Methylurea

Carcinogenicity

Description of key information

In vivo
(1) Multi-organ Carcinogenesis Bioassay: No carcinogenic activity identified in rat (male/female), (no guideline followed, Kitano 1997)
(2) Carcinogenic effect investigated in mongrel rabbits (male / female): negative (no guideline followed, Schneider 1977)
(3) Investigation of neurogenic and lymphoid neoplasms by methylurea given in drinking water to rats: negative (no guideline followed, Koestner 1978). The incidence of non-neurogenic tumours increased with the survival time and was unrelated to the treatment.   
(4) Investigation of colon tumors using intrarectal installations of methylurea in rats (male): negative (no guideline followed, Narisawa 1976)
In vitro
Mammalian cell transformation assay using Chinese hamster lung (CHL) cells: negative up to 40 µg/mL (no guideline followed; Ishidate and Kada 1980)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the data, classification of 1-methylurea for carcinogenicity according to directive 67/548/EEC and Regulation (EC) No. 1272/2008 is not possible. .

Additional information

There are no studies available comparable to guideline. Due to methodological deficiencies, the available studies were not reliable or not assignable.

In vivo

In a ratmulti-organ carcinogenesis modelfollowing no guideline (Kitano 1997) used for carcinogenic risk assessment of combinations of N-nitroso precursors in man, the carcinogenic potential was investigated after feeding methylurea (MU) and / or sodium nitrite (NaN0₂). In experiment 1, to initiate multiple organs, groups of 10 or 20 male F344 rats were treated with 6 carcinogens targeting different organs. Starting a week after completion of this initiation phase, animals were given 0.1% MU in their food and/or 0.15% NaNO₂in their drinking water for 23 weeks. The induction of tumors and/or preneoplastic lesions in the forestomach and esophagus was significantly increased in the group receiving MU plus NaN0₂. The numbers and areas of liver glutathione S-transferase placental form (GST-P)-positive foci were significantly elevated with MU plus NaNO₂. Treatment with initiating carcinogens and MU alone resulted in a not significantly enhanced number of papillary or nodular hyperplasia in the forestomach. There was no treatment group with MU without initiation. Therefore, the treatment related effects of MU without NaNO₂were not assessable.

 

In the second study the carcinogenic activity of ca. 30 mg/kg bw/d methylurea (0.1 % in food) with or without simultaneous application of ca. 59 mg/kg bw/d sodium nitrite (0.1 % in tap water) given continuously for duration of 100 days was studied in 6 to 13 young adult male and female mongrel rabbits (Schneider 1977). After a post-exposure period of > 400 days, the development of neoplasms was investigated.

Only a small number of neoplasms, partly benign, partly malignant, were detected in the digestive tract of the animals at least 500 days after beginning of the study. According to the authors, none of the neoplasms could be clearly attributed to the administered test substances. The authors stated that the negative result of the study might be due to the relatively low substance concentrations that were administered to the animals.

The study was documented rather briefly; results were presented only in tabular form. No information was given on results determined after methylurea administration alone as well as on important parameters, such as tumor type, incidence, and multiplicity or latency time.

 

In a third study, a two year food and drinking water study, 30 days old in total 20 Sprague-Dawley rats in each experiment group were treated 2 years continuously with ca. 10 and 27 mg/kg bw/day methylurea added to the drinking water at concentrations of 0.01 and 0.03 % (w/w) and ca. 135 mg/kg bw/day sodium nitrite in a concentration of 0.3 % (w/w) in the food (Koestner 1975). The induction of neurogenic and lymphoid neoplasms was examined macroscopically in the brain, spinal, cord and major peripheral nerves.

The percentage of rats with non-neurogenic tumors was 80% in the group with methylurea treatment alone compared to 90 % in the combined treatment group. The incidence of non-neurogenic tumours increased with the survival time and was unrelated to the treatment with the carcinogenic precursors.

 

In the forth study, 28 male rats were given intrarectal installations of methylurea (ca. 6.0 mg/kg bw/d (1.8 mg/rat) with and without simultaneous administration of sodium nitrite)3 times per week for 20 weeks (Narisawa 1976). Animals were autopsied and pathologically investigated. One group of animals (20 rats) was held for a total of 56 weeks with a post-exposure period of 36 weeks. In a third group, rats received methylurea alone dissolved in 0.5 ml of a solution buffered to pH 4.5 with 0.1 N hydrochloric acid. No colon tumors were found in rats given the mixture of nitrite and methylurea for 20 weeks and held for an additional 36 weeks, none presented with colon tumors. The control group of 20 rats given NaNO₂alone had no colon tumors. In contrast, the group of 16 rats given methylurea alone in an acidic solution adjusted to pH 4.5 produced tumors in the colon. Adenomas were found in 3 animals; a polyploid lesion was found in another rat of this group.

According to the authors, these findings of a few tumors in rats given methylurea at a pH at which this substrate is readily nitrosable suggest that the large bowel might contain a source of nitrite. However, i.r. administration of a mixture of methylurea and nitrite for 20 weeks and further observation of the rats for an additional 36 weeks yielded no colon tumors. Thus, there is indirect evidence of lack of the in situ formation of carcinogenic MNU in the large bowel under physiological conditions. The study design and the results were presented in a rather brief manner; only one dose level was tested.

 

In vitro

In a mammalian cell transformation assay following no guideline (Ishidate and Kada 1980), Chinese hamster lung (CHL) cells were exposed to Methylurea at the test concentration 40 µg/ml. No cell transforming activity was observed in the colony assay.

A pulse-conductivity technique using the electron attachment constant (ke) was performed to screen potential carcinogenic activity by measure of the rate at which excess electrons in liquid cyclohexane attach to carcinogens and non-carcinogens, respectively (Bakale and McCreary 1987, Chapter 7.12).

The k_eresponse for methylurea resulted in an electron attachment / detachment equilibrium. Since none of the chemicals for which an equilibria had been observed are carcinogens, however, the authors decided to regard an electron attachment / detachment equilibrium as a negative indication of carcinogenicity. 

Accordingly, for methylurea, a negative response was obtained with the k_etest and the authors assessed methylurea as not carcinogenic.

Conclusion: Methylurea has not been tested for its carcinogenic activity in a guideline conform study. It is noted, however, that nitrosation of methylurea may occur with nitrite, resulting in the formation of nitrosoureas. Nitrosoureas have been shown to be carcinogenic (Hill M 1988. N-Nitroso compounds and human cancer. In Nitrosamines: Toxicology and Microbiology, ed Hill M. Ellis Horwood Ltd., Chichester, pp.142-162.Koehl W Eisenbrand G (1999) N-nitroso compounds. Toxicology; eds: Marquardt H et al., London, Academic Press).