Abstracts
Bromethalin

including
Abstracts and bibliography from EPA's 1998 Rodentcide Cluster report
CAS No. 63333-35-7
For more abstracts search PubMed or Toxnet
 
 

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Adverse Effects

ACTIVITY: Rodenticide (diphenylamine)

CAS Name: N-methyl-2,4-dinitro-N-(2,4,6-tribromophenyl)-6-(trifluoromethyl)benzenamine

Structure:

Note that both bromine and fluorine are in this pesticide.
Reports available from
The National Technical Information Service
(NTIS)

Order from NTIS by: phone at 1-800-553-NTIS (U.S. customers); (703)605-6000 (other countries); fax at (703)605-6900; and email at orders@ntis.gov. NTIS is located at 5285 Port Royal Road, Springfield, VA, 22161, USA.
Order Number Title Keywords Source
NTIS/OTS0543306

INITIAL SUBMISSION: LETTER FROM ELI LILLY & CO TO USEPA SUBMITTING RESULTS ON AN ACUTE ORAL STUDY WITH M-6077 IN MONKEY WITH ATTACHMENTS - 1992
ELI LILLY & CO
M-6077
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
MONKEYS
ORAL
GAVAGE
EPA/OTS; Doc #88-920005845
NTIS/OTS0543309 INITIAL SUBMISSION: LETTER FROM ELI LILLY & CO TO USEPA SUBMITTING RESULTS ON AN ACUTE ORAL STUDY WITH R-O-418-78 IN RATS WITH ATTACHMENTS - 1992 ELI LILLY & CO
R-O-418-78
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
ORAL
GAVAGE
EPA/OTS; Doc #88-920005848
NTIS/OTS0543313 INITIAL SUBMISSION: LETTER FROM ELI LILLY & CO TO USEPA SUBMITTING RESULTS ON AN ACUTE ORAL STUDY WITH R-O-21-79 IN RATS WITH ATTACHMENTS - 1992 ELI LILLY & CO
R-O-21-79
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
ORAL
GAVAGE
EPA/OTS; Doc #89-920005851
NTIS/OTS0543314 INITIAL SUBMISSION: LETTER FROM ELI LILLY & CO TO USEPA SUBMITTING RESULTS ON AN ACUTE ORAL STUDY WITH R-O-128-79 IN RATS WITH ATTACHMENTS - 1992 ELI LILLY & CO
R-O-128-79
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
ORAL
GAVAGE
EPA/OTS; Doc #88-920005852
NTIS/OTS0543315
INITIAL SUBMISSION: LETTER FROM ELI LILLY & CO TO USEPA SUBMITTING RESULTS ON AN ACUTE INHALATION STUDY IN RATS WITH R-H-64-77 IN RATS WITH ATTACHMENTS - 1992 ELI LILLY & CO
R-H-64-77
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
INHALATION
EPA/OTS; Doc #88-920005853
NTIS/OTS0543316 INITIAL SUBMISSON: LETTER FROM ELI LILLY & CO TO USEPA SUBMITTING RESULTS ON AN ACUTE INHALATION STUDY WITH R-H-53-77 IN RATS WITH ATTACHMENTS - 1992 ELI LILLY & CO
R-H-53-77
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
INHALATION
EPA/OTS; Doc #88-920005854
NTIS/OTS0543317 INITIAL SUBMISSION: LETTER FROM ELI LILLY & CO TO USEPA SUBMITTING RESULTS ON AN ACUTE INHALATION STUDY WITH R-H-52-77 IN RATS WITH ATTACHMENTS - 1992 ELI LILLY & CO
R-H-52-77
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
INHALATION
EPA/OTS; Doc #88-920005855
NTIS/OTS0543358 INITIAL SUBMISSION: LETTER FROM ELI LILLY & CO TO USEPA SUBMITTING RESULTS ON AN ACUTE ORAL STUDY WITH D-3117 IN DOGS WITH ATTACHMENTS - 1992 ELI LILLY & CO
D-3117
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
DOGS
ORAL
GAVAGE
EPA/OTS; Doc #88-920005896
NTIS/OTS0543359 INITIAL SUBMISSION: LETTER FROM ELI LILLY & CO TO USEPA SUBMITTING RESULTS ON AN ACUTE INHALATION STUDY WITH R-H-59-77 IN RATS WITH ATTACHMENTS - 1992

ELI LILLY & CO
R-H-59-77
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
INHALATION

EPA/OTS; Doc #88-920005897

NTIS/OTS0543473 INITAL SUBMISSION: LETTER FROM ELI LILLY & COMPANY TO USEPA SUBMITTING RESULTS ON COMPOUND #126714 ACUTE RABBIT ORAL STUDY WITH ATTACHMENTS - 1992 ELI LILLY & CO
COMPOUND #126714
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RABBITS
ORAL

