Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-05-02 to 2012-05-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study This study is only a dose range finder for a 90 day repeated dose 90-day oral toxicity study in rodents (OECD guideline 408).

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
(adopted 1998-09-21)
Deviations:
yes
Remarks:
since this is only a dose range finder for a Repeated dose 90-day toxicity study not enough animals per dose group were tested and not all parameters were examined in this study, .
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 stibanylidyne hexahydroxide
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)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: males: 41 days, females: 41 days
- Weight at study initiation: males: 195.9 – 218.6 g, females: 129.8 – 147.0 g
- Housing: animals were kept singly in MAKROLON cages (type III plus) with a basal surface of approximately 39 cm x 23 cm and a height of approximately 18 cm. Granulated textured wood (Granulate A2, J. Brandenburg, 49424 Goldenstedt, Germany) was used as bedding material for the cages.
- Diet (ad libitum): commercial ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest,Germany); Food residue was removed and weighed.
- Water (ad libitum): drinking water
- Acclimation period: 7 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 oral 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.
The control animals received the vehicle at a constant volume of 2 mL/kg bw orally in the same way.
The application formulations were freshly prepared every day.
The amount of the test item was adjusted to the animal's current body weight
daily.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
For each test or reference item that is mixed with a vehicle, tests by appropriate analytical methods will be carried out for a 90-day repeated dose toxicity study (please refer to the Endpoint study record k_Hansen_2013_90 days) to determine the concentration, homogeneity and, if needed, stability of the test item in the formulations.
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5 males / 5 females
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 proposed doses had been selected on the basis of a lack of acute oral toxicity (LD50 > 2000 mg/kg b.w.), an assumed poor oral availability (<1%), the understanding that pentavalent Sb substances are considered less toxic than trivalent Sb substances, and the latter had been tested up to doses of >1000 mg/kg
bw/day in rats for 90 days without signs of overt toxicity.
Positive control:
not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations checked: cageside observations included skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns.
The animals were checked early in the morning of each working day and again in the afternoon to look for dead or moribund animals.

BODY WEIGHT: Yes
- Time schedule for examinations: at the time of group allocation, on the day of commencement of treatment and weekly thereafter always on the same day of the week throughout the experimental period.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/week: Yes
The quantity of food left by individual animals was recorded on a weekly basis throughout the experimental period. Food intake per rat (g/rat/week) was calculated using the total amount of food given to and left by each rat in each group on completion of a treatment week.
The relative food consumption (in g/kg bw/day) was determined using the following formula:
Relative food consumption (g/kg bw/day): (Total food given [g] - Total food left [g])/ (Number of animals days# x Body weight [kg])
#: The term 'animal days' counts one animal day for each animal alive for a whole day; it is assumed that on the day of death an animal does not eat.

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

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: Yes
- Time schedule for examinations: daily by visual appraisal

DETAILED CLINICAL OBSERVATIONS: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
On test day 29 (one day after the last administration), all animals were sacrificed under ether anaesthesia by cutting the aorta abdominalis, exsanguinated, weighed, dissected and inspected macroscopically.
All superficial tissues were examined visually and by palpation and the cranial roof was removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral midline incision and skin reflection all subcutaneous tissues were examined. The condition of the thoracic viscera was noted with due attention to the thymus, lymph nodes and heart.
The abdominal viscera were examined before and after removal, the urinary bladder was examined externally and by palpation. The gastro-intestinal tract was examined as a whole and the stomach and caecum were incised and examined. The lungs were removed and all pleural surfaces were examined under suitable illumination. The liver and the kidneys were examined. Any abnormalities in the appearance and size of the gonads, adrenal glands, uterus, intra-abdominal lymph nodes and accessory reproductive organs were recorded.

HISTOPATHOLOGY: No
Statistics:
The test item-treated groups were compared with the control group.
The following statistical method was used:
1) Multiple t-test based on DUNNETT, C. W. New tables for multiple comparisons with a control Biometrics, 482-491 (Sept 1964): Body weight / Food consumption (p ≤ 0.01); the following limit was used: p = 0.01 ≙ t = 3.39 (for 16 degrees of freedom)
These statistical procedures were used for all data.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
None of the animals treated with 100, 300 or 1000 mg sodium hexahydroxoantimonate/ kg bw/day for 28 days died prematurely.
No signs of systemic intolerance were observed in any of the animals treated with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day for 28 days. The faeces of control and test item-treated animals were normally formed.

BODY WEIGHT AND WEIGHT GAIN
The body weight and body weight gain were not influenced in the male and female animals treated with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day for 28 days compared to the control animals.

FOOD CONSUMPTION AND COMPOUND INTAKE
The food consumption was not influenced in the male and female animals treated with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day for 28 days compared with the control group.

WATER CONSUMPTION AND COMPOUND INTAKE
The visual appraisal of the drinking water consumption did not reveal any test item-related influence in any of the dose groups.

GROSS PATHOLOGY
Macroscopic inspection revealed no test item-related changes in the male and female rats treated orally with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day for 28 days.

Effect levels

Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The aim of this dose-range-finding study was to select the dose levels for a 90-day repeated dose toxicity study of sodium hexahydroxoantimonate/kg bw/day in rats.
Remarks on result:
not measured/tested
Remarks:
Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Oral treatment with 100, 300 or 1000 mg sodium hexahydroxoantimonate/kg bw/day for 28 days did not cause any signs of systemic intolerance. The faeces
were of normal consistency throughout the experimental period. The body weight and the body weight gain were not influenced in the male and female animals at any dose. No test item-related influence was noted on the food and drinking water consumption. Macroscopic examination revealed no test item-related changes.
The following dose levels of sodium hexahydroxoantimonate were suggested for the 90-day repeated dose toxicity study in rats (please refer to Endpoint study record k_Hansen_2013_90 days): 100, 300, and 1000 mg/kg bw/day.