Adverse Effects
Bromethalin
CAS No. 63333-35-7

 
 

Return to Bromethalin Index Page

Activity: Rodenticide (diphenylamine)
Structure:

Note that both bromine and fluorine are in this pesticide.

Adverse Effects:
Ataxia
Brain
CNS
Lung
Tremor/Convulsions
Environmental

Date active Ingredient registered in US: 1984

Bromethalin is currently registered for the control of commensal rats and mice in and around sewers, homes, industrial and agricultural buildings, and similar man-made structures. It may also be used in alleys located in urban areas, inside transport/cargo vehicles such as ships, trains, and aircraft, and in and around related port or terminal buildings. Baits may be placed in rodent burrows. Placement of bromethalin formulated as pellets or meal baits is prohibited in sewers. Baits are not to be applied to water or areas where surface water is present, or where there is the possibility of contaminating food or surfaces that come in direct contact with food. Applications may be made as frequently as necessary. At this time the Agency is aware of only general-use bromethalin products.
Ref: US EPA Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998.

Bromethalin is used under FIFRA emergency exemptions to control introduced rats on US islands in the Pacific Ocean.

Over the past few years, the single dose anticoagulant brodifacoum represented about 30 percent of total pounds of rodenticide active ingredient. Bromadiolone ranked second with about 20 percent of the rodenticide market. Multiple-dose anticoagulants chlorophacinone and diphacinone, and the acute poison bromethalin accounted for another 20 percent market share.
Ref: US EPA Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998.


-- Bromethalin is currently registered for the control of commensal rats and mice in and around sewers, homes, industrial and agricultural buildings, and similar man-made structures. It may also be used in alleys located in urban areas, inside transport/cargo vehicles such as ships, trains, and aircraft, and in and around related port or terminal buildings. Baits may be placed in rodent burrows. Placement of bromethalin formulated as pellets or meal baits is prohibited in sewers. Baits are not to be applied to water or areas where surface water is present, or where there is the possibility of contaminating food or surfaces that come in direct contact with food. Applications may be made as frequently as necessary. At this time the Agency is aware of only general-use bromethalin products.
--
Over the past few years, the single dose anticoagulant brodifacoum represented about 30 percent of total pounds of rodenticide active ingredient. Bromadiolone ranked second with about 20 percent of the rodenticide market. Multiple-dose anticoagulants chlorophacinone and diphacinone, and the acute poison bromethalin accounted for another 20 percent market share.
Ref: US EPA Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998.

-- Bromethalin is used under FIFRA emergency exemptions to control introduced rats on US islands in the Pacific Ocean.
-- Bromethalin, a diphenylamine, is a neurotoxicant that causes respiratory arrest from inadequate nerve impulse transmission after fluid build-up and demyelination inside the central nervous system (Spaulding and Spannring 1988, Hyngstrom et al. 1994).

Ref: Potential Risks of Nine Rodenticides to Birds and Nontarget Mammals: a Comparative Approach. December 19, 2002. US EPA Office of Prevention, Pesticices, and Toxic Substances.

Excerpt: Table 8 - Acute Toxicity Values of Technical Bromethalin
- page 14
Route
Species
Results
Toxicity Category
MRID (reference)
Oral
Rat
LD50 (Males) = 10.7 mg/kg
LD50 (Females) = 9.1 mg/kg
1
00026524
Inhalation
Rat
LC50 = 0.024 mg/L
1
00026524

LD50: Median Lethal Dose. A statistically derived single dose that can be expected to cause death in 50% of the test animals when administered by the route indicated (oral, dermal, inhalation). It is expressed as a weight of substance per unit weight of animal, e.g., mg/kg.

LC50: Median Lethal Concentration. A statistically derived concentration of a substance that can be expected to cause death in 50% of test animals. It is usually expressed as the weight of substance per weight or volume of water, air or feed, e.g., mg/l, mg/kg or ppm.
Ref: US EPA Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998.

