Registration Dossier

Administrative data

Description of key information

In an acute oral toxicity study conducted on rats and according to OECD 401, the LD50 for males/females was calculated to be 1453 mg/kg, for females was calculated to be 1373 mg/kg, and for males was calculated to be 1539 mg/kg. In an acute inhalation toxicity study conducted on rats and according to OECD 403, the rat inhalation LC50 was determined to be in excess of 5.01 mg/L. There were no deaths and no evidence of a systemic response in any animal throughout the study (OECD 402) following a single dermal application of the test substance to rats at a dose level of 2000 mg/kg-bw.  The acute lethal dose was determined to be greater than 2000 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:
1998-03-09 to 1999-06-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Performed per OECD Guideline 401, Acute Oral Toxicity and GLP.
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
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: Harlan UK Ltd, Bicester, Oxon, England.
- Age at study initiation: 4 to 7 wks
- Weight at study initiation: 87 to 125 g
- Fasting period before study: Overnight
- Housing: In groups of 5 rats of the same sex in metal cages with wire mesh floors.
- Diet: ad libitum- standard laboratory rodent diet (Special Diet Services RM1(E) SQC expanded pellet)
- Water: ad libitum
- Acclimation period:5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 22.5 C
- Humidity (%): 29 to 59 %
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: March 9, 1998 To: April 14, 1998
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 800, 1260, and 2000 mg/kg Bodyweight


Doses:
Animals were exposed at a fixed dose volume of 10 mL/kg bodyweight.
800 mg/kg (dose concentration 8 mg/mL).
1260 mg/kg (dose concentration of 12.6 mg/mL)
2000 mg/kg (dose concentration of 20 mg/mL).
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
- Mortalities: Cages of rats were checked at least twice daily for mortalities.
- Clinical signs: Animlas were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, surviving animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature of the clinical signs and time were recorded at each observation. All animals that survived treatment were observed for 14 days after dosing.
- Body weights: Body weights of each rat was recorded on Days 1 (prior to dosing), 8 and 15 or at death. Individual weekly body weight changes and group mean body weights were calculated.
- Necropsy of survivors performed: yes
-Macroscopic pathology: All animals were subjected to macroscopic examination which consisted of opening the cranial, abdominal and thoracic cavities. The macroscopic appearance of all tissues was recorded.
- Other examinations performed: histopathology


Statistics:
The acute median lethal oral dose (LD50) to male and female rats was calculated using the method of Finney (1971).
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
1 539 mg/kg bw
95% CL:
1 206 - 1 965
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 373 mg/kg bw
95% CL:
1 174 - 1 607
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 453 mg/kg bw
95% CL:
1 221 - 1 729
Mortality:
All rats dosed at 2000 mg/kg and one female dosed at 1260 mg/kg died during the study. The majority of deaths occurred within the first six hours following dosing with a lesser number of rats expiring between approximately 24 and 48 hrs. after dosing.
Clinical signs:
Piloerection was observed in all rats within 6 min. of dosing. This sign persisted and was accompanied later on Day 1 and/or at later intervals during the study by:
-Hunched posture, waddling/unsteady gait, lethargy, pallid extremities, walking on toes, partially closed eyelids, respiratory distress, faecal disturbances, and ungroomed appearance observed among rats at all dosages,
-Dulled eyes, increased lacrimation and prostration noted in rats at 1260 and 2000 mg/kg only,
-Blue/cold extremities, body tremors, protruding eyes and swollen abdomen among rats at 2000 mg/kg only.

Recovery of surviving rats was complete by either Day 3 (females 800 mg/kg), Day 4 (males 800 mg/kg) or by Day 5 (1260 mg/kg).
Body weight:
All animals that survived treatment were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
Macroscopic examination of animals that died during the study revealed congestive changes (characterized by inflammation, darkened/pallid coloration, gaseous distension and liquid retention) in all or the majority of organs and tissues.
Macroscopic examination of animals surviving treatment and killed at study termination revealed no abnormalities.

The combined sexes slope of the probit line was 20.73 with standard error of 11.42 using log tranformation of dose. The heterogeneity factor was not significant.

The separate sexes slope of the parallel porbit lines was 22.91 with a standard error of 12.45 using log transformation of dose. The heterogeniety factor was not significant.

The chi-square test for parallelism gave no evidence of non-parallelism.

