Registration Dossier

Administrative data

Description of key information

Oral (OECD 423), rat (m/f): LD50 = 300-2000 mg/kg bw 
Inhalation (OECD 403), rat (m/f): LC50 > 5.10 mg/L
Dermal (OECD 402), rat (m/f): LD50 > 4000 mg/kg bw

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:
25 Oct 2006 - 09 Nov 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
No necropsy performed; not conducted in compliance with GLP; only limited information
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
(adopted 17 Dec 2001)
Deviations:
yes
Remarks:
(no necropsy was performed and no details on test material purity given)
GLP compliance:
no
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Fasting period before study: yes, 12 h pre-dosing until 3 h post-dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 69
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Doses:
2000 and 300 mg/kg bw
No. of animals per sex per dose:
- 2000 mg/kg bw: 3 females
- 300 mg/kg bw: 3 males and 3 females
Control animals:
other: not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Days 1, 7 and 14
- Necropsy of survivors performed: no
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
300 - 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All 3 females treated with 2000 mg/kg bw died on the first day post-dosing.
There was no mortality observed in any of the males or females treated with 300 mg/kg bw throughout the study period.
Clinical signs:
2/3 females dosed with 2000 mg/kg bw showed prostration and ataxia before death.
Animals of the 300 mg/kg bw dose groups did not show any signs of toxicity throughout the study period.
Body weight:
Body weight gain in animals dosed with 300 mg/kg bw was as expected.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
CLP: Acute Oral 4, H302
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable study (reliability 2). The information is suitable for hazard assessment leading to an endpoint conclusion and is therefore sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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:
20 Feb 2014 - 19 Mar 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories, Inc.
- Age at study initiation: 8 weeks
- Weight at study initiation: males 242-267 g; females 170-199 g
- Housing: singly housing in suspended stainless steel perforated bottom caging; enrichment (e.g., toy) was placed in each cage; litter paper was placed beneath the cage and was changed at least three times per week
- Diet: Harlan Teklad Global 16% Protein Rodent Diet® #2016, ad libitum, except during the exposure
- Water: Filtered tap water was supplied ad libitum, except during exposure
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23
- Humidity (%): 45-55
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Nose Only Inhalation Chamber, ADG Developments LTD
- Exposure chamber volume: 28 L
- Method of holding animals in test chamber: Animals were individually housed in polycarbonate holding tubes which seal to the chamber with an “O” ring during exposure.
- Source and rate of air: Approx. 60.0 liters per minute (Lpm) of filtered generator air was supplied by an air compressor (Powerex Model: SES050822).
- Method of conditioning air: Mass Flow Controller (Omega, Model # FMA-5527)
- System of generating particulates/aerosols: The test substance was aerosolized using a Jet-Mill (Fluid Energy Jet-Mill Serial #J2724E). Prior to aerosolization, the test substance was ground in a coffee mill (Cuisinart, Model #DCG-20N).
- Method of particle size determination: An eight-stage 1 ACFM Andersen Ambient Particle Sizing Sampler was used to assess the particle size distribution of the test atmosphere.
- Temperature, humidity, pressure in air chamber: The exposure chamber temperature and relative humidity range during exposure were 20ºC and 22-24%, respectively.

