Thyroid - Adverse Effects
Fluorinated and Fluoride Pesticides

beginning with
A-G • H-Z
 
 
See - brief information on the thyroid

The Endocrine System:


Illustration by K. Born in Our Stolen Future (1996)
by Theo Colborn, Dianne Dumanoski and JP Myers

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

-- Food and Agricultural Organization of the United Nations

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

Benfluralin (Benefin) - Herbicide - CAS No. 1861-40-1

208-079 167288, "Benefin: Two-Year Dietary Chronic Toxicity/Oncogenicity Study in Fischer 344 Rats", (Michael R. Moore, Corning Hazleton Inc, Vienna, VA., Laboratory ID # CHV 174-133, Sponsor Report # DR-0097-3397-005, 1 July 1996). Fifty CDF ® (F-344)CrlBR rats per sex per group received benefin in the diet at 0, 10, 100, 2500, and 5000 ppm for 2 yr. An additional 10 per sex per group at the same dose levels were designated for 1-yr interim sacrifice. Estimated achieved dosages were 0, 0.5, 5.4, 136, and 275 mg/kg/day in males, and 0, 0.7, 6.8, 168, and 331 mg/kg/day in females, respectively over weeks 1-104....Tumor incidence: thyroid follicular tumors (adenomas and carcinomas) increased in males (incidences of 1, 1, 1, 7, and 8 in controls through high dose, respectively) and females (incidences of 0, 0, 1, 5, and 4)... Tumors are possible adverse effects, which should be evaluated in perspective of the many indications of excessive exposures at effective dose levels. Green and Aldous, 4/11/00.
Ref: SUMMARY OF TOXICOLOGY DATA BENEFIN Chemical Code # 000053. June 15, 1998 Revised: April 21, 2000. California EPA, Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/b
enefin.ca.tox.rev.apr.2000.pdf

Benthiavalicarb-isopropyl - Fungicide - CAS No. 177406-68-7

Likely to be Carcinogenic to Humans. Malignant uterine tumors in female Fisher 344 rats; Liver tumors in both sexes of B6C3F1 mice with some supporting evidence of liver tumors in male rats; Thyroid follicular cell tumors in male B6C3F1 mice.
Ref:
April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs.
From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

Bifenthrin - Acaricide, Insecticide - CAS Numbers: 82657-04-3 (Cis); 83322-02-5 (Trans)

Limited data were available regarding endocrine effects in animals following oral exposure to pyrethroids. Serum levels of the thyroid hormones T3 and T4 were significantly decreased in mice administered fenvalerate at a dose level of 120 mg/kg/day for 15 days (Maiti and Kar 1998). Akhtar et al. (1996) reported similar effects in rats administered bifenthrin or lambda-cyhalothrin at daily oral dose levels of 0.5 mg/rat (approximately 0.75 mg/kg/day) and 0.2 mg/rat (approximately 2 mg/kg/day), respectively, for 21 days. Lambda-cyhalothrin treated rats also exhibited a significantly decreased serum T3/T4 ratio, relative to controls. In addition, both bifenthrin and lambda-cyhalothrin treatment resulted in significantly increased serum TSH levels, compared with control rats (p 39)
Ref: September 2001. Draft Toxicological Profile for Pyrethrins and Pyrethroids. US Department of Health and Human Services. Public Health Service Agency for Toxic Substances and Disease Registry.

Endocrine Disruption. EPA is required to develop a screening program to determine whether certain substances (including all pesticides and inerts) ``may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect....'' The Agency is currently working with interested stakeholders, including other government agencies, public interest groups, industry and research scientists in developing a screening and testing program and a priority setting scheme to implement this program. Congress has allowed 3 years from the passage of FQPA (August 3, 1999) to implement this program. At that time, EPA may require further testing of this active ingredient and end use products for endocrine disrupter effects.
Ref: Federal Register: November 26, 1997. Bifenthrin; Pesticide Tolerances. Final Rule.
http://www.fluoridealert.org/pesticides/bifenthrin.fr.nov.1997.htm

1-chloro-1,1-difluoroethane - Solvent, EPA List 2 Inert - CAS No. 75-68-3

Inhalation rat; lowest published toxic concentration: 500 gm/m3/4 hour/4 week- intermittent; Endocrine: Evidence of thyroid hypofunction.
Ref: Toksikologiya Novykh Promyshlennykh Khimicheskikh Veshchestv. Toxicology of New Industrial Chemical Substances. For English translation, see TNICS*. (Izdatel'stvo Meditsina, Moscow, USSR) No.1- 1961-
As cited by The Registery of Toxic Effects of Chemical Substances (RTECS)

http://www.cdc.gov/niosh/rtecs/kh74bad0.html#TPKVAL

Cloransulam-methyl - Herbicide - CAS No. 147150-35-4

-- Cloransulam-methyl was evaluated in 13-week dietary studies in rats, mice and dogs. The primary target organs identified in these studies were the kidneys (rat), the liver (mouse and dog), and thyroid (rat). An NOEL was not determined in the rat based upon minor histopathological changes in the kidney (males) and the liver (females).
-- Chronic toxicity. In a 2-year combined chronic toxicity/ oncogenicity study in the rat, the NOEL for chronic toxicity was 10 mg/ kg/day based upon kidney and thyroid effects: hypertrophy of collecting duct epithelial cells and vacuolation consistent with fatty change in the proximal tubules of males and females, and an increase in the incidence of mineralization of the renal pelvis in males. Thyroid changes were confined to the high dose males and consisted of hyperplasia and hypertrophy of follicular epithelium.
Ref: Federal Register, March 26, 1997. DowElanco; Pesticide Tolerance Petition Filing.

http://www.epa.gov/fedrgstr/EPA-PEST/1997/March/Day-26/p7496.htm

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

Limited data were available regarding endocrine effects in animals following oral exposure to pyrethroids. Serum levels of the thyroid hormones T3 and T4 were significantly decreased in mice administered fenvalerate at a dose level of 120 mg/kg/day for 15 days (Maiti and Kar 1998). Akhtar et al. (1996) reported similar effects in rats administered bifenthrin or lambda-cyhalothrin at daily oral dose levels of 0.5 mg/rat (approximately 0.75 mg/kg/day) and 0.2 mg/rat (approximately 2 mg/kg/day), respectively, for 21 days. Lambda-cyhalothrin treated rats also exhibited a significantly decreased serum T3/T4 ratio, relative to controls. In addition, both bifenthrin and lambda-cyhalothrin treatment resulted in significantly increased serum TSH levels, compared with control rats (p 39)
Ref: September 2001. Draft Toxicological Profile for Pyrethrins and Pyrethroids. US Department of Health and Human Services. Public Health Service Agency for Toxic Substances and Disease Registry.

