(Z)-2-メチル-2-ブテン酸(1S)-7-[[[(2R)-2,3-ジヒドロキシ-2-[(S)-1-メトキシエチル]-3-メチルブタノイル]オキシ]メチル]-2,3,5,7aβ-テトラヒドロ-1H-ピロリザイン-1-イル

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

IT IS BEST STORED UNDER NITROGEN @ -15 °C

PRECAUTIONS FOR "CARCINOGENS": 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. /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/

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the adsorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U143, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.

A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 °C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 °C and residence times of seconds for liquids and gases, and longer for solids.

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/

For more Disposal Methods (Complete) data for LASIOCARPINE (7 total), please visit the HSDB record page.

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 LASIOCARPINE (9 total), please visit the HSDB record page.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

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/

LASIOCARPINE (7.8 MG/KG, IP TWICE WEEKLY FOR 4 WK, THEN ONCE A WK FOR 18 WK) DID NOT PREVENT INITIATION OF LIVER TUMORS BY AFLATOXIN B1 (2 PPM IN DIET), BUT ALTERED THE PATHOGENIC PATTERN IN THAT, IN RATS RECEIVING AFLATOXIN & LASIOCARPINE, THE LIVER TUMORS WERE ASSOC WITH POSTNECROTIC CIRRHOSIS, WHEREAS IN RATS DEVELOPING LIVER TUMORS WITH AFLATOXIN ALONE THEY WERE NOT.

SENSITIVITY OF RATS TO LASIOCARPINE IS REDUCED BY FEEDING A DIET LOW IN LIPOTROPES OR BY SIMULTANEOUS ADMIN OF MERCAPTOETHYLAMINE.

PREGNENOLONE-16ALPHA-CARBONITRILE, SPIRONOLACTONE, ETHYLESTRENOL, PHENOBARBITAL, & DIPHENYLHYDANTOIN PREVENTED THE MORTALITY & LIVER DAMAGE CAUSED BY SINGLE DOSE OF LASIOCARPINE (100 MG/KG, IP) WHEREAS SKF 525-A, OR PARTIAL HEPATECTOMY, GREATLY INCR LETHALITY.

RATS WERE TREATED CONCURRENTLY WITH THIOACETAMIDE & THE PYRROLIZIDINE ALKALOID LASIOCARPINE. THIOACETAMIDE WAS GIVEN IP IN DOSE OF 50 MG/KG BODY WT TWICE WEEKLY & LASIOCARPINE WAS ADMIN IN THE DIET AT CONCN OF 50 PPM. THIOACETAMIDE & LASIOCARPINE PRODUCED NUMEROUS GROSSLY VISIBLE GREY NODULES IN LIVERS OF 26 OF 30 RATS. RAPID DEVELOPMENT OF LIVER LESIONS IN RATS TREATED SIMULTANEOUSLY SUGGEST THAT CELL PROLIFERATION ACCENTUATES THE DEVELOPMENT OF NEOPLASIA.

For more Interactions (Complete) data for LASIOCARPINE (7 total), please visit the HSDB record page.

Lasiocarpine is toxic to liver cells but not to lung cells, which is unable to metabolize the pyrrolizidine alkaloids to pyrroles. The application of lasiocarpine to human liver cells in culture is followed by inhibition of DNA, RNA and protein synthesis; vacuolation of the cells, the prevention of mitosis and the formation of giant cells (“megalocytes”). (A15431) Effects on the liver include hemorrhagic necrosis of parenchymal cells, marked enlargement of parenchymal cells and of their nuclei and nucleoli, fibrosis or cirrhosis, depression of cell division, and possibly neoplasia. (A15432) The inducibility of tryptophan pyrrolase activity by hydrocortisone, in the livers of rats treated chronically with lasiocarpine is an indication that translational mechanisms are intact. However, the increased uptake of 3H-thymidine by megalocytes, in the absence of observable mitotic activity, suggests that these cells are in the process of hypertrophy. They may act as prolonged, potent inhibitors of mitosis in hepatocytes, they are mutagenic in Drosophila and cause chromosome breakage in leukocytes. One of the unusual results of chronic poisoning by lasiocarpine and other members of the pyrrolizidine alkaloids is progressive enlargement of liver cells to up to three times the normal diameter, with an accompanying proportionate increase in nuclear diameter. The term megalocytosis has been applied to this abnormality which may be associated with mild fibrosis of central veins and proliferation of bile ducts. The prominence of rough ER in enlarged hepatocytes is s a sign of increased metabolic activity. (A15433)

