Testes - Adverse Effects
Fluorinated and Fluoride Pesticides
beginning A-G • H-Z
 
 

The Testes are the male gonads, or reproductive glands. When stimulated by the release of pituitary gonadotropins, these glands produce and secrete the hormones that control the development of male sexual characteristics and the reproductive function of the adult male.

The testes produce and secrete testosterone in response to the release of follicle-stimulating hormone from the anterior pituitary. Testosterone and related hormones have both organizing and activating effects on physiology, anatomy, and psychology. The organizing effects of testosterone emerge during the third and fourth months of gestation (pregnancy). When testosterone is present in greater levels than the female sex hormone, the fetus will develop the characteristics of a male. Testosterone will modify the reproductive organs and regions of the central nervous system, including the hypothalamus. The activating effects of testosterone not only trigger sexual prowess and aggressiveness, but also modulate cerebral functions. Recent research indicates that fluctuating levels of estrogen and testosterone modify higher, problem-solving abilities.
Ref:
http://psych.athabascau.ca/html/Psych402/Biotutorials/35/testes.shtml

Seminal Vesicles - glands that help produce semen.

Seminiferous epithelium - the epithelium lining the convoluted tubules of the testis where spermatogenesis and spermiogenesis occur

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.

Acifluorfen, sodium - Herbicide - CAS No. 62476-59-9

-- Increased liver and kidney weights occurred in chronic rat, mouse, and dog studies and were accompanied by microscopic liver and kidney changes in the chronic rat and dog studies. Anemia was present in chronic rat and dog studies. Stomach ulcers were found in chronic rat and mouse studies. Testicular atrophy occurred in the chronic rat study. Increased mortality occurred in the high-dose group in rat and mouse studies.
Ref: January 15, 2002. Preliminary Human Health Risk Assessment. MEMORANDUM SUBJECT: SODIUM ACIFLUORFEN. HED Chapter for the Reregistration Eligibility Decision Document. US EPA, Office of Prevention, Pesticides and Toxic Substances. http://www.fluorideaction.org/pesticides/acifluorfen.na.a.red.jan.02.pdf

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

Abstract: Male rats were subjected to 9-month-long exposure to ammonium fluoride. The performed evaluation covered the seminiferous epithelium and epididymis. The greatest changes in animals used in the experiment were observed in epididymis. A small number of spermatozoa were seen in the lumen of ductus epididymis, while in the epithelial cells there were increased phagocytic processes, providing a proof that injured reproductive cells were eliminated from the genital tract.
Ref: Rozewicka L et al. (1989). Morphological evaluation of the effect of protracted exposure to ammonium fluoride exerted on seminiferous epithelium and epididymis in rat. PATOL POL; 40 (3);. 267-272. Toxline at Toxnet: http://toxnet.nlm.nih.gov/

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

... Cloransulam-methyl 84% DF was not found to be carcinogenic, teratogenic or to cause reproductive effects. In-vitro and animal mutagenicity studies were negative. Target organ effects have been reported in the blood, kidney, liver, testes and thyroid gland...
Ref: Material Safety Data Sheet for Gauntlet Herbicide. MSDS Ref. No: F18-20-2. Date Approved: 09/25/2000. Revision No. 1. FMC Corporation, Agricultural Products Group, 1735 Market Street, Philadelphia, PA 19103, USA.
http://www.fluoridealert.org/pesticides/Gauntlet.HerbicideMSDS.2000.pdf.
Also available at
http://www.cdms.net/ldat/mp48J001.pdf

-- In the rat Chronic Feeding / Carcinogenicity study the NOEL was equal to 75 mg/kg/day and the Lowest Observed Effect Level (LOEL) was 325 mg/kg/day based on significant increase in hemoglobin, hematocrit, and red cell count in males, activities of the liver enzymes aspartate and alanine aminotransferase as well as alkaline phosphatase were decreased in males, cholesterol was decreased in females, specific gravity of urine was decreased in females, increased relative weight in liver and relative weight of testes in males...
-- Chronic Feeding/ Carcinogenicity (rat): NOEL = 75 mg/kg/day LOEL = 325 mg/kg/day based on significant increase in hemoglobin, hematocrit, and red cell count in males, activities of the liver enzymes aspartate and alanine aminotransferase as well as alkaline phosphatase were decreased in males, cholesterol was decreased in females, specific gravity of urine was decreased in females, increased relative weight in liver and
relative weight of testes in males...
Ref: USEPA. Pesticide Fact sheet. Cloransulam-methyl. Reason for Issuance: Conditional Registration Date Issued: October 29, 1997.