Abstract (1996). The effects of organochlorine, organophosphorus, and pyrethroid insecticides on thyroid function were studied in rats. Young adult male albino-rats were gavaged with 0.5 milligram (mg) per rat heptachlor (76448), 0.60mg/rat benzene-hexachloride (58-89-9) (BHC), 0.06mg/rat malathion (121-75-5), 0.2mg/rat O,S-dimethyl-phosphoramidothion (10265-92-6) (Monitor), 0.5mg/rat bifenthrin (82657-04-3) (Talstar), or 0.2mg/rat lamdacyhalothrin (91465-08-6) (Karate) daily for 21 days. They were then killed and weighed. The serum was separated and analyzed for triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) using radioimmunoassays. Except for Talstar, none of the insecticides affected body weight gain. Talstar significantly decreased body weight gain. Heptachlor and Monitor did not significantly affect serum T3, T4, and TSH concentrations. Malathion, BHC, Karate, and Talstar significantly decreased serum T3 and T4 concentrations and increased TSH concentrations. Karate significantly decreased the T43 concentration. None of the other insecticides altered the T4/T3 ratio. The authors conclude that exposure to organochlorine, organophosphorus, and pyrethroid insecticides for a relatively short time can suppress thyroid secretory activity in young adult rats. The decrease in body weight gain induced by Talstar suggests that pyrethroid insecticides can inhibit growth rate.
Ref: Insecticide-Induced Changes in Secretory Activity of the Thyroid Gland in Rats; by Akhtar N, Kayani SA, Ahmad MM, Shahab M. Journal of Applied Toxicology, Vol. 16, No. 5, pages 397-400, 26 references, 1996.

Dichlofluanid - Wood Preservative, Antifoulant, Fungicide, Acaricide - CAS No. 1085-98-9

-- Professional operators would not be expected to use products for prolonged periods, therefore a value from a one year study would be suitable. The other reported end points (thyroid tumours and osteosclerosis) were associated with chronic exposure and much higher doses. Acceptable risk assessments would require a safety margin of about 100 over the NOAEL 2.5 mg kg -1 d -1 . Consequently these would also offer a high margin of safety against the longer term end points.
-- Carcinogenicity - The only carcinogenicity data relate to the oral route of exposure, with studies performed in the rat and mouse. No evidence of carcinogenic potential was observed in the mouse. However, in the rat dichlofluanid was found to cause an increase in the incidence of thyroid follicular cell tumours at the highest dose level of 300-420 mg kg -1 d -1 . These tumours occurred at a single site, were of late onset and generally benign pathology. Dichlofluanid has been thoroughly examined for genotoxic potential and the available data indicate that dichlofluanid was not an in vivo somatic cell or germ cell mutagen. The results of the histopathological examination of the thyroid follicular cell tumours are consistent with a non-genotoxic aetiology. Overall, it can be concluded that dichlofluanid is a non-genotoxic rat thyroid follicular cell carcinogen.
-- Dichlofluanid was found to cause an increase in the incidence of thyroid tumours at highest dose level of 300-420 mg kg -1 d -1 . These tumours occurred at a single site, were of late onset and generally benign pathology. These pathology findings are indicative of a non-genotoxic aetiology, consistent with the overall conclusions from the genotoxicity studies. Rat thyroid tumours arise as a secondary consequence of perturbations in thyroid hormone homeostasis, leading to prolonged stimulation of the thyroid gland via a positive feedback mechanism. Interspecies comparisons of the relative sensitivities of thyroid hormone homeostasis to disturbance by xenobiotics have shown that humans are markedly less sensitive than rats. Overall, the ACP considered that the rat thyroid follicular tumours would not be relevant to human health if they were due to treatment-related hormone imbalance. However it concluded that the in vitro studies did not convincingly demonstrate inhibition of thyroid peroxidase. Whilst it seemed probable that the mechanism was non-genotoxic, a more convincing explanation of the mechanism was required.
-- One-year Study. A repeat-exposure study using Beagles (4/dose/sex) is available; it was GLP and OECD Annex V compliant. Animals were administered either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid (90 % purity) in capsule form for one year. The top dose was reduced at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity. As a NOEL could not be established with the initial dosing regime, a subsequent study was carried out in which 0 or 1.25 mg kg -1 d -1 dichlofluanid was used... Levels of the thyroid hormones T3 (28 %) and T4 (37 %) were elevated at study termination in animals receiving 37.5 mg kg -1 d -1 . At necropsy, treatment-related pathology findings were reported in males receiving 37.5 mg kg -1 d -1 . Externally one animal was pale with discoloration of the kidney, liver and thyroid which was also reduced in size. There were also non-significant decreases in both absolute and relative thyroid weights (39 % and 33 % respectively) and testes weights (25 % and 15 % respectively). Two animals were found to have bilateral testicular degeneration; no control animals were reported with bilateral testicular degeneration. In females absolute (15-60 %) and relative (25-150 %) ovary weights were increased in all treatment groups. These increases were not dose related or statistically significant... Minimal to severe thyroid follicular cell degeneration was reported in all animals from the top-dose group and one male from the middle-dose group. The pituitary glands of several animals from the top-dose group were found to have mild to severe hyperplasia (2 males and 2 females) of large pale staining cells (basophils) in the pars distailis, among pituitary basophils are the thyrotrophs... The thyroids of males exhibited follicular cell hypertrophy; 0/50 (control), 2/10 (180 ppm), 1/10 (900 ppm) and 3/10 (4500 ppm)... In the thyroid gland a statistically significant increase in the lesion described as a focal follicular growth anomaly was established in both sexes at the top dose. In males the following data were presented : 1/50 (controls); 1/50 (180 ppm); 2/50 (900 ppm); and 3/49 (4500 ppm) and in females the data were : 0/50 (controls); 0/50 (180 ppm); 2/50 (900 ppm); and 4/49 (4500 ppm)... Two females sacrificed in extremis were found to have thyroid follicular cell carcinoma; one animal from each of the middle- and top-dose groups. No statistically significant neoplastic events were reported. However, a significant trend in the distribution of thyroid adenomas was found in both sexes. A NOEL could not be set due to the effects of excess fluoride and cranial osteosclerosis at the lowest dose. The NOEL for neoplasms could be set at 900 ppm (equivalent to 54.4 and 73.1 mg kg -1 d -1 for males and females respectively) due to the increase in thyroid tumours seen at the top dose. [Unpublished, 1993(b)]
Table 3.19 : Thyroid Hormone Levels During The Study
 