The Agency [US EPA] has risk concerns for persons exposed to bromethalin in both occupational and residential scenarios. These concerns are based on
(1) very high acute toxicity (category I for acute oral toxicity);
(2) very low short-term and intermediate-term NOELs (0.1 mg/kg/day and 0.025 mg/kg/day respectively);
(3) the potential for acute, short-term, and intermediate-term exposures for occupational handlers, and for acute and short-term homeowner exposures;
(4) a relatively high number of incidents associated with rodenticide baits in general; and
(5) an absence of exposure data for all exposure scenarios considered.
Ref: US EPA Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998.

Ataxia (click on for all fluorinated pesticides)

Ten random source male domestic shorthair cats, 2 to 6 years old and 3.0-4.4 kg body weight, were each given a single oral dose (1.5 mg/kg) of bromethalin (cat Nos. 1-5) or bait vehicle carrier (cat Nos. 6-10). Bromethalin-dosed cats developed a toxic syndrome characterized by ataxia, focal motor seizures, vocalization, decerebrate posture, decreased conscious proprioception, recumbency, depression, and semicoma.
Ref: Neuropathologic findings of bromethalin toxicosis in the cat, by Dorman DC, Zachary JF, Buck WB. Vet Pathol 1992 Mar;29(2):139-44
.

Brain (click on for all fluorinated pesticides)

-- Subchronic Toxicity. Sprague Dawley rats (10/sex/group) received daily gavage doses of 0 (25% polyethylene glycol in H O), 5, 25, or 125 micrograms/kg/day (ug/kg/day) of bromethalin technical for 13 2 weeks. Parameters evaluated included daily observation, weekly body weight and food consumption, ophthalmoscopy, clinical pathology, necropsy, organ weights, and histopathology. The NOEL is 25 g/kg/day. The LOEL is 125 g/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. There were no effects on mortality, clinical chemistry, ophthalmoscopy, body weight, food consumption, clinical pathology and histopathology of other tissues (MRID 43582102).
-- In a second 90-day study, groups of 4 male and 4 female beagle dogs were orally dosed by gavage for 90 days at levels of 0, 5, 25, 125, or 200 ug/kg/day with bromethalin technical. Observations included daily clinical evaluations, ophthalmoscopy, body weight, food consumption, clinical pathology evaluations at weeks 6 and 13, necropsy, organ weights and histopathology. The NOEL is 25 g/kg/day. The LOEL is 125 g/kg/day based on spongy degeneration observed in nervous tissue components (cervical, thoracic, and lumbar spinal cord, brain stem, right and left optic nerves, frontal and median brain, pons, and cerebellum) 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... (MRID 43582101).
-- The following information is in the Agencys [EPA] files and are supportive of the endpoint of toxicological concern identified in the above studies. Ph.D. Dissertation entitled "Bromethalin-Based Rodenticides: Mode of Action, Toxicity, Clinical Effects, and Treatment Efficacy in Rats, Dogs, and Cats", by D. Dorman, University of Illinois, Dept. of Veterinary Biosciences (MRID 42759602). This dissertation is a summary of information found in the literature. According to the summary page of the dissertation, "The purpose of these studies was to define the toxicity of bromethalin-based rodenticides, develop treatments, and determine new modes of action of bromethalin..... Sublethal doses of bromethalin to dogs and cats resulted in delayed CNS depression, hind-limb ataxia, paresis, and paralysis. Higher doses given to dogs resulted in rapid severe muscle tremors and generalized seizures. Bromethalin toxicosis was also associated with increased cerebrospinal fluid pressure and cerebral edema. Bromethalin toxicosis produced acute and chronic EEG changes. Predominant abnormal EEG changes included spike and spike-and-wave EEG patterns; high voltage slow wave activity; photoconvulsive or photoparoxysmal irritative responses, and marked voltage depression. Histologic lesions included diffuse white matter spongiosis, mild microgliosis, and optic nerve vacuolization. Ultramicroscopic examination of brainstem revealed occasional swollen axons, intramyelenic vacuolization, and myelin splitting at the intraperiod line."
Ref: US EPA Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998.

