Registration Dossier

Administrative data

Description of key information

Acute oral toxicity

The oral LD50 for rats was found to be > 2000 mg/kg bw in the key study, which was performed according to the acute toxic class method (OECD guideline 423) and conform GLP requirements (Mátyás, 2016). This study was considered reliable without restrictions (Klimisch 1).

Acute toxicity via inhalation

No key experimental data are available on the acute toxicity of gadolinium oxalate via inhalation, however, this route of exposure was considered not relevant for gadolinium oxalate because typically wet powders or dry powders with median particle size > 50 µm are manufactured.

Acute dermal toxicity

The acute oral LD50 is greater than 2000 mg/kg bw and no systemic effects or macroscopic abnormalities were observed in the study available for this endpoint. According to Annex VIII, column 2 of the REACH Regulation (revision May 2016), acute dermal toxicity can be waived if the substance under consideration is not classified as acute oral toxicant or as STOT SE, and no systemic effects have been observed in in vivo studies with dermal exposure. The latter criterion (in vivo skin sensitisation study, Tarcai, 2016) is also fulfilled. Therefore, it can be safely concluded that no adverse effects are expected upon acute dermal exposure to gadolinium oxalate. No acute dermal toxicity study should be performed.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2016-05-02 to 2016-07-27
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: On the day of administration, the test item was freshly formulated at a concentration of 200 mg/mL (anhydrous form) with the vehicle.
- A correction with the composition of the test item was applied to achieve the target concentration of the formulation expressed in anhydrous form. (i.e. 200 mg/mL anhydrous form equal to 410 mg/mL test item as such).

FORM AS APPLIED IN THE TEST (if different from that of starting material): formulation with 1% methylcellullose at a concentration of 200 mg/mL
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: 6 female Crl:WI rats nulliparous and non-pregnant, Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany
- Age on the day of dosing: young healthy adult rats, 10 weeks old
- Weight on the day of treatment (day 0): 199 - 218 grams. Body weight variation did not exceed +/-20% of the weight mean.
- Fasting period before study: The night before treatment the animals were fasted for a maximum of 16 hours. Food, but not water, was withheld overnight. Food was replaced 3 hours after the treatment.
- Housing: Group caging (3 animals/cage) in type II. polypropylene/polycarbonate cages.“Lignocel® 3/4-S Hygienic Animal Bedding” and “Arbocel® crinklets natural” nest building material produced by J. Rettenmaier & Söhne GmbH & Co.KG (D-73494 Rosenberg, Germany) were available to animals during the study.
- Diet (e.g. ad libitum): ad libitum; ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by Ssniff Spezialdiäten GmbH, D-59494 Soest Germany (batch number: 540 5117, expiry date: 31 July 2016 and batch number: 278 5652, expiry date: 30 November 2016)
- Water (e.g. ad libitum): ad libitum; tap water from the municipal supply, as for human consumption from a 500-mL bottle
- The food is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. Water quality control analysis was performed once every three months and microbiological assessment was performed monthly, by Veszprém County Institute of State Public Health and Medical Officer Service (ÁNTSZ, H-8201 Veszprém, József A. u. 36., Hungary).
- Acclimation period: 19 and 20 days for groups 1 and 2 respectively, before start of treatment under laboratory conditions. Health inspection was performed at arrival of the animals. Only healthy animals were used for the test. The health status was certified by the veterinarian.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6 - 23.9 °C
- Humidity (%): 26 - 70%
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 h/12 h, lighting period from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES:
- From: 2016-05-03 To: 2016-05-17 (females no. 9446, 9447, 9448)
- From: 2016-05-04 To: 2016-05-18 (females no. 9449, 9450, 9451)
Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
aqueous solution of methylcellulose at 1%
Details on oral exposure:
VEHICLE (1% methylcellulose)
- Concentration in vehicle: 200 mg/mL (anhydrous form)
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: The selection of the vehicle was based on trial formulations with the test item. In order of preference, the recommended vehicles were the following: distilled water, 0.5 or 1% methylcellulose or carboxymethylcellulose, PEG 400, corn oil, sunflower oil or DMSO. Trial formulation with distilled water caused a noticeably settling formulation, therefore it was considered as not suitable for treatments. Consequently, 1% methylcellulose was also tried as a vehicle, which resulted in an acceptably stable formulation, suitable for treatments.
- Lot/batch no. (if required): 2H20012N11 for methylcellulose; 8040116 for distilled water
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): Test item was freshly formulated on the day of administration. To limit the impact, the formulations were used within 4 hours after adding the vehicle to the test item and the test item preparation was performed with approved procedures and documented in detail. The formulation was homogenised to visually acceptable levels and was stirred up to finishing the treatment to ensure sufficient homogeneity.