T3 (ng 100 ml -1 )
T4 (mg 100 ml -1 )
day 0 4500 ppm % 0 4500 ppm %
7 55.2 45.7 -17.3 3.9 2.6 -32
21 52.9 45.3 14.5 4.2 3.5 -16
63 67.6 61.8 -8.7 5.7 5.1 -11.5

Table 3.20 : Thyroid Weights At Day 7
dose ppm control 150 500 1500 4500
weight mg 10 14 13 15 16
% increase - 40 30 50 60

Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Also available at:

http://www.pesticides.gov.uk/citizen/Evaluations/206_dichlofluanid.pdf

In July 1998, discussing this pesticide because it was an Accession Treaty priority for A, the CMR Group agreed to classify it with Xn; R20 : Xi; R36 : R43 : N; R50-53. Symbols Xn and N. R-phrases 20-36-43-50/53. S-phrases (2-)24-37-60-61. The proposal was sent to DG XI and included in the 25th ATP. Regarding carcinogenicity, S argued that the evidence was too weak for classification; tumour findings were limited to high dose groups. B expressed doubts about the aetiology of the rat thyroid tumours and, in relation to this, UK noted that dichlofluanid was an inhibitor of thyroid peroxidase. As the carcinogenicity issue was not problematic under the Accession Treaty, the Group agreed to conclude the present discussion with no classification for carcinogenicity. However, dichlofluanid would be referred back to the Pesticides Group for further consideration of carcinogenicity classification. A explained that the thyroid tumours seen in rats were limited to high dose groups and suggested classification with Carc Cat 3; R40. A also noted cranial effects in rodents that justify R48/22. B, with support from IRL, P and E, considered the mechanism of tumour induction to involve liver enzyme induction which did not justify classification for carcino-genicity because it was not-relevant to humans. UK noted, however, data suggesting inhibition of thyroid peroxidase which would justify classification. The Group agreed that more information was required from Industry on these issues. A and UK offered to send their interpretation of the data made available by Ind.
Ref: EUROPEAN COMMISSION DIRECTORATE GENERAL JRC JOINT RESEARCH CENTRE Institute for Health and Consumer Protection Unit: Toxicology and Chemical Substances European Chemicals Bureau ECBI/12/99 Rev. 1 31.03.1999 SUMMARY RECORD Meeting of the Commission Working Group on the Classification and Labelling of Dangerous Substances Pesticides ECB Ispra, 18-20 November 1998

Dithiopyr - Herbicide - CAS No. 97886-45-8

The following results were presented by a Monsanto scientist.
-- Thirteen-week Feeding Study in Rats. Dithiopyr was administered via the diet to groups of 12 male and 12 female F-344 rats for 13 weeks at concentrations of 0, 10, 100, 1000 and 5000 ppm.. Other findings included [no concentrations listed] multiple organ weight effects, thyroid follicular hypertrophy, adrenal cortical hypertrophy, and pulmonary foam cell aggregation. The subchronic NOEL in rats is considered to be 10 ppm. (The Institute of Environmental Toxicology, 1988)
-- REPRODUCTION AND DEVELOPMENTAL TOXICITY STUDIES 1. Two-generation Reproduction Study in Rats •Dithiopyr was administered via the diet to groups of 24 male and 24 female S-D rats over 2 consecutive generations at concentrations of 0, 25, 250 and 2500 ppm... Other findings included [no concentrations listed]: increased kidney weight, focal renal tubular atrophy, thyroid follicular hypertrophy, and adrenal cortical hypertrophy... (The Institute of Environmental Toxicology, 1989)
Ref: Summary of Toxicology Studies With Dithiopyr. Dennis P. WARD. Toxicology Department, The Agricultural Grop, A Unit of Monsanto Company (Received February 20, 1993). Also available at

http://wwwsoc.nii.ac.jp/pssj2/tec_info/dithiopy.pdf

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

Group C -- Possible Human Carcinogen. Thyroid follicular cell adenomas, carcinomas & combined adenomas/carcinomas (M); thyroid follicular cell adenomas and combined adenomas/carcinomas (F); Charles River CD rats.
Ref:
April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs. From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

Chronic toxicity. The NOAEL for systemic toxicity in a 1-year feeding study in the dog was 0.3 mg/kg/day in females and 1 mg/kg/day in males, based on clinical signs of neurotoxicity at 1 and 2 mg/kg/day in females and males, respectively. The NOAEL for systemic toxicity in mice was 0.5 ppm (0.06 mg/kg/day) based on decreased body weight gain, decreased food conversion efficiency in males, increased liver weights, and liver histopathology at 10 ppm (1.3 mg/kg/day). Fipronil was not carcinogenic when administrated to mice at dose levels up to 60 ppm. The NOAEL in a 2-year dietary study in the rat was 0.5 ppm (0.019 and 0.025 mg/kg/day for males and females, respectively) based on clinical signs of toxicity and alterations in clinical chemistry and thyroid parameters at 1.5 ppm (0.059 and 0.078 mg/kg/day for males and females, respectively).
• Cancer. The EPA's Health Effects Division Carcinogenicity Peer Review Committee classified fipronil in Group C - Possible Human Carcinogen, based on thyroid tumors observed in rats at 300 ppm (HDT). Mechanistic data indicate that these tumors are related to a disruption in the thyroid-pituitary status and are specific to the rat. In addition, there was no apparent concern for mutagenic activity. Thus, it was recommended that RfD methodology, i.e. non-linear or threshold, be used for the estimation of human risk.
Reproductive and developmental toxicity. In a two-generation rat study, the NOEL for parental (systemic) toxicity was 3 ppm (0.26 mg/kg/day for both sexes combined), based on increased weight of the thyroid glands and liver in males and females, decreased weight of the pituitary gland in females, and an increased incidence of follicular epithelial hypertrophy in females at 30 ppm.
Subchronic toxicity. The NOAEL for systemic toxicity in rat was 5 ppm (0.35 mg/kg/day for both sexes combined), based on alterations in serum protein values and increased weight of the liver and thyroid at 30 ppm (1.93 and 2.28 mg/kg/day for males and females, respectively).
Endocrine disruption. Data from the reproduction/ developmental toxicity and short- and long-term repeated dose toxicity studies with fipronil in the rat, rabbit, mouse, or dog, do not suggest any endocrine disruption activity. This information is based on the absence of any treatment-related effects from the histopathological examination of reproductive organs as well as the absence of possible effects on fertility, reproductive performance, or any other aspect of reproductive function, or on growth and development of the offspring. Evidence of offspring toxicity was observed only in the presence of significant parental toxicity. Fipronil disrupts the thyroid-pituitary axis. However, mechanistic studies have demonstrated that fipronil decreases thyroid hormone levels in long-term studies via increased clearance, rather than a direct effect on the thyroid. Concerns related to long-term exposure of fipronil are addressed in human risk estimates, as the chronic RfD (0.0002 mg/kg/day) is based on endpoints that include thyroid hormone related effects in rats.
Ref: August 24, 2005. Federal Register. Fipronil; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