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=303-34-4]

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

... SIGNS OF HELIOTROPE TOXICOSIS WERE HEPATOMEGALY, ASCITES & DISTURBANCES OF HEPATIC FUNCTION; HEPATOMEGALY OCCURRED IN ALL CASES, ASCITES IN 85% & JAUNDICE IN 2-3%. RECOVERY WAS COMPLETE IN 60% OF CASES ... WITH SLIGHT RESIDUAL HEPATOMEGALY IN 35%; IN 3% HEPATOMEGALY PERSISTED; & RECURRENT ASCITES WERE SEEN IN 2%.

AFTER TREATMENT WITH LASIOCARPINE, CULTURED HUMAN EMBRYO LIVER CELLS SHOWED MORPHOLOGICAL ALTERATIONS INDICATIVE OF: (1) NUCLEAR & NUCLEOLAR CHANGES, PROBABLY RELATED TO THE ALKYLATION OF DNA & ENSUING INHIBITION OF NUCLEIC ACID & PROTEIN SYNTHESIS; (2) INDUCTION OF POSSIBLE CHROMOSOMAL DAMAGE & MUTATION; (3) GENERALIZED REDUCTION OF THE METABOLIC ACTIVITY OF THE CELLS DUE TO MEMBRANE & MITOCHONDRIAL DAMAGE, & TO ALKYLATION & INACTIVATION OF CELL ENZYMES & PROTEINS; & (4) LONG-TERM INHIBITION OF MITOSIS LEADING TO FORMATION OF GIANT CELLS.

... LASIOCARPINE IS THE MAIN TOXIC ALKALOID OF HELIOTROPIUM LASIOCARPUM, REPORTS OF TOXICITY IN HUMANS DUE TO CONSUMPTION OF BREAD MADE FROM WHEAT, BARLEY OR MILLET CONTAMINATED WITH THE SEEDS OF THIS PLANT ARE RELEVANT. EPIDEMICS IN USSR AFFECTED GROUPS OF AGRICULTURAL WORKERS & THEIR FAMILIES IN SPECIFIC REGIONS ... .

IN CENTRAL ASIAN REPUBLICS OF USSR, CONTAMINATION OF CEREAL GRAIN FOR HUMAN CONSUMPTION BY SEEDS OF HELIOTROPIUM LASIOCARPUM OCCURRED AT LEAST UNTIL 1946. AT THAT TIME THE SEEDS WERE SHOWN TO BE THE CAUSE OF A DISEASE THEN KNOWN AS 'TOXIC HEPATITIS WITH ASCITES' BUT RE-NAMED 'HELIOTROPIC DYSTROPHY OF THE LIVER'.

For more Human Toxicity Excerpts (Complete) data for LASIOCARPINE (6 total), please visit the HSDB record page.

Lasiocarpine

Group 2B: Possibly carcinogenic to humans

Volume 10: (1976) Some Naturally Occurring Substances

1987

1987

Lasiocarpine

25 INBRED MALE FISCHER 344 RATS WERE GIVEN IP INJECTIONS OF 7.8 MG/KG BODY WT OF LASIOCARPINE TWICE WEEKLY FOR 4 WK THEN ONCE/WK FOR 52 WK, WHEREUPON INJECTIONS WERE DISCONTINUED. 18 SURVIVED THE TIME OF THE APPEARANCE OF THE FIRST TUMOR (56 WEEKS), AND 16 DEVELOPED TUMORS 60 TO 76 WK AFTER THE BEGINNING OF THE EXPERIMENT. 10 RATS DEVELOPED HEPATOCELLULAR CARCINOMAS, 6 DEVELOPED WELL DIFFERENTIATED SQUAMOUS CELL CARCINOMAS OF THE SKIN OF THE BACK, 5 DEVELOPED PULMONARY ADENOMAS, 2 DEVELOPED WELL DIFFERENTIATED ADENOCARCINOMAS OF THE SMALL INTESTINE, 1 DEVELOPED A CHOLANGIOCARCINOMA, 1 AND ADENOMYOMA OF THE ILEUM AND 1 AN INTERSTITIAL CELL TUMOR OF THE TESTES.

