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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: Bibliographic source
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Effects of Antimony on Rats Following 90-Day Exposure via Drinking Water
Author:
R. POON, I. CHU, P. LECAVALIER, V. E. VALLI, W. FOSTER, S. GUPTA and B. THOMAS
Year:
1998
Bibliographic source:
Food and Chemical Toxicology 36
Reference Type:
review article or handbook
Title:
Review of Subchronic/Chronic Toxicity of Antimony Potassium Tartrate
Author:
Barry S. Lynch,Charles C. Capen,Earle R. Nestmann,Gauke Veenstra and James A. Deyo
Year:
1999
Bibliographic source:
Regulatory Toxicology and Pharmacology 30, 9–17

Materials and methods

Principles of method if other than guideline:
An appropriate amount of potassium antimony tartrate was dissolved in tap water to make 50-litre batches of drinking water containing 0.5, 5, 50 and 500 ppm
antimony.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Dipotassium bis[μ-[tartrato(4-)-O1,O2:O3,O4]]diantimonate(2-) , stereoisomer
EC Number:
234-293-3
EC Name:
Dipotassium bis[μ-[tartrato(4-)-O1,O2:O3,O4]]diantimonate(2-) , stereoisomer
Cas Number:
11071-15-1
Molecular formula:
C8H4O12Sb2.2K
IUPAC Name:
(2R,3R)-2,3-dihydroxy-butanedioic acid, antimony potassium salt