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

-- Reproduction toxicity studies. The data base for reproductive toxicity is considered complete. No additional studies are required at this time. An acceptable two-generation reproduction study in the rat using fipronil concluded that the LOEL for parental (systemic) toxicity was 30 ppm (2.54 mg/kg/day for males and 2.74 mg/kg/day for females) based on increased weight of the thyroid glands and liver in males and females; decreased weight of the pituitary gland in females; and an increased incidence of follicular epithelial hypertrophy in the females. The NOEL for parental (systemic) toxicity was 3 ppm (0.25 mg/ kg/day for males and 0.27 mg/kg/day for females).
-- Carcinogenic classification and risk quantification. EPA has classified this chemical as a Group C--Possible Human Carcinogen, based on increases in thyroid follicular-cell tumors in both sexes of the rat, which were statistically significant by both pair-wise and trend analyses. EPA has used the RfD methodology to estimate human risk because the thyroid tumors are due to a disruption in the thyroid-pituitary status. There was no apparent concern for mutagenicity.
Ref: Federal Register: July 17, 1998. Fipronil; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/fipronil.fr.july.17.1998.htm

Short-term toxicity.
-- 28 day dietary administration to rats.
Technical-grade fipronil (batch number IGB 464, purity, 93%) was administered in the diet for four weeks to groups of five Cr1:CD (SD) BR rats of each sex at concentrations of 25, 50, 100, 200, or 400 ppm, equal to 3.4, 6.9, 13, 24, or 45 mg/kg bw per day for males and 3.5, 6.7, 13, 25, or 55 mg/kg bw per day for females ... The target organs were the liver and thyroid. Liver weights were significantly increased in females at all doses and in males at 200 and 400 ppm. At necropsy, liver enlargement was observed in one or both sexes starting at 50 ppm, and five males and three females at 400 pm had enlarged livers. Generalised hepatocyte enlargement was observed microscopically in one male at 100 ppm, with increasing incidence in animals of each sex at 200 and 400 ppm. Thyroid follicular-cell hypertropy, generally of minimal severity but of moderate severity in several males at 200 and 400 ppm, was found in almost all treated animals but not in the controls. (page 77)
-- 90-day dietary administration to rats
. In a 13-week study, rats (CD strain 10/sex/group) received dietary administration of either 1, 5, 30 or 300 ppm fipronil (batch number PGS 963, 95.4% purity). This was equivalent to 0.07, 0.3, 2.1 or 22 mg/kg/d. Doses were selected after a preliminary 14-d study showed deaths (3/10 animals by 5 d) and muscular spasms at 30 mg/kg/d ...Absolute thyroid weights were elevated (4.2-100% at 5-300 ppm) achieving statistical significance at ≥30 ppm in females and at 300 ppm in males ... Histopathological examination found treatment-related effects at the top dose in the thyroids and livers of both sexes. Oil red O staining revealed a high incidence of fat deposits in all liver samples, including controls. A statistically significant increase in panacinar hepatic fatty vacuolation (controls 0/10 and 7/10 at 300 ppm) was reported in males only. (page 78-79)
Ref: April 204. Evaluation on : Fipronil (Horticultural Uses). No. 212. UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf

--2 year dietary study in rats. The carcinogenic potential of fipronil was determined in a 2-year study carried out in the rat (CD strain). Animals (50/sex/dose) received dietary administration of fipronil (batch number PGS, 95.4% purity) at either 0.5, 1.5, 30 or 300 ppm; equivalent to 0.02, 0.06, 1.3 and 13 mg/kg/d (males) and 0.03, 0.08, 1.6 and 17 mg/kg/d (females). (page 89)
-- At study termination histopathological findings were confined to a statistically signifiicant increase in progressive senile nephropathy in males and thyroid "follicular cysts" (growth anomaly) at ≤30 ppm in females. (page 91)
--
A significant increase was observed in the incidences of thyroid follicular cell adenomas and carcinomas in both sexes at the top dose (300 ppm); these exceeded the historical control incidence) (page 95)
-- Reproductive Toxicity. Dietary two-generation study in rats. In a two-generation study, CD rats (30 animals/sex/dose) werre administered fipronil (batch number PGS 974, 95.4% purity) in the diet at 3, 30 or 300 pm, equivalent to 0.25, 2.5 or 26 mg/k/g bw per day for males and 0.27, 2.7 an 28 mg/kg bw per day for females. FO adults were treated for 71 d before mating (1 male to 1 female pairing), throughout the mating period (up to 21 d) and then throughout gestation and lactation of the liter (F1a). Approximately 10 d after weaning (25 d post partum) of the F1a pups, animals administered 3 or 30 ppm, as well as the control group, were paired a second time to produce an F1b generation. The F1a litters were randomly adjusted to 8 pups on 4 d post partum and, after weaning, 30 animals/sex/dose were selected to form the F1 parents. F1 parents were treated from weaning for a minimum of 10 weeks and then paired (1 male to 1 female) to produce an F2 generation. F1 adult treatment continued until F2 pups were weaned. ... At necropsy no treatment -related macroscopic changes were noted in adults or pups. In adults there were increases, often significant, in absolute and relative liver (10-15% and 15-40% at 30 and 300 ppm) and thyroid weights (15-25% and 25-50% at 30 and 300 ppm). ... In F1 adults histopathological examination showed a significant increaee in incidence of liver centrilobular fatty vacuolation in females (1/29 in controls, 6/27 at 300 ppm) and thyroid follicular hypertrophy in both sexes (males 0/28 in controls, 9/30 at 300 ppm and females 0/29 in controls, 15/27 at 300 ppm). (pages 96-97)
Ref: April 204. Evaluation on : Fipronil (Horticultural Uses). No. 212. UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf

Excerpts from: Table 5.17 Treatment -related effects in the 24 month rat dietary study (page 92)
Ref: April 204. Evaluation on : Fipronil (Horticultural Uses). No. 212. UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
 
