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    UREA

    First draft prepared by
    Dr P.  Olsen
    Institute of Toxicology, National Food Agency of Denmark
    Ministry of Health, Soborg, Denmark

    1.  EXPLANATION

         Urea is a white crystalline powder with a cooling saline taste
    (Merck, 1968).  Urea occurs naturally in mammals and is an excretory
    end-product of amino acid metabolism.  Urea is formed in the liver. 
    Urea has not been evaluated previously by the Joint FAO/WHO Expert
    Committee on Food Additives.

         Urea is used in sugar-free chewing gum to adjust the texture. 
    A heavy user of chewing gum may consume approximately.  Chewing gum
    may contain up to 3% urea, and intake from this source could be up
    to 300 mg urea/day.  The Committee considered urea only for
    evaluation in relation to its use in chewing gum.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

         Urea has little or no nutritional value to monogastric mammals
    (Briggs, 1967).  Ruminants are able to utilize urea as a source for
    food protein (Blood & Henderson, 1963).  Urea present in the blood
    of ruminants appears to be actively transported across the rumen
    wall into the lumen and used as a nitrogen source (Schmidt-Nielsen,
    1958).

         A study in pregnant rats which were injected subcutaneously
    with urea dissolved in 0.9% NaCl solution showed that urea diffused
    readily through the placenta.  The concentrations of urea in the
    maternal liver, thigh muscle and in the whole fetus were equal two
    hours after injection (Luck & Engle, 1929).

         In dogs injected intraperitoneally with 3% urea solution, urea
    diffused throughout the body and was present in tissue fluid at
    concentrations equal to, or greater than, that present in the
    extracellular fluid (Grollman & Grollman, 1959).

         The distribution of urea was determined in 4 young pigs given
    15N-labelled urea in the diet.  Fifty-two per cent of the
    administered 15N-labelled urea was excreted in the urine after 48
    hours and 1.9% during the subsequent 48 hours.  Faecal 15N
    excretion over 96 hours accounted for only 1.3% of the amount
    administered.  Less than 1% of the 15N was found in the liver,
    muscle and blood cells, study concluded that this indicates
    incorporation of 15N in body proteins.  Only 60% of the
    administered 15N was recovered (Grimson  et al., 1971).

         In another study, the distribution of 14C-labelled urea after
    intraperitoneal injection was determined by radioactivity analysis
    and autoradiography techniques in the brain and spinal fluid of
    fasted cats.  In the brain and cerebrospinal fluid the highest urea
    concentration was reached 6 hours following injection. 
    Autoradiography showed dense areas in the cerebral and cerebellar
    cortex.  White matter showed the least radioactivity (Schoolar
     et al., 1960).

         Renal excretion of urea is rapid and chiefly by glomerular
    filtration (Sollmann, 1957).  Renal tubular secretion (Sollmann,
    1957) and reabsorption also occur (Mountcastle, 1974).

    2.1.2  Biotransformation

         Urea is an excretory end-product of amino acid metabolism in
    mammals.  The formation of urea takes place in the liver.  This is a
    cyclic process in which the initial step is the reaction between
    carbon dioxide and ammonia to yield carbamyl phosphate.  Carbamyl
    phosphate reacts with ornithine to form citrulline which combines
    with aspartate to form argininosuccinate.  This product is cleaved
    to fumarate and arginine.  The terminal step is the hydrolysis of
    arginine, yielding urea and regenerating ornithine.  This cycle of
    reactions involves several enzymes including carbamyl phosphate
    synthetase, ornithine carbamylase, argininosuccinate synthetase and
    arginine-lyase.  The fetal liver was capable of synthesizing urea 28
    days (in pigs), and 19 days (in rats) after gestation (Kennan &
    Cohen, 1959).

    2.1.3  Effects on enzymes and other biochemical parameters

         No information available.

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

         The results of acute toxicity studies with urea are summarized
    in Table 1.

         The clinical symptoms observed in cattle included ataxia,
    weakness, abdominal pain, dyspnoea, excessive salivation, frothing,
    violent struggling and bellowing.  Acute urea toxicity in cattle may
    be due to ammonia formed by the rapid breakdown of urea by rumen
    microorganisms (Blood & Henderson, 1963).

         The clinical signs of acute urea toxicity in ponies were
    typical of severe central nervous system derangement:
    incoordination, dilated pupils, sluggish pupillary response to
    light, depressed palpebral and corneal reflexes, slow respiratory
    rate, rapid and weak peripheral pulse, cold and clammy skin, and
    pressing of the head against fixed objects until falling at death
    (Hintz  et al., 1970).


        Table 1.  Results of acute toxicity studies with urea.