EPA/OTS; Doc #88-920006218

NTIS/OTS0543476 INITIAL SUBMISSION: LETTER FROM ELI LILLY & COMPANY TO USEPA SUBMITTING RESULTS ON COMPOUND #126714 ACUTE CAT NASOGASTRIC STUDY WITH ATTACHMENTS - 1992 ELI LILLY & CO
COMPOUND #126714
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
CATS
ORAL
GAVAGE
EPA/OTS; Doc #88-920006221
NTIS/OTS0543477 INITIAL SUBMISSION: LETTER FROM ELI LILLY & COMPANY TO USEPA SUBMITTING RESULTS ON COMPOUND #126714 ACUTE CAT NASOGASTRIC STUDY WITH ATTACHMENTS - 1992 ELI LILLY & CO
COMPOUND #126714
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
CATS
ORAL
GAVAGE
EPA/OTS; Doc #88-920006222
NTIS/OTS0543478 INITIAL SUBMISSION: LETTER FROM ELI LILLY & COMPANY TO USEPA SUBMITTING RESULTS ON COMPOUND #126714 ACUTE CAT NASOGASTRIC STUDY WITH ATTACHMENTS - 1992 ELI LILLY & CO
COMPOUND #126714
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
CATS
ORAL
GAVAGE
EPA/OTS; Doc #88-920006223
NTIS/OTS0543738 INITIAL SUBMISSION: N-METHYL-2,4-
DINITRO-N-(2,4,6-TRIBROMOPHENYL)-6
-(TRIFLUOROMETHYL)-BENZENAMINE: SUBCHRONIC RAT ORAL PILOT STUDY WITH COVER LETTER DATED 08-18-92

ELI LILLY & CO
N-METHYL-2,4-DINITRO-N-
(2,4,6-TRIBROMOPHENYL)-6-
(TRIFLUOROM*
HEALTH EFFECTS
SUBCHRONIC TOXICITY
MAMMALS
RATS
ORAL
DIET

EPA/OTS; Doc #88-920006666
NTIS/OTS0545087 INITIAL SUBMISSION: THE REVERSIBILITY OF CENTRAL NERVOUS SYSTEM LESIONS FROM CHRONIC BROMETHALIN ADMINISTRATION WITH COVER LETTER DATED 08-21-92 ELI LILLY & CO
BROMETHALIN
HEALTH EFFECTS
CHRONIC TOXICITY
COMBINED CHRONIC TOXICITY/CARCINOGENICITY
MAMMALS
RATS
ORAL
DIET
EPA/OTS; Doc #88-920006488
NTIS/OTS0545109 INITIAL SUBMISSION: ACUTE BOBWHITE ORAL PILOT STUDY WITH N-METHYL-2,4-DINITRO-N-(2,4,6-
TRIBROMOPHENYL)- 6-(TRIFLUOROMETHYL)BENZENAMINE WITH COVER LETTER DATED 08-18-92
ELI LILLY & CO
N-METHYL-2,4-DINITRO-N-
(2,4,6-TRIBROMOPHENYL)-6-
(TRIFLUOROM*
HEALTH EFFECTS
ACUTE TOXICITY
BIRDS
ORAL
GAVAGE
EPA/OTS; Doc #88-920006510
NTIS/OTS0545112 METHYL-2,4-DINITRO-N-(2,4,6-
TRIBROMOPHENYL)- 6-
(TRIFLUOROMETHYL)BENZENAMINE WITH COVER LETTER DATED 08-18-92
ELI LILLY & CO
N-METHYL-2,4-DINITRO-N-
(2,4,6-TRIBROMOPHENYL)-6-
(TRIFLUOROM*
HEALTH EFFECTS
SUBCHRONIC TOXICITY
BIRDS
ORAL
GAVAGE
EPA/OTS; Doc #88-920006513
NTIS/OTS0545113 INITIAL SUBMISSION: ACUTE BOBWHITE ORAL PILOT STUDY WITH N-METHYL-2,4-DINITRO-N-(2,4,6-
TRIBROMOPHENYL)- 6-
(TRIFLUOROMETHYL)BENZENAMINE WITH COVER LETTER DATED 08-18-92
ELI LILLY & CO
N-METHYL-2,4-DINITRO-N-
(2,4,6-TRIBROMOPHENYL)-6-
(TRIFLUOROM*
HEALTH EFFECTS
ACUTE TOXICITY
BIRDS
ORAL
GAVAGE
EPA/OTS; Doc #88-920006514
NTIS/OTS0545129
INITIAL SUBMISSION: ACUTE BOBWHITE ORAL TOXICITY STUDY WITH N-METHYL-2,4-DINITRO-N-(2,4,6-
TRIBROMOPHENYL)- 6-
(TRIFLUOROMETHYL)BENZENAMINE WITH COVER LETTER DATED 08-18-92
ELI LILLY & CO
N-METHYL-2,4-DINITRO-N-
(2,4,6-TRIBROMOPHENYL)-6-
(TRIFLUOROM*
HEALTH EFFECTS
ACUTE TOXICITY
BIRDS
ORAL
GAVAGE
EPA/OTS; Doc #88-920006530
NTIS/OTS0545133 INITIAL SUBMISSION: SUBCHRONIC MALLARD ORAL PILOT STUDY WITH N-
METHYL-2,4-DINITRO-N-(2,4,6-
TRIBROMOPHENYL)- 6-(TRIFLUOROMETHYL)BENZENAMINE WITH COVER LETTER DATED 08-18-92
ELI LILLY & CO
N-METHYL-2,4-DINITRO-N-
(2,4,6-TRIBROMOPHENYL)-6-
(TRIFLUOROM*
HEALTH EFFECTS
SUBCHRONIC TOXICITY
BIRDS
ORAL
DIET
EPA/OTS; Doc #88-920006534
NTIS/OTS0545164 INITIAL SUBMISSION: 14-DAY ACUTE ORAL TOXICITY STUDY WITH BROMETHALIN IN BOBWHITE WITH COVER LETTER DATED 08-21-92 ELI LILLY & CO
BROMETHALIN
HEALTH EFFECTS
ACUTE TOXICITY
BIRDS
ORAL
GAVAGE
EPA/OTS; Doc #88-920006565
NTIS/OTS0545167 INITIAL SUBMISSION: FIVE-DAY DIETARY TOXICITY STUDY WITH BROMETHALIN IN BOBWHITE WITH COVER LETTER DATED 08-21-92 ELI LILLY & CO
BROMETHALIN
HEALTH EFFECTS
SUBCHRONIC TOXICITY
BIRDS
ORAL
DIET

