Heart - Adverse Effects
Fluorinated and Fluoride Pesticides
 
 

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.
-- Ingestion: May cause salivation, nausea, vomiting, diarrhea, and abdominal pain, followed by symptoms of weakness, tremors, shallow respiration, carpopedal spasm, convulsions, and coma. May cause brain and kidney damage. Affects heart and circulatory system. Death may be caused by respiratory paralysis. Lethal dose estimated at between 1 teaspoonful and 1 oz.
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.
Chronic Exposure: Chronic exposure may cause mottling of teeth and bone damage (osteosclerosis) and fluorosis. Symptoms of fluorisis include brittle bones, weight loss, anemia, calcified ligaments, general ill health and joint stiffness.
Ref: 1999 Material Safety Data Sheet prepared by Mallinckrodt Baker, Inc.
http://www.fluoridealert.org/pesticides/Ammonium.F.MSDS.htm

-- INHALATION - May cause severe throat irritation, cough, dyspnea, cyanosis, lung injury and noncardiogenic pulmonary edema.
-- RESPIRATORY. ACUTE EXPOSURE. Dyspnea, bronchospasm (with abnormal PFTs and hypoxia), chemical pneumonitis, pulmonary edema (can be hemorrhagic), tracheobronchitis, upper airway obstruction, chemical burns (larynx, trachea, bronchi) and ARDS may occur following inhalation.
Ref: TOXNET profile from Hazardous Substances Data Bank for Ammonium fluoride.
http://www.fluoridealert.org/pesticides/Ammonium.fluoride.TOXNET.htm

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

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.
Ref: Material Safety Data Sheet for Freon 22. DuPont. 1996.

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

PubMed abstract: Case report of a plumber's fatal work accident. Investigations on the causes of death made at post mortem showed that the worker had absorbed a large quantity of freon 22 (chlorodifluoromethane) which is known to be a narcotic agent and capable of inducing cardiac arrhythmia. It is believed freon inhalation was the cause of loss of consciousness with consequent death from drowning in the water issuing from the pipes. It is concluded that preventive measures need to be reinforced by adequate information to the workforce on the risks connected to this type of gas.
Ref: Med Lav 1992 Jul-Aug;83(4):361-4. [Sudden death caused by freon 22?]. [Article in Italian]; by M Dal Grande et al.

PubMed Abstract: After exposure to decomposed chlorodifluoromethane (freon-22), a 65-year-old man developed respiratory symptoms such as cough, blood-stained sputum, and increasing dyspnea. Three weeks later, his family doctor diagnosed infectious bronchitis. Another week later he died due to myocardial infarction. The discussion focuses on an inflammatory process caused by the inhalation of decomposed freon and its possible association with myocardial infarction.
Ref: Scand J Work Environ Health 2002 Jun;28(3):205-7, Inhalation of decomposed chlorodifluoromethane (freon-22) and myocardial infarction; by
Sjogren B, Gunnare S, Sandler H.

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

Organophosphate esters were studied in terms of their ability to affect neuropeptides in the rat central nervous system. The in vivo biosynthesis of enkephalin peptides in the basal ganglia and of vasopressin and oxytocin in the hypothalamus were studied and the effect of subcutaneous administration of diisopropylfluorophosphate (DFP) in the biosynthesis of these neuropeptides was assessed. It was found that DFP inhibited the biosynthesis of vasopressin and oxytocin. These results suggest that organophosphates exert their effects not only on cholinergic systems but also on neuropeptide systems important in endocrine and cardiovascular function. Annual rept. 1983-1984, {abstgract truncated]
Ref: 1986 - Effects of Organophosphate Esters on Neuropeptide Systems; by McKelvy JF. Report No. NTIS/AD-A186 594/8 from The National Technical Informatin Service.

1,1-Difluoroethane - Propellent, EPA List 2 Inert - CAS No. 75-37-6

Freon 152A ... causes sensitization /of the heart/ to epinephrine in the dog. The mouse exposed to FC 152A showed bronchoconstriction, respiratory depression, and decreased compliance, but not cardiac arrhythmia. In the mouse that developed bronchitis and in the rat with pulmonary emphysema, the administration ... provoked abnormalities in the electrocardiogram. These observations were noteworthy, indicating that bronchopulmonary disease increases the cardiotoxicity to FC 152A ... [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. 3095]
Ref: 1,1-DIFLUOROETHANE CASRN: 75-37-6. Hazardous Substance Data Bank at Toxnet. http://toxnet.nlm.nih.gov/

Dichlorodifluoromethane - Insecticide, Fungicide, Propellant, US EPA List 2 Inert - CAS No. 75-71-8

-- 11 subjects (7 being maintenance technicians of large cooling and refrigerating systems) were exposed for 130 min to CFC-12 (weighted exposure 0.46, 49.9, and 87.7 g/cu m. ... This led to acute reduction of ventilatory lung capacity only at the two highest CFC-12 concentrations, under which conditions a significant decrease in the heart frequency was also observed. [WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons p.90 (1990)]
-- Ten subjects /were exposed/ to CFC-11, CFC-12, CFC-114, two mixtures of CFC-11 and CFC-12, and a mixture of CFC-12 and CFC-114 (breathing concentrations between 16 and 150 g/cu m) for 15, 45, or 60 seconds, and found significant acute reduction of ventilatory lung capacity (FEV50, FEF25) on exposure to each chlorofluorocarbon, as well as bradycardia and increased variability in heart rate in seven subjects, negative T-waves in two subjects (one was exposed to CFC-11 and CFC-12), and atrioventricular block in 1 subject (CFC-114). Mixtures exerted stronger respiratory effects than individual chlorofluorocarbon at the
same level of exposure. [WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons p.90 (1990)]
-- Deaths resulting from cardiovascular collapse after arrhythmias have been reported after inhalation of Freons 11 and 12. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 528]
Ref: TOXNET profile from Hazardous Substances Data Bank for Dichlorodifluoromethane.

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

-- Health Hazards - General ... Inhalation of high concentrations may also result in temporary alteration of the heart's electrical activity by increasing the sensitivity of the heart to the arrhythmogenic action of epinephrine, causing irregular pulse, palpitations, or inadequate circulation (Dupont, 1996A; Dupont, 1996F; OSHA, 1998; Reprotext, 2003). Deliberate inhalation (“sniffing”) may cause death without warning (Dupont, 1996A; Dupont, 1996F; OSHA, 1998).
-- Acute Effects ... Inhalation of high concentrations (~5,000 ppm) is associated with the development of arrhythmias and sudden death due to myocardial sensitization to endogenous catecholamines (e.g., epinephrine).
-- 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.

Other Long-Term Effects - Repeated exposure can cause the heart to beat irregularly.
Ref: HAZARDOUS SUBSTANCE FACT SHEET. RIGHT TO KNOW PROJECT.
Produced by: New Jersey Department of Health and Senior Services.
Provided by: Canadian Centre for Occupational Health and Safety.

http://www.cchst.ca/products/databases/samples/njhsfs.html

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

-- When admin alone to anesthetized mice at concn of 100,000 ppm, CFC-21 induced arrhythmia and sensitized the heart to epinephrine. Tachycardia with hypotension was observed in both monkeys and dogs that were anesthetized and exposed at 50,000-100,000 ppm. Bronchoconstriction was noted at 25,000 ppm. [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]**PEER REVIEWED**
-- /GUINEA PIGS/ ... EXPOSED /UP TO 2 HR/ @ CONCN OF 10.2% DIED &, ON AUTOPSY, CONGESTED LUNGS, CONGESTED KIDNEYS, CONGESTED LIVER, DISCOLORED SPLEEN, & HIGHLY CONTRACTED HEART WERE FOUND. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: AmericanConference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979) 81]**PEER REVIEWED**
Ref: TOXNET profile from Hazardous Substances Data Base for DICHLOROFLUOROMETHANE
http://www.fluoridealert.org/pesticides/Dichlorofluoromethan.TOXNET.htm

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

-- The American Conference of Governmental Industrial Hygienists (ACGIH) has assigned dichlorotetrafluoroethane a threshold limit value (TLV) of 1000 ppm (6990 mg/m(3)) as a TWA for a normal 8-hour workday and a 40-hour workweek [ACGIH 1994, p. 19].
-- Rationale for Limits: The NIOSH limit is based on the risk of respiratory irritation, asphyxia at high concentrations [NIOSH 1992]. The ACGIH limit is based on the risk of systemic toxicity and cardiac sensitization [ACGIH 1991, p. 444].
-- Effects on Animals: dichlorotetrafluoroethane is a cardiac sensitizer, an asphyxiant, and a weak narcotic at extremely high concentrations [ACGIH 1991]. Dogs exposed to 200,000 ppm of dichlorotetrafluoroethane for 16 hours died, but exposures at this level for 8 hours caused tremor and convulsions [Hathaway et al. 1991]. Serious arrhythmia occurred in one of 12 dogs exposed once to 25,000 ppm of dichlorotetrafluoroethane and given intravenous epinephrine. Dichlorotetrafluoroethane is reported to reduce pulmonary compliance and act as a bronchoconstrictor [ACGIH 1991]. Guinea pigs exposed to a dichlorotetrafluoroethane concentration of 47,000 ppm developed respiratory irritation [Hathaway et al. 1991]. Repeated exposure to sprayed dichlorotetrafluoroethane caused localized skin inflammation in rats and irritation of the eyes of rabbits [ACGIH 1991].
Ref: US OSHA (Occupational Safety & Health Administration, U.S. Department of Labor).