- Rationale for the selection of the starting dose: The initial dose level was selected by the Study Director to be that which is most likely to produce mortality in some of the dosed animals. Based on the preliminary toxicological information, 2000 mg/kg bw was selected to be the starting dose. The limit dose (= starting dose level) for this study was 2000 mg/kg bw. Initially, three female animals were treated with 2000 mg/kg bw of the test item. No mortality was observed, therefore further 3 animals were treated at the dose level of 2000 mg/kg bw. As no mortality was observed in this second dose group, further testing was not required according to the test guidelines (OECD 423, Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.Tris).
Doses:
2000 mg/kg
No. of animals per sex per dose:
2 groups; 3 females/group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days (until day 15)
- Frequency of observations and weighing:
- Clinical signs: Animals were observed individually after dosing at 30 minutes, then 1, 2, 3, 4 and 6 hours after the treatment and once each day in the morning for 14 consecutive days thereafter.
- Individual observations were performed on the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
- Body weight: The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0) and weekly thereafter.
- Necropsy of survivors performed: Yes, all animals were subjected to a necropsy and a macroscopic examination. The animals were exsanguinated after verification of narcosis following an injection of pentobarbital sodium (Euthanimal 40%; Lot No.: 1409236-06, Expiry Date: September 2017, Produced by: AlfasanNederland BV, Woerden, The Netherlands). After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. All gross macroscopic changes were recorded for each animal.
Statistics:
No statistical analysis was performed.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Remarks:
anhydrous gadolinium oxalate
Mortality:
Gadolinium oxalate did not cause mortality at a dose level of 2000 mg/kg bw.
Clinical signs:
All animals were symptom free during the study.
Body weight:
Body weight gains of gadolinium oxalate treated animals during the study showed no indication of a test item-related effect.
Gross pathology:
There was no evidence of macroscopic observations at a dose level of 2000 mg/kg bw.
Other findings:
No data
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the study, the acute oral LD50 value of gadolinium oxalate was found to be above 2000 mg/kg bw in female Crl:WI rats. According to these results, gadolinium oxalate needs not to be classified according to CLP criteria.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation)
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity

One study is available on the acute toxicity of gadolinium oxalate in rats. This study was performed according to the acute toxic class method (OECD guideline 423) and conform GLP requirements (Mátyás, 2016). In this study, gadolinium oxalate was administered to rats by oral gavage, formulated in 1% methylcellulose as vehicle. No mortalities were observed at the test dose of 2000 mg/kg bw. The LD50 was therefore > 2000 mg/kg bw. There were no clinical signs of toxicity observed either. Further, no test-item related effects on body weight were found, nor were macroscopic findings of toxicological importance reported after necropsy. This study is considered reliable (Klimisch 1) and is the key study for endpoint coverage.

Acute toxicity via inhalation

According to Annex VIII, Section 8.5, Column 2 of the REACH Regulation, one additional route of exposure should be tested next to the oral route. Testing for acute toxicity via inhalation should be considered when exposure of humans via inhalation is likely. However, as the forms manufactured are typically wet powders or dry powders with a median particle size (d50) > 50 µm, no significant exposure via inhalation is expected for gadolinium oxalate. Therefore, the dermal route is considered more relevant.

Acute dermal toxicity

The acute oral LD50 is greater than 2000 mg/kg bw and no systemic effects or macroscopic abnormalities were observed in this study (Mátyás, 2016). According to Annex VIII, Section 8.5, Column 2 of the REACH Regulation (revision May 2016), acute dermal toxicity can be waived if the substance under consideration is not classified as acute oral toxicant or STOT SE, and no systemic effects have been observed in in vivo studies with dermal exposure. The latter criterion is also fulfilled (in vivo skin sensitisation study (GPMT), Tarcai, 2016). Therefore, an acute dermal toxicity study should not be performed.

Justification for classification or non-classification

Acute oral toxicity

The LD50 is greater than 2000 mg/kg bw and therefore gadolinium oxalate is considered not classified as acute oral toxicant according to the CLP Regulation.

Acute inhalation toxicity

No data are available on the acute toxicity of gadolinium oxalate via inhalation and therefore no conclusion can be drawn on classification.

Acute dermal toxicity

No acute dermal toxicity study is available for gadolinium oxalate. However, based on the acute oral LD50 being > 2000 mg/kg bw, the absence of systemic effects or macroscopic abnormalities in the acute oral study (no STOT SE classification required), and the fact that no systemic effects have been observed in in vivo studies involving dermal exposure (in vivo skin sensitisation study, GPMT), the substance can be safely concluded not to be classified as acute dermal toxicant.