Brain - Adverse Effects
Fluorinated and Fluoride Pesticides

beginning with A-E F-G H-P • Q-Z
 
 
Brain Structures Function From the excellent website: Neuroscience for Kids
Cerebral
Cortex
* Thought
* Voluntary movement
* Language
* Reasoning
* Perception
The word "cortex" comes from the Latin word for "bark" (of a tree). This is because the cortex is a sheet of tissue that makes up the outer layer of the brain. The thickness of the cerebral cortex varies from 2 to 6 mm. The right and left sides of the cerebral cortex are connected by a thick band of nerve fibers called the "corpus callosum." In higher mammals such as humans, the cerebral cortex looks like it has many bumps and grooves. A bump or bulge on the cortex is called a gyrus (the plural of the word gyrus is "gyri") and a groove is called a sulcus (the plural of the word sulcus is "sulci"). Lower mammals, such as rats and mice, have very few gyri and sulci.
Cerebellum * Movement
* Balance
* Posture
The word "cerebellum" comes from the Latin word for "little brain." The cerebellum is located behind the brain stem. In some ways, the cerebellum is similar to the cerebral cortex: the cerebellum is divided into hemispheres and has a cortex that surrounds these hemispheres.
Brain stem * Breathing
* Heart Rate
* Blood Pressure
The brain stem is a general term for the area of the brain between the thalamus and spinal cord. Structures within the brain stem include the medulla, pons, tectum, reticular formation and tegmentum. Some of these areas are responsible for the most basic functions of life such as breathing, heart rate and blood pressure.
Hypothalamus * Body Temperature
* Emotions
* Hunger
* Thirst
* Circadian Rhythms
The hypothalamus is composed of several different areas and is located at the base of the brain. Although it is the size of only a pea (about 1/300 of the total brain weight), the hypothalamus is responsible for some very important functions. One important function of the hypothalamus is the control of body temperature. The hypothalamus acts as a "thermostat" by sensing changes in body temperature and then sending signals to adjust the temperature. For example, if you are too hot, the hypothalamus detects this and then sends a signal to expand the capillaries in your skin. This causes blood to be cooled faster. The hypothalamus also controls the pituitary.
Thalamus * Sensory processing
* Movement
The thalamus receives sensory information and relays this information to the cerebral cortex. The cerebral cortex also sends information to the thalamus which then transmits this information to other areas of the brain and spinal cord.
Limbic System * Emotions The limbic system (or the limbic areas) is a group of structures that includes the amygdala, the hippocampus, mammillary bodies and cingulate gyrus. These areas are important for controlling the emotional response to a given situation. The hippocampus is also important for memory.
Hippocampus * Learning
* Memory
The hippocampus is one part of the limbic system that is important for memory and learning.
Basal Ganglia * Movement The basal ganglia are a group of structures, including the globus pallidus, caudate nucleus, subthalamic nucleus, putamen and substantia nigra, that are important in coordinating movement.
Midbrain * Vision
* Audition
* Eye Movement
* Body Movement
The midbrain includes structures such as the superior and inferior colliculi and red nucleus. There are several other areas also in the midbrain.


The use of high doses increases the likelihood that potentially significant toxic effects will be identified. Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in humans. From a conservative risk assessment perspective however, adverse findings in animal species are assumed to represent potential effects in humans, unless convincing evidence of species specificity is available.

-- Food and Agricultural Organization of the United Nations

Note: This is not an exhaustive list.
When time allows more information will be added.

Quinoxyfen - Fungicide - CAS No. 124495-18-7

-- 040 - 181140 "XDE-795: Two-Year Dietary Chronic Toxicity/Oncogenicity Study in Fischer 344 Rats-Final Report," (Redmond, J.M., Quast, J.F., Bond, D.M., Ormand, J.R.; The Toxicology Research Laboratory, Health and Environmental Sciences – The Dow Chemical Company, Midland, MI; Laboratory ID#: DR-0325-7474-007; 6/29/95). XDE-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 97.4% pure) was fed in diet to Fischer 344 rats at 0, 5, 20 or 80 mg/kg/day for 1 – 2 years. XDE-795 was administered for 2 years to 50/sex/dose for chronic/oncogenicity assessment. A satellite group (15/sex/dose) was sacrificed at 12 months (10/sex/dose for interim assessment of chronic toxicity; 5/sex/dose to assess neurotoxicity). NOEL = 20 mg/kg (Females at 80 mg/kg had increased perineal soiling (satellite & main group). Both sexes had decreased bodyweights and bodyweight gains at 80 mg/kg throughout the study. Urea nitrogen was increased in males at 80 mg/kg at 18 and 24 months. Alanine amino transferase (80 mg/kg) was decreased in males at 24 months. Females had cholesterol levels that were statistically significantly increased at 80 mg/kg at 18 and 24 months. Liver and kidney weights (absolute & relative) were statistically significantly increased in both sexes at 80 mg/kg at 12 months. Relative brain weights in both sexes were increased at 80 mg/kg by 24 months. Males had increased absolute and relative testes weights at 80 mg/kg and females had decreased relative heart and increased relative kidney weights at 80 mg/kg at 24 months. There was an increased incidence in chronic progressive glomerulonephropathy in males at 80 mg/kg—37 versus 19 in control, p < 0.05.) No adverse effects. Acceptable. M. Silva, 8/21/01
-- ** 034 - 181176 "XDE-795: One Year Chronic Dietary Toxicity Study in Beagle Dogs," (Cosse, P.F., Stebbins, K.E., Redmond, J.M., Ormand, J.R.; The Toxicology Research Laboratory, Health and Environmental Sciences – The Dow Chemical Company, Midland, MI; Laboratory ID#: DR-0325-7474-011; 4/21/95). XDE-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 97.4% pure) was fed in diet to Beagle dogs (4/sex/dose) at 0, 5, 20 or 200 mg/kg/day for 1year. NOEL = 20 mg/kg (A male at 200 mg/kg was killed moribund, due to a severe weight decrease (2 kg), decreased hemoglobin and RBC counts. Both sexes had significantly decreased body weights and food consumption at 200 mg/kg. The report stated it was due to unpalatability of diet at the high dose, which persisted throughout the majority of the study. A treatment-related hematological effect was observed in 1/sex at 200 mg/kg. Alkaline phosphatase in both sexes at 200 mg/kg was statistically significantly increased. Liver weights (absolute & relative) were significantly increased in both sexes at 200 mg/kg. Statistically significantly increased relative organ weights were observed in both sexes at 200 mg/kg (brain, kidney, pituitary). Liver histopathology was observed in 3/sex at 200 mg/kg, primarily in the midzonal region (diffuse, increased size in hepatocytes, enlarged nuclei and prominent nucleoli). At 200 mg/kg, 1/sex had increased hepatocyte size, increased bile in centrilobular canaliculi. Possible adverse effect: At 200 mg/kg, 1/sex showed erythroid proliferation in spleen and liver, due to treatment-related anemia.) Acceptable. M. Silva, 8/15/01
Ref: October 4, 2001 - SUMMARY OF TOXICOLOGY DATA QUINOXYFEN (XDE-795 & XR-795). California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

