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PubMed1985

Long-term inhalation toxicity of hydrazine.

Year-long intermittent exposures of rats, mice, hamsters, and dogs to hydrazine were conducted using concentrations of 0.05, 0.25, 1.0, and 5.0 ppm. Rats were held 18 months postexposure; hamsters, 1 year postexposure; mice, 15 months postexposure; and dogs, 38 months postexposure. Male and female rats exhibited dose-dependent incidences of benign nasal adenomatous polyps and smaller numbers of malignant nasal epithelial tumors after 1 year of exposure to hydrazine and 18 months postexposure holding. Nasal tumors were often associated with chronic irritation and were most frequent in male rats, with an incidence of greater than 50% in the highest exposure group. Hamsters exposed to 0.25-ppm and higher concentrations showed pathologic changes characteristic of degenerative disease, including amyloidosis. After exposure to 0.5 ppm hydrazine, hamsters developed a 10% incidence of benign nasal polyps compared to 0.5% in controls. Small numbers of colon neoplasms and thyroid parafollicular cell adenomas were found in hamsters, but only in the highest concentrations tested. Lung adenomas appeared to be marginally increased in mice exposed to 1.0 ppm hydrazine, the highest concentration tested in this species. No consistent clinical or pathological effects were seen in dogs during or after exposure to hydrazine at any concentration. Using amyloidosis as a criterion, a no-effect level was not achieved in hamsters. In rats, there appeared to be a marginal production of nasal tumors at 0.05 ppm, while mice showed no effects at 0.25 ppm. This study has demonstrated that the nasal respiratory epithelia of rats and hamsters are the most sensitive tissues to the tumorigenic action of hydrazine following inhalation exposures. This is similar to the reaction of rats to formaldehyde, another highly reactive water-soluble compound.

Animals↗

PubMed1992

Determination of hydrazine in biofluids by capillary gas chromatography with nitrogen-sensitive or mass spectrometric detection.

Plasma and liver levels of hydrazine were determined at 10, 30, 90 and 270 min in rats given 0.09, 0.27, 0.84 and 2.53 mmol of hydrazine per kg body weight orally by capillary gas chromatography-mass spectrometry of its pentafluorobenzaldehyde adduct (DFBA, m/z 388) using selected ion monitoring with 15N2-labelled hydrazine as the internal standard (adduct, m/z 390). The mean half-life for hydrazine in the plasma was approximately 2 h but varied with dose. Urinary excretion (0-24 h) of hydrazine and its metabolite acetylhydrazine were determined employing nitrogen-phosphorus detection of the adducts utilising a novel internal standard, pentafluorophenylhydrazine, the adduct of which structurally resembles DFBA. The fraction of the original dose excreted as hydrazine (and acetylhydrazine) declined with increasing dose.

Animals↗

PubMed2006

Amperometric determination of hydrazine at manganese hexacyanoferrate modified graphite-wax composite electrode.

Fabrication, characterization and application of a manganese hexacyanoferrate (MnHCF) modified graphite-wax composite electrode are described. The MnHCF mixed with graphite powder was dispersed into molten paraffin wax to yield a conductive composite, which was used as electrode material to construct a renewable three-dimensional MnHCF modified electrode. The characterization of the modified electrode has been studied by electrochemical techniques. The cyclic voltammogram of the MnHCF modified graphite-wax composite electrode prepared under optimum composition, showed a well-defined redox couple due to Fe(CN)(6)(4-)/Fe(CN)(6)(3-) system. The electrocatalytic oxidation of hydrazine by MnHCF modified graphite-wax composite electrode has been investigated in an attempt to develop a new sensor for its determination. It was found that the mediator catalyzed the oxidation of hydrazine. The electrocatalytic oxidation of hydrazine was also studied under hydrodynamic and chronoamperometric conditions. The anodic current increases linearly with increase in the concentration of hydrazine in the range of 3.33x10(-5)M to 8.18x10(-3)M. The detection limit was found to be 6.65x10(-6)M (S/N=3). The modified electrode can also be used for on-line detection of hydrazine. The proposed method has also been applied for the determination of hydrazine in photographic developer solution.