                                                                                         

    Species        Sex       Rte       Dosage,          LD/MLD     Reference
                                       mg/kg bw

                                                                                         

    Dog            ?         sc        3 000-9 000      LD         Abderhalden, 1935

    Dog            ?         iv        3 000            LD         Abderhalden, 1935

    Rabbit         ?         sc        1 000-2 000      LD         Abderhalden, 1935

    Hamster        ?         iv        4 000-8 000      LD         Abderhalden, 1935

    Sheep(1)       ?         po        160              LD         Satapathy & Panda, 1963

    Cattle         M         po        511              MLD        Dinning  et al., 1948

    Cattle(1)      F         po        600              MLD        Stiles  et al., 1970

    Cattle(2)      M         po        1080             MLD        Stiles  et al., 1970

    Ponies         ?         po        3461             LD         Hintz  et al., 1970
                                                                                         

    (1): Not adapted to urea
    (2): Adapted to urea
    

    2.2.2  Short-term toxicity studies

    2.2.2.1  Dogs

         Twelve unilaterally nephrectomized dogs were injected
    subcutaneously with 10% urea solution (3 000-4 000 mg/kg bw) every 8
    hours over a period of 45 days.  Serum urea levels ranged from
    600-700 mg/100 ml ┤ hour after injection.  Except for a mild
    drowsiness and increased diuresis urea did not induce any severe
    toxic symptoms (Balestri  et al., 1971).

    2.2.2.2  Ruminants

         A gradual increase in the amount of urea in rations up to
    1762 mg/kg bw/dy to steers over a period of 70 days did not cause
    distress (Dinning  et al., 1948).  However, without adaptation to
    urea, doses of 166 mg/kg bw/dy and 232 mg/kg bw/dy urea caused
    sudden death in sheep and cattle, respectively (Satapathy & Panda,
    1963).  Tolerance to urea was reduced in starving ruminants and in
    ruminants on a low protein diet (Blood & Henderson, 1963).

    2.2.3  Long-term toxicity/carcinogenicity studies

    2.2.3.1  Mice

         Three groups of 50 C57B1/6 mice of each sex were administered
    either 0.45% (approx.674 mg/kg bw/day) 0.90% (approx.1350 mg/kg
    bw/day), or 4.5% (approx.6750 mg/kg bw/day) urea (no information on
    purity reported) in the diet for 1 year.  The control group
    comprised 100 mice of each sex.  The identity of urea was confirmed
    by melting point comparison.  Biochemical and haematological
    parameters were not included in the study.  No body weight
    depression was noted at terminal necropsy for mice of either sex at
    any dose levels.  Survival of all treated groups were unaffected.

         Among treated female mice there was a significant increased
    occurrence of malignant lymphomas in the middle dose-group.  The
    incidence of malignant lymphomas was 10/92 in controls and 7/43,
    10/38 (p=0.008) and 9/50 in the low-, middle-, and high-dose groups,
    respectively.  The increased incidence of malignant lymphomas among
    middle-dose female mice was of questionable biological significance
    since the occurrence was not dose-related.  Urea was non-
    carcinogenic in this study (Fleischman  et al., 1980).

    2.2.3.2  Rats

         Groups of 50 Fischer 344 rats of each sex were administered
    either 0, 0.45% (approx.225 mg/kg bw/day), 0.90% (approx.450 mg/kg
    bw/day) or 4.5% (approx.2 250 mg/kg bw/day) urea (no information on
    purity reported, identity of urea was confirmed by melting point
    comparison) in the diet for 1 year.  Biochemical and haematological

    parameters were not included in the study.  No body weight
    depression was noted at terminal necropsy for rats of either sex at
    any dose levels.  The middle-dose male rats showed decreased
    survival (89%) relative to controls (95%)(statistics not reported). 
    The survival of the other dose groups remained unaffected.

         Among treated male rats, there was a significant increased
    linear trend (p=0.008), and a higher proportion of interstitial cell
    adenomas of testis in the high-dose group (p=0.004).  The incidence
    of interstitial cell adenomas was 21/50 in the controls, and was
    27/48, 25/48, and 35/50 in the low- middle- and high-dose groups,
    respectively.  The statistically significant increased incidence of
    interstitial cell adenomas in male rats was of questionable
    biological significance since this tumour may occur in 100% of
    controls.  Urea was non-carcinogenic in this study (Fleischman
     et al., 1980).

    2.2.3.3  Ruminants

         A calf received 4.3% urea (approx. 1290 mg/kg bw) in feed over
    a period of 12 months caused.  Increased diuresis was observed
    throughout the experiment.  Histologically, renal hyaline
    degeneration, tubular casts and several areas of liver necrosis were
    found (Hart  et al., 1939).

