Registration Dossier

Administrative data

Description of key information

Acute toxicity studies of sufficient quality and tested in accordance with standard methodology showed that the acute oral LD50 was > 2000 mg/kg in rats, the acute dermal LD50 was >2000 mg/kg, and the acute inhalation LC50 was > 5.4 mg/L/4h for tungsten metal.

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:
1998-03-24 to 1999-06-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan U.K. Ltd, Bicester, Oxon, England
- Age at study initiation: 4 to 7 wks
- Weight at study initiation: 94 to 112 g
- Fasting period before study: over-night prior to and 4 hrs after dosing
- Housing: in groups of 5 rats of the same sex in metal cages with wire mesh floors
- Diet: ad lib on Special Diet Services RM1(E) SQC expanded pellet
- Water:ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 to 22
- Humidity (%): 34 to 59
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1998-03-24 To: 1998-04-09
Route of administration:
oral: gavage
Vehicle:
other: 1% aqueous methylcellulose
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20% w/v in 1% w/v aqueous methylcellulose
- MAXIMUM DOSE VOLUME APPLIED: 10mL/kg bodyweight

DOSAGE PREPARATION (if unusual):
Test substance was prepared on the day of dosing.

PRELIMINARY STUDY
2 rats (one female and one male) were treated at 1600 mg/kg bodyweight to establish a dosing regime for the main study.
Doses:
2000 mg/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: 7 or 14 days
- Frequency of observations and weighing: Animals 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.
- The body weight of each rat was recorded on Days 1 (prior to dosing ), 8 and 15 or at death. Individual weekly bodyweight changes and group mean bodyweights were calculated.
- Necropsy of survivors performed: yes
- Clinical signs: The nature and severity of the clinical signs and time were recorded at each observation.
- Macroscopic pathology: All animals were subjected to a macroscopic examination, which consisted of opening the cranial, abdominal and thoracic cavities. The macroscopic appearance of all tissues was recorded.
Preliminary study:
There were no deaths. Clinical signs included: piloerection and hunched posture was seen in both animals. There was increased sensitivity to touch observed in the male rat only. Bodyweight gains were considered satisfactory for studies of this nature and duration. No macroscopic abnormalities were noted at the terminal necropsy on Day 8 of this preliminary study. On the basis of the above findings, 2000mg/kg was selected as the dosage in the main study.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
In the main study, one female (out of a group of 10 rats-5 males and 5 females) died 2 days after a single oral administration of Tungsten Metal powder at a dose level of 2000 mg/kg. Macroscopic examination, where possible, revealed enlarged tissues and fluid contents in stomach.
Clinical signs:
Piloerection was observed in all rats within seven minutes of dosing. This sign persisted and was accompanied by hunched posture seen in all rats with abnormal faeces (characterised by soft to liquid faeces) and ungroomed appearance (characterised by soiled/stained fur around the ano/genital region) observed in one male only. There were no other signs of reaction to treatment and recovery was complete in all animals by Day 4.
Body weight:
Bodyweight gains were considered satisfactory for studies of this nature and duration.
Gross pathology:
No macroscopic abnormalities were noted at the terminal necropsy on Day 15.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral lethal oral dose (LD50) to rats of Tungsten Metal Powder was demonstrated to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Well documented OECD guideline study, performed under 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:
1998-05-19 to -1999-05-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
: filters for determining chamber concentrations were disposed of following a review of the gravimetric data. Relatve humidity of the control group was below specified levels. These were not expected to affect the integrity of the study.
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Limited, Manston Road, Margate, Kent, England.
- Age at study initiation: Males-7wks : Females-8wk
- Housing: Housed by sex; cages (35cmx53cmx25cm) made of stainless steel sheets and wire mesh, suspended on a movable rack.
- Diet: ad libitum on SDS rat and mouse diet (RMI)
- Water:ad libitum tap water
- Acclimation period: 5 days.


