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
* 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.

A little background on GABA
Synthesis, storage and release

GABA was identified in the mammalian brain in 1950's. It is believed to be the major inhibitory neurotransmitter in the brain. It is this role which is of interest to the neuropsychiatrist. GABA is synthesized from Glutamate. The marker enzymeis Glutamic acid decarboxylase (GAD). GAD is a pyridoxal cofactor dependent enzyme. A congential form of B-6 vitamin deficiency is known to predispose to seizures which are B-6 responsive. Glutamate is a pivotal amino acid in the brain. It is dervied from alpha keto glutarate which is one of the intermediates in the Krebs cycle by way of the addition of an amine group. Glutamate also undergoes transamination to form glutamine by addition of another amine group. Glutamine then proceeds to the liver where it is deaminated to regenerated glutamate which then returns to the brain. This is brain's nitorgen cycle. In situations where the liver is unable to deaminate the glutamine the brain must obtain glutamate by draining the Kreb's cycle intermediates. This in turn begins to impair cerebral energy metabolism.
Following release GABA can be taken back up by the neurons or by astrocytes. It appears that the release of GABA is also under autoreceptor control. GABA is metabolized by the enzym GABA transaminase (GABA-T) to form succinic acid semialdehyde. Succinic acid semialdehyde is metabolized further to form succinic acid which is also a Kreb's cycle intermediate. GABA-T is inhibited by valproic acid. This is the basis for the belief that valproic acid is GABAergic. There are other alternative pathways for GABA metabolism.

There are two basic subtypes, GABA-a and GABA-b.
GABA-a is the most prevalent in the mammalian brain. The GABA-a receptor is similar to acetylcholine receptor in that it is related to an ion channel. In the case of GABA-a it is the chloride ionophore. Binding of GABA to this receptor increases the permeability to chloride ion which causes a hyperpolarization of the neuron or inhibition. The GABA-a receptor has four basic subunits, 2-alpha and 2 beta peptides which surround a chloride channel. There are three basic binding sites on this complex. The first is the GABA site. The second is a benzodiazepine site. The third is in the channel and is essentially a barbiturate site ...

The GABA-b receptor is a G-protein related receptor which is distinct from the GABA-a sites. The highest concentrations of GABA-b receptors is in the interpeduncular nuclie and cerebellum. It appears that one of its prinicple effects is to increase the efflux of K+ from the cell. This would result in a hyperpolarization. Pharmacologically baclofen is considered a GABA-b agonist. The principle effect of GABA-b agonism is muscle relaxation.
A significant relationship of dopamine and GABA exists. In general GABA acts to reduce the firing of the dopaminergic neurons in the tegmentum and substantia nigra. It forms the basis for the use of benzodiazepines as augmentation strategies in the treatment of psychosis. In addition benzodiazepines may be helpful in cases where there is an over activity of dopamine in the motor striatum such as Huntington's Chorea or Tardive Dyskinesia. It is believed that they act by increasing the feedback inhibition. The feedback inhibition from the GABA neurons of the globus pallidus and putamen to the dopaminergic neurons of the substantia nigra is an important modulating force on the activity of the dopamine neurons.

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.

Fentrifanil - Acaricide - CAS No. 62441-54-7

PubMed abstract: Observations on 2'-chloro-2,4-dinitro-5',6-di(trifluoromethyl)-diphenylamine-induced edema in the white matter of the central nervous system of the rat.
Ref: Lock EA, Scales MD, Little RA. Toxicol Appl Pharmacol 1981 Aug;60(1):121-30.

Fipronil - Acaricide, Insecticide - CAS No. 120068-37-3

The NOEL for developmental toxicity is 0.5 ppm (0.05 mg/kg/day). The developmental neurotoxicity LOEL is 200 ppm (15 mg/kg/day) based on: Decreased auditory startle response; reduced swimming direction scores, group mean angle measurements, and water ``Y'' maze times trails; and decreased absolute-brain weights. The NOEL for developmental neurotoxicity is 10 ppm (0.90 mg/kg/day).
Ref: Federal Register. July 17, 1998. Fipronil; Pesticide Tolerance. Final Rule.

Fipronil is the first phenylpyrazole insecticide introduced for pest control. Although fipronil is known to inhibit GABA receptors, the detailed mechanism of action remains to be seen. In order to elucidate the mechanism of fipronil interaction with the mammalian GABAA system, single-channel patch clamp experiments were performed using rat dorsal root ganglion neurons. The amplitude of main conductance state (27pS) current was not significantly altered by co-application of 10 microM fipronil and 10 microM GABA. The histograms of open time distribution were fitted to a sum of three exponential functions. After application of 10 microM fipronil, the proportion of the fastest component increased slightly and that of the slowest component decreased slightly. Thus, the mean open time was decreased from 11.4 ms to 7.8 ms by fipronil. The histograms of closed time distribution were fitted to a sum of four exponential functions. Fipronil 10 microM prolonged the slowest time constant resulting in a prolongation of the mean closed time from 29.7 ms to 52.8 ms. Thus, the frequency of channel openings was reduced. Thus, the fipronil suppression of GABA-induced whole-cell currents is caused in part by decreases in the channel open time and the frequency of channel openings.
Pest Manag Sci. 2004 May;60(5):487-92. Fipronil modulation of GABAA receptor single-channel currents; by Ikeda T, Nagata K, Kono Y, Yeh JZ, Narahashi T.

