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.



         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).


    Acute toxicity


    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


         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.


         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.


         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).


         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


         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

    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


         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.


         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).


         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

         Triethyl citrate was not mutagenic in several microbiological


    Level causing no toxicological effect

    Rat: 2 g/kg bw

    Estimate of temporary acceptable daily intake for man

    0-10 mg/kg bw


    Required by 1981.

         Repeat metabolic studies in several species, preferably including


    1  Changed to 1973 on draft which was seventeenth session.


    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.,

    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)