Tellurium

Endpoint summary

Description of key information

The main effect observed upon oral exposure in the different sub-acute and sub-chronic available studies is reduction of weight and weight gain. At microscopic examination also changes in the liver were noted. However the severeness of the effects vary within the different studies and affected animals recover upon cessation of the treatment.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

14 days subacute exposure

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

no information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Thirty mice were randomly distributed into five groups of six mice per group. The first group (control) was administrated DW orally, and the fifth group received K2TeO3 at the dose of 1/10 LD50 = 12.5 mg/kg or 1.25 mg/kg upon oral administration once per day for 14 consecutive days. Furthermore, the mice were weighted once daily for 14 consecutive days. The experimental design involved certain general toxicological, haematological, serum and histopathological investigations.

GLP compliance:

not specified

Limit test:

yes

Specific details on test material used for the study:

Potassium tellurite (K2TeO3.3H2O)

Species:

mouse

Strain:

NMRI

Sex:

male

Details on test animals or test system and environmental conditions:

Male NMRI mice (body weight 22 ± 2 g) were used in this study. The mice were obtained from Faculty of Medicine, Kerman University of Medical Science Kerman, Iran) and housed in plastic cages (six to ten each) in a standard condition with controlled temperature (22 ± 1 °C) and humidity (50 ± 10%) with a 12/12 h light/dark condition for at least a week prior to experimentation. The mice had free access to food and water.

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

14 consecutive days

Frequency of treatment:

once daily

Dose / conc.:

1.25 mg/kg bw/day (nominal)

No. of animals per sex per dose:

6 male mice/group

Control animals:

yes, concurrent vehicle

Details on study design:

The mice were weighted once daily for 14 consecutive days. At the end of the experiment, all animals were anaesthetized by Ketamine-Xylizine, then the abdomen was opened, and blood samples were collected from cardiac puncture for hematological and serum biochemical assessment. The liver, right kidney, heart, right testis and brain were rapidly excised, rinsed by ice-cold saline and the tissues were homogenized for oxidative stress and antioxidant enzyme activities measurement.
After 14 days, all animals were sacrificed for subsequent experimental studies. Vital organs including liver, kidney, heart, testis and brain were removed and processed for histopathological observation.

Positive control:

none

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: once daily

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the experiment
- Anaesthetic used for blood collection: Yes (Ketamine-Xylizine)
- Animals fasted: Not specified
- How many animals: all animals
- Parameters examined: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (Hb), hematocrit (Hct), and platelet (PLT) count.

CLINICAL CHEMISTRY: Yes / No / Not specified
- Time schedule for collection of blood: at the end of the experiment
- Animals fasted: Not specified
- How many animals: all animals
- Parameters examined: The serum obtained was evaluated to assay aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), urea, creatinine (Cr), fast blood sugar (FBS), cholesterol (Chol), triglyceride (TG), bilirubin (total (TB) and direct (DB)), and creatine phosphokinase (CPK)

Sacrifice and pathology:

After 14 days, all animals were sacrificed for subsequent experimental studies. Vital organs including liver, kidney, heart, testis and brain removed and fixed in formalin 10% (v/v), imbedded in paraffin and processed for histopatological observation. Then the histological sections of 5 mm in thickness were stained using haematoxylin and eosin (H & E) stain and studied by a routine light microscope (Olympus CA.31, Japan).

Other examinations:

Oxidative stress and antioxidant enzyme activities measurement:
The liver, right kidney, heart, right testis and brain were rapidly excised, rinsed by ice-cold saline and stored at 80 °C. An approximately 100 mg of the tissues was then homogenized in Phosphate-Buffered Saline (PBS, pH 7.4) on ice using T-18 Ultra
Turraks Homogenizer (IKA, Germany) and then were centrifuged at 12,000 rpm at 4 °C for 10 min. The supernatants were used to determine GSH and MDA levels and of superoxide dismutase (SOD) and catalase (CAT) activities.
Histopathology examination:
Histopathology was conducted of vital organs including liver, kidney, heart, testis and brain, of all animals.

Statistics:

All statistical analyses were performed using Graphpad Prism software (version 6, San Diego, CA, USA). The results were presented as mean ± SD. The difference between groups was evaluated by one-way ANOVA followed by Tukey test and p-values less than 0.05 were considered statistically significant.

Clinical signs:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The body weight of male mice that received K2TeO3 at the doses of 1.25 mg/kg decreased.

