Monocrotaline

325.36

325.36

2017-001-1

73077K8HYV

DTXSID9020902

Prisms from absolute alcohol|Colorless

29399990

96.3

-0.7

white to light tan powder

1.35 g/cm³

197-198 °C (decomp)

537.3ºC at 760mmHg

278.7±30.1 °C

1.586

In water, 3.7X10+5 mg/L @ 25 deg C /Estimated/

2-8°C

7.5X10-13 mm Hg @ 25 deg C /Estimated/

LD50 orally in rats: 71 mg/kg (Newberne)

-54.8o (C=5 IN CHLOROFORM)

Bitter

Henry's Law constant = 1.3X10-12 atm-cu m/mol @ 25 °C /Estimated/

pKa = 5.83 /Estimated/

172.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Stereoisomer of 4,5,8,10,12,13,13a,13b-octahydro-4,5-dihydroxy-3,4,5-trimethyl- 2H-(1,6)dioxacycloundecino[2,3,4-gh]pyrrolizine-2,6(3H)-dione|Readily hydrolyzed with alkali; reacts readily with oxidizing agents (slowly with atmospheric oxygen) to form dihydropyrrolizine and other derivatives|Hydroxyl radical reaction rate constant = 1.2X10-10 cu cm/molec-sec @ 25 °C /Estimated/

III

6.1(b)

UN 1544 6.1/PG 3

3

25-40-35

36/37/39-45

QB3140000

T

VOLATILITY VERY SLIGHT; STABLE FOR LONG PERIODS AT ROOM TEMP IN CLOSED CONTAINERS

P281-P301 + P310

H301-H351

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/|PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

LINSELL CA; ENVIRONMENTAL CHEMICAL CARCINOGENS AND LIVER CANCER; J TOXICOL ENVIRON HEALTH 5 (2-3): 173 (1979); AN APPRAISAL IS MADE OF CHEMICAL CARCINOGENS AVAILABLE IN HUMAN ENVIRONMENT THAT HAVE BEEN IMPLICATED IN ETIOLOGY OF LIVER CANCER.|CLARK AM; NATURALLY OCCURRING MUTAGENS; MUTAT RES 32: 361 (1976); A REVIEW WITH OCCURRENCE, ACTIVATION & TOXICITY OF PYRROLIZIDINE ALKALOIDS & OTHER MUTAGENS.|GHODSI F, WILL JA; CHANGES IN PULMONARY STRUCTURE AND FUNCTION INDUCED BY MONOCROTALINE INTOXICATION; AM J PHYSIOL 240 (2): H149 (1981); THE TOXICITY OF MONOCROTALINE IS DISCUSSED.|SCHOENTAL R; HEALTH HAZARDS OF PYRROLIZIDINE ALKALOIDS: A SHORT REVIEW; TOXICOL LETT 10 (4): 323 (1982); HEALTH HAZARDS INCLUDING CARCINOGENICITY OF PYRROLIZIDINE ALKALOIDS ARE REVIEWED.|For more Special Reports (Complete) data for MONOCROTALINE (6 total), please visit the HSDB record page.

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P310, P308+P313, P321, P330, P405, and P501|Aggregated GHS information provided by 40 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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 MONOCROTALINE (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/

Both SKF 525a and metyrapone protected older rats against monocrotaline-induced right heart and lung hypertrophy. Mixed-function oxidase inhibition was more effective than sulfhydryl replacement in attenuating monocrotaline toxicity. Protection was less in younger rats.|Dietary ethoxyquin protected mice against lethality as well as acute hepatotoxicity of monocrotaline as measured by levels of alanine and aspartate aminotransferases in plasma. Dietary cysteine (1%) also protected mice against the lethality but not the acute hepatotoxicity of the alkaloid. With the exception of ethoxyquin, none of the other feed additives increased liver glutathione levels. Glutathione S-transferase activity was significantly increased by either dietary ethoxyquin or cysteine using chlorodinitrobenzene as substrate. Dietary ethoxyquin produced an increase in hepatic cytochrome p-450 content and increases in the in vitro conversion of monocrotaline to pyrrole metabolites by liver microsomes. Since ethoxyquin protected mice against monocrotaline lethality and hepatotoxicity, despite no reduction in the in vivo activation of monocrotaline, the mechanisms involved are most probably a result of increased detoxication processes partly because of increased liver glutathione levels.|Dietary butylated hydroxyanisole (BHA) at levels of 0.25 and 0.75% protected young female mice against the acute toxicity of monocrotaline. Protective effect was associated with reduced levels of pyrrole metabolites in liver, decreased activity of hepatic aminopyrine demethylase, and reduced rate of in vitro microsomal conversion of monocrotaline to pyrrole metabolites. BHA also increased liver sulfhydryl levels and activity of cytosolic glutathione s-transferase. Dietary cysteine (1%) was less protective than BHA against monocrotaline toxicity. LD50 values of monocrotaline in control and cysteine-fed mice were 259 and 335 mg/kg, respectively.

