Central Nervous System (CNS) - Adverse Effects
Fluorinated and Fluoride Pesticides
 
 

The Nervous System is divided into:
The Central Nervous System and the Peripheral Nervous System.


The central nervous system is divided into two parts: the brain and the spinal cord.
The brain contains about 100 billion nerve cells (neurons) and trillons of "support cells" called glia. The spinal cord is about 43 cm long in adult women and 45 cm long in adult men and weighs about 35-40 grams. The vertebral column, the collection of bones (back bone) that houses the spinal cord, is about 70 cm long. Therefore, the spinal cord is much shorter than the vertebral column.

The Peripheral Nervous System is divided into two major parts: the somatic nervous system and the autonomic nervous system.
1. Somatic Nervous System
The somatic nervous system consists of peripheral nerve fibers that send sensory information to the central nervous system AND motor nerve fibers that project to skeletal muscle.

2. Autonomic Nervous System
The autonomic nervous system is divided into three parts: the sympathetic nervous system, the parasympathetic nervous system and the enteric nervous system. The autonomic nervous system controls smooth muscle of the viscera (internal organs) and glands.

Some differences between the Peripheral Nervous System (PNS) and the Central Nervous System (CNS):
1. In the CNS, collections of neurons are called nuclei.
In the PNS, collections of neurons are called ganglia.
2. In the CNS, collections of axons are called tracts.
In the PNS, collections of axons are called nerves.
From the excellent website: Neuroscience for Kids


What is Cholinesterase? An enzyme produced by the body Essential to the Central Nervous System (CNS) Lack of Cholinesterase can cause CNS confusion. Symptoms of decreased cholinesterase: Headaches Dizziness Nausea Abdominal pain Anxiety Constricted pupils Muscle twitch or weakness Shortness of breath Diarrhea Convulsions Coma:


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.
As time allows more information will be added.

Ammonium bifluoride - Wood Preservative - CAS No. 1341-49-7

Potential Health Effects: If inhaled or swallowed, this compound can cause fluoride poisoning. Early symptoms include nausea, vomiting, diarrhea, and weakness. Later effects include central nervous system effects, cardiovascular effects and death.
Ref: Analytyka. Material Safety Data Sheet. Online as of September 15, 2003.
http://www.analytyka.com.mx/tabla%20periodica/MSDS/N/AMMONIUM%20BIFLUORIDE.htm

Ammonium fluoride - Wood Preservative - CAS No. 12125-01-8

If inhaled or swallowed, this compound can cause fluoride poisoning. Early symptoms include nausea, vomiting, diarrhea, and weakness. Later effects include central nervous system effects, cardiovascular effects and death.
Ingestion: May cause salivation, nausea, vomiting, diarrhea, and abdominal pain, followed by weakness, tremors, shallow respiration, cardopedal spasm, convulsions, and coma. May cause brain and kidney damage. Death may be caused by respiratory paralysis. Affects heart and circulatory system.
Ref: 1999 Material Safety Data Sheet prepared by Mallinckrodt Baker, Inc.
http://www.fluoridealert.org/pesticides/Ammonium.F.MSDS.htm

Ammonium fluosilicate- Insecticide, Miticide Wood Preservative, EPA List 3 Inert - CAS No. 16919-19-0

LD50 ranges of sodium, potassium, or ammonium fluorosilicates administered intragastrically in rats and mice were 89-128 and 45-64 mg fluoride ion/kg, respectively. Severe cornea damage was observed 3 hr after the administration of 50 mg of any of the salts into rabbits' eyes. Min toxic dose (intragastric) of fluorosilicic acid in rats was 8 mg/kg. Min toxic concn in 4 hr inhalation of the salt aerosols were 7.4-9.6 mg/cu m; nontoxic concn was 0.8 mg/cu m. Main toxic effects were decreased activities of cholinesterase and lactate dehydrogenase in blood serum. The intragastric effects of the fluorosilicates were similar to and additive with those of sodium fluoride. [Rumyantser GI et al; Oig Sanit (11): 80-2 (1988)]
Ref: TOXNET profile from Hazardous Substances Data Bank for AMMONIUM SILICOFLUORIDE.

http://www.fluoridealert.org/pesticides/Ammonium.Silicofluor.TOXNET.htm

Ammonium silicofluoride - Insecticide, Miticide Wood Preservative, EPA List 3 Inert - CAS No. 16919-19-0

-- Human Toxicity Excerpts: SYMPTOMATOLOGY: A. Ingestion of soluble fluoride salts. 1. Salty or soapy taste, salivation, nausea. Repeated small doses (as in drinking water) may produce no other symptoms, but polyuria and polydipsia have also been reported. 2. Large doses lead promptly to burning or crampy abdominal pain, intense vomiting and diarrhea, often with hematemesis and melena. Dehydration and thirst. 3. Muscle weakness, tremors, and rarely transient epileptiform convulsions, preceded or followed by progressive central nervous depression (lethargy, coma and respiratory arrest, even in the absence of circulatory failure).
-- LD50 ranges of sodium, potassium, or ammonium fluorosilicates administered intragastrically in rats and mice were 89-128 and 45-64 mg fluoride ion/kg, respectively. Severe cornea damage was observed 3 hr after the administration of 50 mg of any of the salts into rabbits' eyes. Min toxic dose (intragastric) of fluorosilicic acid in rats was 8 mg/kg. Min toxic concn in 4 hr inhalation of the salt aerosols were 7.4-9.6 mg/cu m; nontoxic concn was 0.8 mg/cu m. Main toxic effects were decreased activities of cholinesterase and lactate dehydrogenase in blood serum. The intragastric effects of the fluorosilicates were similar to and additive with those of sodium fluoride. [Rumyantser GI et al; Oig Sanit (11): 80-2 (1988)]
Ref: TOXNET profile from Hazardous Substances Data Bank for AMMONIUM SILICOFLUORIDE

http://www.fluoridealert.org/pesticides/Ammonium.Silicofluor.TOXNET.htm

Benzotrifluoride - Insecticide - CAS No. 98-08-8

-- TARGET ORGANS: Central Nervous System, Eyes, Skin, Respiratory Tract.
-- SHORT-TERM EXPOSURE (ACUTE) INHALATION: May produce symptoms of central nervous system depression including headache, dizziness, nausea, loss of balance and drowsiness.
Ref: BENZOTRIFLUORIDE Material Safety Data Sheet. OxyChem. Issue Date: 07-08-98

http://www.oxychem.com/products/msds/m7644.pdf

-- Animal Toxicity Studies Non-Human Toxicity Excerpts: Moderate toxic by animal-experiment; effective to central nervous system. [ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 68]
Ref: TOXNET profile from Hazardous Substances Data Base.

http://www.fluoridealert.org/pesticides/Benzotrifluoride.TOXNET.HSD.htm

Beta Cyfluthrin - Insecticide - CAS No. 68359-37-5

-- Short term toxicity. Target / critical effect: CNS / General behavioural disturbances; axonal degeneration. Lowest relevant oral NOAEL / NOEL: 90-d dog: 60 ppm (1.5 mg/kg bw/d. ) Lowest relevant dermal NOAEL / NOEL: 3-wk rabbit: 340 mg/kg bw/d * Lowest relevant inhalation NOAEL / NOEL: 3-mo rat: 0.09 g/l (0.0243 mg/kg bw/d)*
-- Neurotoxicity / Delayed neurotoxicity. Critical effects: Clinical signs indicative of a neurological disorder and a reversible axonal degeneration. No evidence of delayed neurotoxicity in hens. NOAEL (acute oral neurotoxicity, rat) 2 mg/kg bw/d (aqueous vehicle) NOAEL (90-d oral neurotoxicity, rat) 30 ppm (2 mg/kg bw/d)
Ref: December 2002 - Beta-cyflutrin: Review report for the active substance beta-cyfluthrin Finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 3 December 2002 in view of the inclusion of beta-cyfluthrin in Annex I of Directive 91/414/EEC. EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate E Food Safety: plant health, animal health and welfare, international questions E1 - Plant health.

http://www.fluorideaction.org/pesticides/cyfluthrin.beta.eu.dec.2002.pdf

Boron Trifluoride - Fumigant - CAS No. 7637-07-2

Animal Toxicity Studies: Non-Human Toxicity Excerpts: The principal feature in acute action ... is the irritation of mucous membranes of respiratory tract & eyes. In animal acute experiments, a concn of 42 mg/cu m proved fatal in some cases. Exam revealed a fall in inorg phosphorus level in blood & autopsy showed pneumonia & degenerative changes in renal tubules. Long-term (4 mo) exposure to 3 & 10 mg/cu m ... produced irritation of resp tract, dysproteinemia, reduction in cholinesterase activity & increased nervous system lability. Exposure to high concn results in reduction of acetyl carbonic acid & inorg phosphorus levels in blood, & dental fluorosis. [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983. 320]
Ref: TOXNET profile from Hazardous Substances Data Bank for BORON TRIFLUORIDE.

