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Description of key information

 4-Oxo tempo is assimilated rapidly via the oral gavage route but no accumulation occurs. Indications are that the substance is rapidly metabolism in the liver and other tissues by a reductive mechanism. 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

 

Assimilation

The rapid oral assimilation of Oxo Tempo is demonstrated by the acute oral toxicity study in the rat where the acute toxicity of 1464 mg/kg indicated a relatively low acute toxicity. Oxo tempo is readily soluble in water and was administered in aqueous solution. Signs of toxicity were seen within 30 minutes of administration at doses of 1414 and 2000 mg/kg and deaths occurred between 1 and 4 hours of administration in these groups. Clinical signs were minimal at 1000 mg/kg and no deaths occurred at this dose.  

A subsequent 28 day repeat dose study demonstrated little indication of toxicity at the maximum dose of 1000 mg/kg/day. Increased absolute and relative liver weight indicated a possible work hypertrophy response. In a recovery group, the increased liver weight was shown to resolve within 2 weeks.

The acute oral LD50 test indicates a steep dose response curve. The lethal body burden seen in the acute study is not reached by repeat dosages in the 28 day study and tends to indicate that there is rapid assimilation and excretion, with no accumulation.

Metabolism

The metabolism of Oxo Tempo has been investigated in several in-vivo and in-vitro systems.

Komerov et al (1994) used EPR spectroscopy to track the disappearance of the electron spin signature of Oxo Tempo following intravenous administration of 0.13 – 0.22 mmol/kg to mice in vivo. Oxo Tempo was postulated to be metabolised to a hydroxylamine metabolite which does not possess an EPR spin signature. The disappearance of the EPR spin signal was monitored in vivo in the tail of the mouse using a non invasive technique. The T1/2for this process was determined to be 3 minutes indicating a very rapid in-vivo metabolism, however no identification of the metabolites was determined in this study. 

Kroll and Borchart (1999) used an isolated perfused rat liver system to investigate actual metabolites of oxo tempo. In their experimental system they saw rapid disappearance of the parent oxo tempo with approximately 30% only remaining after 3 hours. They identified 5 metabolites. The primary metabolite being tempol (the reduced OH derivative), plus the 1-hyrdoxyl forms of both oxo tempo and tempol and their sterically hindered secondary amines. Whilst the rate of metabolism of the parent is not as rapid as that seen by Komerov et al., it is still rapid. The difference might indicate that whilst the liver is one site of metabolism it may not be the only site and thus the whole body metabolism seen in the in-vivo mouse may be a more accurate reflection of the half life.

By using P450inhibitors, Kroll and Borchart also determined the metabolism was independent of cytochrome P450.   

Kroll and Langer et al (1998) investigated the metabolism of oxo tempo by isolated human kerationcytes (cell line HaCaT). The metabolism of oxo tempo in this system confirms that the liver is not the only metabolic site and so strengthens the kinetic data taken from the intact in-vivo mouse. They determined that the metabolism was inhibited by a thiol blocking agent and postulated a mechanism dependent on the flavoenzyme thioredoxin reductase.

 

Conclusions

The acute and sub acute, in vivo rodent studies indicate that oxo tempo is assimilated rapidly via the oral gavage route but that no accumulation occurs. In-vivo and in-vitro studies indicate a rapid metabolism in the liver and other tissues by a reductive mechanism. Actual excretion of parent or metabolites has not been demonstrated, however the 28 day repeat dosing study, with a 14 day recovery phase would indicate that oxo tempo is quantitatively excreted within a 24 hour period, or that the metabolites have negligible toxicity.