5,5-Dimethylimidazolidine-2,4-dione, reaction products with oxirane

Endpoint summary

Description of key information

There are no specific studies available on the ADME of Dantocol DHE. However, data is available from the physico-chemical parameters, in vitro and in vivo toxicology studies and these have been employed to predict the ADME for this substance.

 

Absorption

Oral route

The physico-chemical characteristics of Dantocol DHE suggest that the UVCB may be absorbed via the gastro-intestinal tract. The UVCB contains mono, di, tri and tetra ethoxylated isomers and the MW covers a range (not more than 500) with approximately 77% of Dantocol DHE comprising of the diethoxylated isomers (MW of 216). The low MW taken together with a Log P of 1.32 and high water solubility are indicative of high absorption following oral exposure. A pKa (dissociation constant) in water has not been determined.

The low toxicity in the oral toxicity studies may be a function of innate low toxicity associated with the structural and functional characteristics of the molecules in the UVCB given that appreciable oral absorption is likely to occur.

 

Dermal exposure

Dantocol DHE is a waxy solid with a range of MW (with approximately 77% of the composition being the diethoxylated isomers with a MW of 216) and a Log P value of 1.32. It is miscible in water at any proportion. These parameters suggest that the substance may be capable of significant systemic absorption through the dermal route. This is because the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis.

The low acute dermal toxicity (as indicated by an LD50 of over 2000 mg/kg bw) taken together with the lack of skin sensitisation and irritation suggests that this UCVB has low toxicological activity to the skin given that absorption is likely.

 

Inhalation route

Dantocol DHE is not expected to be highly volatile given that vapour pressure is 0.0021 Pa at 25°C and boiling temperature is 657K ± 0.5K at 98.7kPa. Therefore, significant exposure as a vapour is unlikely. The substance is a waxy solid and therefore it is not technically possible to determine a particle size. However, in the absence of further information any absorption via this route should be assumed to be 100% given that Dantocol DHE is water soluble.

 

Ocular route

Dantocol DHE is moderately irritating to the eyes as evidenced by effects observed following ocular exposure of New Zealand White rabbits. The substance caused redness and swelling of the conjunctiva in all animals and ocular discharge was seen in 5 of the 6 animals. Moreover, reversible adverse ocular effects were reported in an acute inhalation toxicity study in rats. This may be indicative of some ocular absorption. Equally, this could also be as a result of the toxicological activity of Dantocol DHE via this route of exposure.

 

Distribution

There are no studies available to evaluate the systemic distribution of Dantocol DHE. The low acute toxicity findings from the oral, dermal and oral repeated dose studies provide no evidence regarding the systemic distribution of Dantocol DHE. Given that the UVCB is soluble in water it is likely that Dantocol DHE would be distributed in the organs within the body at appreciable levels. In the absence of other information it is not possible to make conclusions on the distribution of Dantocol DHE in the body.

 

Metabolism

There are no studies available to evaluate the metabolism of Dantocol DHE. However, Dantocol DHE did not induce mutagenicity or genotoxicity in in vitro studies both in the presence and absence of a metabolic activation system. This could be indicative of a lack of metabolism of the parent compounds, however this could also be taken to mean that both the parent compounds and any metabolites that are formed are not mutagenic or genotoxic. Indeed, the substance was also negative in an in vivo genotoxicity assay.

 

Excretion

There are no studies available to evaluate the excretion of Dantocol DHE. The MW of Dantocol DHE is a range because it is a UCVB. Small organic compounds are more likely to be excreted in the urine. Biliary excretion is more likely for high MW compounds either because of biotransformation by phase 2 conjugation or because the parent is innately large (>500 MW). Therefore it is possible that the smaller molecules in Dantocol DHE may be excreted via the urine. This is expected for the majority of Dantocol DHE given that approximately 77% of the UVCB is in the form of the diethoxylated isomers with a MW of 216. The UVCB contains mono, di, tri and tetra ethoxylated isomers and none of these will have a MW >500 so it is likely that urinary excretion will predominate. However, there is no conclusive evidence for this and it will depend on the extent of metabolism.

 

Summary and conclusions

Dantocol DHE is a UCVB and is comprised of a range of MW with the major constituents (diethoxylated species) being approximately 216, it is water soluble and has a Log P of 1.32. The MW range and physico-chemical properties of Dantocol DHE indicate that it is likely to be absorbed via the oral and dermal routes of exposure. The available toxicology studies show that there are no adverse effects associated with acute (oral and dermal) and repeated dose (oral) exposure to Dantocol DHE and it is not a skin sensitiser nor is it a skin irritant. This is suggestive of a function of innate low toxicity as opposed to low bioavailability by the oral and dermal routes of exposure. Exposure via the inhalation route to Dantocol DHE is unlikely given that the substance has a very low vapour pressure. However, in the absence of further information any absorption via this route should be assumed to be 100%. There is no evidence regarding the distribution, metabolism, metabolite fate or excretion of Dantocol DHE. Excretion via the kidneys is considered likely based on the Log P and relatively low MW of the constituents of the UVCB. There was no information on bioaccumulation but based on the Log P of 1.32 significant bioaccumulation is unlikely.