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

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

-- Classification: ``Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential'' based on significant trends in liver tumors (adenomas and combined adenomas/ carcinomas), malignant histiocytic sarcomas, and testicular cell tumors in male rats and uterine polyps in female rats seen at the highest dose.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

August 11, 2003, comments submitted to US EPA by FAN's Pesticide Project on the pesticide petition from BASF Corporation to establish a tolerance for residues of chlorfenapyr on all food items in food handling establishments where food products are held, processed, and/or prepared at 0.01 parts per million (ppm). http://www.fluorideaction.org/pesticides/chlorfenapyr.comments.aug03.htm - Also Online at US EPA Docket OPP-2003-0205.

5. Endocrine Disruption. In the petition, BASF states: ... There is no information available which suggests that chlorfenapyr would be associated with endocrine effects.

5.1 However, US EPA noted endocrine effects in the following study: In the rat chronic toxicity/carcinogenicity study (MRID 43492837), there were increased trends in the incidence of hepatocellular adenomas, hepatocellular adenomas and/or carcinomas combined, malignant histiocytic sarcomas and testicular interstitial cell tumors in males rats. In female rats there were significant increasing trends in endometrial stromal polyps. Significant difference in pair-wise comparison of fibroadenomas at the low dose and carcinomas at the mid-dose existed for female rats. There was no evidence of tumorigenic potential in mice....
Ref: US EPA OPPT. February 12, 1998. SUBJECT: Chlorfenapyr - 129093: Health Effects Division Risk Characterization for Use of the Chemical Chlorfenapyr (Alert, EPA File Symbol 5905-GAI) in/on Citrus (6F04623). Case: 287132. Barcode: D221320-
http://www.epa.gov/opprd001/chlorfenapyr/memohed2.pdf


September 17, 2003, reply to comments from FAN's Pesticide Project, from Daniel J. O’Byrne, Product Registrations Manager, BASF Corporation. http://www.fluorideaction.org/pesticides/chlorfenapyr.basf.sept.2003.pdf
-
Also online at US EPA Docket OPP-2003-0205.

Regarding Point 5: Endocrine Effects This comment addresses findings of endometrial stromal polyps and testicular interstitial cell tumours

The occurrence of benign interstitial cell tumors in male rats was 3/65, 1/65, 3/65 and 7/65 (4.6, 1.5, 4.6, 10.8%) in the control and the low-, mid- and high dose, respectively. There was no statistically significant increase in either group when compared to the control group and no clear dose-response relationship. Moreover the incidence of 7/65 was at the upper limit of the historical control range (10.0%). Therefore, the occurrence of this benign proliferative lesion in males of the high-dose group is not considered treatment related.. Overall, there is no indication of an endocrine effect of chlorphenapyr in any of the studies, including the two-generation study in rats and the oncogenicity studies in rats and mice.

Cyhalofop-butyl - Herbicide - CAS No. 122008-85-9

Palatability and Four-Week Dietary Probe Study in Beagle Dogs”; (M.J. Mizell, K.T. Hart and J.W. Crissman; The Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical Company, Midland, MI; Study ID. DR-0298-8876-004; 9/11/90); In a preliminary palatability study, one beagle dog/group received 250, 500 or 1000 mg/kg/day of XRD-537 nBu (Technical) (AGR 276541, purity: 98.2%) for up to 2 weeks... In the second study, 2 beagle dogs/sex/group received targeted doses of 0, 35, 100 or 350 mg/kg/day for 4 weeks. Based on the food consumption, the low dose animals received doses of 36, 36, 34 or 53 mg/kg/day, the intermediate dose animals consumed doses of 85, 86, 133 or 138 mg/kg/day and the high dose animals received doses of 193, 203, 37 or 292 mg/kg/day, respectively... Gross examination of the tissues revealed slight to very severe atrophy of the thymus in a dose-related manner... In the microscopic examination, multifocal vasculitis and thrombosis was noted in the kidneys of the 2 high dose males and one intermediate and one high dose female, respectively. Diffuse atrophy of the thymus ranged from slight to very severe in a dose-related manner for the males in all of the groups and from moderate to severe for the intermediate and high dose females. In the testes, spermatogenesis was moderately to severely reduced in the high dose males with a concomitant increase in multinucleated spermatids. Apparent target organs: thymus and testes; Possible adverse effect: atrophy of the thymus and reduced spermatogenesis in the testes; NOEL can not be determined; Study supplemental. (Moore, 11/20/00)
Ref: February 16, 2001. California Environmental Protection Agency Department of Peticide Regulation. Medical Toxicology Branch. Summary of Toxicological Data. Cyhalofop-Butyl. Chemical Code # 5748, Tolerance # 52840 SB 950 # New A.I.
http://www.fluoridealert.org/pesticides/Cyhalofop.butyl.CA.Tox.2001.pdf