http://www.fluoridealert.org/pesticides/Boron.Trifluoride.TOXNET.htm

Bromethalin - Rodenticide - CAS No. 63333-35-7

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

Carbon Tetrafluoride - Former US EPA List 3 Inert - CAS No. 75-73-0

-- TARGET ORGANS: Respiratory system, cardio-vascular system, central nervous system.
-- ACUTE: The most significant hazard associated with Tetrafluoromethane [carbon tetrafluoride] is inhalation of high concentrations of Tetrafluoromethane. Such overexposure can cause oxygen deficiency. Symptoms of such exposures include respiratory difficulty, ringing in ears, headaches, dizziness, indigestion, nausea, and possible death...
-- INHALATION: Exposures to high concentrations of this gas may cause sensitization of the heart to adrenaline and nor-adrenaline. Effects of such overexposure can include light-headedness, giddiness, shortness of breath and in extreme cases, irregular heartbeats, cardiac arrest, and death. High concentrations of this gas can cause an oxygen-deficient environment. Individuals breathing such an atmosphere may experience symptoms which include headaches, ringing in ears, dizziness, drowsiness, unconsciousness, nausea, vomiting, and depression of all the senses. The skin of a victim of overexposure may have a blue color. Under some circumstances of overexposure, death may occur. The effects associated with various levels of oxygen are as follows:
CONCENTRATION SYMPTOMS OF EXPOSURE
12-16% Oxygen: Breathing and pulse rate increased, muscular coordination slightly disturbed.
10-14% Oxygen: Emotional upset, abnormal fatigue, disturbed respiration.
6-10% Oxygen: Nausea and vomiting, collapse or loss of consciousness.
Below 6%: Convulsive movements, possible respiratory collapse, and death.
Ref: Material Safety Data Sheet: TETRAFLUOROMETHANE - CF4 MSDS (Document # 001051). Airgas.

http://www.airgas.com/documents/pdf/1051.pdf

HUMAN HEALTH EFFECTS.
-- Overexposure by inhalation may include temporary central nervous system depression with such effects as dizziness, headache, confusion, incoordination, and loss of consciousness; or with gross overexposure (>20%), temporary alteration of the heart's electrical activity with irregular pulse, palpitations or inadequate circulation. Eye or skin contact with the liquid may cause frostbite.
--
Individuals with preexisting diseases of the central nervous or cardiovascular systems may have increased susceptibility to the toxicity of excessive exposures.
Ref: Undated DuPont's Material Safety Data Sheet.
http://www.fluorideaction.org/pesticides/carbon.tetrafluoride.MSDS.pdf

Chlorfenapyr - Acaricide, Insecticide - CAS No. 122453-73-0

-- MRID No. 43492833 (1994). Chronic neurotoxicity rat. NOAEL = 2.6/3.4 mg/kg/day, M/F. LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic alterations in the central nervous system (CNS) in male rats and decreased average body weights/body weight gains, food efficiency, absolute food consumption (females) and water consumption (males)
-- Chronic neurotoxicity study - rat. LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic alterations in the CNS in male rats and decreased average body weights, body weigh gains,
food efficiency, absolute food c
onsumption (F), and water consumption (M). Supporting this endpoint are similar CNS lesions and skin lesions observed in the mouse carcinogenicity study (NOAEL = 2.8).
-- Conditions: A developmental neurotoxicity study to determine the cause/relationship of potential central nervous system/myelinopathic alterations to neurotoxicity in the developing young.

Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

Chlorodifluoromethane - Insecticide, Fungicide, Propellant - CAS No. 75-45-6

The substance may cause effects on the cardiovascular system and central nervous system, resulting in cardiac disorders and central nervous system depression.
Ref: ICSC: 0049. March 2002. International Programme on Chemical Safety (IPCS).
http://www.inchem.org/documents/icsc/icsc/eics0049.htm

Potential Health Effects - Inhalation of high concentrations of vapor is harmful and may cause heart irregularities, unconsciousness or death. .. Human Health Effects: Higher exposures may lead to temporary alteration of the heart's electrical activity with irregular pulse, palpitations, or inadequate circulation. Fatality may occur from gross overexposure. Individuals with preexisting diseases of the central nervous or cardiovascular system may have increased susceptibility to the toxicity of excessive exposures.
Animal Data - INHALATION: 4 hour, LC50, rat: 220,000 ppm. The compound is a skin irritant and a slight eye irritant, but is not a skin sensitizer in animals. Effects from single high exposures include central nervous system depression, anesthesia, rapid breathing, lung congestion and microscopic liver changes...
Ref: Material Safety Data Sheet for Freon 22. DuPont. 1996.

http://www.fluoridealert.org/pesticides/Chlorodifluoromethane.MSDS.pdf
.

Cyhalothrin - Acaricide, Insecticide - CAS No. 68085-85-8

Rationale for US EPA to add Cyhalothrin to the Toxic Release Inventory. Cyhalothrin administered orally (in capsules) to dogs at 10 mg/kg/day for 26 weeks produced occasional disturbances of the nervous system (unsteadiness and/or muscular trembling). The NOEL for these effects was not defined. In a 1-year dog study, ataxia, muscle tremors, and convulsions were observed following oral administration at 3.5 mg/kg/day. Abnormal gait and convulsions were observed at 0.5 mg/kg/day. The LOEL of the study was 0.5 mg/kg/day and the NOEL was 0.1 mg/kg/day. EPA believes that there is sufficient evidence for listing cyhalothrin on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available neurological toxicity data.
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.

-- Cyhalothrin. 28-Day feeding - rat. 00153029. NOAEL: 2 mg/kg/day LOAEL: 10 mg/kg/day clinical signs of neurotoxicity. At higher doses, decreases in body weight gain and food consumption and changes in organ weights.
-- cyhalothrin. 28-Day feeding - rat. 00154806. NOAEL: 1.0 mg/kg/day LOAEL: 2.0 mg/kg/day decreases in mean body weight gain in females.
-- cyhalothrin. 26-Week feeding - dog. 00154795. NOAEL: 1.0 mg/kg/day LOAEL: 2.5 mg/kg/day increase in liquid feces. At 10.0 mg/kg/ day, clinical signs of neurotoxicity.
-- cyhalothrin. 28-Day feeding - rat. 00153029. NOAEL: 2 mg/kg/day 1984/Acceptable LOAEL: 10 mg/kg/day nonguideline. clinical signs of 0, 2, 10, 25, 50, 75 mg/ neurotoxicity. At kg/day. higher doses, decreases in body weight gain and food consumption and changes in organ weights.

-- cyhalothrin. Developmental toxicity - rat. 00154800. Maternal NOAEL: 10 mg/kg/day. Maternal LOAEL: 15 mg/ kg/day. uncoordinated limbs, reduced body weight gain and food consumption. Developmental NOAEL: 15 mg/kg/day, the highest dose tested (HDT) Developmental LOAEL: >15 mg/kg/day
Ref: Federal Register: September 27, 2002. Lambda-cyhalothrin; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Lambda.Cyhalot.FR.Sept27.02.htm

Cyhalothrin, lambda - Insecticide - CAS No. 91465-08-6

-- Short term toxicity. Target / critical effect: Organs Liver, CNS. Lowest relevant oral NOAEL / NOEL: 0.5 mg/kg bw/d, oral, 1 y dog.
Ref: European Commission. Review report for the active substance lambda-cyhalothrin. Finalised in the Standing Committee on Plant Health at its meeting on 19 October 2000 in view of the inclusion of lambda-cyhalothrin in Annex I of Directive 91/414/EEC. 7572/VI/97-final. 25 January 2001.

