Registration Dossier

Administrative data

Description of key information

Acute oral toxicity

The key acute oral toxicity study (Shapiro, 1991a; Klimisch 1) identified an LD50 value for male and female Sprague-Dawley rats of 1650 mg/kg body weight, based on an experiment performed according to a method equivalent or similar to OECD guideline 401.

Acute dermal toxicity

The key acute dermal toxicity study (Salvador, 2015a; Klimisch 1) identified an LD50 value greater than 2000 mg/kg in male and female Sprague-Dawley rats, according to OECD guideline 402.


Acute inhalation toxicity

Based on Column 2, Annex VIII, section 8.5 adaptation in the REACH regulation, no acute inhalation toxicity study is to be performed as a key study via the oral route and the dermal route of exposure is available.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 1991-01-29 to 1991-02-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
according to guideline
Guideline:
other: Code of Federal Regulations 16: 1500.3
Deviations:
not specified
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
The sample was tested as a 50% w/w solution in distilled water. The gravity of the test material was 1.406 (dosage of 1.25 g/kg), 1.382 (dosage of 2.5 g/kg) and 1.354 (dosage of 5.0 g/kg).
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
- Age at study initiation: no data
- Weight at study initiation: male: 208-225 g; female: 202-221 g
- Fasting period before study: approximately 18 hours prior to selection and test initiation
- Housing: individually in suspended stainless steel caging with mesh floors
- Diet (e.g. ad libitum): pelleted purina rat chow ad libitum from 1 h after dosing
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 5, 6 or 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.9 to 22.2°C
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distilled water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The sample was tested as a 50% w/w solution in distilled water.
- Dosing volumes: 1.78 mL/kg (1250 mg/kg); 3.62 mL/kg (2500 mg/kg); 7.43 mL/kg (5000 mg/kg)

Doses:
1250, 2500 and 5000 mg/kg
Data for the highest dose came from a limit test.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed at approximately 1, 2 and 4 hours after dosing and at least once daily thereafter for signs of gross toxicity and mortality. Body weights were recorded initially, at termination (day 14) or after death.
- Necropsy of survivors performed: Yes, necropsies were performed on all decedents.
Statistics:
The LD50 was calculated by the Litchfield-Wilcoxon Method of Probit Analysis or estimated graphically.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 650 mg/kg bw
Based on:
test mat.
95% CL:
1 240 - 2 190
Sex:
male
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
95% CL:
1 570 - 2 540
Sex:
female
Dose descriptor:
LD50
Effect level:
1 300 mg/kg bw
Based on:
test mat.
Remarks on result:
other: estimated graphically
Mortality:
1250 mg/kg: 20% mortality occurred by day 2
2500 mg/kg: 90% mortality occurred by day 2
5000 mg/kg: 100% mortality occurred by day 3
Clinical signs:
1250 mg/kg: Following test material administration, all animals appeared lethargic and had a hunched posture. All surviving animals recovered from the above toxic signs by day 3.
2500 mg/kg: Following test material administration, all animals appeared lethargic and most had a hunched posture. Several decedents were moribund. One male recovered from the above toxic signs by day 5.
5000 mg/kg: Toxic signs prior to death included lethargy, hunched posture and red nasal discharge. All animals lost weight prior to death.
Body weight:
1250 mg/kg: The two decedents, both females, lost body weight prior to death. All surviving animals gained weight over the 14-day observation period.
2500 mg/kg: Several decedents lost weight prior to death. The one male that recovered from the toxic signs by day 5 gained body weight over the 14-day observation period, its increase was less than would be expected for the age and strain used.
5000 mg/kg: All animals lost weight prior to death.
Gross pathology:
1250 mg/kg: Necropsy of the decedents revealed distention of the stomach with discoloration of the pyloric region and intestines.
2500 mg/kg: Necropsy of the decedents revealed distention of the stomach, with discoloration of the pyloric region and intestines.
5000 mg/kg: Necropsy of the decedents revealed distention of the stomach with a cloudy white fluid and discoloration of the intestines. The two animals which died after day 1 also exhibited discoloration of the lungs and liver.
Other findings:
No data
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute oral LD50 calculated by Probit analysis was 1650 mg/kg with 95% confidence limits of 1240 to 2190 mg/kg for male and female animals. Therefore the substance is considered classified as category 4 (H302) according to the criteria of the CLP Regulation.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
From 1990-10-29 to 1990-12-05
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
other: 16 CFR 1500.3
Deviations:
not specified
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
The sample was administered as a 50% w/w dilution in distilled water; specific gravity: 1.354.
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
- Age at study initiation: young adult
- Weight at study initiation: males: 187-197 g, females: 196-211 g
- Fasting period before study: A group of male and female rats were fasted for approximately 18 hours by removing food from their cages, prior to selection and test initiation. Water remained available ad libitum.
- Housing: Individually in suspended stainless steel caging with mesh floors.
- Diet (e.g. ad libitum): ad libitum from 1 h after dosing
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6-21.1°C
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distilled water
Details on oral exposure:
VEHICLE
- The sample was administered as a 50% w/w dilution in distilled water.
- Actual dose received: 7.43 mL/kg bw
Doses:
5000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 3 days
- Frequency of observations and weighing: The rats were observed at 1 and 2 hours post-dosing and at least once daily thereafter for signs of gross toxicity and mortality. Body weights were recorded initially and at death (day 3).
- Necropsy of survivors performed: Yes. Gross necropsies were performed on all decedents.
Statistics:
No data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
< 5 000 mg/kg bw
Based on:
test mat.
Mortality:
100% mortality occurred by day 3.
Clinical signs:
Toxic signs prior to death included lethargy, hunched posture and red nasal discharge.
Body weight:
All animals lost weight prior to death.
Gross pathology:
Necropsy of the decedents revealed distention of the stomach with a cloudy white fluid and discoloration of the intestines. The two animals which died after day 1 also exhibited discoloration of the lungs and liver.
Other findings:
No data
Interpretation of results:
study cannot be used for classification
Conclusions:
All Sprague-Dawley rats died on day 3 after administration of 5000 mg/kg yttrium trinitrate (50% w/w solution in distilled water). This limit test cannot be used for classification of the test substance.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Centre d'élevage d'IFFA CREDO (69210 Saint-Germain sur l'Abresle)
- Age at study initiation: 6 to 7 weeks old
- Weight at study initiation: 150-200 g (males), 140-180 g (females)
- Fasting period before study: yes
- Housing: Animals were housed in groups of 2 to 5 in stainless steel cages (343 x 250 x 140 mm)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 to 70%
- Air changes (per hr): 10 per hour


