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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
REPORTING FORMAT FOR THE CATEGORY APPROACH

1. HYPOTHESIS FOR THE CATEGORY APPROACH: The hypothesis is that properties are likely to be similar or follow a similar pattern because of the presence of a common metal ion, in this case tungstate.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES):
Source: Sodium Tungstate
Target: Tungsten Carbide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
read-across: supporting information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2021
Report date:
2021

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium wolframate
EC Number:
236-743-4
EC Name:
Disodium wolframate
Cas Number:
13472-45-2
Molecular formula:
Na2O4W
IUPAC Name:
Disodium dioxido(dioxo)tungsten
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Sodium tungstate dihydrate
- Source: Fisher Scientific
- Analytical purity: >98%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
SD
Sex:
male/female
Details on test animals or test system and environmental conditions:
Groups of 10 F1 rats per sex continued on in the study after weaning and were provided drinking water containing the same respective sodium tungstate concentration for 3 months. For all exposure concentrations, except the 2,000 mg/L group, two pups per sex from five randomly selected litters per exposure group were chosen. For the 2,000 mg/L group, a third male pup was selected from two of the four available litters and a third female pup was selected from the other two litters to obtain the complete number of animals needed for the study. After assignments to the 3-month study were complete, five pups per sex from the remaining vehicle control pups were randomly selected as the end-of-study sentinel animals. On the day the last litter reached PND 21, dams were removed, and the pups were weaned. Weaning marked the beginning of the 3-month study.
After weaning, F1 rats were housed five per cage. Feed and dosed water were available ad libitum. Water consumption was measured weekly for 3 months. Cages were changed weekly though PND 4, then changed twice weekly. Racks were changed and rotated at least every 2 weeks.


Administration / exposure

Route of administration:
oral: drinking water
Details on route of administration:
deionized drinking water
Vehicle:
water
Details on oral exposure:
- 90 days for dosed-feed and dosed-water studies
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90-days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/L drinking water
Dose / conc.:
125 mg/L drinking water
Remarks:
Approximately 11.8 mg/kg/day for males and 14.0 mg/kg/day for females.
Dose / conc.:
250 mg/L drinking water
Remarks:
Approximately 24.3 mg/kg/day for males and 26.1 mg/kg/day for females.
Dose / conc.:
500 mg/L drinking water
Remarks:
Approximately 48.9 mg/kg/day for males and 54.4 mg/kg/day for females.
Dose / conc.:
1 000 mg/L drinking water
Remarks:
Approximately 91.8 mg/kg/day for males and 101.4 mg/kg/day for females.
Dose / conc.:
2 000 mg/L drinking water
Remarks:
Approximately 157.2 mg/kg/day for males and 160.5 mg/kg/day for females.
No. of animals per sex per dose:
Each group per sex per species contains five animals
Control animals:
yes, concurrent vehicle
Details on study design:
On the day the last litter (exposed from GD 6 to GD21) reached PND 20, pups were randomly assigned to the 3-month study. For all exposure concentrations, except the 2,000 mg/L group, two pups per sex from five randomly selected litters per exposure group were chosen. For the 2,000 mg/L group, a third male pup was selected from two of the four available litters and a third female pup was selected from the other two litters to obtain the complete number of animals needed for the study. After assignments to the 3-month study were complete, five pups per sex from the remaining vehicle control pups were randomly selected as the end-of-study sentinel animals. On the day the last litter reached PND 21, dams were removed, and the pups were weaned. Weaning marked the beginning of the 3-month study.
After weaning, F1 rats were housed five per cage. Feed and dosed water were available ad libitum. Water consumption was measured weekly for 3 months. Cages were changed weekly though PND 4, then changed twice weekly. Racks were changed and rotated at least every 2 weeks.
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
Animals are individually weighed on days one, seven, and at weekly periods thereafter. All animals are observed twice daily for clinical signs of declining health, or death. Animals found near death or showing clinical signs of pain or distress are humanely euthanized. Formal clinical observations are performed and recorded weekly. Food consumption/water consumption is measured and recorded weekly.

Clinical Laboratory Studies
Blood is collected from both sexes of "special study" rats, at days 4 ± 1 and 21 ± 2 and from the core study rats at the end of the study. These are processed for hematology and clinical chemistry determinations. Blood is collected from core study mice at the end of the study for hematology determinations. See clinical measurements:

1. Hematology:
Erythrocyte count
Mean corpuscular volume
Hemoglobin
Packed cell volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin concentration
Erythrocyte morphologic assessment
Leukocyte count
Leukocyte differential
Reticulocyte count
Platelet count and morphologic assessment

2. Clinical Chemistry:
Sorbitol dehydrogenase (SDH)
Alkaline Phosphatase (ALP)
Creatine Kinase (CK)
Creatinine
Total Protein
Albumin
Urea Nitrogen (BUN)
Total Bile Acids
Alanine Aminotransferase (ALT)
Glucose
Cholesterol
Triglycerides
Sacrifice and pathology:
- Liver, thymus, right kidney, right testis, heart, and lung weights are recorded from all animals surviving until the end of the study.
- A complete necropsy is performed on all treated and control animals, and all tissues required for complete histopathology are trimmed, embedded, sectioned, and stained with hematoxylin and eosin for histopathologic evaluation. See necropsy list:

