3-Nitropropionsaeure

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.；SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.；INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.；INGESTION: If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Generally, the induction of vomiting is NOT recommended outside of a physician's care due to the risk of aspirating the chemical into the victim's lungs. However, if the victim is conscious and not convulsing and if medical help is not readily available, consider the risk of inducing vomiting because of the high toxicity of the chemical ingested. Ipecac syrup or salt water may be used in such an emergency. IMMEDIATELY transport the victim to a hospital. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces 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.；STORAGE PRECAUTIONS: You should keep this material in a tightly closed container under an inert atmosphere, keep it away from oxidizing materials and store it at refrigerated temperatures. (NTP, 1992)

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.

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:；IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.；SPILL: Increase the immediate precautionary measure distance, in the downwind direction, as necessary.；FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024)

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)

Systemic administration of 3-nitropropionic acid (3-NPA, a mycotoxin) induces brain damage accompanied by disturbance in the blood-brain barrier (BBB). Since the endothelial cells are important components of the BBB and the first target of a systemic intoxication, in the present study, the effect of 3-NPA on primary cultured rat brain endothelial cells (rBECs) was examined by studying intracellular Ca2+ ([Ca2+]i) response using imaging techniques. Data indicate that a medium to high concentration of 3-NPA induces damage on rBECs as revealed by an accumulation of [Ca2+]i, but the damage was protected by cotreatment with 17 beta-estradiol or tamoxifen, suggesting that estrogen may be protective for the brain vascular damage via estrogen receptor.

The role of impaired mitochondrial function in processes leading to the generation of seizures was studied in mice. An inhibitor of mitochondrial complex III, 3-nitropropionic acid, which is known to evoke convulsions per se, and was used here in subthreshold dose, enhanced seizures generated by electric current and application of 4-aminopyridine. In contrast, 3-nitropropionic acid did not affect convulsions induced by gamma-aminobutyric acid (GABA) receptor antagonists - bicuculline, pentylenetetrazol and picrotoxin, glycine antagonist - strychnine, cholinomimetic drug-pilocarpine, and kynurenine aminotransferase inhibitor - aminooxyacetic acid. It is hypothesised that deranged mitochondrial metabolism renders the central nervous system more susceptible to factors inducing seizures via direct depolarization.

There is currently no effective treatment for Huntington's disease (HD), a progressive, fatal, neurodegenerative disorder characterized by motor & cognitive deterioration. It is well established that Huntington's disease is associated with perturbation of mitochondrial energy metab. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, can stabilize the mitochondrial membrane, inhibit the mitochondrial permeability transition, decrease free radical formation, & derail apoptotic pathways. Here we report that tauroursodeoxycholic acid significantly reduced 3-nitropropionic acid (3-NPA) mediated striatal neuronal cell death in cell culture, In addition, rats treated with tauroursodeoxycholic acid exhibited an 80% reduction in apoptosis & in lesion volumes associated with 3-nitropropionic acid admin. Moreover, rats which received a combination of tauroursodeoxycholic acid + 3-nitropropionic acid exhibited sensor/motor & cognitive task performance that was indistinguishable from that of controls, & this effect persisted at least 6 months. Bile acids have traditionally been used as therapeutic agents for certain liver diseases. This is the first demonstration, however, that a bile acid can be delivered to the brain & function as a neuroprotectant & thus may offer potential therapeutic benefit in the treatment of certain neurodegenerative diseases.

3-Nitropropionic acid is a suicide inhibitor of succinate dehydrogenase, an enzyme required for the activity of the tricarboxylic acid (TCA) cycle as well as mitochondrial respiratory complex II of the electron transport chain. It forms a covalent adduct with the side chain of Arg297, inactivating the succinate dehydrogenase. This affects neurons by leading to NMDA-receptor activation, excessive calcium influx, and formation of reactive oxygen species, eventually causing neuronal cell death. (A2967, A2968)

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=504-88-1]

/HUMAN EXPOSURE STUDIES/ 3-Nitropropionic acid (3-NP), a naturally occurring mycotoxin... is associated with motor disorders in livestock and humans that have ingested contaminated food.