LD50 Rat iv 92 mg/kg|LD50 Mouse ip 259 mg/kg|LD50 Rat oral 66 mg/kg|LD50 Mouse iv 261 mg/kg

/A/ pyrrolizidine alkaloid, the major toxic constituent of Crotalaria spectabilis Roth, Leguminosae.|MONOCROTALINE ... HAS BEEN ISOLATED FROM ... CROTALARIA GRAHAMIANA, CROTALARIA MITCHELLII, CROTALARIA MYSORENSIS, CROTALARIA NOVAEHOLLANDIAE, CROTALARIA QUINQUEFOLIA, CROTALARIA RETUSA, CROTALARIA SERICEA, CROTALARIA SPECTABILIS, CROTALARIA LECHNAULTII, CROTALARIA LEIOLOBA, (CROTALARIA FERRUGINEA), CROTALARIA STIPULARIA, CROTALARIA RECTA, AND CROTALARIA SAGITTALIS.

A major exposure of humans to monocrotaline and related alkaloids has occurred in the West Indies through the consumption of extracts of Crotalaria species as bush teas. An educational campaign to stop consumption of Crotalaria teas, which began in 1959, has apparently been successful in reducing the incidence of veno-occlusive disease.

/Exptl Ther/ Antitumor effects of 22 pyrrolizidine alkaloids and derivatives were studied in mice with adenocarcinomas 755, l-1210 leukemia or sarcoma 180, rats with im or sc walker 256 carcinomasarcoma and in kb carcinoma cell cultures; 1 compound each was also tested in mice with ascites ehrlich carcinoma and hamsters with plasmacytoma number 1. Significant activity against the solid tumors, by CCNSC standards (58% or more decrease in tumor size), was seen with monocrotaline (NSC-28693) in 3 of the above tumors and in p-1. Monocrotaline n-oxide was without significant activity in any of the systems tested.|/Exptl Ther/ Monocrotaline from crotalaria sessiliflora has been shown to be effective against human skin cancer and cancer of uterine cervix.

After sc administration of monocrotaline /in rats/, 50-70% of the dose was found in urine as unchanged monocrotaline... monocrotaline (or metabolite) concentration were highest in the liver, kidney and stomach.|The pyrrolizidine alkaloid monocrotaline has been shown to cause hepatic necrosis and pulmonary hypertension in the rat. To better understand the mechanism of action, tissue distribution and covalent binding studies were conducted at 4 and 24 hr following administration of (14)C monocrotaline (60 mg/kg, 200 microCi/kg, sc). For the 4 hr study, the levels of monocrotaline equivalents were 85, 74, 67, 36, and 8 nmol/g of tissue for RBC, liver, kidney, lung, and plasma, respectively, while the covalent binding levels were 125, 132, 39, 64, 44 pmol/mg of protein for tissues as listed above. The 24 hr tissue distribution levels were 49, 25, 9, 10, 2 nmol/g of tissue for RBC, liver, kidney, lung, and plasma, respectively, while covalent binding was 74, 28, and 55 pmol/mg of protein for liver, kidney, and lung, respectively. We also studied the kinetics of (14)C monocrotaline (60 mg/kg, 10 microCi/kg, iv), which demonstrated rapid elimination of radioactivity with approximately 90% recovery of the injected radioactivity in the urine and bile by 7 hr. The plasma levels of radioactivity dropped from 113 nmol/g of monocrotaline equivalents to 11 nmol/g at 7 hr while RBC levels decreased from 144 to only 81 nmol/g at the same time point. The apparent retention of monocrotaline equivalents in the RBC suggests that this organ may act as the carrier of metabolites from the liver to other organs including the lung and may play a role in the pulmonary toxicity.