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

The physical and behavioral effects of cyhalothrin were studied in rats. Pregnant Wistar rats were administered 0 or 0.018% cyhalothrin topically throughout pregnancy. After delivery the neonates were monitored for development of fur, testes descent, and ear, eye, and vaginal opening. Body weights were recorded on postnatal days 2, 7, 14, and 21. The effects on locomotor activity and inhibitory avoidance behavior were evaluated on postnatal days 21 and 90. The number of head dips occurring in a hole board test was recorded on postnatal day 90. Development of fur and times to testes descent and ear and eye opening were significantly delayed in cyhalothrin exposed pups. Time to vaginal opening was not affected. Body wt of cyhalothrin exposed pups were significantly increased at postnatal days 2, 7, and 14, but not at postnatal day 21. Cyhalothrin did not significantly affect locomotor activity or inhibitory avoidance behavior. Cyhalothrin exposed rats had a significantly smaller number of head dips in the hole board test. The authors conclude that prenatal exposure to cyhalothrin delays development of fur, eye and ear opening, and testes descent and affects motivational behavior. The delays induced in fur development and eye and ear opening suggest that cyhalothrin interferes with maternal or neonatal epidermal growth factor activity. The delay in testes descent suggests that prenatal cyhalothrin exposure induces changes in male sexual development. [da Silva Gomes M et al; Vet Human Toxicol 33 (4): 315-7 (1991)]
Ref: TOXNET profile from Hazardous Substances Data Base for Cyhalothrin.

http://www.fluoridealert.org/pesticides/Cyhalothrin.TOXNET.HSDB.htm

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

AIM: To assess the effect of ICON (trade name of lambda-cyhalothrin) on sexual competence and fertility of male rats.
METHODS: Male rats were gavaged daily for 7 consecutive days with different doses of ICON (63 mg/kg and 100 mg/kg) or vehicle (distilled water). Their sexual behaviour and fertility were evaluated at different time points during treatment and post-treatment using receptive females.
RESULTS: Treatment had no effect on fertility, but sexual competence was seriously impaired: libido (assessed in terms of pre-coital sexual behaviour, and numbers of mounting, intromission and ejaculation), sexual arousability/motivation (in terms of latencies for mounting, intromission and ejaculation), sexual vigour (judged by frequencies of mounting and intromission or copulatory efficiency). In addition, ICON suppressed intromission ratio, indicating erectile dysfunction. These effects on sexual function had a rapid onset and was reversible. ICON-induced sexual dysfunction was mediated by multiple mechanisms, mainly toxicity, stress, sedation and possibly via GABA and dopaminergic systems.
CONCLUSION: Exposure to ICON may cause se
xual dysfunction in male rats.
Ref: Effects of pyrethroid insecticide ICON (lambda cyhalothrin) on reproductive competence of male rats; by Ratnasooriya WD, Ratnayake SS, Jayatunga YN. Asian J Androl. 2002 Mar;4(1):35-41.
Full free text available at http://www.asiaandro.com/1008-682X/4/35.htm

