Tungsten hexachloride

Endpoint summary

Description of key information

There are no data on repeated dose toxicity available for Tungsten hexachloride.

Thus, available data from a 90-day subchronic oral toxicity study in rats treated with 0, 10, 75, 125 and 200 mg/kg bw/day Sodium tungstate dihydrate (source substance) was used to assess in a read-across approach the specific organ toxicity of Tungsten hexachloride (target substance)

There were considerable histopathological changes in the kidneys of male and female rats. Mild to severe regeneration of 18 renal cortical tubules was noted in 1/9 and 10/10 males and 1/10 and 8/10 females in the 125 and 200 mg/kg bw /day dosage groups, respectively. The LOAEL was considered to be 125 mg/kg bw/day based on kidney histopathological results and the NOAEL was considered to be 75 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

Sodium tungsate when given orally for 90 consecutive days showed no overt toxic or clinical signs during the study

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Significant differences between males and females in overall mean body weights were observed for all days except Day 0. No significant differences between treatment groups (10, 75, 125 and 200 mg/kg/day) in mean body weight were observed for females. However, significant treatment group differences in mean body weight were observed for males on Days 70, 77, 84 and 90. The Control group had significantly different mean body weights from the 200 mg/kg group on Days 77, 84 and 90. The 10 mg/kg group had significantly different mean body weights from the 200 mg/kg group on Days 70, 77, 84 and 90. The 75 mg/kg group had significantly different mean body weight from the 200 mg/kg group on Day 77.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

Ophthalmic examinations were performed on all animals prior to the scheduled start of the 90-day study and within a week of the scheduled necropsies. All observations prior to study initiation were within normal limits. Observations taken within a week of the scheduled necropsies revealed no abnormalities.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Significant differences between sexes were observed for WBC, basophils, RBC, MCV, MCH, and RDW. For MCV, MCH and RDW, the females had greater values than the males and for WBC, basophils and RBC the males had greater values than the female. No significant sex by dose interactions or dose group differences were observed.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Since the males and females showed some significant differences in clinical chemistries and there were also significant sex by dose interactions, comparison of dose groups was conducted for males and females separately.
For males only, a significant difference between dose groups was observed for creatinine, the 75 mg/kg dose group (0.32±0.02 mg/dl) was significantly less than the 200 mg/kg dose group (0.40±0.02 mg/dl).
For females only, significant differences between dose groups were observed for glucose, sodium and chloride. The mean glucose for the 75 mg/kg group (188.8±5.09 mg/dl) was significantly greater than the control group (161.3±6.58 mg/dl). This was also greater than the biological range of 120-186 mg/dl14.
The mean sodium for the 10 mg/kg group (148 ± 0.27 mmol/l) was significantly greater than the 200 mg/kg group (146±0.38 mmol/l). The mean chloride for the 125 mg/kg group (107 ± 0.47 mmol/L) was significantly greater than the 200 mg/kg group (106±0.37 mmol/L). Sodium and chloride values for all groups, however were within the biological range of 141-148 mmol/l and 101-108 mmol/L, respectively, for Sprague-Dawley rats.

Urinalysis findings:

no effects observed

Description (incidence and severity):

No significant changes in volume, specific gravity or pH. No distinct dose-related trends were observed in glucose, bilirubin, ketone, blood, protein, urobilinogen, nitrite, or leukocytes

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The decrease seen was primarily due to significant decreases in liver, heart, testes and epididymis weights of male animals given 200 mg/kg sodium tungstate. This was strongly correlated with a decrease in food consumption in these animals. Females given 200 mg/kg had increases in kidney and spleen weight. Histopathology indicated an increase in renal tubular regeneration at this dosage level which may have been responsible for the increase in kidney weight. Most metals are excreted through renal clearance and gastrointestinal excretion. Renal effects are common with heavy metals and this finding was not unexpected.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Rats dosed with sodium tungstate showed considerable histopathological changes in the kidneys of male and female rats. Mild to severe regeneration of renal cortical tubules was noted in 1/9 and 10/10 males and 1/10 and 8/10 females in the 125 and 200 mg/kg/day dosage groups, respectively. For clarity, basophilic tubular profiles bearing thickened basement membranes were diagnosed as chronic progressive nephropathy, and in all affected animals, this lesion was minimal and widely scattered throughout the cortex; incidence was similar between control and test article-treated groups, with males more commonly affected than females.

Some histologic findings were noted in the glandular stomach of males and females in all dosage groups. Subacute inflammation consisting primarily of eosinophils admixed with fewer mononuclear cells was observed throughout the submucosa of 2/10, 1/10, 5/9, 4/10 males and 0/10, 1/10, 8/10, 9/10 females in the 10, 75, 125 and 200 mg/kg/day dosage groups, respectively. Goblet cell metaplasia was also observed throughout the mucosa of the glandular stomach in 1/10, 4/10, 8/9, 8/10 males and 0/10, 4/10, 8/10, 10/10 females in the 10, 75, 125 and 200 mg/kg/day dosage groups, respectively.

Histopathologial analysis of epidydimis of rats dosed with sodium tungstate showed considerable effects at high dose group. Cellular debris within the lumen with and without hypospermia was noted in the epididymides of 3/10 males in the 200 mg/kg/day dosage group. A single male in the 10 mg/kg/day group exhibited a similar lesion; however, the finding in this individual was minimal and unilateral, likely a spontaneous occurrence, and was considered to be unrelated to test article exposure. The lesion was not observed in 75 and 125 mg/kg/day group males.