Electrochemistry↗

PubMed1987

Effect of hydrazine sulphate on whole-body protein breakdown measured by 14C-lysine metabolism in lung cancer patients.

In a prospective double-blind trial twelve malnourished patients with lung cancer were randomised to receive either placebo or hydrazine sulphate (60 mg three times daily) for 30 days. Fasting lysine flux was determined by a primed 4-hour continuous infusion of 14C-lysine before and after one month of hydrazine treatment. Baseline plasma lysine flux was 2580 (SD 580) mumol/h for the placebo group and 2510 (440) mumol/h for the hydrazine group. After one month the placebo group showed a slight rise to 2920 (450) mumol/h (p = 0.08) and the hydrazine group showed a significant fall to 1840 (750) mumol/h (p less than 0.05); serum albumin fell in the placebo group and was unchanged in the hydrazine group. Administration of hydrazine sulphate to reduce aminoacid flux may favourably influence the metabolic abnormalities in cancer cachexia.

Adult↗

PubMed1990

On the question of the carcinogenic action of hydrazine--evaluation on the basis of new experimental results.

Hydrazine has not previously been shown to have any carcinogenic action in man. After the administration of probably clearly toxic doses (the data in earlier publications are very fragmentary) or doses severely irritating to the sensitive nasal epithelium of the rodent over a large part of its life, hydrazine was shown in the majority of the studies described in the literature to be carcinogenic in rodents. Even under these severe experimental conditions, however, the carcinogenic action was not very pronounced or was even very weak. In the study in mice described below, which was carried out according to modern guidelines, no carcinogenic action was detected for hydrazine even after the administration of toxic doses over the entire lifespan of the animals. Administration of a still higher dose would have conflicted with all current recommendations. On the basis of the results available in the literature, indirect alkylation of DNA was assumed to be the mechanism of the carcinogenic action of hydrazine. According to the current level of knowledge, this effect, like the mutagenic and the carcinogenic action of the substance, is closely linked with the toxic activity of hydrazine. Overall, hydrazine should be regarded as a substance having a probably indirect weakly carcinogenic action after toxic doses administered over the entire lifespan.

Animals↗

PubMed2002

Hydrazine detection limits in the cigarette smoke matrix using infrared tunable diode laser absorption spectroscopy.

Infrared absorption lines of hydrazine are broad and typically not baseline resolved, with line strengths approximately 100 times weaker than the more widely studied compound ammonia. Hardware and software improvements have been made to a two-color infrared tunable diode laser (IR-TDL) spectrometer in order to improve the limit of detection (LOD) of hydrazine (N2H4) in the cigarette smoke matrix. The detection limit in the smoke matrix was improved from 25 parts-per-million-by-volume (ppmv) to 4.2 ppmv using a 100 m pathlength cell with acquisition of background spectra immediately prior to each sample and 100 ms temporal resolution. This study did not detect hydrazine in cigarette smoke in the 964.4-964.9 cm(-1) spectral region, after mathematically subtracting the spectral contributions of ethylene, ammonia, carbon dioxide, methanol, acrolein, and acetaldehyde. These compounds are found in cigarette smoke and absorb in this spectral region. The LOD is limited by remaining spectral structure from unidentified smoke species. The pseudo random noise (root mean square) in the improved instrument was 2 x 10(-4) absorbance units (base e) which is equivalent to a 0.09 ppmv hydrazine gas sample in the multipass cell. This would correspond to a detection limit of 0.44 ppmv of hydrazine, given the dilution of the smoke by a factor of 5 by the sampling system. This is a factor of 10 less than the 4.2 ppmv detection limit for hydrazine in the smoke matrix, and indicates that the detection limit is primarily a result of the complexity of the matrix rather than the random noise of the TDL instrument.

Hydrazines↗

PubMed1996

Free radicals produced during the oxidation of hydrazines by hypochlorous acid.