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
The animals were housed individually in stainless-steel mesh cages with free access to food (Purina Chow 5001, Ralston Purina) and water.
The laboratory conditions were maintained as follows: 50 + 10% relative humidity, 22_+ 3°C temperature, and a 12-hr light/dark cycle.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
treatment was initiated by replacing tap water with tap water containing 0.5, 5, 50 and 500 ppm antimony as potassium antimony tartrate. Control groups received tap water as drinking water.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The antimony concentrations were verified by inductive coupled plasma emission spectroscopy (ICP). New batches were prepared
monthly and stored in 50-1itre screw-capped Nalgene ~R' containers and kept at 4°C. The stability of potassium antimony tartrate in drinking water
was confirmed by the ICP method.
Duration of treatment / exposure:
90 day exposure
Doses / concentrationsopen allclose all
Dose / conc.:
0.5 ppm
Dose / conc.:
5 ppm
Dose / conc.:
50 ppm
Dose / conc.:
500 ppm
No. of animals per sex per dose:
95 male (127 + 10 g) and 95 female (136+ 10g) were randomly divided into 10 groups, with the control and highest dose (500 ppm) groups
each containing 25 animals per sex and the three lower dose groups each containing 15 animals per sex.
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
Body weight, water consumption and food intake were measured weekly, and clinical
observation was made daily. At the end of the 13-wk treatment period, all but 10 animals per sex inthe control and highest dose groups were terminated.
At the 13th wk, half of the rats were transferred to individual metabolism cages and their urine collected overnight into refrigerated beakers containing 2.0 ml of a preservative.
Sacrifice and pathology:
HISTOPATHOLOGY:At the termination of the study, a sample of blood was taken. During necropsy, the following tissues and organs were examinated: brain, pituitary, thyroid and trachea, salivary glands, thymus, lung, heart, liver, kidneys, adrenals, spleen, pancreas, oesophagus, gastric cardia, fundus and pylorus, duodenum, jejunum, ileum, caecum, colon, urinary bladder, skin, bone marrow and gonadal tissues.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
no mortality observed
Description (incidence):
mild biochemical and haematological changes, and adaptive histological changes in the thyroid, liver, thymus, spleen and pituitary gland.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At the highest dose, suppression of body weight gain was associated with reduced water intake and was largely reversible, but mild hepatic cirrhosis may represent a progression of the milder liver changes observed at lower doses.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption in the 500 ppm groups of both sexes was reduced by about 12% by the end of the treatment period, but returned to the control level during the recovery period.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Highest-dose males and females consumed approximately 35% less water than the controls, but quickly regained the normal rate
of water consumption as soon as tap water replaced the 500 ppm antimony solution during the recovery period.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Blood glucose was also a sensitive endpoint with significant decrease detectable in females at 5 ppm.
Increased thyroid hormone binding radio was found in the serum of females at 50 and 500 ppm.
Male rats at 500 ppm antimony had decreased red blood cell and platelet counts and slighty increased mean corpuscular volume.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Thyroid changes, which were detectable at 0.5 ppm, were the most sensitive endpoints.In the thyroid gland, changes, including decreased follicular size, increased epithelial height, and nuclear vesiculation were observed. Some of these changes such as reduced follicle size in male and female rats and increased epithelial height in female rats, showed reductions in both incidence and severity in the 500 ppm recovery groups but did not return to normal. On the other hand, collapsed follicles, whitch were not observed in the control and treatment groups of both sexes, were present in nine of ten male rats in the 500 ppm recovery group.
It is considered the subtle changes to represent normal physiological variation and not to be of toxicological significance.
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Immunological findings:
effects observed, treatment-related
Description (incidence and severity):
In the thymus, very mild treatment-related changes were observed in female rats consisting of reduced cortical volume and increased medullary volume. While the males in the 500 ppm treatment group had normal thymus, all 10 males of the recovery group had minimal to mild reduction in cortical volume.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Females in the 50 ppm dose group had significantly decreased thymus to body weight ratios in comparison to control. Significantly increased
kidney to body weight ratio was observed in the highest dose group of both males and females.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At necropsy one male in the 5 ppm dose group and three males in the highest dose (500 ppm) group had gross haematuria. A male rat in the
highest dose group had a cirrhotic liver and a female rat in the lowest dose group had a nodular, fibrotic, spleen.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Mild and predominantly reversible histological changes were observed in the thyroid gland and the liver. Lesser changes were found in the thymus, spleen and pituitary gland.
Changes in the thyroid, including reduced follicle size, increased epithelial height and nuclear vesiculation, were detected starting at the lowest dose group of both sexes. Some of these changes showed reductions in both incidence and severity in the 500 ppm recovery groups but did not return to normal. On the other hand, collapsed follicles, which were not observed in the control and treatment groups of both sexes, were present in nine of ten male rats in the 500 ppm recovery group.
In the liver, anisokaryosis was a significant, dose-related change that appoached a moderate degree of severity in all males and females of the highest dose group. This change was still detectable at recovery but with a decreased degree of severity.
MInimal changes in the pituitary consisting of cytoplasmic vacuolation and cytoplasmic inclusions were observed in treated males starting at 0.5 ppm but there was a lack of dose-related increase in incidence or severity. Minimal to mild levels of cytoplasmic inclusions were detected in females starting at 50 ppm. These changes were not seen in the recovery groups of both sexes.
In the thymus, very mild treatment-related changes were observed in female rats.
Histopathological findings: neoplastic:
no effects observed

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 50 ppm
Basis for effect level:
other: histopathologic findings reported and serum clinical chemistry data supports a NOAEL of 50 ppm

Target system / organ toxicity

Critical effects observed:
no
Lowest effective dose / conc.:
0.5 ppm
System:
haematopoietic
Organ:
liver
pituitary gland
spleen
thymus
thyroid gland

Any other information on results incl. tables

Male treatment Thyroid hormone binding radio (%)
0 1,38 +/- 0,76
0,5 14,2 +/- 1,14
5 13,9 +/- 1,34
50 13,2 +/- 1,04
500 15,9 +/- 3,70
Recovery
0 ND
500 ND
Female treatment
0 5,06 +/- 0,85
0,5 5,46 +/- 0,90
5 6,06 +/- 1,54
50 5,85 +/- 1,00
500 5,90 +/- 1,32
Recovery
0 ND
500 ND

Applicant's summary and conclusion

Conclusions:
Based on the decreased body weight gain and decreased food and water consumption at the 500 ppm dose level, even though. At this dose level, one animal of each sex was found to have bridging fibrosis of the liver, ampotential sign of liver toxicity. A no-observed-adverse-effect level (NOAEL) is considered to be at 50 ppm antimony in drinking water (equivalent to a calculated intake of 6 mg kg body weight/day).