http://www.fluoridealert.org/pesticides/Bromethalin.RED.EPA..1998.pdf

Abstract: Ten random source male domestic shorthair cats, 2 to 6 years old and 3.0-4.4 kg body weight, were each given a single oral dose (1.5 mg/kg) of bromethalin (cat Nos. 1-5) or bait vehicle carrier (cat Nos. 6-10). Bromethalin-dosed cats developed a toxic syndrome characterized by ataxia, focal motor seizures, vocalization, decerebrate* posture, decreased conscious proprioception, recumbency, depression, and semicoma. Bromethalin-dosed cats were euthanatized if seizure activity or hindlimb paralysis developed. Survival times were 48 hours (cat No. 1), 89 hours (cat No. 2), 90 hours (cat No. 3), and 97 hours (cat No. 4). Control cats (cat Nos. 6-10) and one bromethalin-dosed cat (cat No. 5) were euthanatized on day 20 after dosing. Spongy change (edema--characterized by the formation of vacuoles in extracellular spaces and myelin lamellae), hypertrophied fibrous astrocytes, and hypertrophied oligodendrocytes were observed in the white matter of the cerebrum, cerebellum, brain stem, spinal cord, and optic nerve of all bromethalin-dosed cats. Spongy change occasionally extended into contiguous cerebellar Purkinje cell layer and cerebral cortical gray matter. The severity of lesions varied among cats but was most pronounced in cat No. 5 (480 hours after dosing). A leukocytic inflammatory response, gitter cell (macrophage) response, or axonal degeneration was not observed in the vacuolated areas. Ultrastructural findings included separation of myelin lamellae at the interperiod lines with the formation of intramyelinic vacuoles (intramyelinic edema), rupture and coalescence of intramyelinic vacuoles into larger extracellular spaces (spongy change), and pronounced cytosolic edema of astrocytes and oligodendroglial cells. PMID: 1632057 [PubMed - indexed for MEDLINE]
Ref: Vet Pathol 1992 Mar;29(2):139-44. Neuropathologic findings of bromethalin toxicosis in the cat. Dorman DC, Zachary JF, Buck WB.

Abstract: 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). Ultramicroscopic examination of midbrain stem revealed occasional swollen axons, intramyelinic vacuolization, and myelin splitting at the intraperiod line. Bromethalin was detected in kidney, liver, fat, and brain tissues, using gas chromatography with electron capture detection. Photodegradation of extracted bromethalin may limit accurate quantification of tissue residues.
Ref: J Vet Diagn Invest 1990 Apr;2(2):123-8. Diagnosis of bromethalin toxicosis in the dog; by Dorman DC, Simon J, Harlin KA, Buck WB
.

Abstract: Bromethalin is a new rodenticide for the control of commensal rodents. Doses in excess of the LD50 (2 mg/kg in rats) will cause death within 8-12 hr and it is preceded by one to three episodes of clonic convulsions with death usually due to respiratory arrest. Multiple low doses or sublethal intoxication yields hind leg weakness and loss of tactile sensation in rodents. Histopathology of the brain and spinal cord of these animals revealed a spongy degeneration of the white matter which was shown upon ultramicroscopic examination to be intramyelenic edema. No inflammation or cellular destruction of neuronal tissue was noted. LD50 values ranged from 1.8 mg/kg in the cat to approximately 13 mg/kg in rabbits. The only apparent nonsusceptible species was the guinea pig which could tolerate doses in excess of 1000 mg/kg without effect. Identification of the desmethyl metabolite was demonstrated in the blood and liver of treated animals by comparison of chromatographic retention times to that of a reference standard, but direct mass spectral identification was unsuccessful in part due to the low dose which could be administered. Therefore, the metabolism of bromethalin was studied by indirect means. Animals were pretreated with three inducers of microsomal drug metabolism: phenobarbital, 3-methylcholanthrene (3MC), and Aroclor 1254 (Aroclor) and one inhibitor, SKF-525A. Pretreated mice or rats were given an LD50 dose of bromethalin or the desmethyl analog and the percentage of surviving animals was determined. (ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3229590
Ref: Fundam Appl Toxicol 1988 Nov;11(4):664-72 The toxicity and mechanism of action of bromethalin: a new single-feeding rodenticide; van Lier RB, Cherry LD. Toxicology Division, Lilly Research Laboratories, Greenfield, Indiana 46140.