EPA/OTS; Doc #88-920006568

NTIS/OTS0545168 INITIAL SUBMISSION: 14-DAY ACUTE ORAL TOXICITY STUDY WITH BROMETHALIN IN BOBWHITE WITH COVER LETTER DATED 08-21-92 ELI LILLY & CO
BROMETHALIN
HEALTH EFFECTS
ACUTE TOXICITY
BIRDS
ORAL
GAVAGE
EPA/OTS; Doc #88-920006569
NTIS/OTS0545174 INITIAL SUBMISSION: FIVE-DAY DIETARY TOXICITY STUDY WITH BROMETHALIN IN BOBWHITE WITH COVER LETTER DATED 08-21-92 ELI LILLY & CO
BROMETHALIN
HEALTH EFFECTS
SUBCHRONIC TOXICITY
BIRDS
ORAL
DIET
EPA/OTS; Doc #88-920006575

 

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12580294&dopt=Abstract

J Vet Diagn Invest 2003 Jan;15(1):42-5

Thin layer chromatography convulsant screen extended by gas chromatography-mass spectrometry.

Braselton WE, Johnson M.

Animal Health Diagnostic Laboratory, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.

Acute onset convulsive disorders in the canine may result from exposure to a variety of toxicants including strychnine, insecticides, metaldehyde, zinc phosphide, methylxanthines, drugs of abuse, bromethalin, and the tremorgenic mycotoxins (roquefortine and penitrem A). Although several of the above can be identified in a single gas chromatography-mass spectrometry (GC-MS) screen most have to be determined by separate tests. This report describes a modification of the strychnine extraction procedure, which allows thin layer chromatographic (TLC) identification of strychnine, bromethalin, roquefortine, and penitrem A in suspect baits, stomach contents or vomitus, and extends the identification to a wide variety of drugs, pesticides, and environmental contaminants by GC-MS. Samples were mixed with base, extracted into CH2Cl2 and the organic fraction back-extracted with acid. The organic fraction (neutrals) was purified by gel permeation chromatography (GPC) and analyzed by TLC to determine penitrem A and bromethalin. The acidic aqueous fraction was adjusted to pH > 9 and extracted into CH2Cl2. The resulting CH2Cl2 layer (bases) was then analyzed by TLC to determine strychnine and roquefortine. The organic basic and neutral fractions were recombined with a late eluting GPC fraction and analyzed by GC-MS. Of 312 samples analyzed by TLC from 1995 to 2001, 35 were positive for strychnine alone, 58 were positive for both roquefortine and penitrem A, 4 were positive for roquefortine alone, and 1 was positive for bromethalin. None of the samples were positive for penitrem A alone. Samples negative by TLC were analyzed by the GC-MS extended procedure since mid-1999, and 14 have shown positive for a wide variety of compounds with convulsant activity.

PMID: 12580294 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12012748&dopt=Abstract

Vet Clin North Am Small Anim Pract 2002 Mar;32(2):469-84, viii

Rodenticides.

Murphy MJ.

School of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA. murph005@tc.umn.edu

Rodenticides are second only to insecticides in the prevalence of pesticide exposure. Hundreds of rodenticide products currently exist, yet only a handful of them are involved in most toxicoses of companion animals. The most commonly reported toxicoses in the United States are those caused by anticoagulant rodenticides, bromethalin, cholecalciferol, strychnine, and zinc phosphide. The pathophysiologic findings, diagnosis, and treatment of each of these five rodenticides are discussed.

