Organic Fluoride Compounds

Organic Fluoride Compounds


1996 – 2004 PFPC

  Over 60 years ago it was first proven that all fluoride compounds – inorganic or organic – were anti-thyroid agents (Kraft, 1937). It was merely a matter of amplification. Some compounds were more powerful than others. Below is a list of a few fluoride compounds whose anti-thyroid effects are established, and which are included in many of today’s medications, as well as in pesticides.

COMPOUND

REFERENCE

3-fluoro-4-methoxy-phenylacetic acid Kraft & Dengler, 1952
3-fluoro-4-oxy-phenylacetic acid (Capacin) Kraft & Dengler, 1952
May, 1950
Casterra, 1947 etc.
[p-fluorophenyl]-ethylketone Kraft & Dengler, 1952
3-fluoro-5-bromotyrosine Euler & Eichler, 1949
Iodofluorotyrosine Euler & Eichler, 1949
Fluorotyramine Euler & Eichler, 1949
1-(3-fluoro-4-oxy) -phenyl-1-methyl-2-methyl-
amino-ethane
Euler & Eichler, 1949
1-acetamino-2-fluoro-benzene-
sulfonic-acid amide(fluorinated Prontalbin)
Euler & Eichler, 1949
Fluorphtiocol Euler & Eichler, 1949
Fluorobenzoic acid Kraft, 1937
Fluorotyrosine (Pardinon) Kraft, 1937
PFOS (Scotchgard)
perfluorooctance sulfonate
Lau et al, 2002
PFDA
perfluorodecanoic acid
Langley & Pilcher, 1985
Gutsall et al, 1989
1,1-dichloro-N-[(dimethylamino)
sulfonyl]-1-fluoro-N-
(4-methylphenyl)
methanesulfenamide
(Tolylfluanid)
U.S. Federal Register, 2002
Fluoxetine (Prozac)
Paroxetine (Paxil)
Jackson & Luo, 1988
Shelton et al, 1993
PMSF
phenylmethanesulfonyl fluoride
Brtko et al, 1993
Trifluoroiodomethane Dodd et al, 1999
Fluoroacetate Paterson, 1976
N-2-fluorenylacetamide Stora et al, 1981
Trifluoperazine Zofkova & Bednar, 1988; 1986
Cyano(4-fluoro-3-phenoxyphenyl) methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate
(Cyfluthrin)
Federal Register, April 15, 1998
N-(4-fluorophenyl)-N-(1-methylethyl)-2-[[5-(trifluoromethyl)- 1,3,4-thiadiazol-2-yl]oxy]acetamide (Pesticide Flufenacet – Bayer; FOE 5043) Federal Register, August 6, 1999;
Bayer MSDS
N-(p-fluorophenyl)-6-[3-(trifluoromethyl)phenoxy]-2-pyridinecarboxamide (Picolinafen) Australia NRA, 2000
[R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate (Fluvastatin) IHP New Zealand, 2002
N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+ -) (Casodex – AstraZeneca) CTC Consult., 2002
8-chloro-6-(2-fluorophenyl) -1-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine (Midazolam) IHP New Zealand, 2002, Robison et al, 1994
a,a,a-trifluro-2,6-dinitro-N,N-dipropyl-p-toluidine (Trifluralin) US EPA, 1996
5-methoxy-4′-(trifluoromethyl) valerophenone       (E)-O-(2-aminoethyl)oxime maleate (Luvox) De Mendonca et al, 1997