    2.2.3  Long-term toxicity/carcinogenicity studies

         No information available.

    2.2.4  Reproduction studies

         No information available.

    2.2.5   Special studies on genotoxicity

         The results of genotoxicity studies with urea are summarized in
    Table 1.

    2.3  Observations in humans

    2.3.1  Blood values, distribution, metabolism, excretion and effects
           on other parameters.

         The absorption of urea was studied in 8 healthy fasting male
    volunteers  by means of a colon perfusion technique.  Only 5% of the
    urea perfused through the colon was absorbed.  The authors concluded
    that the colon was relatively impermeable to urea (Wolpert  et al.,
    1971).

         The mean concentrations of blood urea in healthy human subjects
    were 28.9 mg/100 ml (range 16-54 mg/100 ml) in 298 men and 21.7
    mg/100 ml (range 12-47 mg/100 ml) in 278 woman.  Urea levels tended
    to increase with age (Keating  et al., 1969).

         Correlation between blood urea and the content of urea in
    parotid fluid has been found (Shannon & Prigmore, 1961).

         The normal value of urea in saliva (unstimulated) was reported
    to be 3.3 mM/l (200 mg/l) with a range of 2.4-12.5 mM/l.  Daily
    production of saliva varied from 500-1 500 ml (Geigy, 1981a).

         Average daily urinary excretion of urea in adults was estimated
    to be 20.6 g.  The urinary excretion of urea was proportional to
    protein intake and was increased on a high protein diet.  Urea
    excretion was decreased during growth and pregnancy or due to action
    of insulin, growth hormone and testosterone (Geigy, 1981b).

         Urea excretion was also diminished in cases of reduced urea
    formation due to liver diseases (Geigy, 1981b) and nephropathies
    (Mountcastle, 1974).

         The enzyme system necessary for urea synthesis in human fetuses
    was functional when mesonephric glomeruli were present (Kennan
     et al., 1959).

         Urea has been shown to have a neutralizing effect on acidified
    plaque layers produced in the oral cavity after consumption of
    fermentable carbohydrates (Imfield, 1984 & 1985).

    2.3.2  Toxicity

         Four healthy male human subjects received an oral dose of
    15 grams urea (approx.250 mg/kg bw), blood urea rose from 30 mg/100
    ml (mean level prior to treatment) to a mean level of 42 mg/100 ml
    (range: 40-46) within 15 to 60 minutes.  The increased blood urea
    levels returned to normal after 3 hours.  Fifteen patients with
    renal impairment, after similar oral treatment with 15 g urea,
    showed a rise in blood urea from 50 mg/100 ml (mean level prior to
    treatment; range: 26-220) to a mean level of 75 mg/100 ml (range:
    38-299).  The increased blood urea levels returned to the levels
    observed prior to treatment after more than 4 hours (Archer & Robb,
    1925).


    
    Table 1. Results of genotoxicity tests for urea

                                                                                                                          

    Test System                 Test Object                      Concent.        Result       Reference
                                                                 of urea

                                                                                                                          

    In vitro bacterial          S.typhimurium TA98, TA100        ?               Neg.         Ishidate,  et al., 1981
    mutagenicity assay          TA1537

    Mammalian cell              Mouse lymphoma TK locus          329-628 ÁM/l    Pos. (2)     Garberg,  et al., 1988
    mutation assay (1)          assay

    Chromosomal aberration      Chinese hamster fibroblast       16 mg/ml        Pos. (2)     Ishidate & Odashima, 1977
    assay (1)                   cell

    Chromosomal aberration      Chinese hamster fibroblast       13 mg/ml        Pos. (2)     Ishidate  et al., 1981
    assay (1)                   cell

    Chromosomal aberration      Human leucocytes                 50 ÁM (4)       Pos. (3)     Oppenheim & Fishbein, 1965
    assay

    In vivo Chromosomal         Bone marrow cell                 25 g/kg         Pos.         Chaurasia & Sinha, 1987
    aberration assay                                             bw (5)
                                                                                                                          

    (1)  With and without metabolic activation.
    (2)  Only positive without metabolic activation; negative with metabolic activation.
    (3)  The authors considered the positive result as a non-specific effect of high-molarity urea solution on cell division.
    (4)  Concentration, probably per l.
    (5)  The applied oral dose appears unrealistically high, it exceeds lethal dose by several times.
    

         Six healthy subjects were given oral treatment of 2 000 to
    3 000 mg/kg bw urea hourly for a period of 24 hours to induce
    azotaemia.  Serum urea-nitrogen values ranged from 60-120 mg/100 ml
    (approx. blood urea of 128-257 mg/100 ml; [conversion factor for
    "blood urea" {serum urea} to "blood urea-nitrogen" = 2.14]) (Eknoyan
     et al., 1969).