http://europa.eu.int/comm/food/fs/ph_ps/pro/eva/existing/list1-24_en.pdf

-- lambda-cyhalothrin. 21-Day inhalation toxicity - rat. 41387702. NOAEL: 0.08 mg/kg/day. LOAEL: 0.90 mg/kg/day. clinical signs of neurotoxicity, decreased body weight gains, increased incidence of punctuate foci in cornea, slight reductions in cholesterol in females, slight changes in selected urinalysis parameters
--
lambda-cyhalothrin. 1- Year oral - dog. 40027902. NOAEL: 0.1 mg/kg/day. LOAEL: 0.5 mg/kg/day. clinical signs of neurotoxicity.
-- lambda-cyhalothrin. Acute neurotoxicity - rat. 44861510. NOAEL: 10 mg/kg. LOAEL: 35 mg/kg. clinical observations indicative of neurotoxicity and changes in functional observational battery (FOB) parameters
Ref: Federal Register: September 27, 2002. Lambda-cyhalothrin; Pesticide Tolerance. Final Rule.

http://www.fluoridealert.org/pesticides/Lambda.Cyhalot.FR.Sept27.02.htm

Abstract (2003). Synthetic pyrethroids such as cyhalothrin are extensively used in agriculture for the control of a broad range of ectoparasites in farm animals. It has been suggested that type II pyrethroids might induce anxiogenic-like effects in laboratory animals. The present study was undertaken to investigate a possible anxiogenic-like outcome of cyhalothrin in rats. Adult male rats were orally dosed for 7 days with 1.0, 3.0, or 7.0 mg/kg/day of cyhalothrin, present in a commercial formulation (Grenade Coopers do Brazil S.A.). The neurobehavioral changes induced by cyhalothrin as well as those produced on corticosterone serum levels were measured 24 h after the last treatment. Picrotoxin (1.0 mg/kg) was also acutely used as a positive control for anxiety. Results showed that cyhalothrin:
(1) induced some signs and symptoms of intoxication that included salivation, tremors, and liquid feces;
(2) reduced total locomotor activity in the open-field;
(3) reduced the percentage of time spent in open-field central zones;
(4) increased immobility time in the open-field;
(5) reduced the percentage of time spent in plus-maze open arms exploration;
(6) reduced the time spent in social interactions, and
(7) increased the levels of serum corticosterone.
The behavioral changes reported for cyhalothrin (3.0 mg/kg/day) were similar of those induced by picrotoxin. The no effect level dose obtained for cyhalothrin in this study was 1.0 mg/kg/day. These results provide experimental evidence that cyhalothrin induces anxiety-like symptoms, with this effect being dose-related. Thus, anxiety must be included among the several signs and symptoms of pesticide intoxication.
Ref: Behavioral effects of type II pyrethroid cyhalothrin in rats; by Righi DA, Palermo-Neto J. Toxicol Appl Pharmacol. 2003 Sep 1;191(2):167-76.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12946652

DFP: Diisopropyl fluorophosphate - Insecticide - CAS No. CAS No. 55-91-4

Organophosphate insecticides such as ... DFP are potent cholinesterase enzyme inhibitors that act by interfering with the metabolism of acetylcholine, resulting in the accumulation of acetylcholine at neuroreceptor transmission sites. [Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. 979]
-- MUSCARINIC (PARASYMPATHETIC) EFFECTS may include bradycardia, bronchospasm, bronchorrhea, salivation, lacrimation, diaphoresis, vomiting, diarrhea, and miosis. NICOTINIC (SYMPATHETIC AND MOTOR) EFFECTS may include tachycardia, hypertension, fasciculations, muscle cramps, weakness, and RESPIRATORY PARALYSIS. CENTRAL EFFECTS may include CNS depression, agitation, confusion, delirium, coma, and seizures.
-- Children may have different predominant signs and symptoms than adults: CNS depression, stupor, flaccidity, dyspnea, and coma are the most common signs in children.
-- ... Its high lipid solubility, low molecular weight, and volatility facilitate inhalation and transdermal absorption. DFP also readily penetrates the central nervous system. [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. 167]
Ref: TOXNET Hazardous Substances Data Base for DIISOPROPYL FLUOROPHOSPHATE.
http://www.fluoridealert.org/pesticides/Isofluorphate-TOXNET.htm

Abstract: Diisopropyl phosphorofluoridate (DFP) produces organophosphorus-ester induced delayed neurotoxicity (OPIDN) in the hen, human and other sensitive species. We studied the effect of a single dose of DFP (1.7 mg/kg/sc) on the expression of c-jun, which is one of the heterodimerizing ITFs (Inducible Transcriptional Factors) of the AP-1 family. The hens were sacrificed at different time points ie 0.25,.0.50, 1 and 2 hrs. Total RNA was extracted from the following brain regions: cerebrum, cerebellum, brainstem, midbrain and as well as spinal cord. Northern blots prepared using standard protocols were hybridized with c-jun as well as b-actin and 18S RNA cDNA (control) probes. The results indicate differential regulation of c-jun levels which may be due to the activation of both cholinergic and non-cholinergic pathways of CNS, besides changing roles of c-jun (as mediator of degeneration or regeneration) depending on heterodimerization with other ITFs. In the highly susceptible tissues like brainstem and spinal cord c-jun transcript levels increased at 15 minutes and continued to increase gradually till it reached the maximum at 2 hrs. Overall spinal cord showed the maximum levels of c-jun induction (207%) at 2 hrs time point of all the CNS tissues. The enhancement of cholinergic transmisson by the inhibition of cholinestrase may be responsible for the gradual increase mediated by neural and vascular factors. In contrast, less susceptible tissue, cerebellum showed almost immediate induction to high level of (179%) at 15 minutes and the levels stayed more or less the same until it peaked to 185% at 2 hrs. Relatively low abundance of cholinergic neurons and high number of sensitized specialized cell types like Bergman glia and Purkinje cells may be responsible for the immediate higher induction. Non-susceptible tissue cerebrum did not show any changes in the c-jun levels. In midbrain the induction pattern was very similar to that of brainstem. This differential induction pattern of c-jun encomposing the differences in the quantity and time course was directly proportionate to the degree of susceptibility and cellular heterogeneity of different regions of CNS. The significant increase in c-jun levels along with our earlier observation on the increased c-fos levels indicate that AP-1 family of genes may be one of the IEGs involved in the long term changes which eventually lead to OPIDN.
Ref: Early Differential Induction of C-jun in the Central Nervous System of Hens Treated with Diisopropylphosphorofluoridate (DFP) by TV Damodaran et al. Neurochemical Research 25 (12): 1579-1586, December 2000.

Abstract: A single dose of diisopropyl phosphorofluoridate (DFP), an organophosphorus ester, produces delayed neurotoxicity (OPIDN) in hen. DFP produces mild ataxia in hens in 7–14 days, which develops into severe ataxia or paralysis as the disease progresses. Since, OPIDN is associated with alteration in the expression of several proteins (e.g., Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) [alpha]-subunit, tau, tubulin, neurofilament (NF) protein, vimentin, GFAP) as well as their mRNAs (e.g., NF, CaM kinase II [alpha]-subunit), we determined the effect of a single dose of DFP on the expression of one of the best known immediate-early gene (IEG), c-fos. C-fos expression was measured by Northern hybridization in cerebrum, cerebellum, brainstem, midbrain, spinal cord, and the sciatic nerves of hens at 0.5 hr, 1 hr, 2 hr, 1 day, 5 days, 10 days, and 20 days after a single 1.7 mg/kg, sc. injection of DFP. All the tissues (cerebrum, 52%; cerebellum, 55%; brainstem, 49%; midbrain, 23%; spinal cord, 80%; sciatic nerve, 157%;) showed significant increase in c-fos expression in 30 min and this elevated level persisted at least up to 2 hr. Expressions of [beta]-actin mRNA and 18S RNA were used as internal controls. The significant increase in c-fos expression in DFP-treated hens suggests that c-fos may be one of the IEGs involved in the development of OPIDN.
Ref: C-fos mRNA Induction in the Central and Peripheral Nervous Systems of Diisopropyl Phosphorofluoridate (DFP)-Treated Hens; by RP Gupta et al. Neurochemical Research 25 (3): 327-334, March 2000.

Daily subcutaneous (s.c) injections of the organophosphate diisopropylfluorophosphate caused prolonged inhibition of cholinesterase (ChE) activity in whole blood and brain and downregulation of muscarinic receptors in the central nervous system; these changes were accompanied by progressive, persistent deterioration of working memory and motor function.
Ref: 1994 - Repeated Inhibition of Cholinesterase by Chlorpyrifos in Rats: Behavioral, Neurochemical and Pharmacological Indices of Tolerance; by Bushnell PJ, Kelly KL, Ward TR. NTIS report no.NTIS/PB95-148979 [The National Technical Information Service).