/HUMAN EXPOSURE STUDIES/ 3-Nitropropionic acid (3-NPA) - a suicide inhibitor of succinate dehydrogenase - is a widely distributed plant and fungal neurotoxin known to induce damage to basal ganglia, hippocampus, spinal tracts and peripheral nerves in animals. Recent reports from Northern China indicate that 3-NPA is also likely to be responsible for the development of putaminal necrosis with delayed dystonia in children after ingestion of mildewed sugar cane. This article discusses the role of 3-NPA in the causation of the disease in China, its neurotoxic effects in animals and the potential role for this compound as a probe of selective neuronal vulnerability.

/EPIDEMIOLOGY STUDIES/ There have been 217 outbreaks of acute mildewed sugar cane poisoning between 1972 & 1989 in China resulting in 884 patients & 88 deaths. Epidemiologic & experimental studies have found that 3-nitropropionic acid , a mycotoxin produced by Arthrinium-contaminated sugar canes, is the probable etiologic factor of the disease. ... Initial symptoms were nausea, vomiting, abdominal pain without diarrhea, & anorexia that followed headache & dizziness. Coma & convulsions develop within 3-18 hr after onset. Coma lasted 20 days in one case. Following the coma motor aphasia, inability of voluntary movement, & urinary & fecal incontinence appeared. There was no fever. The focal cerebral impairments were reversible. Dystonia began 11-60 days after the coma. CT scans indicated bilateral lenticular lesions in the putanes & pallidum.

3-Nitropropionic acid

TR-052: Bioassay of 3-Nitropropionic Acid for Possible Carcinogenicity (CASRN 504-88-1) (1978 )

01/18/78

Equivocal Evidence

No Evidence

No Evidence

/LABORATORY ANIMALS: Acute Exposure/ N-acetylaspartate (NAA) quantification by 1H-magnetic resonance spectroscopy has been commonly used to assess in vivo neuronal loss in neurodegenerative disorders. ... Ex vivo and in vivo 1H-magnetic resonance spectroscopy /were used/ in rat & primate models of progressive striatal degeneration induced by the mitochondrial toxin 3-nitropropionate (3NP) to determine whether early N-acetylaspartate depletions could also be associated with neuronal dysfunction. In rats that were treated for 3 days with 3-nitropropionate & had motor symptoms, the authors found a significant decr in N-acetylaspartate concns, specifically restricted to the striaturn. No cell loss or dying cells were found at this stage in these animals. After 5 days of 3-nitropropionate treatment, a further decr in striatal N-acetylaspartate concns was observed in association with the occurrence of dying neurons in the dorsolateral striatum. In 3-nitropropionate treated primates, a similar striatal selective & early decr in N-acetylaspartate concns was observed after only a few wks of neurotoxic treatment, without any sign of ongoing cell death. This early decr in striatal N-acetylaspartate was partially reversed after 4 wks of 3-nitropropionate withdrawal. These results demonstrate that early N-acetylaspartate depletions reflect a reversible state of neuronal dysfunction preceding cell degeneration & suggest that in vivo quantification of N-acetylaspartate 1H-magnetic resonance spectroscopy may become a valuable tool for assessing early neuronal dysfunction & the effects of potential neuroprotective therapies in neurodegenerative disorders.