Publication Types: Review Review, Tutorial

PMID: 12012748 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11245225&dopt=Abstract

J Chromatogr Sci 2001 Feb;39(2):49-53

Determination of bromethalin in commercial rodenticides found in consumer product samples by HPLC-UV-vis spectrophotometry and HPLC-negative-ion APCI-MS.

Mesmer MZ, Flurer RA.

United States Food and Drug Administration, Forensic Chemistry Center, Cincinnati, OH 45237-3097, USA.

A small amount of green particulate material is encountered in a consumer complaint sample. The green particulates in the sample are identified as a bromethalin-containing rodenticide using high-performance liquid chromatographic (HPLC)-UV-vis spectrophotometric and HPLC-negative-ion atmospheric pressure chemical ionization (APCI)-mass spectrometric (MS) approaches, which are commonly used for the detection and confirmation of bromethalin in grain-based rodenticides. The selective and sensitive nature of the MS detector makes it possible to determine bromethalin without extensive sample cleanup and preconcentration. The estimated detection limit with the UV-vis detector is 500 pg of bromethalin injected into the column. The extensive fragmentation of the bromethalin molecule under APCI conditions provides sufficient structural information for positive identification.

PMID: 11245225 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=9823589&form=6&db=m&Dopt=b

Vet Pathol 1998 Nov;35(6):479-87

Epizootic vacuolar myelinopathy of the central nervous system of bald eagles (Haliaeetus leucocephalus) and American coots (Fulica americana).

Thomas NJ, Meteyer CU, Sileo L

Biological Resources Division, National Wildlife Health Center, Madison, WI, USA.

Unprecedented mortality occurred in bald eagles (Haliaeetus leucocephalus) at DeGray Lake, Arkansas, during the winters of 1994-1995 and 1996-1997. The first eagles were found dead during November, soon after arrival from fall migration, and deaths continued into January during both episodes. In total, 29 eagles died at or near DeGray Lake in the winter of 1994-1995 and 26 died in the winter of 1996-1997; no eagle mortality was noted during the same months of the intervening winter or in the earlier history of the lake. During the mortality events, sick eagles were observed overflying perches or colliding with rock walls. Signs of incoordination and limb paresis were also observed in American coots (Fulica americana) during the episodes of eagle mortality, but mortality in coots was minimal. No consistent abnormalities were seen on gross necropsy of either species. No microscopic findings in organs other than the central nervous system (CNS) could explain the cause of death. By light microscopy, all 26 eagles examined and 62/77 (81%) coots had striking, diffuse, spongy degeneration of the white matter of the CNS. Vacuolation occurred in all myelinated CNS tissue, including the cerebellar folia and medulla oblongata, but was most prominent in the optic tectum. In the spinal cord, vacuoles were concentrated near the gray matter, and occasional swollen axons were seen. Vacuoles were uniformly present in optic nerves but were not evident in the retina or peripheral or autonomic nerves. Cellular inflammatory response to the lesion was distinctly lacking. Vacuoles were 8-50 microns in diameter and occurred individually, in clusters, or in rows. In sections stained by luxol fast blue/periodic acid-Schiff stain, the vacuoles were delimited and transected by myelin strands. Transmission electron microscopy revealed intramyelinic vacuoles formed in the myelin sheaths by splitting of one or more myelin lamellae at the intraperiodic line. This lesion is characteristic of toxicity from hexachlorophene, triethyltin, bromethalin, isonicotinic acid hydrazide, and certain exotic plant toxins; however, despite exhaustive testing, no etiology was determined for the DeGray Lake mortality events. This is the first report of vacuolar myelinopathy associated with spontaneous mortality in wild birds.

PMID: 9823589, UI: 99040923


Source: 1996 ANNUAL MEETING OF THE NORTH AMERICAN CONGRESS OF CLINICAL TOXICOLOGY, PORTLAND, OREGON, USA, OCTOBER 10-15, 1996. JOURNAL OF TOXICOLOGY CLINICAL TOXICOLOGY; 34 (5). 1996. 572-573.

POSSIBLE BROMETHALIN-INDUCED TOXICITY IN A HUMAN A CASE REPORT

BULLER G, HEARD J, GORMAN S

BIOSIS COPYRIGHT: BIOL ABS. RRM MEETING ABSTRACT MEETING POSTER HUMAN MALE ADULT PATIENT BROMETHALIN RODENTICIDES NEUROTOXINS VENGEANCE TOXICOLOGY RAT POISON NEUROLOGIC SYMPTOMS SEIZURE MUSCLE TREMORS NERVOUS SYSTEM DISEASE TOXICITY MUSCLE DISEASE


Prevention and Control of Wildlife Damage. 1994.

Hygnstrom, S.E., R.M. Timm, and G.E. Larson.

Univ. Nebraska Cooperative Extension, USDA Animal Damage Control, and Great Plains Agric. Council.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1632057&dopt=Abstract

Vet Pathol 1992 Mar;29(2):139-44

Neuropathologic findings of bromethalin toxicosis in the cat.

Dorman DC, Zachary JF, Buck WB.

Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana.