Sodium bifluoride - Insecticide, Former US EPA List 3 Inert - CAS No. 1333-83-1

In addition to cardiovascular, neuromuscular and gastrointestinal derangements, acute fluoride poisoning causes major adverse effects on two other organ systems, the brain and the kidneys. The more critical dysfunctions are those of the brain. Toxic signs occasionally include headache, excessive salivation, nystagmus and dilated pupils. Transient convulions have been described, but lethargy, stupor and coma are far more common, and death is often ascribed to respiratory failure, presumably of central origin. Whatever the causes of these brain derangements, it is noteworthy that coma and respiratory arrest may develop in the presence of a normal blood pressure. Apparently the central neural effects of fluoride are not solely secondary to an inadequate cerebral circulation. /Fluoride/ [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-187]
Ref: Hazardous Substances Data Bank for SODIUM HYDROGEN DIFLUORIDE CASRN: 1333-83-1
http://www.fluorideaction.org/pesticides/sodium.bifluoride.toxnet.htm

Sodium fluoride - Wood preservative, EPA List 4B Inert - CAS No. 7681-49-4

Due to length, see special section on brain for Sodium fluoride


Sodium fluoroacetate (also known as Sodium monofluoroacetate, Compound 1080) - Insecticide, Rodenticide - CAS No. 62-74-8

PubMed abstract: The case reported developed an acute brain syndrome, including cerebellar signs, shortly after the ingestion of sodium monofluoroacetate. After insiduous improvement of the clinical symptoms, the patient remained with an "end-stage" cerebellar ataxia for 18 months following the acute intoxication. The development of brain atrophy, proven by computed tomography, is considered to represent a direct influence of sodium monofluoroacetate on the brain and to reflect the unique disturbances in cellular metabolism of glucose.
Ref: J Toxicol Clin Toxicol 1983 Mar;20(1):85-92; Computed tomography demonstration of brain damage due to acute sodium monofluoroacetate poisoning; Trabes J, Rason N, Avrahami E.

A case study reported a deliberate ingestion of an unspecified dose of sodium fluroacetate by a healthy female. The woman experienced nausea, vomiting, and abdominal pain 30 minutes after ingestion, with subsequent seizures occurring 60 minutes after the initial onset of symptoms. Neurological examination after 2 weeks revealed severe cerebellar dysfunction. By 18 months, memory disturbances and depressive behavior persisted... EPA believes that there is sufficient evidence for listing sodium fluoroacetate on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the neurologic, reproductive, and myocardial toxicity data for this chemical.
Ref: USEPA/OPPT. Support Document for the Health and Ecological Toxicity Review of TRI Expansion Chemicals. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

-- Sodium fluoroacetate and fluoroacetamide are readily absorbed by the gut, but only to a limited extent across skin. The toxic mechanism is distinct from that of fluoride salts. Three molecules of fluoroacetate or fluoroacetamide are combined in the liver to form a molecule of fluorocitrate, which poisons critical enzymes of the tricarboxylic acid (Krebs) cycle, blocking cellular respiration. The heart, brain, and kidneys are the organs most prominently affected... Crimidine and sodium fluoroacetate are no longer registered for use as pesticides.
Ref: US EPA. Rodenticides. Chapter 17.

http://www.epa.gov/oppfead1/safety/healthcare/handbook/Chap17.pdf

Abstract: To clarify the contribution of glial cells to octanoate uptake into the brain, we determined the effects of fluoroacetate, a selective inhibitor of glial metabolism, on in vitro brain uptake of [1-14C]octanoate, using rat brain slices. The [1-14C]octanoate uptake significantly decreased, depending on the concentration of fluoroacetate (p = 0.001). The [1-14C]octanoate uptakes at 5 mM (0.23 +/- 0.05% uptake/mg slice) and 25 mM fluoroacetate (0.12 +/- 0.01% uptake/mg slice) were significantly lower than that at control (0.29 +/- 0.02% uptake/mg slice, p < 0.05 and p < 0.001, respectively). The results demonstrate the contribution of glial cells to octanoate uptake into the brain. The potential of [1-11C]octanoate as a PET tracer for studying glial functions is suggested.
Ref: Kuge Y et al. (2002). In vitro uptake of [1-14C]Octanoate in brain slices of rats: basic studies for assessing [1-11C]Octanoate as a PET tracer of glial functions. Nucl Med Biol 2002 Apr;29(3):303-6.

