Bromethalin

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Soak up with inert absorbent material and dispose of as hazardous waste. Keep in suitable, closed containers for disposal.

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

The following drugs ... may increase ... response to coumarin or indandione derivatives: alcohol (acute intoxication), allopurinol, aminosalicylic acid, amiodarone, anabolic steroids, chloral hydrate, chloramphenicol, cimetidine, clofibrate, co-trimoxazole, danazol, dextrothyroxine sodium, diazoxide, diflunisal, disulfiram, erythromycin, ethacrynic acid, fenoprofen calcium, glucagon, ibuprofen, indomethacin, influenza virus vaccine, isoniazid, meclofenamate, mefenamic acid, methylthiouracil, metronidazole, miconazole, nalidixic acid, neomycin (oral), pentoxifylline, phenylbutazone, propoxyphene, propylthiouracil, quinidine, quinine, salicylates, streptokinase, sulfinpyrazone, sulfonamides, sulindac, tetracyclines, thiazides, thyroid drugs, tricyclic antidepressants, urokinase, vitamin E. /Coumarin & indandione derivatives/

The following drugs ... may ... decrease ... response to coumarin or indandione derivatives: alcohol (chronic alcoholism), barbiturates, carbamazepine, corticosteroids, corticotropin, ethchlorvynol, glutethimide, griseofulvin, mercaptopurine, methaqualone, oral contraceptives containing estrogen, rifampin, spironolactone, vitamin K. /Coumarin & indandione derivatives/

...Treatment of bromethalin-dosed rats (10/group) with EGB /(Gingko biloba extract)/ was associated with a statistically significant (P<0.05) decr in clinical sign severity, compared with bromethalin-dosed saline soln-treated rats. All rats given bromethalin and saline soln developed clinical signs of toxicosis including CNS depression, hind limb weakness, ataxia, paralysis, and coma. Some rats given bromethalin and EGB developed clinical signs, however, none developed hind limb paralysis. ...

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6.3X10+4(SRC), determined from a structure estimation method(2), indicates that bromethalin is expected to be immobile in soil(SRC). Volatilization of Bromethalin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.0X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Bromethalin is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 9.70X10-8 mm Hg at 25 °C(3). A biodegradation half-life in soil of 178 days(4) suggests that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6.3X10+4(SRC), determined from a structure estimation method(2), indicates that bromethalin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.0X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 6100(SRC), from an estimated log Kow of 7.68(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is very high, provided the compound is not metabolized by the organism(SRC). A biodegradation half-life in soil of 178 days(5) suggests that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), bromethalin, which has a vapor pressure of 9.70X10-8 mm Hg at 25 °C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase bromethalin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 8 days(SRC), calculated from its rate constant of 2.1X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase bromethalin may be removed from the air by wet and dry deposition(SRC). Bromethalin absorbs UV light at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Brometalin is a solid. It is a rodenticide, effective against rodents resistant to anticoagulant rodenticides. HUMAN STUDIES: Mild gastrointestinal upset is possible. CNS target symptoms: include hyperexcitability, altered mental status, ataxia, tremor, seizures, coma, cerebral edema, increased intracranial pressure and paralysis. A delusional 21-year-old male presented to a hospital with altered mental status the day after ingesting a bromethalin-based rodenticide. He died 7 days after his self-reported exposure. His clinicopathologic course was characterized by altered mental status, obtundation, increased cerebrospinal fluid pressure, cerebral edema, death, and diffuse histologic vacuolization of the white matter in the central nervous system seen on microscopic examination at autopsy. The presence of a demethylated form of bromethalin in the patient's liver and brain was confirmed by gas chromatography with mass spectrometry. There were 129 calls related to human bromethalin exposures. The age range of cases was 7 months-90 years old, with the majority of exposures (89 cases; 70.6%), occurring in children younger than 5 years of age (median age of 2 years). Most exposures occurred in the pediatric population as a result of exploratory oral exposure. One hundred and thirteen patients (89.7%) had no effects post exposure, while 10 patients (7.9%) had a minor outcome. Adverse effects were minor, self-limited, and mostly gastrointestinal upset. ANIMAL STUDIES: Rats received daily gavage doses of 0, 5, 25, or 125 ug/kg/day of bromethalin technical for 13 weeks. The NOEL in rats was 25 ug/kg/day. The LOEL in rats was 125 ug/kg/day, based on spongy degeneration (leukoencephalomyelopathy) observed in most of the central white fiber tracts of the brain, cerebellum, pons, brain stem, and thoracic spinal cord of both sexes and optic nerves of males. Dogs given a single oral dose of bromethalin at 6.25 mg/kg developed a toxic syndrome characterized by hyperexcitability, tremors, seizures, depression, and death within 15-63 hours after bromethalin administration. Gross lesions included mild cerebral edema (2/5) and mild pulmonary congestion (2/5). Histologic lesions included diffuse white matter spongiosis (5/5), mild microgliosis (3/5), optic nerve vacuolization (3/5), mild thickening of Bowman's capsule (2/5), and occasional splenic megakaryocytes (2/5). Electroencephalogram (EEG) recordings were obtained before and during the clinical syndrome induced by a bromethalin rodenticide given to dogs. Nine dogs given 6.25 mg bromethalin/kg po developed clinical signs and EEG abnormalities 15-58 hr postdosing. Predominant abnormal EEG changes included spike and spike-and-wave EEG patterns (66%), high voltage slow wave (HVSA, 50-150 microV, 1-6 Hz) activity (44%) photoconvulsive or photoparoxysmal irritative responses (44%), and marked voltage depression (dominant activity <10 microV) in all leads (33%). Male and female dogs were orally dosed by gavage for 90 days at levels of 0, 5, 25, 125, or 200 ug/kg/day with bromethalin technical. The NOEL in dogs was 25 ug/kg/day. The LOEL in dogs was 125 ug/kg/day based on spongy degeneration observed in nervous tissue components in both sexes of dogs. At the high dose, 3 male dogs displayed the following neurotoxic signs before death or being sacrificed moribund: salivation and hypoactivity, followed by trembling, myoclonia, hyperesthesia, groaning, and decubitus. Bromethalin did not produce acute delayed neurotoxicity in the hen. Cats typically develop paralytic syndrome irrespective of dose of bromethalin. In rats, there were no compound-related external, visceral or skeletal effects in bromethalin-treated fetuses in comparison to controls on either a litter or fetal basis. Definitive post mortem confirmation of intoxication by the neurotoxic rodenticide bromethalin can be challenging. Brain lesions are not specific and detection of bromethalin and its metabolites are unpredictable due to rapid photodegradation and inconsistent behavior in tissues. ECOTOXICITY STUDIES: In cases of wildlife species with unknown deaths or inconsistent clinical signs with normal or minimal histological findings, bromethalin toxicosis should be considered as a differential. Adipose tissue is the tissue of choice and can be easily harvested from a live or deceased animal to help confirm or rule out bromethalin exposure or intoxication.

