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EC number: 225-716-2
CAS number: 5026-74-4
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.
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
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).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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