 
-Males-
-Females-
ppm   0 0.5 1.5 30 300 0 0.5 1.5 30 300
Mg/kg/bw   0 0.02 0.06 1.3 13 0 0.03 0.08 1.6 17
  Week                    
T4 24 4.58 3.81* 3.35*** 2.43*** 0.76*** 2.85 3.09 3/49** 2.98 1.46***
  50 5.95 5.51 4.83** 3.9*** 23.07*** 3.31 3.46 3.00 2.06*** 1.38***
Organ weights (g) and macro-patholgology  
89 weeks males, 91 weeks females
Thyroid weight 89/91 0.042 0.051* 0.053* 0.063** 0.094** 0.036 0.038 0.036 0.044 0.072*
*P<0.05, **P<0.01, ***P<0.001

Effects on thyroid hormone levels. A further study was carried out to determine the effects of fipronil on circulating TSH, T3 and T4 levels. The concentrations of the three hormones were determined by radioimmunoassay. Animals (10/sex/group, Crl:CD (SD)BR) received dietary administration of fipronil (batch number PGS 963, 98.4% purity) for 28 d ... The concentrations of thyroid hormones and TSH for males and females respectively can be found in Tables 5.35 and 5.36. The data presented are corrected means, to allow an analysis of covariance to be carried out ... The NOAEL for this study was 1 ppm (equivalent to 0.1 mg/kg/d), based on increased thyroid follicular epithelial height at ≥5 ppm in males. (pages 123-125)
Ref: April 204. Evaluation on : Fipronil (Horticultural Uses). No. 212. UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf

Table 5.35 - Thyroid hormone and TSH levels in males (page 124)
Ref: April 204. Evaluation on : Fipronil (Horticultural Uses). No. 212. UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf

 
Day 7
Day 28
Dose of fipronil (ppm) T3 ng/dl T4 ug/dl TSH ng/ml T3 ng/dl T4 ug/dl TSH ng/ml
0 76.6 8.8 2.2 46.7 4.95 2.89
0.1 70.8 5.62 2.51 43.8 4.91 3.13
1 66.1* 5.62 2.87 43.2 4.61 3.54
5 66.5* 5.14* 3.05 47.9 4.63 4.84
30 65.3* 4.41*  334*
[sic? - 3.34]
 51.1  3.54* 6.27* 
      *statistically significant
Table 5.36 - Thyroid hormone and TSH levels in females (page 124)
Ref: April 204. Evaluation on : Fipronil (Horticultural Uses). No. 212. UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
 
Day 7
Day 28
Dose of fipronil (ppm) T3 ng/dl T4 ug/dl TSH ng/ml T3 ng/dl T4 ug/dl TSH ng/ml
0  76.3 4.08 0.83  76.5  3.72  0.93 
0.1  79.5 4.44  0.98  82.7  0.79 
1  82.3 4.27  0.77  86.3  3.88  0.67 
5  79.5 4.28  1.02  86.3  3.69  0.82 
30  66.7 3.32*  1.13  91.3  3.69  1.72* 
*statistically significant        

Abstract: Of 240 pesticides screened for carcinogenicity by the U.S. Environmental Protection Agency Office of Pesticide Programs, at least 24 (10%) produce thyroid follicular cell tumors in rodents. Thirteen of the thyroid carcinogens also induce liver tumors, mainly in mice, and 9 chemicals produce tumors at other sites. Some mutagenic data are available on all 24 pesticides producing thyroid tumors. Mutagenicity does not seem to be a major determinant in thyroid carcinogenicity, except for possibly acetochlor; evidence is less convincing for ethylene thiourea and etridiazole. Studies on thyroid-pituitary functioning, including indications of thyroid cell growth and/or changes in thyroxine, triiodothyronine, or thyroid-stimulating hormone levels, are available on 19 pesticides. No such antithyroid information is available for etridiazole, N-octyl bicycloheptene dicarboximide, terbutryn, triadimefon, and trifluralin. Of the studied chemicals, only bromacil lacks antithyroid activity under study conditions. Intrathyroidal and extrathyroidal sites of action are found: amitrole, ethylene thiourea, and mancozeb are thyroid peroxidase inhibitors; and acetochlor, clofentezine, fenbuconazole, fipronil, pendimethalin, pentachloronitrobenzene, prodiamine, pyrimethanil, and thiazopyr seem to enhance the hepatic metabolism and excretion of thyroid hormone. Thus, with 12 pesticides that mode of action judgments can be made, 11 disrupt thyroid-pituitary homeostasis only; no chemical is mutagenic only; and acetochlor may have both antithyroid and some mutagenic activity. More information is needed to identify other potential antithyroid modes of thyroid carcinogenic action.
Ref: Environ Health Perspect. 1998 Aug;106(8):437-45. Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. By Hurley PM. Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC 20460 USA.

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

Suggestive Evidence of Carcinogenicity to Humans. An increase in thyroid gland follicular cell tumors in male rats, and an increased incidence of hepatocellular tumors observed in the male mice was treatment-related.
Ref:
April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs. From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

-- Combined chronic toxicity/carcinogenicity rats. NOAEL = Males: 0.38 mg/kg/day; Females: 0.47 mg/kg/day LOAEL = Males: 3.8 mg/kg/day; Females: 4.9 mg/ kg/day based on liver toxicity in both sexes, pancreatic exocrine atrophy in females and testicular atrophy in males. Some evidence of carcinogenicity (thyroid gland follicular cell tumors) in male rats, but not in females.
Ref: Federal Register: April 18, 2002. Fluazinam; Pesticide Tolerance. Final Rule.

http://www.fluoridealert.org/pesticides/f
luazinam.fr.apr.18.2002.htm

-- In a carcinogenicity study in rats, an increased incidence of thyroid gland follicular cell tumors was observed in males. In this study, there were statistically significant positive trends for thyroid gland follicular cell adenocarcinomas and combined follicular cell adenomas/adenocarcinomas. There was also a statistically significant increase by pair-wise comparison of the high dose group (40 mg/kg/day) with the control group for combined follicular cell adenomas/adenocarcinomas. There was no treatment-related increase in tumor incidence in female rats. The highest dose level tested in this study was considered to be adequate but not excessive. It was concluded that there was some evidence that the thyroid tumors observed in the male rats in this study were treatment-related. There were insufficient data to determine whether the thyroid gland tumors may have been due to disruption of thyroid-pituitary homeostasis.
Ref: US EPA Pesticide Fact Sheet. Fluazinam. August 10, 2001.