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

IN-LIFE DATES: From: 1998-05-19 To: 1998-06-04
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: Diluent air supply
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Cylindrical, snout-only exposure chambers made of an aluminium alloy.
- Exposure chamber volume: 30 litres
- Method of holding animals in test chamber: Restrained in moulded polycarbonate 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.
- System of generating particulates/aerosols: The particulate aerosol was generated by a Wright dust feeder (WDF), using a diluent air supply and a glass concentric jet atomiser.

TEST ATMOSPHERE
- Brief description of analytical method used: The test atmosphere was passed through an elutriation column to reduce, by sedimentation, the amount of non-respirable particulate in the atmosphere.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Eight samples of air were removed from the test chamber at various times during exposure in order to determine the concentration of the test aerosol. Each air sample was withdrawn, at a rate of 2 litres/minute, through a pre-weighed glass fibre filter.
Duration of exposure:
4 h
Concentrations:
The mean gravimetric concentration of tungsten carbide powder during the exposure period was 5.40 mg/L.
No. of animals per sex per dose:
5 male and 5 female
Control animals:
yes
Details on study design:
The WDF was positioned on a stand at the side of the exposure chamber and the output was connected to the top inlet port of the chamber via the elutriation column. The initial speed controller setting was selected as a result of preliminary generation of a concentration of total particulate close to the target (5 mg/L).
A supply of clean dried compressed air was connected to the dust generator and the supply pressure was adjusted to give a flow rate of 10 litres/minute measured at the generator outlet nozzle. A diluent air supply, adjusted to give 10 litres/minute, was connected to the glass atomiser to provide a total air supply of 20 litres/minute. The chamber exhaust airflow was calibrated at the point of attachment to the chamber and adjusted to maintain the chamber at a slight negative pressure.
Each rat was placed into a separate restraining tube and the tubes were attached to the exposure chamber.
The powder container of the WDF was advanced manually until a trace of suspended dust was seen to emerge from the outlet. The gearing on the generator was then engaged and the generator motor switched on to start the exposure. After a 5 minute equilibration period, the exposure was timed for 4 hours. The generator was then switched off and the chamber allowed to clear before the rats were removed for examination.
Following exposure, the rats were returned to the holding cages and food and water supplies were restored. The test rats were kept in a ventilated cabinet overnight and then returned to the holding room for the remainder of the observation period.
The control group was treated similarly but exposed to air only for 4 hours. The control rats were returned to the holding room at the end of the exposure procedure.

OBSERVATIONS:
The rats were observed intermittently for signs of reaction to the test substance during exposure and at least twice daily throughout the observation period.

CLINICAL SIGNS:
The clinical signs were recorded at the end of the chamber equilibration period, at 0.25, 0.5 and 1.0 hours then at hourly intervals during the exposure. Clinical signs were also recorded immediately following exposure and at 1 and 2 hours post exposure. During the observation period, the clinical signs were recorded once in the morning and then as necessary following a later check for clinical signs.

BODYWEIGHT:
All rats were weighed at least twice during the week prior to exposure, immediately before the exposure (Day 0), and weekly during the observation period.

FOOD CONSUMPTION:
The amounts of food consumed by each cage of rats were 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 water bottles was conducted daily.

TERMINAL STUDIES:
At the end of the 14-day observation period, the rats were killed by intraperitoneal injection of pentobarbitone sodium and exsanguinated when clinically dead. All rats were subjected to a detailed macroscopic examination. The lungs, liver, and kidneys were removed, dissected, cleared of surrounding tissue, and the organ weights recorded. The kidneys were weighed together.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.4 mg/L air
Mortality:
There were no unscheduled deaths.
Clinical signs:
other: There were no treatment-related clinical signs seen during the exposure. There were no clinical signs indicative of an irritant or toxic effect. Soiling of the fur with excreta was noted in all control and test rats immediately following exposure. Br
Body weight:
The mean bodyweight gain of male test rats was lower than that of controls following exposure to tungsten metal powder. The mean bodyweight gain of female test rats was similar to control values.
Gross pathology:
Macroscopic pathology:
There were no treatment-related findings at necropsy. Incidental findings noted in control rats included 2 dark foci on the right posterior lobe of 1 female and a red area on the cranium of 1 male and 1 female.
Other findings:
- Organ weights: The mean lung weight was higher in the female test group rats than female control rats. No other significant differences were noted in any organ weight data.

