Registration Dossier

Administrative data

Endpoint:
acute toxicity: other routes
Type of information:
experimental study
Adequacy of study:
supporting study

Data source

Reference
Reference Type:
publication
Title:
A study on the comparative toxic effects of citric acid and its sodium salts
Author:
Grueber & Helbeisen
Year:
1948
Bibliographic source:
Department of Pharmacology and the Charlotte Drake Cardeza Foundation, Jefferson Medical College, Philadelphia, Pennsylvania
Report Date:
1948

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
White mice, albino rats, rabbits and dogs were used as experimental animals. Equal molecular concentrations of citric acid, monosodium citrate, disodium citrate and trisodium citrate were compared. 599 intraperitoneal injections of 0.0477 molar solutions were made in 477 mice. 384 intraperitoneal injections of 0.381 molar solutions were made into 299 rats. 361 intravenous injections of 0.0119 molar solutions were made into the tail veins of 279 mice. 158 intravenous injections of 0.477 molar solutions were made into lateral ear veins of 100 rabbits.The LD50 was determined each method of administration for each substance. 80 intravenous injections of 0.25 molar solutions were made into the tail veins of 80 mice. 20 mice were used for each compound. Under ether anesthesia lumbar cordotomies were performed on 7 dogs. As soon as the animals recovered fromt he anesthetic the left femoral artery was cannulated and connected to a mercury manometer using heparin asti anticoagulant. Four animals received trisodium citrate (2.94g/kg/100cc) and the other three were given equual molar quantities of citric acid (2.1g/kg/100cc) intravenously at a constant rate of 0.67 cc/minute until death resulted.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
other: various

Results and discussion

Effect levelsopen allclose all
Dose descriptor:
LD50
Effect level:
1.77 other: mM/kg
Remarks on result:
other: disodium citrate, rabbit, i.v.
Dose descriptor:
LD50
Effect level:
0.3 other: mM/kg
Remarks on result:
other: disodium citrate, mice, i.v.
Dose descriptor:
LD50
Effect level:
7.5 other: mM/kg
Remarks on result:
other: disodium citrate, mice, i.p.
Dose descriptor:
LD50
Effect level:
7.3 other: mM/kg
Remarks on result:
other: disodium citrate, rat, i.p.
Dose descriptor:
LD50
Effect level:
1.74 other: mM/kg
Remarks on result:
other: trisodium citrate, rabbit, i.v.
Dose descriptor:
LD50
Effect level:
0.66 other: mM/kg
Remarks on result:
other: trisodium citrate, mice, i.v
Dose descriptor:
LD50
Effect level:
5.5 other: mM/kg
Remarks on result:
other: trisodium citrate, mice, i.p.
Dose descriptor:
LD50
Effect level:
6 other: mM/kg
Remarks on result:
other: trisodium citrate, rats,i.p.

Any other information on results incl. tables

The visible responses of mice, rats, rabbits and dogs to toxic doses of citric acid, monosodium citrate, disodium citrate and trisodium citrate were similar and consisted primarily of increased general activity, hyperapnea, vasodilation of the peripheral vessels, salivation, muscle twitching, clonic and tonic convulsions, cyanosis, Cheyne-Stokes respiration and some deaths. In all of the animals receiving single injections, except those injected intraperitoneally with citric acid, if recovery occurred it was apparently complete within a few minutes. These findings are explained adequately by the fact that there is formation of double salts with calcium which do not liberate calcium ions. Citric acid and its sodium salts have the same toxicity when given slowly intravenously to rabbits. When citric acid was given intraperitoneally to rats and mice a number of animals died as long as one week after recovery from the immediate toxic effects. Gross post-mortem examinations performed upon many of these animals did not reveal the cause of death. If these compounds are injected rapidly intravenously in mice significant differences in toxicity are observed. It would appear that the acid rather than the citrate part of the molecule is the cause of this difference in toxicity. In those experiments on mice which intravenous injections of 0.25 molar solutions were made at a constant rate of six cubic centimeters per minute (1.5mM of the drug per minute) no significant differences in the averages of the individual lethal doses were noted. In the 80 experiments (20 for citric acid and 20 for each of its sodium salts) the average dose necessary to kill all of the animals witht he standard deviation was 2.08 +/-0.11, 2.01 +/-0.09, 2.21 +/-0.1 and 2.24 +/-0.51 for citric acid, monosodium citrate, disodium citrate and trisodium citrate respectively. In the experiments on dogs in which blood pressures were recorded there was a gradual fall in blood pressure during citric acid injection until near death when the pressure fell precipitously to zero. When sodium citrate was used the blood pressure remained fairly normal during the injection until just prior to death of the animal when it fell abruptly to zero.

Applicant's summary and conclusion