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). 

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 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 

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 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 

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

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 BALESTRI, P.L., RINDI, P. & BIAGINI, M. (1971). Chronic urea 

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 Recognized As Safe (GRAS) Food Ingredients - Urea. Report No.: 

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 See Also: 

 Toxicological Abbreviations

 Urea (ICSC)

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 UREA (JECFA Evaluation)

 Urea (SIDS)

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