Excerpt from absract: The long-term objective is to define the fundamental basis for the selective toxicity of insecticides acting at the gamma-aminobutyric acid (GABA) receptor of mammals and insects. This is the target of major neurotoxic insecticides acting as both blockers and activators of the GABA-gated chloride channel. More than 5,000,000,000 pounds of these channel blockers have been used for pest control in the past 50 years and they range in chlorine content from 52-73%. The major channel blockers used at present, representing 6% of the insecticide market, are endosulfan and lindane and this market share will increase with expanded use of the newly-commercialized polyhalogenated fipronil....

The long-term goal of the proposed study is to elucidate the mechanism by which neuroactive insecticides exert their toxic actions ... In order to elucidate the physiological mechanisms of selective toxicity, patch clamp data on the kinetics of receptors/channels and those of insecticide modification will be compared between rat and cockroach neurons for fipronil modulation of GABA receptors, imidacloprid modulation of neuronal nicotinic acetylcholine receptors (nnAChRs) ...

Flonicamid - Insecticide - CAS No. 158062-67-0

“IKI-220 Technical: Combined Chronic Toxicity and Carcinogenciity Study in Rats,” (M. Kuwahara; IET 98-0142; 8/16/04). ... This volume contains discussion of questions concerning the bone/bone marrow effects and cerebellar granular tumors observed in the original study.... In this document the U.S. EPA also questioned whether the cerebellar granular cell tumors (observed histopathologically) were treatment related. It was reported that GCT involving the meninges of the brain is the most frequently reported benign neoplasm occurring in many strains of rat. Historical controls obtained from 38 2-year studies in Wistar rats (1981 - 2000) at RCC Ltd., Switzerland showed a range of 0 - 7.14% (M) and 0 - 4.35% (F). The report concluded that since GCTs of meninges are observed only microscopically, small ones may be included in the sections examined only by chance. The tumors do not metastasize and are possibly underreported. Thus their true incidence is not really known. The report considered these observations to be incidental and unrelated to treatment. DPR considers the GCTs to be marginally increased in females when compared to historical controls but essentially equivocal. (Silva, 4/11/05)
Reference: April 28, 2005 - Summary of toxicology data. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

Fluazifop-butyl - Herbicide - CAS No. 69806-50-4

Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically... . Testis and epididymis weights in the males (80, 250 ppm), and pituitary gland (80, 250 ppm), uterus (80, 250 ppm), brain (250 ppm) and lung weights (250 ppm) in females were significantly reduced... [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.

Fluazinam - Fungicide - CAS No. 79622-59-6

-- In subchronic and chronic toxicity studies, fluazinam targeted the following organs: liver, lung, uterus, testes, pancreas, thymus, thyroid, stomach, eyes and brain...
-- In acute and subchronic neurotoxicity studies, treatment with fluazinam resulted in marked neuropathology in the form of vacuolation of the white matter of the brain.
Special studies have been submitted that show this effect is not due to fluazinam itself, but rather to a manufacturing impurity. In the subchronic study, generalized toxicity was observed as decreased body weight and food efficiency. A developmental neurotoxicity study was suggested upon preliminary review of the data and the applicant submitted a rationale. Upon full review of the dataset, a developmental neurotoxicity study is a requirement for full registration. Special studies were generated to determine the cause of the white matter vacuolation. All nine impurities were tested at doses that reflected their relative content in the technical product. Only one impurity was found to produce the vacuolation effects and all subsequent special studies focus on this chemical. The vacuolation was determined to be in the myelin sheaths surrounding axons in the white matter. Dogs, mice and rats were found to have comparable results when tested in similar manners. Older animals were found to be more susceptible than the young. All vacuolation effects were found to be reversible. Neurotoxic findings were common at high doses and included decreased motor activity, partial paralysis and ataxia. This effect was observed at high doses (LOAEL was 50 mg/kg/d) when the dose level of impurity no. 5 was sufficiently high to cause these effects. Therefore, the presence of this impurity will be limited to 0.1% of the technical active.
-- Determination of acceptable daily intake (ADI). The recommended ADI for fluazinam is 0.0011 mg/kg bw/day. The chronic toxicity and oncogenicity study in mice was considered the most appropriate study to assess chronic dietary exposure. The no observed adverse effect level (NOAEL) was 1.1 mg/kg bw/day, based on increased incidences of brown pigmented macrophages in the liver, increased incidences of eosinophilic vacuolated hepatocytes in males and increased liver weights relative to body weights. The standard uncertainty factor of 100-fold is applied to account for intraspecies and interspecies variability, an additional 10-fold safety factor is recommended to firstly, protect for endocrine-related effects and secondly, to account for the lack of a developmental neurotoxicity (DNT) study. This provides margins of safety of 9100 to the NOEL for white matter vacuolation and 6350 to the NOEL for developmental effects in the rabbit developmental study.
-- The USEPA has chosen an ADI of 0.00367 mg/kg bw/d based on a 2-year carcinogenicity study in mice (1.1 mg/kg bw/d with 100-fold uncertainty factor (UF) and three-fold Food Quality Protection Act (FQPA) safety factor.) They have also requested a developmental neurotoxicity study.