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]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1539906&dopt=Abstract

Am J Vet Res 1992 Jan;53(1):138-42

Effects of an extract of Gingko biloba on bromethalin-induced cerebral lipid peroxidation and edema in rats.

Dorman DC, Cote LM, Buck WB.

Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana 61801.

The effects of administration of a commercially available extract of Gingko biloba (EGB) on bromethalin-induced brain lipid peroxidation and cerebral edema in adult male Sprague-Dawley rats was determined. Gingko biloba extract was given (100 mg/kg) by gavage immediately after bromethalin (1.0 mg/kg) administration. Rats were euthanatized at 24 hours after dosing. Brain lipid peroxidation was determined by measurement of brain malonaldehyde-thiobarbituric acid chromophore (MDA-TBA) concentration, brain sodium concentration, and brain water content. Treatment of bromethalin-dosed rats (10/group) with EGB was associated with a statistically significant (P less than 0.05) decrease in clinical sign severity, compared with bromethalin-dosed saline solution-treated rats. All rats given bromethalin and saline solution 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. The brain MDA-TBA concentration (2.4 +/- 0.5 delta MDA-TBA concentration/mg of protein), percentage of water in brain tissue (80.3 +/- 0.30%), and brain sodium concentration (6.68 +/- 0.21 mg/g of dry weight) were significantly increased in rats given bromethalin and saline solution, compared with control rats given saline solution (1.0 +/- 0.1 delta MDA-TBA concentration/mg of protein; 78.1 +/- 0.33% water in brain tissue; 4.83 +/- 0.30 mg of brain Na+/g of dry weight) and rats given bromethalin and EGB (1.6 +/- 0.2 delta MDA-TBA concentration/mg of protein; 79.3 +/- 0.31% water in brain tissue; 5.37 +/- 0.34 mg of brain Na+/g of dry weight). (ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 1539906 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2017873&dopt=Abstract

Vet Hum Toxicol 1991 Feb;33(1):9-11

Electroencephalographic changes associated with bromethalin toxicosis in the dog.

Dorman DC, Parker AJ, Buck WB.

Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana 61801.

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 to 58 h 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 less than 10 microV) in all leads (33%).

PMID: 2017873 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2094433&dopt=Abstract

J Vet Diagn Invest 1990 Apr;2(2):123-8

Diagnosis of bromethalin toxicosis in the dog.

Dorman DC, Simon J, Harlin KA, Buck WB.

Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana 61801.

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.

PMID: 2094433 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bromethalin%5bAll%20Fields%5d

Vet Clin North Am Small Anim Pract 1990 Mar;20(2):339-52

Toxicology of selected pesticides, drugs, and chemicals. Anticoagulant, cholecalciferol, and bromethalin-based rodenticides.

Dorman DC.

Department of Veterinary Biosciences, University of Illinois, Urbana-Champaign College of Veterinary Medicine.

The control of rodent pests is a continuing goal of mankind. To this end, a multitude of rodenticides have been produced, each designed to kill rodents by exerting their toxic effects on various body systems. As examples, veterinarians have had to manage companion animal poisonings due to anticoagulant, sodium fluoroacetate (compound 1080), thallium, barium carbonate, and zinc phosphide-based rodenticides. Many of these rodenticides were introduced because of their anticipated safety in relation to nontarget species; unfortunately, this has not been the case. Veterinarians must attempt to identify the specific rodenticide involved in poisoning cases. Therapeutic success in these poisonings is often more dependent upon symptomatic and supportive care rather than the use of antidotal therapy.

Publication Types: Review Review, Tutorial

PMID: 2156370 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2741313&dopt=Abstract

Vet Hum Toxicol 1989 Jun;31(3):239-40

No Abstract available

A suspected case of bromethalin toxicity in a domestic cat.

Martin T, Johnson B.

California Veterinary Diagnostic Laboratory System, University of California, Davis 95616.

PMID: 2741313 [PubMed - indexed for MEDLINE]


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.

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. Phenobarbital and SKF-525A were protective when bromethalin was given, but SKF-525A increased lethality when the desmethyl analog was administered. Aroclor and 3MC both promoted lethality. It was concluded that SKF-525A could block the conversion of bromethalin to the desmethyl analog and beyond but each of the inducers promoted conversion of bromethalin to the desmethyl analog. Induction of subsequent pathways also must have occurred so that the net level of the desmethyl metabolite was higher than control when Aroclor and 3MC were given but lower than control when phenobarbital was given. Mechanistic studies showed that bromethalin is rapidly converted to the desmethyl analog which is an extremely potent uncoupler of oxidative phosphorylation. It was theorized that if this occurs in the central nervous system, a fluid imbalance may ensue due to insufficient ATP. Fluid buildup in the cranium was determined by measuring cerebrospinal fluid pressure (CSFP), brain and spinal cord moisture, and cation concentrations. These studies demonstrated that rats had mean CSFP of 251 ± 23 mm water 24 hr after being treated with 1 mg/kg bromethalin compared to a control value of 68 ± 5 mm water. Pressures could be reduced within 1 to 2 hr by infusion of an osmotic diuretic such as mannitol or urea; however, CSFP would rise again when the infusion was stopped. CSFP returned to normal values within 7 days after a single dose of 1 mg/kg bromethalin. Subcutaneous injections of dexamethasone hastened reduction of CSF pressure.