Hypochlorous acid (HOCl) derived from activated neutrophils and monocytes has been implicated in the activation of hydrazine-containing drugs to toxic intermediates. However, reactive intermediates formed during the reaction between HOCl and these drugs have not been identified. We investigated the oxidation of the hydrazine derivatives isoniazid, iproniazid, and hydralazine by HOCl. The reaction between HOCl and all three hydrazines resulted in O2 consumption, indicating that free radicals were produced, but the rate and extent of O2 consumption were different for each hydrazine. Moreover, reduction of nitroblue tetrazolium (NBT) was observed only during the reaction between HOCl and isoniazid, suggesting that different radical species may be produced from HOCl reaction with each hydrazine. The oxidation of iproniazid by HOCl in the presence of the radical trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) resulted in the formation of a carbon-centered radical adduct. In contrast, the reaction between HOCl and hydralazine resulted in the formation of a nitrogen-centered DMPO radical adduct. The oxidation of isoniazid by HOCl resulted in the formation of two oxygen-centered radical adducts, DMPO-OOH and DMPO-OH. Myeloperoxidase-catalyzed oxidation of these hydrazines in the presence of Cl- and H2O2 produced radical species that were identical to those observed with HOCl. Thus, some of the toxic side effects of these drugs may be the result of the production of free-radical intermediates from reaction with neutrophil-derived oxidants, such as HOCl. The types of radicals produced and the consequences of generating these reactive species are discussed.

Electron Spin Resonance Spectroscopy↗

PubMed1982

Studies on hydrazine hepatotoxicity. 2. Biochemical findings.

Hydrazine causes a dose-related increase in liver triglycerides and in liver weight and causes a decrease in hepatic glutathione. The threshold dose for the toxic effect is around 10 mg/kg, and the optimal effect is seen after a dose of 40 mg/kg. The effect of hydrazine on liver weight and glutathione was detectable within 30 min of dosing, but the elevation of hepatic triglycerides was not detectable until 4 h after dosing. At 24 h after a dose of 60 mg hydrazine/kg, hepatic reduced glutathione was approximately 50% of the control value and triglycerides were about 7 times the normal level. In vitro studies indicated that hydrazine is metabolized by rat liver microsomal enzymes, this being dependent on NADPH and oxygen. Pretreatment of animals with phenobarbital or piperonyl butoxide respectively decreases and increases the hepatotoxicity. Prior depletion of hepatic glutathione by administration of diethyl maleate had no effect on the toxicity. Pyruvate azine, a probable metabolite of hydrazine, is much less toxic than hydrazine itself on a molar basis. These and other results suggest that although hydrazine is metabolized via several routes, the hepatotoxicity may well be due to the parent compound rather than a metabolite.

Animals↗

PubMed2006

Estimated effects of hydrazine exposure on cancer incidence and mortality in aerospace workers.

BACKGROUND: Animal studies suggest that hydrazine is a lung carcinogen, but human studies have been rare, rather small, and limited to cancer mortality. METHODS: We examined cancer mortality and incidence in a cohort of aerospace workers with varying exposure to hydrazine contained in rocket fuels-extending previous mortality follow-up from 1994 to 2001 and investigating cancer incidence for the period 1988-2000 using population-registry data. We newly estimated hydrazine effects adjusting for occupational exposures to other carcinogens assessed through a job-exposure matrix. Rate-ratio estimates were derived from Cox proportional hazards and random-effects models using time-dependent exposure measures for hydrazine adjusting for trichloroethylene, polycyclic aromatic hydrocarbons, benzene, and mineral oil exposures. RESULTS: Exposure to hydrazine was positively associated with lung cancer incidence (estimated rate ratio for high vs low exposure with 20-year lag = 2.5; 95% confidence interval = 1.3-4.9) and with colorectal cancer incidence (2.2; 1.0-4.6). Dose-response associations were observed for both outcomes; similar associations were found for lung cancer mortality but not for colorectal cancer mortality. Effect estimates for cancers of the pancreas, blood and lymph system, and kidneys were based on small numbers rendering our analyses uninformative, and patterns considering exposure levels and lags were inconsistent. Use of random-effect models did not change our results. CONCLUSIONS: The findings reported here are consistent with our previous results for lung cancer mortality; our new results suggest that exposure to hydrazine increases the risk of incident lung cancers. We also found, for the first time, an increased risk of colon cancers. Results for other cancer sites are inconclusive.

