Nitrothiazole

214.199

214.20

200-512-6

N116U8Y5QQ

136947

DTXSID6045244

Yellow crystals from dimethylformamide/methanol

P - Antiparasitic products, insecticides and repellents

2934999090

119

0.95

1.549g/cm3

260-262 °C

278.6ºC at 760 mmHg

122.3ºC

1.614

In water, 1.3X10+2 mg/L at 25 deg C

Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ) that bears appropriate label. An inventory should be kept, showing quantity of carcinogen & date it was acquired Facilities for dispensing should be contiguous to storage area.

3.56X10-7 mm Hg at 25 deg C (est)

TDLo orl-rat: 8 g/kg/90W-I:NEO CALEDQ 4,305,78 orl-rat LD50:900 mg/kg FAZMAE 17,108,73

Henry's Law constant = 1.1X10-14 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 7.1X10-12 cu cm/molecule-sec at 25 °C (est)

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/|For more Disposal Methods (Complete) data for NIRIDAZOLE (6 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/|For more Preventive Measures (Complete) data for NIRIDAZOLE (9 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

Administration of niridazole to rats poisoned with copper caused a significant increase in both the urinary and biliary excretion of the metal. Although the urinary excretion of iron was increased by the drug, iron excretion was significantly decreased during the drug-induced excretion of copper after copper poisoning. Formation of a copper-niridazole chelate or chelates before excretion in the bile or urine may explain these findings. Polarity and molecular weights of the metal-drug chelates formed in vivo may be the directing forces not only in the selection of the metal for chelation, but also for its urinary or biliary excretion. The laboratory preparation of two copper-niridazole complexes lends support to these conclusions.|Oral acute toxicity of niridazole was increased 3-fold by the simultaneous administration of carbaril (carbaryl) and 2-fold by the administration of malathion in rats.

Anthelmintic|One hundred patients with active schistosomiasis mansoni were treated with niridazole (25 mg/kg/day po for 7 days). The most serious side effects were those connected with the neuropsychic area (convulsion, hallucination, etc.). Therapeutic activity, based on repeated stool examinations, was about 90% in adults and 60% in children. Because of the side effects, as well as the long-term schedule of treatment, niridazole is not recommended for use under field conditions. ...|Niridazole is a nitrothiazole anthelmintic agent used to treat schistosomiasis. Its antibacterial activity was found to require the presence of the nitro group; a synthetic desnitro analog was completely inactive.

The side-effects of niridazole used for urinary schistosomiasis were studied prospectively over a 3-month period in male patients receiving the standard dose of 25 mg day-1 kg-1 for 7 days. Side-effects were detected in 80% of in-patients but only in 33% of out-patients. The range of side-effects was greater in in-patients taking their daily doses in two portions than in those taking theirs in three. Cure rates and degree of schistosoma egg suppression were significantly lower in out-patients suggesting that compliance with treatment was poorer.|One hundred sixteen male patients with uncomplicated Schistosoma mansoni infection were randomized to treatment with oxamniquine (20 mg/kg a day for 3 days) or niridazole (15 mg/kg a day for 8 days) in an in-hospital study. ... Sixty-two patients were treated with niridazole; four patients (one child and three adults) had serious side effects which necessitated discontinuing the drug. Seventy-one percent of children and 84% of adults were cured. Egg reduction was 84%. Minor clinical side effects occurred during therapy with both drugs (26% with oxamniquine, 48% with niridazole) but cleared after completion of therapy.

Agents that act systemically to kill adult schistosomes. (See all compounds classified as Schistosomicides.)|Agents which are destructive to amebae, especially the parasitic species causing AMEBIASIS in man and animal. (See all compounds classified as Amebicides.)

Orally administered niridazole is well absorbed; it is metabolized in the liver and eliminated largely and almost equally in the urine and feces.|In rats, rabbits and dogs, orally administered (14)C imidazinone ring-labeled niridazole is slowly but well absorbed and excreted in the urine and feces within a few days. In experiments involving rat tissue homogenates, it was degraded most rapidly by liver and kidney and to a lesser extent by testis, spleen, heart, lung, brain, muscle and thymus - this order corresponds to the levels of nitroreductase in these tissues. Similarly, it is metabolized most rapidly in vitro by mouse liver and then in descending order by the liver of rats, rabbits, sheep, pigs and bovines. In blood, the metabolites attain a higher level than the parent drug.

