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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:
Unnamed
Year:
1988

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tellurium lumps
- Substance type: element
- Analytical purity: 99.99 %, determined by atomic absorption spectroscopy

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Kingston, New York
- Age at study initiation: young adult
- Weight at study initiation: females 209 to 337 g
- Fasting period before study: no
- Housing: individually in wire-bottom cages
- Diet (e.g. ad libitum): Ralston Purina Certifieed Laboratory Animal Meal 5002 ad libitum, day 6 to 15 of gestation, feed containing the appropriate quantity of test substance
- Water (e.g. ad libitum): Reverse-osmosis treated local water ad libitum
- Acclimation period: no less than 6 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 +/- 2 °F (22.2 °C)
- Humidity (%): 55 +/- 10 %
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hrs light/dark cycle

Administration / exposure

Route of administration:
oral: feed
Details on exposure:

DIET PREPARATION
Tellurium lumps were ground by ball mill until the resulting powder would pass through a 325-mesh screen, indication a nominal particle diameter of less than 40 µm.
The sieved tellurium was mixed at the appropriate concentration with Certified Laboratrory Animal Meal 5002 from Ralston Purina Co in a drum tumbler.
The mixture of powdered feed and test aged was fed to rats as a powder.
Samples of each concentration were measured prior to use, and the analyses verified that, on the average, the tellurium content of the feed was within 2.7 % of the target value.
Individual milligrams per kilogram per day dosages consumed were calculated were calculated using the observed food consumption for the designated period divided by the average body weight during this period.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of each concentration were measured prior to use, and the analyses verified that, on the average, the tellurium content of the feed was within 2.7 % of the target value.
Details on mating procedure:
Females were mated with males of the same strain and Day 0 if gestation was considered as the day sperm were observed microscopically in a smear of vaginal contents.
Duration of treatment / exposure:
Gestation day 6 to 15; during day 0-5 and after day 15 feed from the same batch, lacking test substance was provided
Duration of test:
On day 20 of gestation two-thirds of the females in each dosage group were killed.
One-third of the females in each dosage group were permitted to deliver naturally. Dams and pubs were killed 7 days post partum.
No. of animals per sex per dose:
32 or 33 persumed pregnant femals rats per dose group
Control animals:
yes, plain diet