Abstract: The effect of sodium-fluoroacetate (62-74-8) on electrical activity in the brain was investigated in rats. Electrical activity was recorded in the reticular nucleus of the thalamus and in the caudate nucleus of male albino-rats using bipolar electrodes. Twenty four hours after electrode implantation, animals were dosed intraperitoneally with sodium-fluoroacetate at 5 milligrams per kilogram. At various times thereafter, the complete electrical activity was recorded in selected brain structures using a loop oscillograph. The electrical activity was summed with an integrator enabling relative changes in complete electrical activity to be detected. Readings were taken for 5 minutes, every 15 minutes. Control animals showed characteristic slow waves, 4 to 6 per second, mainly in the reticular nucleus of the thalamus throughout the 6 hour experiment. Upon sodium-fluoroacetate treatment, slow waves were recorded and later faster waves, 12 to 15 per second, superceded the slow waves. At the end of the first hour and thereafter waves of slow frequency disappeared and those of faster frequency prevailed. Later, the frequency and amplitude of waves increased, particularly pronounced in the period of paroxysms in the reticular nucleus of the thalamus. After 3 hours, the fast waves were depressed and the complete electrical activity was not reversible. The authors conclude that the increase in complete electrical activity after the initial stage reflects participation of the central nervous system in compensatory processes evoked by deepening hypothermia and anoxia caused by sodium-fluoroacetate poisoning. (Russian)
Ref: Combined Electrical Activity Of Some Subcortical Structures In The Brain Of Albino Rats At Various Stages Of Sodium Fluoroacetate Poisoning; by Artyushkova VA, Kirzon MV, Timeiko VN. Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 67, No. 4, pages 69-73, 9 references, 1969. [From Toxline at Toxnet]

Sulfentrazone - Herbicide - CAS No. 122836-35-5

TERATOLOGY, RABBIT **52988-0038 217369, “F6285 Technical, Teratology Study in Rabbits (Oral)”, ©. Freeman, FMC Corporation, Toxicology Laboratory, Princeton, NJ., Study No. A92-3540, 22 June 1993). 20 mated female New Zealand White rabbits per group received F6285 Technical (94.2 ± 0.5% sulfentrazone) by oral gavage at 0 (corn oil), 100, 250, and 375 mg/kg/day on gestation days 7 through 19. There were no treatment-related deaths. Two dams per group at 100 and 250 mg/kg/day died due to misdosing. One 375 mg/kg/day dam was sacrificed due to misdosing. Five dams at 375 mg/kg/day aborted (two on day 21 and one each on days 22, 23, and 24). The mean number of implants and the mean number of early resorptions were significantly increased at 250 and 375 mg/kg/day. 13, 13, 16, and 18 dams at 0, 100, 250, and 375 mg/kg/day respectively exhibited decreased feces during the study and hematuria was recorded for 1 and 16 dams at 250 and 375 mg/kg/day respectively. Significantly reduced bodyweights were recorded for dams at 250 and 375 mg/kg/day on gestation days 19 and 29 compared to controls and bodyweight gains were significantly reduced during the dosing period and overall for days 0 through 29. Fetal weights were significantly reduced at 250 and 375 mg/kg/day. No treatment-related findings for fetal external and internal exams. Two treatment related skeletal malformations were noted at 375 mg/kg/day. One fetus had incompletely or not ossified frontals, parietals, interparietals, suppraoccipital bones, and execenphaly. Although not statistically significant, the findings were considered treatment-related since they occurred only at the high dose and because execenphaly is uncommon in the rabbit strain. Additionally, 3 fetuses from 3 different dams had fused caudal vertebrae. The incidence was statistically significant and was higher than the historical control values. Treatment-related skeletal variations included statistically significant litter and fetal incidences of partially fused nasal bones at 375 mg/kg/day. Also, 4 litter mates at 375 mg/kg/day had unossified pubes. Finally, the average number of ossified sternal centers, tarsal bones, forepaw and hindpaw phlanges and metacarpal bones was significantly reduced in fetuses at 375 mg/kg/day. Maternal NOEL = 100 mg/kg/day (reduced bodyweight). Developmental NOEL = 100 mg/kg/day (reduced fetal weight, increased early resorptions). No teratogenicity. Acceptable. (Green and Leung, 12/13/05)

Note from EC: Was execenphaly a spelling error? Should it read exencephaly? Definition exencephaly - A condition in which the skull is defective, causing exposure or extrusion of the brain.