Abstract: Behavioral effects of organophosphates (OPs) typically decrease with repeated exposure, despite persistence of OP-induced inhibition of acetylcholinesterase (AChE) and downregulation of muscarinic acetylcholine (ACh) receptors. To characterize this tolerance phenomenon, rats were trained to perform an appetitive operant task which allowed daily quantification of working memory (delayed matching-to-position), reference memory (visual discrimination) and motor function (choice response latencies and inter-response times (IRTs) during delay). Findings indicate that animals showing a definitive sign of tolerance to OP administration (subsensitivity to a cholinergic agonist) were also functionally impaired on both the motoric and mnemonic demands of a working memory task. The nature of this impairment suggests further that it results from compensatory changes in the CNS, e.g., muscarinic receptor downregulation, considered to produce 'tolerance' to OPs in exposed animals.
Ref: 1991 - Behavioral and Neurochemical Changes in Rats Dosed Repeatedly with Diisopropylfluorophosphate; by Bushnell PJ, Padilla SS, Ward T, Pope CN, Olszyk VB. Report No. NTIS/PB91-200238 from Tge National Technical Information Service.

The Morris water task was used to measure the effects of chronic diisopropylfluorophosphate (DFP) treatment on C57BL/6Ibg mice. Control mice showed good task acquisition and searched accurately for the platform after it was removed from the pool, suggesting that they had formed a spatial map of the platform's location relative to distal cues. In contrast, mice chronically treated with DFP prior to training showed a marked deficit in spatial learning. Chronic DFP treatment did not affect ability to locate a visible platform and did not impair task retention in mice trained to find the hidden platform prior to DFP treatment. The chronic DFP treatment decreased muscarinic binding in cortex, hippocampus, and striatum. These results indicate that C57BL mice are capable of spatial learning in the water task. The ability of chronic DFP treatment to impair place but not cue learning suggests that the cholinergic dysfunction produced by DFP is similar to those produced by lesions of central cholinergic s [abstract truncated]
Ref: 1987 - Effects of Chronic Diisopropylfluorophosphate Treatment on Spatial Learning in Mice; by Upchurch M, Wehner JM. Report No. NTIS/AD-A188 368/5 from The National Technical Information Service.

Dichlorofluoromethane (CFC-21) - Propellant, EPA List 2 Inert - CAS No. 75-43-4

-- IN HIGH CONCN, IT MAY CAUSE CENTRAL NERVOUS DEPRESSION. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-159]
-- Exposure to 100,000 ppm killed rats and guinea pigs within an hour. Clinical signs included loss of coordination, tremors ... /CNS depression/ and prostration; limited pathologic examination, partly obscured by post-mortem change, revealed lung and liver changes. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 434]
Ref: TOXNET profile from Hazardous Substances Data Base for DICHLOROFLUOROMETHANE

http://www.fluoridealert.org/pesticides/Dichlorofluoromethan.TOXNET.htm

Dichlorodifluoromethane (Freon 12 or CFC 12)- Insecticide, Fungicide Propellant, EPA List 2 Inert - CAS No. 75-71-8

-- Health Hazards - General. ...At high concentrations, Freon vapor may cause pulmonary edema and neurological problems such as central nervous system depression, dizziness, headache, drowsiness, tremors, seizures, confusion, in-coordination, loss of consciousness, and paralysis (Hazardtext, 2003B; Dupont, 1996A; OSHA, 1998; NIOSH, 2003C).
-- Predisposing Conditions. Individuals with pre-existing diseases of the central nervous or cardiovascular system may have increased susceptibility to the effects of Freons (Dupont, 1996A; OSHA, 1998; Dupont, 1996B; Dupont, 1996D). Persons exposed to epinephrine or other sympathomimetic amines, e.g., bronchodilators and nasal decongestants (e.g., Sudafed ), might be at increased risk for the cardiotoxic effects of Freons (Reprotext, 2003).
-- Special Concerns for Children. Children may inhale relatively larger doses of Freon because, relative to their body weight, they have a greater lung surface area and larger minute volume than adults. Since Freon has a high vapor density, children could also receive high doses due to their short stature and the higher levels of Freon vapor that may be present near the ground when Freon is spilled.

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.

Dichlorotetrafluoroethane (CFC-114) - Propellant, Former EPA List 2 Inert - CAS No. 76-14-2

-- SUMMARY TOXICITY STATEMENT: MILD IRRITANT ... /CNS DEPRESSANT/ IN HIGH CONCN. ASPHYXIANT. [Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 567]
-- Chlorinated hydrocarbons may cause systemic toxicity through percutaneous absorption. Systemic toxicity includes convulsion, delirium, and central nervous system depression /From table/. /Chlorinated hydrocarbons/ [Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 160]
Ref: 1,2-DICHLORO-1,1,2,2-TETRAFLUOROETHANE. CASRN: 76-14-2. TOXNET profile from Hazardous Substances Data Base.
http://www.fluorideaction.org/pesticides/dichlorotetrafluoroe.toxnet.htm

Dimefox - Acaricide, Insecticide - CAS No. 115-26-4

Abstract: The neurobehavioral toxicity of three organophosphate pesticides, sumithion, dimefox and trichlorphon, was evaluated in rats using measures of open field activity, rotorod performance, conditioned escape from shock, and nerve conduction velocity. These measures were correlated with blood and brain cholinesterase level determinations. All three chemicals disrupted behavior ranging from transient disruptions accompanied by alterations in nerve conduction to disruption throughout the exposure. Even in the case of prolonged behavioral disruption, however, some recovery of performance occurred. Cholinesterase in both blood and brain decreased with initial dosing and remained low with continued dosing regardless of changes in the behavioral measures. The results are discussed in terms of the necessity of using mammalian behavioral tests to determine the toxicity of organophosphorous compounds in order to safeguard the health of the human population.
Ref: Lehotzky K (1982). Effect of pesticides on central and peripheral nervous system function in rats. Neurobehav Toxicol Teratol. Nov-Dec;4(6):665-9.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7170026&dopt=Abstract

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

Acute neurotoxicity. The NOEL was 2 mg/kg, based on decreases in body weight gain and food consumption in males and females during the week following treatment, decreases in locomotor activity, hind-limb splay and rectal temperature 6-hour post dosing in males and females, and decreases in the proportion of males with an immediate righting reflex on days 7 and 14, at 12 mg/kg/day.
• Subchronic toxicity. The NOAEL in the rat was 3 ppm (0.18 and 0.21 mg/kg/day in males and females, respectively), based on clinical signs of toxicity in both sexes and decreased body weight and body weight gain in males at 10 ppm. The NOEL for the mouse was 0.5 ppm (0.08 mg/kg/day), based on the aggressive and irritable behavior with increased motor activity in males at 2 ppm. The NOEL for the dog was 9.5 ppm (0.29 mg/kg/day), based on behavioral changes in females at 35 ppm (1.05 mg/kg/day).
Subchronic neurotoxicity study in rats, the NOEL was 5 ppm (0.301 and 0.351 mg/kg/day for males and females, respectively), based on results of the functional observational battery (FOB) at 150 ppm (8.89 and 10.8 mg/kg/day for males and females, respectively).
Chronic toxicity. The NOAEL for systemic toxicity in a 1-year feeding study in the dog was 0.3 mg/kg/day in females and 1 mg/kg/day in males, based on clinical signs of neurotoxicity at 1 and 2 mg/kg/day in females and males, respectively.
In a developmental neurotoxicity study in the rat, the NOAEL for maternal toxicity was 10 ppm (0.91 mg/kg/day), based on decreased body weights and body weight gain at 200 ppm (HDT; 15 mg/kg/day). Considerable maternal toxicity at the HDT prevented adequate neurotoxicity evaluation of pups at this dose level. There was no evidence of neurotoxicity at 10 ppm (0.91 mg/kg/day), which was the NOAEL for developmental neurotoxicity.
Ref: August 24, 2005. Federal Register. Fipronil; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html

(pages 127-128) - Diagnosis of poisoning. The applicant [Aventis] submits the following proposal (shown by italic text). (The ACP advised that some amendments should be made, these are indicated by struckthrough/bold font for deleted/new text respectively).

