Digadolinium trioxide

Endpoint summary

Description of key information

Acute oral toxicity

Two reliable acute toxicity studies via the oral route of administration are available. After single dosing of 2000 mg/kg to rats, the LD50 was established as greater than 2000 mg/kg bw (Clouzeau, 1994). In a second study, the single dose acute oral LD50 was established as greater than 5000 mg/kg bw when administered as a 50% w/w solution with distilled water (Shapiro, 1990a). Based on these results, the test substance is considered not classified as acute oral toxicant.

Acute toxicity via inhalation

In a reliable acute inhalation toxicity study performed according to OECD guideline 436, no deaths occurred in a group of 6 rats exposed to the concentration of 5.04 mg/L for 4 hours (Tóth, 2016). The 4-h LC50 was therefore considered greater than 5.04 mg/L and the substance is thus not classified as acute toxicant via inhalation.

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 reliable studies 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 irritation study) is also fulfilled. Moreover, in addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For gadolinium oxide, a key study is available for the inhalatory route of exposure. Therefore, an acute dermal toxicity study should not be performed.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

from 1994-03-02 to 1994-05-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 5 male and 5 female Sprague-Dawley rats ICO: OFA-SD (IOPS Caw)
- Source: Iffa Crédo, 69210 L'Arbresle, France
- Age on day of treatment: approx 6 weeks old
- Weight on day of treatment: 168 +/- 8 grams for males and 159 +/- 4 grams for females
- Fasting period before study: The animals were fasted for an overnight period of approx 8 hours before dosing, but had free access to water.
- Feeding after treatment: Food was given approximately 4 hours after administration of the test substance.
- Housing: the animals were housed in polycarbonate cages (48x27x20 cm) covered with a stainless steel lid. Each cage contained 4 to 7 animals of the same sex during the acclimatisation period and 5 rats of the same sex during the treatment period. Each cage contained graded, dust-free sawdust (SICSA, 94142 Alfortville, France). Bacteriological analysis of the sawdust and detection of possible contaminants (pesticides, heavy meals) are performed periodically.
- Diet (e.g. ad libitum): ad libitum; AO4 C pelleted diet (U.A.R., 91360 Villemoisson-sur-Orge, France), each batch of food was analysed by the supplier
- Water (e.g. ad libitum): ad libitum; drinking water filtered by a F.G. Millipore membrane (0.22 micron), contained in bottles, bacteriological and chemical analysis of the water and detection of possible contaminants (pesticides, heavy metals and nitrosamines) were performed periodically
- There were no contaminants in the diet, water or sawdust at levels likely to have influenced the outcome of the study.
- Acclimatisation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 50 +/- 20%
- Air changes (per hr): about 13 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: 1994-03-02 To: 1994-03-16

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

aqueous solution of methylcellulose at 0.5 %

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg test item/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): water for injections batch no. 7860, methylcellulose batch no. 73H0365
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION: on the day of treatment, the test substance wars ground using a mortar and pestle, then was suspended in the vehicle.

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 males and 5 females

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: The animals were observed frequently the hours following administration of the test substance, for detection of possible treatment-related clinical signs. Observation of the animals was made at least once a day for a period of 14 days, to determine whether any of the clinical sings were reversible or not.
- Mortality: The animals were checked frequently during the hours following administration of the test substance for mortality or signs of morbidity, then at least twice a day thereafter.
- Body weight: The animals were weighed individually just before administration of the substance, and then on days 5, 8 and 15 for the animals. The body weight gain of the treated animals was compared to a reference curve of C.I.T. control animals with the same weight.
- Necropsy of survivors performed: Yes, on day 15, the animals were sacrificed by CO2 inhalation in excess and a microscopic examination was performed. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.

Statistics:

No data

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the observation period.

Clinical signs:

other: No clinical signs were observed during the study.

Gross pathology:

Macroscopic examination of the main organs of the animals sacrificed at the end of the study revealed no apparent abnormalities.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of the study, the LD50 of the test substance, when administered by oral route in rats, was higher than 2000 mg/kg. No signs of toxicity were observed at this dose. Based on these results , the test substance is not classified as acute oral toxicant according to CLP regulation.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1990-10-29 to 1990-11-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

equivalent or similar to guideline

Guideline:

other: FHSA 16 CFR 1500.42

Deviations:

not specified

Principles of method if other than guideline:

No further data.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hilltop Lab Animals, Scottdale, PA, USA
- Females (if applicable) nulliparous and non-pregnant: No data
- Age at study initiation: No data
- Weight at study initiation: 187-212 g
- Fasting period before study: Yes, 18 hours prior to selection and test initiation. Water was provided ad libitum.
- Housing: Individually in suspended stainless steel caging with mesh floors.
- Diet (e.g. ad libitum): ad libitum, pelleted Purina Rat Chow
- Water (e.g. ad libitum): ad libitum, tap water supplied by automatic water system
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 65-70°F
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: 1990-10-29 To: 1990-11-12