http://www.osha-slc.gov/SLTC/healthguidelines/dichlorotetrafluoroethane/recognition.html

-- In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of Refrigerant 114 might cause exacerbation of symptoms due to its irritant properties. ... In persons with impaired cardiovascular function, especially those with history of cardiac arrhythmias, the inhalation of Refrigerant 114 might cause exacerbation of disorders of the conduction mechanism due to sensitizing effects on the myocardium. [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) PublicationNo. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. 1]
-- In one study, ten subjects were exposed to CFC-11, CFC-12, and CFC-114; two mixtures of CFC-11 and CFC-12; & a mixture of CFC-12 and CFC-114 )breathing concn between 16 & 150 g/cu m [2300 & 21,400 ppm]) for 15, 45, or 60 sec. Significant acute reduction of ventilatory lung capacity was reported in each case, as well as bradycardia & increased variability in heart rate & atrioventricular block. It was concluded that the mixtures exerted stronger respiratory effects than individual chlorofluorocarbons at the same level of exposure. [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. 444]
-- 10 PERSONS WERE EXPOSED TO FREON 114 FOR LENGTHS OF 15, 45, OR 60 SEC. IT INDUCED BIPHASIC REDN OF VENTILATORY CAPACITY. MOST PERSONS DEVELOPED VARIATIONS IN HEART RATE EXCEEDING THOSE NOTED BEFORE EXPOSURE. IN A FEW THERE WERE INVERSION OF T-WAVE & 1 CASE OF HEART BLOCK. [VALIC ET AL; BR J IND MED 34 (2): 130-6 (1977)]
-- Fluorocarbon propellants are anesthetic and cardiotoxic. ... Aerosol propellants produce hallucinogenic effects, and, rarely, contact dermatitis. /Fluorocarbon propellants/ [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 528]
-- Clinical pathologists exposed to fluorocarbons in the preparation of frozen tissue sections have been seen to develop coronary heart disease. /Fluorocarbons/ [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1209]
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

1,2-Difluoroethane (Freon 152) - List 3 Inert - CAS No. 624-72-6

Abstract: The inhalation toxicity of a series of fluorinated ethanes which are metabolized to fluoroacetate (144490) were studied in the male CD-rat. When the rats were exposed by inhalation to 1,2-difluoroethane (624-72-6), 1-chloro-2-fluoroethane (762505), 1-bromo-2-fluoroethane (762492), or 1-chloro-1,2-difluoroethane (338647) for 4 hours, the lethal concentrations for each compound were less than 100 parts per million (ppm). Tests with 1,1-difluoroethane (75376) showed a 4 hour median lethal dose of over 400,000ppm in rats. Clinical signs of fluoroacetate toxicity were noted including lethargy, hunched posture, and convulsions. Concentrations of citrate increased in serum and heart tissue on exposure to 1,2-difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroethane. Fluoroacetate was present in the urine of rats exposed to each of the toxic compounds. Rats exposed to 1,2-difluoroethane showed fluorocitrate in the kidneys. Rats exposed to 1,2-difluoroethane showed a concentration related elevation of serum and heart citrate up to 1000ppm of the compound. Serum citrate was up five fold and heart citrate 11 fold over control levels. The authors suggest that the metabolism of the toxic fluoroethane was initiated at the carbon/hydrogen bond, with metabolism to fluoroacetate via an aldehyde or an acyl fluoride. The authors conclude that 1-(di)halo-2-fluoroethanes are highly toxic to rats and should be viewed as a hazard to humans.
Ref: Fluoroacetate-Mediated Toxicity of Fluorinated Ethanes; by Keller DA, Roe DC, Lieder PH. Fundamental and Applied Toxicology, Vol. 30, No. 2, pages 213-219, 1996.

Ethylene fluorohydrin - Rodenticide - CAS No. 371-62-0

REPRODUCTIVE HAZARDS: An increase in sternebral ossification defects, hydronephrosis, runting (pup weight less than 2.7 g), variant rib ossifications, extra vertebral ossification centers, cardiac septal defects, and intrauterine growth retardation were noted in rats.
Ref: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Ethylene.fluorohydri.TOXNET.htm

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

"Chronic Dietary Toxicity Study in Dogs." (IRDC, 1/5/84.) Flucythrinate (85.4%) fed in the diet at 0, 30, 100 and 300 ppm of 24 months; eye exam included; 6/sex/group; NOEL stated in report = 100 ppm (emesis); reviewer’s NOEL = 30 ppm (emesis, others); adverse "pharmacological" effect on heart (arrythmia, slower rate); ACCEPTABLE, Possible adverse effect. JG, 7/14/86.
Ref: Summary of Toxicological Data for Flucythrinate. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch. July 18, 1986 Revised August 12, 1987. Also available at

http://www.cdpr.ca.gov/docs/toxsums/pdfs/2168.pdf

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

-- In the rat chronic feeding / carcinogenicity study the NOEL was less than 1.2 mg/kg/day in males and less than 1.5 mg/kg/day in females and the LOEL was 1.2 mg/kg/day in males and 1.5 mg/kg/day in females based on methemoglobinemia and multi-organ effects in blood, kidney, spleen, heart, and uterus. Under experimental conditions the treatment did not alter the spontaneous tumor profile. In the mouse carcinogenicity study the NOEL was less than 7.4 mg/kg/day in males and was 9.4 mg/kg/day for females and the LOEL was 7.4 mg/kg/day for males and was 38.4 mg/kg/day for females based on cataract incidence and severity. There was no evidence of carcinogenicity for flufenacet in this study.
-- A 55-day dog study subcutaneous via mini-pump with 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. Non-guideline studies provide evidence supporting the hypothesis of an extra thyroidal mechanism to explain alterations in circulating thyroid hormone concentrations.
-- Chronic Feeding/ Carcinogenicity (rat): NOEL < 25 ppm [1.2 mg/kg/day in males and 1.5 mg/kg/day in females]. LOEL = 25 ppm [1.2 mg/kg/day in males and 1.5 mg/kg/day in females] based on methemoglobinemia and multi-organ effects in blood, kidney, spleen, heart, and uterus.
Under experimental conditions the treatment did not alter the spontaneous tumor profile.
-- 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. Non guideline studies provide evidence supporting hypothesis of an extra thyroidal mechanism to explain alterations in circulating thyroid hormone concentrations.

Ref: US EPA. Pesticide Fact Sheet. Flufenacet Reason for Issuance: Conditional Registration Date Issued: April 1998.
http://www.epa.gov/opprd001/factsheets/flufenacet.pdf

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

-- "Teratology Study of S-53482 Administered Dermally to Rats"; (S. Kawamura; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Osaka, Japan; Project ID 2018; 3/14/91); The skin of twenty four mated Slc:SD® female rats was treated with 0, 30 or 100 mg/kg/day of S-53482 (lot no. PYG-89021-M, purity: 94.8%) for 6 hours/day from day 6 through day 15 of gestation. An additional group of 25 females were treated in the same manner with 300 mg/kg/day of the test material... There was an increased incidence/litter of cardiac malformations (0:1/23 vs. 300:9/17). The predominant cardiac malformation was a ventricular septal defect... Among the visceral variations noted for the 300 mg/kg group, there was an increased incidence/litter of persistent right azygous vein (0: 1/23 vs. 300: 7/17) and supernumerary coronary orifice in the heart (0:0/23 vs. 300: 3/17). Indicated adverse effect: increased incidence of a ventricular septal defect in the heart; Maternal NOEL: 100 mg/kg/day (based upon decreased weight gain noted for the 300 mg/kg treatment group); Developmental NOEL: 30 mg/kg/day (based upon the increased incidence of cardiovascular variations experienced by the 100 mg/kg treatment group); Study acceptable. (Moore, 6/7/02)
Ref: January 32, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- "Preliminary Teratology Study of SB-1297, SB-1335 or SB-1855 Administered Orally to Rats"; (S. Kawamura; Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Osaka, Japan; Project ID 599; 1/9/89); Six mated female SPF Slc:SD rats/group were dosed by oral gavage with 0, 30, 100, 200, or 500 mg/kg of SB-1855 (lot no. OK-86-01, purity: 98.2%, also identified as S-53482 in vol. 52894-082) from gestation day 6 through day 15... The developing fetuses were adversely affected at all of the treatment levels. There were no surviving fetuses in the 200 and 500 mg/kg treatment groups. Excessive death was noted for both the 30 and 100 mg/kg groups. The mean fetal body weights of the 30 mg/kg group were less than those of the control (p<0.05). Teratologic abnormalities for the 30 mg/kg group included ventricular septal defects in the heart (0:0/38 vs. 30:11/25, p<0.01)), persistent left umbilical artery (0:0/38 vs. 30:3/25), and wavy ribs (0:0/42 vs. 30:9/28). These data indicate that, even at the 30 mg/kg treatment level, significant developmental defects occurred. Possible adverse effect: ventricular septal defects in the heart. Maternal NOEL: not determinable. Developmental NOEL: < 30 mg/kg/day (based upon the incidence of developmental defects in the 30 mg/kg treatment group). Study supplemental (non-guideline study). (Moore, 7/29/02)
Ref: January 32, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- Prenatal developmental - Maternal NOAEL = 30 mg/kg/day (HDT) LOAEL = rat (oral) >30 mg/kg/day (HDT) Developmental NOAEL = 3 mg/kg/day LOAEL = 10 mg/kg/day based on cardiovascular effects (especially ventricular septal defects).
-- Prenatal developmental - Maternal NOAEL = 300 mg/kg/day (HDT) LOAEL rat (dermal) = >300 mg/kg/day (HDT) Developmental NOAEL = 30 mg/kg/day LOAEL = 100 mg/kg/day based on cardiovascular effects (especially ventricular septal defects).
-- Special Study - Rat Developmental: Critical Time for Defects: Pregnant females were administered 400 mg/ kg by gavage on gestation day 11 or 12 or 13 or 14 or 15. Day 12 administration showed: largest incidence of embryonic death, lowest fetal body weights and greatest incidence of ventricular spetal defects.
Ref: Federal Register: April 18, 2001. Flumioxazin; Pesticide Tolerances. Final Rule.