Examinations

Maternal examinations:
All animals were observed twice daily for clinical signs, and body weights were recorded seven or nine times during the acclimation period prior to mating, on Day 0 and daily during the dosage and post-dosage periods. Feed consumption was recorded for days 0 -5, 6 -10, 11 -16 and 17 -20.
Ovaries and uterine content:
The abdomen of each rat was opened, and the uterus was examined for number and placement of implantations, fetuses and early and late resorptions. Ovaries were preserved in 10 % neutral buffered formalin prior to microscopic examination to determine the number of corpora lutea. Maternal tissues were discarded after evaluation with the exception of gross lesions observed at caesarean sectioning, which were preserved in 10 % neutral-buffered formalin and retained for possible histologic evaluation.
Fetal examinations:
Each fetus was removed from the uterus, weighed, individually identified with a tag noting its litter and uterine placement, and examined for gender and gross external variations. Approximately one-half of the fetuses in each litter were fixed in Bouin´s solution and examined for soft tissue anomalies using a variation of Wilson´s sectioning technique. The remainder of the fetuses in each litter were eviscerated, skinned, cleared and stained with alizarin red S, and examined for osseous skeletal status.
Heads of pubs which were stillborn, found dead or killed on postnatal Day 7 were fixed in Bouin´s solution and examined by means of multiple free-and cross sections at the level of the lateral ventricles.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No maternal death occurred. Maternal toxicity was evident by decreased body weight gain during gestation in the groups receiving 300, 3000 and 15,000 ppm. These effects were concentration dependent and statistically significant.
Adverse maternal clinical signs included thin appearance (3000 and 15,000 ppm dosage groups), pre-parturitional vaginal bleeding, and decreased motor activity. The observed incidences for thin appearance and pre-parturitional vaginal bleeding were significantly increased (at p ≤ 0.01 for the high dosage group, as compared with the vehicle control group.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
30 ppm
Based on:
test mat.
Remarks:
in diet
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Day 20 caesarean-delivered fetuses:
Compared to vehicle control animals, administration of the test agent to female rats did not affect the incidence of pregnancy, average numbers of
corpora lutea, implantations, live and dead fetuses, resorptions, or litter size.
Tellurium related effects observed in the fetuses from the 3000 and 15,000 ppm groups included dose-dependent decreased male fetal body weights, increased incidences of fetuses and litters with variations, malformed fetuses, and fetuses with delayed ossification. The most common malformation observed in these fetuses was internal hydrocephalus with light to marked dilation of the lateral ventricles.
More severely affected fetuses frequently also had slight to marked dilation of the third and/or fourth ventricles. Externally obvious hydrocephalus was observed only for two high-dosage group fetuses, one of which had an enlarged fontanelle bordered by a hemorrhagic area. Moderate dilation of the fetal renal pelvis was also associated with these two dosages. Other malformations occurred only in fetuses of dams receiving 15,000 ppm tellurium. These included kinked and/or stubbed tails, rotation of a hindlimb or hind foot, al malformed retina, mal-positioned manubrium and clavicles, short radius, ulna and/or femur, wavy ribs, and a thickened or split rib. Many of these fetuses from severely affected mothers also had delays in ossification of the parietals, interparietals, supraossipitals, vertebral and sternal centra, pubes, ischia, and/or ribs.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
300 ppm
Based on:
test mat.
Remarks:
in diet
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
18 mg/kg bw/day
Based on:
test mat.
Remarks:
in diet
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Naturally delivered pups:

Administration of tellurium to pregnant rats did not affect the duration of gestation. In naturally delivered litters, there were instances of stillbirth evident in each dosage group, but there was no clear dose-response relationship evident for this phenomenon that also occurred among untreated pregnancies. Pup viability during the 7-day post-parturition period was decreased to a statistically significant extent in the high-dose group. The high dosage group, as compared with the vehicle control group, had smaller litter sizes and decreased pup survival. Although not statistically significant (≤0.05), pup body weights per litter were slightly decreased in the 3000 and 15,000 ppm dosage groups as compared with the vehicle control on Day 7 postpartum. No gross, externals, or visceral anomalies were observed in pups sacrificed on Day 7 post-partum, but there was a significant increase (p≤0.01) in the incidence of slight to extreme dilation of the lateral ventricles in pups of dams that ate 15,000 ppm tellurium diet.

Applicant's summary and conclusion

Executive summary:

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

"The developmental toxicity of tellurium was evaluated in Crl Sprangue-Dawley rats and New Zealand white rabbits by means of standard segment II-type studies. Groups of pregnant rats were fed a diet containing 0, 30, 300, 3000, or 15000 ppm of tellurium on Days 6 through 15 of gestation (microscopic detection of sperm in a smear of vaginal contents considered as Day 0), and artificially inseminated rabbits were fed a diet containing 0, 17.5, 175, 1750, and 5250 ppm of tellurium during Days 6 through 18 of gestation (day of insemination considered as Day 0).

Signs of maternal toxicity were observed during the treatment period in a statistically significant and dose-related manner at dietary concentrations of 300 ppm and greater in rats and 1750 ppm and greater in rabbits. Exposure of these pregnant rats and rabbits to tellurium had no effect upon reproduction as measured by pregnancy rate, litter size, dead or resorbed implantations, or fetal sex ration. Both skeletal (primarily skeletal maturational delays) and soft tissue malformations (primarily hydrocephalus) were noted in the offspring of pregnant rats exposed to the highest levels (3000 and 15,000 ppm) of tellurium. Rabbit fetuses of the highest dosage group (5250 ppm) had a slightly elevated evidence of skeletal delays and nonspecific abnormalities."