Haematological findings:

no effects observed

Description (incidence and severity):

No change was found with regards to the treatment of K2TeO3 at the dose of 1.25 mg/kg as compared to the control group.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Liver enzymes including AST, ALT and ALP significantly increased following exposure to K2TeO3 at the dose of 1/10 LD50 (1.25 mg/kg; AST, ALT, ALP) when compared with the control. Urea and Cr which are biomarkers of renal toxicity significantly increased after treatment with K2TeO3 when compared with the control while, no change was observed in FBS, Chol, TG, TB and DB serum parameters when K2TeO3 was administered as compared to the control group. Creatine phosphokinase (CPK) is an enzyme found mainly in the heart, brain and skeletal muscle, and was significantly elevated following the administration of K2TeO3 (1.25 mg/kg) when compared with the control, which indicated that toxicity may have occurred in some degree in these organs.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Treatment-related changes in mouse liver, kidney, heart, testis and brain were confirmed by H & E histology analyses in the group of K2TeO3 (1.25 mg/kg) as compared to the control group.
In the kidney, focally mild infiltration of mononuclear inflammatory cells especially lymphocytes around the tubules and epithelial cells degeneration of medullary tubules were observed. In the testis, sever testicular damage as immature and mature spermatocytes necrosis or disorganization and sloughing of the stages of the spermatogenesis were indicated. In the brain, neuronal vacuolization, reactive astrocytes proliferation, mild edema in cerebral cortex and some necrotic neurons defined as pyknotic nuclei and eosinophilic cytoplasm in cerebral cortex and hippocampel region CA1 were seen. In the liver, sinusoidal congestion, bile stasis, congestion of dilated central veins, hydropic degeneration, focal mild lobular and moderate portal chronic inflammatory cells infiltration and edema in portal area were indicated. In the heart, edema in the space between muscle fibers were observed.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Lipid peroxidase:
There were significant increase in these indexes in mouse liver, heart and brain following treatment with K2TeO3 (1.25 mg/kg), when compared with the control. Furthermore, the highest increase in MDA level was found in mouse kidney and testis after 14 days treatment with K2TeO3 at the dose of 1.25 mg/kg (both kidney and testis) as compared to the control.
Glutathione content:
There were significant reduction in these indexes in mouse liver, kidney, testis and brain in K2TeO3 group (1.25 mg/kg), when compared with the control group. Also, in mouse heart a significant decrease in GSH level was found following K2TeO3 treatment at the dose of 1.25 mg/kg as compared to the control.
Super oxide dismutase (SOD) activity:
There were significant reduction in these indexes in mouse liver, kidney and testis in the K2TeO3 group at the dose of 1.25 mg/kg, when compared with the control. In addition, significant decrease in SOD activity was found in mouse heart and brain tissue after 14 days treatment with K2TeO3 (1.25 mg/kg), when compared with the control group.
Catalase (CAT) activity:
There were significant decrease in these indexes in mouse liver, heart and brain in the K2TeO3 group at the dose of 1.25 mg/kg. Significant decrease in CAT activity was found in mouse kidney and testis tissue following 14 days treatment with K2TeO3 at the dose of 1.25 mg/kg (both kidney and testis p < 0.001) when compared with the control.

Dose descriptor:

LOAEL

Effect level:

1.25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical biochemistry

histopathology: non-neoplastic

serum/plasma biochemistry

Conclusions:

Mild to severe histopathological changes in kidney, testis, brain, liver and heart after the 14 days exposure to K2TeO3 (1.25 mg/kg) were observed as well as increased marker level indicating organ toxicity. The organ changes were indicated to be permanent and induced by oxidative stress in line with signs of systemic toxicity. Based on these results a LOAEL of 1.25 mg/kg bw/day can be derived.

Executive summary:

In the present study, thirty male mice were randomly distributed into five groups of six mice per group. The first group (control) was administrated DW orally, and the fifth group received K2TeO3 at the dose of 1/10 LD50 (= 12.5 mg/kg) or 1.25 mg/kg upon oral administration once per day for 14 consecutive days. Furthermore, the mice were weighted once daily for 14 consecutive days. The experimental design involved certain general toxicological, haematological, serum and histopathological investigations.

Signs of systemic toxicity were evident by a reduction of the mean body weight following treatment with K2TeO3 as compared to the concurrent control group.

Liver toxicity was observed, as shown by histopathological changes as well as significant elevation of liver enzyme activities such as ALT, AST and ALP following exposure to K2TeO3.

Urea and Cr, as biomarkers of kidney functions, also significantly increased following subacute oral administration of K2TeO3 at the dose of 1.25 mg/kg indicating renal toxicity, expected to have likely occurred after 14 days treatment.

Also, the CPK levels were significantly elevated following 14 days treatment with K2TeO3 and this enhancement may be in accordance with heart, brain and skeletal muscle injury.