Dichlofluanid - Wood Preservative, Antifoulant, Fungicide, Acaricide - CAS No. 1085-98-9
-- 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... 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. Testicular degeneration was noted in 2 animals receiving 37.5 mg kg -1 d -1 , the lesion was widespread and of moderate/severe grade. Thymic atrophy was also reported in males receiving 37.5 mg kg -1 d -1 (3/4 animals). In the second study (0 or 1.25 mg kg -1 d -1 ), no obvious treatment-related effects were reported in the clinical chemistry, haematology or urinalysis parameters measured. At necropsy the following findings were reported. Both absolute and relative testes weights were decreased (29 % and 25 % respectively). However in the absence of a dose response (when compared to the higher doses used in the first study), and as the weights were within the range of historical control values, this observation was not thought to be of toxicological significance. No statistically significant treatment-related organ weight changes were reported in females. Inspection of the data revealed absolute and relative ovary weight increases (60 % and 175 % respectively). The large SD values and small numbers make it difficult to assess the significance of these data. One incidence of testicular degeneration was reported at necropsy in both control and treated animals. Overall the ACP concluded that the ovarian weight increases were not relevant and that a NOAEL of 2.5 mg kg -1 d -1 could be determined from these studies. [Unpublished, 1992] ... In males at study termination the absolute organ weights of the kidney (5 %) and testes (5.6 %) were significantly increased at the top dose. At study termination the relative testes weight was increased in the top-dose group (18 %)...
-- Two-year Study. The following study is considered to be flawed due to the lack of histopathological evaluation and it was not GLP compliant. Beagles (4/sex/group) received dietary administration of either 0, 100, 300, 1000 or 3000 ppm dichlofluanid (90 % purity); equivalent to 3.6, 10.5, 34 and 107 mg kg -1 d -1 (males) and 3.4, 11, 34 and 101.4 mg kg -1 d -1 (females) respectively, for a two year study period... Absolute organ weights in males of the liver, lung, spleen, kidneys, adrenals, pancreas and heart were all decreased at 3000 ppm; the greatest being a 35 % decrease in testes weight. Decreases in relative organ weights were reported in males in the thyroid, heart, spleen and testes (20 % at 3000 ppm) at the top dose. The relative kidney and liver weights were elevated at both 1000 (21 and 3.4 %) and 3000 ppm (18 and 10 %). In females absolute organ weights were reduced : the thyroid in all treatment groups, by 32-36 %; ovaries 31-55 % from 100 ppm; and heart by 14-27 % at 1000 and 3000 ppm. The absolute spleen weights were raised in females at 1000 ppm and above by 18-20 %. In females there was a slight increase in the relative organ weights of the pancreas above 1000 ppm and spleen weight was elevated by 25 and 60 % at 1000 and 3000 ppm. A decrease in ovary weight was reported at all doses (55 % at 3000 ppm). The changes in organ weight in females preclude the setting of a NOEL. [Unpublished, 1969]
-- Dichlofluanid (unspecified purity) was given by gavage at 200 mg kg -1 in DMSO (4 or 5 animals). Autoradiography of 3 H-thymidine labeled samples was used to measure testicular DNA synthesis. Dichlofluanid was reported to cause a statistically significant decrease in the incorporation of 3 H-thymidine into DNA and was therefore positive. [Unpublished, 1977]
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

-- Dichlofluanide has been reported as a hormonal active substance in the environment in a review of the German Umweltbundesambt (Schramm et al., 1996). However, a concentration range for which this "hormonal activity" was found, was not reported (page 44). [Schramm K.-w., thumm W. * Kettrup A. (1996). Hormonal active substances in the environment: exposition, impact and detection. Expert Round. Endocrinically active chemicals in the environment. UBA Texte 3/96. Umweltbundesamt, Germay.]
Ref: RIVM report 601506005. BIOCIDES (II). Refined aquatic environmental risk assessment of 28 priority biocides. B.J.W.G. Mensink. November 2000. RIVM = Rijksinstituut voor Volksgezondheid en Milieu. National Institute of Public Health and the Environment.

