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EC number: 200-315-5
CAS number: 57-13-6
Negative results are reported in three Ames tests. Positive in vitro
results are reported in assays for mutagenicity and clastogenicity in
mammalian cells, however the value of these studies are limited by the
extremely high test concentrations.
vivo results for chromosome aberration have been reported are at
high doses and test concentrations, however specific conclusions are not
possible due the lack of study details, especially in studies that
evaluated the genotoxicity of multiple chemicals. Urea did not induce
sperm head abnormalities. Based on its physiological role and presence
in the body at high concentrations, urea is not considered to be
Genotoxicity in vitro
The potential mutagenicity of urea was investigated in a screening assay
performed in S. typhimurium TA98, TA100 and TA1537 according to
the published method of Ames et al (1977), with a pre-incubation
step and in the absence and presence of an exogenous source of metabolic
activation. No evidence of mutagenicity was seen under the conditions of
this assay (Ishidate et al, 1981).
The mutagenicity of urea was determined in the Ames test using Salmonella
typhimurium and Escherischia coli, with and without S9
metabolic activation. The substance was not mutagenic at any of the 7
concentrations tested (Shimizu et al, 1985).
The potential mutagenicity of urea was investigated in a
guideline-comparable Ames test (pre-incubation assay). Triplicate
cultures of S. typhimurium TA97, TA98, TA100, TA1535 and TA1537
were exposed to urea (dissolved in water) at five concentrations between
10 -10000 ug/plate in the presence and absence of an exogenous metabolic
activation system (Aroclor 1254 -induced male Sprague-Dawley rat and
male Syrian hamster liver S9;). Exposure to urea caused cytotoxicity in
some strains. The numbers of revertant colonies were not increased by
exposure to urea. Appropriate positive controls confirmed the
sensitivity of the assay (Mortelmans et al, 1986).
Ishidate et al (1981) report the results of a chromosomal
aberration assay performed in CHL cells with a number of chemicals,
including urea. Approximately 10e5 cells were plated and exposed to
concentrations of urea up to the concentration causing 50% growth
inhibition, in the absence and presence of PCB-induced Wistar rat liver
S9-fraction. Cells were harvested at 24 and 48 hours (-S9) or at 24
hours following a 3-hour pre-incubation step (+S9). Chromosomal
aberrations (including numerical aberrations) were scored from 100
well-spread metaphases per concentration. A positive result is reported
in this assay, however the DT20 value (the concentration at which 20% of
cells or approximately 4x background) of 13.0 mg/mL or 216 mM is well in
excess of the limit concentration of 5 mg/ml or 10 mM recommended by
OECD 473 (1997). The authors note a very low clastogenic potential.
Considering the high concentrations of urea required to produce a
response in this assay, which are well in excess of the limit
concentration, it cannot be concluded that urea is clastogenic. The
finding in this study is very likely to be a false positive due to
The same group (Ishidate & Odashima, 1977) tested urea for the ability
to cause chromosomal aberrations in a screening assay in CHL cells in
vitro in the absence of metabolic activation and at concentrations up to
those causing 50% growth inhibition. A positive result is reported at a
concentration of 266.4 mMol/L, which is well in excess of the limit
concentration of 10 mM. The result is considered to be a false positive
and is attributable to the effects of osmolarity.
Mammalian cell mutation
The potential mutagenicity of urea was investigated in a mouse lymphoma
assay in the absence of metabolic activation. A weak positive response
was seen at concentrations of 265 -662 mMol/L, concentrations which also
caused cytotoxicity and which are well in excess of the limit
concentration of 10 mMol/L recommended in OECD 476 (1997). The result is
considered to be a false positive. The authors conclude that the effect
is due to the influence of high concentrations of urea on the osmolarity
of the culture medium (Wangenheim & Bolcsfoldi, 1988).
The ability of urea to cause DNA damage was assessed in two
DNA-unwinding/alkaline elution assays. Garberg et al (1987),
report positive effects in mouse lymphoma cells at high concentrations
of 628 and 718 mMol/L, however negative results are reported by Sina
et al (1983) at concentrations of up to 3 mMol/L in cultured rat
Genotoxicity in vivo
Chaurasia & Sinha (1987) investigated the potential of urea to cause
chromosomal aberrations in the bone marrow of Swiss mice. Mice (number
unspecified) were administered urea in the diet at a dose level of 500
mg/day for 5 days. Animals were sacrificed after a recovery period of 7
days and the bone marrow harvested. A total of 300 metaphases from
treated animals and untreated controls were assessed for chromosomal
aberration. A marked increase in the incidence of chromosomal
aberrations was seen in the treated group (7x controls). However the
dose level administered in this study is equivalent to 16 -17 g/kg
bw/day and is thus far in excess of the limit dose of 1000 mg/kg bw.
Signs of toxicity are not reported, but marked toxicity can be predicted
at this dose level.
Chaurasia (1991) and
Chaurasia and Sinha (1987) conducted in vivo experiments in 7–10-week-old
male Swiss albino mice fed with urea (500 mg/kg-day) for 5–7 days. Bone
marrow samples were collected 7 days after the last treatment and a
minimum of 100 metaphases were examined. Both studies showed that urea
was capable of inducing chromosomal aberrations. Among several types of
chromosomal aberrations found, chromatid breaks were the most frequent.
The authors concluded that urea may be a potent clastogen. On the
of 3–4-month-old male Swiss albino mice to 0.1825–0.7300 mg/day via food
for up to 28 days did not show an increase in bone marrow chromosomal
aberrations (Kommadath et al., 2001). The lack of consistency between
the two groups of studies is likely due to the difference in the dose.
Additionally, urea did not induce sperm head abnormalities in five male
(CBA BALB/c) F1 mice that were assayed 5 weeks after receiving five
daily i.p. injections of urea (up to 2,000 mg/kg-day) (Topham, 1980).
Positive results obtained in vitro are associated with
concentrations well in excess of the recommended limit concentrations
are not considered to be of biological relevance. A positive result in
vivo is also associated with an excessive dose level. Considering
the physiological role and presence of substantial quantities of urea in
the human body, it is not considered likely that this substance is
genotoxic. Further testing for genotoxicity is not proposed.
No classification is proposed for genotoxicity. Urea is produced by the
body in large quantities as a normal product of metabolism and is
present in the bloodstream at high concentrations. Urea is therefore
considered extremely unlikely to be genotoxic.
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