Route of administration:
oral: gavage
Vehicle:
other: arabic gum
Details on oral exposure:
VEHICLE
Oral administration of the product in suspension in a dispersion of 10% aqueous arabic gum.
Dose volume: 5 mL/kg
Doses:
Dose-range finding: 1000, 2500 and 5000 mg/kg bw
Final study: 0, 2520, 3160, 3980 and 5000 mg/kg bw
No. of animals per sex per dose:
2 in the range finding study
5 in the final study
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 1/4 hr, 1 hr, 2 hrs, 4 hrs and thereafter each day during 14 days; body weight: day -1, day 1, day 8, day 15 and at death of the animal if it survived more than 24 hours.
- Necropsy of survivors performed: yes
Statistics:
The LD50 was determined according to the method of Litchfield and Wilcoxon.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 839 mg/kg bw
Based on:
test mat.
95% CL:
3 288 - 4 482
Mortality:
2520 mg/kg: 1 male died 2 days after administration
3160 mg/kg: 2 females died 2 days after administration
3980 mg/kg: 6 animals died
5000 mg/kg: 8 animals died
Clinical signs:
2520 mg/kg: Exhaustion or prostration with piloerection in all animals and diarrhea in some animals until 4 hours.
3160 mg/kg: Exhaustion with ataxia, piloerection, hypothermia and paleness of the skin in all animals with diarrhea, mostly during 4 hours after administration. Red snout and fur was noted in 3 animals on day 3. A swollen and hard belly was observed in 3 rats from day 6-15.
3980 mg/kg: Exhaustion with ataxia, piloerection, hypothermia and paleness of the skin in all animals with diarrhea, mostly during 4 hours after administration. A red snout and fur were noted in half of the animals at day 2. A swollen and hard belly was observed in 8 rats from day 3 to 5 until day 15.
5000 mg/kg: Exhaustion with ataxia, piloerection, hypothermia and paleness of the skin in all animals with diarrhea, and hypersalivation in some animals was observed during 4 hours after treatment. All surviving rats were observed to have swollen and hard belly from day 3 until day 15.