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50%
- Amount of vehicle (if gavage): No data
- Justification for choice of vehicle: No data
- Lot/batch no. (if required): No data

Doses:

5.0 g/kg

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: For signs of gross toxicity and mortality 1 and 2 hours after dosing, and at least once daily thereafter for 14 days. Body weights were recorded initially and at termination.
- Necropsy of survivors performed: No data
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: No data

Statistics:

No data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

All animals survived.

Clinical signs:

other: Two males had hunched posture 2 hours post dose but recovered by day 2. All other animals appeared active and healthy. There were no signs of gross toxicity, adverse pharmacologic effects or abnormal behavior.

Interpretation of results:

GHS criteria not met

Conclusions:

The single dose acute oral LD50 of the test item is greater than 5.0 g/kg when administered as a 50% w/w solution with distilled water. Based on these results, the test substance is not to be classified according to CLP Regulation.

Executive summary:

A single dose of 5.0 g/kg of the test item was administered to 10 fasted Sprague-Dawley rats, using 5 animals per sex. Animals were observed for 14 days following dosing. The single dose acute oral LD50 of the test item is greater than 5.0 g/kg when administered as a 50% w/w solution with distilled water.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Published data with limited level of detail. Only one dose tested, lower than the limit test dose.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Gd2O3 was obtained from the St. Eloi Corporation, Cincinnati, Ohio, USA.
Purity: > 98%

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Females (if applicable) nulliparous and non-pregnant: No data
- Age at study initiation: Adult
- Weight at study initiation: 190-250 g
- Fasting period before study: No data
- Housing: air-conditioned quarters
- Diet (e.g. ad libitum): ad libitum, Rockland Rat diet
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): air conditioned
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: No data To: No data

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

aqueous 0.2% solution of CMC

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50% suspension
- Amount of vehicle (if gavage): No data

Doses:

1000 mg/kg (only dose tested)

No. of animals per sex per dose:

20 females

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 30 days
- Other examinations performed: clinical signs

Statistics:

LD50 and 95% confidence limits were calculated by the method of Litchfield and Wilcoxon (1949).

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 000 mg/kg bw

Based on:

test mat.

Mortality:

No data

Clinical signs:

other: No data

Gross pathology:

No data

Other findings:

No data

Interpretation of results:

study cannot be used for classification

Conclusions:

The LD50 of the test item for female rats was found to be > 1000 mg/kg body weight.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1963

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

The test item was injected into the stomach of mice in increasing quantities.

GLP compliance:

not specified

Species:

mouse

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Doses:

Highest dose was 10000 mg/kg bw. No information on lower doses.

Control animals:

not specified

Sex:

not specified

Dose descriptor:

LD0

Effect level:

>= 10 000 mg/kg bw

Based on:

test mat.

Mortality:

None, it was reported that no deleterious effect was observed when administering a dose of 10000 mg/kg bw.

Interpretation of results:

GHS criteria not met

Conclusions:

Up to 10000 mg/kg bw (test item injected into the stomach of mice) has no apparent deleterious effects.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 2016-08-24 to 2016-11-22

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

- Treatment of test material prior to testing: the test item was used as supplied
- With a correction factor of 1.002, no correction was done during formulation preparation

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 3 male and 3 female rats, CRL:(WI) rats; Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D97633 Sulzfeld
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at dosing: 12 weeks
- Weight at dosing: 437-449 g (males) and 250-254 g (females)
- Fasting period before study: no data
- Housing: Group of 3 (by sex) in type III polypropylene solid floor cages with stainless steel mesh lids. Lignocel Bedding for Laboratory Animals and Arbocel nesting material were available to animals during the study. Rodents were housed with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Diet (e.g. ad libitum): ad libitum, the animals were provided with ssniff SM R/M “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” (ssniff Spezialdiäten GmbH, D-59494 Soest Germany; batch: 278 5652; expiry: November 2016)
- Water (e.g. ad libitum): ad libitum, tap water fit for human consumption
- Acclimation period: 34 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.1 - 25.9 °C
- Humidity (%): 39 - 86%
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12/12, light from 6.00 a.m. to 6.00 p.m.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

3.64 µm

Geometric standard deviation (GSD):

2.03

Remark on MMAD/GSD:

inhalable fraction (% < 4µm): 55.3%

Details on inhalation exposure:

TECHNICAL TRIALS
- Prior to animal exposures, test material atmospheres were generated within the exposure chamber. During these technical trials, air-flow settings and test material input rates were varied to achieve the required atmospheric characteristics.

