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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2012-10-08 to 2012-11-19 (in-life phase)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across from a guideline study with GLP
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes (incl. certificate)
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633, from SPF colony
- Age at study initiation: Young adult rats, approximately 7-8 weeks old
- Weight at study initiation: Males: 234-253 g, Females: 174-204 g
- Fasting period before study: no data
- Housing: Standard laboratory conditions during the study, Type III polycarbonate cage, up to 5 animals of the same sex and group/cage.
- Diet (e.g. ad libitum): ssniff® SM R/M-Z+H ad libitum
- Water (e.g. ad libitum): tap water from municipal supply ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.2 – 23.8 °C
- Humidity (%): 30 - 62 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): light 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Route of administration:
oral: gavage
Vehicle:
other: 1% aqueous Methylcellulose
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): 1% aqueous Methylcellulose (abbreviation: 1% MC) was used as vehicle.
- Concentration in vehicle:
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. (if required): O16147824 (Dow Chemicals)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of test item formulations for concentration and homogeneity was performed two times during the treatment period (during the first and
last weeks of treatment), using a validated ICP method based on the tellurium content.
Duration of treatment / exposure:
28 days
Frequency of treatment:
7 days/week
Remarks:
Doses / Concentrations:
0 mg/kg bw/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
25 mg/kg bw/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
120 mg/kg bw/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
600 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
5 animals/ sex/ dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were set based on available data and information from previous experimental work, including the results of a preliminary dose range finding study
- Rationale for animal assignment (if not random): randomization based on body weights
- Rationale for selecting satellite groups: to assess the reversibility of any changes
- Post-exposure recovery period in satellite groups: 14-day
Positive control:
No positive control
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily. General clinical observations were made daily, after treatment.
- Cage side observations: Animals were inspected for signs of morbidity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before the first treatment and weekly thereafter.
Observation was performed on the skin, fur, eyes and mucous membranes, autonomic activity (lachrymation, piloerection, pupil size, respiratory pattern, occurrence of secretions and excretions), circulatory and central nervous system, somatomotor activity and behaviour pattern, changes in gait, posture and response to handling.
Special attention was directed towards the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weight was recorded on Days 0, 7, 14, 18, 21, 25 and 27.
During the recovery period, body weight was measured twice weekly.
Before scheduled necropsy the animals were weighed following overnight food deprivation.

FOOD CONSUMPTION AND COMPOUND INTAKE :
Animal food consumption was determined by re-weighing the non-consumed diet with a precision of 1 g on Day 7 then weekly.
The weekly and mean daily food consumption was calculated.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE : No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: collected immediately prior to the scheduled necropsy
- Anaesthetic used for blood collection: Yes (identity): cardiac puncture under pentobarbital anaesthesia
- Animals fasted: Yes, overnight period of food deprivation
- How many animals: all surving animals
- Parameters checked in table below were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: collected immediately prior to the scheduled necropsy
- Animals fasted: Yes, overnight period of food deprivation
- How many animals: all surving animals
- Parameters checked in table below were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During the last week of the treatment period
The examination was repeated on the Recovery Group animals (on Day 39), due to possible changes observed during the Irwin screen conducted on Day 22 and the grip strength measurements in males by the end of the treatment period.
- Dose groups that were examined: each animal
- Battery of functions tested: sensory activity / grip strength / motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table) Gross necropsy was performed on each animal irrespective of the date of death
HISTOPATHOLOGY: Yes (see table) Full histopathology was performed in Control and High Dose Groups animals.
All macroscopic abnormalities in other groups were also examined.
Other examinations:
Examination of vaginal smears
Prior to necropsy, the oestrus cycle of all females was determined by taking vaginal smears, which were prepared and stained with 1% aqueous methylene blue solution. The smear was examined with a light microscope, in order to provide information regarding the stage of oestrus cycle at the time
of sacrifice and assist in histological evaluation of oestrogen sensitive tissues.

Statistics:
The statistical analysis was performed using SPSS PC+4.0 software. The heterogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected, a one-way analysis of variance was carried out. If the obtained result was positive, Duncan’s Multiple Range test was used to assess the significance of inter-group differences. Where significant heterogeneity is found, the normal distribution of data was examined by Kolmogorov-Smirnov test. If the data were not normal distributed, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was used. If there was a positive result, the inter-group comparisons were performed using Mann-Whitney U-test.
Recovery groups were compared using Student T-test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
One High dose female treated at 600 mg/kg bw/day was found dead on Day 24. Clinical signs (hunched posture, piloerection and moderately
decreased activity) and marked body weight loss preceded the death of this animal.

Clinical signs were observed in males and females treated at 120 and 600 mg/kg/day.
At 600 mg/kg/day, clinical signs were noted from Day 3 (males) and Day 2 (females) and included hunched back, piloerection, dark faeces, soft faeces and decreased activity. From Day 10 (4 of 10 males) and Day 22 (1 of 10 female), transient weakness in the hind limbs was also observed. With the exception of dark faeces, the signs were not seen in all animals on each occasion. Following the end of the treatment period the clinical signs ceased although decreased activity, piloerection were still observed for 2-3 days, and hunched posture for 5-7 days. The animals were symptom-free from Day 33 (males) and Day 35 (females).
At 120 mg/kg/day, dark faeces was noted in all animals, transient weakness in the hind limbs was observed only in males (4 of 5) and hunched back was noted occasionally in one male and female.
No clinical signs were observed during the study at 25 mg/kg/day.

