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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-05-01 to 2012-05-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study This study is only a dose range finder for a prenatal developmental toxicity study (OECD guideline 414).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(adopted 2001-01-22)
Deviations:
yes
Remarks:
since this is only a dose range finder not enough animals and not all parameters of a full study were examined.
GLP compliance:
yes (incl. QA statement)
Remarks:
signed 2009-11-12
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium hexahydroxoantimonate
EC Number:
251-735-0
EC Name:
Sodium hexahydroxoantimonate
Cas Number:
33908-66-6
Molecular formula:
NaSb(OH)6
IUPAC Name:
sodium hexahydroxoantimonate
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): Sodium hexahydroxoantimonate
- Molecular formula: NaSb(OH)6
- Molecular weight: 246.75 g/mol
- Physical state: white, odourless, crystalline solid inorganic powder
- Storage condition of test material: at room temperature, in tightly closed containers in a well-ventilated place
- Melting point: >600°C
- Boiling point: >600°C
- Water solubility: 594 mg/L at 20°C

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at day 0 of pregnancy: 8 to 9 weeks
- Weight at day 0 of pregnancy: 200.8 – 221.8 g
- Housing: except during the mating period, the dams were kept singly in MAKROLON cages (type III plus) with a basal surface of approx. 39 cm x 23 cm and a height of approx. 18 cm. Granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt/ Arkeburg, Germany) was used as bedding material in the cages.
- Diet (ad libitum): commercial ssniff® R-Z V1324 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany); Food residue was removed and weighed.
- Water (ad libitum): tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C ± 3°C (maximum range)
- Humidity: 55% ± 15% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.8% aqueous hydroxypropylmethylcellulose gel
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was suspended in the vehicle to the appropriate concentrations and was administered orally at a constant volume of 2 mL/kg bw to the animals once daily.
The dose of the test item was adjusted to the animal's body weight daily.
The control animals received the vehicle at a constant volume of 2 mL/kg bw orally once daily in the same way.
The test item-vehicle preparations were freshly prepared every day.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
not applicable
Details on mating procedure:
Sexually mature ('proved') male rats of the same breed served as partners.
- Impregnation procedure: cohoused
- M/F ratio per cage: 1 male and 1 female
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Day 6 to 19 of pregnancy
Frequency of treatment:
once daily
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
2 female rats
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dose levels of 100, 300 and 1000 mg sodium hexahydroxoantimonate/kg bw/day had been selected in agreement with the Sponsor.
The dose levels had been selected based on a lack of acute oral toxicity (LD50 > 2000 mg/kg bw), an assumed poor oral availability (<1%), the understanding that pentavalent Sb substances are considered less toxic than trivalent Sb substances which had been tested up to doses of >1000 mg/kg bw/day in rats for 90 days without signs of overt toxicity.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations checked: any signs of behavioural changes, changes of external appearance or faeces
Further checks were made early in each working day and again in the afternoon to look for dead or moribund animals.
Animals showing signs of abortion or premature delivery were sacrificed on the same day. Foetuses obtained this way were examined for abnormal development whenever possible.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: on day 0 of gestation (the day of detection of a positive mating sign), followed by daily weighings - always at the same time of theday.
The body weight gain was calculated in intervals (i.e. 0-3, 3-6, 6-9, 9-12, 12-15, 15-18, 18-20). Furthermore the net weight change* from day 6 is given.

* net weight change from day 6 = carcass weight minus day 6 body weight carcass weight = terminal body weight minus uterine weight

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
The quantity of food consumed by each rat was recorded. The absolute food intake per rat (g/rat/day) was calculated using the total amount of food given to and left by each rat in each group on completion of a treatment day.
The relative food consumption (g/kg bw/day) was calculated using the following formula:
Daily food consumption [g/kg bw/day] = total food intake in g/body weight in kg
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily monitoring by visual appraisal

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: a dissection with macroscopic examination of the internal organs and placentae of the dams was carried out. In case of macroscopical findings, the affected organs were prepared in 7% buffered formalin for possible future histopathological examinations.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- number and weight of placentae was determined.
- location of foetuses
- number of foetuses (alive and dead) was determined.
Fetal examinations:
1) External examinations: Yes, especially for malformations
- sex and viability of foetuses were determined.
- weight of foetuses
2) Soft tissue examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
- Skeletal examinations: No
- Head examinations: No
Statistics:
No statistical analysis was conducted as only 2 animals/group were evaluated.
Indices:
Malformation rate per group [%] = (malformed foetuses/foetuses) x 100
Variation rate per group [%] = (foetuses with variations/foetuses) x 100
Pre-implantation loss [%] = (corpora lutea - implantations/corpora lutea)/ x 100
Post-implantation loss [%] = ((implantations - living foetuses)/implantations)/ x 100

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
- no premature deaths were noted in the dams treated orally with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day.
- no test item-related changes of behaviour or external appearance were noted in the dams treated orally with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day.
- no test item-related influence was noted on the body weight of the dams treated with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day.
- no test item-related influence was observed on the food intake of the dams treated with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day.
- visual appraisal of the drinking water consumption revealed no differences between the control and the test item-treated rats.
- no test item-related influence was noted on the gravid uterus weight, the carcass weight and the net weight change from day 6 onwards (carcass weight minus day 6 body weight) of the two evaluated dams/group treated with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day.
- no test item-related influence on the prenatal fetal development was detected at 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day with respect to the number of corpora lutea, implantation sites, resorptions and live foetuses or the values calculated for the pre- and post-implantation losses. The differences observed in comparison to the control are without any biological relevance.
- no test item-related findings at necropsy were noted in the female animals treated with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- no dead foetuses were noted at any tested dose level nor in the control group at laparotomy.
- sex distribution of the foetuses in test groups 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day was comparable with that of the control
foetuses. The differences observed in comparison to the control are without any biological relevance.
- mean placental weights in the test groups 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day were not influenced by the administration of the test item to the dams as compared to the control groups.
- mean foetal weights were not influenced by the administration of 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day to the dams as compared to the control group.
- no test item-related differences between the control and the test groups 100, 300 and 1000 mg/kg bw/day concerning external malformations and variations.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
external malformations

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL (maternal toxicity) > 1000 mg/kg bw/day
NOAEL (developmental toxicity) > 1000 mg/kg bw/day
Based on the data obtained in this dose-range-finding study, the following dose levels were selected for a prenatal developmental toxicity study of sodium hexahydroxoantimonate in rats (please refer to the Endpoint study record k_Hansen_2013): 100, 300 and 1000 mg/kg bw/day.

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