Faeces of animals treated at the 3 highest doses were shapeless and abundant.
Body weight:
2520 mg/kg: same body weight changes as control animals
3 highest doses: decrease of body weight that was +/- significant
Gross pathology:
- Observations of animals that died during the observation period:
2520 mg/kg: thickening and hardening of the glandular wall of the stomach, whitening of the right lobe of the liver in contact with the stomach and whitening of the intestines in one male.
3160 mg/kg: glandular part of the stomach is heavily contracted in two females and the non glandular part is distended in one of them and the intestines are white in two females.
3980 mg/kg: the glandular part of the stomach is white and hard in three males and ± contracted and hard in two females of which the stomach is heavily dilated and of which the content is brown in three males. A white zone is present on the liver in contact with the stomach in two males. Adherence of the liver with the glandular part of the stomach in one female. White colour of the intestines in one female or containing a yellow liquid in one male.
5000 mg/kg: Adherence of the liver and/or the spleen and/or the intestines and the pancreas with the stomach +/- contracted within two males and four females. A stomach of which the non glandular part is distended in one male and three females. A pale liver and spleen and kidneys covered by a white film in one male. Yellowish or white intestines were observed in two males and two females. The presence of yellow ascites in males and females.
- Observations in animals sacrificed at the end of the observation period (day 15):
2520 mg/kg: A tonic stomach in 4 males and four females.
3160 mg/kg: A stomach of which the non glandular part is ± hard in four males and one female. A stomach of which the non glandular part is distended and of which the glandular part is hard in one male and two females.
3980 mg/kg: A stomach of which the non glandular part is ± distended and/or of which the glandular part is hard in two males and three females. Blackish intestines in one male.
5000 mg/kg: A stomach of which the glandular part is hard in two males and in one male the non glandular part is distended.
Interpretation of results:
not classified
Conclusions:
Under the conditions of this test, the acute oral LD50 in male and female rats is estimated to be 3839 mg/kg. Therefore the test substance is not to be classified according to the CLP Regulation.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 650 mg/kg bw

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
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2015-07-01 to 2015-10-19
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
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: 5 male and 5 female (nulliparous and non-pregnant) rats, Hsd: Sprague Dawley SD; from Harlan Italy s.r.l. San Pietro al Natisone (UD), Italy
- Age at order: 6 to 8 weeks
- Weight at arrival: 173-183 grams
- Fasting period before study: no data
- Housing: Up to 5 animals of one sex per cage during acclimatisation, individually caged during the study; polysulphone solid bottomed cages measuring 59.5x38x20 cm during acclimatisation period and 42.5x26.6x18.5 cm during the study with nesting material provided into suitable bedding bags; daily inspected and changed as necessary (at least 3 times/week).
- Diet (e.g. ad libitum): ad libitum, 4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy)
- Water (e.g. ad libitum): ad libitum, drinking water supplied to each cage via a water bottle
- Acclimation period: at least 5 days, veterinary health check during acclimatisation period

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +/- 2°C
- Humidity (%): 55 % +/- 15%
- Air changes (per hr): approximately 15-20 per hour
- Photoperiod (hrs dark / hrs light): daily light/dark cycle of 12/12 hours, artificial lighting (fluorescent tubes)
Type of coverage:
semiocclusive
Vehicle:
corn oil
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal surfaces of the trunk of each animal, clipped free of hair on the day before dosing
- % coverage: approximately 10% of the body surface
- Type of wrap if used: A patch of surgical gauze covered by a strip of synthetic film was placed over the treated site and the whole assembly held in place by encircling the trunk of the animal with a lenght of elastic adhesive bandage, this forming a semi-occlusive barrier.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The treatment area was cleaned by gentle swabbing of the skin with cotton wool soaked with lukewarm water.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Concentration (if solution): no data
- Constant volume or concentration used: yes
- On the day of dosing, aliquots of the test item to be administered were weighed according to the body weight of each animal measured prior to dosing.

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): no data
- Lot/batch no. (if required): no data
- Purity: no data
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
*mortality and morbidity: throughout the study, all animals were checked twice daily
*clinical signs: Day of dosing: Session 1: on dosing; Session 2: approximately 1 hour after dosing; Session 3: approximately 2 hours after dosing; Session 4: approximately 4 hours after dosing. Daily thereafter for a total of 14 days (Session 1).
*body weight: All animals were weighed at allocation to the study, on the day of dosing (day 1) and on days 8 and 15. Body weight change calculated for days 8 and 15 of the dosing phase was relevant to day 1 of the phase.
- Necropsy of survivors performed: Yes, all animals were sacrificed on day 15 by carbon dioxide narcosis.
- Necropsy was carried out on all animals (gross necropsy examination for both external and internal abnormalities, with particular attention to the treatment site). All abnormalities were recorded.
Statistics:
No data
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Clinical signs were limited to scabs on the dorsal/thoracic region observed in male and female animals from day 5 up to day 13/14 of the observation period. In addition, desquamation of the dorsal region was observed in three females on day 7 and in one female only from day 9 to the end of the study.
Body weight:
Body weights and body weight changes were within the expected range for this species and age of animals at the end of the study.
Gross pathology:
No abnormalities were found at the external examination performed in all animals at the end of the study, with the exception of multiple scabs observed on the treatment site of one female (animal no. A1463003). No internal abnormalities were found in any treated animal.
Interpretation of results:
not classified
Conclusions:
The results indicated that the test item, yttrium trinitrate, has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg (corrected for water content, 28.7%). The lack of mortality demonstrates the acute toxicity expected (ATE) to be greater than 2000 mg/kg. European Directives concerning the classification, packaging and labelling of dangerous substances (Council Regulation (EC) No. 1272/2008 and subsequent revisions) would suggest that the substance is not to be classified.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Acute toxicity: oral