Studies with monocrotaline have confirmed the formation of pyrrolic metabolites by the mixed-function oxidase system of the microsomal fraction of rat liver. Dehydromonocrotaline (monocrotaline pyrrole) is highly cytotoxic, producing pulmonary, cardiac, vascular and hepatic lesions similar to those produced by the parent alkaloid. It is a highly reactive alkylating agent which, on formation within the cell, reacts immediately with cell constituents to give soluble or bound secondary metabolites or hydrolyzes to the dehydroaminoalcohol, dehydroretronecine.|Using microsomes from livers of phenobarbital-pretreated male rats, all 13 alkaloids tested were metabolized to n-oxide and pyrrole formation. The 2 pathways appeared to be independent. Ratio of n-oxide to pyrrolic metabolites varied, depending on type of ester: it was highest for open diester alkaloids and lowest for 12-membered macrocyclic diesters and for monoesters. Monocrotaline was one of those tested.|The comparative metabolism of the pyrrolizidine alkaloid, (14)C monocrotaline, was studied using rat and guinea pig hepatic microsomes. ... Esterase hydrolysis accounted for 92% of the metabolism in the guinea pig; the rat displayed no esterase activity. This result may explain the guinea pig's resistance to pyrrolizidine alkaloid toxicity. Dehydropyrrole was found to be the major pyrrolic metabolite in the guinea pig, although colorimetric analysis indicated multiple pyrrolic moieties in the rat microsomal incubations.|This report demonstrates that an Ehrlich reagent positive metabolite of monocrotaline and senecionine is excreted in the urine of male rats as an N-acetylcysteine conjugate of (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine ... This finding suggests that reactive metabolites of pyrrolizidine alkaloids generated in the liver can survive the aqueous environment of the circulatory system as glutathione conjugates or mercapturic acids.|For more Metabolism/Metabolites (Complete) data for MONOCROTALINE (7 total), please visit the HSDB record page.

The toxicology of monocrotaline is complex, and the mechanisms by which it causes lung injury, pulmonary hypertension, and right heart enlargement have remained elusive. ... Monocrotaline is bioactivated by the liver to a reactive, electrophilic pyrrole that travels via the circulation to the lung, where injury results. When low, iv doses of monocrotaline pyrrole are given to rats, a delay of several days occurs before lung injury and pulmonary hypertension become apparent. Moderate depletion of blood platelets around the time of the onset of lung injury lessens the subsequent development of right ventricular enlargement, suggesting a reduction in the pulmonary hypertensive response to monocrotaline pyrrole. This observation prompted a study of the role of platelet-derived mediators in the cardiopulmonary response to monocrotaline pyrrole. A stable analog of thromboxane A2(TxA2) caused a greater increase in right ventricular pressure in monocrotaline pyrrole treated rats compared to controls, and lungs isolated from monocrotaline pyrrole treated rats produced more TxB2 than those of controls. However, administration of drugs that either inhibited thromboxane synthesis or antagonized the effects of thromboxane did not afford protection from monocrotaline pyrrole in vivo. Serotonin, another vasoactive mediator released by platelets, caused an exaggerated vasoconstrictor response in isolated lungs from rats treated with monocrotaline pyrrole. Moreover, removal and inactivation of circulating serotonin by the pulmonary vasculature was impaired by treatment of rats with monocrotaline pyrrole. However, administration of serotonin receptor antagonists did not attenuate the cardiopulmonary effects of monocrotaline pyrrole in vivo. These results suggest that neither TxA2 nor serotonin is the sole mediator of the pneumotoxicity due to monocrotaline pyrrole. Thus, the mechanism by which platelets are involved in the pathogenesis of the pneumotoxic response to monocrotaline pyrrole remains an unsolved puzzle.|Monocrotaline propagates changes in the contractile response of arterial smooth muscle, changes in smooth muscle Na/K-ATPase activity, release of platelet factors, and decreased serotonin transport by vascular endothelial cells.|Effect of ip administration of monocrotaline on activities of hepatic epoxide hydrolase, and arylhydrocarbon hydroxylase was investigated in young, male long-evans rats. Monocrotaline failed to stimulate epoxide hydrolase while diminishing the activity of glutathione s-transferase, aminopyrine demethylase and AHH. There was no effect in vitro on hepatic drug-metabolizing enzymes studied except for slight stimulation of epoxide hydrolase activity and small reduction of aminopyrine demethylase activity.|... An active metabolite of monocrotaline, dehydromonocrotaline (DHM), alkylates guanines at the N7 position of DNA with a preference for 5'-GG and 5'-GA sequences. In addition, it generates piperidine- and heat-resistant multiple DNA crosslinks, as confirmed by electrophoresis and electron microscopy. On the basis of these findings, we propose that DHM undergoes rapid polymerization to a structure which is able to crosslink several fragments of DNA.