/BIRDS and MAMMALS/ Submission of a raccoon (Procyon lotor) for necropsy following exhaustion at a California wildlife care center revealed minimal gross pathologic changes and only mild vacuolar changes in the white matter of the brain. Turquoise granular material was noted in the gastrointestinal tract and was submitted for toxicological testing along with portions of the brain, liver, kidney, and mesenteric and perirenal adipose tissues. Testing of the turquoise material for 7 anticoagulant rodenticides, strychnine, 4-aminopyridine, starlicide, and salts revealed none of these compounds; however, desmethylbromethalin was detected by high-performance liquid chromatography-tandem mass spectrometry. Other tissues were subsequently analyzed; the mesenteric and perirenal adipose tissues contained desmethylbromethalin. Desmethylbromethalin is the active metabolite of bromethalin, uncouples oxidative phosphorylation, and results in cerebral edema. Bromethalin is a rodenticide that is visually indistinguishable from many other rodenticides, making identification of poisonings by appearance alone nearly impossible. Based on the pathological and toxicological findings, a diagnosis of bromethalin toxicosis was established. In cases of wildlife species with unknown deaths or inconsistent clinical signs with normal or minimal histological findings, bromethalin toxicosis should be considered as a differential. Adipose tissue is the tissue of choice and can be easily harvested from a live or deceased animal to help confirm or rule out bromethalin exposure or intoxication.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of bromethalin can be estimated to be 6.3X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that bromethalin is expected to be immobile in soil(SRC). Bromethalin contains a diphenylamine moiety. The pKa of dibenzylamine is 9.0(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/SIGNS AND SYMPTOMS/ Based on animal and limited human data. Mild GI upset possible. CNS target symptoms: hyperexcitability, altered mental status, ataxia, tremor, seizures, coma, cerebral edema, increased intracranial pressure and paralysis.