-Food Consumption: Mean food consumption of test rats was similar to control values.

-Water Consumption: A visual appraisal of the water bottles indicated that the amount of water consumed by the test rats was similar to that of the control rats.
Interpretation of results:
GHS criteria not met
Conclusions:
There were no deaths following a four-hour exposure of rats to a particulate aerosol generated from tungsten metal powder at a concentration of 5.40 mg/L. The LC50 ( 4-hour) is therefore in excess of 5.40 mg/L of air.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5.4 mg/m³
Quality of whole database:
Well documented study similar to OECD guideline, performed under 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:
1998-03-24 to 1999-06-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
One animal was found to be above the specified weight range of 200-300 g on Day 1 prior to dosing. The deviation was not considered to have affected the integrity of the study.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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 304 g
- Housing: Individually in metal cages with wire mesh floors in Building R14 Rm 6
- Diet: ad libitum Special Diet Services RM1(E) SQC expanded pellet
- Water: ad libitum
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 to 22
- Humidity (%): 34 to 59
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 1009-03-23 To: 1998-04-07
Type of coverage:
occlusive
Vehicle:
other: 1% w/v aqueous methylcellulose
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorso-lumbar region
- % coverage: 10%
- Type of wrap if used: The test substance was applied by spreading it evenly over the prepared skin. The treatment area (50 x 50 mm ) was covered with porous gauze held in place with a non irritating dressing, and further covered by a waterproof dressing encircled firmly around the trunk of the animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The dressings were removed and the treated area of skin was washed with warm water to remove any residual test substance. The treated area was blotted dry with absorbent paper.
- Time after start of exposure: 24 hrs

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.56 ml/kg bodyweight (200 mg/kg bodyweight)
- Concentration (if solution): 357% w/v in 1% w/v aqueous methylcellulose

VEHICLE
- Concentration (if solution): 1% w/v aqueous methylcellulose
Duration of exposure:
24 hrs
Doses:
2000 mg/kg bodyweight.
No. of animals per sex per dose:
5 male and 5 female
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:Frequently on day 1 and then twice daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology

One day prior to treatment, hair was removed from the dorso-lumbar region of each rat, exposing an area equivalent to approximately 10% of the total body surface area.
The test substance was applied by spreading it evenly over the prepared skin. the treatment area (approximately 50 mm x 50 mm) was covered with porous gauze held in place with a non irritating dressing, and further covered by a waterproof dressing encricled firmly around the trunk of the animal.
Treatment in this manner was performed on Day 1 (day of dosing) of the study only.
At the end of the 24 hours exposure period the dressings was carefully removed and the treated area of skin was washed with warm water (30 to 40 C) to remove any residual test substance. The treated area was blotted dry with absorbent paper.

-Bodyweights: 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 wihich consisted of opening the abdominal and thoracic cavities. The macroscopic appearance of all tissues was recorded.
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths.
Clinical signs:
Dermal responses were confined to a residual staining (grey) from the test substance on Day 2 only (staining did not impair dermal assessment) in all ten rats and accompanied at this time in one rat only by slight erythema (resolving by Day 3).
Body weight:
A minor bodyweight loss was evident in two female rats at Day 8 only. All remaining animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
No abnormalities were recorded at the macroscopic examination on Day 15.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal lethal dose to rats of Tungsten Metal Powder was demonstrated to be greater than 2000 mg/kg bodyweight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Well documented performed per OECD guidelines under GLP.

Additional information

Justification for classification or non-classification

Acute toxicity studies of sufficient quality and tested in accordance with standard methodology showed that the acute oral LD50 was > 2000 mg/kg in rats, the acute dermal LD50 was >2000 mg/kg, and the acute inhalation LC50 was > 5.4 mg/L/4h for tungsten metal. The oral LD50 cutoff value for classification is 2000 mg/kg, the dermal LD50 cutoff value is 2000 mg/kg, and the inhalation LC50 cutoff value for classification is 5.0 mg/L/4 hr for dusts and mists. Therefore, no classification is required for acute toxicity.