http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Apr.18.2001.htm

-- 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.
-- A second 90-day subchronic toxicity study was conducted with a sample of flumioxazin technical of typical purity (94.8%) at dietary concentrations of 0, 30, 300, 1,000, and 3,000 ppm. The NOAEL was 30 ppm based on anemia and related hematological changes; increases in liver, heart, kidney, 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.

http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Feb.14.2001.htm

-- there is concern for the severity of the effects observed in fetuses and young animals when compared to those observed in the maternal and parental animals (dose- and treatment-related increase in the incidence of cardiovascular abnormalities, particularly ventricular septal defect, in the developmental studies; and decreases in the number of live born pups and pup body weights in the absence of parental toxicity in the reproduction study).
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.

http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

Pregnant females were admin 400 mg/kg by gavage on gestation day 11 or 12 or 13 or 14 or 15. Day 12 admin showed: largest incidence of embryonic death, lowest fetal body weights & greatest incidence of ventricular spetal defects.
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.

http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

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

-- Mechanism of action:... 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]
-- Cardiac effects may include tachycardia, ventricular fibrillation, and sudden onset of asystole.

-- 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]

Ref: FLUOROACETAMIDE CASRN: 640-19-7. Hazardous Substances Data Bank.
http://www.fluorideaction.org/pesticides/fluoroacetamide.hsdb.htm

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.

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

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]
--
Animal Toxicity Studies: Non-Human Toxicity Excerpts: VENTRICULAR ARRHYTHMIAS, MARKED VENTRICULAR ALTERATION, MYOCARDIAL DEPRESSION & VENTRICULAR FIBRILLATION ARE SEEN IN HORSES, GOATS, RABBITS & MONKEYS; IN DOG & GUINEA PIG, CONVULSIONS OCCUR WITHOUT PARALLEL CARDIAC ABNORMALITIES; CAT, PIG, RAT & HAMSTER SHOW BOTH CARDIAC & CNS RESPONSES.
/FLUOROACETATES/ [Clarke, E.G., and M. L. Clarke. Veterinary Toxicology. Baltimore, Maryland: The Williams and Wilkins Company, 1975. 234]
Ref: TOXNET profile from Hazardous Substances Data Bank.

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

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

POTENTIAL ADVERSE EFFECTS ON FETUS: Exposure in first trimester resulted in skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus.
Ref: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

Haloxyfop-methyl - Herbicide - CAS No. 69806-40-2

-- 7) 36-Week Feeding - mouse: Dietary levels tested: 0, 0.02, and 2.0 mg/kg/day; B6C3F1 mice (10/sex/group) were administered haloxyfop-methyl in the diet for 9 months. A significant increase in serum alkaline phosphatase was reported for males at the 2.0 mg/kg/day level with a slight increase in serum alkaline phosphatase for females. The liver was slightly enlarged and darkened for both males and females at 2.0 mg/kg/day. A significant increase in the liver absolute weight and organ-to-body weight ratio of both males and females fed 2.0 mg/kg/day was observed. Males also exhibited a significant decrease in kidney and heart weights compared with the control organ weight. Livers of males and females at the 2.0 mg/kg/day dose exhibited an enlargement of centrilobular hepatocytes cells with an increase cytoplasmic homogenity and increased eosinophilia. Kidneys of males fed 2.0 mg/kg/day showed a decrease of cytoplasmic vacuolation of the proximal convoluted tubular cells. Based on the above effects, the LEL for systemic toxicity is 2.0 mg/kg/day. The NOEL for systemic toxicity is 0.02 mg/kg/day; core supplementary (Dow Chemical U.S.A., 1982d)
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

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)... Red fluid in plural cavity noted after gross necropsy corresponded with heart lesions in high-dose males (e.g., necrosis, hemorrhage and inflammation)... 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... NOEL(M/F)=20 ppm (M: 2.63 mg/kg/day based on neurotoxicity, heart lesions at 125 ppm and decreased body weight gain at 100 ppm; F: 3.99 mg/kg/day based on neurotoxicity at 100 and 125 ppm).
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

Nissol (also known as MNFA or MNAF) - Acaricide, Insecticide - CAS NO. 5903-13-9

Abstract. The selective toxicity of N-methyl-N- ( 1-naphthyl ) monofluoroacetamide ( MNFA ) in various species of animals and the effects of the compound on the central action, the peripheral action and the fluctuations in the cardiovascular and respiratory systems were investigated. Tabulated data present the physiological function or activity investigated, the test animal, the dosage of MNFA administered and the route of administration. Results showed that below the toxic level, MNFA had little or no general pharmacologic effect and only a minute effect on the central and peripheral nervous systems and various peripheral organs of the differenct animals tested. When a toxic dose of MNFA was administered, respiratory depression, a fall of blood pressure and body temperature and a decrease in heart rate were generally observed. Both the rat and cat developed convulsions. Just prior to death, a flat wave was observed in the electrical activity of the brain which was indicative of a serious impediment. A drop in blood pressure of about 30% was observed at 24 hr in rats that received 50 mg/kg of MNFA orally. Cardiac response revealed the characteristic feature of this compound to be cardiac depression in every species tested. In addition, among animals that have a high sensitivity to MNFA, such as the guinea pig, dog and cat, bigeminal or trigeminal ventricular premature beats were observed. An enhancement of epinephrine activity by MNFA was also noted. MNFA had a slight effect on the red cell count, but the white cell count in rabbits decreased markedly accompanied by a decrease of pseudoeosinophils and an increase of lymphocytes. The blood sugar level in mice showed an initial increase prior to a final decrease, while in rats and guinea pigs there was a decrease and the value remained unchanged in rabbits and dogs. Ketone bodies were only detected in the mouse.
Ref. Some pharmacologic properties of a new fluorine pesticide, N-methyl- N- ( 1-Naphthyl ) monofluoroacetamide; by Hasimoto Y, Noguchi T, Mori T, Kitagawa H. Toxicol. Appl. Pharmacol.; 13(2), 174-88, 1968.

Abstract. General aspects of pesticide intoxication and therapy have been reported previously. Since most pesticides act on the nervous system, appreciable pathological alterations can be produced there, especially in the CNS. Four cases of pesticide intoxication are described: one with endrin, two with ceresin(!) (O-methyl O-cyclohexyl S(p-chlorophenyl)thiophosphate), and one with Nissol (MNFA)... In the MNFA intoxication case the patient's condition was serious with unconsiousness and a very low blood sugar value (50 mg/dl). The EEGs recorded on the first and seventh days of hospitalization showed flat, low-voltage waves without any slow waves or spikes. Intravenous administration of 40 ml of 40% glucose solution restored the alpha-waves, although at low-voltage, and the EEG returned to normal after one month. ...
Ref. Electroencephalograms in pesticide poisoning cases; by Hiraki K, Iwasaki, Namba M. Rinsho Noha (Clin. Electroencephalog.) ; 14(6): 333-340; 1972. [Abstract from Toxnet.].

Abstract. A brief discussion of the use of fluoroacetic acid as a pesticide, and a brief history of studies on this acid are given. More detailed discussions include those of MNFA, comparative toxicity of MNFA, pre-clinical test of antidotes, fluoroacetic poisoning of men and antidote treatment, the mechanism of detoxication, and various experiments of fluoroacetic acid effects on the brains of mice. The effects that have been detected on men include: mild nausea, vomiting, headache, dizziness; medium ataxia, clouding of consciousness, epileptic convulsion, repetition of tonic and clonic convulsion, decrease in heart rate; and serious coma, cyanosis, lack of abdominal reflex, arrhythmia, increase of tracheal secretion, and hypotension. Clinical findings include: sudden decrease or increase of blood sugar, increase of hemogram leucocyte, increase of pseudo acidophils, lymphocytes, and decrease of electrolyte K. The blood pressure gradually decreases, and various types of premature beats, myocardial infarction, and coronary insufficiency are found on electrocardiogram, as the heart rate increases and respiration decreases, In hepatic function, GOT and GPT gradually or slightly increase. Electroencephalogram shows a slow malfunction, or irregular slow wave; when serious, a flat pattern appears. The body temperature increases temporarily and then gradually decreases. The article is a review of previously published material by other researchers.
Ref. Pre-clinical evaluation of detoxication of organic fluoride toxins; by Hashimoto Y. Eisei Kagaku (Journal of Hygienic Chemistr; 17(6): 363-379; 1971. [Abstract from Toxnet.].