Aged↗

PubMed1988

Genotoxicity of a variety of hydrazine derivatives in the hepatocyte primary culture/DNA repair test using rat and mouse hepatocytes.

The genotoxicity of a variety of hydrazine derivatives was examined in the DNA-repair test on rat or mouse hepatocytes. Out of 32 hydrazine derivatives, 6 chemicals, i.e., N'-acetyl-4-(hydroxymethyl)phenylhydrazine, 1,2-dimethylhydrazine.2HCl, 1-hydrazinophthalazine.HCl, methylhydrazine.sulfate, p,p'-oxybisbenzene disulfonylhydrazide and phenylhydrazine.HCl, elicited positive DNA repair responses in the test on rat hepatocytes. In the test on mouse hepatocytes, 4 more hydrazine derivatives, i.e., 1,1-dimethylhydrazine, hydrazine hydrate, hydrazine sulfate and 2-methyl-4-chlorophenoxyacetic acid hydrazide.HCl also generated positive responses, in addition to the 6 positive compounds in the rat assay. These results suggest that mouse hepatocytes are more susceptible to the genotoxicity of hydrazine derivatives, and that the species differences in genotoxicity appear to be in agreement with the in vivo carcinogenicity of these agents.

Animals↗

PubMed2006

Isolation of a multiheme protein with features of a hydrazine-oxidizing enzyme from an anaerobic ammonium-oxidizing enrichment culture.

A multiheme protein having hydrazine-oxidizing activity was purified from enriched culture from a reactor in which an anammox bacterium, strain KSU-1, was dominant. The enzyme has oxidizing activity toward hydrazine but not hydroxylamine and is a 130-kDa homodimer composed of a 62-kDa polypeptide containing eight hemes. It was therefore named hydrazine-oxidizing enzyme (HZO). With cytochrome c as an electron acceptor, the V(max) and K(m) for hydrazine are 6.2 +/- 0.3 micromol/min.mg and 5.5 +/- 0.6 microM, respectively. Hydrazine (25 microM) induced an increase in the proportion of reduced form in the spectrum, whereas hydroxylamine (500 microM) did not. Two genes coding for HZO, hzoA and hzoB, were identified within the metagenomic DNA from the culture. The genes encode the same amino acid sequence except for two residues. The sequences deduced from these genes showed low-level identities (<30%) to those of all of the hydroxylamine oxidoreductases reported but are highly homologous to two hao genes found by sequencing the genome of "Candidatus Kuenenia stuttgartiensis" (88% and 89% identities). The purified enzyme might therefore be a novel hydrazine-oxidizing enzyme having a critical role in anaerobic ammonium oxidation.

Bacteria, Anaerobic↗

PubMed1994

Hydrazine production in children receiving isoniazid for the treatment of tuberculous meningitis.

OBJECTIVE: To study the generation of the hepatotoxin hydrazine in 32 malnourished children receiving isoniazid for the treatment of tuberculous meningitis. DESIGN AND SETTING: This observational study was undertaken in the pediatric ward of a teaching hospital admitting children with advanced forms of tuberculous meningitis for treatment and management of complications. METHODS: Thirty-two children (mean age 2.28 years) receiving isoniazid 20 mg/kg/d were studied. Plasma isoniazid, acetylisoniazid, and hydrazine concentrations were determined by an HPLC method. Fourteen children were studied at weekly intervals for the first month of treatment and again after six months of therapy; 18 additional children were studied on one or more occasions during the first month of treatment only. RESULTS: The area under the curve for hydrazine two to five hours after the isoniazid dose correlated with the isoniazid elimination rate and with acetylisoniazid generation. Hydrazine production increased significantly during the first month of treatment, but decreased to approximate initial values at six months. No correlation was found between any clinical or biochemical indicator of liver dysfunction and hydrazine production. CONCLUSIONS: Hydrazine is formed in significant concentrations during the metabolism of isoniazid in young children. However, additional factors such as preexisting liver damage (e.g., from viral hepatitis) may be necessary for it to reach its toxic potential.