A complete gross necropsy is an external examination of the animal including body orifices and examination and fixation of all of the following organs/tissues from animals from all treatment groups for histopathologic examination.
Adrenal glands
Brain
Clitoral glands
Esophagus
Eyes
Femur
Gallbladder (mouse)
Gross lesions
Harderian glands
Heart and aorta
Intestine, large (cecum, colon, rectum)
Intestine, small (duodenum, jejunum, ileum)
Kidneys
Liver
Lungs and mainstem bronchi
mandibular and mesenteric
bronchial mediastinal (inhalation studies)
Mammary gland with adjacent skin
Muscle, thigh
Nerve, sciatic
Nasal cavity and nasal turbinates
Oral cavity, larynx, and pharynx
Ovaries
Pancreas
Parathyroid glands
Pituitary gland
Preputial glands
Prostate
Salivary glands
Seminal vesicles
Skin, site of application (dermal studies)
Spinal cord
Spleen
Stomach (forestomach and glandular)
Testes, epididymides, and vaginal tunics of testes
Thymus
Thyroid gland
Tissue masses
Tongue
Trachea
Urinary bladder
Uterus
Vagina
Zymbal glands

- A complete histopathologic evaluation inclusive of treatment-related gross lesions shall be done on all animals. Treatment-related lesions for target organs shall be identified and these organs plus gross lesions shall be examined to a no-effect level. TIssues examined:
Adrenal glands
Brain (3 sections including frontal cortex and basal ganglia, parietal cortex and thalamus, and cerebellum and pons)
Clitoral glands
Esophagus
Eyes
Femur, including diaphysis with marrow cavity and epiphysis (femoral condyle with epiphyseal cartilage plate, articular cartilage and articular surface)
Gallbladder (mouse)
Gross lesions
Harderian glands
Heart and aorta
Intestine, large (cecum, colon, rectum)
Intestine, small (duodenum, jejunum, ileum)
Kidneys
Larynx (inhalation studies)
Liver (2 sections including left lateral lobe and median lobe)
Lungs and mainstem bronchi
Lymph nodes
mandibular and mesenteric
bronchial & mediastinal (inhalation studies)
Mammary gland with adjacent skin
Muscle, thigh (only if neuromuscular signs were present)
Nasal cavity and nasal turbinates (3 sections)
Ovaries
Pancreas
Parathyroid glands
Pituitary gland
Preputial glands
Prostate
Salivary glands
Seminal vesicle
Skin, site of application (dermal studies)
Spinal cord and sciatic nerve (if neurologic signs were present)
Spleen
Stomach (forestomach and glandular)
Testes with epididymides
Thymus
Thyroid gland
Tissue masses
Trachea
Urinary bladder
Uterus
Other examinations:
- Tungsten concentrations in blood and urine
- Genotoxicity (micronucleus and Comet assay): Blood for Micronuclei samples were taken from rats at study termination for micronuclei determinations.

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no clinical observations related to exposure, and all exposed animals were similar in overt behavior and general appearance to the vehicle control animals
Mortality:
no mortality observed
Description (incidence):
There were no early deaths during the 3-month study
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Initial mean body weights were 9% and 16% below those of the vehicle control group for the 1,000 and 2,000 mg/L males, respectively; and 14%, 11%, and 13% below those of the vehicle control group for the 500, 1,000, and 2,000 mg/L females, respectively. Final mean body weights were lower for the 1,000 and 2,000 mg/L males and females, with the 2,000 mg/L males weighing approximately 29% less than the vehicle control group and the 2,000 mg/L females weighing approximately 18% less than the vehicle control group.

Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption was lower for the 1,000 and 2,000 mg/L males and females, with overall reductions of 27% and 42% for males and females, respectively, in the 2,000 mg/L groups compared to the respective vehicle control groups.
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In female rats, there was a mild (<10%) significant decrease in the erythron characterized by a significant decrease in the hemoglobin concentration in the 2,000 mg/L group and a significant negative trend in the hematocrit concentration, hemoglobin concentration, and erythrocyte count with increasing exposure. Although there were no significant pairwise changes observed in the male erythron, there were significant negative trends in hematocrit concentration, hemoglobin concentration, and erythrocyte count with increasing exposure concentration. The reticulocyte count was unchanged in both males and females. These mild erythron changes were most likely due to the stress of exposure,
which is supported by the lower mean body weights
observed in the 2,000 mg/L groups.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In male rats, blood urea nitrogen (BUN) was significantly increased, and the total protein, globulin concentrations, and insulin concentrations were significantly decreased in the 2,000 mg/L group. The BUN was likely increased due to the lower water consumption values in that exposure group. The toxicological relevance of the observed decreases in the total protein and globulins is uncertain; these changes could be a secondary effect of exposure.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
The urine xanthine/creatinine ratios were significantly increased in all male and female exposed groups relative to the vehicle control groups
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute kidney weights were reduced in males in all exposed groups, relative to the vehicle control group, with a significant decrease observed in the 2,000 mg/L group (approximately 21%). Relative kidney weights were higher in 1,000 mg/L females and significantly increased in the 2,000 mg/L males and females, relative to the vehicle control group. Although the kidney was a target tissue, it is unlikely that the lesions observed were responsible for the differences in kidney weights; it is more likely that these organ weight differences are an effect of body weight differences.
When compared to vehicle control groups, significant differences were also observed in other organ weights, including decreased absolute heart and lung weights in males and females; decreased absolute liver weights in males and increased relative liver weights in females; decreased absolute thymus weights in males and increased relative testis weights. These changes were considered secondary to body weight reductions.
Rats administered 2,000 mg/L exhibited significantly decreased left cauda epididymis (14%) and epididymis (13%) weights, and lower testis weights (8%) compared to the vehicle control group.
Although these were significant (cauda and epididymis) and/or displayed a significant negative trend with increasing exposure concentration (right testis), rats in the 2,000 mg/L group displayed mean body weights that were 28% lower than the vehicle control group. There were no changes in reproductive parameters or alterations in contralateral testis and epididymis or in histopathology. Given the magnitude of the body weight effect and the absence of changes in other endpoints, the lower reproductive organ weights are likely secondary to effects on body weight.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No exposure-related gross lesions were recorded
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Exposure-related histological lesions were found in the kidneys. Renal tubule regeneration was increased in the male and female 1,000 and 2,000 mg/L groups; the increases in the 2,000 mg/L groups were significant relative to the vehicle control groups. The lesion was characterized by hyperplasia of proximal convoluted tubular epithelial cells that manifested as cytoplasmic basophilia, nuclear crowding, and occasional mitotic figures. Renal tubule regeneration occurs as a response to previous degeneration or necrosis and is one of the most common exposure-related lesions in the kidney.90
Degeneration and necrosis were not present in this study, perhaps due to the fact that by the time of necropsy, the response of the kidney had progressed from degeneration to regeneration. Renal tubule regeneration differed from chronic progressive nephropathy (CPN) by the lack of thickened basement membranes, associated inflammatory cells, proteinaceous casts, and cytoplasmic pigment—all features typically seen with CPN. The incidences and severities of CPN were not increased in exposed groups of animals.

Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
Neoplasms were not identified in male or female rats
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Although the weights of the left epididymis and the left cauda were significantly decreased in the 2,000 mg/L males, there were no corresponding changes in sperm parameters, including number of sperm/mg cauda epididymis, total number of sperm/cauda, sperm motility, number of homogenization-resistant spermatids/mg testis, or total number of spermatids.

Effect levels

open allclose all
Key result
Dose descriptor:
LOAEL
Effect level:
ca. 1 000 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 500 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/L drinking water
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Any other information on results incl. tables

In both males and females, the total tungsten concentration in blood increased proportionally to the exposure concentration with no observed sex difference. The blood tungsten concentration in vehicle control animals was below the limit of detection (LOD; 0.0016 μg/g) of the assay. The urine tungsten concentration is presented as both μg/g of urine and after correcting for urinary creatinine concentrations (μg/mg creatinine). Low concentrations of tungsten were detected in urine from vehicle control male and female groups. The concentrations of creatinine-corrected tungsten in urine increased proportionally to the exposure concentration in both males and females and were significantly increased in all exposed groups compared to the corresponding vehicle control groups. As with blood, there was no observed sex difference in urinary tungsten concentrations.
The micronucleus assay was negative in rats. The Comet assay was positive in the liver of rats but negative in the blood and kidney.

Applicant's summary and conclusion

Conclusions:
There were no early deaths during the 3-month study. When compared to the vehicle control group, final mean body weights were lower for the 1,000 and 2,000 mg/L males and 2,000 mg/L females. Water consumption was lower for the 1,000 and 2,000 mg/L males and females. The urine xanthine/creatinine ratios were significantly increased in all male and female exposed groups. Serum insulin concentrations were significantly decreased in the 2,000 mg/L males relative to the vehicle control males. Significantly decreased absolute weights were observed in several organs but were considered secondary to body weights reductions. Exposure-related histological lesions were limited to the kidneys and included increased incidences of renal tubule regeneration in the 1,000 and 2,000 mg/L males and females; the increases in the 2,000 mg/L groups were significant relative to the vehicle control group.
Executive summary:

No oral repeated dose toxicity data of sufficient quality are available for tungsten carbide (target substance). However, oral repeated dose toxicity data are available for sodium tungstate (source substance), which is used for read-across. Due to lower water solubility and lower toxicity for the target substance compared to the source substance, the resulting read-across from the source substance to the target substance is appropriate as a conservative estimate of potential toxicity for this endpoint. In addition, read-across is appropriate because the classification and labelling is more protective for the source substance than the target substance, the PBT/vPvB profile is the same, and the dose descriptors are, or are expected to be, lower for the source substance. For more details, refer to the tungstate read-across category approach in the Category section or Annex 3 in the CSR.