Abstract. The effects of N-methyl-N-(1-naphthyl)-monofluoroacetamide (MNFA) on cardiac function were studied in rabbits. Rabbits received 5 milligrams per kilogram (mg/kg) MNFA orally, or 2mg/kg MNFA subcutaneously (sc). Electrocardiographic (ECG) recordings were made from subcutaneously implanted electrodes before and up to 2 hours after oral MNFA, and for up to 10 hours after sc MNFA. Serum electrolytes and enzymes were determined 30 minutes before and after, and 3 and 6 hours after MNFA. One hour after oral MNFA, and ECG showed small deflections and almost discernible P-waves and T-waves in lead 1, with tall peaked T-waves in leads 2, 3, and aVF; after 2 hours, the QRS complex was widened and the ST junction was lowered. Leads 1 and aVL had ST depression consisting of wide S-waves and inverted T-waves. One hour after sc MNFA, the ECG revealed tachycardia; after 3 hours the ST junction was lowered. Leads 1 and aVL had ST depression consisting of wide S-waves and inverted T-waves. One hour after sc MNFA, ECG revealed tachycardia; after 3 hours the ST junction was lowered and T-waves were flattened or inverted. After 6 hours, there were wide S-waves and QRS was prolonged in leads 1, 2, and aVF. At 10 hours R-deflections were decreased in most leads, and tachycardia and ST junction depression were improved. Serum calcium was decreased slightly 6 hours after MNFA, but serum levels of sodium, potassium, chlorine, transaminases, and lactic-dehydrogenase were not affected. The authors conclude that the ECG changes of the QRS, ST, and T-waves are probably caused mainly by metabolic disturbances during MNFA intoxication.
Ref. Agricultural Organofluoride Poisoning: II. Cardiac Damage; by Iwasaki I, Nawa H, Hara A, Takagi S, Hyodo KFluoride, Vol. 3, No. 3, pages 127-130, 1970.

Abstract. Patients suffering from severe organofluoride intoxication (MNFA, Oxylan) were treated with glucose. Prior to treatment the electroencephalograms (EEG) demonstrated flat curves. Dysrhythmic patterns were observed in less severely affected patients which suggest the presence of impaired cerebral function associated with abnormal carbohydrate metabolism. The appearance of paroxysmal waves is also indicative of organofluoride poisoning. It is evident that EEG findings are valuable in the prognostic evaluation and diagnosis of organofluoride poisoning.
Ref: Studies on organofluoride poisoning IV. Electroencephalographic (EEG) observations; by Iwasaki I, Namba, Nawa H, Hara, Tagaki S, Hyodo K. Fluoride; 3(3): 133-136; 1970.

Abstract. The accumulation of citrate was studied in spider-mites, house-flies and mice after treatment with the acaricide Nissol (5903139). Male Swiss-Webster-mice were injected with various concentrations of Nissol. House-flies were treated topically with Nissol at various concentrations or received thoracic injections. A slide/dip technique was used to dose two-spotted-spider mites with Nissol. Mortality was recorded at 24 hours after treatment and the median lethal dose (LD50) was calculated for each species. The citric-acid (77929) content was determined in homogenates of whole mice in brains, hearts, livers, and kidneys photospectrometrically. Citric-acid content was also determined in homogenates of flies and mites. The LD50 for intraperitoneal administration in mice was 200 milligrams per kilogram (mg/kg). The topical LD50 in house-flies was 525mg/kg and the injected LD50 was 14mg/kg. The LD50 for contact administration to spider mites was 250 parts per million. Citric-acid increased substantially in each species even by 3 hours after dosing. The maximum accumulation in mice occurred at 6 hours. Flies and mites continued to show increased accumulation through 12 hours. In the mouse citric-acid was accumulated in decreasing order in the heart, kidney, brain, and liver. The authors conclude that mites, flies and mice accumulate citrate when treated with Nissol. The toxicity of this acaricide may be related to inhibition of aconitase which catalyzes transformation of citric-acid.
Ref. Citrate Accumulation In Twospotted Spider Mites, House Flies, And Mice Following Treatment With The Acaricide 2-Fluoro-N-methyl-N-(1-naphthyl) Acetamide; by Johannsen FR. Knowles CO. Journal of Economic Entomology, Vol. 65, No. 6, pages 1754-1756, 14 references, 1972.

Abstract. The effects of a single dose and repeated doses of N-methyl-N- ( 1- naphthyl ) monofluoroacetamide (MNFA) on the fluctuation of citrate in animals and the replationship between the activity of MNFA hydrolysis and the acute toxicity of MNFA in various species were investigated. MNFA was administered intraperitoneally at 25 mg/kg to male Wistar strain rats, 2.0 mg/kg to guinea pigs and 300 mg/kg to monkeys. At specified periods after dosing, the animals were sacrificed and the citrate content of heart, kidneys, liver and brain was determined. For the multiple dose study, MNFA was administered orally to male rats at doses of 0.625, 1.25, 2.5, 5.0 and 10.0 mg/kg/ day for 180 days and the citrate content was determined in the brain, heart, liver, kidney, testis and blood. In the rat, after a single dose of MNFA, the citrate level increased to 27, 10, 10 and negligible times the normal value in heart, kidneys, brain and liver, respectively. In the chronic toxicity experiment, the only increase (3 times the control value) was in the testes of rats receiving 10 mg/ kg/day of MNFA. In all other groups, the level in liver and kidney decreased significantly in comparison with the levels in animals receiving a single dose. It is suggested that this difference was due to metabolism and to the detoxification mechanism of the liver and kidney which may have been accelerated by the chronic administration of MNFA. The citrate level in the monkeys after a single dose was much lower than in the rat. In guinea pigs it increased to the maximum at 9 hr when it reached 30 times the control value in the kidney, 10 times in the heart, 6 times in the brain while no appreciable increase was found in the liver. The hydrolysis of MNFA by liver homogenates was closely related to the acute toxicity and the product of the hydrolysis was determined as N-methyl-1-naphthylamine. The enzyme activity in the guinea pig was about 35 times that of the rat or mouse. The LD50 of MNFA was 3.1 times that of N- ( 1-naphthyl ) monofluoroacetamide ( NFA ) and the amount hydrolyzed after 30 min incubation was about one- fifth.
Ref: Studies of the biochemical lesions caused by a new fluorine pesticide, N-methyl-N- ( 1-naphthyl ) monofluoroacetamide; by Noguchi T, Hashimoto Y, Miyata H. Toxicol. Appl. Pharmacol.; 13(2), 189-98, 1968.

TOXICITY
Ref: ChemIDplus for Nissol. Available at Toxnet.
Organism
Test Type Route Reported Dose (Normalized Dose) Effect Source
dog LDLo intraperitoneal 2mg/kg (2 mg/kg)

BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD

BEHAVIORAL: EXCITEMENT

CARDIAC: CARDIOMYOPATHY INCLUDING INFARCTION

Toxicology and Applied Pharmacology. Vol. 12, Pg. 536, 1968.

 

PFOS - Insecticide, US EPA List 3 Inert

The maternal and developmental toxicities of perfluorooctane sulfonate (PFOS) were evaluated in the rat and mouse. PFOS is an environmentally persistent compound used as a surfactant and occurs as a degradation product of both perfluorooctane sulfonyl fluoride and substituted perfluorooctane sulfonamido components found in many commercial and consumer applications. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestational day (GD) 2 to GD 20; CD-1 mice were similarly treated with 1, 5, 10, 15 and 20 mg/kg PFOS from GD 1 to GD 17. Controls received 0.5% Tween-20 vehicle (1 ml/kg for rats and 10 ml/kg for mice). Maternal weight gain, food and water consumption, and serum chemistry were monitored. Rats were killed on GD 21, and mice on GD 18. PFOS levels in maternal serum, maternal and fetal livers were determined. Maternal weight gains in both species were suppressed by PFOS in a dose-dependent manner, likely attributed to reduced food and water intake. Serum PFOS levels increased with dosage, and liver levels were approximately 4-fold higher than serum. Serum thyroxine (T4) and triiodothyronine (T3) in the PFOS-treated rat dams were significantly reduced as early as one week after chemical exposure, although no feedback response of thyroid-stimulating hormone (TSH) was observed. A similar pattern of reduction in T4 was also seen in the pregnant mice. Maternal serum triglycerides were significantly reduced, particularly in the high dose groups, although cholesterol levels were not affected. In the mouse dams, PFOS produced a marked enlargement of the liver at 10 mg/kg and higher dosages. In the rat fetuses, PFOS was detected in the liver, but at levels nearly half of those in the maternal counterparts, regardless of administered doses. In both rodent species, PFOS did not alter the numbers of implantations or live fetuses at term, although small deficits in fetal weight were noted in the rat. A host of birth defects including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium were seen in both rats and mice, primarily in the 10 and 20 mg/kg dosage groups, respectively. Our results demonstrate both maternal and developmental toxicity of PFOS in the rat and mouse.
Ref: Toxicol Sci 2003 May 28; Exposure to Perfluorooctane Sulfonate During Pregnancy in Rat and Mouse. I. Maternal and Prenatal Evaluations; by Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Barbee BD, Richards JH, Butenhoff JL, Stevenson LA, Lau C. Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.