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

-- Cancer (oral, dermal, inhalation). Increases in thyroid gland follicular cell tumors in male rats; increases in hepatocellular (liver) tumors in male mice.\2\
-- iii. Cancer. Since fluazinam has been classified as Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential, an exposure assessment was not performed.
Ref: Federal Register. September 7, 2001. Fluazinam; Pesticide Tolerance. Final Rule.

http://www.fluoridealert.org/pesticides/fluazinam.fr.sept.7.2001.htm

-- In subchronic and chronic toxicity studies, fluazinam targeted the following organs: liver, lung, uterus, testes, pancreas, thymus, thyroid, stomach, eyes and brain... Thyroid toxicity was less common, but included follicular hyperplasia and cystic thyroid follicles. Endocrine-related effects included small and/or flaccid testes, testicular tubular atrophy, pancreatic exocrine atrophy and thymic hyperplasia.
-- Long-term studies in both rats and mice provided some evidence of treatment-induced oncogenicity of the thyroid (follicular cell adenomas and adenocarcinomas) and liver (hepatocellular adenomas and carcinomas). Although tumours of this type may be the result of a non-genotoxic and non-linear mode of action, no data was provided on potential modes of action (e.g., enzyme induction, thyroid hormone levels). There was insufficient mechanistic data to determine the mode of action. A Q was generated at 5.40 • 10 -2 in the absence of a demonstrated mode of action.
Ref: Canada: Regulatory Note REG2003-12. Fluazinam. Pest Management Regulatory Agency. Health Canada. Ottawa. October 27, 2003.
http://www.fluorideaction.org/pesticides/fluazinam.canada.report2003.pdf

Flubendiamide - Insecticide - CAS No. 272451-65-7

Results of a reproductive toxicity study in rats (exposure route not stated):
Thyroid
, liver, uterine, thymus, and spleen weight changes in 2000 and 20000 ppm F1 and F2 pups.

Ref: TSCA Health & Safety Study Cover Sheet "Public Display Copy"
http://www.epa.gov/opptintr/tsca8e/doc/8ehq/2004/november04/8ehq-1004-15768a.pdf
•• This document was cited at EPA's site: "TSCA 8(e) and FYI Submissions Received from 11-15-04-11-26-04". It is important to note this as the document itself does not identify flubendiamide or its CAS No.
•• This study was conducted in the laboratory of The Institute of Environmental Toxicology - Japan
•• Source of Data/Study Sponsor: Bayer Material Science Corporation, 100 Bayer Road, Pittsburg PA 15205

Flucarbazone-sodium - Herbicide - CAS No. 181274-17-9

-- 90-Day oral toxicity in nonrodents (dogs). NOAEL = 33.8 mg/kg/day in males and 35.2 mg/kg/day in females with the occurrence of slight, adaptive induction of hepatic microsomal enzymes LOAEL = 162 mg/kg/ day in males and 170 mg/kg/day in females based on decreased T4 levels, increased thyroxine-binding capacity, induction of microsomal enzymes, gross pathology and histopathology in the stomach, and histopathology in the liver in both sexes.
-- One year dog feeding LOAEL = 183 mg/kg/day based on decreased body weight gain, decreased thyroxine, increased N- demethylase, and increased liver weight.
-- 28-Day oral toxicity in nonrodents (dogs). NOAEL = 164 mg/kg/ day in males and 171 mg/kg/day in females LOAEL = 1,614 mg/kg/ day in males and 1,319 mg/kg/day in females based on decreased body weight gain, decreased food consumption, decreased T4 levels and increased thyroxine-binding capacity, induction of microsomal enzymes, increased liver weight and liver histopathology in both sexes.
Ref: Federal Register. September 29, 2000. Flucarbazone-sodium; Time-Limited Pesticide Tolerances. Final Rule.

http://www.fluoridealert.org/pesticides/flucarbazone_na.fr.sept2000.htm

SUBCHRONIC/CHRONIC TOXICITY
-- Study # 870.3100. 28-Day oral toxicity in rodents (rats) NOAEL = 27 mg/kg/day in males and 25 mg/kg/day in females. LOAEL = 266 mg/kg/day in males and 251 mg/kg/day in females based on immunological changes in both sexes.
-- Study # 870.3150. 90-Day oral toxicity in nonrodents (dogs) NOAEL = 33.8 mg/kg/day in males and 35.2 mg/kg/day in females with the occurrence of slight, adaptive induction of hepatic microsomal enzymes. LOAEL = 162 mg/kg/day in males and 170 mg/kg/day in females based on decreased T4 levels, increased thyroxine-binding capacity, induction of microsomal enzymes, gross pathology and histopathology in the stomach, and histopathology in the liver in both sexes.
-- Study # 870.3100. 90-Day oral toxicity in rodents (rats) NOAEL = 73.5 mg/kg/day in males and 102 mg/kg/day in females LOAEL = 287 mg/kg/day in males and 358 mg/kg/day in females based on immunological findings in both sexes

-- Study # 870.4300. 2-Year Chronic toxicity/carcinogenicity in rats NOAEL = 125 mg/kg/day in males and females LOAEL = 1,000 mg/kg/day in males and females based on decreased body weight and increased food consumption in females, thickened mucosa of the glandular stomach in both sexes, inflammatory infiltrates (males), vacuolation of the squamous epithelium in the fore-stomach (females) and immunological effects in males. no evidence of carcinogenicity
-- Study # 870.4100b. Chronic toxicity in dogs NOAEL = 35.9 mg/kg/day in males and 37.1 mg/kg/day in females. LOAEL = 183 mg/kg/day in males and 187 mg/kg/day in females based upon body weight gain depression and increased N-demethylase levels in both sexes, decreased T4 levels and marginally increased liver weight in females.
-- Study # 870.3150. 28-Day oral toxicity in nonrodents (dogs) NOAEL = 164 mg/kg/day in males and 171 mg/kg/day in females. LOAEL = 1,614 mg/kg/day in males and 1,319 mg/kg/day in females based on decreased body weight gain, decreased food consumption, decreased T4 levels and increased thyroxine-binding capacity, induction of microsomal enzymes,
increased liver weight and liver histopathology in both sexes.
Ref: US EPA Pesticide Fact Sheet for Flucarbazone-sodium. September 29, 2000.
http://www.epa.gov/opprd001/factsheets/flucarbazone.pdf

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

-- 21-day dermal (rats): Dermal Irritation NOEL = 1000 mg/kg/day (males and females) Systemic NOEL = 20 mg/kg/day (males) Systemic NOEL = 150 mg/kg/day (females) Systemic LOEL = 150 mg/kg/day for males and 1000 mg/kg/day for females based on clinical chemistry data (decreased T4 and FT4 levels in both sexes) and centrilobular hepatocytomegaly in females.
-- 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