Fipronil is a reversible gamma-aminobutyric acid (GABA) receptor inhibitor. During intoxication, it will induce neurological stimulation with possible convulsions. Signs and symptoms which appear the most relevant for humans may be observed after acute or repeated over-exposure. These signs mainly consist of central nervous system (CNS) hyperexcitability: over-activity, irritability, tremors, and, at a more severe state, lethargy or convulsions. These symptoms are reversible after termination of exposure.
In the rat, clear signs of toxicity were observed following a single oral administation of fipronil at a dose of 50 mg/kg/body weight while minimal symptoms were observed at 5 mg/kg bodyweight. Due to slow absorption through the gut, symptoms of intoxication may be delayed for several hours to one day. Fipronil does not readily penetrate skin. Therefore absorption should be minimal following dermal exposure. Symptoms are expected only after repeated excessive exposure.
Measurement of fipronil and its metabolites in the blood (or in the gastric lavage) is the only way to definitively confirm exposure. In cases of suspected intoxication evidenced by symptoms, a blood sample should be taken as soon after the alleged exposure as possible and may be sent to:
Aventis Rhone-Poulenc Agro
Toxicology Department
Centre de Recherche
355, Rue Dostoievski
B.P. 153
F-06903 Sophia Antipolis Cedex
FRANCE
Attention: Dr Pierre-Gerard Pontal
Ref: April 204. Evaluation on : Fipronil (Horticultural Uses). No. 212. UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf

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

Human Toxicity Excerpts: SYMPTOMATOLOGY INDICATES OVERDOSING MAY PRODUCE /CNS DEPRESSION/ AND OTHER GENERAL CNS INVOLVEMENT. [Weed Science Society of America. Herbicide Handbook. 5th ed. Champaign, Illinois: Weed Science Society of America, 1983. 238]
Ref: Hazardous Substance Data Bank for FLUCHLORALIN CASRN: 33245-39-5 from Toxnet.

Abstract. Male Swiss mice, 25-30 g, were utilized to define some of the behavioral effects of the herbicides Lasso [alachlor 43%; (A)], Basalin [fluchloralin 45%; (F)], Premerge 3 [dinoseb 51%; (D)], and the fungicide Maneb-80 [maneb 80%; (M)]. These compounds were tested for their effects on locomotor activity and for their ability to establish a conditioned taste aversion following oral or dermal exposure. Individual and grouped (N = 5) activity measures were assessed immediately following the dermal administration of the commercially available pesticide formulations. Grouped activity measures were also assessed following the oral administration of the compounds. Total activity was significantly (p less than 0.05) increased over vehicle controls in both grouped and individual subjects by A, F, and D following dermal administration. Grouped activity measures were also increased by A, F, D, and M following the oral administration of the compounds...
Ref: The behavioral effects of pesticides in male mice; by Mitchell JA, Long SF, Wilson MC, Kallman MJ. Neurotoxicol Teratol 1989 Jan-Feb;11(1):45-50.

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.

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

EPILEPTIFORM CONVULSIONS ALTERNATE WITH COMA & DEPRESSION; DEATH MAY RESULT FROM ASPHYXIA DURING CONVULSION OR FROM RESP FAILURE. MOST PROMINENT FEATURES ... ARE CARDIAC IRREGULARITIES, NOTABLY VENTRICULAR FIBRILLATION & SUDDEN CARDIAC ARREST. [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983. 895]
-- Moderately fast-acting rodenticide which is less likely to lead to poison shyness because of sublethal dosing. It acts chiefly on the heart, with secondary effects on CNS. [Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994. 492]
-- Mechanism of Action: FLUOROACETATE PRODUCES ITS TOXIC ACTION BY INHIBITING THE CITRIC ACID CYCLE. THE FLUORINE SUBSTITUTED ACETATE BECOMES INCORPORATED, AS A NORMAL ACETATE, INTO FLUOROACETYL COENZYME A, WHICH CONDENSES WITH OXALOACETATE TO FORM FLUOROCITRATE. FLUOROCITRATE INHIBITS THE ENZYME ACONITASE & THEREBY INHIBITS THE CONVERSION OF CITRATE TO ISOCITRATE. AS A RESULT THERE IS AN ACCUMULATION OF LARGE QUANTITIES OF CITRATE IN THE TISSUE, & THE CYCLE IS BLOCKED. ... THE HEART & CNS ARE THE MOST CRITICAL TISSUES INVOLVED IN POISONING BY GENERAL INHIBITION OF OXIDATIVE ENERGY METABOLISM. /FLUOROACETATE/
[Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 565]
Ref: FLUOROACETAMIDE CASRN: 640-19-7. Hazardous Substances Data Bank.
http://www.fluorideaction.org/pesticides/fluoroacetamide.hsdb.htm

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

-- ACUTE TOXICITY. ... It may be fatal if inhaled, swallowed, or absorbed through skin, as it is irritating to the mucous membrane lining the skin, gastrointestinal tract, and respiratory system (2). While there have been no reports of cases of fluometuron poisoning in humans, this herbicide is considered a mild inhibitor of cholinesterase. Cholinesterase is an essential enzyme of the nervous system. Cholinesterase inhibition was observed in guinea pigs exposed by inhalation to 588 mg/m3 for 2 hours (18)... Fluometuron caused an increased white blood cell count in agricultural workers (3).
Ref: Flumeturon. EXTOXNET. Pesticide Information Profile. March 1994.

http://pmep.cce.cornell.edu/profiles/extoxnet/dienochlor-glyphosate/fluometuron-ext.html

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

Human Toxicity Excerpts: ... /MAJOR EFFECTS/ INVOLVE CNS & CARDIOVASCULAR SYSTEM. SEVERE EPILEPTIFORM CONVULSIONS ALTERNATE WITH COMA & DEPRESSION; DEATH MAY RESULT FROM ASPHYXIA DURING CONVULSION OR FROM RESP FAILURE. MOST PROMINENT FEATURES ... ARE CARDIAC IRREGULARITIES, NOTABLY VENTRICULAR FIBRILLATION & SUDDEN CARDIAC ARREST.
[International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I
&II. Geneva, Switzerland: International Labour Office, 1983. 895]
Ref: TOXNET profile from Hazardous Substances Data Bank.

http://www.fluoridealert.org/pesticides/Fluoroacetic.Acid.TOXNET.htm

Gliftor - Rodenticide - Rodenticide - CAS No. 8065-71-2

Abstract. Acute poisoning with gliftor, a pesticide composed of 30% glycerol chlorofluorohydrin and 70% glycerol difluorohydrin, was studied in three tractor drivers who, mistaking it for alcohol, ingested 30 ml each of this liquid. Motor disorders comprising complex chloreiform hyperkinesis (Kulenkampff-Tarnow syndrome) due to lesions in the cortical and subcortical structures of the corpus striatum and of the limbicoreticular portion of the brain, were the principal poisoning symptoms. There were no symptoms of fluorine poisoning. One patient, who presented the first symptoms 48 hr after ingestion of the poison, died in respiratory collapse 6 days later. Leukocytosis (up to 20% rod neutrophilis) hyperglycemia, a serum potassium level of 2.7 mEq/liter, proteinuria, pyuria, and hematuria were observed. Histopathological examination revealed acute circulatory disturbances in the internal organs, parenchymatous dystrophy, and dystrophic changes in the central nervous system.
Ref: Three cases of gliftor poisoning; by Kovalenko LI, Bulkina VA, Panteleev RI. Gig. Tr. Prof. Zabol. (12): 53-54; 1975. [Abstract from Toxline at Toxnet.]

Abstract. Under conditions of the acute inhalation effect of the vapors of gliftor (I) the LD50 for rats was 580 plus or minus 65 and for mice 1260 plus or minus 15 mg/m-3. The threshold concentration (TC) for rats with respect to brief disturbance of the functional state of the CNS was 50 and the subthreshold 10 mg/m-3; for mice the TC was 190 mg/m-3. Chronic (4 mo.) inhalation by rats of I in a concentration of 110 and 64 mg/m-3 disturbed the functional state of the CNS and antitoxic and protein-forming functions of the liver and reduced oxidation-reduction processes. I in a concentration of 1.0 mg/m-3 increased the concent of eosinophils and reduced the number of lymphocytes by the end of the poisoning period. I is a hazardous compound. A maximum allowable concentration of I of 0.05 mg/m-3 in the air of production shops is recommended for worker exposure.
Ref: Effect of gliftor on certain metabolic processes of experimental animals under inhalation poisoning conditions; by TKACH NZ, KNYSH VS, MILOVANOVA VI, SHISHKOVA NK, SLEPOVA LI. TR INST KRAEV PATOL AKAD NAUK KAZ SSR; 22 1971 5-12. [Abstract from Toxline at Toxnet.]