/LABORATORY ANIMALS: Acute Exposure/ 3-Nitropropionic acid (3-NPA) is a toxin sometimes produced on moldy crops (sugarcane, peanuts, etc.) in amounts sufficient to cause severe neurological disorders when consumed by humans. In vitro, 3-nitropropionic acid irreversibly inactivates succinate dehydrogenase, a Complex 11 respiratory enzyme required for mitochondrial energy production. A single dose of 3-nitropropionic acid (30 mg/kg s.c.) was given to singly caged adult male Sprague Dawley rats. Rectal temperature was measured after dosing as a potential biomarker of exposure to 3-nitropropionic acid, & animals were sacrificed at various times after 3-nitropropionic acid exposure for histochemical visualization of succinate dehydrogenase activity. 3-Nitropropionic acid treated rats experienced a progressive hypothermia, which reached a loss of 3 °C or more in core body temperature by 3 hr after dosing. The optical density of the succinate dehydrogenase stain in brain was reduced according to a similar time course, most prominently in the cerebellum & least sharply in the thalamus. The caudate nucleus had the greatest density of succinate dehydrogenase staining that we measured in brain; it also has been reported to be the region most consistently lesioned by 3-nitropropionic acid. However, within other areas of brain such as subdivisions of the hippocampus, neither endogenous succinate dehydrogenase activity nor its sensitivity to inhibition by 3-nitropropionic acid could predict the susceptibility to neurodegenerative changes. Although succinate dehydrogenase activity remained significantly reduced in most areas of brain (except thalamus) for up to 5 days after dosing, core temperatures had returned to control values by 5 days suggesting that animals can utilize an alternate method of heat production to withstand insult by 3-nitropropionic acid.

IF METHEMOGLOBINEMIA OCCURS & IS SEVERE, THEN TREAT WITH METHYLENE BLUE & OXYGEN.

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. For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . /Etiological Agents/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Proparacaine hydrochloride should be used to assist eye irrigation ... . /Etiological Agents/

A bioassay of 3-nitropropionic acid (95% pure) for possible carcinogenicity was conducted by admin the test chemical by gavage to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were admin 3-nitropropionic acid at one of the following doses by gavage 5 days/wk. For male rats, the doses were 0.425 or 0.85 mg/animal/day; for females, they were 0.6 or 1.2 mg/animal/day. For both sexes of mice, the doses were 0.375 or 0.75 mg/animal/day. The rats were admin the test chemical for 110 wk and the mice for 104 wk. The controls consisted of 50 untreated rats and 50 untreated mice of each sex. All surviving rats were /sacrificed/ at 111 wk and all surviving mice at 104-105 wk. Mean body weights and mortality of the dosed animals were not markedly affected by 3-nitropropionic acid under the conditions of this bioassay, indicating that the maximum tolerated dose may not have been reached. The various clinical signs observed were common to both dosed and control groups. In rats, the combination of neoplastic nodule of the liver and hepatocellular carcinoma occurred in the males with a significant dose related trend (p=0.010) and with a higher incidence (p=0.012) in the high dose group of animals than in the controls (controls 0/49, low dose 3/50, high dose 6/49). All but one of these tumors were neoplastic nodules. In the females, only two neoplastic nodules occurred, one in each of the dosed groups. Biliary hyperplasia occurred at a higher incidence in dosed males than in the corresponding controls (controls 19/50, low dose 32/50, high dose 36/50), but the incidence of this lesion in dosed females was not incr as compared with controls. There was also a dose related trend (p=0.033) in the incidence of pancreatic islet cell adenoma in male rats (controls 4/49, low dose 6/50, high dose 11/50); however, direct comparisons of incidences in the dosed and control groups were not statistically significant. The historical incidence of pancreatic islet cell a

A naturally occurring mycotoxin that is associated with motor disorders in livestock and humans that have ingested contaminated food; Used as a research chemical; Not commercially produced in the US; [HSDB]

RESEARCH CHEMICAL

Research mitochondrial inhibitor for injection into test animals

3-Nitropropionic acid is a neurotoxin produced by certain plants and fungi, such as those of the genus Astragalus, Coronilla, Lotus, Hippocrepis, Scorpiurus, and Securigera. It produces symptoms similar to that of Huntington disease and this thus often used to produced animal models for the study of the disease. (A2967, A2968, A2970)

(1977) NOT PRODUCED COMMERCIALLY IN US

(1979) NOT PRODUCED COMMERCIALLY IN US