Carcinogens

Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison 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 respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|Presentation depends on the active toxic agent. In most cases, vomiting, abdominal pain, and diarrhea occur within 60 to 90 minutes of significant ingestion. With some toxins, severe gastroenteritis may result in massive fluid and electrolyte loss. ... Maintain open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, arrhythmias, and hypotension if they occur. Replace fluid loss caused by gastroenteritis with intravenous crystalloid solutions. ... Administer activated charcoal if available ... Gastric emptying is not necessary if activated charcoal is given promptly. /Plants and Herbal Medicines: Group 1/

/HUMAN EXPOSURE STUDIES/ The two main sources of pyrrolizidine alkaloid poisoning reported in human beings are the consumption of cereal grain contaminated by weeds containing the alkaloids and the use of alkaloid-containing herbs for medicinal and dietary purposes. ...Three of the largest outbreaks of the disease have been reported from South Asia, two from the same site in central India and one from North-West Afghanistan. The first Indian outbreak... occurred in a group of 5 tribal villages in central India in 1972-73. ...Out of a total population of 2,060 in these villages, 71 households with 366 members were investigated. Among these, 39 cases had developed and 19 had died before commencement of the investigations. The incidence rate was 1.1% and the case fatality rate was 50%. All cases occurred among 20 households. In many households, several members were affected. In one household, 4 out of 5 cases died. ...The etiological factor of this outbreak was not established, though dietary contamination with pyrrolizidine alkaloids was considered. A second outbreak occurred at the same site in 1975... . A total population of 486 was affected, 67 cases were reported, of whom 28 (46%) had died. There was a strong family history... . In a later survey, 108 patients were studied and the mortality rate was estimated to be 63%. This time the etiological factor was identified as the plant Crotalaria nana Burm, which had been growing in the fields of millet (Panicum miliare), their staple food crop. The seeds of this plant became mixed with the cereal grain during harvesting. The toxic seeds contained pyrrolizidine alkaloids that were identified as a macrocyclic ester closely similar to monocrotaline. The total alkaloid content was estimated to be 5.3 g/kg of seed, expressed as monocrotaline. The levels of contamination of the millet with seeds were reported to be 0-3.4 g/kg in the unaffected and 0-19 g/kg in the affected households... . /Pyrrolizidine alkaloids/|/HUMAN EXPOSURE STUDIES/ The largest outbreak reported to date occurred in the Gulran district of Herat Province in northwest Afghanistan, close to the border of the USSR. ...The outbreak, was estimated to have affected a population of approximately 35,000 in 98 villages. Examination of 7,200 inhabitants of the affected villages showed evidence of disease in 22.6%, which was more serious in 15%. Thus, it was estimated that approximately 8,000 subjects suffered from the disease including 5,000 who were seriously affected. All age groups were affected, but 46% of subjects were below 14 years of age. However, no sign of disease was found in children below 2 years of age. A detailed report concerning the pathological material obtained from 14 liver biopsies and 8 autopsies was made... /although/ the time interval between the onset of symptoms and the biopsy/autopsy was not indicated. Pathological findings were characteristic, ranging from acute disease with characteristic veno-occlusion to non-portal cirrhosis, which was observed in 5 of the above 22 cases. The outbreak was ascribed to massive contamination of wheat, the staple food crop, following 2 years of drought, with the seeds of Heliotropium popovii H. Riedl subsp. gillianum H. Riedl, which had been growing profusely among the wheat crop. The seeds contained pyrrolizidine alkaloids at concentrations reported by 2 laboratories to be 7.2 and 13.2-14.9 g/kg, identified mainly as the N-oxide of heliotrine (74%)..., and one or two other compounds similar in character to lasiocarpine. Samples of wheat from several villages contained an average of 40 seeds/kg, i.e., 0.03% by weight. It was estimated that an adult consumed at least 700 g flour/day, containing approximately 2 mg alkaloid (based on a mean of the seed analyses). /Pyrrolizidine alkaloids/|/SIGNS AND SYMPTOMS/ Well established as a cause of veno-occlusive disease are the pyrrolizidine alkaloids (e.g., monocrotaline, retrorsine, and seneciphylline) found in some plants used for herbal teas and in some seeds that contaminate food grains. Numerous episodes of human and animal poisoning by pyrrolizidine alkaloids have been reported around the world, including massive problems affecting thousands of people in Afghanistan in 1976 and 1993.