Ref: Canada: Regulatory Note REG2003-12. Fluazinam. Pest Management Regulatory Agency. Health Canada. Ottawa. October 27, 2003.

90-Day oral toxicity dogs NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on retinal effects, increased relative liver weight, liver histopathology and possible increased serum alkaline phosphatase in females and possible marginal vacuolation of the cerebral white matter (equivocal)...
Carcinogenicity mice NOAEL = Males:<126 mg/kg/day, Females: <162 mg/kg/day LOAEL = Males: 126 mg/kg/day; Females: 162 mg/kg/day based on increased liver weights and liver and brain histopathology in both sexes
Special study: 4-Week dietary (Range-finding) mice NOAEL = not identified (Males; <555 mg/kg/day; Females: <658 mg/ kg/day) LOAEL = Males: 555 mg/kg/day; Females: 658 mg/kg/day based on vacuolation of white matter in brain, increased liver weights, histopathology in liver...
Eight special mechanistic studies to assess the CNS white matter vacuolation: White matter vacuolation in the CNS of mice, rats, and dogs was found to be due to Impurity-5.
Ref: Federal Register. September 7, 2001. Fluazinam; Pesticide Tolerance. Final Rule.

A second oncogenicity study in mice was conducted at 1,000, 3,000 and 7,000 ppm to ensure that an maximum tolerance dose (MTD) was studied. Findings included increased female mortality, reduced body weight gains, increased brain weights and/or liver weights. An impurity in the test material used in this study resulted in vacuolation of the white matter of the brain and cervical spinal cord in treated animals. A statistically significant higher incidence of hepatocellular adenomas was observed in the 3,000 ppm dose males. Hepatocellular adenomas are common tumors in male mice. There was no dose relationship in the induction of the adenoma and no increase in hepatocellular carcinomas. It was concluded that fluazinam is not carcinogenic in the mouse.
Ref: Federal Register: December 6, 2000 [Page 76253-76258].

Of particular concern was a neurotoxic lesion described as vacuolation of the white matter of the brain and sometimes cervical spinal cord which was initially observed in long-term (1-2 year) chronic studies in mice and dogs and later, upon careful re-examination of the central nervous system (CNS), also in shorter-term (4-week to 90-day) subchronic studies. Although this lesion was also observed in control animals, the increased incidence and/or severity of the lesion in test animals was clearly treatment-related and dose-related. Further investigation of this finding in a series of special studies demonstrated the same lesion could also be induced in rats. In the special studies, the following were also determined.
• Fluazinam, per se, was not responsible for the induction of this lesion. Evaluation of the effects of impurities present in technical grade fluazinam revealed that one single impurity, Impurity-5, was solely responsible for the induction of this lesion.
• No significant differences in susceptibility or in incidence or severity of vacuolation of the white matter of the CNS were observed between species (mice, dogs, or rats). Similarly, no significant differences were attributed to sex.
Electron microscopy of the white matter (cerebellum) of mice treated with technical grade fluazinam indicated that treatment-related effects were confined to the myelin sheaths. Large vacuoles were observed in the intramyelin sheaths due to the accumulation of fluid between the sheaths. The nucleus and mitochondria in the oligodendroglia were observed to remain intact, suggesting no damage to these cells.
• White matter vacuolation in the CNS was reversible. The myelin sheaths appeared to recover completely during a recovery period of up to 56 days.
• There appears to be a non-linear dose-response with a clear threshold below which no effect occurs. It was concluded that a LOAEL of 0.1 mg/kg/day and a NOAEL of 0.02 mg/kg/day for CNS effects could be established for Impurity-5.
-- At the current maximum concentration of Impurity-5 in technical grade fluazinam of 0.1%, the NOAEL for CNS effects of 0.02 mg/kg/day for Impurity-5 is equivalent to a NOAEL for CNS effects of 20 mg/kg/day for technical grade fluazinam. The NOAEL of 20 mg/kg/day for CNS effects for technical grade fluazinam is comparable to the NOAEL for chronic effects for technical grade fluazinam of 1.1 mg/kg/day used to establish the chronic RfD for fluazinam. Therefore, based on a consideration of all the available data and information relating to this treatment-related neurotoxic lesion, it was concluded that the chronic dietary RfD of 0.011 mg/kg/day for “all populations”, including infants and children, is protective of the CNS effects caused by the presence of Impurity-5 in technical-grade fluazinam.
Ref: US EPA Pesticide Fact Sheet. Fluazinam. August 10, 2001.