A 84-day rat feeding study with a No Observed Effect Level (NOEL) less than 100 ppm (6.0 mg/kg/day) for males and a NOEL of 100 ppm (7.2 mg/kg/day) for females and with a Lowest Observed Effect Level (LOEL) of 100 ppm (6.8 mg/kg/day) for males based on suppression of thyroxine (T4) level and a LOEL of 400 ppm (28.8 mg/kg/day) for females based on hematology and clinical chemistry findings.
Ref: Federal Register. September 23, 1998. Flufenacet; Time-Limited Pesticide Tolerance. Final Rule.

http://www.fluoridealert.org/pesticides/flufenacet.fr.sept.23.1998.htm

-- Based on the toxicological findings for flufenacet relating to endocrine disruption effects, flufenacet should be considered as a candidate for evaluation as an endocrine disrupter when the criteria are established ... there is concern for thyroid hormone disruption.
Subchronic toxicity
:
-- A 13-week mouse feeding study with a NOAEL of 100 ppm (18.2 mg/ kg/day for males and 24.5 mg/kg/day for females), and a LOAEL of 400 ppm (64.2 mg/kg/day for males and 91.3 mg/kg/day for females) based on histopathology of the liver, spleen and thyroid.
-- A 13-week dog dietary study with a NOAEL of 50 ppm (1.70 mg/ kg/day for males and 1.67 mg/kg/day for females), and a LOAEL of 200 ppm (6.90 mg/kg/day for males and 7.20 mg/kg/day for females), based on evidence that the bio-transformation capacity of the liver has [[Page 16601]] been exceeded (as indicated by increase in LDH, liver weight, ALK and hepatomegaly), globulin and spleen pigment in females, decreased T4 and ALT values in both sexes, decreased albumin in males, and decreased serum glucose in females.
-- A 21-day rabbit dermal study with the dermal irritation NOAEL of 1,000 mg/kg/day for males and females, and a systemic NOAEL of 20 mg/kg/day for males and 150 mg/kg/day for females, and a systemic LOAEL of 150 mg/kg/day for males and 1,000 mg/kg/day for females based on clinical chemistry data (decreased T4 and FT4 levels in both sexes) and centrilobular hepatocytomegaly in females.
-- Chronic toxicity - A 1-year dog chronic feeding study with a NOAEL was 40 ppm (1.29 mg/kg/day in males and 1.14 mg/kg/day in females), and a LOAEL of 800 ppm (27.75 mg/kg/day in males and 26.82 mg/kg/day in females) based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T2, T4 and ALT values in both sexes, and increased incidences of microscopic lesions in the brain, eye, kidney, spinal cord, sciatic nerve, and liver.
Ref: Federal Register. March 29, 2000. Notice of Filing a Pesticide Petition to Establish a Tolerance for Certain Pesticide Chemicals in or on Food.

http://www.fluoridealert.org/pesticides/flufenacet.fr.mar.29.2000.htm

Flufenoxuron - Acaracide, Insecticide, Herbicide - CAS No. 101463-69-8

-- Abstract: Flufenoxuron (Benzoylphenyl urea derivative) - antimoulting insecticide – is recently used for controlling insect reproduction in cultivated areas. The study determined the hazardous effects of the applied dose-treatment during the critical period of rat embryonic development and the induction of growth retardation. In the present work, flufenoxuron was intragastrically administered by stomach intubation to pregnant rats at concentration levels 0 & 20 mg/kg b.wt. in saline solution every other day on gestation day 7 till parturition. Experimental and control pregnant rats were sacrificed on days 13 & 16 of gestation and the foetuses were fixed in 10 percent formol saline. Histological abnormalities of thyroid, liver and kidneys of mothers as well as of skeletal axial and appendicular regions of foetuses were investigated. Foetuses maternally treated with flufenoxuron exhibited delayed differentiation of chondrification and ossification of axial and appendicular regions. The observed defects in foetuses may be attributed to the histological abnormalities of thyroid, liver and kidneys of maternal tissues as well as to the direct effect of the parents as a result of the insecticide or its metabolites on the affected structures during early morphogenesis and differentiation.
Ref: J. Egypt. Ger. Soc. Zool., Vol. 25(B), 65-81, 1998. PATTERNS OF DEVELOPMENTAL DEFECTS OF RAT FOETUSES MATERNALLY TREATED WITH AN ENVIRONMENTAL ANTIMOULTING INSECTICIDE FLUFENOXURON; by
Karim, S.A. http://www.egsz.org/BiologicalCurrentContent/Zoology/Comparative%20Physiology/TOXICOLOGY.htm

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

-- 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

Fluoxastrobin - Fungicide - CAS No. 193740-76-0

-- Subchronic toxicity... A 14-week feeding study in dogs demonstrated a NOAEL of 3.0 mg/kg bwt/day based on decreased body weights and food consumption, and liver effects (enzyme induction, increased liver weights, cytoplasmic change), and thyroid effects (decreased T3)
Ref: Federal Register: April 23, 2003. Fluoxastrobin; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

http://www.fluoridealert.org/pesticides/f
luoxastrobin.fr.Apr23.2003.htm

-- In response to a comment submitted to EPA by FAN Pesticide Project, EPA stated:
FAN suggested that a 14-week feeding study using dogs showed an effect on the thyroid, which seems to conflict with the statement that ``...There is no evidence to suggest that fluoxastrobin has any primary endocrine disruptive potential.'' FAN stated that a ``discussion or rationale'' addressing this should have been provided. EPA does believe that the thyroid effects seen in the dog study indicated that fluoxastrobin is an endocrine disruptor. An effect on the thyroid gland, even though this gland is part of the endocrine system, does not necessarily mean that endocrine disruption has or will occur. In this case, the effects observed in the thyroid gland were induced by effects fluoxastrobin had on liver enzymes and are therefore considered secondary.
-- Combined chronic toxicity / carcinogenicity--rats. decreased body weight, decreased body weight gain, and decreased food efficiency in both sexes; decreased spleen weight in males; and microscopic lesions in the uterus of females. The apparent increase in tumors in the uterus and thyroid were addressed and resolved by an Agency committee, which concluded that no carcinogenic concern exists for fluoxastrobin.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Fluquinconazole - Fungicide - CAS No. 136426-54-5