Ref: January 13, 2006: Summary of toxicology data: Sulfentrazone (F2685). California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/sulfentrazone.ca.epa.2006.pdf

 

Sulfuryl fluoride - Fumigant insecticide - CAS No. 2699-79-8

Ref: January 23, 2004. Sulfuryl Fluoride; Pesticide Tolerance.
40 CFR Part 180 [OPP-2003-0373; FRL-7342-1]. Final Rule. Federal Register
Excerpts from: Table 1.--Subchronic, Chronic, and Other Toxicity
Study Guideline Type of Study NOAEL
mg/kg/day
LOAEL
mg/kg/day
Based on:
None cited
2-Week inhalation study--rabbit
30/30 (M/F) 90/90
(M/F)

malacia (necrosis) in cerebrum, vacuolation of cerebrum

None cited
2-Week inhalation study--rabbit
- 180/180
(M/F)

malacia (necrosis) in cerebrum, vacuolation of cerebrum

(870.3100) 90-Day inhalation toxicity--rat 24/25 (M/F) 90/90
(M/F)

malacia (necrosis) in cerebrum, vacuolation of cerebrum

(870.3100) 90-Day inhalation toxicity--rat - 180/180
(M/F)

malacia (necrosis) in cerebrum, vacuolation of cerebrum

(870.3100) 90-Day inhalation toxicity--rat - 240/250
(M/F)
vacuolation of caudate-putamen nucleus and white
fiber tracts of the internal capsule of the brain
(870.3100) 90-Day inhalation toxicity--mouse 38/36 (M/F) 125/121
(M/F)
miscroscopic lesions in caudate-putamen nucleus and external capsule of the brain
(870.3150)
90-Day inhalation toxicity--dog
25/26 (M/F) 50/51
(M/F)
slight histopathology of the caudate nucleus of the basal ganglia
(870.3150)
90-Day inhalation toxicity-- rabbit
8.6/8.5 (M/F) 29/28
(M/F)
vacuolation of white matter of the brain (F only)
(870.3150) 90-Day inhalation toxicity-- rabbit - 86/85
(M/F)
malacia (necrosis) and vacuolation of putamen, globus pallidus and internal and external capsules in the brain
(870.4100)
Chronic toxicity--rodents

3.5 for M

16 for F

14 for M

62 for F

histopathology in brain (vacuolation in cerebrum and
thalmus/hypothalmus
)
(870.4100)
1-Year chronic inhalation toxicity--dog
5.0/5.1 (M/F)

50/51
(M/F)

malacia (necrosis) in caudate nucleus of brain
(870.4200)
18-Month carcinogenicity inhalation study--mouse
25/25 (M/F) 101/101
(M/F)
cerebral vacuolation in brain
(870.4300)
2-Year combined chronic/
carcinogenicity--rat

3.5 for M

16 for F

14 for M

62 for F

histopathology in brain (vacuolation in cerebrum and
thalmus/hypothalmus
)

Ref: January 23, 2004. Sulfuryl Fluoride; Pesticide Tolerance.
40 CFR Part 180 [OPP-2003-0373; FRL-7342-1]. Final Rule. Federal Register
Excerpts: Table 2.--Summary of Toxicological Dose and Endpoints for sulfuryl fluoride for Use in Human Risk
Exposure Scenario Dose Used in Risk Assessment, Interspecies and Intraspecies and any Traditional UF Special FQPA SF and Level of Concern for Risk Assessment Study and Toxicological Effects

Chronic dietary (all populations)
NOAEL = 8.5 mg/kg/day
UF = 3,000...
Chronic RfD = 0.003 mg/kg/day.
Special FQPA SF = 1X
cPAD = chronic RfD/
Special FQPA SF = 0.003 mg/kg/day.

Rabbit - 90-Day inhalation
LOAEL = 28 mg/kg/day based on vacuolation of white matter in the brain of females.


Short-term inhalation (1 to 30 days)
Inhalation study
NOAEL = 30 mg/kg/day
(100 ppm; 0.42 mg/L).
Residential LOC for MOE = 1,000 Occupational
LOC = 100
Rabbit - 2-Week inhalation
LOAEL = 90 mg/kg/day (300 ppm; 1.25 mg/L) based on malacia (necrosis) and vacuolation in brain, inflammation of nasal tissue and trachea

Intermediate-term inhalation (1 to 6 months)
Inhalation study
NOAEL = 8.5 mg/kg/day (100 ppm; 0.42mg/L).
Residential LOC for MOE = 1,000
Occupational LOC for MOE = 100.

Rabbit - 90-Day inhalation
LOAEL = 28 mg/kg/day (100 ppm; 0.42 mg/L) based on vacuolation of white matter in the brain of females.


Long-term inhalation (>6 months)
Inhalation study
NOAEL = 8.5 mg/kg/day
(30 ppm; 0.13 mg/L).
Residential LOC for MOE = 3,000
Occupational LOC for MOE = 300.
Rabbit - 90-Day inhalation
LOAEL = 28 mg/kg/day based on vacuolation of white matter in the brain of females

Federal Register: September 5, 2001. Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances. Volume 66, Number 172. Proposed Rules. Page 46415-46425.

Excerpt from Table 1.
Summary of Toxicological Doses and Endpoints for sulfuryl fluoride for Use in Human Risk Assessment

