N,N'-diacetylhydrazine

Endpoint summary

Description of key information

Diacetylhydrazine is rather stable and its hydrolysis to acetylhydrazine is rather slow. Systemic absorption takes place with a high efficiency via the oral route, the substance is readily distributed in the body, and excreted rather quickly. Bioaccumulation is not to be expected in humans. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Several studies are available that touch on the toxicokinetic of diacetylhydrazine, though none of them explicitly focus on this substance. The results are usually present as a supplement to analysis on the toxicokinetics of isoniazid or acetylhydrazine.

In Turnbull 1962, a study that followed no guideline and predates the implementation of GLP the metabolism of aroylhydrazines was analysed. The study is well documented, meets generally accepted scientific principles and therefore is deemed acceptable for assessment. Rats, rabbits and a dog were treated singly with 1-acetyl-2-benzoylhydrazine, benzhydrazide, acetylhydrazine and diacetylhydrazine via different routes, in some cases as C14 labelled substances. 1-acetyl-2-benzoylhydrazine, diacetylhydrazine and in the case of the dog hydrazine was quantified in urine via isolation and paper chromatography. In the case of the rats label was analysed in urine, feces and exhaled air. It was shown that man, rat and rabbit metabolise aroylhydrazines via 1 -aroyl-2-acetyl-hydrazine and acetylhydrazine to diacetylhydrazine.Significant amounts of CO2 were formed from 1-acetyl-2-benzoylhydrazine via acetylhydrazine, while hardly any CO2 was formed from diacetylhydrazine (via acetylhydrazine). This indicates that diacetylhydrazine is rather stable and its hydrolysis to acetylhydrazine is rather slow as compared to the reacetylation to diacetylhydrazine and the excretion of diacetylhydrazine. Diacetylhydrazine is excreted rather fast in the rat, therefore no potential for bioaccumulation is indicated.

Wright 1978 ip injected acetylhydrazine and hydrazine into male Sprague Dawley rats of about 180 to 200 mg bw and the metabolism of these substances was analysed. In the case of acetylhydrazine some dose groups were pretreated with isoniazid, acetylisoniazid and p-aminosalicylic acid. Higher exposure to acetylhydrazine led to reduced relative acetylation to diacetylhydrazine. Pretreatment of rats with isoniazid, acetylisoniazid or p-aminosalicylic acid had an inhibitory effect on the acetylation of acetylhydrazine to diacetylhydrazine. Acetylhydrazine and diacetylhydrazine are the main metabolites of hydrazine in the rat. While at high acetylhydrazine concentrations its acetylation is obviously limited by saturation, at low concentrations the acetylation is swift. If not inhibited by coadministration of other substances the excretion of acetylhydrazine is complete within 24 h. There is no bioaccumulation potential of acetylhydrazine indicated by the study results. This result can also be extended to diacetylhydrazine as it is the final metabolite of the acetylhydrazine.

Distribution and and excretion of hydrazine, acetylhydrazine and diacetylhydrazine was determined in young adult male Wistar rats after sc injection of 0.31 mmol/kg bw of either hydrazine of acetylhydrazine by Kaneo 1984. It was shown that diacetylhydrazine is formed slowly and excreted slowly in both cases. The highest amounts of diacetylhydrazine were found in the kidneys.

In Bollard 2005 hydrazine hydrochloride was administered to male Sprague–Dawley rats (30 mg/kg, n = 10 and 90 mg/kg, n = 10) and male B6C3F mice (100 mg/kg, n = 8 and 250 mg/kg, n = 8) by oral gavage. In each species, the high dose was selected to produce the major histopathologic effect, hepatocellular lipid accumulation. In the rat, the urine metabolites acetyl hydrazine,diacetylhydrazine, 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid were identified in the first 24 h. In the mouse, urine metabolites identified in the first 24 hours were diacetylhydrazine, 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid. In both cases these amount to 10 % of the total administered dose. The fact that in mice, monoacetyl hydrazine is not found in the urine and the predominance of diacetylhydrazine in the mouse is indicative for a higher N-acetylase activity in mice as compared to rats and that the hydrolysation of diacetylhydrazine to acetylhydrazine is very to extremely slow relative to the excretion of diacetylhydrazine. The severity of liver lesions and kidney lesions is significantly higher in rats as compared to mice. This suggests that the fast acetylation of acetylhydrazine to diacetylhydrazine is protective in the mouse against this lesions and further supports the aforementioned conclusion.

Some studies were disregarded:

- Huq 2006, disregarded: In the publication only the thermodynamic stability of metabolites of hydrazine are calculated. No significant information on kinetic parameters or ADME parameters is given. The presented data does not give significant information on the metabolism of hydrazine or diacetylhydrazine.

- Thomas 1984, disregarded: The study does not deliver significant information on the metabolism of diacetylhydrazine. It is shown that New Zeeland White rabbits are faster acetylators than Wistar rats and that metabolites of acetylisoniazid and acetylhydrazine are readily distributed throughout the organism, but the distribution pattern of diacetylhydrazine was not disclosed in this study. The reliability rating given here only relates to the relevance for diacetylhydrazine.

- Preece 1991, disregarded: The study does not deliver significant information on the metabolism of diacetylhydrazine. It is shown via 15N-NMR in urine samples that hydrazine is metabolized to a limited extent to diacetylhydrazine after single oral treatment of rats. The reliability rating given here only relates to the relevance for diacetylhydrazine.

Taking the above presented animal data as well as the available human data on metabolism into account, it can be stated that diacetylhydrazine is a metabolite inter alia of isoniazid and hydrazines. Results from both animal studies (Turnbull 1962) and human studies (Ellard 1976) showed that diacetylhydrazine is rather stable and its hydrolysis to acetylhydrazine is rather slow. After systemic absorption, which takes place with a high efficiency via the oral route (no data for the dermal or inhalation route, Ellard 1976) the substance is readily distributed in the body (Kaneo 1984) and excreted rather quickly (half-life of 5 h, Ellard 1976). Accordingly, bioaccumulation is not to be expected in humans.