BODY WEIGHT AND WEIGHT GAIN
Treatment at 600 mg/kg/day affected body weight gain in both sexes (body weight loss in 3 of 10 males and in 4 of 10 females) resulting in terminal body weights lower by 26-20% and reduction of body weight gain by 66% in males and 90% in females.
Treatment at 120 mg/kg/day caused a reduction in body weight gain by 35% in males and 14% in females. The effect in females was attributed to body weight gain suppression of one animal.
Males at 25 mg/kg/day had slightly lower mean body weight by approximately 8% and overall (Days 0-27) body weight gain by approximately 21%. In one male, slight body weight loss (7%) was noted between Days 25-27. No effect on body weight was observed in females.
Significantly higher body weight gain was observed for both males and females during the 14-day recovery period, indicating reversibility of the effect, however the terminal body weight of males was lower by 15% than control mean.

FOOD CONSUMPTION AND COMPOUND INTAKE
The mean daily food consumption was lower than controls at 120 and 600 mg/kg/day (both sexes) throughout entire treatment period and in males at 25 mg/kg/day during the last week of the treatment period.

HAEMATOLOGY
At 600 mg/kg/day, lower mean platelet count, lower relative lymphocyte count with concomitantly higher relative neutrophil granulocyte count was noted in both males and females and lower relative eosinophil granulocyte count was noted in females.
In females only, a slight decrease in APPT was also noted.
Following the 14-day recovery period slightly increased relative reticulocyte count and higher erythrocyte volume distribution width were recorded in both males and females. In addition, in males slightly lower haematocrit value, slightly lower lymphocyte and higher relative monocyte counts were measured.

CLINICAL CHEMISTRY
Clinical chemistry parameters evaluated on Day 28 were comparable with the controls in all groups of males, except individual values of one male at 600 mg/kg/day. In this animal elevated transaminases (ALT and AST), alkaline phosphatase and gamma GT activity, increased total bilirubin and bile acid concentration and decreased serum creatinine were found.
For females at 600 mg/kg, slightly increased aspartate aminotransferase activity (AST) activity, higher bile acid, slightly higher triglycerides, glucose, urea and sodium concentration was recorded. Slightly higher bile acid and urea concentration was found also at 120 mg/kg.
Following the 14-day recovery period, the above parameters were comparable with the control. Higher phosphorus concentration was measured for both sexes and slightly higher calcium concentration was found in females.

NEUROBEHAVIOUR
During neurological assessment on Day 22, slight differences were recorded for animals treated at 600 mg/kg/day. Findings observed in the Irwin screen included lower performance in the transfer arousal and touch escape response, slightly decreased body tone score or an increased piloerection score in females only and were attributable to poor condition of the animals.
Compared to controls, lower values in grip strength tests were recorded for males and in a few females and were in agreement with observed
transient weakness of the hind limbs. No differences were recorded on Day 39.

ORGAN WEIGHTS
At 600 mg/kg/day higher liver weights (20% in males and 38% in females for body weight relative values) and spleen weights (42-43% for body weight relative values) and lower thymus weights (34-40% for brain relative values) were observed.

GROSS PATHOLOGY
At necropsy on Day 28, black/grey discoloration/foci were observed in a number of organs, including the adrenal gland, brain, stomach, intestines, thymus, mesenteric lymph node and testis. Pale discoloration of the liver in 1 of 5 High dose male, small thymus in 1 of 5 High dose male, 1 of 5 Mid dose female and 2 of 4 High dose females were seen and also corresponded with organ weight changes.

HISTOPATHOLOGY: NON-NEOPLASTIC
Test-item related microscopic findings were observed in the liver, thymus and vagina at a dose level of 600 mg/kg bw.
In the liver, mild or marked (predominantly mild) centrilobular/periportal or diffuse hepatocellular vacuolation was seen in 5 of 5 males and 4 of 4 females associated with mainly minimal mononuclear cell infiltrate. In one male, mild hepatocellular necrosis and increased mitotic activity were also recorded.
In the thymus, mild lymphoid atrophy in 1 of 5 males and 2 of 4 females was in correlation with organ weight changes. Atrophic changes were accompanied with minimal to mild increased apoptosis of lymphocyte in 3 of 5 males and 3 of 4 females. Similar change was observed in one female at 120 mg/kg/day.
The evidence of both findings among animals likely indicated a combined effect of the test item administration (atrophy) and secondary stress (apoptosis) associated with decreased food consumption and body weight gain, increased neutrophils and decreased lymphocytes (stress leukogram) in haematology data of the affected animals.

In 2 of 4 High dose females, moderate diffuse epithelial atrophy of the vagina was noted.


Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
LOAEL
Effect level:
25 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: Based on effects on body weight gain at the low dose of 25 mg/kg bw/d no NOAEL could be identified. Lower mean body weight by approximately 8% and overall (Days 0-27) body weight gain by approximately 21%.
Critical effects observed:
not specified

DOSE FORMULATION ANALYSIS

Test item content and homogeneity of the dosing formulations was determined twice during the treatment period (during the first and the last weeks of the treatment). No test item was detected in the Control solution samples. All formulations were shown to be homogeneous. All formulations were found to be in the range of 94 to 104% of nominal concentrations. Based on these results, test item formulations were considered suitable for the study purposes.

Conclusions:
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%).

Executive summary:

In a subchronic 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%).

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
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

Mode of Action Analysis / Human Relevance Framework

Additional information

In a subchronic 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%).

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.

Justification for classification or non-classification