-- Comparative— susceptibility to neurotoxicity. 97.0% Impurity-5, 2.0 mg/kg/d, 5 Crj:CD (ICR) mice, 5 Crj:CD (SD) rats, 3 beagles, all male 9 Spontaneous motor activity in rats and mice. 9 Mean body weight in mice and rats. 8 Brain weights in mice and rats. Vacuolation of white matter and swelling of the brain in all treated animals. Dogs appear to be slightly less susceptible.
-- Comparative— brain sensitivity rats and mice. 99.5% Impurity-5, 0, 0.5 mg/kg, 5 Crj:CD-1 mice, 5 Crj:CD(SD) SPF/VAF rats, all female. Incidence and severity of white matter vacuolation in brains of mice and rats were similar. Brain weights were comparable to controls.
-- Comparative— brain sensitivity 3- and 10-week old rats and mice—14 days. 99.5% Impurity-5, 0, 0.5 mg/kg/d, 10 Crj:CD-1 (ICR) SPF/VAF mice and Crj:CD(SD) SPF/VAF rats, all male, half 3 weeks old, the other half 10 weeks old Edema in brains of 1 rat and 2 mice (10 weeks old). Vacuolation in white matter of brains similar between species of same age, but more severe in older animals compared to younger.
-- Effect on brain/optic nerves 99.5%. Impurity-5, 2.5 mg/kg, Crj:CD-1(ICR) mice, 5 males/group, aged 3, 5, 8, 10, 12, 16, 20, 24 weeks All treated mice except 3 week olds had vacuolation of the optic nerve. The effect was less severe than in the brain. The eyes themselves were normal. Ages 3, 5, 8 weeks. Trace vacuolation of white matter in brains Ages 10, 12, 16, 20, 24 weeks Trace to minimal vacuolation of white matter in brains.
-- Various impurities— effect on brains. 96–100% Impurities 1 through 9, doses correspond to 5000 mg/kg dose of technical, 5 male Crj:CD-1 mice (Impurity-5 was dosed at 5 mg/kg) Only Impurity-5 was toxic. Coarse fur, paralysis of hind legs, staggering gait, sedation, moribund. 9 Mean body weight. 8 Brain weight, edema. Vacuolation of white matter.

-- Recommended ADI. 0.0011 mg/kg bw/d based on 2 year carcinogenicity in mice (1.1 mg/kg/d with 100- fold UF, three-fold SF for endocrine-related effects (testicular atrophy, pancreatic exocrine atrophy), and three-fold for lack of DNT). MOS for other critical endpoint(s) White matter vacuolation/Neurotox NOEL for white matter vacuolation was 10 mg/kg/d in chronic dog study (equivalent to 0.02 mg/kg/d Impurity-5). MOS = 9100. Tumours NOEL for tumours was 3.8 mg/kg bw/d in 2-year rat study. MOS = 3450. Developmental effects NOAEL for developmental effects was 7 mg/kg bw/d in developmental rabbit study. MOS = 6350
[ MOS = Margin of Safety ]
Ref: Canada: Regulatory Note REG2003-12. Fluazinam. Pest Management Regulatory Agency. Health Canada. Ottawa. October 27, 2003.

Fluazolate - Herbicide - CAS No. 174514-07-9

• 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:

1H-Pyrrole-3-carbonitrile, 4-bromo-2-(4-chlorophenyl)-5-trifluoromethyl

Fluazuron - Acaricide - CAS No. 86811-58-7

Note: As there is little data available on Fluazuron, we include this.

Cattle Oral application of 2.0 mg/kg b.w. of fluazuron gives rise to more rapid absorption and maintains higher level of fluazuron in the bloodstream of cattle than a dermal treatment at the same dose level (Bull and Strong, 1994). The compound distributed to the tissues such as muscle, kidney, liver, lung and brain but deposited preferentially in the fat. When the radiolabelled fluazuron was administered subcutaneously to cattles at 1.5 mg/kg b.w., the mean maximum plasma level of total radioactivity was reached in 48 hours post dose. The radioactivity was absorbed slowly from the site of injection. Half life of the radioactivity in the blood was around 78 days (Cameron, B.D., Somers, K. and Speirs, G.C. (1992). The Distribution and Excretion of [U-14C]Cl-Phenyl CGA 157419 after Subcutaneous Injection to Cattle. Unpublished report No. 141232. Inveresk Research International Limited, Tranent, Scotland. Submitted to JECFA by Ciba-Geigy Limited, Basle, Switzerland.)
Ref: Fluazuron. UN Food and Agriculture Organization. First draft prepared by Dr. P. S. Tantiyaswasdikul, Department of Pharmacology, Faculty of Pharmaceutical Sciences Chulalongkorn University, Bangkok, Thailand.

