2011 EPA Toxicological review of urea

2011 EPA Toxicological review of urea

6.1. HUMAN HAZARD POTENTIAL

Urea (CASRN 57-13-6), also known as carbamide, is an endogenous product of protein and amino acid catabolism. It can also be produced synthetically by combining ammonia, carbon monoxide, and sulfur in methanol. It is used in a variety of applications including fertilizers, animal feed, plastics, flame-proofing agents, diesel-SCR, flavoring agent in foods, and in the manufacture of consumer goods such as liquid soaps, detergents, and household cleaning products.

In the occupational setting, the most notable routes of exposure are inhalation and dermal, while the general population might be exposed to urea through consumption of food and drinking water and through dermal contact with urea-containing products.

There is limited ADME information on exogenous urea. There are limited studies that evaluate the possible association between oral exposure to urea and noncancer effects in humans. There is limited information to suggest that the liver, kidney, and pituitary could be targets of urea toxicity. Results from reproductive and developmental studies have been inconclusive. There have been few studies that have evaluated the effects of urea via inhalation. The available studies suggest that the impact of urea exposure on lung function is minimal. With regard to dermal effects, the available studies showed that there is a dependence on the vehicle used and effects are typically manifested in the form of skin irritations.

The human carcinogenic potential of urea and urea-containing mixtures has been evaluated in a limited number of studies. Some studies that evaluated urea-containing mixtures indicate that urea exposure may have contributed to the occurrence of tumor development, or increased sister chromatid exchange and chromosome aberration frequency, but its role in producing the observed effects was not clearly established. One occupational study showed that exposure to urea increased levels of potential carcinogenic biomarkers but these increases were within the normal physiologic range Chronic studies in rats and mice have shown no treatment-related increase in tumors following either oral or s.c. administration.

Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), there is "inadequate information to assess the carcinogenic potential" of urea. Epidemiologic studies of humans chronically exposed to urea alone or urea-containing mixtures are limited. Urea has been tested for genotoxic potential and has shown no mutagenic effects in bacterial systems; however, chromosome aberrations have been noted in certain mammalian test systems, and hence, the role of genotoxicity in the process of urea-induced carcinogenicity cannot be eliminated.

6.2. DOSE RESPONSE

6.2.1. Noncancer-Oral and Inhalation

Oral exposure studies of urea were not adequate for the determination of an RfD. The available animal studies identify the liver and kidney as potential target organs for the toxicity of urea; however, the available information is insufficient to fully characterize toxicity outcomes or dose-response relationships. Inhalation data were inadequate for the determination of an RfC. The occupational data lacked quantitative exposure measurements. The cited therapeutic study on lung function was based on acute exposure and had limited information on which to derive an RfC. No studies of inhaled urea in experimental animals were identified.

6.2.2. Cancer-Oral and Inhalation

One oral cancer bioassay is available for consideration for the derivation of an oral slope factor for urea. However, the limitations of the study data preclude the derivation of an oral cancer slope factor. Inhalation studies for urea were not adequate for the determination of an inhalation unit risk value. Route extrapolation from oral bioassay data was not performed due to the lack of oral data and suitable kinetic data.