Lanthanum trinitrate

Endpoint summary

Description of key information

Skin irritation/corrosion:

A weight-of-evidence approach is used for this endpoint (sequential testing strategy).

Based on the determination of the pH of 3.25 and the acidic reserve (0.4), lanthanum trinitrate was considered not to be corrosive as the calculation for corrosivity was 3.245 (higher than -0.5) (Rhodia Operations, 2012).

An in vitro skin corrosion test in an EPISKIN reconstructed human epidermis model was performed according to OECD Guideline 431 and EU Method B.40 (Warren, 2013a). Lanthanum trinitrate was considered to be non-corrosive to the skin.

An in vitro skin irritation test in an EPISKIN reconstructed human epidermis model was performed according to OECD Guideline 439 and EU Method B.46 (Warren, 2013b). Lanthanum trinitrate was considered to be non-irritating to the skin.

Finally, an in vivo skin irritation study was performed according OECD Guideline 404 in New Zealand White rabbits (Bradshaw, 2013b). The results of this test indicated that the substance does not require a classification for skin irritation.

Eye irritation:

Based on the data of a study performed according to a method similar to OECD Guideline 405 study (Guillot, 1980b), the product containing 75% lanthanum trinitrate and 25% neodymium nitrate was considered to be corrosive to unwashed and washed eyes respectively, when instilled as received (undiluted).

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:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

10 March until 15 March 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP study with performed with a mixture of lanthanum trinitrate (75%) and neodymium trinitrate (25%), containing the following deviations: observation period limited to 7 days, limited details on test animals and conditions.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

observation period limited to 7 days instead of 21 days

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2 - 3 kg

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:

0.1 g of the product was instilled in the conjunctival sac of the left eye.

Observation period (in vivo):

1 hour and 1, 2, 3, 4 and 7 days after instillation.

Number of animals or in vitro replicates:

4

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): scoring was done if no washing done and if washing was done after 30 seconds. As the guideline prescribes a wash-out only after at least 24h, the scores of the eyes that were washed after 30s are not taken into account for the purpose of REACH.

SCORING SYSTEM: Draize scoring system, Kay and Calandra (1962) J. Soc. Cosmet. Chem. 13, 281: "Interpretation of eye-irritation tests"

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

other: 7 days

Score:

91.75

Max. score:

110

Reversibility:

not fully reversible within: 7 days

Remarks on result:

other: Without washing

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

of 4 animals

Time point:

other: 24, 48, 72h

Score:

2.3

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Remarks on result:

other: Individual mean scores: 2.67, 2, 2, 2.67

Irritation parameter:

iris score

Basis:

mean

Remarks:

of 4 animals

Time point:

other: 24, 48, 72h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 7 days

Remarks on result:

other: Individual mean scores: 1, 1, 1, 1

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Remarks:

of 4 animals

Time point:

other: 24, 48, 72h

Score:

2.5

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Remarks on result:

other: Individual mean scores: 2.7, 2.7, 2.3, 2.3

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

of 4 animals

Time point:

other: 24, 48, 72h

Score:

4

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Remarks on result:

other: Individual mean scores: 4, 4, 4, 4

Irritant / corrosive response data:

Based on the scoring of Draize and Kay and Calandra, the substance was judged to be extremely irritating.
Other effects: iris scores increasing from 1 to 2 after 7 days in 3 of 4 animals with no pupil reflex; reduced pupil reflex from day 3 onwards; myosis after 1 h in 1 animal and after day 1 in all animals, whitish moisture on the eyelids.

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the criteria as specified in the test report, the product containing 75% lanthanum nitrate and 25% neodymium nitrate is classified as extremely irritating. Based on the criteria of the CLP Regulation, the substance is classified as Eye Dam 1 H318 based on the severe effects that have been observed. Reversibility is not expected.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation/corrosion:

Four studies are used in a weight-of-evidence approach: one K1 test (Rhodia Operations, 2012), two K1 in vitro studies (Warren, 2013a,b) and one K1 acute dermal irritation study (Bradshaw 2013b).