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric samples were withdrawn at 6 intervals from the breathing zone of the animals. Samples were collected using 37 mm glass fiber filters (WhatmanTM GF/B) in a filter holder attached by ¼ inch Tygon® tubing to a vacuum pump (GAST, Model #1531-107B-G557X). Filter papers were weighed before and after collection to determine the mass collected. This value was divided by the total volume of air sampled to determine the chamber concentration. The collections were carried out for 1 minute at airflows of 4.0 Lpm. Sample airflows were measured using a Mass Flow Controller (Aalborg, Model #GFC-17).
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: An eight-stage 1 ACFM Andersen Ambient Particle Sizing Sampler was used to assess the particle size distribution of the test atmosphere. Samples were withdrawn from the breathing zone of the animals at two intervals. The filter paper collection stages were weighed before and after sampling to determine the mass collected upon each stage.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined graphically using two-cycle logarithmic probit axes.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5.1 mg/L
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: All animals were observed for mortality during the exposure period. The animals were examined for signs of gross toxicity, and behavioral changes upon removal from the exposure tube and at least once daily thereafter for 14 days or until death occurred. Individual body weights of the animals were recorded prior to test substance exposure (initial) and again on Days 1, 3, 7, and 14 (terminal) or after death.
- Necropsy of survivors performed: yes. Surviving rats were euthanized via CO2 inhalation on Day 14. Gross necropsies were performed on all decedents and euthanized animals. Tissues and organs of the thoracic and abdominal cavities were examined.
- Other examinations performed: Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, and coma.
Statistics:
Statistical analysis was limited to the calculation of the mean and standard deviation.
Key result
Sex:
female
Dose descriptor:
LC50
Effect level:
< 5.1 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
> 5.1 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.1 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
One male and three females died within seven days of exposure to the test atmosphere. Prior to death, the animals were hypoactive and exhibited abnormal respiration and/or ano-genital staining.
Clinical signs:
other:
Body weight:
Although all animals lost weight through Day 3, the animals gained body weight during Days 7 to 14. However, two of the survivors did not surpass their initial body weights by the end of the 14-day observation period.
Gross pathology:
Gross necropsy of the decedents revealed discoloration of the lungs, distention of the stomach, discoloration of the liver and/or distention of the intestines. No gross abnormalities were noted for any of the surviving animals when necropsied at the conclusion of the 14-day observation period.

TABLE 1: GRAVIMETRIC CHAMBER CONCENTRATIONS

Sample Number

Time of Sample (hour)

Mass Collected (mg)

Airflow Sampled (Lpm)

Collection Time (min)

Chamber Concentration (mg/L)

1

0.5

22.2

4

1

5.55

2

1

17.4

4

1

4.35

3

2

20.6

4

1

5.15

4

2.5

21.1

4

1

5.28

5

3.5

20.6

4

1

5.15

6

3.75

20.5

4

1

5.13

Average ± Standard Deviation

5.10±0.40

 

TABLE 2: SUMMARY OF PARTICLE SIZE DISTRIBUTION

Sample No.

Time of Sample (hours)

Collection Time (minutes)

Mass Median Aerodynamic Diameter1

(µm)

Geometric Standard Deviation

1

1.5

1

2.80

2.32

2

3

1

3.06

2.51

Average

2.93

2.42

 1This figure is an estimation based on graphic analysis of the particle size distribution as measured with a 1 ACFM Andersen Ambient Sizing Sampler.

 

TABLE 3: INDIVIDUAL BODY WEIGHTS AND MORTALITY (5.10 mg/L)

Animal No.

Sex

Body Weight (g)

Mortality

Initial

Day 1

Day 3

Day 7

Day 14

Day

Weight (g)

3301

M

253

215

215

237

279

E

-

3302

M

267

229

201

216

236

E

-

3303

M

242

211

201

223

238

E

-

3304

M

248

211

192

-

-

7

178

3305

M

265

230

240

269

298

E

-

3306

F

193

169

155

168

197

E

-

3307

F

199

172

158

-

-

5

139

3308

F

179

157

-

-

-

2

149

3309

F

196

171

171

-

-

6

169

3310

F

170

163

167

173

183

E

-

E - Euthanized via CO2inhalation after weighing on Day 14

 

TABLE 4: INDIVIDUAL CAGE-SIDE OBSERVATIONS (5.10 mg/L)

Animal                                                                                                            Day of

Number                                        Findings                                                    Occurrence

 

MALES  

 

3301                                             Rales (moist)                                             CR1-1

                                                     Hypoactivity                                             CR-2

                                                     Irregular respiration                                  CR-3, 5-11

                                                     Gasping                                                    0 (2 hrs)-1

                                                     Ano-genital staining                                  2

                                                     Ocular discharge (black, left eye)             3-8

                                                     Active and healthy                                    12-14

 

3302                                             Rales (moist)                                            CR-3

                                                     Hypoactivity                                             CR-4

                                                     Irregular respiration                                  CR-13

                                                     Gasping                                                    0 (2 hrs)-1, 8-11

                                                     Nasal discharge (red)                                1-2

                                                     Facial staining (black)                               3-5

                                                     Active and healthy                                    14

 

3303                                             Rales (moist)                                            CR-1

                                                     Irregular respiration                                  CR-4

                                                     Hypoactivity                                             0 (1 hr)-1

                                                     Active and healthy                                    5-14

 