Poly(difluoromethylene), alpha-chloro-omega-(2,2-dichloro-1,1,2- trifluoroethyl) - EPA List 3 Inert - CAS No. 79070-11-4

-- Inhalation of the decomposition products of Poly TFE may cause polymer fume fever; a lung irritation requiring medical treatment for fluorine compounds which can cause delayed pulmonary edema. A polymer fume fever is a flu-like condition which occurs several hours after exposure and subsides within 24 hours even in the absence of treatment. Polymer fume fever does not cause permanent injury and the effects are not cumulative.
--
Human health effects of overexposure by inhalation to very high concentrations may cause temporary alteration of the heart's electrical activity with irregular pulse, palpitations, or inadequate circulation. Individuals with preexisting diseases of the central nervous or cardiovascular system may have increased susceptibility to the toxicity of excessive exposures.
Ref: Material Safety Data Sheet for: VDX Dry Lubricant
Prepared: Sat
Apr 05 2003. Also available at:
http://www.microcare.com/MSDS/MSDS-VDX.US.phtml
Manufacturer: Micro Care Corporation, 595 John Downey Drive, New Britain, CT. 06051 USA

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

Title: [Potassium hexafluorosilicate]
Source: English/French versions: Internet documents, 1999. Spanish version: Instituto Nacional de Seguridad e Higiene en el Trabajo, Ediciones y Publicaciones, c/Torrelaguna 73, 28027 Madrid, Spain, 1991. 2p. Illus.
Abstract: International Chemical Safety Card. Exposure routes: inhalation and ingestion. Short term exposure effects: irritation of the skin, eyes and respiratory tract; effects on the calcium metabolism, resulting in cardiac disorders and impaired function. Long-term exposure effects: effects on the bone, resulting in fluorosis. Threshold limit value: 2.5mg/m3 (TWA) as fluorine (ACGIH 1997-1998).
Ref: Toxline at Toxnet.

Prosulfuron - Herbicide - CAS No. 94125-34-5

-- Short term toxicity Target / critical effect: Liver (hepatocyte hypertrophy), heart (myocardial degeneration), hematopoietic system (red blood cells decreased) Lowest relevant oral NOAEL / NOEL: NOAEL = 6 mg/kg b.w./day (90-day, dog)
Ref: July 2, 2002 - Review report for the active substance prosulfuron. Finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 26 February 2002 in view of the inclusion of prosulfuron in Annex I of Directive 91/414/EEC.European Commission Health & Consumer Protection Directorate-General.

http://www.fluoridealert.org/pesticides/Prosulfuron.EU.July.2002.pdf

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

Abstract: SUMMARY: Young albino rabbits were administered 5, 10, 20, and 50 mg of sodium fluoride/kg body weight/day subcutaneously for 3.5 months. The control animals were given 1 mL of double distilled water/kg body weight/day. In the fluoridated rabbits, the myocardium showed cloudy swellings, sarcoplasmic vacuolization, and small hemorrhages followed by fibrous necrosis. The degenerative changes were most pronounced in animals treated with 50 mg of sodium fluoride/kg body weight/day. The myocardium exhibited fibrous necrosis, dissolution of nuclei, fibrillolysis, extensive vacuole formation and interstitial cells in the connective tissue. The degree of myocardial damage seemed to be directly proportional to the dosage of fluoride administered. In the control animals, the myocardium showed normal structure without any of the changes mentioned above.
Ref: Fluoride 2001; 34(1):43-50. Histopathology of myocardial damage in experimental fluorosis in rabbits; by A Shashi and SP Thapar. Full report available at
http://www.fluoride-journal.com/01-34-1/341-43.pdf

Abstract: The purpose of this study was to determine the mechanism responsible for alterations in NaF-induced contractions of blood vessels from streptozotocin-induced diabetic rats. In the presence of AlCl3, NaF (¥7.5 mM) produced significantly greater contractions in diabetic aorta and mesenteric artery compared with age-matched controls. Pretreatment with 1 microM nifedipine eliminated the enhanced contractile responses of diabetic vessels to NaF, resulting in no difference in the magnitude of NaF-induced contractions between control and diabetic vessels. In the presence of 100 microM deferoxamine, an Al 3+ chela-tor, NaF-induced contractions of diabetic vessels were markedly attenuated, whereas only the responses to lower concentrations of NaF were reduced in control vessels. No significant difference was found in the peak amplitude of transient contractions induced by 10 microM cyclopiazonic acid between control and diabetic vessels. The addition of 10 microM okadaic acid produced attenuated contractions in diabetic vessels. These findings indicate no involvement of the inhibitory effects of NaF on endoplasmic reticular Ca 2+ -pump ATPase and protein phosphatases in the genesis of the enhanced responsive-ness of diabetic vessels to NaF. Western blot analysis showed a 2.5-fold in-crease in the expression of G(qalpha) in diabetic aortic membranes. In contrast, the G(ialpha) level was modestly decreased and the G(salpha) and G(betagamma) levels were unchanged in diabetes. The present results suggest that enhanced vascular contractions to NaF in diabetes is attributed predominantly to a G protein-mediated Ca 2+ channel acti-vation that results from markedly increased G(qalpha) expression in vascular tissues under this pathological state.
Ref: Predominant contribution of the G protein-mediated mechanism to NaF-induced vascular contractions in diabetic rats: association with an increased level of G(qalpha) expression
Hattori Y, Matsuda N, Sato A, Watanuki S, Tomioka H, Kawasaki H, Kanno M. J Pharmacol Exp Ther 2000 Feb;292(2):761-8 - As cited and abstracted in Fluoride 2000; 33(2):97-98

• Mesenteric artery, arteria mesenterica -- (one of two branches of the aorta that pass between the two layers of the mesentery to the intestines)

Abstract:
1. Previous studies from this laboratory have demonstrated that alpha 1-adrenoceptor-mediated increases in tension and phosphoinositide metabolism are enhanced in the aorta and mesenteric arteries from diabetic rats. The purpose of the present investigation was to determine whether contractile responses to sodium fluoride (NaF), which directly stimulates GTP-binding proteins (G-proteins), are also enhanced in diabetic arteries.
2. NaF (1-20 mM) in the presence of 10 microM aluminium chloride produced slowly developing, concentration-dependent contractions in mesenteric arteries from three month streptozotocin-diabetic (60 mg kg-1, i.v.) male Wistar rats and age-matched control rats. The maximum contractile response but not the sensitivity to NaF was significantly greater in mesenteric arteries from diabetic than from control rats, as was the response to noradrenaline (NA). Maximum contractile responses of aorta and caudal artery from diabetic rats to NaF were also significantly enhanced.
3. Removal of the endothelium and denervation with 6-hydroxydopamine did not significantly alter the maximum contractile response of mesenteric arteries from either control or diabetic rats to NaF. Similarly, NaF had no effect on cyclic AMP levels in aorta, and no difference in cyclic AMP levels, either basally or in the presence of NaF, was detected between control and diabetic rat aorta.
4. Contractile responses of mesenteric arteries from both control and diabetic rats to NaF were diminished in calcium-free Krebs solution, but the NaF response remained significantly elevated in mesenteric arteries from diabetic rats compared to control.
5. Ryanodine (30 microM) which depletes intracellular calcium stores, nifedipine (3 microM) which blocks dihydropyridine-sensitive calcium channels and calphostin C (0.5 microM) which selectively inhibits protein kinase C, all significantly inhibited maximum contractile responses of mesenteric arteries from control and diabetic rats to NaF. There were no significant differences between control and diabetic arteries in the relative magnitude of the inhibition produce by the three antagonist.
6. These data suggest that there may be increased activation of the same signalling processes that mediate NA-stimulated vasoconstriction, perhaps contraction-associated G-proteins or the effectors coupled to these G-proteins, in response to NaF in mesenteric arteries from diabetic rats. This may also be responsible for the enhanced contractile responses of these arteries to alpha 1-adrenoceptor stimulation.
Ref: Br J Pharmacol 1996 May;118(1):115-22. Enhanced contractile responses of arteries from streptozotocin diabetic rats to sodium fluoride. Weber LP, Chow WL, Abebe W, MacLeod KM.