Fluchloralin - Herbicide - CAS No. 33245-39-5

Abstract. Basalin, a formulation of fluchloralin (N-(2-chloroethyl)-2-6-dinitro-N-propyl-4-(trifluoromethyl)-aniline), is being very widely used as herbicide in large number of important crops. But very limited data on its toxicological profile is available. Its adverse effects on central nervous system and locomotor alterations in sheep given 5 mg/kg orally have been reported. Preliminary studies in our laboratory indicated alteration in gait in chicken given Basalin orally @ 200-500 mg/kg followed by ataxia at higher doses. Since chicken is a suitable model for neurotoxicity assay, present studies were conducted on one week old broiler chicks given Basalin daily for four weeks through feed at different dose levels of 50 mg/kg (Gr I), 100 mg/kg (Gr II) and 150 mg/kg (Gr III). Each group contained ten chicks. The control chicks (Gr C) were given equal amount of normal feed. Activities of brain, liver and plasma acetylcholinesterase (ACHE), carboxylesterase (CE) and brain neurotoxicesterase (NTE) were estimated, the tissue esterases after four weeks treatment and plasma esterases at weekly intervals. The locomoter activity was determined using inclined plane at alternate days. Histopathological examinations of brains and spinal cords of four birds from each group were conducted after four weeks treatment. The data on all these experiments indicated inhibition of all tissue and plasma esterases in a dose dependent manner, which were significant in chicks of Gr III receiving maximum dose for four weeks. (Brain NTE 70%, brain and liver ACHE 85.71 and 85.45% respectively and liver CE 85.58% of control activity). The plasma ACHE and CE activities were significantly inhibited in this group after two weeks onwards (ACHE90.8-90.3%, CE 84.9-84.5% of control). Alteration in gait in Gr III chicks was observed after three weeks treatment and was correlated with NTE inhibition. Histopathological examinations of brain and spinal cords of chicks receiving maximum dose revealed increased number of Schwann cells in brain and small numbers of myelinated nerve fibers in spinal cord. The studies thus indicated possibility of neuropathic effects of Basalin on prolonged exposure or at higher doses.
Ref: Basalin induced neurotoxic effects in broiler chicks; by Sushma Rishi and Uma Arora. Toxicology Letters; Volume 95, Supplement 1 , July 1998, Pages 144-145.

Flucythrinate - Acaricide, Insecticide - CAS No. 70124-77-5

-- Groups of 50 male and 50 female CD-1 mice received technical flucythrinate (80% pure) in the diet at 0, 30, 60, or 120 ppm daily for 18 months. Skin lesions (abrasions, ulceration and scabs) were observed in high-dose males and females. No treatment-related symptoms or treatment-related changes in survival were found. No haematology, clinical chemistry or urinalysis were undertaken. At necropsy, hepatocellular adenomas were found in all control and treated groups. The incidence was variable and statistically- significant only in high-dose males. Hepatocellular adenocarcinoma and hepatocellular carcinoma were found in low incidence in all male groups, but only in control and low-dose female mice. The incidences of these neoplasms were similar to those previously found in mice and were apparently unrelated to treatment. Mild sciatic nerve degeneration occurred in all groups, but at slightly increased incidence in treated groups, especially high-dose males. There was no apparent dose-response relationship. The incidence of mild axonal degeneration was similar in all groups. The no-effect level for this study was therefore set at 30 ppm (Lang, 1981b).
Ref: 1985 World Health Organization Review for Flucythrinate.
Note from FAN:
-- axonal degeneration is associated with Multiple Sclerosis
-- "Interestingly, although about 30% of individuals with HIV/AIDS will develop the symptoms of sensory neuropathy, axonal degeneration is almost universal at autopsy."

Ref: Griffin, et al., Peripheral neuropathy in AIDS: New Investigative Approaches. Technical advances in AIDS. In: Major E, ed. Research in Human Nervous System. Plenum Press: 1994.
see - ]

Flufenacet - Herbicide - CAS No. 142459-58-3

NOEL = 40 ppm [1.29 mg/kg/day in males and 1.14 mg/kg/day in females] LOEL = 800 ppm [27.75 mg/kg/day in males and 26.82 mg/kg/day in females] based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T3, T4 and ALT values in both sexes, and increased incidence of microscopic lesions in the brain [axonal degeneration], eye [vacuolization of the ciliary body epithelium], kidney [hyperplasia of the epithelial cells], spinal cord [axonal degeneration], sciatic nerve [axonal degeneration] and liver [hepatocytomegaly].
Ref: EPA Pesticide Fact Sheet, April 1998.
Note from FAN:
-- axonal degeneration is associated with Multiple Sclerosis
-- "Interestingly, although about 30% of individuals with HIV/AIDS will develop the symptoms of sensory neuropathy, axonal degeneration is almost universal at autopsy."