PMID: 3229590 [PubMed - indexed for MEDLINE]


FULL REPORT AVAILABLE AT http://www.fluorideaction.org/pesticides/bromethalin.1988.full.pdf

Proceedings of the Thirteenth Vertebrate Pest Conference 1988;13:64-69.

Status of bromethalin outside the United States.

Spaulding, S.R. (a) and H. Spannring (b)

(a) Ciba-Geigy Animal Health/Hygiene, Basel, Switzerland
(b) Ciba-Geigy Agricultural Research Centre, St. Aubin, Switzerland

Bromethalin has been extensively researched over the past decade in the United States, Switzerland, England, Denmark, and France. United States EPA registrations were received in 1982 and commercial pelleted formulations containing 0.01% bromethalin were developed and introduced in the USA by Ralston Purina (ASSAULT) in 1985 and Velsicol (VENGEANCE) in 1986. Ciba-Geigy is currently developing new formulations under the tradename DORATID® for use outside the United States. Bromethalin acute toxicity and 14-day subchronic studies are reviewed and data from recently completed 90-day subchronic studies required for registration outside the US are presented. Pharmacodyamic studies have shown that bromethalin acts as an uncoupler of oxidative phosphorylation, thus interrupting the vital production of ATP necessary to maintain essential metabolic functions. Laboratory and field trial data are presented from Switzerland, France, England, and Denmark that indicate the effectiveness of new bromethalin formulations against anticoagulant resistant and susceptible rodents. A comparative rodenticide pen testing system is described from which test results confirm bromethalin's quick action and feed consumption efficiency when compared to second-generation anticoagulants.

Excerpt: The search for a novel rodenticide with a mode of action different from anticoagulants began in the mid-1970s when leads from a fungicide screening program at Lilly Research Laboratories indicated the rodenticidal potential of a group of compounds classified as dipheylamines. After several years of screening and structure-activity relation tests, bromethalin was identified as the compound with the greatest biological potential. At the 1979 British Crop Protection Conference, Dreikorn (1979) presented the first biological results from laboratory tests with white rats and mice...
Marketing rights were subsequently licensed by Eli Lilly to Ralston Purina and Velsicol in the United States and Ciba-Geigy for all countries outside the United States...


American Chemical Society. 1984, 45-63.

The Discovery and Development of Bromethalin, an Acute Rodenticide with a Unique Mode of Action.

Dreikom,B.,O'Dorherty, GO.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6666021&dopt=Abstract

Vet Med Nauki 1983;20(8):72-80

[Toxic action and deratization effect of acute rodenticide]

[Article in Bulgarian]

Kesiakova S, Nikiforov I.

Tested was the toxic action and the deratization effect of the new acutely acting rodenticide EL614 [bromethalin] recently introduced into deratization practice. The experiments were carried out with laboratory rats and pigs as well as with the rats found in a swine breeding complex. Studied were the morphologic and histopathologic changes in the internal organs of rats that had swallowed baits carrying the preparation in various concentration. It was found that LD50 for rats up to the 24th hour after swallowing the poison was 4.13 mg/kg, and it was 1.78 mg/kg at the 48t hour, and 1.32 mg/kg at the 72nd hour. Intoxication and death set in as the result of impaired function of almost all organs, which was explained by the lipidotropic action of the preparation. Particularly severe were the lesions (hemodynamic and degenerative) in the brain. In field trials the baits contained EL614 in concentration of 0.005 per cent, showed a low deratization effect the first day after setting them. In this case the effect could be explained by the stress developing among the rodent population. The same baits in amounts surpassing 300-400 g caused intoxication and death in pigs of 20 kg live weight.

PMID: 6666021 [PubMed - indexed for MEDLINE]


Proc. Vertebr. Pest Conf. 1982;10:10-16.

Bromethalin - a promising new rodenticide.

Jackson, W.B., S.R. Spaulding, R.B.L. van Lier, and B.A. Dreikorn.


Unpubl. report submitted to EPA by Eli Lilly Co. 1981.

A secondary toxicity study in beagle dogs maintained for two weeks on diets derived from bromethalin (EL-614, Compound 126814) treated rodents.

van Lier, R.B.L.

