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Description of key information

12-month carcinogenicity screening studies in the rat and mouse demonstrate that urea is of very low chronic toxicity by the oral route.  Similarly, no evidence of local or systemic toxicity was seen in 4-week and 25-week dermal toxicity studies in the rat.  No clear toxicity was seen in dogs administered high doses of urea by subcutaneous injection over a period 45 days.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
2 250 mg/kg bw/day

Additional information

Repeated dose oral toxicity

In 12 -month carcinogenicity screening assays (Fleischman et al, 1980), F-344 rats and C57BL/6 mice (50/sex/group) were exposed to urea in the diet at concentrations of 4500, 9000 or 45000 ppm for 12 months. Five animals/sex/group were sacrificed at the end of the 365-day exposure period and a comprehensive list of tissues was investigated histopathologically; interim deaths were similarly investigated. All remaining animals were sacrificed after the 4-month recovery period and investigated histopathologically. There were no signs of toxicity. Survival and bodyweights were unaffected by treatment. Gross and microscopic pathology did not reveal any treatment-related effects. It is concluded that urea is of very low chronic toxicity. Using default conversion factors, the dose level of 45000 ppm is calculated to be equivalent to approximately 2250 mg/kg bw/d in the rat and 6750 mg/kg bw/d in the mouse.

Repeated dose dermal toxicity

In 4 -week and 25 -week dermal toxicity studies, urea (formulated as an ointment) was applied to the shorn dorsal skin of groups of male and female Wistar rats. Bodyweights were measured; food and water consumption were assessed. Clinical chemistry, urinalysis and haematological parameters were investigated. At necropsy, organ weights were recorded; gross necropsy and histopathology were performed. No dose-dependent toxicity was observed. Bodyweights, food and water consumption were unaffected by treatment. Clinical chemistry, haematology and urinalysis parameters were comparable in all groups. There was no effect of treatment on organ weights or pathology (Sato et al, 1977).

Repeated exposure inhalation toxicity

Urea is demonstrated to be of very low toxicity by the oral and subcutaneous routes. The substance is a non-volatile solid produced as crystals with particle sizes of >0.1 mm. There is therefore no potential for inhalation exposure. The data requirement is therefore waived on scientific grounds and on exposure considerations. Testing is additionally not justified on animal welfare grounds.

Repeated dose toxicity by other routes of exposure

Twelve unilaterally nephrectomised dogs were injected subcutaneously with 10% urea solution (3000-4000 mg/kg bw) every 8 hours over a period of 45 days. Administration led to increased diuresis, plasma urea levels were 200 - 700 mg/100ml. The dogs displayed mild drowsiness. Haematocrit, platelet counts and EEG were not affected. The study indicates that urea is of very low toxicity in the dog following repeated administration (Balestri et al, 1971).

Justification for classification or non-classification

No classification is proposed. Urea only showed signs of very low chronic toxicity.

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