1-chloro-1,1-difluoroethane
(Freon 142, Freon 142b)
CDC – The Registry of Toxic Effects of Chemical Substances
2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol -1-YL-dihydroxy-heptanoic acid atorvastatin (Lipitor) McCord & Goenka, 2000; Smith et al, 1991
RS)-2-{4-[3-chloro-5-(trifluoromethyl)-2-pyridyloxy]phenoxy}propionic acid (Haloxyfop) Quast et al, 1990
1,3-dichloro-6-(trifluoromethyl)-9-phenanthrene-methanol hydrochloride (Mefloquine – Lariam) Croft & Herxheimer, 2002;Conget et al, 1993
4-(2-Methylsulfonyl-4-trifluoro-
methyl-benzoyl)-5-cyclopropyl isoxazole (Isoxaflutole
)
European Commission – Isoxaflutole (2003)
2-chloro-4-trifluoromethyl-3′-ethoxy-4′-nitrodiphenyl ether (Oxyfluorfen) US EPA, 2001
4-chloro-5-(methylamino)-2-(3-(trifluoromethyl)phenyl-3(2H)-pyridazinone (Norflurazon) Federal Register, January 12, 1994
2-[4,6-bis(difluoromethoxy)pyrimidin-2-ylcarbamoylsulfamoyl] benzoic acid (Primisulfuron) Federal Register, January 12, 1994
2,4-dinitro-N3,N3-dipropyl-6-(trifluoromethyl)-1,3-benzenediamine
(Prodiamine – “Barricade”)
Hurley, 1998
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-(1,R,S)-(trifluoromethyl)sulfinyl)-1H-pyrazole-3-carbonitrile (Fipronil) Federal Register, June 20, 1997
(2,3,5,6-tetrafluoro-4-methylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Tefluthrin) Federal Register, November 26, 1997
(RS)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propyl 1,1,2,2-tetrafluoroethyl ether (Tetraconazole) Federal Register, October 19, 1999
[3-(3-chloro-5-trifluoromethyl-2-pyridinyloxy)-4-chlorophenyl]-1-(2,6-difluorobenzoyl)-urea (Fluazuron) WHO, 1997
1-(4-chlorophenyl)-3-(2,6-difluorobenzoyl)urea (Diflubenzuron) Federal Register, September 21, 1995
2-{4{(5-chloro-3-fluoro-2-pyridinyl)oxy}phenoxy}-, 2-propynyl ester (Clodinafop-propargyl) Federal Register, June 20, 2000
1-chloro-4-(trifluoromethyl)
benzene (CTFT, PCBTF)
Lilly Research Laboratories, 1983
3-trifluoromethyldiphenylamine-2-carboxylic acid (Flufenamic acid) Chalmers et al, 1993
4-fluoro-3-nitroaniline (in hair-dyes) Barbee et al, 1984
Telomer BA, telomer ethoxylate,telomer urethane polymer EWG, 2002
1-octanesulfonamide,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-
heptadecafluoro-N-(2-hydroxyethyl)-N-ethyl-(N-EtFOSE alcohol)
EWG, 2002
2-(difluoromethyl)-5-(4,5-dihydro-2-thiazolyl)-4-(2-methylpropyl)-6-(trifluoromethyl)- (Thiazopyr) US EPA – Pesticide Fact Sheet: Thiazopyr (February 20, l997)         
1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3(S)-hydroxypropyl)-4(S)- (4-hydroxyphenyl)-2-azetidinone (Ezetimibe – ZETIA;also in Vytorin) More to come…