Shapiro (1991a) performed an acute oral toxicity study in which a single dose of yttrium trinitrate (50% aqueous solution) was administered to 5 Sprague-Dawley rats per sex per dose (GLP compliant, performed according to a method equivalent or similar to OECD guideline 401). The dose levels tested were 1250, 2500 and 5000 mg/kg body weight. The animals were observed for 14 days. At 1250 mg/kg, 20% mortality occurred by day 2, at 2500 mg/kg, 90% mortality occurred by day 2, and at 5000 mg/kg, all animals died by day 3.

Following test material administration at 1250 and 2500 mg/kg, all animals appeared lethargic and most had a hunched posture. All surviving animals (low dose) recovered from the above toxic signs by day 3. Several decedents were moribund (mid dose). One male (mid dose) recovered from the above toxic signs by day 5. At 5000 mg/kg, toxic signs prior to death included lethargy, hunched posture and red nasal discharge. All animals lost weight prior to death.

Necropsy of the decedents revealed distention of the stomach with discoloration of the pyloric region and intestines at the low and mid dose tested. At the high dose, necropsy of the decedents revealed distention of the stomach with a cloudy white fluid and discoloration of the intestines. The two animals which died after day 1 also exhibited discoloration of the lungs and liver. These local findings are most likely the result of the pH lowering effect of the counter anion (nitrate) when in contact with aqueous media such as bodily fluids.

The acute oral LD50 (males and females) calculated by Probit analysis was 1650 mg/kg with 95% confidence limits of 1240 to 2190 mg/kg. Males seemed less sensitive (LD50 = 2000 mg/kg) when compared with females (LD50 = 1300 mg/kg). This study was selected as key study as it identified the lowest LD50 value.

In addition, two supporting Klimisch 2 studies are available. A limit test performed by Shapiro (1990) resulted in an LD50 value for Sprague-Dawley rats below 5000 mg/kg (unbounded). Guillot (1986) performed an acute toxicity study (according to a method equivalent to OECD guideline 401) in 5 rats per sex per dose (oral gavage) with following doses tested: 2520, 3160, 3980 and 5000 mg/kg. Mortality was observed at 2520 mg/kg (1 male), 3160 mg/kg (2 females) and 3980 mg/kg (6 animals), resulting in an LD50 for males and females of 3839 mg/kg body weight.

Acute toxicity: inhalation

Based on column 2, Annex VIII, section 8.5 adaptation in the REACH regulation, no acute inhalation toxicity study is to be performed as a key study via the oral route and the dermal route of exposure is available.

Acute toxicity: dermal

Salvador (2015a; Klimisch 1) studied the acute dermal toxicity of yttrium trinitrate in 5 Sprague-Dawley rats per sex (OECD guideline 402). The dose level tested was 2000 mg/kg. After 15 days of observation the dermal LD50 was concluded to be > 2000 mg/kg body weight. No mortality occurred.

Clinical signs were limited to scabs on the dorsal/thoracic region observed in male and female animals from day 5 up to day 13/14 of the observation period. In addition, desquamation of the dorsal region was observed in three females on day 7 and in one female only from day 9 to the end of the study.

Body weights and body weight changes were within the expected range for this species and age of animals at the end of the study.

No abnormalities were found at the external examination performed in all animals at the end of the study, with the exception of multiple scabs observed on the treatment site of one female (animal no. A1463003). No internal abnormalities were found in any treated animal. This study is assigned key status for endpoint coverage.

Justification for classification or non-classification

Based on the results of the key acute oral toxicity study and according to the criteria of the CLP Regulation, yttrium trinitrate should be classified as acute oral toxicant Category 4 (H302).

Yttrium trinitrate is not to be classified as acute dermal toxicant according to the CLP Regulation.

No data available to conclude on classification for acute inhalation toxicity.