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- The animals were exposed, nose-only, to an atmosphere of the test item using a TSE Rodent Exposure System (TSE Systems GmbH, Bad Homburg, Germany). This system comprises of two, concentric anodised aluminium chambers and a computer control system incorporating pressure detectors and mass flow controllers.
- Fresh aerosol from the generation system was constantly supplied to the inner plenum (distribution chamber) of the exposure system from where, under positive pressure, it was distributed to the individual exposure ports.
- Method of holding animals in test chamber: The animals were held in polycarbonate restraint tubes located around the chamber which allowed only the animal’s nares to enter the exposure port.
- Source and rate of air: Compressed air was supplied by means of an oil-free compressor passed through a suitable filter system prior to introduction to the nebuliser. The flow of air through each port was at least 0.7 L/min. This flow rate was considered adequate to minimise re-breathing of the test atmosphere as it is about twice the respiratory minute volume of a rat.
- System of generating particulates/aerosols: The test item was aerosolised using Palas RBG1000 (Palas GmbH, Karlsruhe, Germany) located at the top of the exposure chamber. The rate of formulation use was controlled by the rotation speed. Compressed air was supplied by means of an oil-free compressor passed through a suitable filter system prior to introduction to the nebuliser.
- Method of particle size determination: The particle size of the test atmosphere was determined three times during the exposure period using a 7-stage impactor of Mercer style (TSE Systems GmbH, Bad Homburg, Germany). Such devices employ an inertial separation technique to isolate particles in the discrete aerodynamic size ranges. Samples were taken from an unoccupied exposure port (representing the animal’s breathing zone). The collection substrates and the backup filter were weighed before and after sampling and the weight of the test item, collected at each stage, calculated by this difference. The total amount collected for each stage was used to determine the cumulative amount below each cut-off point size. In this way, the proportion (%) of aerosol less than 0.55, 0.96, 1.55, 2.11, 3.56, 6.66 and 10.55 µm was calculated. From these data, using software supplied with the impactor, the Mass Median Aerodynamic diameter (MMAD), and Geometric Standard Deviation (GSD) were calculated. In addition, the proportion (%) of aerosol less than 4 µm (considered to be the inhalable portion) was determined.
- Treatment of exhaust air: After passing through the breathing zone, used aerosol entered the outer cylinder from where it was exhausted through a suitable filter system. Atmosphere generation was therefore dynamic.
- Temperature, humidity, pressure in air chamber: 23.5 °C (22.0 - 24.1 °C), 1.9% (1.6 - 2.1 %) relative humidity

TEST ATMOSPHERE
- The test atmosphere was sampled at regular intervals during each exposure period. Samples were taken from an unoccupied exposure port (representing the animal’s breathing zone) by pulling a suitable, known volume of test atmosphere through weighed GF10 glass fibre filters (Whatman GmbH, Hahnestraße 3 – D-37586 Dassel, Germany).
- The difference in the pre- and post-sampling weights, divided by the volume of atmosphere sampled, was equal to the actual achieved test atmosphere concentration. The nominal concentration was calculated by dividing the mass of test material disseminated into the chamber by the total volume of air that went through the chamber during the same period.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: no data

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetrical determination

Duration of exposure:

4 h

Concentrations:

5 mg/L (nominal concentration)

No. of animals per sex per dose:

3 males and 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- Morbidity/mortality: Animals were checked hourly during exposure, one hour after exposure and twice daily (early and late in the working day) during the 14-day observation period;
- Clinical signs: All animals were observed for clinical signs at hourly intervals during exposure, as soon as practically possible following removal from restraint at the end of exposure, one hour after exposure and subsequently once daily for fourteen days;
- Body weight: Individual body weights were recorded prior to treatment on the day of exposure (Day 0) and on Days 1, 3, 7 and 14.
- Necropsy of survivors performed: Yes. At the end of the 14-day observation period, the animals were euthanised by exsanguination under anaesthesia (intra-peritoneal injection of pentobarbital solution – Euthanimal 40%) and gross macroscopic examination was performed. All animals were subject to a gross necropsy which included a detailed examination of the abdominal and thoracic cavities. Special attention was given to the respiratory tract for macroscopic signs of irritancy or local toxicity.

Statistics:

No data

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.04 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

0/3 for males
0/3 for females

Clinical signs:

other: Wet fur, fur staining was recorded mostly on the day of exposure. These observations were considered to be related to the restraint and exposure procedures and, in isolation, were considered not to be biologically significant. Laboured respiration (slight

Body weight:

The exposure procedure caused slight body weight loss in the animals (1.0% - 6.0%). After day 3, normal body weight gain was observed.