         No toxic effects were found in humans if the blood
    urea-nitrogen was below 45 mg/100 ml (approx. blood urea of
    96 mg/100 ml).  Loss of appetite, nausea and vomiting developed at
    about 70 mg/100 ml (approx. blood urea of 150 mg/100 ml) (Crawford &
    McIntosh 1925).

         Signs of malaise, vomiting, weakness, lethargy, and bleeding
    were noted in patients with renal failure who were loaded with urea
    in the blood at levels of 300-600 mg/100 ml for 60 to 90 days. 
    Blood urea concentrations below 300 mg/100 ml were well tolerated by
    the patients (Johnson  et al., 1972).

         80 patients were hospitalized after ingestion of urea
    fertilizer mistaken for table salt.  The symptoms observed were
    nausea, persistent violent vomiting, excitement, and severe general
    convulsions.  Complete recovery of all patients was observed within
    a few days (Steyn, 1961).

         Six healthy human subjects were maintained at serum
    urea-nitrogen concentrations at 60 to 120 mg/100 ml (approx. blood
    urea of 128-257 mg/100 ml) over a period of 24 hours.  Prolonged
    bleeding time and a drastic reduction of the blood platelet
    adhesiveness was observed in 5/6 subjects (Eknoyan  et al., 1969).

         Oxygen uptake in human blood platelets in vitro was reduced
    7%, 14%, and 19% at urea levels of 100, 300, and 500 mg/100 ml,
    respectively (Schneider  et al., 1967).

         The relationship between plasma urea concentration and low
    birth weight in infants of non-toxaemic mothers was investigated. 
    16 infants with low birth weight had a statistically significantly
    higher mean plasma urea concentration of 23.2 mg/100 ml in
    comparison with a mean value of 18.6 mg/100 ml in 90 infants with
    normal birth weight (p<0.02) (McKay & Kilpatrick, 1964).

         Ingestion of 60 grams of urea per day (approx. 1 000 mg/kg
    bw/day), in divided doses, over a period of 3 1/4 days, resulted in
    prolonged clearance time of glucose in adults (Perkoff  et al.,
    1958).

         The irritant potential of urea dissolved in water was
    determined on human scarified skin.  On the third day following
    daily application, a solution of 7.5% urea showed slight skin
    irritation, and a solution of 30% urea showed marked skin

    irritation.  A solution of 30% urea did not affect normal skin
    (Frosch & Kligman, 1977).

         Intra-amniotic injection of up to 300 ml 30% urea solution has
    been used to induce therapeutic abortion (Anteby  et al., 1973).

    2.3.3  Drug interactions

         Treatment of 40 men suffering from sulfonamide-resistant
    gonorrhoea with urea (500 mg/kg bw/dy) for a period of 3 days
    enhanced the effect of sulfonamide in 52% of the patients.  A
    combination of urea and sulfathiazole inhibited the growth of
    gonococci  in vitro, although neither alone was effective
    (Schnitker & Lenhoff, 1944).

         The inhibitory effect of sulfadiazine on the growth of  E.coli
     in vitro was enhanced in combination with urea (Tsuchiya  et al.,
    1942).

    2.3.4  Use in human medicine

         Urea has been used in human medicine as diuretic at doses of 15
    to 60 grams/day.  The mechanism of the diuretic effect originates
    from increased glomerular filtration due to osmotic action of urea
    (Sollmann, 1957).

         In the oral therapy of sickle-cell anaemia, urea at doses of
    667-2 000 mg/kg bw/day, in divided doses, was given for periods of
    3 weeks to 9 months.  Side effects included increased diuresis,
    thirst, gastrointestinal discomfort, nausea and vomiting (Bensinger
     et al., 1972).

    3.  COMMENTS

         The Committee reviewed biochemical studies, short-term toxicity
    studies in dogs and ruminants, carcinogenicity studies in rats and
    mice, mutagenicity studies, and studies on effects in human
    volunteers.  It noted that most of the available data were either
    inadequate or of little relevance for the evaluation of urea as a
    food additive.  As urea is a naturally-occurring constituent of the
    body, the Committee carried out its  evaluation in accordance with
    the principles relating to materials of this type outlined in
    Annex 1, reference 76.

    4.  EVALUATION

         Since urea is a natural end-product of amino acid metabolism in
    humans, and that approximately 20 grams/day is excreted in the urine
    in adults (proportionately less in children) the Committee concluded
    that the use of urea at levels of up to 3% in chewing-gum was of no
    toxicological concern.

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    See Also:
       Toxicological Abbreviations
       Urea (ICSC)
       UREA (JECFA Evaluation)
       Urea  (SIDS)