Ref: Griffin, et al., Peripheral neuropathy in AIDS: New Investigative Approaches. Technical advances in AIDS. In: Major E, ed. Research in Human Nervous System. Plenum Press: 1994.
see -

-- Chronic toxicity: A 1-year dog chronic feeding study with a NOAEL was 40 ppm (1.29 mg/kg/day in males and 1.14 mg/kg/day in females), and a LOAEL of 800 ppm (27.75 mg/kg/day in males and 26.82 mg/kg/day in females) based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T2, T4 and ALT values in both sexes, and increased incidences of microscopic lesions in the brain, eye, kidney, spinal cord, sciatic nerve, and liver.
-- Metabolite toxicology. A 55-day dog study with subcutaneous administration of thiadone flufenacet metabolite supports the hypothesis that limitations in glutathione interdependent pathways and antioxidant stress result in metabolic lesions in the brain and heart following flufenacet exposure.
-- A rat subchronic neurotoxicity study with a NOAEL of 120 ppm (7.3 mg/kg/day in males and 8.4 mg/kg/day in females), and a LOAEL of 600 ppm (38.1 mg/kg/day in males and 42.6 mg/kg/day in females) based on microscopic lesions in the cerebellum/medulla and spinal cords.
Ref: Federal Register. March 29, 2000. Notice of Filing a Pesticide Petition to Establish a Tolerance for Certain Pesticide Chemicals in or on Food.

Chronic feeding studies in dog and rat showed structural or functional alterations in liver, kidney, haematology, spleen, and thyroid. Flufenacet induces neuropathogical changes in the brain and spinal cord (axonal swelling) in rat and dog. The overall evaluation of the observed changes demonstrates that these effects occur only after repeated and prolonged exposure to high dose levels of flufenacet, which saturate metabolic pathways, and exceed the animal capacity to rapidly metabolise and excrete it. The liver was considered the primary target organ, with increases in organ weight, cell size and number, and/or associated changes in liver function tests.
Ref: European Commission, Health & Consumer Protection Directorate-General, Scientific Committee on Plants, October 17, 2001. SCP/FLUFEN/002-Final.

Special Studies: In a 55-day dog study subcutaneous via mini-pump with Thiadone [flufenacet metabolite] support the hypothesis that limitations in glutathione interdependent pathways and antioxidant stress result in metabolic lesions in the brain and heart following flufenacet exposure.
Ref: US EPA. Pesticide Fact Sheet. Flufenacet Reason for Issuance: Conditional Registration Date Issued: April 1998.

Flumioxazin - Herbicide - CAS No. 103361-09-7

-- ONCOGENICITY, MOUSE ** 050; 184618; "Oncogenicity Study of S-53482 by Dietary Administration in Mice"; (T. Seki; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Osaka, Japan; Project ID 1928; 9/24/93); Fifty one Crj:CD-1 (ICR) mice/sex/group were treated in the diet with 0, 300, 3000 or 7000 ppm of S-53482 (lot no. PYG-89021-M, purity: 94.8%) for 78 weeks ((M): 0, 31.1, 314.9, 754.1 mg/kg/day, (F) 0, 36.6, 346.4, 859.1 mg/kg/day). An additional 15 animals/sex/group were treated for 52 weeks (satellite)... An increased incidence of calcification in the brain was noted for the 3000 and 7000 ppm males which survived to the conclusion of the study (0: 3/37 vs. 3000: 11/36 (p<0.05), 7000: 13/38 (p<0.01).
-- "The Pharmacokinetics of [ 14 C]S-53482 in the Rat 1 , Biliary Excretion of [ 14 C]S-53482 in the Rat 2 , Tissue Distribution of [ 14 C]S-53482 in the Rat 3 "; (Gibson, N.A., G.R. Krautter, K. Jalali, and L.O. Ruzo; PTRL East, Inc., Richmond, CA and PTRL West, Inc., Richmond, CA; Project IDs: 1034E 1 , 1035E/588W 2 , 1036E/589W 3 ; 2/19/97 1 , 3/6/97 2 , 3/17/97 3 ); In the pharmacokinetic study, 7 Sprague-Dawley (Crl:CD:BR) rats/sex were dosed by oral gavage with 1 or 100 mg/kg of [Tetrahydrophthaloyl-1,2-14 C]S-53482 (Flumioxazin Technical) (lot no. RIS96014, specific activity: 121 mCi/mmole, radiochemical purity: 98.9%, chemical purity: 99.0%) mixed with; unlabeled S-53482 (lot no. 60208AG, purity: 99.9%)... Only a minimal amount of the radiolabel appeared to penetrate the blood-brain barrier.

Ref: January 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- Rats. A 90-day subchronic toxicity study was conducted in rats, with dietary intake levels of 0, 30, 300, 1,000 and 3,000 ppm flumioxazin technical (98.4% purity). The NOAEL of 300 ppm was based on decreased bwts; anemia; increases in absolute and/or relative liver, kidney, brain, heart, and thyroid weights, and histological changes in the spleen, liver, and bone marrow related to the anemia.
Ref: Federal Register: February 14, 2001 [Notices] [Page 10292-10301]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

Fluometuron - Herbicide - CAS No. 2164-17-2

-- Organ Toxicity. Toxic injury to the liver, kidneys, gut and brain is induced when lethal doses of fluometuron are administered experimentally (TOXNET. 1986. National library of medicine's toxicology data network. Hazardous Substances Databank. Public Health Service. National Institute of Health, U. S. Department of Health and Human Services. Bethesda, MD: NLM.).