• Mesenteric artery, arteria mesenterica -- (one of two branches of the aorta that pass between the two layers of the mesentery to the intestines)

Sodium fluoroacetate (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: Groups of Sprague-Dawley rats received sodium monofluoroacetate (Compound 1080) at 0.025, 0.075, and 0.25 mg/kg by oral gavage once daily for 90 days and were then euthanized. The control and 0.25 mg/kg/day groups included additional rats of each sex that were treated for 90 days, then maintained without treatment for a further 56-day recovery period. Microscopic changes were restricted to the testes and the heart, and were seen only in males dosed with 1080 at 0.25 mg/kg/day and included severe hypospermia in the epididymides, severe degeneration of the seminiferous tubules of the testes, and cardiomyopathy. Sperm evaluation indicated severe decreases in all three sperm parameters evaluated (concentration, % motile, and % abnormal) at 0.25 mg/kg/day. There were no microscopic changes or 1080-related effects on sperm parameters at 0.025 and 0.075 mg/kg/day. The no observable effects level (NOEL) for rats administered 1080 via oral gavage for 90 days was 0.075 mg/kg/day. The lowest observable effects level (LOEL) dose was 0.25 mg/kg/day. After dosing with the LOEL dose of 0.25 mg/kg/day, mean concentrations of 1080 in rat plasma were 0.26 micro g/ml at 1 h and 0.076 microg/ml at 12 h. Rat urine collected from the same animals contained 0.059 microg/ml.
Ref: A 90-day toxicological evaluation of Compound 1080 (sodium monofluoroacetate) in Sprague-Dawley rats; by Eason CT, Turck P.Toxicol Sci. 2002 Oct;69(2):439-47.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12377993

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

In a 13-week oral study in rats, gavage administration of sodium fluoroacetate (0.02 mg/kg/day) resulted in decreased testis weight and altered spermatogenesis in males (the NOAEL was 0.05 mg/kg/day). In addition, increased heart weight was noted in females and males administered 0.20 mg/kg/day of sodium fluoroacetate. The increase in heart weight, however, was only accompanied by subacute, minimal inflammation (not dose-related). Also, fluorocitrate levels were significantly increased after 4 weeks in males administered 0.50 mg/kg/day and after 13 weeks in both male and female rats administered 0.20 or 0.50 mg/kg/day. The testicular and cardiac effects were reported to be consistent with those noted in the literature. EPA believes that there is sufficient evidence for listing sodium fluoroacetate on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the neurologic, reproductive, and myocardial toxicity data for this chemical.
Ref: USEPA/OPPT. Support Document for the Health and Ecological Toxicity Review of TRI Expansion Chemicals. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

Subchronic Toxicity: ... Technical sodium fluoroacetate was administered by gavage for 13 weeks to Crl:CD(SD)Br rats. The doses were 0, 0.05, 0.20, or 0.50 mg/kg/day. The NOEL was 0.05 mg/kg/day. The LOEL was 0.20 mg/kg/day, based on dose-related findings in histopathology (hypospermatogenesis, fusion bodies, and immature or abnormal sperm) and decreased size and weight of testes and epididymides in males. Females had dose-related increases in absolute and relative heart weights at the mid and high doses (Wolfe, 1988).
Ref: US EPA Reregistration Eligibility Decision (RED) for Sodium fluoroacetate. September 1995
.
http://www.fluoridealert.org/PESTICIDES/Sodium_fluoroacetate.RED.95.pdf

Sodium fluorosilicate (Sodium Hexafluorosilicate) - Insecticiide, Wood Preservative, EPA List 3 Inert - CAS No. 16893-85-9

-- Toxicological Data. Human Data. Chronic exposure to sodium hexafluorosilicate dust at levels above the eight-hour TWA can result in severe calcification of the ribs, pelvis, and spinal column ligaments; effects on the enzyme system; pulmonary fibrosis; stiffness; irritation of the eyes, skin, and mucous membranes; weight loss; anorexia; anemia; cachexia; wasting; and dental effects. Long-term or repeated exposure to the skin can result in skin rash. A probable oral lethal dose of 50-500 mg/kg, classified as very toxic, has been reported for a 150-pound (70-kg) person receiving between 1 teaspoon and 1 ounce of sodium hexafluorosilicate. Cases of sodium hexafluorosilicate ingestion reported symptoms such as acute respiratory failure, ventricular tachycardia and fibrillation, hypocalcemia, facial numbness, diarrhea, tachycardia, enlarged liver, and cramps of the palms, feet, and legs.
-- -- Guinea pigs, 13- 55 mg/ m 3 (1.2- 7.2 ppm) in air for • 6 h; Pulmonary irritation was observed. The lowest concentration that caused death when inhaled for 6 h was 33 mg/ m 3 . Patty (1963; cited by HSDB, 2000b)
-- -- Mice orally given sodium hexafluorosilicate (70 mg/kg; 0.37 mmol/kg) exhibited toxic effects in the peripheral nerves, sensation, and in behavior. In rats, an oral dose (248 mg/kg; 1.32 mmol/kg) administered intermittently for one month produced toxic effects in the kidney, ureter, and/or bladder, as well as musculoskeletal and biochemical effects (RTECS, 1997). Using guinea pigs, inhalation experiments (13-55 mg/m 3 [1.7-7.2 ppm] sodium hexafluorosilicate in air for •6 hours) resulted in pulmonary irritation; the lowest concentration that caused death was 33 mg/m 3 (4.3 ppm) (Patty, 1963; cited by HSDB, 2000b).
Ref: Sodium Hexafluorosilicate [CASRN 16893-85-9] and Fluorosilicic Acid [CASRN 16961-83-4]. Review of Toxicological Literature. October 2001. Prepared for Scott Masten, Ph.D. National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, North Carolina 27709 Contract No. N01-ES-65402. Submitted by Karen E. Haneke, M.S. (Principal Investigator) Bonnie L. Carson, M.S. (Co-Principal Investigator) Integrated Laboratory Systems P.O. Box 13501 Research Triangle Park, North Carolina 27709.

http://www.fluoridealert.org/pesticides/Fluorosilicates.NIH.2001.pdf

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

Poisonings and fatalities have been reported in humans following inhalation exposure to sulfuryl fluoride... A second person died of cardiac arrest after sleeping in the house overnight following fumigation. A plasma fluoride level of 0.5 mg/L (10 times normal) was found in this person following exposure. Prolonged chronic inhalation exposure to concentrations of sulfuryl fluoride gas significantly above the TLV of 5 ppm have caused fluorosis in humans because sulfuryl fluoride is converted to fluoride anion in the body. Fluorosis is characterized by binding of fluoride anion to teeth (causing mottling of the teeth) and to bone.
Ref: Federal Register: September 5, 2001 (Volume 66, Number 172). Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances.

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

-- Two fatalities occurred when the owners of a home re-entered after the dwelling had been fumigated with 250 pounds of sulfuryl fluoride. The concentration to which the occupants were exposed was not determined. The man died within 24 hr, and the woman expired 6 days after exposure. Signs of intoxication included severe dyspnea [abnormal breathing], cough, generalized seizure, cardiopulmonary arrest (in the male), and weakness, anorexia, nausea, repeated vomiting, and hypoxemia [subnormal oxygenation of arterial blood, short of anoxia]; ventricular fibrillation and diffuse pulmonary infiltration were also reported in the female. [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, 1991.1471]
Ref: Hazardous Substances Data Bank for SULFURYL FLUORIDE CASRN: 2699-79-8.
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB
Note: Ventricular fibrillation (VF) is a severely abnormal heart rhythm (arrhythmia) that, unless treated immediately, causes death. VF is responsible for 75% to 85% of sudden deaths in persons with heart problems.
http://www.1uphealth.com/health/ventricular_fibrillation_info.html

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

Abstract. This report describes for the first time a novel anionic background current (I(AB)) identified in guinea-pig isolated ventricular myocytes. It also shows that I(AB) has both novel and differential pharmacology from other (cardiac) chloride currents. Using the whole-cell patch-clamp technique and external anion substitution, I(AB) was found to be outwardly rectifying and highly permeable to NO(-)(3), with a relative permeability sequence of NO(-)(3) > I(-) > Cl(-). I(AB) was not blocked by 50 microM DIDS, by hypertonic external solution, or by the nonselective protein kinase inhibitor H7-DHC. Exposure to the pyrethroid agent tefluthrin (10 microM) increased the current density of I(AB) significantly at positive voltages (P < 0.05), but had no significant effect on other cardiac chloride currents. We conclude that I(AB) possesses a distinct pharmacology and does not fall into the three major classes of cardiac chloride conductance commonly reported. (C)2002 Elsevier Science (USA).
Ref: Borg JJ et al. (2002). Tefluthrin modulates a novel anionic background conductance (I(AB)) in guinea-pig ventricular myocytes. Biochem Biophys Res Commun. Mar 22;292(1):208-15.