Histopathological findings: neoplastic:

not examined

Details on results:

BODY WEIGHT AND WEIGHT GAIN: Significant differences between males and females in overall mean body weights were observed for all days except Day 0. No significant differences between treatment groups (10, 75, 125 and 200 mg/kg/day) in mean body weight were observed for females. However, significant treatment group differences in mean body weight were observed for males on Days 70, 77, 84 and 90. The Control group had significantly different mean body weights from the 200 mg/kg group on Days 77, 84 and 90. The 10 mg/kg group had significantly different mean body weights from the 200 mg/kg group on Days 70, 77, 84 and 90. The 75 mg/kg group had significantly different mean body weight from the 200 mg/kg group on Day 77.
OTHER FINDINGS: General - Sodium tungsate when given orally for 90 consecutive days showed no overt toxic or clinical signs during the study. Significant dose related alterations in weights, weight ratios, were observed in animals receiving 200 mg/kg. No significant dose related adverse alterations were observed for hematological and clinical chemistry parameters for any treatment group.

Dose descriptor:

NOAEL

Effect level:

75 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effect observed

Dose descriptor:

LOAEL

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: histopathological changes in the kidneys

Critical effects observed:

yes

Lowest effective dose / conc.:

125 mg/kg bw/day (nominal)

System:

other: kidney

Organ:

kidney

Treatment related:

yes

Conclusions:

The LOAEL for subchronic oral toxicity in male and female Sprague-Dawley rats is 125 mg/kg and the NOAEL for the subchronic oral toxicity in male and female Sprague-Dawley rats is 75 mg/kg bw/day.

Executive summary:

In a 90-day subchronic toxicity study, Sodium tungstate dihydrate was administered to 10 Sprague-Dawley rats/sex/dose via oral gavage at dose levels of 0, 10, 75, 125, and 200 mg/kg bw/day. All animals were provided drinking quality water and certified laboratory diet ad libitum. Controls were only given the vehicle of deionized water.

The test item showed no overt toxic or clinical signs during the study. Dose related alterations in weights and weight ratios were observed in animals receiving 200 mg/kg bw/day. While females had no significant differences in mean body weights between treatment groups, males had significantly different mean body weights between control groups near the end of the study. Controls, 10 mg/kg bw, and 75 mg/kg bw had significantly different mean body weights than the 200mg/kg bw group in the end of the study. No significant dose related adverse alterations were observed for hematological, clinical chemistry, urinalysis and ophthalmic parameters. All macroscopic changes were considered to be spontaneous and/or incidental in nature and unrelated to test article exposure. All tissues evaluated showed no treatment related effects. There were considerable histopathological changes in the kidneys of male and female rats. Mild to severe regeneration of 18 renal cortical tubules was noted in 1/9 and 10/10 males and 1/10 and 8/10 females in the 125 and 200 mg/kg/day dosage groups, respectively. The LOAEL is 125 mg/kg bw/day based on kidney histopathological results.  The NOAEL is 75 mg/kg bw/day.

This subchronic toxicity study in the Sprague-Dawley rat is acceptable and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in rodents.

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

75 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Study conducted equivalent to guideline study OECD 408

Organ:

kidney

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No repeated dose toxicity studies were available for Tungsten hexachloride (target substance). Thus, available data from a suitable read-across partner Sodium tungstate dihydrate (source substance) was used in a read-across approach. Due to a lower water solubility of Tungsten hexachloride compared to the source substance the resulting bioavailability (toxicity potential) would also be expected to be lower. Therefore, the read across to the source substance Sodium tungstate dihydrate is adequately protective. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

In a 90-day subchronic toxicity study, Sodium tungstate was administered to 10 Sprague-Dawley rats/sex/dose via oral gavage at dose levels of 0, 10, 75, 125, and 200 mg/kg bw/day. All animals were provided drinking quality water and certified laboratory diet ad libitum. Controls were only given the vehicle of deionized water. Sodium tungstate dihydrate showed no overt toxic or clinical signs during the study. Dose related alterations in weights and weight ratios were observed in animals receiving 200 mg/kg bw. While females had no significant differences in mean body weights between treatment groups, males had significantly different mean body weights between control groups near the end of the study. Controls, 10 mg/kg bw, and 75 mg/kg bw had significantly different mean body weights than the 200 mg/kg bw group at the end of the study. No significant dose related adverse alterations were observed for haematological, clinical chemistry, urinalysis and ophthalmic parameters. All macroscopic changes were considered to be spontaneous and/or incidental in nature and unrelated to test article exposure. All tissues evaluated showed no treatment related effects. There were considerable histopathological changes in the kidneys of male and female rats. Mild to severe regeneration of 18 renal cortical tubules was noted in 1/9 and 10/10 males and 1/10 and 8/10 females in the 125 and 200 mg/kg bw/day dosage groups, respectively. The LOAEL can be considered to be 125 mg/kg bw/day based on kidney histopathological results and the NOAELcan be considered to be 75 mg/kg bw/day.

Justification for classification or non-classification

Based on the available data from the read-across partner Sodium tungstate dihydrate, the target substance Tungsten hexachloride does not warrant classification for specific target organ toxicity in accordance with CLP regulation 1272/2008.