Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
26 September 1997 (Received for publication)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test has not been performed to GLP standards and no guideline required.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1998

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Metabolism of 14C-NTO in vitro in rat liver microsomes.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material : 3-NITRO-1 ,2,4-TRIAZOL-5-0NE (NTO)
- Substance type: energetic explosive
- Physical state: light green to white crystalline solid with no odor
- Purity ca.99%
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Rat liver microsomes were harvested from the livers of the rats which had been pre-treated with either phenobarbital, 3-methylcholanthrene, dexamethasone or clofibrate.

Administration / exposure

Details on exposure:
Anaerobic incubations were performed by bubbling argon over the phosphate buffer for 1 hour, microsomal suspensions and NTO and NADPH - generating system were added. Incubations were also performed in the presence of oxygen in the same manner but without the argon deaeration stage. Reactions were stopped and samples concentrated and analysed by HPLC.

Results and discussion

Main ADME results
Type:
metabolism
Results:
Nitroreduction of NTO was principally catalysed by the microsomal fraction of rat liver cells. This reaction required a NADPH-generating system and led to the formation of two metabolites, 5-amino-1,2,4-triazol-3-one 2 and 5-hydroxy-1,2,4-triazol-3-one 3.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The amounts of metabolites (ATO and urazole were determined by monitoring the radioactivity of the HPLC effluent, and are reported as a percentage of the initial C-NTO radioactivity.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: No bioaccumulation tested .
The reported results indicate that NTO is metabolized by liver microsomes via two distinct pathways. The first reaction is the nitroreduction of NTO, which is the only reaction that occurs in anaerobiosis. In contrast with reported results, nitroreduction is only partially inhibited by oxygen.
The second reaction leads to the formation of urazole via the oxidative denitrification of NTO.