2-oxoglutaric acid

Endpoint summary

Description of key information

Non-GLP, non-OECD compliant study, rats (Wistar), male/female, oral: gavage, doses: 2.0, 4.0, 5.0 and 10.00 g/kg bw, LD50 > 5.0 g/kg bw.

Non-GLP, non-OECD compliant study, rats (Wistar), female, oral: gavage, doses: 0.5, 1.0, 2.0, 3.5 and 4.0 g/kg bw., reduction of cyanide mortality by 50% at 2.0 g/kg bw. administered 10 min prior to poisoning. In the same study: rats (Wistar), female, intraperitoneal, doses: 1.0, 2.0, 4.0 g/kg bw., adverse effects observed at 4.0 g/kg bw., LD 50 > 2.0 g/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

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

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

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

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.

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.

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.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

The animals were administered potassium cyanide (KCN), sodium nitride (SN), sodium thiosulfate (STS) and alpha-ketoglutarate by oral (p.o.), subcutaneous (s.c.), intraperitoneal (i.p.) and p.o. routes, respectively. Alpha-ketogluarate was administered once or in repeated dose following different dosing schedules. For the detailed dosing schedules please refer to any other information on materials and methods.

GLP compliance:

not specified

Test type:

other: evaluation of the protective effects of alpha-ketoglutarate

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Obtained from the animal facility of Defence Research and Development Establishment (DRDE), Gwalior
- Weight at study initiation: 130-150g
- Fasting period before study: overnight
- Housing: maintainence on rice husk in polyproylene cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

Route of administration:

oral: gavage

Vehicle:

physiological saline

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: < 10 mL/kg bw (max. dose 4.0 mg/kg bw)

Doses:

0.5, 1.0, 2.0 g/kg bw

No. of animals per sex per dose:

no data

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 6 hrs
- Frequency of observations: hourly until 3hrs after poisoning then every second hour.
- Necropsy of survivors performed: no

Mortality:

The occurring mortality is based on cyanide poisoning and was reduced to 50% by usage of alpha-ketoglutarate

Clinical signs:

other: no data

Gross pathology:

no data

Interpretation of results:

study cannot be used for classification

Conclusions:

The aim of this study was to evaluate whether the test substance is able to reduce cyanide poisoning. Three different concentrations of the substance , i.e. 0.5, 1.0, 2.0, 3.5 and 4.0 g/kg bw were administered in different time intervals. There was rather an increase in survival than in mortality. Mortality was reduced to 50% even in repeated treatments.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Based on the available information, the acute toxicity of 2 -oxoglutaric acid is low for oral and intraperitoneal exposure. The dose descriptor obtained from the existing acute oral and intraperitoneal toxicity studies performed on 2 -oxoglutaric acid are the respective LD50 values.

Since the vapour pressure of 2 -oxoglutaric acid is very low and it is not handled as a solution exposure via the inhalative route is unlikely.

Due to its hydrophilicity (log P = -2.08) it is also unlikely that 2 -oxoglutaric acid penetrates the stratum corneum and thus, dermal absorption of the substance is low. On the other hand, due to its low molecular weight (146.08g/mol) 2 -oxoglutaric acid may be absorbed via aquatic pores, but the dermal absorption is considered to be very slow.

However, the testing of acute dermal toxicity of 2 -oxoglutaric acid is scientifically not justified based on retrospective data analyses undertaken by Creton et al. (2010) and Seidle et al. (2010) to ascertain the value of regulatory requirements prescribing multiroute testing for acute systemic toxicity. These analyses have examined the concordance among regulatory classifications for acute oral, dermal, and/ or inhalation toxicity for ~500 agrochemical and biocidal active substances and nearly 2000 industrial chemicals. The findings from these two independent reviews have revealed that acute dermal studies of pure substances do not add value above and beyond oral data for hazard classification of pesticides, biocides, or chemicals. According to the Draft COMMISSION REGULATION (EU) amending Annexes VII and VIII to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards skin corrosion/irritation, serious eye damage/eye irritation, skin sensitisation and acute toxicity, recent “scientific analysis of available data from in vivo acute toxicity studies have shown that substances that are not toxic via the oral route may be expected with high certainty to be also non-toxic via the dermal route. Therefore, testing those substances via the dermal route does not provide essential information for their safety assessment. The oral LD50 was determined to be > 2000 mg/kg bw based on two well documented non-GLP, non-guideline studies. Thus, no toxicity via the dermal route is to be expected. 

There are no data gaps in acute toxicity.

Justification for classification or non-classification

Based on the available data 2 -oxoglutaric acid does not need to be classified for acute toxicity according to Regulation (EC) 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labeling of Chemicals (GHS). Thus, no labelling is required.