/CASE REPORTS/ Bromethalin is a neurotoxin found in some rodenticides. A delusional 21-year-old male presented to a hospital with altered mental status the day after ingesting a bromethalin-based rodenticide. He died 7 days after his self-reported exposure to c. 17 mg bromethalin (equivalent to 0.33 mg bromethalin/kg). His clinicopathologic course was characterized by altered mental status, obtundation, increased cerebrospinal fluid pressure, cerebral edema, death, and diffuse histologic vacuolization of the white matter in the central nervous system seen on microscopic examination at autopsy. The presence of a demethylated form of bromethalin in the patient's liver and brain was confirmed by gas chromatography with mass spectrometry. Clinical signs and lesions observed in this patient are similar to those seen in animals poisoned with bromethalin. This case illustrates the potential for bromethalin ingestion to result in fatal human poisoning.

/SURVEILLANCE/ BACKGROUND: Bromethalin is an increasingly used alternative to long-acting anticoagulant and cholecalciferol rodenticides. There are few reports of human exposures, and no existing professional society guidelines on medical management of bromethalin ingestions. The aim of this retrospective data review is to characterize bromethalin exposures reported to the California Poison Control System (CPCS) between 1997 and 2014. METHODS: This is an observational retrospective case review of our statewide poison control system's electronic medical records. Following Institutional Board Review and Research Committee approvals, poison center exposures related to bromethalin were extracted using substance code and free text search strategies. Case notes of bromethalin exposures were reviewed for demographic, clinical, laboratory, and outcome information; inclusion criteria for the study was single-substance, human exposure to bromethalin. RESULTS: There were 129 calls related to human bromethalin exposures (three cases met exclusion criteria). The age range of cases was 7 months-90 years old, with the majority of exposures (89 cases; 70.6%), occurring in children younger than 5 years of age (median age of 2 years). Most exposures occurred in the pediatric population as a result of exploratory oral exposure. One hundred and thirteen patients (89.7%) had no effects post exposure, while 10 patients (7.9%) had a minor outcome. Adverse effects were minor, self-limited, and mostly gastrointestinal upset. There were no moderate, major, or fatal effects in our study population. The approximate ingested dose, available in six cases, ranged from 0.067 mg/kg to 0.3 mg/kg (milligrams of bromethalin ingested per kilogram of body weight), and no dose-symptom threshold could be established from this series. Exposures were not confirmed through urine or serum laboratory testing. DISCUSSION: The prognosis for most accidental ingestions appears to be excellent. However, bromethalin exposures may result in a higher number of symptomatic patients than long-acting anticoagulant agents. Parents, physicians and poison control specialists are encouraged to maintain a high index of suspicion for bromethalin-related complications in all cases of rodenticide exposures. CONCLUSIONS: Accidental bromethalin exposures in children appear to be self-limited in toxicity. Additional studies are warranted to determine whether more severe effects are precipitated when larger amounts are involved, particularly in suicidal ingestion.

AEROBIC: In a soil study, bromethalin was confirmed to be slowly biodegraded, with a half-life of 178 days(1). 102.4% of the applied radioactivity was decreased to 22.3% by the end of the study; 2.2% CO2 was identified in C14-volatiles. One degradate was identified as desnitrobromethalin(1).

An estimated BCF of 6100 was calculated in fish for bromethalin(SRC), using an estimated log Kow of 7.68(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is very high, provided the compound is not metabolized by the organism(SRC).

The Henry's Law constant for bromethalin is estimated as 4.0X10-9 atm-cu m/mole(SRC) developed using a fragment constant estimation method(1). This Henry's Law constant indicates that bromethalin is expected to be essentially nonvolatile from water and moist soil surfaces(2). Bromethalin is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 9.70X10-8 mm Hg(3).

Based on the reviews of the generic data for the active ingredients brodifacoum, bromethalin, bromadiolone, chlorophacinone, and diphacinone and its sodium salt, the Agency has sufficient information on the health effects of these chemicals and on their potential for causing adverse effects in fish, wildlife, and the environment. The Agency has determined that these chemicals, labeled and used as specified in this Reregistration Eligibility Decision document, will not pose unreasonable risks or adverse effects to humans or the environment. Therefore, the Agency concludes that products containing brodifacoum, bromethalin, bromadiolone, chlorophacinone, and diphacinone and its sodium salt, are eligible for reregistration.

As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their continued use. Under this pesticide reregistration program, EPA examines newer health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether the use of the pesticide does not pose unreasonable risk in accordance to newer safety standards, such as those described in the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA '88 were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern than those on List C, and with List C containing pesticides of greater concern than those on List D. Bromethalin is found on List B. Case No: 2765; Pesticide type: rodenticide; Case Status: RED Approved 9/1997; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): N-Methyl-2,4-dinitro-N-(2,4,6-tribromophenyl)-6-(trifluoromethyl)benzenamine; Data Call-in (DCI) Date(s): 02/04/1991, 11/24/1992; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) for the case/AI.