Child↗

PubMed2001

[The glutathione-dependent antioxidant system in rats during acute intoxication by hydrazine].

Intensity of lipid peroxidation in the liver, kidney and brain tissues, and functioning of the glutathione system were studied in purebred rats after acute intoxication by 1.1-dimethyl hydrazine at the dose of 104.5 mg/kg of body mass (LD50) and phenyl hydrazine at the dose of 170 mg/kg of body mass (LD50). According to results of the investigation, the character and direction of changes in LPO and the antioxidant system due to intoxication by hydrazines are materially dependent on their structure and affected organs and tissues. For instance, intoxication by phenyl hydrazine markedly activates free-radical activation in all analyzed tissue with accumulation of malone dialdehyde against depletion of reduced glutathione in tissue and deactivation of enzymes involved in the antioxidant defense. Intoxication by dimethyl hydrazine was associated with moderate activation of free-radical oxidation in liver with a downward LPO trend in kidney and brain at the cost of exaggerated activity of enzymes in the glutathione system and maintenance of sufficient reserve of reduced glutathione. Hence, aryl hydrazine derivatives possess more distinct pro-oxidant properties.

Animals↗

PubMedDate not supplied

Teratogenic hydrazines: a review.

The review summarizes the results of 30 hydrazines, which were studied in humans and in six animal species for teratogenic activities. Of these, 23 chemicals were found to induce physical defects in the developing embryos of animals. Six hydrazines failed to induce teratogenic abnormalities in animals under the experimental conditions. Three hydrazine analogues, some of which were given in combination with other drugs to pregnant women, gave ambiguous results concerning teratogenic effects. Some of these investigations were aimed at revealing the teratogenic mode of action of hydrazines. The mechanistic aspect focused on the dose requirements of chemicals and the time period in the development of the fetus susceptible to malformation and chemoprevention. Of interest is the base compound hydrazine, which was found to be teratogenic in five animal species. In general, the hydrazines were found to be powerful teratogens, which coincided in most cases with their known carcinogenic activities.

Animals↗

PubMed1998

Effects of hydrazine sulfate on galactosamine-sensitized endotoxic shock in ten-day-old rats.

Patients who have liver diseases are susceptible to septic shock. Galactosamine induces liver damage and increases endotoxin-sensitivity. Hydrazine stimulates pituitary-adrenal axis and decreases mortality in galactosamine-sensitized endotoxic shock in the adult. However, as pituitary-adrenal function in the newborn is immature, the effects of hydrazine on galactosamine-sensitized endotoxic shock in the newborn remained unclear. In the present study, galactosamine-sensitized endotoxic shock was induced and treated with hydrazine in ten-day-old rats. Galactosamine (600 mg/kg) plus Salmonella enteritidis lipopolysaccharide (LPS; 0.01 mg/kg) induced hypoglycemia, lactacidemia and resulted in high mortality. Hydrazine at the dose of 20, 50 or 80 mg/kg did not alter the hypoglycemia, lactacidemia or morality. Dexamethasone ameliorated the hypoglycemia and lactacidemia (p < 0.05) and decreased the morality (p < 0.05). The lack of beneficial effects of hydrazine in galactosamine-sensitized endotoxic shock in ten-day-old rats may be related to immature pituitary-adrenal function and suppression of gluconeogenesis by hydrazine.

Animals↗

PubMed1989

Free radical activation of monomethyl and dimethyl hydrazines in isolated hepatocytes and liver microsomes.