National Toxicology Program. Records with Morphology = Gliosis, Code = 4802.
Chemical Name C No. Contract Grp Role Dose Grp An. No Spec/Strain Sex Route Organ Site
FEED Brain Nos
FEED Brain Nos

National Toxicology Program. Records with Morphology = Meningioma, Benign, Code = 9530.
Chemical Name C No. Contract Grp Role Dose Grp An. No Spec/Strain Sex Route Organ Site
FEED Cerebellum Nos

Fluoroacetamine - Insecticide, Rodenticide - CAS No. 640-19-7
(also known as Fluoroacetamide or Compound 1081)

Health Hazards (Acute, Delayed, and Chronic): This material is super toxic; probable oral lethal dose in humans is less than 5 mg/kg, or a taste (less than 7 drops) for a 150-lb. person (*Gosselin 1976). Chemically inhibits oxygen metabolism by cells with critical damage occurring to the heart, brain, and lungs resulting in heart failure, respiratory arrest, convulsions, and death (Gilman 1980, p. 1644).
Ref: US EPA Chemical Profile. October 31, 1985

Neurologic sequelae have been noted following acute poisoning, including hypertonicity with arm and leg spasms, severe mental deficits, and moderate residual paresis. Severe cerebellar dysfunction, ataxia, and depression were described in a 15-year-old patient who survived acute fluoroacetate poisoning.
Ref: FLUOROACETAMIDE CASRN: 640-19-7. Hazardous Substances Data Bank.

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.

Fluoroacetic Acid - Rodenticide - CAS No. 144-49-0

Little specific data were available specifically about the toxicity of fluoroacetic acid; its toxicity is expected to be similar to that of FLUOROACETATE.
-- Neurologic sequelae have been noted following acute poisoning, such as hypertonicity with arm and leg spasms, severe mental deficits, and moderate residual paresis. Severe cerebellar dysfunction, ataxia, and depression were described in a 15-year-old patient who survived acute fluoroacetate poisoning.
Ref: TOXNET profile from Hazardous Substances Data Bank.

Fluorophene - Molluscicide - CAS No. 4776-06-1

• 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:

1H-Pyrrole-3-carbonitrile, 4-bromo-2-(4-chlorophenyl)-5-trifluoromethyl

Fluorouracil - Former insect Chemosterilant; now used as a pharmaceutical - CAS No. 51-21-8

Chronic neurotoxic effects were noted in dogs fed fluorouracil at a dietary dose of 2 mg/kg/day for 6 months. In this study, animals were examined at the end of 3 months and 6 months. At the end of the experiment, or at death, the brain was removed and examined (only one dog survived the entire 6-month period). Histological sections of the brain showed the presence large multiple monolocular vacuoles in the wall of the fornix of the third ventricle.
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.

-- Absorption, Distribution & Excretion : Fluorouracil is distributed into tumors, intestinal mucosa, bone marrow, liver, and other tissues. Despite its limited lipid solubility, the drug readily crosses the blood-brain barrier and distributes into CSF and brain tissue... [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993).
-- Potential Adverse Effects on Fetus: Exposure in first trimester: skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus... the incidence of malformations, particularly those affecting the tail, hindlimb bud, and brain, was increased.
Ref: TOXNET profile from Hazardous Substances Data Base.

-- PubMed abstract: Two metabolites of 5-fluorouracil (FU), monofluoroacetic acid (FA) and alpha-fluoro-beta-alanine (FBAL), were continuously administered into the left ventricle of the brain in cats for up to 1 month to investigate the mechanism of neurotoxicity of FU and its derivatives. The cumulative doses of FU and FBAL over a 1-month period were 1.5-45 mg (20 cats) and 0.2-4.8 mg (21 cats), respectively. As controls for each experimental group, acetic acid (AA) and beta-alanine (BAL) were administered. In terms of survival time in relation to the cumulative dose and molecular weight, FBAL was more toxic than FA. Neuropathologically, two types of change, vacuoles and necrosis/softening-like change, were found. The vacuoles were 20-50 microns in diameter, and distributed mainly in the cerebellar nuclei, white matter and the tectum and tegmentum of the brain stem in both experimental groups. Electron microscopically, these vacuoles were due to splitting of the myelin intraperiod line or separation between the axon and the innermost layer of myelin. Necrosis/softening-like change occurred preferentially in the FBAL group and was located symmetrically in the superior and inferior colliculi, oculomotor nuclei and thalamus. Both types of neuropathological change, especially those in the FBAL group, were similar to those found in cats orally administered with FU and its derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)
Ref: Acta Neuropathol (Berl) 1990;81(1):66-73;
Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and alpha-fluoro-beta-alanine; Okeda R, Shibutani M, Matsuo T, Kuroiwa T, Shimokawa R, Tajima T.