CNS (click on for all fluorinated pesticides)

Bromethalin, a diphenylamine, is a neurotoxicant that causes respiratory arrest from inadequate nerve impulse transmission after fluid build-up and demyelination inside the central nervous system (Spaulding and Spannring 1988, Hyngstrom et al. 1994).
Ref: Potential Risks of Nine Rodenticides to Birds and Nontarget Mammals: a Comparative Approach. December 19, 2002. US EPA Office of Prevention, Pesticices, and Toxic Substances.

Lung (click on for all fluorinated pesticides)

Abstract: Bromethalin is a new rodenticide for the control of commensal rodents. Doses in excess of the LD50 (2 mg/kg in rats) will cause death within 8-12 hr and it is preceded by one to three episodes of clonic convulsions with death usually due to respiratory arrest.
Ref: Fundam Appl Toxicol 1988 Nov;11(4):664-72. The toxicity and mechanism of action of bromethalin: a new single-feeding rodenticide by van Lier RB and Cherry LD.

Tremors/Convulsions (click on for all fluorinated pesticides)

PubMed Abstract: 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). Ultramicroscopic examination of midbrain stem revealed occasional swollen axons, intramyelinic vacuolization, and myelin splitting at the intraperiod line. Bromethalin was detected in kidney, liver, fat, and brain tissues, using gas chromatography with electron capture detection. Photodegradation of extracted bromethalin may limit accurate quantification of tissue residues.
Ref: Diagnosis of bromethalin toxicosis in the dog, by Dorman DC, Simon J, Harlin KA, Buck WB. J Vet Diagn Invest 1990 Apr;2(2):123-8

http://www.fluoridealert.org/pesticides/Bromethalin-MEDLINE.htm

Abstract: Bromethalin is a new rodenticide for the control of commensal rodents. Doses in excess of the LD50 (2 mg/kg in rats) will cause death within 8-12 hr and it is preceded by one to three episodes of clonic convulsions with death usually due to respiratory arrest. Multiple low doses or sublethal intoxication yields hind leg weakness and loss of tactile sensation in rodents. Histopathology of the brain and spinal cord of these animals revealed a spongy degeneration of the white matter which was shown upon ultramicroscopic examination to be intramyelenic edema.
Ref: Fundam Appl Toxicol 1988 Nov;11(4):664-72 The toxicity and mechanism of action of bromethalin: a new single-feeding rodenticide. by van Lier RB and Cherry LD.

http://www.fluoridealert.org/pesticides/Bromethalin-MEDLINE.htm

Environmental (click on for all fluorinated pesticides)

Ecological Toxicity Data. Primary toxicity to mammals is very high for all five of these rodenticides. Primary toxicity to birds is high to very high for the single-feeding compounds (brodifacoum, bromadiolone, bromethalin)... Toxicity to aquatic organisms ranges from moderate to very high.
Ref: US EPA Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998

Table 46 - Bromethalin Freshwater Fish Acute Toxicity (page 64)
Ref: US EPA Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998 
Fish % of active ingredient (a.i.) LC50 ppm a.i. Toxicity Category MRID, Author, Year
Bluegill sunfish
(Lepomis macrochirus)
99 598 Very highly toxic 42733501 Conner, 1993
Rainbow trout
(Oncorhynchus mykiss)
99 38 Very highly toxic 42733502 Conner, 1993

 

 

 
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