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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Acute Toxicity Studies of α-Ketoglutarate: a Promising Antidote for Cyanide Poisoning
Author:
R. Bhattacharya, Deo Kumar, K. Sugendran, S. C. Pant, R. K. Tulsawani and R. Vijayaraghavan
Year:
2001
Bibliographic source:
J. Appl. Toxicol. 21, 495-499

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(adopted February 24 th, 1987)
Principles of method if other than guideline:
The animals were fasted overnight and were given food 1 h after treatment. Fourty female rats, all weighing 150-200g were used for the test . Sixteen animals were used for LD50 determination and the remaining 24 were divided further into groups of 6 (0.9% saline; p.o.) and 18 (2.0 g/kg alpha-Ketoglutarate p.o.) rats each. Two rats each of the saline-treated control group and six each receiving α-KG were sacrificed 1 h, 24 h and 7 days after treatment for haematology, biochemistry, organ/body weight index (OBI; organ weight × 100/animal body weight) and histology. Sixteen male rats weighing 150–200 g and 32 male rats weighing 350–380 g were used for the LD50 determination and physiological studies, respectively. All the solutions were prepared fresh in 0.9% saline and were administered p.o. in a volume of <10 ml/kg bw. The LD50 of α-KG (p.o.) for both male and female rats was determined by the moving average method of Gad and Weil (1989). Surviving animals were weighed daily and observed for various signs and symptoms and mortality up to 14 days.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-oxoglutaric acid
EC Number:
206-330-3
EC Name:
2-oxoglutaric acid
Cas Number:
328-50-7
Molecular formula:
C5H6O5
IUPAC Name:
2-oxopentanedioic acid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: female: 150-200 g, male: either 150-200 g or 350-380 g
- Fasting period before study: overnight
- Housing: Grouped according to sex and dose in polypropylene cages containg bedding of rice husk
- Diet (e.g. ad libitum):before the fasting period and from 1 h after administration; standard pellet diet ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
physiological saline
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL, 400 mg/mL, 500 mg/mL and 1000 mg/mL
- Amount of vehicle (if gavage): < 10mL/kg
MAXIMUM DOSE VOLUME APPLIED: < 10mL/kg

Doses:
2000 mg/kg, 4000 mg/kg, 5000 mg/kg, 10000 mg/kg
No. of animals per sex per dose:
male: 16 and 32 for LD50 determination
female: 16 for LD50 determination, 6 (control), 18 (2.0 g/kg bw)
Control animals:
other: 6 female received vehicle only
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs were recorded for every animal. Body weight, biochemical determinations, haematological determinations, urine analysis, physiological determinations, histological determinations from 6 anmials each per group at 1 h, 24 h and 7 days
Statistics:
Data was analysed by one-way ANOVA followed by Dunnett´s test for comparing the control and the various groups using SigmaStat software, significance was considered if p < 0.05.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 - <= 10 000 mg/kg bw
Based on:
act. ingr.
Mortality:
The p.o. LD50 of α-ketoglutaric acid in male and female rats was 7.1 (5.0–10.0) g/kg. All the animals receiving 10 g/kg α-ketoglutaric acid died within 2–3 h.
Clinical signs:
other: Although there was no delayed mortality, the surviving animals were observed for gross signs and symptoms, food and water intake and body weight gain for 14 days. No abnormalities were observed except that in a few animals lethargy and purging occurred fo
Gross pathology:
no effects observed
Other findings:
- Other observations: no significant change was observed in the haematological profile of α-KG-treated rats compared with saline controls. A marginal increase in serum ALP and urea levels 1 h after treatment and a decrease in inorganic phosphorus levels 7 days after treatment were observed in α-KG treated animals.

-physiological parameters: A persistent decrease up to 4 h was observed in MAP and NMT following treatment with 4.0 g/k α-KG. Although the heart rate and respiratory rate also decreased, they were not statistically significant. No significant change was produced by 2.0 g/kg α-KG on any of the parameters, including rectal temperature. Experiments on haemodynamic parameters show that 2.0 or 4.0 g/kg α-KG did not alter the left ventricular pressure (systolic), arterial pressure (systolic) or arterial pressure (diastolic) at any of the time points.

-Histology: Histology of lung, liver, kidney, spleen and ovary also did not show any abnormalities produced by α-KG when observed 1 h, 24 h and 7 days after exposure.

Applicant's summary and conclusion

Interpretation of results:
other: LD50 ≥ 5000 mg/kg bw
Conclusions:
The present study was performed to evaluate the LD50 of α-ketoglutaric acid which is used as an antidote for cyanide poisoning. Although documentation about the exact dose finding test is incomplete, the study provides important informations about the toxicity of the test item. α-ketoglutaric acid was applied in doses of 2.0, 4.0, 5.0 and 10.0 g/kg bw, and deaths occurred in doses > 5.0 g/kg bw. The animals were observed at least for 14 days. There was no sign of acute oral toxicity in animals treated with 2.0 g/kg bw. Based on the moving average method of Gad and Weil (1989) the LD50 of α-ketoglutaric acid was determined to be 7.1 g/kg bw.