Indoxacarb - Insecticide - CAS No. 173584-44-6

52425-040 162205 "Oncogenicity Study with DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127) Eighteen-Month Feeding Study in Mice" (Frame, S. 832-E. I. du Pont de Nemours and Company, Haskell Laboratory, Elkton Road, Newark, Delaware, Study HLR 799-96, 3/24/97). DPX-JW062-106 technical (Batch DPX-JW062-106, approximately 48% DPX-KN128) was given in the diet daily to 70 Crl:CD -1(ICR)BR mice/sex/dose at 0, 20, 100, or 125/150/200 ppm for 18 months (200 ppm level reduced to 150 ppm on day 126 and to 125 ppm on day 287 due to excessive mortality). The cause of death was either central nervous system disorder (determined from clinical signs of abnormal gait/mobility and head tilt) or heart inflammation/ necrosis (males only). Non-neoplastic changes were noted in the brain of both sexes and in the heart of males only of mice that died or were sacrificed in extremis. Neuronal necrosis was reported in two high-dose males and two females and in one female at 100 ppm. Both high-dose males were sacrificed in extremis, one while receiving the 150 ppm diet (day 133) and the other while receiving the 125 ppm diet (test day 302). The two affected females died or were killed in extremis (day 83 and 108, respectively) while receiving 200 ppm. Residual vacuolation of the piriform cortex was observed in 2 female high-dose mice that survived to the 18-month scheduled sacrifice.
Ref:
March 11, 1999: Summary of Toxicology Data - Indoxycarb. California EPA Department of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf

Neurotoxicity was present in both rats and mice; however, it did not occur in the absence of other signs of toxicity. Neurotoxicity was characterized by one or more of the following symptoms in both male and female rats and mice: weakness, head tilting, and abnormal gait or mobility with inability to stand, ataxia. Acute and subchronic neurotoxicity screening batteries were performed using DPX-MP062 in rats. Neurotoxicity was characterized by clinical signs (depression, abnormal gait, head shake, salivation) and functional-observation battery (FOB) (circling behavior, incoordination, slow righting reflex, decreased forelimb grip strength, decreased foot splay, decreased motor activity). However, there was no evidence of neurohistopathology in any study. Learning and memory parameters were affected in the pups in the developmental neurotoxicity study in rats with DPX-KN128.
Ref: USEPA. May 23, 2007. Indoxacarb. Health Effects Division (HED) Risk Assessment for Grapes; Vegetable, Brassica, Leafy, Group 5; Turnip Greens; Vegetable, Leafy, Except Brassica (Group 4); Pome Fruits (Group 11, except pear); Tuberous and Corm Vegetables (Subgroup 1C); Cucurbit Vegetables (Group 9); Stone Fruits (Group 12); Cranberry; Mint; Okra; Southern Pea; and Fire Ant Bait.
http://www.fluoridealert.org/pesticides/EPA-HQ-OPP-2005-0149-0005.pdf

Methanesulfonyl fluoride - Fumigant, Insecticide - CAS No. 558-25-8

Range of Toxicity:
-- Minimum lethal human exposure is unknown. In rats exposed by inhalation to a concentration of 2.2 ppm for 1 hour, only minimal salivation was seen; at 5 ppm for the same duration, copious salivation, eye and nose exudates, diarrhea, depression, ataxia, and tremors were observed.
-- Only subclinical alterations of blood glucose, serum creatinine, total bilirubin, a
nd depression of acetylcholinesterase were noted in rats exposed by inhalation to 19 or 91 ppb of methanesulfonyl fluoride for 61 exposures, each lasting 7 hours.
-- ACUTE EXPOSURE. Methanesulfonyl fluoride is an irreversible inhibitor of acetylcholinesterase in vitro. It also inhibits butyrylcholinesterase and trypsinogen in vitro.
-- NEUROLOGIC. ACUTE EXPOSURE. Symptoms noted in experimental animals included CNS depression, tremors, ataxia, and convulsions. ANTICHOLINESTERASE COMPOUNDS can affect the CENTRAL NERVOUS SYSTEM, producing restlessness, anxiety, headaches, convulsions, and coma.
Ref: TOXNET profile from Hazardous Substances Data Base.

http://www.fluoridealert.org/pesticides/Methanesulfonyl.fluo.TOXNET.htm

Mipafox - Acaricide, Insecticide - CAS No. 371-86-8

There are seversal abstracts on this effect - see
http://www.fluorideaction.org/pesticides/mipafox.pubmed.htm

CHOLINESTERASE INHIBITOR. [The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 889]
Ref: TOXNET profile for Mipafox from Hazardous Substances Data Base.
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Abstract: Chick embryo dorsal root ganglia (DRG) cultures were used to explore early pathological events associated with exposure to neuropathy-inducing organophosphorus (OP) compounds. This approach used an in vitro neuronal system from the species that provides the animal model for OP-induced delayed neuropathy (OPIDN). DRG were obtained from 9-day-old chick embryos, and grown for 14 days in minimal essential medium (MEM) supplemented with bovine and human placental sera and growth factors. Cultures were then exposed to 1 microM of the OP compounds phenyl saligenin phosphate (PSP) or mipafox, which readily elicit OPIDN in hens, paraoxon, which does not cause OPIDN, or the DMSO vehicle. The medium containing these toxicants was removed after 12 h, and cultures maintained for 4-7 days post-exposure. Morphometric analysis of neurites was performed by inverted microscopy, which demonstrated that neurites of cells treated with mipafox or PSP but not with paraoxon had decreased length-to-diameter ratios at day 4 post-exposure. Ultrastructural alterations of neurons treated with PSP and mipafox included dissolution of microtubules and neurofilaments and degrading mitochondria. Paraoxon-treated and DMSO control neuronal cell cultures did not show such evident ultrastructural changes. This study demonstrates that chick DRG show pathological changes following exposure to neuropathy-inducing OP compounds.
Ref: Morphological effects of neuropathy-inducing organophosphorus compounds in primary dorsal root ganglia cell cultures; by Massicotte C, Jortner BS, Ehrich M. Neurotoxicology. 2003 Dec;24(6):787-96.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14637373

Abstract: Short term clinical and neuropathological effects induced by tri-ortho-tolyl-phosphate (78308) (TOTP), diisopropyl-fluorophosphate (55914) (DFP), phenyl-saligenin-phosphate (4081236) (PSP), mipafox (371868), malathion (121755), dichlorvos (62737), and carbaryl (63252) were studied in rats. Male Long-Evans-rats were administered 300 to 1000mg/kg TOTP or 300 to 2000mg/kg malathion orally, injected intramuscularly with 5 to 24mg/kg PSP, injected subcutaneously with 1 to 3mg/kg DFP, or injected intraperitoneally with 3 to 30mg/kg mipafox or dichlorvos or 30 to 160mg/kg carbaryl. The rats were also treated with atropine-sulfate to protect against cholinergic symptoms. Selected rats were killed 4 hours after DFP, PSP, mipafox, dichlorvos, and carbaryl or 48 hours after TOTP and malathion and the brains and spinal cords were removed and assayed for acetylcholinesterase (AChE) and neurotoxic-esterase (NTE) activity. The remaining rats were weighed and evaluated on a functional observational battery (FOB) that measured motor activity and responses to being handled or approached 1, 7, 14, and 21 days after dosing. The rats were then killed and the brains, spinal cords, and tibial nerve branches leading to the gastrocnemius muscle were examined for histopathological changes. The highest doses of all compounds except PSP induced transient cholinergic symptoms and caused 8.3 to 61% mortality within 48 hours. The highest doses of TOTP, DFP, and malathion significantly decreased body weight after 14 days. All compounds caused dose related inhibitions of brain and spinal cord AChE and NTE activity. DFP was the most potent and PSP the least potent. All compounds induced significant changes in FOB parameters related to behavioral and central nervous system excitability 21 days after dosing. Mipafox, PSP, dichlorvos, and carbaryl induced these changes 1 day after dosing. TOTP, DFP, PSP, and mipafox caused mild to moderate myelinated fiber degeneration in the rostral fasciculus gracilis 21 days after dosing. Mipafox was the most potent. DFP also induced Wallerian like degeneration in the tibial nerve branches. Dichlorvos, malathion, and carbaryl did not cause any neurological changes. The authors conclude that some cholinesterase inhibitors cause behavioral changes even after cholinergic signs are no longer evident.
Ref: Short-Term Clinical and Neuropathologic Effects of Cholinesterase Inhibitors in Rats; by Ehrich M, Shell L, Rozum M, Jortner BS. Journal of the American College of Toxicology, Vol. 12, No. 1, pages 55-68, 1993.

