6-methyl-2-oxoperhydropyrimidin-4-ylurea

Endpoint summary

Description of key information

No studies are available. Based on molecular structure, molecular weight, water solubility, and octanol-water partition coefficient it can be expected that 6-methyl-2-oxoperhydropyrimidin-4-ylurea (Crotodur, CAS 1129-42-6) is likely to be absorbed via the oral route, but not via the dermal route. If inhalation exposure occurs, the particles are not considered to be inhaled. However, once available in the alveolar region, the submission substance has the potential to be absorbed from the respiratory tract epithelium.
Due to the moderate water solubility and the low molecular weight, distribution in the body is likely, and excretion via the renal route can be expected. Data from a close structural analogue substance (N,N”-(2-methylpropane-1,1-diyl) diurea, Isodur, CAS 6104-30-9) support metabolism of the submission substance. The bioaccumulation potential is expected to be low. 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic properties of 6-methyl-2-oxoperhydropyrimidin-4-ylurea (Crotodur, CAS 1129-42-6) have been investigated. Therefore, the toxicokinetic behaviour assessment of the registration substance was estimated by its physico-chemical properties and the available toxicology studies.

 

The molecular weight and the predicted water solubility of Crotodur are 172.2 g/mol and 5100 mg/l at 20°C, respectively. Thus, the submission substance is small in size and water soluble, suggesting that it will have the potential to be absorbed through biological membranes. Furthermore, the measured moderate log Kow of -1.34) indicates that this substance is lipophilic enough to efficiently pass through biological membranes by passive diffusion. However, due to its low molecular weight and its high water solubility, it also has the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

 

Absorption

Oral: Based on the low molecular weight, the moderate log Kow, and its water solubility, absorption of the submission substance via the gastrointestinal tract is considered possible. The predicted water solubility (5100 mg/l) suggests that registered substances will readily dissolve in the gastrointestinal fluids. Together with the low molecular weight (172.2 g/mol) the substance is assumed to have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Furthermore, the moderate log Kow of -1.34 suggests that Crotodur is lipophilic enough to be absorbed by passive diffusion.

However, an acute oral toxicity study in rats (BSL, 2012a) with Crotodur given by gavage did not show signs of systemic toxicity and reported a LD50 of >2000 mg/kg body weight. Thus, the submission substance is expected to be of low toxicological activity once it is systemically available.

 

Inhalation: No acute inhalation toxicity data are available to assess the bioavailability of Crotodur, therefore, the toxicokinetc behaviour assessment for the inhalation route will be estimated solely by its physico-chemical properties.

The submission substance is a solid at ambient conditions. The low vapour pressure of Crotodur indicates that inhalation of the registered substance as a vapour is not likely to occur. Similarly, the particle size distribution revealed that 94.2% of the test article particles have a diameter of >1000 µm and are therefore not respirable. Only 1.4% of the particles are smaller than 500 µm. However, no data is given on the fraction of inhalable particles (<100 µm), especially not on those particles <15 µm, which may reach the alveolar region of the respiratory tract. Nevertheless, due to the overall distribution of the particle size, the inhalable fraction, especially the alveolar fraction, is expected to be very small and inhalation of the submission substance is therefore considered negligible.

However, if inhalation accidentally occurs, absorption from the respiratory tract epithelium by passive diffusion is likely, based on the predicted moderate water solubility (5100 mg/l) and log Kow (-1.34) of the submission substance. Deposition of Crotodur in the mucociliary blanket is not expected, since the submission substance is considered to be not hydrophilic enough.

 

Dermal: Since the submission substance is a solid, it has to dissolve first before absorption via the dermal route is possible. The moderate water solubility (5100 mg/l), log Kow (-1.34) and low molecular weight (172.2 g/mol) of Crotodur suggest that absorption via the dermal route is possible. However, QSAR based dermal absorption calculation revealed a dermal penetration rate of 0.00004 mg/cm²/h (DERMWIN 2012), indicating a very low dermal absorption potential (10%). Since the submission substance does not exhibit skin irritating properties, dermal absorption is not further enhanced. Data from a skin sensitisation study with Crotodur showed no skin sensitising potential, indicating that dermal absorption of the substance might not have occurred. Additionally, acute toxicity data from a close structural analogue substance (N,N”-(2-methylpropane-1,1-diyl) diurea, Isodur, CAS 6104-30-9) showed no systemic toxicity after dermal application and revealed a LD50 exceeding the limit dose of 2000 mg/kg bw (Bioassay, 2008). It can therefore be concluded, that systemic availability of Crotodur after dermal application is unlikely.

 

Distribution

The low molecular weight (172.2 g/mol) and moderate water solubility (5100 mg/L) of the submission substance suggest it will diffuse through aqueous channels and pores and will be widely distributed. The log Kow of -1.34 suggests that Crotodur is unlikely to distribute into cells and therefore the extracellular concentration may be higher than the intracellular concentration. Accumulation in the body is not favorable for the registered substance. Data from a close structural analogue substance N,N”-(2-methylpropane-1,1-diyl) diurea (Isodur, CAS 6104-30-9) support that Crotodur will be distributed via blood plasma (Bergner H., et al., 1977, Bergner H. et al, 1978 and Görsch R., 1980, as cited in: Anonymous, 1993).

 

Metabolism

No data are available for the submission substance. Data obtained from genotoxicity studies with and without metabolic activation system (rat liver S9 microsomal fraction) showed no differences in bacteriotoxicity or mutagenicity, thus giving no indication for the formation of genotoxic metabolites of Crotodur (BSL, 2012). However, data from the close structural analogue substance Isodur suggest that the submission substance will be broken down into nitrogen-free and nitrogen-containing metabolites (Bergner H., et al., 1977, as cited in: Anonymous, 1993).

 

Excretion

Crotodur is water soluble and has a molecular weight below 300 g/mol. Therefore, traces of the submission substance, which were not metabolised, are expected to be excreted predominantly via the renal route. Data from the close structural analogue substance Isodur suggest that nitrogen-free and nitrogen-containing metabolites will have different major excretion pathways: nitrogen-free metabolites will be mainly excreted via the respiratory tract; nitrogen-containing metabolites are assumed to be predominantly excreted via the gut and the urine (Bergner H., et al., 1977, as cited in: Anonymous, 1993).

 

 

References: 

Anonymous (1993). Toxikologische Bewertung. Heidelberg, Berufsgenossenschaft der chemischen Industrie 204:17.

Bergner H., et al. (1977). Arch. Tierernaehrung 27:3-23.

Bergner H., et al. (1978). Arch. Tierernaehrung 28(8):575-583.

Görsch R. (1980). Arch.Tierernaehrung 30:221-228.