Gross pathology:

A single four hour nose-only exposure of digadolinium trioxide to CRL: (WI) Wistar rats dosed at 5.04 mg/L, with a 14-day observation period, was not associated with any test item-related gross changes.

Other findings:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of the study, no deaths occurred in a group of six rats exposed to the concentration of 5.04 mg/L for four hours. The acute inhalation median lethal concentration (4-h LC50) of digadolinium trioxide, in CRL: (WI) Wistar strain rats, was therefore considered to be greater than 5.04 mg/L. Based on these results, the test substance is considered not classified as acute toxicant via inhalation according to CLP Regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity

Two reliable acute toxicity studies via oral administration are available. Both reliable studies are considered in a weight-of-evidence approach.

In a first study, 5 male and 5 female Sprague-Dawley rats were dosed on a single occasion with the test substance in 0.5% methylcellulose at 2000 mg/kg bw (according to OECD guideline 401 and GLP; Clouzeau, 1994). During the subsequent 14-day observation period, no deaths or clinical signs were observed. Body weight gain and macroscopic examination at necropsy demonstrated no deviations. The LD50 was higher than 2000 mg/kg bw. No signs of toxicity were observed at this dose. Based on these results, the test substance is considered not classified as acute oral toxicant.

In a second study, the test substance was administered on a single occasion as a 50% solution in distilled water to 5 male and 5 female Sprague-Dawley rats at a dose level of 5000 mg/kg bw (generally accepted method, Shapiro, 1990a). No mortality was observed during the 14-day observation period. Two males demonstrated clinical signs (hunched posture) 2 hours after dosing but recovered by day 2. There were no other clinical signs or signs of gross toxicity or abnormal behavior. Body weight gain was normal. The single dose acute oral LD50 was greater than 5000 mg/kg bw.

The results obtained in these two studies were supported by the results of two more studies. Bruce et al. (1963) reported the LD50 to be > 1000 mg/kg bw for female rats. A single dose was tested, which was lower than the limit dose for acute oral toxicity testing (2000 mg/kg) and could therefore not be used for classification. Because of this, and because of the limited details reported on methodology as well as results, the study was scored Klimisch 3. Finally, Mogilevskaya and Roshchina (1964) injected increasing doses of gadolinium oxide in the stomach of mice and reported that no deleterious effects were observed at a dose of 10000 mg/kg bw. This study was scored Klimisch 4 because the extremely limited information reported on the experiment did not allow assessment of reliability.

Acute toxicity via inhalation

Only one reliable study is available. In this study, the acute inhalation toxicity of the test item was assessed following a 4-hour exposure period (according to OECD 436, Tóth, 2016). Three male and three female rats were exposed for 4 hours to the concentration of 5.04 mg/L. As no deaths occurred at this concentration, the study was terminated according to the OECD guideline flow chart. The animals were exposed for 4 hours using a nose-only exposure system, followed by a 14-day observation period. Aerosol concentrations were measured gravimetrically. The particle size distribution of the test aerosol was determined regularly during the exposure period. Clinical observations and body weights were recorded throughout the study and at the end of the scheduled period, the animals were euthanised and subjected to a gross examination post mortem. No control group was exposed in this study. The mean achieved concentration was 5.04 +/- 0.27 mg/L, the MMAD was 3.64 µm and the GSD 2.03. The inhalable fraction was determined to be 55.3% (< 4 µm). Wet fur and fur staining was recorded mostly on the day of exposure. These observations were considered to be related to the restraint and exposure procedures and, in isolation, were considered not to be biologically significant. Laboured respiration (slight) was observed during the exposure in 1 female. There were no other clinical signs observed during the study. The exposure procedure caused slight body weight loss in the animals. After day 3, normal body weight gain was observed. No test item-related gross changes were observed. The 4-h LC50 was therefore considered to be greater than 5.04 mg/L.

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 reliable studies 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 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 irritation study). Moreover, in addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For gadolinium oxide, a key study is available for the inhalatory route of exposure. 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 the test substance is considered not classified as acute oral toxicant according to the CLP Regulation.

Acute inhalation toxicity

The 4-h LC50 is considered greater than 5.04 mg/L, and therefore the test substance is considered not classified as acute toxicant via inhalation according to the CLP Regulation.

Acute dermal toxicity

No acute dermal toxicity study is available. However, based on the acute oral LD50 being > 2000 mg/kg bw and based on the fact that no adverse effects have been observed in other studies involving dermal exposure (in vivo skin irritation study by Lambert et al., 1993), the substance can be safely concluded not to be classified as acute dermal toxicant according to the CLP Regulation.