http://www.rivm.nl/bibliotheek/rapporten/601506005.pdf

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

TSCA Test Submissions: A subchronic inhalation toxicity study was conducted with groups of male (35) and female (35) albino rats (strain not reported) receiving whole body exposure to dichloromonofluoromethane at a nominal concentration of 0, 50, 150 or 500ppm in a dynamic air flow chamber for 6 hours per day, five days per week for approximately 90 days. On day 45 and day 90, 5 animals per sex and 20 animals per sex, respectively were sacrificed. The remaining animals were observed for an additional 30 days and then sacrificed. Four high dose males were found dead during the exposure period and one female and six males from the high dose group were found dead during the recovery period. High dose rats were observed to have statistically significant (p < 0.01) lower body weights than controls during the exposure period, but were comparable after the 30 day recovery period. Hematology, clinical chemistry and urine analysis values were similar between all dosed animals and control animals, with the exception of a slightly higher total blood leukocytes counts and elevated mean SAP and SGPT values for high dose animals at approximately 45, 90 and 120 days. A dose related increase in urine fluoride levels was also observed. Histopathology evaluation of treated animals revealed portal cirrhosis of the liver, interstitial edema of the pancreas and degeneration of the seminiferous epithelium. Three cases of leukemia were observed in high dose male rats. [Industrial Bio-Test Laboratories; Subacute Inhalation Toxicity Study with Genetron 21 in Albino Rats, (1979), EPA Document No. FYI-OTS-0779-0045, Fiche No. OTS0000045-0 ]
[Note from FAN: seminiferous epithelium = the epithelium lining the convoluted tubules of the testis where spermatogenesis and spermiogenesis occur.]
Ref: TOXNET profile from Hazardous Substances Data Base for DICHLOROFLUOROMETHANE.

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

Diflubenzuron - Insecticide, Chemosterilant - CAS No. 35367-38-5

-- In another 21-day dermal study, technical diflubenzuron (96.7% a.i.) was administered in 0.25% gum tragacanth in distilled deionized water to the dorsal skin on the backs of 10 rats/sex/dose at 0, 20, 500, or 1000 mg/kg bwt/day for 6 hour periods each day. At 1000 mg/kg/day, dermal irritation was seen in the males as a trace of acanthosis and hyperkeratosis. Females also exhibited the same type and degree of dermal irritation at 1000 mg/kg/day. Kidney and liver changes of trace levels of mineralization and chronic inflammation of the liver were similar to that seen in the controls of both male and female test animals. Only increased absolute organ weight changes of testes were reported in the mid- and high-dose males... (MRID 43954101)
-- In a 14-week feeding study technical grade diflubenzuron was administered in the diet to mice at dose levels of 0 (control), 80, 400, 2000, 10000 or 50000 ppm (equivalent to 0, 12, 60, 300, 1500 or 7500 mg/kg/day). Methemoglobinemia and sulfhemoglobinemia (accompanied by Heinz bodies) were observed in male and female mice at all dose levels. The study noted decreased erythrocyte counts, decreased packed cell volume, and increased reticulocytes at dose levels of 60 mg/kg/day and higher. The terminal sacrifice showed the following effects: increased spleen weights at 60/mg/kg/day dose levels and above; increased liver weights and decreased seminal vesicle weights at dose levels of 300 mg/kg/day and above; and decreased kidney weights at dose levels of 1500 mg/kg/day and above... (MRIDs 00074534 and 00114330)
Ref: August 1997. US EPA Reregistration Eligibility Decision (RED) for Diflubenzuron. EPA 738-R-97-008.

http://www.fluorideaction.org/pesticides/diflubenzuron.red.pdf

Diflufenican - Herbicide - CAS No. 83164-33-4

-- Subchronic and chronic toxicity studies. Rat. ... In a 24-month feeding study, groups of 50 male and 50 female F344 rats (main study groups, except the control group which consisted of 85 males and 85 females) were administered diflufenican (98.4% purity) in the diet, at concentrations of 0 (control), 500, 2500 or 12500 ppm. A further 30 male and 30 female rats per dose group (satellite study) were similarly treated to generate toxicity dta. An interim-kill was performed on 10 males and 10 females per dose group of the satellite study after 52-weeks... The organ weight changes noted after 104 weeks in the main group... There was an increase in the incidence of marked/severe degeneration of the tubular geminal epithelium of the testes at dose levels of 500 ppm (32/37), 2500 ppm (31/32) and 12500 (33/39) compared to controls (44/64). However, the incidence of slight/moderate degeneration of the geminal epithelium was greater in controls (20.64) compared to top dose males (6/39). Testicular geminal tubular degeneration was considered to be related to pressure atrophy arising from the high incidence of benign intestitial cell tumours (75 - 90%) in treated and control animals...
Ref: September 1995. Evaluation on Diflufenican. 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 7PX, UK. Available at:
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Diflufenzopyr - Herbicide - CAS No. 109293-97-2