Interpretation of results:
GHS criteria not met
Conclusions:
The rat oral LD50s( w/ 95% CI) were calculated to be :
Males: 1539 (1206 to 1965) mg/kg bodyweight
Females : 1373 (1174 to 1607) mg/kg bodyweight
Males and females : 1453 (1221 to 1729) mg/kg bodyweight
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
1 539 mg/kg bw
Quality of whole database:
Scientific reliable study (K1) conducted under OECD guidelines and GLP

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:
1998-5-12 to 1999-05-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Conducted similar or equivalant to OECD 403 and per GLP guidelines.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
however, the deviations from the protocol did not affect the objectives and integrity of the study.
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: Charles River UK Ltd Manston Rd, Margate, Kent, England.
- Age at study initiation: 7 to 8 wks
- Housing: By sex in groups of 5 in metal cages and wire mesh.
- Diet: SDS rat and mouse diet (RM1) ad libitum
- Water: tap water ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2
- Humidity (%): 55+/- 10%
- Air changes (per hr): 12 to 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: May 6, 1998 To: May 26, 1998
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The snout-only exposure chambers used for the exposures were of cylindrical form and made of aluminium alloy. The chambers have an enclosed volume of 30 litres.

- Method of holding animals in test chamber: The rats were held for exposure in molded polycarbonate restraining tubes which were attached at evenly spaced ports in the cylindrical section of the chamber, and were designed to allow only the snout to project into the chamber. Each rat was restrained in a forward position by an adjustable foamed plastic stopper which also provided a seal for the tube.

- Source and rate of air: A supply of clean dried compressed air was connected to the WDF generator and the supply presure was adjusted to give a flow rate of 15 litres/min. measured at the generator outlet nozzle. The chamber exhaust airflow was calibrated at the point of attachment to the chamber and adjusted to maintain the chamber at a slightly negative pressure.

- Method of conditioning air: The test atmosphere was passed through an elutriation column to reduce, by sedimentation, the amount of non-respirable particulate in the test atmosphere.

- System of generating particulates/aerosols: The Wright Dust Feed mechanism (WDF), the Fast WDF was used for generation of test atmosphere. The generator was designed to produce and maintain atmospheres containing dust by suspending material scraped from the surface of a compressed powder in a stream of dry air. The concentration of dust in the air is determined by the rate at which the scraper blade is advanced into the compressed powder.

- Method of particle size determination: The Mass median aerodynamic diameter (MMAD) of the airborne dust was 5.1 um. Approximately 65% of the particles were less than 7 um in aerodynamic diameter and of a respirable size.

- Temperature, humidity, pressure in air chamber: The air temperature in the exposure chamber was measured with a thermometer and the relative humidity was measured using a Casella Type T6900 relative humidity meter. The temperature and relative humidity were recorded at the start of exposure and then at 30-min. intervals during the 4-hr exposure.


TEST ATMOSPHERE
- Brief description of analytical method used: The nominal concentration of the test substance was calculated from the total amount of sodium tungstate dihydrate dispersed by the generator and the total volume of air flowing through the exposure system during the period of generation.

- Samples taken from breathing zone: yes, in the fist instance, samples were obtained following equilibration and at approximately hourly intervals after. An addtional sample was obtained to monitor the chamber concentration following adjustment to the exposure system. Each air sample was withdrawn, at a rate of 2 litres per minute, through a pre-weighed glass fibre filter (Whatman GF/A) mounted in an open face filter holder. The filters were weighed again following sampling for gravimetric analysis of the test aerosol. The volume of air sampled was measured using a wet-type gas meter.


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Two additional air samples were taken during the exposure, at a sampling rate of 2 litres per min., using a Marple cascade impactor. The samples were taken at 98 and 225 min. of exposure. The volume of air sampled was measured using a wet-type gas meter.

The amount of test material collected on the stages of the sampler was determined gravimetrically. The particle size distribution of the test atmosphere was assessed using linear regression analysis. The probit of the cumulative percentage of the total particles collected, smaller than the cut-point of each stage, was plotted against the logarithm of the cut-point of each stage.