Exposure Scenario \1\ Dose (mg/kg/day) Endpoint Study
Chronic Dietary (General Population including Infants and Children) NOAEL = 8.5;
UF = 300;
FQPA Factor = 3
Vacuolation of white matter in the brain of females.
Chronic RfD = 0.028 mg/ kg/day
Chronic Population- Adjusted Dose (cPAD) = 0.0093 mg/kg/day
90-Day inhalation- rabbits
Inhalation Short-Term (Occupational) NOAEL = 30;
MOE = 100;
FQPA Factor = N/A
Malacia (necrosis) and vacuolation in the cerebrum, inflammation of nasal tissues and trachea. 2-Week inhalation- rabbits
Inhalation Short-Term (Residential) NOAEL = 30;
MOE = 300;
FQPA Factor = 3
Malacia (necrosis) and vacuolation in the cerebrum, inflammation of nasal tissues and trachea. 2-Week inhalation- rabbits
Inhalation Intermediate-Term (Occupational) NOAEL = 8.5;
MOE = 100;
FQPA Factor = N/A
Vacuolation of white matter in the brain of females. 90-Day inhalation- rabbits
Inhalation Intermediate-Term (Residential) NOAEL = 8.5;
MOE = 300;
FQPA Factor = 3
Vacuolation of white matter in the brain of females. 90-Day inhalation- rabbits
\*\ The reference to the FQPA Safety Factor refers to any additional safety factor retained due to concerns unique to the FQPA.
\1\ The only significant route of exposure for inorganic fluoride is dietary exposure, which includes residues in drinking water. This risk assessment uses the maximum concentration limit goal (MCLG) of 4.0 ppm for fluoride as the basis for a maximum allowable exposure to inorganic fluoride (see the Cryolite Reregistration Eligibility Decision, 8/96, EPA- 738-R-96-016). Using the Agency default values of body weight (70 kg) and water consumption (2 liters/day), the MCLG converts to an exposure limit of 0.114 mg/kg/day. This exposure is used as the cPAD for inorganic fluoride in this risk assessment.  

-- In 2-week inhalation studies in rats, dogs and rabbits, different target organs were affected... In rabbits, the primary target organ was the brain, in which malacia (necrosis) and vacuolation were observed in the cerebrum...
-- In subchronic (90-day) inhalation studies in rats, dogs, rabbits and mice, the brain was the major target organ. Malacia and/or vacuolation were observed in the white matter of the brain in all four species. The portions of the brain most often affected were the caudate-putamen nucleus in the basal ganglia, the white fiber tracts in the internal and external capsules, and the globus pallidus of the cerebrum. In dogs and rabbits, clinical signs of neurotoxicity (including tremors, tetany, incoordination, convulsions and/or hind limb paralysis) were also observed...
-- In chronic (1-2 year) inhalation studies in rats, dogs and mice, target organs were the same as in the 90-day studies. In rats, severe kidney damage caused renal failure and mortalities in many animals. Additional gross and histopathological lesions in numerous organs and tissues were considered to be secondary to the primary effect on the kidneys. Other treatment-related effects in rats included effects in the brain (vacuolation of the cerebrum and thalamus/hypothalamus) and respiratory tract (reactive hyperplasia and inflammation of the respiratory epithelium of the nasal turbinates, lung congestion, aggregates of alveolar macrophages). In dogs and mice, increased mortalities, malacia and/or vacuolation in the white matter in the brain, histopathology in the lungs, and follicular cell hypertrophy in the thyroid gland were observed.
-- In specially designed acute and subchronic inhalation neurotoxicity studies in rats, several electrophysiological parameters (EEGs) were recorded in addition to observations for clinical signs of neurotoxicity, functional observational battery (FOB) and motor activity testing, and/or neurohistopathologic examination. Following two exposures on consecutive days for 6 hours/day at 300 ppm of sulfuryl fluoride (354 mg/kg/day), no treatment-related neurotoxic effects were noted. In a 90-day study, changes in some EEG patterns were observed at 100 ppm (80 mg/kg/day) and in several additional patterns at 300 ppm (240 mg/kg/day). Vacuolation of the white matter in the cerebrum was also observed at 300 ppm in this study. In a specially designed 1-year chronic inhalation neurotoxicity study in rats, no treatment-related neurotoxic effects were observed at 80 ppm (56 mg/kg/ day). EEGs were not recorded in this study.
Ref: Federal Register: September 5, 2001 (Volume 66, Number 172). Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances.

http://www.fluorideaction.org/pesticides/sulfuryl.flu.fr.sept.5.2001.htm

Vikane, sulfuryl fluoride, Lot No. TWP 830919-408, 99.8%, was administered to New Zealand White rabbits via inhalation for 6 hours/day, 5 days/week for 13 weeks at 0, 30, 100 or 300 ppm. Seven animals per sex per group. NOEL = 30 ppm; [cerebral vacuolation in regions of internal and external capsules, putamen, and globus pallidus of one female: and nasal tissue inflammation in one male]. At 300 ppm, common brain findings were vacuolation to severe malacia of cerebrum (both sexes, in the above regions), and gliosis and/or hypertrophy of vascular endothelial cells in some females in the same regions.
Ref: CA EPA, Summary of Toxicolgy Data, August 1, 1986.
http://www.cdpr.ca.gov/docs/toxsums/pdfs/618.pdf

The primary effects of sulfuryl fluoride in humans are respiratory irritation and central nervous system depression, followed by excitation and possibly convulsions. Rabbits exposed via inhalation (6 hours/day, 5 days/week, for 2 weeks) to sulfuryl fluoride showed hyperactivity, convulsions and vacuolation of the cerebrum at 600 ppm (2.5 mg/L). Renal lesions were present in all rats exposed by inhalation (6 hours/day, 5 days/week, for 2 weeks) to 600 ppm (2.5 mg/ L) sulfuryl fluoride. Minimal renal changes were noted in rats exposed to 300 ppm (1252 mg/L), whereas no effects occurred at 100 ppm (4.2 mg/ L). Convulsions at near lethal concentrations were reported in rabbits, mice, and rats. In a 30-day inhalation study, loss of control, tremors of the hind quarters, and histopathological changes in the lung, liver, and kidney were reported in rabbits exposed to 400 ppm (1.6 mg/L) for 7 hours/day, 5 days/week for 5 weeks. The NOEL was 200 ppm (0.83 mg/L). Cerebral vacuolation and/or malacia and inflammation of nasal tissues were observed in rabbits exposed by inhalation to 100 or 300 ppm (0.4 or 1.25 mg/L) for 13 weeks. The NOEL was 30 ppm (0.125 mg/L). Rats exposed by inhalation to 100 to 600 ppm (0.4 to 0.25 mg/L) sulfuryl fluoride for 13 weeks developed mottled teeth (indicative of fluoride toxicity), renal and respiratory effects, and cerebral vacuolation. EPA believes that there is sufficient evidence for listing sulfuryl fluoride on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available neurological, renal, and respiratory toxicity data for this chemical.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