Subschronic toxicity: Histopathological findings were an increased incidence of foamy macrophages in the lungs in the 10,000 and 20,000 ppm groups, both sexes, and testicular atrophy in the 20,000 ppm group. Following the 47-week recovery period, the only treatment-related effects which showed partial or no evidence of recovery were foamy macrophages in the lungs and testicular atrophy.
Ref: Federal Register: December 12, 2001 [Page 64257-64262]. Notice of Filing a Pesticide Petition to Establish a Tolerance fora Certain Pesticide Chemical in or on Food.

http://www.fluoridealert.org/pesticides/Diflufenzopyr.FR.Dec12.2001.htm

015; 173127; "SAN 835 H: A 13-Week Dietary Toxicity Study in Rats with a 4-Week Recovery Period" (Simon, F.P.W. et al., Sandoz Agro Ltd., Department of Toxicology, Muttenz, Switzerland, Study No. 448-R, BASF Reg. Doc. No. 92/5244, 10/7/92). 821. SAN 835 H (Lot No. 5131-65C, purity=96%) was admixed to the diet at dose levels of 0 (untreated diet), 1000, 5000, 10000, or 20000 ppm (0, 65, 350, 720, or 1500 mg/kg/day, respectively, for males and 0, 70, 430, 890, or 1750 mg/kg/day, for females) and fed to 10 Wistar rats per sex per dose for 13 weeks (an additional 10 rats per sex per dose at the control and high dose levels were included to test recovery for 4 weeks following dosing). No mortalities occurred. A treatment-related decrease in mean body weight was observed in males at 10000 ppm and in both sexes at 20000 ppm persisting in recovery group males. A treatment-related increase in mean serum alanine aminotransferase level was observed in both sexes at 10000 and 20000 ppm but not in recovery group animals. Microscopic examination revealed treatment-related foam cells in the lungs in both sexes at 10000 and 20000 ppm and testicular atrophy at 20000 ppm with both conditions persisting in recovery group animals. Possible adverse effect: testicular atrophy at 20000 ppm (1500 mg/kg/day). NOEL (M)=350 mg/kg/day (5000 ppm) and (F)=430 mg/kg/day (5000 ppm) based on decreased body weight (in males), increased serum alanine aminotransferase levels (in both sexes), and foamy macrophages in the lungs (in both sexes). Acceptable. (Corlett and Leung, 5/11/00) (21-day dermal study)
Ref: Summary of Toxicology Data for Diflufenzopyr. CA EPA, Department of Pesticide Regulation, Medical Toxicology Branch. July 13, 2000.

http://www.fluorideaction.org/pesticides/diflufenzopyr.ca.epa.2000.pdf

In a 2-generation reproduction study, technical diflufenzopyr (98.1% a.i.) was administered continuously in the diet to 26 Wistar rats/sex/dose at dose levels of 0, 500, 2,000 or 8,000 ppm in the diet (0, 27.3-42.2, 113.1-175.9, or 466.2-742.0 mg/kg/day). The systemic LOAEL is 2,000 ppm (113.1-175.9 mg/kg/day) based on reduced body weight gain, increased food consumption, and increased seminal vesicle weights. The systemic NOAEL is 500 ppm (27.3-42.2 mg/kg/day). The reproductive LOAEL is 8,000 ppm (466.2-742.0 mg/kg/day) based on lower live birth and viability indices, total pre-perinatal loss, reduced body weights and body weight gain during lactation, a higher proportion of runts, and a higher percentage of offspring with no milk in the stomach. The reproductive NOAEL is 2,000 ppm (113.1-175.9 mg/kg/day).
Ref: Federal Register: January 28, 1999. Diflufenzopyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/diflufenzopyr.fr.jan.1999.htm

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

The following results were presented by a Monsanto scientist.
-- Four-week Feeding Study in Mice. Dithiopyr was administered via the diet to groups of 6 male and 6
female CD-1 mice for 4 weeks at concentrations of 0, 300, 1000, 3000, 10,000 and 30,000 ppm... [No concentrations listed for the following effects:]-- Liver enlargement and discoloration, adrenal enlargement, and atrophy of the thymus, spleen, seminal vesicles, ovaries and uterus were noted on gross post-mortem examination... (The Institute of Environmental Toxicology, 1987)
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