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Time weighted average: 5.01 mg/L Gravimetric concentration
No. of animals per sex per dose:
10 males and 10 females divided into 2 groups (5 males and 5 females).
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Rats were observed intermittently for signs of reaction to the test substance during exposure and at least twice daily through the observation period.
- Necropsy of survivors performed: yes, At the end of the 14-day observation period, the rats were killed by intraperitoneal injection.
- Clinical signs: The clinical signs were recorded at the end of the chamber equilibration period, at 0.25, 0.5 and 1.0 hours and then at hourly intervals during the exposure. Clinical signs were recorded immediately post exposure and than at 1 hour and 2 hours post exposure.
-Bodyweight: All rats were weighed at least twice during the week prior to the exposure, immediately before exposure (Day 0) and weekly during the observation period.
-Food consumption: The amounts of food consumed by each cage of rats was measured from weighday to weighday throughout the study. The daily mean intakes of food for each cage were calculated from the recorded data.
-Water consumption: A visual inspection of the water bottle was conducted each day.
-Macroscopic examination: All rats were subjected to a complete macroscopic examination. The lungs, liver and kidneys were removed, and weighed.
Statistics:
no data
Preliminary study:
The conditions used during Preliminary Generation Trials were selected for exposure of rats in order to generate an anticipated chamber concentration close to target (5 mg/L). Re-milling of the test substance and modification of generation conditions did not significantly reduce the particle size of the dust aerosol.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.01 mg/L air
Exp. duration:
4 h
Mortality:
There were no unscheduled deaths during the study.
The LC50 (4-hour) for sodium tungstate dihydrate was determined to be in excess of 5.01 mg/L.
Clinical signs:
other: DURING EXPOSURE Wet fur on the head and around the mouth was observed in all test rats from 1 hour of exposure. Soiling of fur with excreta was noted in both control and test rats and was associated with the method of restraint used during exposure. OBSE
Body weight:
The mean bodyweight gain of male test rats was lower than that of the controls following exposure to sodium tungstate dihydrate. The mean bodyweight gain of female test rats was similar to control values.
Gross pathology:
There was slight congestion of the lungs of 2 male and 2 female test rats. Moderate congestion of the liver was also noted in 2 male test rats.
Dark foci were seen on the lungs of 2 male test rats; this finding is not uncommon in untreated rats.
Other findings:
- Organ weights: Mean organ weights for test rats were similar to control values.
-Food consumption: There was no treatment-related effect.
-Water consumption: A visual appraisal of the water bottles indicated that the amount consumed by the test rats was similar to that of the control rats.
Interpretation of results:
GHS criteria not met
Conclusions:
The rat inhalation LC50 was determined to be in excess of 5.01 mg/L.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5.01 mg/m³
Quality of whole database:
Scientific reliable study (K1) conducted under OECD guidelines and GLP

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:
1998-03-09 to 1999-06-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study was performed per OECD guideline 402 and per GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
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
- Source: Harlan UK Ltd,Bicester, Oxon, England
- Age at study initiation: 8 to 11 wks
- Weight at study initiation: 235 to 300 g
- Housing: Individually in metal cages with wire mesh floors.
- Diet: ad libitum - Special Diet Services RM1(E) SQC expanded pellet.
- Water: ad libitum
- Acclimation period: 18 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 22.5 C
- Humidity (%): 29 to 50%
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: March 9, 1998 To: March 23, 1998
Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: dorso-lumbar region
- % coverage: 10%
- Type of wrap if used: Porous gauze with a non-irritating dressing covered by a waterproof dressing encircled firmly around the trunk of the animal.


REMOVAL OF TEST SUBSTANCE
- Washing: with warm water and blotted dry with absorbent paper.
- Time after start of exposure:24 hrs


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bodyweight
- Constant volume or concentration used: yes
-Test material was applied by spreading it evenly over the prepared skin.
Duration of exposure:
24 hrs
Doses:
2000 mg/kg bodyweight, single dose.
Maximum practical concentration of 250% w/v in distilled water and administered at a dose volume of 0.8 mL/kg bodyweight.
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
- Frequency of observations and weighing: Animals were observed at lest twice daily for mortalities through 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
-Clinical signs: Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity of the clinical signs and time were recorded at each observation.
-Bodyweight: The bodyweight of each rat was recorded on Days 1 (prior to dosing), 8 and 15. Individual weekly bodyweight changes and group mean bodyweights were calculated.
-Macroscopic pathology: All animals were subjected to a macroscopic examination, which consisted of opening the abdominal and thoracic cavities. The macroscopic appearance of all tissues was recorded and macroscopic abnormalities were preserved.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths and no evidence of a systemic response in any animal throughout the study.
Clinical signs:
Slight erythema only was observed in three rats following removal of the dressings on Day 2 which was still evident in two animals on Day 3 before resolving in all instances by Day 4. No dermal irritation was seen in the remaining seven animals.
Body weight:
A slightly low bodyweight gain was evident in one female on Day 8 and Day 15. All other rats were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
No macroscopic abnormalities were observed for animals killed at study termination on Day 15.
Interpretation of results:
GHS criteria not met
Conclusions:
There were no deaths and no evidence of a systemic response in any animal throughout the study following a single dermal application of the test substance to rats at a dose level of 2000 mg/kg-bw. The acute lethal dose was determined to be greater than 2000 mg/kg bw.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Scientific reliable study (K1) conducted under OECD guidelines and GLP

Additional information

Justification for classification or non-classification

In an acute oral toxicity study conducted on rats and according to OECD 401, the LD50 for males/females was calculated to be 1453 mg/kg, for females was calculated to be 1373 mg/kg, and for males was calculated to be 1539 mg/kg. For substances with an LD50 between 300 and 2000 mg/kg, a classification category 4 is warranted. As such, based on the available data, sodium tungstate is classified under CLP as a category 4 acute toxicant under CLP and R22 Harmful if swallowed under DSD. The 4hr-LC50 for sodium tungstate was reported to be >5.01 mg/L, which is greater than the cutoff inhalation LC50 value of 5.0 mg/L/4 hr. The dermal LD50 for sodium tungstate was reported to be >2000 mg/kg, which is greater than the classification cutoff level. As such, sodium tungstate is not classified for the inhalation and dermal routes.