PubMed abstract: This study assessed the health effects associated with occupational exposure to methyl bromide and sulfuryl fluoride among structural fumigation workers... Sulfuryl fluoride exposure over the year preceding examination was associated with significantly reduced performance on the Pattern Memory Test and on olfactory testing... Occupational sulfuryl fluoride exposures may be associated with subclinical effects on the central nervous system, including effects on olfactory and some cognitive functions.
Ref: Am J Public Health 1998 Dec;88(12):1774-80. Health effects associated with sulfuryl fluoride and methyl bromide exposure among structural fumigation workers by
Calvert GM et al.

Teflon (PTFE: polytetrafluoroethylene) - EPA List 3 Inert - CAS No. 9002-84-0

Note: tetrafluoroethylene is a major thermal breakdown product of Teflon.

Abstract: The toxic properties of the tetrafluoroethylene (9002-84-0) monomer and of products of the thermal treatment of the tetrafluoroethylene polymer in acute experiments on cats, rabbits, albino rats and albino mice are reported. In rats and rabbits the inhalation of monomer induced hyperemia of organs, especially the brain, hemorrhage in the spleen and lungs, and dystrophic changes in the kidneys. Emphysema and atelectasis was observed in the lungs, desquamation of the epithelium in the bronchi also was observed. The threshold mortality for the monomer was 2.5 volume percent for albino rats and 4.0 volume percent for rabbits. The pyrolytic decomposition of tetrafluoroethylene polymer was lethal to cats, rabbits, mice, and rats. Death was caused by acute pulmonary edema, sometimes accompanied by pneumonia. Renal dystrophy was observed in the cats. There was acute irritation of the upper respiratory tract mucosa in all test animals. It is concluded that the pathology observed upon inhalation of the products of thermal decomposition of the polymer is apparently explained by the presence in the pyrolyses gas of difluorophosgene, perfluoroisobutylene (382-21-8), and other highly toxic hydrocarbons. (Russian: English translation available)
Ref: Toxicity of Tetrafluoroethylene by Zhemerdi A. Trudy Leningradskogo Sanitarno-gigienicheskogo Meditsinskogo Instituta, Vol. 44, pages 164-176, 1958. Document Number: NIOSH/00080478.

Tefluthrin - Insecticide - CAS No. 79538-32-2

In a 3-month rat study, dietary administration of 10 mg/kg/day produced plasma, red blood cell, and brain cholinesterase inhibition. The NOEL was 5 mg/kg/day. In a 6-month dog study, dietary administration of 10 mg/kg/day (LOEL) produced plasma cholinesterase inhibition. The NOEL was 1 mg/kg/day.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

Tembotrione - Herbicide - CAS No. 335104-84-2

-- Evidence of neurotoxicity was noted in the subchronic and chronic toxicity studies in the dog and the acute and developmental neurotoxicity studies in the rat (page 20).
--
Rats: decreased absolute brain weight
(pp 7, 16, 20, 56, 68, 88).
-- Developmental Neurotoxicity/ Rat study: brain morphometric changes and decreased acoustic startle response were observed in offspring at the lowest dose tested (0.8 mg/kg/day). These effects were observed at a dose lower than that which caused maternal toxicity (16.3 mg/kg/day, corneal opacity). (p 16) ... the brain morphometric changes were presumed to occur following a single exposure (p 21-22).
-- Relative brain weight was significantly (p<0.01) increased in both males and females by 11 and 12% respectively, at 7000 ppm. Absolute brain weight decreased significantly (p<0.001) by 6% in 7000 ppm males only and was comparable to controls in females (p 56).
-- absolute brain weights were dose-dependently decreased (p≤0.05) in both sexes in both generations. In F1 male and female pups, absolute brain weights significantly decreased 3-10% in all treatment groups. In the F2 generation, absolute brain weights significantly decreased 5-9% in males and females at ≥ 200 ppm. Relative brain weights were significantly increased (p≤0.05) in only F1 males and females by 8-9% at ≥200 ppm (p 68).
-- In an acute neurotoxicity study (MRID 46695723), groups of non- fasted, young-adult Wistar rats (12/sex/dose) were given a single oral (gavage; 10 mL/kg) dose of AE 0172747 at doses of 0, 200, 500 or 2000 mg/kg (limit dose) and observed for 14 days. The brain and peripheral nervous system tissues collected from the perfused animals in the control and 2000 mg/kg groups were subjected to histopathological evaluation. Positive control data were not provided; however, data previously reviewed by the Agency have been included in this DER. (p 85)
* [definition of morphometric: (Science: technique) method that involves measurement of shape.]
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.
Dose and Endpoint for Establishing RfD: (page 22)
------ Study Selected: Chronic Toxicity/Carcinogenicity (Feeding)/Rat MRID No.: 46695708
------ The NOAEL of 0.04 mg/kg/day was based on neovascularization and edema of the cornea and snow flake-like corneal opacity, unilateral or bilateral keratitis of the eye, decreased mean body weight and mean body-weight gain, increased total cholesterol, higher ketone levels and lower pH values, higher protein levels, increased kidney weight, kidney to body weight and kidney to brain weight ratios, chronic nephropathy and atrophy of the sciatic nerve observed in the male at 0.79 mg/kg/day (LOAEL).
------ UF(s): An UF of 100 was applied to account for interspecies extrapolation (10X)
------ Comments about Study/Endpoint/UF: This study provided the lowest NOAEL in the database (most sensitive endpoint) and will also provide the most protective limits for human effects.
• Evidence of neurotoxicity was seen in the subchronic and chronic toxicity studies in the dog (uncoordinated movement, disturbance in locomotion) and in the acute (decreased arousal, decreased body temperature, decreased motor and locomotor activities) and developmental neurotoxicity (brain morphometric changes, decreased acoustic startle response) studies in the rat. In the developmental neurotoxicity study in rats, increased susceptibility was observed as fetal neurological effects and occurred at a dose that was lower than the dose at which maternal toxicity occurred (corneal opacity). (page 6-7)
• The decreased accoustic startle response observed in adult rats was statistically significant at the mid and high dose but not at the low dose.
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.