Etoxazole - Acaricide - CAS No. 153233-91-1

Rat chronic feeding/oncogenicity study. In the first study, etoxazole technical was fed to male and female Sprague Dawley rats for two years at dietary concentrations of 4, 16, and 64 mg/kg/day. A trend toward decreased body weight gain for males at 64 mg/kg/day in the latter half of the study was observed. Hemotology and clinical chemistry changes, increased liver weights and hepatic enlargement at 16 mg/kg/day or above were observed. Testicular masses, centrilobular hepatocellular swelling and testicular interstitial (Leydig) cell tumors occurred at or above 16 mg/kg/day. The interstitial (Leydig) cell tumors were believed to be incidental. The NOAEL was 4 mg/kg/day for males and 16 mg/kg/day for females.
Ref: August 13, 2003. [Federal Register: August 13, 2003 (Volume 68, Number 156)] [Notices]. Etoxazole; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

http://www.fluorideaction.org/pesticides/etoxazole.fr.aug.13.2003.htm

Non-guideline 13-Week study: Effect on proliferative activity of testicular interstitial cells in rat. A toxic level of the test substance did not affect the proliferative activity of testicular interstitial cells.
Ref: Federal Register: September 26, 2003. Etoxazole; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/etoxazole.fr.sept.26.2003.htm

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

-- In a developmental neurotoxicity study, fipronil was administered to 30 female rats/group in the diet at dose levels of 0, 0.5, 10, or 200 ppm (0.05, 0.90, or 15 mg/kg/day, respectively) from gestation day 6 to lactation day 10. This study found that the maternal LOEL was 200 ppm (15 mg/kg/day), based on decreased body weight, body- weight gain, and food consumption. The maternal NOEL was 10 ppm (0.90 mg/kg/day). The developmental toxicity LOEL is 10 ppm (0.9 mg/kg/day), based on a marginal but statistically significant decrease in group mean pup weights during lactation and significant increase in time of preputial [forseskin] separation in males. The NOEL for developmental toxicity is 0.5 ppm (0.05 mg/kg/day). The developmental neurotoxicity LOEL is 200 ppm (15 mg/kg/day) based on: Decreased auditory startle response; reduced swimming direction scores, group mean angle measurements, and water ``Y'' maze times trails; and decreased absolute-brain weights. The NOEL for developmental neurotoxicity is 10 ppm (0.90 mg/kg/day).
Ref: Federal Register: July 17, 1998. Fipronil; Pesticide Tolerance. Final Rule.

http://www.fluoridealert.org/pesticides/Fipronil.FR.July.17.1998.htm

In a developmental neurotoxicity study in the rat, the NOAEL for general developmental toxicity was 0.5 ppm (0.05 mg/kg/day), based on systemic effects consisting of decreases in pup weights during lactation and increases in time of preputial separation in males at 10 ppm.
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

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

Results of a reproductive toxicity study in rats (exposure route not stated):
Decreased sperm head count per testis in F1 parental males

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

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

Sprague-Dawley-rats were used to prepare a nonsacrificial model for the easy collection and measurement of spermatozoa for reproductive studies. In preparing this model the ductus deferens was anastomosed to the bladder (vasocystostomy) and urinary sperm was collected daily. Vasocystostomy insured that all sperm went into the bladder. Collection of the bladder urine allowed sperm count measurements to be made over time. Sperm counts were recorded over a 20 week period for two groups of rats. The first group had the two vas deferentia, one from each testis, connected to the bladder. The second group had the vas deferens from only one side connected. The group with bilateral connections produced a sperm count approximately double that of the group with a unilateral anastamosis. The reliability of this model was demonstrated by the correlation between testicular histology and sperm counts. The inhibition of sperm production by fluoroacetate (144-49-0) was demonstrated using this model. Sperm counts for five vasocystostomy rats before, during and after fluoroacetate exposure were recorded. Normal pretreatment counts were recorded. During treatment there were sharp increases in sperm counts. Post treatment values dropped in all five animals and all sperm counts were practically zero in about 3 weeks. Advanced patchy degenerative changes were noted in all five fluoroacetate treated rats. The main alteration was sloughing and aggregation of spermatozoa, which fused to form striking multinucleated forms. No ill effects as a result of the surgery were noted.
Ref: Vasocystostomy: A Model for Studying Male Reproductive Toxicity in the Rat; by Al-Juburi AZ, Clarkson TW amd Cockett ATK. Reproductive Toxicology, Vol. 3, No. 3, pages 181-186, 10 references, 1989.

