Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Objective of study:
other: adsorption, desorption, metabolism and excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
QSAR
GLP compliance:
no

Results and discussion

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
the toxic effects of 2-propenenitrile, reaction products with 1,3-benzenedimethanamine will depend mainly on the capability to act as organic bases and also to be included in metabolic reactions leading to the formation of the reactive metabolites β-aminopropionitrile and 3,3′-iminodipropionitrile.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results see it in the attachement
the toxiceffects of2-propenenitrile, reaction products with 1,3-benzenedimethanaminewill depend mainly on the capability to act as organic bases and also to be included in metabolic reactions leading to the formation of the reactive metabolitesβ-aminopropionitrile and 3,3′-iminodipropionitrile.
Executive summary:

1.     The possible mechanisms of toxicity of2-propenenitrile, reaction products with 1,3-benzenedimethanaminecould be associated with the presence of some structural fragments or the formation of certain metabolites such as:

·        Benzylamine andβ-aminopropanenitrile fragments included in the parent structures of MXDA and constituents A, B, C, and D.

·        β-Aminopropionitrile and 3,3′-iminodipropionitrile metabolites that are able to be generated as a result of oxidative dealkylation of the constituents A, B, C, and D.

 

2.     The toxic potency of arylaliphatic benzylamine groups could be associated with:

·        The possibility to act as organic Lewis bases able to form the corresponding alkylammonium salts with the acidic residues of proteins.

·        The formation of reactive metabolites, such as aldehydes, isocyanates and arene epoxides, that may form adducts with nucleophilic sites of proteins and cause different adverse effects.

In addition, the toxic effects related to the benzylamine fragments are not expected to be highly expressed, because a large portion of the metabolizing benzylamine-containing constituents is possible to be excreted as hippuric acid conjugates.

 

3.     β-aminopropionitrile and 3,3′-iminodipropionitrile could cause toxic effects such as neurotoxicity, osteolathyrism and acute lethality. In this respect it may be noted that:

·        β-aminopropionitriles (as fragments and metabolites) are considerably less toxic thanα-aminopropionitriles due to the reduced propensity to release cyanide ions. However,β-aminopropionitrile metabolites are more potent inhibitors of lysine oxidase compared to the 3,3′-iminodipropionitrile metabolite that might be formed after metabolism of constituents C and D. Inhibition of lysine oxidase by aminonitriles containing primary amine groups decreases the rate of collagen and elastin cross-link formation and produces osteolathyrism in animals.

·        On the other hand, 3,3′-iminodipropionitrile is a neurotoxin with distinctive neurologic effects and pathophisiology. It induces neurobehavioral aberrations in experimental animals and massive focal accumulations of neurofilaments. These effects could be associated with the oxidative metabolism of its secondary amine group and the subsequent cyanoethenylation of the epsilon-amino groups of critical lysine residues of the neurofilament fibers.

     Thus, the toxiceffects of2-propenenitrile, reaction products with 1,3-benzenedimethanaminewill depend mainly on the capability to act as organic bases and also to be included in metabolic reactions leading to the formation of the reactive metabolitesβ-aminopropionitrile and 3,3′-iminodipropionitrile.