-- Groups of 40 male Sprague Dawley rats were fed a diet containing fluquinaconazole at concentrations of 0 (control) or 100 ppm for 14 days. Twenty rats per dose group were killed and necropsied on day 15. The remaining animals were kept for a further 14 days on a treatment-free diet then killed and necropsied... Hormone assays for thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH) and reverse triiodothyronine (RT3) were conducted but the details of the assay methods were not provided... Histopathology of the thyroid was reported and focussed on 3 parameters; colloid depletion, follicular cell hypertrophy and follicular cell hyperplasia... Histopathology of the thyroid showed the most distinctive finding to be the increased incidences of follicular epithelial hyperplasia of the thyroid (11/20) compared with 0/20 in controls at day 15). An increase in the incidence of severe folicular hypertrophy and severe or very severe colloid depletion was considered to be also indicative of increase in thryoidtoxicity in fluquinconazole-treated animals. Severe to very severe colloidal depletion (5/20 animals compared with 1/20 in controls), severe follicular cell hypertrophy (3/20 compared wtih 0/20 in controls) and slight to moderate follicular epithelial hyperplasia (4/20 compared with 1/20 in controls) was present in the thyroid at the end of the recovery period. In conclusion, administration of fluquinconazole to male rats resulted in changes in thyroid hormone homeostasis manifested by histopathological changes int he thyroid... (DP 47301)
-- Oral long-term toxicity and carcinogenicity. 2-year dietary study in rats. groups of 50 male and 50 female outbred albino Sprague-Dawley CRL :COBS CD(SD)BR rats were administered fluquinconazole (93.2% purity) in the diet at concentrations of 0 (control), 1, 20 or 100 ppm. Additionally 20 animals/sex/dose designated for the interim-kill received the test compound at concentrations of 0, 1, 5, 10 or 100 ppm for 12 months... In the thyroid gland a significantly higher incidence in follicular cell tumors were noted in the 100 ppm dose level in both sexes. Historical tumor incidences provided showed that the slight statistically non-significant increase in thyroid follicular cell tumors at the lowest and intermediate dose levels were at the upper limit of the historical control range and therefore in the absence of a dose response they were considered to be not of toxicological significance.
-- The rat was the most sensitive species to fluquinconazole compared with the dog and mouse. The main target organs were the liver, kidney and thyroid... For the thyroid tumors in the rat, a correlation between induction of liver UDGPT and imbalances in thyroid hormone (increase in TSH and reduction in T4) and histopathological changes in the thyroid was demonstrated. Disturbance of thyroid hormone homeostasis is a well recognised mechanism for the induction of thyroid tumours. Futher this is considered to be secondary to the observed liver enzme induction. A clear NOEL for thyroid tumors and the induction of thryoid effects was established.
-- Acute inhalation toxicity. Groups of 5 male and 5 female Crl:CD (SD)BR Spraque-Dawley rats were exposed head-only to a dust aerosol of fluquinconzole (98.7% purity), at mean analytical concentrations of 0, 0.082, 0.24, 1.08 or 4.56 mg/l for four hours. All surviving animals were killed and necropsied after a 14-day observation period... signs of toxicity inclding ataxia, hunched posture and respiratory distress were observed at the 0.24 mg/l dose for up to 4 days and at the higher dose levels until death... In the thyroid, the incidence and severity of thyroid effects including colloid depletion, follicular cell hyperplasia and hypertrophy did not show a clear treatment-relationship (statistically significant compared with controls at 100 and 200 ppm but not at 400 ppm and 10 mg/kg bw/day dose levels). The NOEl was 5 ppm (0.45 mg/kg bw/day) based on increased liver and kidney weights and histopathological changes in the liver, kidney and thyroid at the higher dose level of 20 ppm... The liver, thyroid and kidneys were noted to be the target organs of the test compound and significant changes in these organs indicative of significant hepatic enzyme induction were considered to be relevant for risk assessment.
Ref: Evaluation on: Fluquinconazole. May 1999. No. 184. Evaluation of Fully Approved or Provisionally Approved Products. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7 PX, UK. Available online:

http://www.pesticides.gov.uk/citizen/evaluations/evallist.htm

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

Subchronic toxicity. A 84-day rat feeding study with a No Observed Effect Level ( NOEL) less than 100 ppm [6.0 mg/kg/day] for males and a NOEL of 100 ppm [7.2 mg/kg/day] for females and with a Lowest Observed Effect Level (LOEL) of 100 ppm [6.8 mg/kg/day] for males based on suppression of thyroxine (T4) level and a LOEL of 400 ppm [28.8 mg/kg/day] for females based on hematology and clinical chemistry findings. A 13-week mouse feeding study with a NOEL of 100 ppm [18.2 mg/kg/day for males and 24.5 mg/kg/day for females] and a LOEL of 400 ppm [64.2 mg/kg/day for males and 91.3 mg/kg/day for females] based on histopathology of the liver, spleen and thyroid. A 13-week dog dietary study with a NOEL of 50 ppm [1.70 mg/kg/day for males and 1.67 mg/kg/day for females] and a LOEL of 200 ppm [6.90 mg/ kg/day for males and 7.20 mg/kg/day for females] based on evidence that the bio-transformation capacity of the liver has been exceeded, (as indicated by increase in LDH, liver weight, ALK and hepatomegaly), globulin and spleen pigment in females, decreased T4 and [[Page 34180]] ALT values in both sexes, decreased albumin in males, and decreased serum glucose in females. A 21-day rabbit dermal study with the dermal irritation NOEL of 1,000 mg/kg/day for males and females and a systemic NOEL of 20 mg/kg/day for males and 150 mg/kg/day for females and a systemic LOEL of 150 mg/kg/day for males and 1,000 mg/kg/day for females based on clinical chemistry data (decreased T4 and FT4 levels in both sexes) and centrilobular hepatocytomegaly in females.
Ref: Federal Register: June 23, 1998 [Page 34176-34184]. Notice of Filing of Pesticide Petitions.

http://www.fluoridealert.org/pesticides/flutolanil.fr.june.23.1998.htm

Fluxofenim - Herbicide safener - CAS No. 88485-37-4

Chronic/Subchronic Toxicity Studies. Fluxofenim: Liver and kidney effects; Thyroid effects at high doses (dogs)...
Target Organs - Fluxofenim: Liver, kidney, and
thyroid.
Ref: Ciba-Geigy Material Safety Data Sheet for Concep-III.

http://www.fluoridealert.org/pesticides/Fluxofenim.MSDS.Ciba.1996.htm
also available at http://www.horizononline.com/MSDS_Sheets/737.txt

 
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