Abstract: Various structurally unrelated chemicals [2,5 hexandione, acrylamide, organophosphates like mipafox, beta,beta iminodipropionnitrile (IDPN), 3-nitropropionic acid (3-NP), potassium cyanide (KCN), paraquat, and NMDA (N-methyl-D-apartic acid)] are known to cause degenerative damage of the peripheral or central nervous system. Differentiated neuronal cell cultures obtained from fetal rats have been used to differentiate the mechanisms underlying this type of neurotoxicity. Cytotoxicity as measured by a viability assay was not sensitive enough and had to be supplemented by further endpoints covering effects on cytoskeleton and on the energy state of the cells [glucose consumption, mitochondrial membrane potential and adenosine 5'-triphosphate (ATP) concentration]. Compounds like the delayed neurotoxic organophosphates, exert a selective direct effect on cytoskeleton elements in this model at concentrations distinctly below cytotoxic concentrations. Other compounds, like KCN, paraquat, and 3-NP selectively disrupt the balance between energy supply and demand of the neurons either by interacting with mitochondrial respiration or glycolysis. For these compounds cytoskeletal damage seemed to be secondary to the energy depletion. For NMDA, 2,5 hexandione and acrylamide, both mechanisms may contribute to the neuronal damage. In conclusion, primary cortical neuronal cultures of the rat are well suited to detect a neurotoxic potential and to differentiate its underlying mechanisms. Damage of the cytoskeleton may be considered as an endpoint mechanistically related to degenerative neuropathic effects.
Ref: Schmuck G et al. (2000). Rat cortical neuron cultures: an in vitro model for differentiating mechanisms of chemically induced neurotoxicity. In Vitr Mol Toxicol; Spring;13(1):37-50.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10900406&dopt=Abstract

Abstract: This study compares two direct-acting neuropathy target esterase (NTE) inhibitors (mipafox and 2-octyl-4H-1,3,2-benzodioxophosphorin 2-oxide (OBDPO)), a metabolic precursor to an NTE inhibitor (tri-o-cresyl phosphate or TOCP) and a potent acetylcholinesterase inhibitor (chlorpyrifos oxon or CPO) for their effects on outgrowth of neurite-like and cell processes and on viability in differentiated cultured cells (rat adrenal pheochromocytoma (PC-12) and brain glial tumor (C6)). The direct-acting NTE inhibitors block process outgrowth by 50% or more at 50-100 microM for OBDPO and 100-200 microM for mipafox, well below their cytotoxic levels (EC50 values, 445-474 microM for OBDPO and 1021-1613 microM for mipafox). In contrast, the effects on process development for TOCP and CPO parallel their cytotoxicity. These findings suggest that inhibition of neurite-like and cell process outgrowth by OBDPO and mipafox may be associated with NTE inhibition.
Ref: Li W et al. (2000). Organophosphorus neuropathy target esterase inhibitors selectively block outgrowth of neurite-like and cell processes in cultured cells. Toxicol Lett; Sep 15;98(3):139-46

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9788582&dopt=Abstract

Novaluron - Insecticide, Insect growth regulator - CAS No. 116714-46-6

52846-001; 174426; "'Rimon' Technical: Neurotoxicity Study by a Single Oral Gavage Administration to CD Rats Followed by a 14-Day Observation Period"; (A. Broadmeadow, W.D. Harvey and M.J. Collier; Huntingdon Life Sciences Ltd, Huntingdon, Cambridgeshire, PE18 6ES, England; Report No. MAK 480/983207; 2/3/99); Ten CD rats/sex/group were dosed orally by gavage with 0, 200, 650 or 2000 mg/kg of Rimon Technical (Novaluron Technical) (batch no. 970211/4; purity: 99.3%). The animals were examined in the functional observational battery (FOB) and motor activity assessments prior to dosing, on day 1 (at one hour post-dose) and on days 8 and 15. Five animals/sex/group in the control and high dose group were chosen for histological evaluation of the nervous system and muscle. No mortality resulted from the treatment. The incidence of the clinical signs, piloerection and irregular or fast breathing occurred in a dose-related manner for all of the treatment groups between days 3 and 5 post-dose. Among the parameters evaluated in the FOB and the motor activity measurements, only the forelimb grip strength was apparently affected by the treatment. The mean forelimb grip strength of the 2000 mg/kg males was less than that of the control animals at 1 hour post-dose (p<0.05). There was an increased incidence of degenerated fibers (minimal) in the peripheral nerves of the high dose group (M: (0) 0/5 vs. (2000) 2/5, F: (0) 1/5 vs. (2000) 3/5). Possible adverse effect: increased incidence of degenerated fibers in the peripheral nerves. The study data were insufficient to establish a NOEL for neurotoxicity. Acute NOEL: < 200 mg/kg (based upon the incidence of clinical signs in the 200 mg/kg group). Study unacceptable, possibly upgradeable to acceptable with the submission of histopathology data for the 200 and 650 mg/kg treatment groups. (Moore, 11/2/00)
Ref: 2001. Summary of Toxicology Data for Novaluron. California Environmental Protection Agency, Department of Pesticide Regulation, Medical Toxicology Branch. Chemical Code # 5754, Tolerance # 52846 3/23/01.
http://www.fluoridealert.org/pesticides/Novaluron.CAepa.ToxTst.2001.pdf

Potassium fluorosilicate - Insecticide, Wood Preservative - CAS No. 16871-90-2

LD50 ranges of sodium, potassium, or ammonium fluorosilicates administered intragastrically in rats and mice were 89-128 and 45-64 mg fluoride ion/kg, respectively. Severe cornea damage was observed 3 hr after the administration of 50 mg of any of the salts into rabbits' eyes. Min toxic dose (intragastric) of fluorosilicic acid in rats was 8 mg/kg. Min toxic concn in 4 hr inhalation of the salt aerosols were 7.4-9.6 mg/cu m; nontoxic concn was 0.8 mg/cu m. Main toxic effects were decreased activities of cholinesterase and lactate dehydrogenase in blood serum. The intragastric effects of the fluorosilicates were similar to and additive with those of sodium fluoride. [Rumyantser GI et al; Oig Sanit (11): 80-2 (1988)]
Ref: TOXNET profile from Hazardous Substances Data Bank for AMMONIUM SILICOFLUORIDE.
http://www.fluoridealert.org/pesticides/Ammonium.Silicofluor.TOXNET.htm

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

Abstract: In an attempt to elucidate the mechanism by which excessive fluoride damages the central nervous system, the effects of exposure of PC12 cells to different concentrations of fluoride for 48 h on nicotinic acetylcholine receptors (nAChRs) were characterized here. Significant reductions in the number of binding sites for both [3H]epibatidine and [125I]alpha-bungarotoxin, as well as a significant decrease in the B(max) value for the high-affinity of epibatidine binding site were observed in PC12 cells subjected to high levels of fluoride. On the protein level, the alpha3 and alpha7 subunits of nAChRs were also significantly decreased in the cells exposed to high concentrations of fluoride. In contrast, such exposure had no significant effect on the level of the beta2 subunit. These findings suggest that selective decreases in the number of nAChRs may play an important role in the mechanism(s) by which fluoride causes dysfunction of the central nervous system.
Ref: Toxicology 2003 Feb 1;183(1-3):235-42. Selective decreases of nicotinic acetylcholine receptors in PC12 cells exposed to fluoride by Chen J, Shan KR, Long YG, Wang YN, Nordberg A, Guan ZZ.

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

Effects of Short-Term Exposure: The substance may cause effects on the cardiovascular system and central nervous system, resulting in cardiac disorders and respiratory failure. Exposure may result in death.
Ref: IPSCS INCHEM. ICSC: 0484. Date of Peer Review: April 1997. Prepared in the context of cooperation between the International Programme on Chemical Safety (IPCS) and the Commission of the European Communities.
http://www.inchem.org/documents/icsc/icsc/eics0484.htm

Abstract: A TLV-TWA of 0.05 mg/m3 is recommended for occupational exposure to highly toxic sodium fluoroacetate. This value is intended to minimize the potential for progressive central nervous system and cardiovascular system effects. These may include nausea, womiting, apprehension, nystagmus, facial twitching, and convulsions that are usually followed or accompanied by tachycardia, ventricular fibrillation, and death due to cardiac failure or respiratory arrest. Rapid absorption through intact and abraded or cut skin warrants a Skin notation. Sublethal sodium fluoroacetate is reported to cause changes in testicular morphology in exposed rodents. Sufficient data were not available to recommend SEN or carcinogenicity notations or a TLV-STEL.
Ref: Anon (2001). Sodium Fluoroacetate. TA:ACGIH. Documentation of the threshold limit values and biological exposure indices PG:4 p YR:2001 IP: VI:7th Ed

Abstract: IPA COPYRIGHT: ASHP A case is described of poisoning in a boy who ingested wheat previously impregnated with 1080 (sodium fluoroacetate) to poison rabbits. The product causes vomiting, convulsions, coma, respiratory depression and cardiac irregularities. The boy was treated for convulsions with I.V. thiopentone sodium and diazepam. He was resuscitated from cardiac arrest but was left with severe neurological impairment. 1080 is a widely used agricultural poison with cardiotoxic and neurotoxic effects and stingent precautions exist to control its use.
Ref: McTaggart DR (1970). Poisoning due to sodium fluoroacetate (1080). Med. J. Aust.; VOL 2 ISS Oct 3 1970, P641-642,

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

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.