References:

Barbee SJ, Goldenthal EI, Rajasekaran DE, Spicer EJ – “Subchronic oral toxicology of 4-fluoro-3-nitroaniline in the rat” Toxicol Appl Pharmacol 72(3):400-5 (1984)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=671 0491

Bayer Flufenacet MSDS – http://www.fs.fed.us/foresthealth/pesticide/data/Domain_msds.pdf

Brtko J, Knopp J, Baker ME – “Inhibition of 3,5,3′-triiodothyronine binding to its receptor in rat liver by protease inhibitors and substrates” Mol Cell Endocrinol 93(1):81-6 (1993)

Casterra H – “Erfahrungen mit einem neuen organischen Fluorpräparat bei Hyperthyreosen” Das Deutsche Gesundheitswesen 2(22):704-705 (1947)

CDC- The Registry of Toxic Effects of Chemical Substances, CAS #: 75-68-3 [Toksikologiya Novykh Promyshlennykh Khimicheskikh Veshchestv. Toxicology of New Industrial Chemical Substances.]

Chalmers DK, Scholz GH, Topliss DJ, Kolliniatis E, Munro SL, Craik DJ, Iskander MN, Stockigt JR – “Thyroid hormone uptake by hepatocytes: structure-activity relationships of phenylanthranilic acids with inhibitory activity” J Med Chem 36(9):1272-7 (1993)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=848 7264

Conget JI, Navarro M, Navarro P, Corachan M – “Changes in the thyroid hormone profile following the prophylactic administration of mefloquine” Med Clin (Barc) 100(13):516 (1993)

Croft AM, Herxheimer A – “Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement?” BMC Public Health 2(1):6 (2002) FULL TEXT

CTC Consult – Drug Info:Casodex
http://www.ctclconsult.com/pdrdruginfo/html/03900200.htm

  • “…increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 2/3 human therapeutic concentrations*)”

De Mendonca Lima CA, Vandel S, Bonin B, Bechtel P, Carron R – “Maprotiline versus fluvoxamine: comparison of their effects on the hypothalamo-hypophyseal-thyroid axis” Encephale 23(1):48-55 (1997)

Dodd DE, Leahy HF, Feldmann ML, English JH, Vinegar A – “Reproductive Toxicity Screen of Trifluoroiodomethane (CF(3)I) in Sprague-Dawley Rats” Inhal Toxicol 11(11):1041-1055 (1999)

Euler H, Eichler O, Hindemith H – “Über die Wirkung einiger organischer Fluoride bei chronischer Darreichung” Arch exp. Pathol Pharmakol 206:75-82 (1949)

Euler H, Eichler O – “Ueber die Wirkung von Fluor in organischer Bindung auf das Zahnsystem der Ratte” Arch exp Pathol Pharmakol 199:179-187 (1942)

EUROPEAN COMMISSION – Isoxaflutole Sanco/3136-99/Final (2003) PDF

EWG – Presentation to CDC – “Perfluorinated chemicals: Justification for Inclusion of this Chemical Class in the National Report on Human Exposure to Environmental Chemicals” (2002) PDF

“The fluorinated telomer alcohols also affect the thyroid gland. Although detailed study information is claimed as CBI (Confidential Business Information) and redacted from the public record, presentations made by the Telomer Research Group to the US EPA indicate that the thyroid was a target for all of the fluorinated telomers tested (telomer BA, telomer ethoxylate, telomer urethane polymer) (DuPont 2002a). In addition, PFOA is a metabolic product of telomer 8:2, which is a mixture of telomers (DuPont 2002c).”

Federal Register: 67 (186):60130-60142 (September 25, 2002)
http://www.epa.gov/fedrgstr/EPA-PEST/2002/September/Day-25/p24094.htm

“…the examination also noted a decrease in thyroxine levels in females (~ 45%) and a non-significant decrease in triiodothyronine (~ 40%)…”

“TTCA [tolyfluanid metabolite]… behaves as a goitrogenic compound with a potency approximately equal to propylthiouracil (PTU), a known thionamide inhibitor of initial thyroid hormone synthesis.”

Federal Register: 65 (121):38765-38774 (June 22, 2000)

Federal Register: 64 (151):42839-42846 (August 6, 1999) http://www.epa.gov/fedrgstr/EPA-PEST/1999/August/Day-06/p20317.htm

Federal Register: 64 (198):55714-55721 (October 14, 1999)
http://www.epa.gov/fedrgstr/EPA-PEST/1999/October/Day-14/p26861.htm

Federal Register: 63 (72):18411-18420 (April 15, 1998)

Federal Register: 62 (228) :62954-62961 (November 26, 1997)

Federal Register: 62 (119): 33641-33647 (June 20, 1997)

Federal Register: 60 (183):49141-49149 (September 21, 1995)

Federal Register: January 12, 1994
http://www.epa.gov/tri/frnotices/59fr1788.htm

Gutshall DM, Pilcher GD, Langley AE – “Mechanism of the serum thyroid hormone lowering effect of perfluoro-n-decanoic acid (PFDA) in rats” J Toxicol Environ Health 28(1):53-65 (1989)
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=2506363&form=6&db=m&Dopt=r

Hurley PM – “ Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents” Environ Health Perspect 106(8):437-45 (1998)

“prodiamine..enhance the hepatic metabolism and excretion of thyroid hormone”.

