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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Principles of method if other than guideline:
Range-finding study (14-day administration)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
. Supplier : Bruno Bock Chemische Fabrik GmbH & Co KG
. Name : SODIUM THIOGLYCOLATE
. Batch number : 13483
. Description : white powder
. Purity : 98%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
ANIMALS
- Number: 6 males and 6 females per dose 
- Strain : Sprague-Dawley Crl CD (SD) IGS BR
- Breeder: Charles River Laboratories France, L'Arbresle, France
- Age at the beginning of the treatment period: 6-7 weeks old
- Weight at the beginning of the treatment period: ca. 207 g (196-217)  for the males and ca. 162 g (147-176) for the females
- Acclimation: 7-days before the beginning of the treatment period

ENVIRONMENTAL CONDITIONS
- Temperature : 22 ± 2°C
- Relative humidity : 50 ± 50%
- Light/dark cycle : 12h/12h (7:00 - 19:00)
- Ventilation : about 12 cycles/hour of filtered, non-recycled air.

HOUSING
The animals were housed individually in polycarbonate cages or in  wire-wesh cages. Autoclaved wood shavings were provided as nesting  material, a few days before delivery and during the lactation period

FOOD and WATER
- Food: SSNIFF R/M-H pelleted maintenance diet ad libitum
- Water: filtered (0.22 µm filter) tap water ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: degassed purified wate
Details on oral exposure:
Four groups of six male and six female Sprague-Dawley rats received the  test item, SODIUM THIOGLYCOLATE, daily for 14 days, by gavage at  dose-levels of 15, 30, 60 or 75 mg/kg/day.  Following absence of toxicity, the 15 mg/kg/day dose-level was increased,  on day 8 of dosing, to 100 mg/kg/day and was further increased, on day 11  of dosing, to 150 mg/kg/day. Due to mortalities at 150 mg/kg/day, the  remaining animals in the group were not dosed on day 14. An additional  group of six males and six females received the vehicle, degassed  purified water, alone, under the same experimental conditions and acted  as a control group.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
14 days
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 15/100/150, 30, 60, 75 mg/kg
Basis:

No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
- Morbidity and mortality: at least twice a day
- Clinical signs: at least twice a day
- Body weight: once before group allocation, on the first day of  treatment,  and on days 4, 7, 11 and 14.
- Food consumption: twice weekly, over 3- or 4-day period, during the  treatment period.
Sacrifice and pathology:
- Sacrifice: on completion of the treatment period, after at least 14  hours fasting.
- Organ weights: The body weights of all animals sacrificed at the end of  the treatment period were recorded before sacrifice. The liver, kidneys,  testes, epididymides, ovaries and uterus were weighed wet as soon as  possible after dissection. The ratio of organ weight to body weight  (recorded immediately before sacrifice) was calculated.
- Examination: A complete macroscopic post-mortem examination was  performed on all study animals. This included examination of the external  surfaces, all orifices, the cranial cavity, the external surfaces of the  brain, the thoracic, abdominal and pelvic cavities with their associated  organs and tissues and the neck with its associated organs and tissues. 
- Preservation of tissues: For all study animals, macroscopic lesions and  different tissues (Epididymides, Kidneys, Liver, Ovaries with oviducts,  Testes, Uterus with cervix) were preserved in 10% buffered formalin  (except for the testes and epididymides which were preserved in Bouin's  fluid).
- No microscopic examination was performed

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
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:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL EXAMINATIONS
- Mortality:
One male was prematurely sacrificed on day 13 of dosing, during the period of dosing at 150 mg/kg/day. Prior to sacrifice, the male showed ventral recumbency, vocalization, hypotonia, dyspnea, lacrimation and mydriasis in both eyes. Three females were found dead prior to dosing on day 14 of dosing, during the period of dosing at 150 mg/kg/day. No clinical signs had been observed prior to death.