N-(5-nitro-2-thiazolyl)-N'-carboxymethylurea (NTCU) has been identified as a urinary metabolite of the antischistosomal drug niridazole (1-(5-nitro-2-thiazolyl)-2-imidazolidinone). When DBA/2J mice were treated with (14)C niridazole, a metabolite comprising 12-14% of the total radioactivity in 24-hr urine samples was resolved by HPLC. The compound was subsequently isolated from pooled urine of niridazole-treated patients. It was identified as NTCU by mass spectrometry, and the deduced structure was confirmed by chemical synthesis. NTCU is unique among known niridazole metabolites, because it lacks an intact imidazolidinone ring. Its structure allows for a ketoenol tautomerism in which the enolate is stabilized by conjugation with the nitrothiazole ring, as evidenced by a pH-dependent 80-nm red shift in the absorption spectrum. /It was/ hypothesized that NTCU arises via oxidation of an acyclic aldehyde tautomer of 5-hydroxyniridazole, one of two proximate oxidative niridazole metabolites. Indirect evidence for the aldehyde tautomer included the fact that 5-hydroxyniridazole displayed the same pH-dependent spectral shift as NTCU with a single isobestic point at 388 nm. The proposed precursor-product relationship was confirmed when /it was/ found that NTCU formation from 5-hydroxyniridazole was catalyzed by NAD(+)-dependent aldehyde dehydrogenase (EC 1.2.1.3). The activity copurified with benzaldehyde dehydrogenase activity from mouse liver cytosol. Furthermore, benzaldehyde was a competitive inhibitor of 5-hydroxyniridazole dehydrogenase activity. These results demonstrate that 5-hydroxyniridazole is not an end product of niridazole metabolism. Because biotransformation of niridazole to its 4- and 5-hydroxy derivatives has been implicated in the drug's carcinogenicity and central nervous system toxicity, NTCU formation appears to represent a detoxication pathway in mammals.|The principal metabolite of niridazole formed by rat liver microsomes was the hydroxylamine (N-hydroxyaminothiamidazol), formed by reduction of the nitro group of niridazole. This reduction was also mediated by rat liver xanthine oxidase.|4-Keto niridazole, isolated by high-pressure liquid chromatography, was identified by high resolution electron impact mass spectral analysis as a major drug metabolite of niridazole in the serum or plasma of rats and mice treated orally or i.p. with niridazole. This metabolite has a pKa of 5.8 and is approximately 40% bound at physiologic pH to serum proteins of mice receiving therapeutic doses of niridazole. ...

The results of studies on the reductive activation of the schistosomicidal agent, niridazole /were reported/. Intact rat embryos in vitro reduced this compound, generating a stable metabolite in the presence of 5% O2. By contrast, embryo and yolk sac homogenates or liver microsomes appeared to require anaerobiasis. Malformation incidence--specifically, axial asymmetry--showed a strong correlation with nitroreductase activity rates when the latter were modulated by oxygen tension. Data presented here suggest that when embryos are exposed to niridazole under conditions of low oxygen in vitro, redox cycling ensues with molecular oxygen serving to oxidize early reduction products. This process continues, regenerating the parent compound until oxygen is depleted locally. The basis of this localized depletion is unknown, but inability of the immature supply system to replete oxygen or demand by precociously aerobic tissues may be involved. Once local anaerobiasis is attained, further reduction could generate toxic metabolites capable of covalently binding cellular macromolecules. Localized hypoxia represents another potential mechanism of dysmorphogenesis.

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ The antispermatogenic effect of niridazole was studied in 20 bilharzial male patients. Niridazole was found to induce defective spermatogenesis in the form of focal spermatocyte arrest and or germinal cell hypoplasia. The effect was transient, with active recovery occurring 3 months after therapy. Niridazole therapy must be postponed or changed for those subjects whose semen parameters prove to be subfertile.|/CASE REPORTS/ Niridazole caused red/brown urine pigment in a man during treatment for Schistosoma mansoni infection. The urine pigment has been observed during niridazole treatment of schistosomiasis, but has not been documented during treatment of other diseases. Urinary beta-glucuronidase (EC 3.2.1.31) concentration increased proportionately to the amount of red/brown pigment in the urine. Concurrently, sterile pyuria developed. The duration of the time urine was in the bladder was directly related to the concentration of beta-glucuronidase and to the intensity of the red/brown urine color, there being much more in infrequently than in frequently voided urine specimens. Pigment development appears to occur in the bladder. The associated and possibly contributing components appear to be niridazole or one of its metabolites, beta-glucuronidase from the kidneys or from urinary granulocytes, and possibly a schistosomal factor. Given time, this combination generated the red/brown pigment.|/CASE REPORTS/ A discussion of the various ECG changes frequently associated with the use of niridazole (Ambilhar; I), using a case report in a 35-yr-old male, is presented. The only laboratory abnormality was a type IV hyperlipoproteinemia pattern-increased cholesterol, triglycerides, and uric acid. ECG changes manifested were consistent with anterolateral ischemia. The type and location of these changes are consistent with reports from other investigators. Although the etiology of these changes is not clear, it appears that the primary T wave abnormalities are related to changes in myocardial cellular metabolism.|/CASE REPORTS/ A severe pulmonary sensitivity reaction occurred in an 18-year-old man treated for a Schistosoma mansoni infection with niridazole (Ambilhar). The reaction was reproducible when the drug was administered a second time.

Ambilar

Trade names: Ambilhar (Ciba-Geigy); Ambilhar Ciba (Biogalenica Q Farm).