|
Sodium fluoroacetate
CASRN 62-74-8
Contents
0469
Sodium fluoroacetate; CASRN 62-74-8
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Sodium fluoroacetate
File On-Line 05/01/1991
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 07/01/1993
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Sodium fluoroacetate
CASRN -- 62-74-8
Last Revised -- 07/01/1993
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ----------
Increased heart weight NOAEL: 0.05 mg/kg/day 3000 1 2E-5
in females and males; mg/kg/day
decreased testis LOAEL: 0.20 mg/kg/day
weight and altered
spermatogenesis in males
13-Week Rat Oral Study
(gavage)
U.S. EPA, 1988
*Conversion Factors: None
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
U.S. EPA. 1988. Subchronic Toxicity Study in Rats with Sodium Fluoroacetate.
HLA study No. 2399-118. Office of Solid Waste and Emergency Response,
Washington, DC.
Sodium fluoroacetate was administered by gavage to male and female Sprague-
Dawley rats (20/sex/group) at doses of 0, 0.05, 0.20 or 0.50 mg/kg/day for 13
weeks. Individual body weight measurements, food consumption and
opthalmoscopic examination indicated no signs of toxicity. During weeks 4 and
13, blood samples were collected and examined for hematology (hemoglobin;
hematocrit; leukocyte, erythrocyte, platelet, reticulocyte and differential
leukocyte count; and cell morphology) and complete serum chemistry analysis
including fluorocitrate measurement. Following sacrifice at week 13, all
animals were necropsied, after which organ weights were recorded, tissue
samples taken, and complete histopathological examinations performed.
Observed dose-related effects in organ weights were: increased absolute and
relative heart weight in mid- and high-dose females and high-dose males;
significantly decreased absolute and relative testis weights in mid- and high-
dose males; and significantly decreased absolute spleen weights in high-dose
males. In mid- and high-dose males, changes in the testes included bilateral
hypospermatogenesis with fusion bodies in the seminiferous tubules, and in the
epididymides, immature and/or abnormal sperm and reduced sperm count were
noted. Histopathological changes in heart tissue, if any, consisted of
subacute, minimal inflammation, but were not dose related. One female rat (in
the high-dose group) that died before week 13 could not be classified as an
accidental death. Four high-dose female rats exhibited convulsions on study
day 79 (week 12), with no recurrences for the remainder of the study.
Fluorocitrate levels were significantly increased after 4 weeks in the high-
dose males and after 13 weeks in both the mid- and high-dose groups of both
sexes. No significant hematological changes were recorded in female groups.
Blood urea nitrogen was significantly decreased in low-dose males at week 4,
but increased in high-dose males at week 13. High-dose females exhibited
decreased total serum protein, and mid- and high-dose females had decreased
globulin. The treatment-related findings of increased sodium fluorocitrate,
increased heart weight, decreased testes weight with accompanying microscopic
lesions of the testes, and central nervous system effects such as convulsions
are consistent with those reported in the literature (discussed below). Based
on increased heart weight in mid-dose females and testicular changes in mid-
dose males, the LOAEL is considered to be 0.2 mg/kg/day and the NOAEL to be
0.05 mg/kg/day.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- An uncertainty factor of 3000 was used: 10 to account for interspecies
extrapolation, 10 for differences in human sensitivity, 10 for use of a
subchronic study for a chronic RfD derivation, and 3 for the lack of
reproductive/developmental studies and toxicity studies in a second species.
MF -- None
___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD)
Sodium fluoroacetate (compound 1080) had been previously used as a potent
rodenticide which has a well-characterized mechanism of action. Fluoroacetate
is converted to fluorocitrate in vivo which in turn inhibits the enzyme
aconitase of the tricarboxylic acid (TcA or Krebs) cycle. This enzyme
converts citric acid to cis-aconitic acid/isocitric acid. The inhibition of
aconitase by fluorocitrate results in a lethal accumulation of citric acid
which in turn causes violent convulsions and death from cardiac failure or
respiratory arrest (Gribble, 1973). Administration of an intraperitoneal dose
of 5 mg sodium fluoroacetate/kg in rats 3 hours prior to liver perfusion
resulted in a dramatic inhibition of TCA cycle activity. Citric acid
accumulated 5-fold, glycolysis and gluconeogenesis activity decreased by 50-
90% and mixed function oxidation was decreased by 50% (Zhou et al., 1984).
Although administration of fluoroacetate following a single intravenous
injection results in SUBSTantial bone accumulation indicative of
defluorination of the molecule (Sykes et al., 1986), the acute and subchronic
toxicological effects of fluoroacetate are clearly due to aconitase
inhibition.
Fluoroactate exhibits a varied pharmacological activity in different species.
The LD50 ranges from 0.06 mg/kg in dogs to >500 mg/kg in the South African
clawed toad. Typical LD50s of other species of common interest are: 2-5
mg/kg for humans (extrapolated value), 5.0 mg/kg for albino rats, 5-20 mg/kg
for albino mice, 0.25-1.0 mg/kg for rabbits and 0.06 mg/kg for dogs. The
major site of pharmacodynamic action is typically the central nervous system
or the heart. Death usually results from either respiratory arrest following
severe convulsions, gradual cardiac failure or ventricular fibrillation, or
progressive depression of the CNS with either respiratory or cardiac failure
as the terminal event. There is a general tendency for herbivores to exhibit
cardiac effects, carnivores to develop CNS convulsions or depression, and
omnivores to exhibit effects upon both organ systems. Tolerance to increasing
doses of fluoroacetate has been demonstrated in mice, rats and the rhesus
monkey, although this phenomena has not been shown in the dog or rabbit
(Chenoweth, 1949). The wide range of LD50 values among the various species
listed above may be due to the ability of a particular species to metabolize
monofluoroacetate compounds to nontoxic metabolites. Rodents and nonhuman
primates have increased tolerance to challenging doses following repeated
sublethal doses of monofluoroacetate. Dogs have not shown this response.