3304                                             Rales (moist), irregular respiration            CR-6

                                                     Hypoactivity                                             0 (1 hr)-6

                                                     Ano-genital staining                                  1-3

                                                     Dead                                                         7

 

3305                                             Hypoactivity                                             CR-0 (2 hrs)

                                                     Irregular respiration                                  CR-2

                                                     Active and healthy                                    3-14

 

FEMALES  

 

3306                                             Irregular respiration                                  CR-6

                                                     Hypoactivity                                             0 (1 hr)-3

                                                     Rales (moist)                                             1-4

                                                     Ano-genital staining                                  2-8

                                                     Active and healthy                                    9-14

 

3307                                             Irregular respiration                                  CR-4

                                                     Hypoactivity                                             0 (1 hr)-2

                                                     Rales (moist)                                             1-4

                                                     Ano-genital staining                                  2

                                                     Dead                                                         5

 

3308                                             Irregular respiration, hypoactivity             CR-1

                                                     Rales (moist)                                             1

                                                     Dead                                                         2

 

3309                                             Hypoactivity                                            CR-1, 6 (am)

                                                     Irregular respiration                                  CR-3, 5-6 (am)

                                                     Rales (moist)                                            1

                                                     Ano-genital staining                                  1-2

                                                     Active and healthy                                    4

                                                     Dead                                                         6 (pm)

 

3310                                             Hypoactivity                                             CR-0 (2 hrs)

                                                     Irregular respiration                                  CR-2

                                                     Active and healthy                                    3-14

1CR - removal from the exposure tube

 

TABLE 5: INDIVIDUAL NECROPSY OBSERVATIONS (5.10 mg/L)

Animal

Number                                        Tissue                                                 Findings

 

MALES

 

3301-3303, 3305                         All tissues and organs                          No gross abnormalities

 

3304                                             Lungs                                                 Extremely red

                                                     Intestines                                            Slightly distended

 

FEMALES

 

3306, 3310                                   All tissues and organs                          No gross abnormalities

 

3307                                             Lungs                                                 Slightly red

                                                     Stomach, intestines                             Slightly distended

 

3308                                             Lungs                                                 Extremely red

                                                     Liver                                                  Mottled

                                                     Stomach, intestines                             Slightly distended

 

3309                                             Lungs                                                 Slightly red

                                                     Liver                                                  Mottled

Interpretation of results:
other: Irritating to the respiratory tract according to Regulation(EC) No. 1272/2008
Conclusions:
CLP: STOT Single Exp. 3, H335
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating conc.
Value:
5 100 mg/m³
Quality of whole database:
The available information comprises an adequate and reliable study (reliability 1). The information is suitable for hazard assessment leading to an endpoint conclusion and is therefore sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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:
25 Oct 2006 - 08 Nov 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Test site not covered, no necropsy performed; not conducted in compliance with GLP; only limited information.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(adopted 24 Feb 1987)
Deviations:
yes
Remarks:
(test site was not covered, ingestion of test material was prevented by complete immobilisation of animals, no necropsy was performed, no details on test material purity given)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 69
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
open
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area
- % coverage: 10% of total body surface

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24 h

TEST MATERIAL
- Constant volume or concentration used: no
- For solids, paste formed: yes

OTHER
- Approximately 24 hours before the test, the dorsal hair of animals was removed by cutting and scraping.
- To keep the product in contact with the animals' skin and avoid ingestion or inhalation, the animals were housed individually in small boxes, in order to hinder any movement of animals.
Duration of exposure:
24 h
Doses:
4000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Days 1, 7 and 14
- Necropsy of survivors performed: no
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred throughout the study period.
Clinical signs:
There were no clinical signs noted in any of the animals throughout the study period.
Body weight:
All animals showed weight gain during the trial period. The weight variation observed among males was higher than that observed among females. Other changes were not observed in animals treated during the 14-day trial.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation(EC) No. 1272/2008
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
4 000 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable study (reliability 2). The information is suitable for hazard assessment leading to an endpoint conclusion and is therefore sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Acute Toxicity: via oral route

A reliable key acute oral toxicity study with Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is available, conducted according to OECD test guideline 423 (acute toxic class method), but not in compliance with GLP (CBMM Europe BV, Key, 2006, AOT). A first group of 3 female Wistar rats received the test item dissolved in water at a dose of 2000 mg/kg bw via gastric intubation. All animals died on the first day post-dosing, two of them showing prostration and ataxia before death. Consequently, a second group consisting of 3 males and 3 females received the test item at a dose of 300 mg/kg bw. There was no mortality observed in any of the males or females treated in this dose group, and no signs of toxicity were noted in any of these animals throughout the study period. Body weight gain in animals dosed with 300 mg/kg bw was as expected. The LD50 is therefore concluded to be in the range of 300-2000 mg/kg bw for both males and females under the conditions of this test.

