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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across from an acceptable, well-documented publication, which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Teratogenicity of Tellurium dioxide in the Wistar rat: prenatal assessment
Author:
Perez-D’Gregorio RE et al
Year:
1988
Bibliographic source:
Teratology, 37/4, 307-16 (1988)

Materials and methods

Principles of method if other than guideline:
Developmental toxicity study, rats were exposed subcoutaneous from day 15 to 19 of gestation.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Tellurium dioxide (TeO2) 99.99 % purity, lot 0908PH Aldrich Chemical Company

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Biological Laboratories, Wilmengotn, MA
- Age at study initiation: no data
- Weight at study initiation: 170 – 200 g
- Fasting period before study: no data
- Housing: Dams recognized as pregnant were housed individually in standard plastic cages on Pine-Dri shavings.
- Diet (e.g. ad libitum): Purina Chow 5001 ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C
- Humidity (%): 40 -50 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hour dark/light cycle

Administration / exposure

Route of administration:
subcutaneous
Vehicle:
olive oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Tellurium dioxide was suspended in olive oil given as 1 mL/kg maternal body weight
Details on mating procedure:
Rats were bred by individual housing with a male overnight.
Day zero for pregnancy was determined by the presence of sperm plugs in cage debris.
Duration of treatment / exposure:
females: day 15 to 19 of gestation
Frequency of treatment:
females daily from day 15 to 19 of gestation
Duration of test:
At day 20 dams were euthanatized by ether
No. of animals per sex per dose:
10 dams per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: No details reported; previously published information was taken into account.

Examinations

Maternal examinations:
Maternal toxicity was evaluated by using the following parameters: maternal lethality, gross morphological changes, body weight changes during the period of exposure and histological evaluation of kidney and liver at day 20 of gestation.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: no
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
The viability of the fetuses was determined by the presence of spontaneous breathing or response to a tactile stimulus.

Live fetuses were killed by CO2 and assigned for soft-tissue examination; half were scheduled for fresh internal exam and the other half for the Wilson section technique (Wilson, ´64). All dead pups were analyzed via the Wilson technique.

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: 2 per litter
Statistics:
The litter was used as the experimental unit. Normality test was performed by the Kolmogorov – Smirnov test (Massey, ´51). Comparison of normally distributed groups of parametric data was performed by one-way analysis of variance (ANOVA) (Armitage, ´71). A significant F value in the ANOVA was followed by the unpaired Student´s t-test to establish which groups differ significantly from controls.
Historical control data:
no information

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
In this study, doses of 500 and 1000 µmol /kg of TeO2 were maternally toxic. This toxicity was expressed as weight loss, centrolobular fatty change in the liver, and as a 40% lethally (4/10) at the highest dose. Neither maternal weight loss nor liver changes were found in the 10 and 100µmol/kg group.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
100 other: µmol/kg bw/d Tellurium as Tellurium dioxide
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At 500 and 100 µmol/kg 11 and 81 % fetal mortality rates were recorded. No fetal mortality was observed in the other exposure groups.
A dose-related decrease in fetal weight was observed.
A dose-related decrease in fetal size was observed. This decrease was particularly evident when body length was compared among groups. A significant increase in the measurements at the level of the neck was observed at doses of 100 and 500 µmol/kg. This increase in diameter could be explained ba the presence of soft tissue with many skin folds which are very easily distensible; thus edema could be documented.

The presence of abnormal accumulation of fluid in the subcutis was recorded as edema during the external examination. This process of fluid accumulation, which produced a subsequent distention of the sin and generalized deformity, was corroborated after fixation of the fetuses in Bouin´s solution.

Edema was externally evident in fetuses posed to TeO2 at doses ≥ 100 µmol/kg and the severity of this process was dose-related. No edema was observed at 10 µmol/kg dose or in the control groups.
Fetuses with dilation of the cerebral ventricles were considered hydrocephalic. The hydrocephalus in all cases was defined as communicating. This hydrocephalus was observed to be expansion of all cavities in the CSF pathways and no obstruction within the brain itself as determined in sagittal section of brains. There was 100 % incidence of this phenomenon in animals exposed to doses ≥ 100 µmol/kg. different degrees of hydrocephalus were noted, from moderate ventricular dilation with a thick cortical area at 100mmol/kg level, to severe cases at 500 and 1000 µmol/kg dose, where the cortex was reduced to a very thin layer. This severity was dose related. Hydrocephalus was not observed upon fetal examination at the 10 µmol/kg dose or in the controls.
Open eyes were noted in fetuses exposed to TeO2 at dosed ≥ 500 µmol/kg. Cases in which the eye was externally protruded were classified as exophthalmia. Ocular hemorrhage was also present in fetuses exposed to 100 µmol/kg where no open eyes were observed. None of these abnormalities was observed at the 10 µmol/kg level and controls.

Internal examination of the pelvis revealed the presence of small kidneys and undescended testis in day 20 fetuses. Both of these effects were dose related. The presence of intestine in the umbilical cord and subsequent distension of this structure were recorded as umbilical hernia. This herniation was present in some fetuses exposed to ≥ 500 µmol/kg.

Skeletal analysis was unremarkable.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
10 other: µmol/kg bw/d Tellurium as Tellurium dioxide
Based on:
act. ingr.
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL (F1 generation) for developmental toxicity for male/female off-spring: NOAEL 10 µMol/kg bw/d as Tellurium dioxide
The most prominent effects were observation of hydrocephalus followed by increase in fetal mortality at higher doses.
The adverse effects on the fetuses were also observed without evidence of maternal toxicity.
Executive summary:

The following information was considered relevant and is cited from the publication:

"The effects of multiple maternal subcutaneous injections of Tellurium dioxide (TeO2) suspended in olive oil (0-1,000 μMol/kg) from day 15 to day 19 of gestation were evaluated in the Wistar rat.

External and internal soft-tissue examinations were performed on day 20 fetuses. Multiple maternal injections, at doses higher than 10 μMol/kg, resulted in a dose-related appearance of hydrocephalus, edema, exophthalmia, ocular hemorrhage, umbilical hernia, undescended testis, and small kidneys in fetuses on day 20 of gestation.

 

At 500 μMol/kg, reduction in maternal weight gain was also observed. At this level, the incidence of the above anomalies was 100 %. The 100 μMol/kg dose of Tellurium, which did not produce apparent maternal toxic responses, resulted in a 100 % incidence of hydrocephalus and edema but no fetal mortality. Thus, Tellurium can be teratogenic to the rat fetus without concomitant maternal toxicity.

Also, the fetal period may be more sensitive than the organogenic period for the induction of hydrocephalus. Such evidence is consistent with the development of the choroid plexus and an effect of TeO2 on the production/resorption of cerebrospinal fluid."