Information for Health Professionals (New Zealand) – Datasheet – Fluvastatin (Lescol) http://www.medsafe.govt.nz/Profs/Datasheet/l/Lescolcap.htm

see also: FDA, 2002

Information for Health Professionals (New Zealand) – Datasheet – Midazolam
http://www.medsafe.govt.nz/Profs/Datasheet/m/Midazolaminj.htm

also: Midazolam – Biodocs http://www.bidocs.com/renetnt:/Prescribing+Information/PIs/Roxane/Midazol am/Midazolam+Hydrochloride+Syrup.pdf

“In addition, an increased incidence of thyroid
follicular cell adenomas and carcinomas was recorded in male rats treated with 18-24 mg/kg per day.”

IRIS – Health Assessment – Haloxyfop-methyl [CASRN 69806-40-2]US EPA Integrated Risk Information System (IRIS)
http://mng-unix1.marasconewton.com/iris/iris_dev/subst/0467.htm

“A significant decrease in male and female triiodothyronine and free thyroxine values was accompanied by a significant decrease in male and female relative thyroid/parathyroid weights”

Jackson IM, Luo LG – “Antidepressants inhibit the glucocorticoid stimulation of thyrotropin releasing hormone expression in cultured hypothalamic neurons” J Investig Med 46(9):470-4 (1988) MEDLINE

Kraft K – “Beiträge zur Biochemie des Fluors I.Über den Antagonismus zwischen Fluor und Thyroxin.” Hoppe-Seglers Z.Physiol. Chem 245:58 -65 (1937)

Kraft K, Dengel F – “Verfahren zur Herstellung kernsubstituierter Phenylessigsäuren”, German Patent DE 819,696; filed Feb. 3, 1943; pat. Nov. 5, 1951 (A
compound acting similarly as fluorotyrosine, 3-Fluoro-4-hydroxyphenylacetic acid, was patented by
Kraft and Dengel of Knoll, pharmaceutical company of Ludwigshafen, and became known under the names of “Capacin”, “Kapacin”, and “Wiflucin” (marketed by Knoll) as a treatment against hyperthyroidism. -> s.a. The Merck Index, 9th edition, Merck & Co., Rahway, N.J., 1976)

Kraft K – “Über die Synthese einiger aromatischer Fluorverbindungen” Knoll Research, Chem Ber. 84(2):150-156 (1951)

Kraft K, Dengel F – “Über die Synthese einiger aromatischer Fluorverbindungen, II. Mitteilung” Chem Ber 85(6):577-582 (1952)

Lau C, Rogers JM, Thibodeaux JR, Hanson RG, Grey BE, Barbee BD, Richards J, Butenoff JL – “Maternal and developmental toxicity of perfluorooctane sulfonate (PFOS)in the rat” Toxicologist 66(1-S):25 (2002)

Langley AE, Pilcher GD – “Thyroid, bradycardic and hypothermic effects of perfluoro-n-decanoic acid in rats.” J Toxicol Environ Health 15(3-4):485-91 (1985)
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=4032495&form=6&db=m&Dopt=r

Lilly Research Laboratories – “ A subchronic (three-month) toxicity study in Fischer 344 rats given daily gavage doses of 4-chlorobenzotrifluoride (PCBTF)” (1983) EPA Document No. 40-8452058, Fiche No. OTS0507306 (1983)

McCord EL, Goenka S – “Development of thyroid follicular adenoma on simvastatin therapy” Tenn Med 93(6):210-2 (2000)

