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

15 N-labelled urea in the diet. Fifty-two per cent of the

administered 15 N-labelled urea was excreted in the urine after 48 hours and 1.9% during the subsequent 48 hours. Faecal 15 N excretion over 96 hours accounted for only 1.3% of the amount

administered. Less than 1% of the 15 N was found in the liver, muscle and blood cells, study concluded that this indicates incorporation of 15 N in body proteins. Only 60% of the

administered 15 N was recovered (Grimson et al., 1971).

In another study, the distribution of 14 C-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). 

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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 

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9/23/2009 htt p ://www.inchem.or g /documents/ j ecfa/ j ecmono/v32 j e16.htmparameters 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 

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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 μM/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 μM (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 

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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.

5. REFERENCES

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ANTEBY, S.O, SEGAL, S. & POLISHUK, W.E. (1973). Termination of midtrimester pregnancy by intra-amniotic injection of urea. Obstetrics & Gynaecology, 43, 765-768.

ARCHER, H.E & ROBB, G.D. (1925). The tolerance of the body for urea

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BLOOD, D.C & HENDERSON, J.A. (1963). Veterinary Medicine . 2nd Edition, Balliere, Tyndall & Cassell, London. p.1077.

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Lancet, 2, 1387-1390.

See Also: Toxicological Abbreviations Urea (ICSC) 

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