Bromethalin Bibiography Citation [p 163-164] in US EPA Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998.
MRID * Study Citation to study in RED
  (Unpublished study received Oct 29, 1981 under 1471-121; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL: 246173-M) -
42733503 Holmes, C.; Swigert, J. (1993) Bromethalin: A 48-Hour Flow-Through Acute Toxicity Test with the Cladoceran (Daphnia magna): Final Report: Lab Project Number: 199A-101. Unpublished study prepared by Wildlife International Ltd. 46 p. Acute Toxicity to Freshwater Invertebrates p 66

Ecological Effects, Invertebrate Toxicity, p 147
00026524 Van Lier, R.B.L.; Arthur, B.H.; Ansley, A.D.; et al. (1979) Acute Hazard Evaluation of Compound 126714 Including Dermal, Ocular, and Inhalation Testing: Study Nos. B-D-59-77, B-D-74-77, B-E-75-77, R-H-50-77, R-H-52-77, R-H-53-77, R-H-58-77, R-H-59-77, R-H-64-77. (Unpublished study received Dec 13, 1979 under 1471-EX-72; submitted by Elanco Products Co., Div. of Eli Lily and Co., Indianapolis, Ind.; CDL:241521-G) Toxicology: p 148

Acute Oral Toxicity - Rat;
Acute Dermal Toxicity - Rabbit/Ratp;
Acute Inhalation Toxicity - Rat;
Primary Eye Irritation - Rabbit;
Primary Dermal Irritation - Rabbit;
41653001 Rock, G.; Sites, D.; Van Lier, R. (1990) A Guinea Pig Sensitization Study with Bromethalin (Compound 12671): Lab Project Number: GOO390. Unpublished study prepared by Lilly Research Labs. 39 p.

Acute Toxicity Values of Technical Bromethalin - Dermal Sensitization; p 14

Toxicology
Dermal Sensitization - Guinea Pig, p 148.

00101543 Cochrane, R.; Kehr, C.; Van Lier, R.; et al. (1982) The Toxicity of Bromethalin (EL-614, Compound 126714) to Hen Chickens in a 24-day Acute Oral Delayed Neurotoxicity Study: Study A00981. (Unpublished study received Apr 29, 1982 under 1471-121; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, IN; CDL:247447-B)

An acute delayed neurotoxicity study was conducted in the hen. White rock strain hen (30 animals) were initially dosed with bromethalin in PEG-400 at 9 mg/kg and redosed on day 3 with 15 mg/kg. Observation was for 24 days. Bromethalin did not produce acute delayed neurotoxicity in the hen. p 14

Toxicology
Acute Delayed Neurotoxicity - Hen, p 148

 

43582102 Monnot, G. (1987) 13-Week Oral Toxicity Study in the Rat: Bromethalin (CGA 175156): Lab Project Number: 610209: 601326-D. Unpublished study prepared by Hazleton-Institut Francais de Toxicologie. 277 p.

Bromethalin Subchronic Toxicity, p 22
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.

Toxicology - 90-Day Feeding - Rodent, p 148

43582101 Monnot, G. (1987) 13-Week Oral Toxicity Study in the Beagle Dog: Bromethalin (CGA 175156): Lab Project Number: 610203: 601325-D. Unpublished study prepared by Hazleton-Institut Francais de Toxicologie. 273 p.

Bromethalin Subchronic Toxicity
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. Other measured parameters were considered comparable between control and treated dogs of both sexes. The above two subchronic toxicity studies in rats and beagle dogs are not guideline-type subchronic neurotoxicity studies. However, these studies will satisfy the data requirements for a 90-day neurotoxicity screening battery because a NOEL and a LOEL was established in both studies. p 22-23

Toxicology, p 148
90-Day Feeding - Non-rodent;
90-Day Neurotoxicity - Mammal

42793101 Ponnock, K. (1993) An Acute Neurotoxicity Study of Bromethalin in the Rat Via Oral Gavage Administration: Lab Project Number: 92-3807. Unpublished study prepared by Bio/dynamics, Inc. 334 p.

Acute Toxicity, p 15
An acute neurotoxicity study was conducted in rats. Male and female Sprague-Dawley CD rats were orally gavaged with bromethalin in mineral oil at doses of 0, 0.8, 1.5 or 3 mg/kg. The NOEL was greater than 3 mg/kg (HDT) and the LOEL was not determined in this study. Although this study was classified as unacceptable, the study can be upgraded if the registrant can provide the following data: the rationale of vehicle choice and volume used, the stability of test material in mineral oil, the rationale for choice of testing time on dosing day, and body temperature measurements. Body temperature is a measurement that should have been taken, given the mechanism of action of bromethalin (uncoupler of oxidative phosphorylation) (MRID 42793101). However, a new study will not be required since adequate information is available to determine an acute NOEL for bromethalin neurotoxicity. p 15

Toxicology, p 148 - 90-Day Neurotoxicity - Mammal

00086731 Miller, B.J.; Van Lier, R.B.L.; Owen, N.V.; et al. (1981) A Teratology Study with Bromethalin (EL-614, 126714) in the Wistar Rat: Study R02181. (Unpublished study received Oct 29, 1981 under 1471-121; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL:246172-I)

Developmental Toxicity, p 30-31

A developmental toxicity study was conducted with Harlan Wistar rats (25 rats/group). Rats were orally gavaged on gestation days 6 through 15 at a dosing volume of 5 ml/kg with 0 (vehicle, PEG-200), 0.1, 0.3, or 0.5 mg/kg/day bromethalin technical. Surviving dams were sacrificed on gestation day 20, necropsied and reproductive findings were recorded. The NOEL for developmental toxicity is 0.5 mg/kg/day (HDT). 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.