Tetraconazole - Fungicide - CAS No. 112281-77-3

• Metbolism nd Toxicokinetics. Tetraconazole was broadly distributed to all organs and tissues tested, with the highest level detected in the liver, followed by kidneys, gonads, brain and bones. Low residua levels were still detected in the liver and gastrointestinal tract (sometimes bones) at 72 hr.
Chronic & Carcinogenicity Studies. Dorsal compression was seen in the brain of some mice at 1250 ppm, and thickening of compact bones in the cranium, ribs and collar bones, myelofibrosis, pale, thickened, broken, chipped and/or overgrown incisors were observed at 800 and 1250 ppm, indicating abnormal bone metabolism. (pp 4-5)
-- Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to males only) of tetraconazole in the diet for 2 years... In the brain of males at 640 and 1280 ppm, dorso-lateral compression, dilated ventricles, and white thickened cranium and parietal bones were probably secondary to the osseous hypertrophy. Increased numbers of rats had pale, thickened and overgrown incisors at 640 and 1280 ppm. (page 5)
Ref: August 2005 - Evaluation of Tetraconazole in the product Domark 40ME Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf

1,2,4-triazole targets the nervous system, both central and peripheral, as brain lesions (most notably in the cerebellum) were seen in both rats and mice, and peripheral nerve degeneration was also seen in the subchronic neurotoxicity study in rats. In addition, brain weight decreases were seen in several studies, including in the offspring in the reproductive toxicity study. In the subchronic/neurotoxicity study, there is evidence that effects progress over time, with an increase in incidence of clinical signs (including tremors and muscle fasciculations) during weeks 8 and 13 that were not seen during earlier evaluations. Effects were also seen on reproductive organs in both sexes, most notably ovaries (in rats) and testes (in rats and mice), in both the reproductive toxicity and subchronic toxicity studies. Hematological changes, including slightly decreased hemoglobin and/or hematocrit, have also been seen in multiple studies and species (in rats at doses of 33 mg/kg/day and above, and in mice at doses of 487 mg/kg/day and above). Studies depicting the effects of chronic exposure to free triazole or its conjugates are not currently available.
Ref: Human Health Aggregate Risk Assessment for Triazole-derivative Fungicide Compounds (1,2,4-Triazole, Triazole Alanine, Triazole Acetic Acid). US EPA, February 7, 2006.

1,1,1,2-Tetrafluoroethane (HFC-134a) - Propellant, US EPA List 4B Inert - CAS No. 811-97-2

-- NEUROLOGIC 0.2.7.1. ACUTE EXPOSURE - Headache, dizziness, and disorientation are common. Cerebral edema may be found on autopsy. A syndrome of impaired psychomotor speed, impaired memory and learning, and emotional lability has been described in workers with chronic occupational exposure to fluorinated hydrocarbons.
-- THERE IS A SIGNIFICANT ACCUMULATION OF FLUOROCARBONS IN BRAIN, LIVER & LUNG COMPARED TO BLOOD LEVELS, SIGNIFYING A TISSUE DISTRIBUTION OF FLUOROCARBONS SIMILAR TO THAT OF CHLOROFORM. /FLUOROCARBONS/ [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3076]
Ref: Hazardous Substances Data Bank for 1,1,1,2-TETRAFLUOROETHANE CASRN: 811-97-2.

http://www.fluorideaction.org/pesticides/1,1,1,2-tetrafluoroe.toxnet.htm

Thifluzamide - Fungicide - CAS No. 130000-40-7

• No toxicological data available as of February 2005.
• Note:
This pesticide contains both bromine and fluorine; a combination that has the potential to produce severe adverse effects - particularly to the brain.

• Other fluorinated pesticides that contain both bromine and fluorine are:

Bromethalin
Chlorfenapyr
Fluazolate
Fluorophene
Halfenprox
1H-Pyrrole-3-carbonitrile, 4-bromo-2-(4-chlorophenyl)-5-trifluoromethyl

Transfluthrin - Insecticide - CAS No. 118712-89-3

-- 3.2.4 Carcinogenicity Studies. The two available studies, in the rate and mouse both combine chronic toxicity and carcinogenicity... Single incidences of tumours occurring in treated groups but not controls were reported in the kidneys, ovaries, brain, parathyroid and skeletal muscle. Neither these, nor the occasional incidences of systemic tumors presented in Table 3.3 were considered to be treatment related (page 23).
Ref: Evaluation on: Transfluthrin Use as a Public Hygiene Insecticide. September 1997. Prepared by: the UK Health and Safety Executive, Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct, Bootle, Merseyside L20 3QZ. Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX. UK. Also at
http://www.pesticides.gov.uk/citizen/evaluations/165_confirm-box.htm
• Note: This was transcribed from the copy available on the web. While one can easily read this report on the web, the report is inaccessible, or locked, to any attempt to copy it. Any errors are mine. EC.