Moreover, the data showed markedly increased MDA level, accompanied by depletion of GSH, CAT and SOD activities following administration of K2TeO3, which are known to be biomarkers for ROS. Thus, it was suggested that oxidative stress was the underlying mechanism of organ toxicity inducted by K2TeO3. In addition, these results showed that intoxication of heart and brain was less than that of kidney, testis and liver organs.

Overall, mild to severe histopathological changes in kidney, testis, brain, liver and heart after the 14 days exposure to K2TeO3 (1.25 mg/kg) were observed, which were indicated to be permanent and induced by oxidative stress in line with signs of systemic toxicity. Based on these results a LOAEL of 1.25 mg/kg bw/day can be derived.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

15 days subacute exposure

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

no information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: lack of parameters investigated, not assignable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

The aim of the present study was to evaluate the hepatotoxicity of inorganic Te compound. Sodium tellurite 4.15, 8.3 and 16.6 mg/kg (1/20, 1/10 and 1/5 of LD50, respectively) was given to male Wistar rats orally in saline for a period of 15 days. On day 16, the blood was collected and the livers were dissected out for biochemical assays.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Sodium tellurite was purchased from Sigma-Aldrich, Co., Germany

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

The male Wistar rats 200-220 g were taken from the Animal House of Jazan University, Jazan, Kingdom of Saudi Arabia.

Route of administration:

oral: unspecified

Vehicle:

physiological saline

Details on oral exposure:

The animals were divided into four groups each having 8 animals. Group 1 was control group and vehicle (saline) was given orally. Groups 2-4 were experimental and sodium telluride 4.15, 8.3 and 16.6 mg/kg bw (1/20, 1/10 and 1/5 of LD50, respectively; oral LD50 in rat is 83 mg/kg) were given orally in saline for 15 days.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

for 15 consecutive days

Frequency of treatment:

daily

Dose / conc.:

4.15 mg/kg bw/day (nominal)

Remarks:

equivalent to 2.4 mg Te/kg bw/d

Dose / conc.:

8.3 mg/kg bw/day (nominal)

Remarks:

equivalent to 4.8 mg Te/kg bw/d

Dose / conc.:

16.6 mg/kg bw/day (nominal)

Remarks:

equivalent to 9.6 mg Te/kg bw/d

No. of animals per sex per dose:

8 male rat/group

Control animals:

yes, concurrent vehicle

Details on study design:

Animals were given saline or sodium tellurite in saline for 15 days. On day 16, blood was taken out from orbital sinus of overnight fasted animals from each group for biochemical assays. Thereafter, animals were sacrificed and liver of each animal was dissected out. Liver was homogenized and processed. Thereby, the post mitochondrial supernatant (PMS) was used for the assays of GSH, GPx, GR, GST, SOD and CAT.

Positive control:

none

Observations and examinations performed and frequency:

On day 16, blood was taken out from orbital sinus of overnight fasted animals from each group for biochemical assays. Thereafter, animals were sacrificed and liver of each animal was dissected out. Subsequently, serum markers bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were measured.

Other examinations:

A 10% homogenate of the liver was prepared in 20 mM Tris-HCl (pH 7.4, having protease inhibitors 10 μl/mL). The homogenate was centrifuged at 800 x g for 5 min at 4°C to remove cell debris. The supernatant- 1 (S-1) was used for lipid peroxidation and
rest of the S-1 was again centrifuged at 10,500 x g for 30 min at 4 °C to separate the post mitochondrial supernatant (PMS). The PMS was used for the assays of GSH, GPx, GR, GST, SOD and CAT.
For the assays of all serum markers such as bilirubin, AST, ALT and ALP the kits of Human Gesellschaft fur Biochemical and Diagnostic were used.
Also, non enzymatic assays and assays of antioxidant enzymes were conducted (i.e. LPO, GSH and GPx, GR, GST, CAT, SOD). For details see any other information on materials and methods.

Statistics:

The one-way ANOVA and post hoc Dunnett's test were used for the significance and p < 0.05 was considered as significant.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

The content of bilirubin was increased significantly (*p < 0.05, **p < 0.001) and dose dependently in the serum of the rats treated with various doses of Te as compared to control group. Administration of Te to rats caused significant elevation (*p < 0.001) on the activities of AST and ALT in the serum. The activity of alkaline phosphatase (ALP) was increased significantly (**p < 0.001) and dose dependently in the serum of rats.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

The level of TBARS was increased significantly (*p < 0.05; **p < 0.01 and ***p < 0.001) and dose dependently in Te treated groups as compared to control group.
The content of GSH was decreased significantly (*p < 0.05 and **p < 0.001) and dose dependently in Te treated groups as compared to control group. Also, the activity of NADPH dependent antioxidant enzymes; GPx and GR was decreased significantly
(*p < 0.05; **p < 0.01 and ***p < 0.001) and dose-dependently in the PMS of the liver of Te treated groups as compared to control group as well as the activity of GST (*p < 0.01 and **p < 0.001). The activity of other antioxidant enzymes such
as SOD (*p < 0.01 and **p < 0.01) and CAT (*p < 0.05 and**p < 0.01 and ***p <0.001) were also decreased significantly and dose dependently in Te treated groups as compared to control group.