- Clinical signs:
Two males and two females given 75 mg/kg/day had ptyalism from day 13 until the end of the study. No other clinical signs were recorded.

- Body weight and body weight change
One male given 75 mg/kg/day gained markedly less weight than the control group mean weight gain from day 1 to day 4 of dosing, however all other males in this group had weight gains which were comparable with the controls. From day 4 onwards, mean weight gain was comparable with the control group.
Male groups given 30 or 60 mg/kg/day had mean weight gains comparable with the controls, with the exception of the period day 7 to day 11 of dosing when one male given 30 mg/kg/day had a low weight gain and skewed the group mean.
Group 2 males had mean weight gains comparable with the controls when they received 15 and 100 mg/kg/day. During the period of dosing at 150 mg/kg/day, weight gain was 32% less than that of the controls.
Females groups given 15/100, 30, 60 or 75 mg/kg/day had weight gains comparable with the control group. When group 2 females were given 150 mg/kg/day, the group had a mean weightloss.

- Food consumption
All groups had food consumption comparable with the control group throughout the study, except during the period of dosing at 150 mg/kg/day for group 2, when food consumption of both males and females was reduced (p<0.05 for males).

PATHOLOGY
- Organ weights
Statistically significant lower kidney weights were noted in males given 30 mg/kg/day. As this difference was minimal and not found at higher doses, this was considered to be of no toxicological importance.
Slightly lower uterus weights were noted in females from all groups. A relationship to treatment cannot be excluded.
The other differences noted between treated and control rats in the absolute and relative organ weights were considered to be of no toxicological importance as they were minimal, not dose-related, sometimes of opposite trends in both sexes and/or were due to the decrease in body weight.

- Macroscopic post-mortem examination
. Unscheduled deaths
J27007 (male given 15/100/150 mg/kg/day sacrificed on day 13): the following changes were noted: dilated pelvis of left kidney, liver paleness and marked lobular pattern, small spleen, and dilated urinary bladder.
J27058 (female given 15/100/150 mg/kg/day found dead on day 14): small spleen was noted.
J27060 (female given 15/100/150 mg/kg/day found dead on day 14): no necropsy observation was noted.
J27062 (female given 15/100/150 mg/kg/day found dead on day 14): small spleen and dilated uterus horn with serous contents were noted.
In absence of microscopic examination, the major factor contributing to the moribundity could not be established for these animals.

. Final sacrifice
At macroscopic post-mortem examination, the following changes were noted:
. liver:
- marked lobular pattern in 1/6 males given 60 mg/kg/day, in 1/6 males and 1/6 females given 75 mg/kg/day,
- paleness in 3/6 females given 75 mg/kg/day and in 1/6 females given 15/100/150 mg/kg/day,
- irregular color in 1/6 females given 30 mg/kg/day.
. kidneys:
- dilated pelvis in 1/6 females given 60 mg/kg/day,
- irregular color in 2/6 males given 60 mg/kg/day, in 1/6 females given 75 mg/kg/day, and in 2/6 males given 15/100/150 mg/kg/day.
These changes were considered to be related to treatment.
All the other necropsy findings were sporadic and recognized as the changes commonly observed in the rat of these strain and age kept under laboratory condition, and none were considered to be of toxicological importance.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
SODIUM THIOGLYCOLATE was administered daily, for 14 days, by the oral route (gavage), to Sprague-Dawley rats at dose-levels of 15/100/150, 30, 60 or 75 mg/kg/day. The dose-level of 150 mg/kg/day resulted in mortality, reduced body weight gain (males) or body weight loss (females) and reduced food consumption. There were no group mean effects of treatment on body weight performance or food consumption at dose-levels of 15/100, 30, 60 or 75 mg/kg/day. Four animals given 75 mg/kg/day had ptyalism at the end of the study and one male given 30 mg/kg/day and one male given 75 mg/kg/day had low body weight gains between day 7 to day 11 or day 1 to day 4, respectively.
Macroscopic abnormalities were observed in the liver at 30 (females), 60 (males), 75 and 15/100/150 (females) mg/kg/day and in the kidneys in females given 60 or 75 mg/kg/day and in males given 60 or 15/100/150 mg/kg/day.
150 mg/kg/day is considered to exceed the maximum tolerated dose because mortality occurred after 3 days of treatment.
Executive summary:

The objective of this study was to evaluate the potential toxicity of SODIUM THIOGLYCOLATE, following daily oral administration (gavage) to rats for 2 weeks.