Ref: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 1014
Website search for "Ammonium silicofluoride" (CAS No. 16919-19-0) at:

Flurtamone - Herbicide - CAS No. 96525-23-4

-- Two-year dietary study in mice. In a carcinogenicity study, groups CD-1 mice (60/sex/dose) were fed diets containing 0, 30, 300, 3500 and 7000 ppm flurtamone (91.9% purity) for at least 78 weeks... The mean intake of flurtamone for males and females was estimated to be 4.5, 45, 525 and 1050 mg/kg bwday at 30, 300, 3500 and 7000 ppm, respectively. After 78 weeks of treatment, the mortality rate for the 7000 ppm female mice was significantly higher than controls and a significant negative survival trend was found in both sexes. The test laboratory pathologist considered systemic amyloidosis to be the major cause of death (Table 5.34) [page 102]... Mean relative brain weights were significantly increased in F0 females at dose-levels ≥2000 ppm, and in F1 males and females at 5000 ppm. While mean absolute brain weights were significantly reduced in F1 males and females at dose levels ≥2000 ppm. Other small but statistically significant changes in mean organ weight were considered to be incidental, related to body weight effects or lacked a dose-response relationship. No macroscopic changes were observed which could be related to treatment. The only microscopic finding which could be attributed to compound administration was centrilobular hypertrophy of the liver. Dose-related increases in the incidence of centrilobular hypertrophy were observed in F0 and F1 animals at dose levels ≥500 ppm (Table 5.31). this centrilobular hypertrophy was considered to be an adaptive biological response [page 108].
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Available online at:

Flusilazole - Fungicide - CAS No. 85509-19-9

Abstract: Triazole-derivatives alter the pharyngeal apparatus morphogenesis of rodent embryos cultured in vitro. The hindbrain segmentation and the rhombencephalic neural crest cell (NCCs) migration are altered by Fluconazole exposure in vitro. The aim of the present work is to identify if a common pathogenic pathway is detectable also for other molecules of this class of compounds. 9.5 days post coitum (d.p.c.) old rat embryos were exposed in vitro to the teratogenic concentrations of Flusilazole, Triadimefon and Triadimenol and cultured for 24, 48 or 60 h. The expression and localisation of Hox-b1 and Krox-20 proteins (used as markers for hindbrain segmentation) were evaluated after 24 h of culture. The localisation and distribution of NCC was evaluated after 24, 30 and 48 h of culture. The morphology of the embryos was analysed after 48 h, while the branchial nerve structures were evaluated after 60 h of culture. Hindbrain segmentation and NCC migration alteration as well as pharyngeal arch and cranial nerve abnormalities were detected after exposure of the tested molecules. A common severe teratogenic intrinsic property for the tested molecules of this chemical class has been found, acting through alteration of the normal hindbrain developmental pattern.
Reference: Menegola E, Broccia ML, Di Renzo F, Massa V, Giavini E (2005). Study on the common teratogenic pathway elicited by the fungicides triazole-derivatives. Toxicol In Vitro. Sep;19(6):737-48.
Abstract available at:

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.

abnormalities at the level of the branchial apparatus; disorganisation and fusions at the level of the cranial nerves; abnormalities in the migration of NCC, not able to form 3 distinct migration stripes from the rhomboencephalon to the branchial apparatus; alteration of the hindbrain segmentation, with reduced and scattered immunolocalised stripes.
Reference: Massa et al. Mechanisms Involved In Triazole-Induced Teratogenesis: In Vitro Study. Toxicol Lett 2003 Sep ;144 (Suppl 1 ):S107

Flutolanil - Fungicide - CAS No. 66332-96-5

Chronic toxicity. A 1-year dog chronic feeding study with a NOEL was 40 ppm [1.29 mg/kg/day in males and 1.14 mg/kg/day in females] and a LOEL of 800 ppm [27.75 mg/kg/day in males and 26.82 mg/kg/day in females] based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T2, T4 and ALT values in both sexes, and increased incidences of microscopic lesions in the brain, eye, kidney, spinal cord, sciatic nerve and liver.
Federal Register: June 23, 1998 [Page 34176-34184]. Notice of Filing of Pesticide Petitions.

Fluvalinate - Acaricide, Insecticide - CAS No. 69409-94-5

Eight days after a pregnant cow was given a single a single dose of 14 C-fluvalinate, only trace amounts (approximately 1x10 -5 % of the administered dose) of 14 C were detected in the fetus (Quistad et al. 1982). However, given the fact that exposure of rat fetuses to pyrethroids via their mothers resulted in persistent alterations in brain neurotransmitter numbers (Malaviya et al. 1993), it would appear that concentrations that reached the fetal brain were sufficient to cause a consistent effect. (p 94-95)
Ref: September 2001. Draft Toxicological Profile for Pyrethrins and Pyrethroids. U.S. Department of Health and Human Services. Public Health Service. Agency for Toxic Substances and Disease Registry

Fluvalinate, at dose rates of 10.5 and 21 mg/kg (1/10th and 1/5th of LD50, respectively) by ip route in rats, impaired acquisition (learning), while no such effect on permanent memory was observed. Consolidation process of memory traces (temporary memory) was impaired at lower doses whereas it was completely suppressed at higher dose. However, at both the dose levels retrieval of passive avoidance reaction was completely suppressed. [Maity NK, Punia JS; Indian J Exp Biol 29 (2): 178-9 (1991)]
Ref: Hazardous Substances Data Bank for FLUVALINATE CASRN: 69409-94-5.

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