Abstract: Pyrethroid insecticides are known to modify neuronal sodium channels, inducing persistent, steady-state sodium current at depolarized membrane potentials. Cardiac myocytes are also rich in sodium channels but comparatively little is known about the effect of pyrethroids on the heart, or on the cardiac sodium channel isoform. In the present study therefore, we determined the actions of type I and type II pyrethroids against rat and guinea pig ventricular myocytes under current and voltage clamp, and on isolated perfused rat hearts. In myocytes, tefluthrin (type I) and fenpropathrin and alpha-cypermethrin (type II) prolonged action potentials and evoked afterdepolarizations. The time course of sodium current (I(Na)) was also prolonged by these compounds. Pyrethroids delayed I(Na) inactivation, when measured under selective conditions as current sensitive to 30 microM tetrodotoxin, by increasing the proportion of slowly inactivating current at the expense of fast inactivating current. Further experiments, focusing on fenpropathrin, revealed that its effects on I(Na) inactivation time course were dose-dependent, and the Na(+) "window-current" was increased in its presence. In unstimulated, isolated hearts perfused with the same pyrethroids, the variability in contraction amplitude increased due to variations in the intervals between heartbeats. These potentially arrhythmogenic changes are consistent with the effects observed at the cellular level. The type I pyrethroid tetramethrin had little effect in any of the preparations. These findings suggest that some pyrethroids possess considerable mammalian cardiac arrhythmogenic potential, the manifestation of which in vivo may depend on the route of exposure.
Discussion from full paper: The principal findings of the present study at the cellular level are that the type I pyrethroid tefluthrin and the type II pyrethroids fenpropathrin and -cypermethrin
1) prolonged ventricular action potentials and evoked afterdepolarizations;
2) modified the time course of INa by altering the relative proportions of fast and slowly inactivating current; and
3) altered the voltage dependence of INa. At the whole heart level, these effects corresponded with a pyrethroid-induced increase in the variability of contractile force, suggestive of proarrhythmic activity. Several aspects of these findings merit detailed consideration.
Ref: Spencer CI et al. (2001). Actions of pyrethroid insecticides on sodium currents, action potentials, and contractile rhythm in isolated mammalian ventricular myocytes and perfused hearts. J Pharmacol Exp Ther. 2001 Sep;298(3):1067-82. Erratum in: J Pharmacol Exp Ther 2001 Oct;299(1):399.
Full free report available at
http://jpet.aspetjournals.org/cgi/content/full/298/3/1067

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

4.2 Mechanism of Toxicity (pages 143 - 144)
At high concentrations, HFC-134a has anesthetic and narcotic properties; cardiac sensitization may also occur. The biochemical mechanism(s) of action of these two efects is not well understood. The anesthetic effect was fully reversible. Inhalation of certain hydrocarbons, including some anesthetics, can make the mammalian heart abnormally sensitive to epinephrine, resulting in ventricular arrhythmias, which is some cases can lead to sudden death (Reinhardt et al. 1971). The mechanism of action of cardiac sensitization is not completely understood but appears to involve a disturbance in the normal conduction of the electrical impulse through the heart, probably by producing a local disturbance in the electrical potential across cell membranes. The hydrocarbons themselves do not produce arrhythmia; the arrhythmia is the result of the potentiation of endogenous epinephrine (adrenalin) by the hydrocarbon ... In the study with human volunteers exposed to HFC-134a (Emmen and Hoogendijk 1998), the relationship between exposure concentration and blood level was linear, and at all exposure concentrations (1,000, 2,000, 4,000, and 8,000 ppm), blood concentrations approached equilibrium at 55 min. Cardiac sensitization is considered a concentration threshold phenomenon (page 146).

-- Emmen HH, Hoogendijk EMG. 1998. Report on an ascending dose safety study comparing HFA-13a with CFC-12 and air, administered by whole-body exposure to healthy volunteers. MA-250B-82-306, TNO Report V98.754, The Netherlands Organization Nutrition and Food Research Institute, Zeist, The Netherlands.
-- Reinhardt CF, Azar A, Maxfield ME, Smith PE, Mullin LS. 1971. Cardiac arrhythmias and aerosol "sniffing." Arch Environ Health 22:265-279.
Ref:
National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels. Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. National Academy Press, Washington DC. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X.
Online at: http://books.nap.edu/books/030908511X/html/index.html

Subject #3 was the first volunteer exposed to HFC-134a. The exposure concentration was 4000 ppm (0.4% v/v) and was scheduled to last for 30 minutes with a 5-minute postexposure evaluation period as was accomplished in the Halon 1301 portion of the study. Approximately 4.5 minutes into the exposure, the subject lost consciousness and both pulse and blood pressure dropped to zero. The exposure was immediately aborted and the subject was removed from the exposure apparatus. Medical personnel intervened and after pulse and blood pressure were restored the subject was administered 100% oxygen. Blood pressure and pulse remained low (approximately 1/2 of baseline) and the subject could not maintain consciousness in a seated position. The subject was reclined and moved to an operating room recovery area where he rested for approximately 1 hour after which the subject's vital signs had returned to pre-exposure values... Subject #5 was also exposed to 4000 ppm (0.4% v/v) HFC-134a. There was some difficulty with blood collection and manipulation of the cannula was noted, but exposure was uneventful through the first 10 minutes of exposure. Breathing effort and rate appeared normal. At approximately 10.5 minutes into the exposure the subject's blood pressure and pulse began to rise rapidly and the subject gave the hand signal for possible trouble. His pulse rose rapidly until it was double the pre-exposure value, at which time the subject gave the hand signal to terminate the exposure. The exposure was aborted and the subject began breathing room air, but the in-dwelling cannula was not removed from the subject. After 30 seconds, the subject's blood pressure and pulse were at pre-exposure levels. The HFC-134a concentration in blood reached 0.70 mg/L at the point where the exposure was terminated (Figure 3). Subject #5 breathed room air for 1 hour and was then re-exposed to 2000 ppm (0.2% v/v) HFC-134a. After 2.5 minutes of exposure, the subject's blood pressure and pulse again rose rapidly, the subject signaled trouble and the exposure was terminated. The subject's vital signs returned to pre-exposure levels within 30 seconds after the exposure was terminated... No further human HFC-134a exposures were conducted. In addition to the monitored effects, there were several subjective effects associated with the inhalation exposures to HFC-134a. Subject #3 reported problems with dizziness and balance following the exposure. At the time of this report (6 weeks post exposure), both the dizziness and balance problems still persisted. Subject #5 reported chest tightness and a headache with associated dizziness immediately following the exposure. The headache subsided by the time the subject woke up the day following the exposure. The day following the exposure, subject #5 reported unusual feelings in the chest resembling "flutters". The chest tightness was reported to subside within 3 days of the exposure and the "flutters" within 2 weeks of the exposure. As with subject #3, subject #5 was still experiencing dizziness and balance problems at the time of this report (6 weeks post exposure). Subject #5 also reported persistent ringing in the ears which was still present at the time of this report. The adverse events observed during the exposures to HFC-134a and HFC-227ea were unexpected and inconsistent with the published data... Based on published work, regulatory approval and commercial use of Halon 1301, HFC-134a and HFC-227ea, the exposure levels selected for the 30-minute inhalation exposures were expected to be without adverse effects in humans.
Ref:
1997. Human Inhalation of Halon 1301, HFC-134a and HFC-227ea for Collection of Pharmacokinetic Data.

http://www.fluoridealert.org/pesticides/1.1.1.2.3.3.3-Hep.97.REPORT.htm

- also available at http://www.autofrost.com/r134atox.txt

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

-- Health Hazards - General ... Inhalation of high concentrations may also result in temporary alteration of the heart’s electrical activity by increasing the sensitivity of the heart to the arrhythmogenic action of epinephrine, causing irregular pulse, palpitations, or inadequate circulation (Dupont, 1996A; Dupont, 1996F; OSHA, 1998; Reprotext, 2003). Deliberate inhalation (“sniffing”) may cause death without warning (Dupont, 1996A; Dupont, 1996F; OSHA, 1998).
-- Acute Effects ... Inhalation of high concentrations (~5,000 ppm) is associated with the development of arrhythmias and sudden death due to myocardial sensitization to endogenous catecholamines (e.g., epinephrine).
-- 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.