The pH of a 10% lanthanum trinitrate solution was determined electrochemically at 20°C with a calibrated pH meter: a pH value of 3.25 was determined. In addition, the acidic reserve of the solution was determined via titration of a 1 mol/L NaOH solution, which was required to achieve a pH of 4 of a 10% solution (or slurry) at 20°C. The acidic reserve value was determined to be 0.4. The calculation for the corrosivity, based on the pH value and on the acidic reserve value, was 3.245 (higher than -0.5) and the substance was considered not to be corrosive (Rhodia Operations, 2012).

An in vitro skin corrosion test (K1) using EPISKIN reconstructed human epidermis model was performed according to OECD Guideline 431 and EU Method B.40 (Warren, 2013a). Duplicate tissues were treated with 20 mg of the solid test item for exposure periods of 3, 60 and 240 minutes. At the end of the exposure period the test item was rinsed from each tissue before each tissue was taken for MTT loading. After MTT loading a total biopsy of each epidermis was made and placed into micro tubes containing acidified isopropanol for extraction of formazan crystals out of the MTT-loaded tissues. At the end of the formazan extraction period each tube was mixed thoroughly and duplicate 200 µL samples were transferred to the appropriate wells of a pre-labeled 96-well plate. The optical density (OD) was measured at 540 nm (OD540). Data were presented in the form of percentage viability (MTT reduction in the test item treated tissues relative to negative control tissues). The relative mean viability of the test item treated tissues after the 240 minutes exposure was 83.9% (>= 35, relative mean tissue viability percentage of the negative control criteria). Lanthanum trinitrate was considered to be non-corrosive to the skin.

An in vitro skin irritation test (K1) in an EPISKIN reconstructed human epidermis model was performed according to OECD Guideline 439 and EU Method B.46 (Warren, 2013b). Ten mg of ground-up test substance was applied to tissues moistened with 5 µL sterile distilled water for 15 minutes. EPISKIN tissues were exposed in triplicate to test item, positive control and negative control. At the end of the exposure period each tissue was rinsed before incubating for 42 hours. At the end of the post-exposure incubation period each tissue was taken for MTT-loading. The maintenance medium from beneath each tissue was taken for MTT-loading. The maintenance medium from beneath each tissue was transferred to pre-labelled micro tubes and stored in a freezer for possible inflammatory mediator determination. After MTT loading a total biopsy of each epidermis was made and placed into micro tubes containing acidified isopropanol for extraction of formazan crystals out of the MTT-loaded tissues. At the end of the formazan extraction period each tube was mixed thoroughly and duplicate 200 µL samples were transferred to the appropriate wells of a pre-labeled 96 -well plate. The optical density was measured at 540 nm. Data were presented in the form of percentage viability (MTT reduction in the test item treated tissues relative to negative control tissues). The relative mean viability of the test item treated tissues was 103.7% after the 15-minute exposure period. Lanthanum trinitrate was considered to be non-irritating to the skin (>50% relative mean tissue viability percentage of negative control).

Following a sequential testing strategy for the assessment of the irritant/corrosive properties of lanthanum trinitrate, an in vivo acute dermal irritation study was performed (Bradshaw, 2013b) with lanthanum trinitrate (hydrated form) in New Zealand White rabbits.

In this study (scored K1) performed according to OECD 404 guideline, 2 male rabbits were exposed to lanthanum trinitrate for respectively 3 min, 1h and 4h and observed for 7 days after exposure. When necessary, additional observations were made on days 7 and 14 to assess the reversibility of skin reactions. 3-minute and 1-hour semi-occluded applications of the test item to the intact skin of one rabbit produced no corrosive effects. The test sites were observed for 7 days after dosing. A single 4 -hour, semi-occluded application of the test item to the intact skin of two rabbits produced well-defined erythema (grade 2) and very slight edema (grade 1). No corrosive effects were noted. The individual mean scores for erythema were 1.7 or 1.0 and the individual mean scores for edema were 0.3 for both animals. Slight desquamation, which is considered to be completely reversible, was noted at one treated skin site at the 7-day observation and the observations were terminated on this animal. Moderate desquamation was noted at the other treated skin site at the 7-day observation with no evidence of skin irritation at the 14-day observation. Observations were therefore terminated on this animal at the 14-day observation period. Testing was conducted on two animals and the response in these animals was such that exposure of a third animal would not affect classification of the test item, therefore no further testing was needed.