Four groups of six male and six female Sprague-Dawley rats received SODIUM THIOGLYCOLATE, daily for 14 days, by gavage at dose-levels of 15, 30, 60 or 75 mg/kg/day. Following absence of toxicity, the 15 mg/kg/day dose-level was increased, on day 8 of dosing, to 100 mg/kg/day and was further increased, on day 11 of dosing, to 150 mg/kg/day. Due to mortalities at 150 mg/kg/day, the remaining animals in the group were not dosed on day 14. An additional group of six males and six females received the vehicle, degassed purified water, alone, under the same experimental conditions and acted as a control group.

The animals were checked twice daily for mortality and clinical signs. During the study, body weight was recorded on days -5, 1, 4, 7, 11 and 14 of the study and the food consumption was recorded over 3- or 4-day intervals. On completion of the treatment period, the animals were sacrificed and a full macroscopic post-mortem examination was performed. Designated organs were weighed and selected tissues were preserved. No microscopic examinations were performed.

One male receiving 150 mg/kg/day was prematurely sacrificed on day 13 of dosing after marked clinical signs were observed, including ventral recumbency, vocalization and dyspnea. In the same treated group, three females were found dead prior to dosing on day 14 of dosing. No clinical signs had been observed prior to death. No macroscopic findings were considered to be treatment-related, although these events were consecutive to the administration of the test item at 150 mg/kg/day. Two males and two females given 75 mg/kg/day had ptyalism from day 13 until the end of the study. No other clinical signs were recorded. There were no effects of treatment on mean body weight performance at dose-levels of 15/100, 30, 60 or 75 mg/kg/day. The dose-level of 150 mg/kg/day resulted in reduced body weight gain (males) or body weight loss (females). There were no effects of treatment on mean food consumption at any dose-level, except during the period of dosing at 150 mg/kg/day for group 2, when food consumption of both males and females was reduced. Lower uterus weights (between -9% and -17% relative uterus weight in comparison to control

value) were observed at all dose-levels. Liver with a marked lobular pattern was observed at 60 and 75 mg/kg/day, paleness of liver at 75 and 15/100/150 mg/kg/day and irregular liver color at 30 mg/kg/day. Dilated pelvis of kidneys was observed at 60 mg/kg/day, irregular color at 60, 75 and 15/100/150 mg/kg/day.

SODIUM THIOGLYCOLATE, was administered daily, for 14 days, by the oral route (gavage), to Sprague-Dawley rats at dose-levels of 15/100/150, 30, 60 or 75 mg/kg/day. The dose-level of 150 mg/kg/day resulted in mortality, reduced body weight gain (males) or body weight loss (females) and reduced food consumption. There were no group mean effects of treatment on body weight performance or food consumption at dose-levels of 15/100, 30, 60 or 75 mg/kg/day. Four animals given 75 mg/kg/day

had ptyalism at the end of the study and one male given 30 mg/kg/day and one male given 75 mg/kg/day had low body weight gains between day 7 to day 11 or day 1 to day 4, respectively. Macroscopic abnormalities were observed in the liver at 30 (females), 60 (males), 75 and 15/100/150 (females) mg/kg/day and in the kidneys in females given 60 or 75 mg/kg/day and in males given 60 or 15/100/150 mg/kg/day. 150 mg/kg/day is considered to exceed the maximum tolerated dose because mortality occurred after 3 days of treatment.