The NOEL for maternal toxicity is 0.3 mg/kg/day and the LOEL is 0.5 mg/kg/day. Several effects occurred at the 0.5 mg/kg/day including four deaths during gestation (gestation days 12, 16, 17, and 17). Three high-dose females revealed upper respiratory tract infections which was regarded as secondary due to physiological stress from treatment. Additionally, in 10 of the 25 high-dose females, including the four which died, clinical signs consisting of hind leg weakness and decreased muscle tone were seen. Other observations included poor grooming, weakness, ventral soiling, chromodacryorrhea, decreased respiration, labored respiration, hypothermia, hind leg paralysis, prostration and dehydration.

During the dosing period, high-dose dams had a 30.2% decrease in weight gain in comparison to controls. During the post dosing period, weight gain in the high-dose females was decreased by only 11.7% in comparison to controls. Due to the substantial decreased weight gain during the dosing period, the high-dose females experienced a 13.9% decrease in weight gain for the entire gestation period in comparison to controls. These decreased weight gains are considered to be treatment-related. Food consumption was decreased by 8.7% in high-dose animals in the post dosing period in comparison to controls. The observed decrease in weight gain during the post dosing period may be because of decreased food consumption. The food consumption was comparable between controls and treated groups, including the high-dose group at other times.

Toxicology, p 148 - Developmental Toxicity - Rabbit

* MRID = Master Record Identification (number).
US EPA's system of recording and tracking studies submitted.

Bromethalin Bibliography (p 162) for
US EPA. Reregistration Eligibility Decision (RED) Rodenticide Cluster. EPA738-R-98-007. July 1998.
MRID * -
42333401 Rose, J. (1992) Product Identity and Disclosure of Ingredients; Description of Beginning Materials and Manufacturing Process: Bromethalin. Unpublished study prepared by Purina Mills, Inc. 55 p.
42403001 Rose, J. (1992) Product Identity and Disclosure of Ingredients and Discussion of the Formation of Impurities: Bromethalin. Unpublished study prepared by Purina Mills, Inc. 15 p.
42333401 Rose, J. (1992) Product Identity and Disclosure of Ingredients; Description of Beginning Materials and Manufacturing Process: Bromethalin. Unpublished study prepared by Purina Mills, Inc. 55 p.
42403001 Rose, J. (1992) Product Identity and Disclosure of Ingredients and Discussion of the Formation of Impurities: Bromethalin. Unpublished study prepared by Purina Mills, Inc. 15 p.
00086718 Koenig, D.K.; Loh, A.; Wilson, J.T.; et al. (1981) Test Article Characterization of Bromethalin: Technical Lot B31-72C-18R. (Unpublished study received Oct 29, 1981 under 1471-121; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL:246169-F)
41599601 Davis, M. (1990) Physical Characterization of Bromethalin: Final Report: Lab Project Number: SC900029. Unpublished study prepared by Battelle. 13 p.
41599603 Davis, M. (1990) Determination of the n-Octanol/Water Partition Coefficient of Bromethalin: Lab Project Number: SC900030. Unpublished study prepared by Battelle. 35 p.
00086741 Cochrane, R.L.; Kehr, C.C.; Van Lier, R.B.L.; et al. (1981) The Toxicity of Bromethalin (EL-614, Compound 126714) to Bobwhite in a 14-day Acute Oral Study: Study A008-80. (Unpublished study received Oct 29, 1981 under 1471-121; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL: 246173-C)
00086745 Kehr, C.C.; Van Lier, R.B.L.; Jordan, W.H.; et al. (1981) The Toxicity of Bromethalin (EL-614, Compound 126714) to Bobwhite in a Five-day Dietary Study: Study A007-80. (Unpublished study received Oct 29, 1981 under 1471-121; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL: 246173-G)
42733501 Conner, B.; Holmes, C.; Swigert, J. (1993) Bromethalin: A 96-Hour Flow-Through Acute Toxicity Test with the Bluegill (Lepomis macrochirus): Final Report: Lab Project Number: 199A-102. Unpublished study prepared by Wildlife International Ltd. 43 p.
42733502 Conner, B.; Holmes, C.; Swigert, J. (1993) Bromethalin: A 96-Hour Flow-Through Acute Toxicity Test with the Rainbow Trout (Oncorhynchus mykiss): Final Report: Lab Project Number: 199A-103. Unpublished study prepared by Wildlife International Ltd. 45 p.
00086751 Kehr, C.C.; Van Lier, R.B.L.; Brannon, D.R.; et al. (1981) The Toxicity of Bromethalin (EL-614, Compound 126714) to Bluegills in a 96-hour Static Test: Study F151-80. (Unpublished study received Oct 29, 1981 under 1471-121; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL: 246173-M)
* MRID = Master Record Identification (number).
US EPA's system of recording and tracking studies submitted.

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