Furthermore, dogs and rabbits have been shown to accumulate monofluoroacetate
following repeated sublethal doses until lethal levels are attained. Mice and
rats, on the other hand, have demonstrated the ability to tolerate such a
regimen possibly through a more efficient detoxification mechanism (U.S. Dept.
of the Interior, 1971).
Trabes et al. (1983) has presented a case report in which a previously healthy
15-year-old female attempted suicide by ingesting sodium fluoroacetate.
Nausea, vomiting and abdominal pain occurred 30 minutes after ingestion with a
subsequent gran mal seizure occurring 60 minutes after the initial onset of
symptoms. Over the next 4 hours, three additional gran mal seizures occurred
before the patient became comatose. The patient regained consiousness after 3
days and grew progressively alert after 2 weeks. Upon neurological
examination after the 2-week recovery period, severe cerebellar dysfunction
with moderate diffuse brain atrophy with widening of the basal cysterns,
quadrigeminal cystern, interhemispheric fissure, lateral ventricles and the
third ventricle was established. By 18 months, memory disturbances and
depressive behavior persisted as did a moderate cerebellar ataxia. The
symptoms exhibited in human poisoning by fluoroacetate are consistent with the
effects of fluorocitrate inhibition of aconitase in the cat, pig and rhesus
monkey. The prolonged anoxic state of the brain in the acute phase of
poisoning induced the severe CNS disabilities observed in this patient.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Low
RfD -- Low
The principal study identified both a NOAEL and a LOAEL for relevant
toxicological endpoints in both genders, and is considered to be of medium
confidence. The data base for this compound is limited, lacking chronic and
reproductive/developmental studies; low confidence in both the data base and
RfD follow.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA documentation -- U.S. EPA, 1988
Agency Work Group Review -- 02/21/1990, 03/21/1990, 02/20/1991
Verification Date -- 02/20/1991
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Sodium fluoroacetate
CASRN -- 62-74-8
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Sodium fluoroacetate
CASRN -- 62-74-8
This substance/agent has not undergone a complete evaluation and determination
under US EPA's IRIS program for evidence of human carcinogenic potential.
_VI. BIBLIOGRAPHY
Substance Name -- Sodium fluoroacetate
CASRN -- 62-74-8
Last Revised -- 05/01/1991
__VI.A. ORAL RfD REFERENCES
Chenoweth, M.B. 1949. Monofluoroacetic acid and related compounds.
Pharmacol. Rev. 1: 383-427.
Gribble, G.W. 1973. Fluoroacetate toxicity. J. Chem. Educ. 50(7): 460-462.
Sullivan, J.L., F.A. Smith, R.M. Wilkenfeld, R.H. Garman and P.J. Kostyniak.
1978. Monofluoroacetate and trifluoroethanol as testicular poisoning in rats.
Toxicol. Appl. Pharmacol. 45: 291-292.
Sykes, T.R., T.J. Ruth and M.J. Adam. 1986. Synthesis and murine tissue
uptake of sodium[18F]fluoroacetate. Nucl. Med. Biol. 13(5): 497-500.
Trabes, J., N. Rason and E. Avrahami. 1983. Computed tomography
demonstration of brain damage due to acute sodium monofluoroacetate
poisoning. Clin. Toxicol. 20(1): 85-92.
U.S. Department of the Interior. 1971. A review of sodium monofluoroacetate
(compound 1080): Its properties, toxicology and use in predator and rodent
control. Special Scientific Report -- Wildlife No. 146. Washington, DC.
U.S. EPA. 1988. Subchronic Toxicity Study in Rats with Sodium Fluoroacetate.
HLA study No. 2399-118. Office of Solid Waste and Emergency Response,
Washington, DC.
Zhou, J., F.C. Kauffman, C.H. Ballows and R.G. Thurman. 1984. Inhibition of
mixed-function oxidation in perfused rat liver by fluoroacetate treatment.
Biochem. Pharmacol. 33(2): 319-323.
__VI.B. INHALATION RfC REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
None
_VII. REVISION HISTORY
Substance Name -- Sodium fluoroacetate
CASRN -- 62-74-8
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
05/01/1991 I.A. Oral RfD summary on-line
05/01/1991 VI. Bibliography on-line
01/01/1992 IV. Regulatory Action section on-line
07/01/1993 I.A.6. Other EPA Documentation added
VIII. SYNONYMS
Substance Name -- Sodium fluoroacetate
CASRN -- 62-74-8
Last Revised -- 05/01/1991
62-74-8
Acetic acid, fluoro-, sodium salt
Caswell No. 770
Compound 1080
EPA Pesticide Chemical Code 075003
Fluoacetato de sodio [Spanish]
Fluoracetate de sodium [French]
Fluoressigaeure [German]
Fluoroacetate de sodium [ISO-French]
Fluoroacetic acid
FLUOROACETIC ACID, SODIUM SALT
FLUOROCTAN SODNY [Czech]
Fratol
Furatol
HSDB 743
LATKA 1080 [Czech]
MONOFLUORESSIGSAURES NATRIUM [German]
Natriumfluoracetaat [Dutch]
Natriumfluoracetat [German]
NSC 77690
Ratbane 1080
RCRA WASTE NUMBER P058
SMFA
SODIO, FLUORACETATO DI [Italian]
Sodium fluoacetate
SODIUM FLUOACETIC ACID
Sodium fluoracetate
Sodium fluoroacetate
SODIUM FLUOROACETATE DE [French]
Sodium monofluoroacetate
UN 2629
Yasoknock
1080
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0469.HTM
|