Isolated hepatocytes and liver microsomes incubated with monomethyl-1,1 dimethyl- and 1,2 dimethyl-hydrazines produced free radical intermediates which were detected by ESR spectroscopy by using 4-pyridyl-1-oxide-t-butyl nitrone (4-POBN) as spin trapping agent. The spectral features of the spin adducts derived from all three hydrazine derivatives corresponded to the values reported for the methyl free radical adduct of 4-POBN. In the microsomal preparations inhibitors of the mixed function oxidase system and the destruction of cytochrome P450 by pretreating the rats with CoCl2 all decreased the free radical formation. Methimazole, an inhibitor of FAD-containing monoxygenase system, similarly decreased the activation of 1,1 dimethyl-hydrazine, but not that of monomethyl- and 1,2 dimethyl-hydrazines. The addition to liver microsomes of physiological concentrations of glutathione (GSH) lowered by approx. 80% the intensities of the ESR signals. Consistently, incubation of isolated hepatocytes with methyl-hydrazines decreased the intracellular GSH content, suggesting that GSH can effectively scavenge the methyl free radicals. The results obtained suggest that methyl free radicals could be the alkylating species responsible for the toxic and/or carcinogenic effect of methyl-hydrazines.

Animals↗

PubMed1981

Environmental chemistry and management of hydrazine.

The recent use of 70% hydrazine-water fuel in the F-16 emergency power unit (EPU) presents problems for organizations responsible for protection of personnel and the environment because of the worldwide deployment of this aircraft and the requirement for fuel handling in a flightline environment. Hydrazine has a low vapor pressure (14 mm Hg at 25 degrees C) but still evaporation rates (16-100 mg/cm2h) from liquid pools are sufficient to generate hazardous atmospheric concentrations greater than the permissible exposure level (3 ppm) up to 2 km downwind under worst-case meteorological conditions (F Stability). In contrast to the general feeling that hydrazine degrades in the presence of atmospheric oxygen, studies show hydrazine is relatively stable in both air (t1/2 approximately 6 h) and oxygenated aqueous solutions (t1/2 approximately 5 d). The toxicity and stable character of hydrazine in the environment required quick and thorough management of any accidental spills to preclude hazards to personnel and serious environmental degradation. The Air Force has established comprehensive containment and treatment procedures which will be used in the event of inadvertent releases of hydrazine from the EPU or during handling or transport of the bulk fuel. The simple spill management procedures used to support the F-16 aircraft EPU are described.

Accidents↗

PubMed1997

Determination of N7- and O6-methylguanine in rat liver DNA after oral exposure to hydrazine by use of immunochemical and electrochemical detection methods.

Hydrazine belongs to a group of compounds for which there is evidence that the in vivo genotoxic effects become manifest only upon exposure to toxic dose levels. The present study was performed to investigate whether this phenomenon is also reflected in the pattern of DNA methylation. The induction of N7- and O6-methylguanine (MeGua) was studied in liver DNA of rats, 16 hr after treatment with various doses of hydrazine. After DNA isolation, the presence of N7-MeGua in DNA was assessed with an immunochemical method and with a physicochemical technique (HPLC with electrochemical detection). Application of these two methods resulted in almost identical patterns of dose-dependent induction of guanine N7-methylation in rats dosed orally with 0.1 to 10 mg hydrazine per kilogram of body weight, increasing from 1.1-1.3 to 39-45 N7-MeGua per 10(6) nucleotides. At lower dosages a constant adduct level was observed, equivalent to that in untreated rats (background level). The O6-MeGua level was analyzed by a combination of HPLC separation and competitive radioimmunoassay. A background level was observed for untreated rats and no increase was visible up to the 0.2 mg/kg dose group. After hydrazine doses from 0.2 to 10 mg/kg, O6-MeGua increased from 0.29 to 134 per 10(9) nucleotides. These data show that even at dosages below the maximum tolerated dose (0.6 mg/kg/day), for which carcinogenic effects have not been described, DNA adducts are formed. A comparison is made of the data obtained in this study with models that describe the mechanism of hydrazine-induced DNA methylation.

Animals↗