In conclusion, the test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labeling and Packaging of Substances and Mixtures.

One supportive study is also included in this endpoint. Guillot (1980a) investigated the in vivo skin irritation potential of a mixture containing 75% lanthanum nitrate and 25% neodymium nitrate in a study performed according to a method equivalent to OECD Guideline 404 in New Zealand White rabbits. After 24 hours exposure to 0.5 mL of the substance using an occlusive wrap, skin irritation (edema and erythema) was scored at 25 and 72 hours after application of the test substance. Based on the scoring system used in the study (mean value of the abraded skin observations and intact skin observations), the product containing 75% lanthanum nitrate and 25% neodymium nitrate can be considered as a slightly primary skin irritant when applied as received. Based on the criteria of the CLP Regulation, the mixture would not be classified as a skin irritant, assuming that the effects are reversible within 14 days and are not increased after 72h. However some deficiencies were observed in the test.

Although the substance tested was a mixture instead of lanthanum trinitrate pure, the main component was lanthanum trinitrate. Therefore, this study is used to support the non-classification of lanthanum trinitrate for skin irritation/corrosion.

Eye irritation/corrosion:

No GLP study evaluating the eye irritation/corrosion potential of the pure lanthanum trinitrate is available. However one study has been identified (Guillot, 1980b), where four rabbits were instilled 0.1 g of a mixture of 75% lanthanum nitrate and 25% neodymium nitrate, in the left eye. This study was performed according to a method similar to the OECD 405 guideline. The eyes were examined at 1 hour and 1, 2, 3, 4 and 7 days after instillation. The calculated index of ocular irritation for unwashed eye was 97.75 at day 7. Based on the scoring of Draize and Kay and Calandra, the substance was judged to be extremely irritating. Other effects observed: iris scores increasing from 1 to 2 after 7 days in 3 of 4 animals and no pupil reflex; reduced pupil reflex from day 3 onwards; myosis after 1 hour in 1 animal and after day 1 in all animals, whitish moisture on the eyelids.

Although the substance tested was a mixture instead of lanthanum trinitrate pure, the main component was lanthanum trinitrate. In addition, the response obtained is such that it meets the criteria for classification. Thus, this study is considered sufficient to cover this endpoint. Therefore, it is proposed to classify lanthanum trinitrate for eye damage in a worst case approach, assuming that observed effects are not reversible.

Justification for selection of skin irritation / corrosion endpoint:

Four studies are selected as a 'weight-of-evidence' approach to cover this endpoint.

Justification for selection of eye irritation endpoint:

There is only one study available for this endpoint. This study is performed on mixture of lanthanum trinitrate with neodymium trinitrate in which lanthanum trinitrate was the main component (75%). Although the substance tested was a mixture instead of lanthanum trinitrate pure, the response obtained was such that it meets the criteria for classification. As such, this study is considered sufficient to cover this endpoint. Therefore, it is proposed to classify lanthanum trinitrate for eye damage as a worst case, assuming that observed effects are not reversible.

Effects on eye irritation: corrosive

Justification for classification or non-classification

Based on the results of the available data and the criteria of the DSD and CLP Regulation, lanthanum trinitrate should not be classified for skin irritation.

Based on test results with a product containing 75% lanthanum trinitrate and 25% neodymium trinitrate and the criteria of the DSD and CLP Regulation, lanthanum trinitrate is classified as corrosive (R41) and Eye Dam 1 (H318), respectively.