TRIETHYL CITRATE Explanation The citrate ion is widely distributed in plant and animal tissues and is a naturally occurring component of man's diet. It is a common metabolic intermediate in oxidative metabolism. Citrate was evaluated by the ninth session of the JECFA and was given an ADI not limited. BIOLOGICAL DATA BIOCHEMICAL ASPECTS Triethyl citrate is an odourless, nearly colourless, oily liquid. No absorption or metabolism studies have been reported, however, it is expected that the compound would rapidly metabolize in the body and liberate the citrate ion which would be handled through the usual biochemical pathways (FASEB, 1976). TOXICOLOGICAL STUDIES Acute toxicity LD50 Species Route (mg/kg bw) Reference Rat p.o. 8 000 Finkelstein & Gold, 1955 Cat p.o. 4 000 Finkelstein & Gold, 1955 Short-term studies Mouse A group of 20 mice given intraperitoneal doses of 350 mg/kg bw of triethyl citrate daily for 14 days had a slightly lower mean growth rate than control animals. No differences were seen in the two groups in erythrocyte and leucocyte blood cell count, clotting time and haemoglobin levels. Examination of the liver, lung and kidney tissues of two animals at necropsy revealed no pathological cellular changes. Rat Young rats were fed triethyl citrate at an initial rate of 1, 2 and 4 g/kg bw for eight weeks (Finkelstein & Gold, 1955). Urinalysis, blood counts and growth measurement, performed periodically, revealed no toxic effects. At necropsy, no gross abnormalities were seen in the thoracic or abdominal organs. Histological sections of the heart, lungs, gastrointestinal tract, liver, pancreas, spleen and kidneys were comparable in appearance to those from the untreated controls. Cat Cats receiving daily doses of 7% of the LD50 (280 mg/kg bw) for eight weeks did not differ from control animals with respect to weight, blood count, haemoglobin, blood sugar and blood nitrogen. However, weakness, ataxia and depression appeared after the fourth or fifth dose and progressed. After treatment was discontinued, the animals recovered within 24-96 days (Finkelstein & Gold, 1959). Dog Two young adult male and two young adult female beagle dogs were given daily doses of triethyl citrate of 0.05 and 0.25 ml/kg bw for six months. Measurement of body and organ weights, blood and urinalysis and the results of histological examination of tissues revealed no adverse effects (Hodge, 1954). Increasing the daily dose to 2.5 to 3.5 ml/kg bw for seven to 12 weeks resulted in liver pathology in three treated animals. A fourth dog that had previously reacted adversely to a 2 ml/kg bw dose showed no histological changes after receiving 1.5 ml/kg bw daily for an additional month. Long-term studies Rat Three groups of 15 male and 15 female weanling Sprague-Dawley rats were fed diets containing 0.33, 1.0 and 3.0% triethyl citrate in a two-year feeding study (LaWall & Harrison, 1954). The initial doses were from 0.2 to 2.0 g/kg bw. Weight gain and food intake were reduced below that of the control groups when the level of the compound in the diet was increased. (No specific numbers were given for these results.) No adverse effects of haematologic, urinalysis, survival, gross or histopathologic parameters could be attributed to triethyl citrate. Special studies on reproduction and teratology At doses ranging from 0.5 to 10 mg/kg b.w. triethyl citrate was nonteratogenic in the chicken embryo. When injected into the air cell, the LD50 was 1349.86 mg/kg bw (67.49 mg/egg) (Verrett, 1976). Special studies on mutagenesis Triethyl citrate was not mutagenic in plate and suspension tests using the Ames Salmonella microsome mutagenesis assay in strains TA 1535, TA 1537 and TA 1538 and the Saccharomyces cerevesiae D4 yeast assay with and without tissue homogenate activating systems (Litton Bionetics, Inc., 1976). Special studies on neurological activity Rat In Wistar rats dose intraperitoneally at 400 mg/kg bw triethyl citrate produced a loss of the righting reflex, an effect reversible within 15 minutes. Rabbit Intravenous administration of a 100 mg/kg bw dose of triethyl citrate to rabbits produced a marked increase in motor activity and respiration (Meyer et al., 1964). Comments Citrate was evaluated by the ninth session of JEFCA (1966)1 and ADI not limited was given. It is likely that triethyl citrate will be hydrolyzed to its component parts, citrate and ethanol in vivo. Data from two-year feeding studies suggest that rats can tolerate up to 2.0 g/kg. Dogs tolerated up to 0.25 ml/kg bw for six months without effects. Triethyl citrate was not mutagenic in several microbiological assays. EVALUATION Level causing no toxicological effect Rat: 2 g/kg bw Estimate of temporary acceptable daily intake for man 0-10 mg/kg bw FURTHER WORK OR INFORMATION Required by 1981. Repeat metabolic studies in several species, preferably including man. 1 Changed to 1973 on draft which was seventeenth session. REFERENCES FASEB (1976) SCOGS, 84, Contract No. FDA 223-75-2006, submitted to FDA, Washington, D.C. Finkelstein, M. & Gold, H. (1959) Tox. Appl. Pharmacol., 1, 283 Hodge, H. C. (1954) Unpublished data submitted to FASEB LaWall, (?) & Harrison, (?) (1954) Unpublished, prepared for Fleishmann Laboratories, Standard Brands, Inc., Stamford, Conn., USA Litton Bionetics, Inc. (1976) FDA-75-10 LBI Project No. 2468, unpublished data submitted to the FDA Meyer, D., Aulian, J. & Guess, W. L. (1964) J. Pharm. Sci., 53, 776 Smith, H. et al. (1976) Health Physics, 30, 318 Verret, M. J. (1976) Unpublished data, Food and Drug Administration
See Also: Toxicological Abbreviations Triethyl citrate (ICSC) Triethyl citrate (WHO Food Additives Series 19) TRIETHYL CITRATE (JECFA Evaluation)