Dose descriptor:

LOEL

Effect level:

4.15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

serum/plasma biochemistry

Remarks on result:

other: no assessment of adversity possible due to missing information

Conclusions:

The authors concluded that Te accelerated hepatotoxicity and oxidative stress in liver tissue of rats as evident by increase of hepatotoxicity biomarkers [bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)] and thiobarbituric reactive substances as well as decrease of the content of glutathione and activities of antioxidant enzymes.

Executive summary:

The aim of the present study was to evaluate the hepatotoxicity of inorganic Te compound.

Sodium tellurite 4.15, 8.3 and 16.6 mg/kg (1/20, 1/10 and 1/5 of LD50, respectively) was given to male Wistar rats orally in saline for a period of 15 days. On day 16, the blood was collected and the livers were dissected out for biochemical assays.

The hepatotoxicity biomarkers [bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)] were elevated significantly at 4.15 mg/kg sodium tellurite and increased dose dependently in the serum of Te treated groups as compared to control group. The content of thiobarbituric reactive substances in Te treated groups was increased significantly following exposure to sodium tellurite at 4.15 mg/kg and increased dose-dependently as compared to control group. Conversely, the content of glutathione and activities of antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione-S-transferase, superoxide dismutase and catalase) were decreased significantly in all Te treated groups as compared to control group.

The authors concluded that Te accelerated hepatotoxicity and oxidative stress in liver tissue of rats.

However, as information is missing on several other parameters, including the general health of animals (i.e. clinical signs, signs of systemic toxicity, body weight, etc.) and information regarding the state of the tissue investigated, an assessment of the adversity of the reported effects is not possible.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

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

In a toxicity study according to OECD guideline 407, tellurium dioxide was administered to groups of 5 Wistar rats by gavage at dose levels of 0, 25, 120 and 600 mg/kg/day.A recovery group was observed for additional 14 days.

Treatment at 600 mg/kg/day caused clinical signs, body weight loss and reduction of mean body weight gain by 66% in males and 90% in females, lower platelet counts in both sexes, black/grey discoloration/foci were observed in the variety of organs, increase in liver and spleen weights and lower thymus weights in both sexes, centrilobular/periportal or diffuse hepatocellular vacuolation associated with mainly minimal mononuclear cell infiltrate in liver, mild lymphoid atrophy accompanied with minimal to mild increased apoptosis of lymphocyte in the thymus, moderate diffuse epithelial atrophy in the vagina. Following 14-day recovery period, signs of reversibility were observed, however no histopathology examination was performed.

Treatment at 120 mg/kg/day was associated with slight clinical signs, including transient weakness of the hind limbs in males, reduction of body weight gain by 35% in males and 14% in females, mild lymphoid atrophy accompanied with minimal to mild increased apoptosis of lymphocyte in thymus in one female.

Treatment at 25 mg/kg/day was associated with lower mean body weight by approximately 8% and overall (Days 0-27) body weight gain by approximately 21% in males.

In conclusion, the NOAEL of tellurium dioxide administered by oral gavage to Wistar rats for 28 consecutive days is considered to be the low-dose level of 25 mg/kg/day for females. For males the low dose of 25 mg/kg/day was considered to be the LOAEL, based on reduced body weight gain (21%).

In the subsequent 90-day oral toxicity study (OECD 408), Tellurium dioxide was administered to groups of 10 Wistar rats (males and females) by gavage at dose levels of 0, 10, 30 and 100 mg/kg/day. At the highest dose and the control, an additional recovery group with 5 animals was observed for 4 weeks.

Slight signs of treatment-related effets (clinical signs, reduction in body weight and food consumption) were observed during the in-vivo phase of the study, mainly at the high dose level of 100mg/kg/day and, with a lower extent at the mid-dose level of 30 mg/kg/day. At microscopic examination, changes were observed at the end of the treatment period in the liver of animals dosed at ≥ 10 mg/kg/day. However, these changes were no longer present at the end of the recovery period. Although the changes were observed at all the dose levels investigated with a dose related trend, they were completely reversible and, as such, they were not considered to be adverse. 

Therefore, it was concluded that the NOAEL for this study is 100 mg/kg/day.

For extrapolation of a NAEL for repeated dose toxicity refer to the attached Expert Statement.

Justification for read-across is outlined in the attached document.