Paterson RA – “Metabolic control of rat heart glycolysis after acute ischaemia. Fluoracetate treatment and thyroid interactions” J Mol Cell Cardiol 2(3):193-210 (1971)

Picolinafen – Natural Registration Authority for Agricultural and Veterinary Chemicals (November 2000)

Quast JF, Yano BL, Dietz FK, Marler RM, Hayes WC – “Subchronic and reproductive toxicity and teratology of haloxyfop herbicide”Toxicologist 10(1):175 (1990)

Robison RL, Suter W, Cox RH – “Carcinogenicity and mutagenicity studies with fluvastatin, a new, entirely synthetic HMG-CoA reductase inhibitor” Fundam Appl Toxicol 23(1):9-20 (1994)

Shelton RC, Winn S, Ekhatore N, Loosen PT – “The effects of antidepressants on the thyroid axis in depression” Biol Psychiatry 33(2):120-6(1993)

Smith PF, Grossman SJ, Gerson RJ, Gordon LR, Deluca JG, Majka JA, Wang RW, Germershausen JI, MacDonald JS – “Studies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the rat” Toxicol Pathol 19(3):197-205 (1991)

Stora C, Aussel C, LaFaurie M, Formento JL – “Thyroid activity during hepatocarcinogenesis by N-2-fluorenylacetamide” J Cancer Res Clin Oncol 100 (1):41-50 (1981)

Umemoto et al – “N-fluoropyridinium salt and process for preparing same” US: 4,996,320, Sagami Chemical Research Center (JP) (1991)

Zofkova I, BednarJ – “Trifluoperazine inhibits thyrotropin-releasing hormone-stimulated TSH secretion” Horm Metab Res 18(9):621-4 (1986)

Zofkova I, Bednar J – “Effects of calcitonin, 1,25(OH)2 vitamin D3 and trifluoperazine on thyrotropic secretion and their mutual interactions” Exp Clin Endocrinol 92(3):268-74 (1988)

US EPA – Toxicology Chapter for RED (August 8, 2001)
http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxytoxchapter.pdf

US EPA – Reregistration Eligibility Decision (RED): Trifluralin (EPA 738-R-95-040;April 1996)

US EPA – Pesticide Fact Sheet: Thiazopyr (February 20, l997)            http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

“The primary target organs for thiazopyr toxicity in the rat, mouse and dog were the liver, thyroid, kidney and blood, with the liver being the most sensitive indicator of toxicity…Reverse T3 was increased at 28 days, and T3 was either not affected or increased…Results of the three studies suggest that increased glucuronidation, deiodination of T4 and T3, and increased rate of clearance of T4 from the blood and excretion of the hormone and its metabolites in the bile could significantly reduce the level of circulating T4 in the male rat. Results of these studies support the hypothesis that thiazopyr may induce thyroid tumors through a disruption of the thyroid-pituitary hormonal feedback mechanism circulating T4 in the male rat.”

WHO – Fluazuron: Toxicological Evaluation – WHO Food Additives Series 39 (1997)

Teli G – “Effects of fluoro-hydrocortisone on the rat thyroid” Riv Patol Clin 13(5):191-6 (1958)

======================

O’Hagan D, Schaffrath C, Cobb SL, Hamilton JT, Murphy CD – “Biochemistry: biosynthesis of an organofluorine molecule” Nature 416(6878):279 (2002)
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11907567&dopt=Ab stract

Buckle FJ, Saunders BC – “Toxic Fluorine Compounds Containing the C-F Link. Part VIII. Omega-Fluoro-carboxylic Acids and Derivatives Containing an Oxygen Atom as a Chain Member” Journal of the Chemical Society (England) 2774-8 (1949) OSTI ID: 443098

Saunders BC, Stacey GJ, Wilding IGE – “Toxic Fluorine Compounds Containing the C-F Link. Part II. Fluoroethanol and Its Derivatives” Journal of the Chemical Society (England) 1949: 773-7 (1949) OSTI ID: 4442839

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