accordance with the standardised guidelines OECD 405 and EU Method B.5. A single application of 0.1 mL of the test material was sequentially administered to the right eye of two New Zealand White rabbits. The treated eyes were not irrigated; the left eye remained untreated and served as the control. The animals were observed for ocular effects 1, 24, 48 and 72 hours after administration of the test material.

The individual mean scores for corneal opacity and iritis were 0.0 for both animals. The individual mean scores for conjunctival redness and chemosis were 0.3 for both animals. Both treated eyes appeared normal at the 48 hour observation and the study was terminated after the 72 hour observation. Under the conditions of the study the test material was considered to be non-irritating.

Based on both the in vitro and in vivo data, the test material is concluded to be non-irritating and therefore does not require classification for skin or eye irritation.

Justification for selection of skin irritation / corrosion endpoint:
No key study selected due to this endpoint being addressed on a Weight of Evidence approach using read across data from three analogous materials.
Six studies are provided, two per material; each was assigned a reliability score of 2 in accordance with the criteria set forth by Klimisch (1997).

Justification for selection of eye irritation endpoint:
The key study was performed in vivo, under GLP conditions and in accordance with OECD 405 and EU Method B.5. Accordingly the study was assigned a reliability score of 1 in line with Klimisch (1997).

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the test material does not require classification for skin or eye irritation.