... HIGH DOSES CAUSE RAPID DEATH /IN GUINEA-PIGS & MONKEYS/ WITHIN FEW HR, OFTEN WITH CONVULSIONS ... LOWER DOSES ... PRODUCE SEVERE HEMORRHAGIC NECROSIS OF LIVER, GI HEMORRHAGE ... CONGESTION & EDEMA OF LUNGS, CONGESTION OF ADRENALS & ... PYLORIC, DUODENAL & RECTAL ULCERATION. LEUCOCYTOSIS & ... HYPOPROTHROMBINEMIA ALSO OCCUR.

CHRONIC TOXICITY /IN GUINEA-PIGS & MONKEYS/ GIVES RISE TO SMALL, NODULAR LIVERS, ... FOCAL HEPATIC NECROSIS & BILE-DUCT PROLIFERATION, ANEMIA, BILIRUBINEMIA, PERSISTENT HYPOPROTHROMBINEMIA, GI HEMORRHAGE, PULMONARY, PANCREATIC, SUBCUTANEOUS OR GENERALIZED EDEMA, SPLENIC ENLARGEMENT & DAMAGED KIDNEYS, THYMUS & PANCREAS.

HIGH DOSE ... CAUSES ... DROP IN THE ACTIVITY OF DNA-DEPENDENT RNA POLYMERASE OF RAT LIVER NUCLEI. HOWEVER, THE ALKALOID DOES NOT INHIBIT THE TRANSCRIPTION OF RAT LIVER DNA BY MICROCOCCUS LYSODEIKTICUS-RNA POLYMERASE ... SYNTHESIS OF DNA IN 24-HR REGENERATING LIVER IS ... INHIBITED TO 70-92% BY ADMIN ... 1-3 HR BEFORE ASSAY.

For more Non-Human Toxicity Excerpts (Complete) data for LASIOCARPINE (25 total), please visit the HSDB record page.

It has been suggested that iodoform prophylaxis may be a useful protective measure in the field for sheep exposed to Heliotropium europaeum grazing during a single season ... . /Heliotropium europaeum/

Management is entirely supportive. Since massive hepatic necrosis represents the greatest threat to life, the usual measures ... for hepatic dysfunction should be administered. Profound hypoglycemia is a definite risk so that any obtunded patient should receive intravenous glucose immediately after blood samples are drawn. /Pyrrolizidine alkaloids/

A BIOASSAY OF LASIOCARPINE FOR POSSIBLE CARCINOGENICITY WAS CONDUCTED BY ADMIN THE TEST CHEM IN THE DIET TO FISCHER 344 RATS. GROUPS OF 24 RATS OF EACH SEX WERE ADMIN LASIOCARPINE AT 7, 15, OR 30 PPM, FOR 104 WK. MATCHED CONTROLS CONSISTED OF GROUPS OF 24 UNTREATED RATS OF EACH SEX. THERE WAS A POS DOSE-RELATED TREND IN THE INCIDENCE OF ANGIOSARCOMA OF THE LIVER. METASTATIC ANGIOSARCOMAS WERE PRESENT IN THE LUNGS FROM A FEW RATS IN ALL 3 TREATED GROUPS OF BOTH SEXES. THUS, UNDER THE CONDITIONS OF THIS BIOASSAY LASIOCARPINE WAS CARCINOGENIC FOR LIVER OF FISCHER 344 RATS.

U143; As stipulated in 40 CFR 261.33, when lasiocarpine, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).

Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b).