Monocrotaline

The seeds of Crotalaria retusa, Crotalaria sericea and Crotalaria spectabilis contain high levels of monocrotaline and are good sources for isolation purposes.

THE ANALYSIS OF PLANT MATERIAL FOR PYRROLIZIDINE ALKALOIDS IS BASED ON A GENERAL PROCEDURE FOR EXTRACTION OF THE TERTIARY BASE ALKALOIDS BEFORE AND AFTER REDUCTION OF THE ALKALOID N-OXIDES WHICH ARE ALSO USUALLY PRESENT. THE DIFFERENCE IN THE TWO RESULTS IS AN APPROXIMATE MEASURE OF THE N-OXIDE CONTENT OF THE PLANT MATERIAL. THE LEVELS OF BOTH TERTIARY BASE AND N-OXIDE FORMS OF THE ALKALOID ARE RELEVANT TO AN EVALUATION OF THE TOXICITY OF THE PLANT MATERIAL. THE INDIVIDUAL BASES ARE SEPARATED AND ESTIMATED BY PARTITION CHROMATOGRAPHY OR THIN-LAYER, PAPER OR GAS CHROMATOGRAPHY. /PYRROLIZIDINE ALKALOIDS/|PYRROLIZIDINE ALKALOIDS, UNSATURATED AT THE 1,2 POSITION, WERE DETECTED FOLLOWING TLC DIRECT OXIDATION TO PYRROLES BY USING O-CHLORANIL, FOLLOWED BY SPRAYING WITH EHRLICH'S REAGENT. N-OXIDES WERE DETECTED BY SPRAYING WITH AC20 FOLLOWED BY EHRLICH'S REAGENT. /PYRROLIZIDINE ALKALOIDS/|Underivatized pyrrolizidine alkaloids ... from natural sources (plants and insects) have been analysed by capillary gas chromatography-mass spectrometry. Thin-layer chromatography (TLC) and nuclear magnetic resonance (NMR) spectroscopy have also been used to detect pyrrolizidine alkaloids in plant extracts. /Pyrrolizidine Alkaloids/

The rapid and sensitive identification and quantification of important pyrrolizidine alkaloid metabolites using tandem mass spectrometry (MS/MS) and GC/MS is described. Identifications of N-oxide and hydrolytic metabolites of the pyrrolizidine alkaloids senecionine and monocrotaline in extracts of mouse hepatic microsomal incubations were accomplished by comparing collisionally activated decomp/mass-analyzed ion kinetic energy spectra of specific ions from microsomal extracts with spectra obtained from synthetic stds. of suspected metabolites. Trace amt of the toxic metabolite dihydropyrrolizine were observed by GC/MS of trimethylsilyl deriv, but the amt present in hepatic microsomal extracts were below the MS/MS limit of detection. Quant detn of senecionine N-oxide were performed by fast atom bombardment MS/MS. Suppression of N-oxide ionization by other substances in the extracts was judged to be minimal. The trimethylsilyl deriv of the metabolites senecic acid, monocrotalic acid, and dihydropyrrolizine were quantified using capillary GC/MS. The relative contributions of the 3 major pathways of pyrrolizidine alkaloid metab. (N-oxidn, hydrolysis, and oxidn to pyrrolic cmpd) can be assessed using a single analysis instrument and minimal sample prepn.|Pyrrolizidine alkaloids may be estimated in animal tissues and fluids by removing protein, chromatographing on Florisil and estimating colorimetrically with methyl orange. /Pyrrolizidine Alkaloids/

Health Hazards -> Carcinogens