"Sulphuryl fluoride induces CNS depression."
Ref: Pesticide Policies in Zimbabwe. Status and Implications for Change. Godfrey D. Mudimu Hermann Waibel Gerd Fleischer (eds). A Publication of the Pesticide Policy Project Hannover, September 1999 Special Issue Publication Series, No. 1.

http://www.ifgb.uni-hannover.de/ppp/ppp_s01.pdf

A review of unpublished reports of animal experiments apparently ... /indicated/ that dosages sufficient to produce illness from a single exposure produce respiratory irritation, CNS depression, and possible liver and kidney injury. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. 564]
Ref: Hazardous Substances Data Bank for SULFURYL FLUORIDE CASRN: 2699-79-8.
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

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.

http://www.epa.gov/tri/frnotices/59fr1788.htm

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

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

3.2.5.1.2 Rabbit. In an adequately conducted teratology study, pregnant Himalayan rabbits (15/group) were administered transfluthrin (94% purity) in 0.5% (v/v) aqueous Cremophor EM emulsion by gavage at doses of 0, 15, 50 and 150 mg kg d during days of 6-18 of gestation. Control animals received vehicle alone... Dams were necropsied on day 29 of gestation following delivery of the foetuses by caesarean section. Two deaths occurred, one on day 18 at 50 mg kg d and one on day 19 at 150 mg kg d. Immediately prior to death both animals displayed symptoms consistent with CNS involvement inclusing spasms, severe tremor and prostration (animals found lying on their side). Autopsy of these animals revealed an enlarged lobulated liver and pale lobulated lungs at 50 mg kg d whereas no pathological fingings were observed at 150 mg kg d.
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.

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

-- Health Hazards - General. ...At high concentrations, Freon vapor may cause pulmonary edema and neurological problems such as central nervous system depression, dizziness, headache, drowsiness, tremors, seizures, confusion, in-coordination, loss of consciousness, and paralysis (Hazardtext, 2003B; Dupont, 1996A; OSHA, 1998; NIOSH, 2003C).
-- 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).
-- Predisposing Conditions. Individuals with pre-existing diseases of the central nervous or cardiovascular system may have increased susceptibility to the effects of Freons (Dupont, 1996A; OSHA, 1998; Dupont, 1996B; Dupont, 1996D). Persons exposed to epinephrine or other sympathomimetic amines, e.g., bronchodilators and nasal decongestants (e.g., Sudafed ), might be at increased risk for the cardiotoxic effects of Freons (Reprotext, 2003).
-- Special Concerns for Children. Children may inhale relatively larger doses of Freon because, relative to their body weight, they have a greater lung surface area and larger minute volume than adults. Since Freon has a high vapor density, children could also receive high doses due to their short stature and the higher levels of Freon vapor that may be present near the ground when Freon is spilled.

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.

-- MAY BE /CENTRAL NERVOUS SYSTEM DEPRESSANT/ ... IN HIGH CONCN. [Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1517]
-- Workers ... /involved in a spill of/ large volume of CFC-11 were exposed to high concentrations and developed /CNS depressant/ effects. In one case, unconsciousness occurred, and in another, potentiation of the endogenous adrenaline effect and tachycardia. [WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons p.93 (1990)]
-- Freons are toxic to humans by several mechanisms. Inhaled fluorocarbons sensitized the myocardium to catecholamines, frequently resulting in lethal ventricular arrhythmias. Because they are gases heavier than air, fluorocarbons can displace atmospheric oxygen, thus resulting in asphyxiation. These compounds also have a central nervous system (CNS) anesthetic effect analogous to a structurally similar general anesthetic, halothane. Pressurized refrigerant or liquid fluorocarbons with a low boiling point have a cyrogenic effect on exposed tissues, causing frostbite, laryngeal or pulmonary edema, and gastrointestinal perforation. Certain fluorocarbons degrade at high temperatures into toxic products of chlorine, hydrofluoric acid, or phosgene gases. /Freons/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. 1281]
-- Non-occupational exposure and accidental or abusive inhalation of aerosols /due to Fluorocarbon propellants/ have also been documented, the main symptoms being CNS depression and cardiovascular reactions.
Cardiac arrhythmia, possibly aggravated by elevated levels of catecholamines due to stress or by moderate hypercapnia, is suggested as the cause of these adverse response, which may lead to death. /Aerosols/ [WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons p.20 (1990)]
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

-- Human Toxicity Values: TCLO HUMAN INHALATION 4500 PPM; TOXIC EFFECT: CNS EFFECTS [Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1458]
-- Animal Toxicity Studies: Non-Human Toxicity Excerpts: THE CHIEF EFFECTS OF EXPOSURE TO ... /TRICHLOROTRIFLUOROETHANE/ ARE DEPRESSION OF THE CENTRAL NERVOUS SYSTEM AND IRRITATION OF THE RESPIRATORY TRACT. SUCH EFFECTS OCCUR IN ANIMALS AT CONCENTRATIONS ABOVE 12000 PPM. MILD LIVER CHANGES HAVE BEEN NOTICED AT LEVELS SOMEWHAT BELOW THIS. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979)267]
-- Psychomotor performance was evaluated using CFC-113 at concentrations of 0.15% (12 g/cu m), 0.25% (19 g/cu m), 0.35% (27 g/cu m) or 0.45% (35 g/cu m) for 165 min. There was no effect at the lowest concentration, but there was difficulty in mental concentration and some decrease in test scores beginning at 0.35% (27 g/cu m). [WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons p.19 (1990)]
-- GUINEA PIGS EXPOSED ... FOR PERIODS OF 5 MINUTES TO 2 HOURS SHOWED INCREASING SIGNS OF IRRITATION AND /CNS DEPRESSION/; NASAL IRRITATION WAS APPARENT IN 5 MINUTES AT 25000 PPM, AND LOSS OF COORDINATION AT 50000 PPM AFTER 30 MINUTES; DEATHS OCCURRED AFTER 1 HOUR AT THIS LEVEL. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979)267]

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

-- Health Hazards - General. ...At high concentrations, Freon vapor may cause pulmonary edema and neurological problems such as central nervous system depression, dizziness, headache, drowsiness, tremors, seizures, confusion, in-coordination, loss of consciousness, and paralysis (Hazardtext, 2003B; Dupont, 1996A; OSHA, 1998; NIOSH, 2003C).
-- Predisposing Conditions. Individuals with pre-existing diseases of the central nervous or cardiovascular system may have increased susceptibility to the effects of Freons (Dupont, 1996A; OSHA, 1998; Dupont, 1996B; Dupont, 1996D). Persons exposed to epinephrine or other sympathomimetic amines, e.g., bronchodilators and nasal decongestants (e.g., Sudafed ), might be at increased risk for the cardiotoxic effects of Freons (Reprotext, 2003).
-- Special Concerns for Children. Children may inhale relatively larger doses of Freon because, relative to their body weight, they have a greater lung surface area and larger minute volume than adults. Since Freon has a high vapor density, children could also receive high doses due to their short stature and the higher levels of Freon vapor that may be present near the ground when Freon is spilled.

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.

Trifloxysulfuron-sodium - Herbicide - CAS No. 199119-58-9

Note from FAN: We are including this under CNS even though no information was presented to clarify the lesions.

Acute dietary (general population) NOAEL = 600 mg/kg UF = 100. Acute RfD =6.0 mg/kg... Special FQPA SF = 1 aPAD = acute RfD/Special FQPA SF = 6.0 mg/kg. Acute Neurotoxicity Studies in Rats. LOAEL = 2,000 mg/kg based on decreased motor activity on day 1 and histopathological lesions in nervous system tissues of males and females.
Ref: Federal Register: September 17, 2003 (Volume 68, Number 180)] Rules and Regulations. Trifloxysulfuron; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/trifloxysulfuron.fr.sept.03.htm

 
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