p-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline

Endpoint summary

Description of key information

It is known from similar substances that the glycidyl ether substituents are determining the toxicity profile of the substance.  It is considered that  genotoxicity and skin sensitization and irritation are due to the  glycidyl ether substituent. Glycidyl ethers are rapidly cleaved by hydrolysis by epoxyde hydrolases present in the skin, in the liver and in most tissues. Epoxyde hydrolases are therefore a very efficient mechanism of detoxification.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The available toxicity data show that the substance as described in section 1 is bioavailable. No data on the absorption rate is available. The substance is not lipophilic and therefore there is a very low bioaccumulation potential. The substituent determining toxicity are likely the glycidyl ethers because they can bind to DNA and/or protein. Following absorption the glycidyl ether functions of the substance are considered to be rapidly hydrolysed and the substance detoxified. At high doses this metabolic pathway may be overloaded resulting in the presence of the unmetabolised substance in circulation. It is considered that the hydrolysed substance is either further metabolised or excreted by the kidneys.

Bioavailability is defined as the proportion of a drug or other substance which enters the circulation when introduced into the body and so has the ability to have an active effect. It is well documented within literature that LogKow, molecular weight and molecular flexibility, measured by number of rotatable bonds, low polar surface area or total hydrogen bond count are all important predictors of oral bioavailability (Veber et al. (2002)). Based on these principles it can be concluded that the bioavailability of p-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline and m-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline will be comparable. It should however, be noted that for p-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline the LogKow is fractionally lower and subsequently this leads to improved aqueous solubility. This increased solubility may result in better gastrointestinal dispersion thereby toxicological endpoints for this isomer may be more conservative than those determined with the m-isomer.

Further supporting the hypothesis that bioavailabilty will be slightly improved and that data generated with the p-isomer will be conservative e.g. protective of the m-isomer is the difference in hydrolysis whereby at all pHs the DT50 of the p-isomer was ca. 2 days compared to 5 days for the m-isomer. It should also be noted that following oral gavage hydrolysis and production of transformation products will be fastest under the acid conditions of the stomach. This is concluded based on the positive correlation between increasing pH and increasing DT50. Any untransformed parent material that passes from the acid condition into the neutral pH duodenum/intestine could therefore lead to some target organ toxicity as the rate of transformation is likely to reduce with pH and residence time increase due to the slower transit times that occur in the duodenum (ca. 25 mins in stomach and 30 to >120 mins depending on which quarter of the duodenum/intestine that site of contact is occurring Purdon and Bass (1973).