Tributyltin fluoride - Antifoulant, Fungicide, Microbiocide - CAS No. 1983-10-4

... In rats given a single oral dose of 40 mg/kg tributyltin fluoride (15 mg Sn/kg), transient elevations in tributyltin, dibutyltin, monobutyltin, and inorganic tin were observed in brain and liver over the 8-day period following the dose, indicating that dealkylation had occurred (Iwai et al. 1981, see Section 3.4.3). ..
Ref: DRAFT TOXICOLOGICAL PROFILE FOR TIN AND COMPOUNDS. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Public Health Service Agency for Toxic Substances and Disease Registry. September 2003.

http://www.atsdr.cdc.gov/toxprofiles/tp55.pdf

Trichlorofluoromethane - Insecticide, Fungicide, Propellant, US EPA List 2 Inert - CAS No. 75-69-4

-- Chronic effects ... Chronic Effects Chronic use of Freon 11 has been linked to diseases of the mucous membranes, lungs, and central nervous system (Hazardtext, 2003B). In the occupational setting, chronic fluorocarbon exposure has been associated with a syndrome of impaired psychomotor speed, impaired memory and learning, and emotional instability (Reprotext, 2003). Repeated or prolonged skin contact may cause dermatitis (NIOSH, 2001E; NIOSH, 2001D).
Ref: September 24, 2003 (Revised) - FREON [11, 12, 113]. Technical Support Document: Toxicology. Clandestine Drug Labs/ Methamphetamine. Volume 1, Number 11. California EPA, Office of Environmental Health Hazard Assessment (OEHHA), Department of Toxic Substances Control.

-- An estimated BCF of 49 was calculated for trichlorofluoromethane(SRC), using a log Kow of 2.53(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate. The levels of trichlorofluoromethane in three species of mollusks and five species of fish are only slightly enriched (usually 2-25 times on a dry weight basis) over the seawater levels(4). The usual order of enrichment was found to be brain > liver > gill > muscle(4). [(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 3 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) Dickson AG, Riley JP; Mar Pollut Bull 7: 167-9 (1976)]
-- There is a significant accumulation of propellant in the brain, liver and lung compared to blood levels, signifying a tissue distribution of propellant similar to that of chloroform. /Fluorocarbons/ [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1203]
-- Aerosol sprays containing fluorocarbon propellants are another source of solvent intoxication. Prolonged exposure or daily use may result in damage to several organ systems. Clinical problems include cardiac arrhythmias, bone marrow depression,
cerebral degeneration, and damage to liver, kidney, & peripheral nerves. Death occasionally has been attributed to inhalant abuse, probably via the mechanism of cardiac arrhythmias, especially accompanying exercise or upper airway obstruction. /fluorocarbon propellants/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 575]
Ref: Hazardous Substances Data Base for TRICHLOROFLUOROMETHANE.
http://www.fluoridealert.org/pesticides/Trichlorofluorometha.TOXNET.htm

Trichlorotrifluoromethane (CFC 113) - Solvent, US EPA List 2 Inert - CAS No. 76-13-1

.. A single case /was reported/ of sensorimotor neuropathy in a woman who had worked as a laundress with trichlorotrifluoroethane (Freon 113) for several years. Weakness, pain, and paresthesias were most severe distally in the legs. Electrodiagnostic testing was consistent with axonal damage. Removal from exposure to trichlorotrifluoroethane resulted in gradual recovery. [O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume II. Boca Raton, FL: CRC Press, Inc., 1985. 110]
-- There is a significant accumulation of fluorocarbons in brain, liver and lung compared to blood levels, signifying a tissue distribution of fluorocarbons similar to that of chloroform. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1203]
Ref: Hazardous Substances Data Bank for 1,1,2-TRICHLORO-1,2,2-TRIFLUOROETHANE CASRN: 76-13-1.
http://www.fluorideaction.org/pesticides/trichlorotrifluorome.toxnet.htm

Chronic effects ... In the occupational setting, chronic fluorocarbon exposure has been associated with a syndrome of impaired psychomotor speed, impaired memory and learning, and emotional instability (Reprotext, 2003). Repeated or prolonged skin contact may cause dermatitis (NIOSH, 2001E; NIOSH, 2001D).
Ref: September 24, 2003 (Revised) - FREON [11, 12, 113]. Technical Support Document: Toxicology. Clandestine Drug Labs/ Methamphetamine. Volume 1, Number 11. California EPA, Office of Environmental Health Hazard Assessment (OEHHA), Department of Toxic Substances Control.

Triflusulfuron-methyl - Herbicide - CAS No. 126535-15-7

In a rat reproduction study (2-generation, 1 litter/generation), the NOEL for systemic (parental) toxicity was 5.81 mg/kg bw/d based on lower body weights and food consumption. The NOEL for reproductive toxicity was 44 mg/kg bw/d (750 ppm) based on lower pup body weights and histopathological effects on the cerebellum consistent with undernutrition (decreased cellularity in the internal granular layer and increased cellularity in the external germinal layer) in the 2500 ppm group...
Ref: Dec 3, 1999 - Report on Triflusulfuron methyl. Regulatory Note REG99-03. Pest Management Regulatory Agency, Health Canada, Ottawa.
http://www.fluorideaction.org/pesticides/triflusulfuron.methy.canada.pdf

 
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