 

Acute Toxicity: via inhalation route

A reliable key acute inhalation toxicity study with Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is available, conducted according to OECD test guideline 403, and in compliance with GLP (CBMM Europe BV, Key, 2014, AIT). Ten healthy Sprague Dawley rats (5 per sex) were exposed to the test atmosphere for 4 hours via the inhalation (nose-only exposure) route. Chamber concentration and particle size distributions of the test substance were determined periodically during the exposure period. The gravimetric chamber concentration was 5.10 mg/L. The average mass median aerodynamic diameter (MMAD) was estimated to be 2.93 µm based on graphic analysis of the particle size distribution. The animals were observed for mortality, signs of gross toxicity, and behavioural changes at least once daily for 14 days following exposure or until death occurred. Body weights were recorded prior to exposure (initial)and again on Days 1, 3, 7, and 14 (terminal) or after death. Necropsies were performed on all animals. One male and three females died within seven days of exposure to the test atmosphere. Prior to death, the animals were hypoactive and exhibited abnormal respiration and/or ano-genital staining. Following exposure, all surviving animals were hypoactive and exhibited abnormal respiration. In addition, several survivors exhibited ano-genital staining, ocular discharge, facial staining, and/or nasal discharge. Although all animals lost weight through Day 3, the animals gained body weight during Days 7 to 14. However, two of the survivors did not surpass their initial body weights by the end of the 14-day observation period. Gross necropsy of the decedents revealed discoloration of the lungs, distention of the stomach, discoloration of the liver and/or distention of the intestines. No gross abnormalities were noted for any of the surviving animals when necropsied at the conclusion of the 14-day observation period.

Under the experimental conditions of this study, the acute inhalation LC50 of the test substance is greater than 5.10 mg/L in male rats and less than 5.10 mg/L in female rats. The combined acute inhalation LC50 for both sexes is greater than 5.10 mg/L.

It can be concluded that the deaths are contributed to local corrosive effects to the respiratory tract rather than to systemic toxicity. None of the observations indicate systemic toxicity, but observations such as irregular breathing, rales, nasal discharge, ocular discharge, gasping, etc., as well as gross necropsy findings (red lungs) are commonly seen in animals suffering from local irritating/corrosive effects to the respiratory tract. Therefore, as local corrosive effects are generally not sex specific, using the combined LC50 for the human health hazard assessment is justified.

 

Acute Toxicity: via dermal route

A reliable key acute dermal toxicity study with Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is available, conducted in principle according to OECD test guideline 402 (standard acute method), but not in compliance with GLP (CBMM Europe BV, Key, 2006, ADT). A group of 5 Wistar rats per sex were applied the test item dissolved in water at a dose of 4000 mg/kg bw on the dorsal area of the trunk. The treated area covered approximately 10% of the total body surface. The test site was not covered following treatment, but the animals were housed individually in small boxes, in order to hinder any movement of animals and to keep the product in contact with the animals’ skin and avoid ingestion or inhalation. 24 h post-dosing, the test item was removed and the animals were observed for the following 14 days. No mortality occurred and no clinical signs were noted in any of the animals throughout the study period. There were no effects of toxicological relevance noted on body weight gain. The LD50 was concluded to be > 4000 mg/kg bw for both males and females under the conditions of this test.

Justification for classification or non-classification

The available data are reliable and suitable for classification. Based on these data, Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate meets the criteria to be classified for acute oral toxicity (Cat 4, H302) according to EC/1272/2008. Furthermore, based on expert judgement a labelling as STOT SE Cat 3 (H335) is warranted, because of the severe local effects in the respiratory tract of the animals which led to mortality in the acute inhalation toxicity study in combination with the facts that Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is corrosive to eyes (mucous membranes) and the pH in aqueous solution is 0.4.