-- Populations at Special Risk: Employees /with cardiovascular disease are/ at increased risk. [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) PublicationNo. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.]
-- There are isolated reports of poisoning from exposure to refrigerants and solvents, and some studies showing a higher incidence of coronary heart disease among hospital personnel are required to establish causal relationship between fluorine containing organic compounds, and cardiovascular and bronchopulmonary diseases among exposed workers. The high incidence of cancer among hospital personnel repeatedly exposed to fluorine-containing general anesthetics raises a fundamental need to examine other chlorofluorocarbon-exposed workers for similar effects. /Fluorocarbons/ [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1209]
-- Clinical pathologists exposed to fluorocarbons in the preparation of frozen tissue sections have been seen to develop coronary heart disease. /Fluorocarbons/ [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1209]
-- Fluorocarbon propellants are anesthetic and cardiotoxic. ... Aerosol propellants produce hallucinogenic effects, and, rarely, contact dermatitis. /Fluorocarbon propellants/ [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 528]
-- Deaths resulting from cardiovascular collapse after arrhythmias have been reported after inhalation of Freons 11 and 12. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 528]
-- The toxicity of Chlorofluorocarbons (CFCs) had been considered to be low; it is absorbed via the lungs and undergoes little subsequent biotransformation. In the United States when sudden unexplained deaths of aerosol "sniffers" were reported they were considered to be possibly due to cardiac arrhythmias induced by the CFC propellants. /CFCs/ [Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992. 1299]
-- Ten subjects /were exposed/ to CFC-11, CFC-12, CFC-114, two mixtures of CFC-11 and CFC-12, and a mixture of CFC-12 and CFC-114 (breathing concentrations between 16 and 150 g/cu m) for 15, 45, or 60 seconds, and found significant acute reduction of ventilatory lung capacity (FEV50, FEF25) on exposure to each chlorofluorocarbon, as well as bradycardia and
increased variability in heart rate in seven subjects, negative T-waves in two subjects (one was exposed to CFC-11 and CFC-12), and atrioventricular block in 1 subject (CFC-114). Mixtures exerted stronger respiratory effects than individual chlorofluorocarbon at the same level of exposure. [WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons p.90 (1990)]
-- Propellant /fluorocarbon/ gases were generated from commercial aerosol units and applied to the from distance of 50 cm for periods of 15 to 60 sec. At a measured concn of 95,000 mg/cu m (1700 ppm), there was a biphasic change in ventilation capacity, the first reduction occurring within a few minutes after exposure, and second delayed until 13 to 30 min after exposure, and second delayed until 13 to 30 min after exposure. Most subjects developed bradycardia, and inversion of the T-wave. /Propellant gases/ [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1201]
-- Freon 11, inhaled at 5% concentration, sensitizes the myocardium to epinephrine. A 6% concentration results in apnea and areflexia. A 10% concentration produces cardiac arrhythmias. Deaths resulting from cardiovascular collapse after arrhythmias have been reported after inhalation of /Freon 11/ ... . [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 528]
-- 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)]
-- A SPECIAL CLASS OF CHEMICALS SUBJECT TO ABUSE BY INHALATION ARE THE FLUOROHYDROCARBONS ... THE "SNIFFING" OF SUCH AEROSOL SPRAYS IS HAZARDOUS PRACTICE. ... 110 "SUDDEN SNIFFING DEATHS" /HAVE BEEN IDENTIFIED/ ... IN EACH CASE THE VICTIM SPRAYED THE AEROSOL INTO A PLASTIC BAG, INHALED THE CONTENTS, BECAME EXCITED, RAN 90 M OR SO, COLLAPSED, & DIED. NECROPSY FINDINGS WERE LARGELY NEGATIVE ... ALTHOUGH AMOUNT OF PROPELLANT ABSORBED INTO BLOOD FROM USE OF HAIRSPRAY, COSMETIC, HOUSEHOLD, & MEDICATED AEROSOLS MUST VARY WITH CIRCUMSTANCES, PHYSICIAN IS ADVISED TO COUNSEL ... PATIENT ON POTENTIAL DANGERS, PARTICULARLY FROM THEIR USE IN POORLY VENTILATED CONFINED AREAS. IT IS POSSIBLE THAT PATIENTS WITH CARDIAC OR RESPIRATORY DISORDERS MAY PROVE ESPECIALLY SUSCEPTIBLE. /FLUOROHYDROCARBONS/ [Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 910]
-- -- 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]
-- ... Workers who spilled a large volume of CFC-11 were exposed to high concentrations & developed signs of narcosis. One of the workers became unconscious, & another experienced tachycardia. [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. 1621]

Ref: Hazardous Substances Data Base for TRICHLOROFLUOROMETHANE.
http://www.fluoridealert.org/pesticides/Trichlorofluorometha.TOXNET.htm

Trichlorotrifluoromethane - Solvent, US EPA List 2 Inert - CAS No. 76-13-1

-- Interactions: The interaction of Freon 113 and hypoxia on the heart conduction system was investigated by using the isolated perfused hearts from Wistar rats. The mean preexposure heart rate was 214.8 beats per minute and the mean preexposure atrioventricular conduction time (PQ interval was 42.9 milliseconds. Freon 113 alone elicited significant change to control levels in heart rate which was enhanced by the coadministration of hypoxia. An enhanced delayed PQ interval was noted following coadministration of Freon 113 and hypoxia, although significant PQ interval changes were noted with Freon 113 alone or with hypoxia alone. In the coadministration group, a 2:1 atrioventricular block was elicited in two of four hearts. It was suggested that in occupational deaths among Freon 113 workers, there may be complex interactions between hypoxia, enhanced cardiac sensitivity to circulating epinephrine, and direct alterations of cardiac muscle cell membrane potentials which result in arrhythmias following Freon 113 exposures. [Kawakami T et al; Toxicol Indust Health 6 (3/4): 493-8 (1990)]
-- .. CARDIOTOXIC EFFECTS, MANIFESTED IN ARRHYTHMIAS ... ARE ASSOCIATED WITH PULMONARY EXPOSURE TO FLUOROCARBONS, ESPECIALLY ... FLUOROCARBON 113 ... . [Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 293]
-- .. Working with high conc of CFC-113 or other chlorofluorocarbons in confined spaces has the potential to cause death by cardiac arrhythmia, asphyxiation, or both. ... 4 reports of 12 fatalities resulting from occupational exposure to CFC-113 under conditions typical of situations in which CFC-113 can cause death. In most of the reports, the conc of CFC-113 was not specified. However, in one of the deaths from cardiac arrhythmia, the exposure was for 1 min & the CFC-113 concn measured 24 hr after exposure was 7600 ppm. In a death from asphyxiation, the CFC-113 conc was estimated to be 300,000 ppm, but the duration of exposure was not stated; however from the description of the incident, the exposure was relatively brief. [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, 1991.1633]
-- IN EXPERIMENTAL ANIMALS VARIABLE DEGREES OF TACHYCARDIA, MYOCARDIAL DEPRESSION, AND HYPOTENSION HAVE BEEN DESCRIBED. [Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 293]
-- TRICHLOROTRIFLUOROETHANE CAUSED TACHYCARDIA, HYPOTENSION IN ANESTHETIZED RHESUS MONKEYS WHEN INHALED @ 2.5-5%. [AVIADO DM, SMITH DG; TOXICOL 3 (2): 241-52 (1975)]
-- TRICHLOROTRIFLUOROETHANE @ 2.5 & 5% DEPRESSED VENTRICULAR FUNCTION IN HEART-LUNG PREPN FROM DOG. [AVIADO DM, BELEJ M; TOXICOLOGY 3 (1): 78-86 (1975)]
-- Various animal studies (non-human primates and dogs) have indicated that acute exposure to high concn of CFC-113
(as low as 2,000 ppm or 15,400 mg/cu m in a 6 hr exposure period) followed by a large injected dose of epinephrine resulted in cardiac arrhythmias. [USEPA; Health Assessment Document for 1,1,2-Trichloro-1,2,2-Trifluoroethane p.2 (1983) EPA-600/58-82-002F]
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 ... Inhalation of high concentrations may also result in temporary alteration of the heart’s electrical activity by increasing the sensitivity of the heart to the arrhythmogenic action of epinephrine, causing irregular pulse, palpitations, or inadequate circulation (Dupont, 1996A; Dupont, 1996F; OSHA, 1998; Reprotext, 2003). Deliberate inhalation (“sniffing”) may cause death without warning (Dupont, 1996A; Dupont, 1996F; OSHA, 1998).
-- Acute Effects ... Inhalation of high concentrations (~5,000 ppm) is associated with the development of arrhythmias and sudden death due to myocardial sensitization to endogenous catecholamines (e.g., epinephrine).
-- 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

Prenatal developmental in nonrodents (rabbit). Maternal NOAEL: 100 mg/kg/day Maternal LOAEL: 250 mg/kg/day based on increased mortality, increased vaginal/ anal bleeding. Developmental NOAEL: 50 mg/kg/day Developmental LOAEL: 100 mg/kg/day based on abnormally shaped heart (one fetus at 100 mg/kg/day and 3 fetuses from 2 litters at 250 mg/kg/day)... In historical control data provided by the registrant, there were no reported instances of abnormally shaped hearts.
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

Trifluralin - Herbicide - CAS No. 1582-09-8

-- ** 089 036915 "A Teratology Study (I) of Trifluralin (EL-152, Compound 36352) Administered Orally to Dutch Belted Rabbits." (Lilly Research Labs., 10/31/84, Study B02283 and Study BO1784) Trifluralin (96.7% pure), lot 00554AP2; 0, 100, 225, 500, or 800; oral gavage, days 6 - 18; 20/group; maternal NOEL = 225 mg/kg (maternal death and abortions), developmental toxicity NOEL = 225 mg/kg (decreased fetal weight); Complete and ACCEPTABLE WITH 036916. No adverse developmental toxicity reported. JAP, 11/18/85. EPA one-liner: Maternal NOEL = 225 mg/kg (abortions and anorexia), fetotoxic NOEL = 225 mg/kg (decreased percentage of live fetuses - cardiomegally and wavy ribs at 500 mg/kg/day); Core grade = Supplementary
Ref: SUMMARY OF TOXICOLOGY DATA TRIFLURALIN. California EPA, Department of Pesticides, Medical Toxicology Branch. Revised as of 11/29/95.
http://www.cdpr.ca.gov/docs/toxsums/pdfs/597.pdf
Note: Definition of "Cardiomegaly" - an abnormal enlargement of the heart.

 
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