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

-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic oral toxicity in beagle dogs (4/sex/group) administered doses of 0 (vehicle control, corn oil), 5, 25 and 250 mg/kg/day in gelatin capsules for 13 weeks. Severe corneal ulceration, requiring humane sacrifice of 2 males and 1 female of a 250 mg/kg/day dosage during Week 4, prompted adjustment of this regimen to 125 mg/kg/day for the remainder of study... Histopathological evaluation confirmed treatment-related lesions of the eyes, liver, testes and gastrointestinal tract... Conversely, all dogs surviving 13-week treatment showed no clinical signs of toxicity, and no treatment-related changes on physical and ophthalmic examinations at Weeks 4, 8 and 12. .. Upon terminal necropsy, organ weights and gross pathology of dogs surviving 13-week study were unremarkable and histopathological analysis identified a solitary incidence of arrested maturation in the testicular germinal epithelium of one high-dose male. [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate: 13-Week Oral Toxicity Study in Beagle Dogs; 04/24/80; EPA Doc No. 88-920006846; Fiche No. OTS0543851]
-- Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically... Necropsy of F0 parents revealed no gross pathology and, although testes and epididymis of F0 males of a 250 ppm exposure were reduced, histological review identified no treatment-related changes. Conversely, F1 parents were found with gross indications of toxicity.. . Testis and epididymis weights in the males (80, 250 ppm), and pituitary gland (80, 250 ppm), uterus (80, 250 ppm), brain (250 ppm) and lung weights (250 ppm) in females were significantly reduced. Female F1 ovarian weights were increased relative to controls in association with a 250 ppm dietary exposure. Upon histological investigation, increased incidence geriatric nephropathy [kidney](both sexes, 80 and 250 ppm), distension of mesenteric and/or cervical lymph nodes (250 ppm) and increased severity of nephrocalcinosis (females, 80 and 250 ppm), and an increased slight testicular tubular atrophy in males (250 ppm) were noted... [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

-- 411-083 069476 Virgo, D. M., “Fluazifop-butyl: 55 week oral toxicity study in beagle dogs,” Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... Male reproductive toxicity included testicular tubular degeneration and reduced/absent spermatozoa in epididymides. Possible adverse effects (many-faceted toxicity, including mortalities, at 125 mg/kg/day). Acceptable. Aldous, 5/20/02.
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf

Fluazifop-P-butyl - Herbicide - CAS No. 79241-46-6

4.1.3 Dose-response. A statistically significant, but marginally adequate dose-response was shown in the testes weight, and epididymal weight, decrement in the parental and F1 generation in the adult rat, potentially due to reduced sperm content. The cancer study in hamsters showed a good dose response in testes weight decrement. Since the statistically significant effects were seen in the male P0 and F1 parents and in the hamster study, the effects were considered treatment related. The testicular endpoint from the reproduction study was selected for the chronic RfD, intermediate-term oral incidental exposure, intermediate and long-term dermal and inhalation exposure. Other studies showed testes weight decrement and epididymal effects at higher dose levels, but there were only equivocal histological effects shown. Although extensive short-term studies on the testes weight decrement and epididymal effects were conducted, all failed to show that the effect was incidental or find an explanation for the effect. However, the more sensitive studies on sperm count were not among the extra studies conducted. An acceptable negative study of sufficient duration on sperm parameters would add confidence to the possibility that the testes and epididymal weight decrement seen in the rat reproduction study were incidental and not reproducible. The uterine weight decrement seen in the reproduction study showed a good dose-response and was supported by a dose-response in the pituitary weight decrement at the same doses. In addition, in the hamster, hyperplasia in the ovary was seen at high dose levels. One of the subchronic studies in the rat with fluazifop-P-butyl showed testicular weight decrement, while the other one with fluazifop-butyl did not at approximately the same doses as in the reproduction study; at the highest dose tested in the subchronic study with fluazifop-butyl absolute testes weights were increased 30%. The reason is unknown, but may be due to animal variation or other unknown factors such as edema. The testes and epididymal weight decrement and uterine and ovarian effects suggest possible endocrine related effects. However, negative in vitro studies suggest estrogen and androgen hormones were not involved. Agonistic and antagonistic studies with fluazifop-butyl, fluazifop-P-butyl and the fluazifop acid metabolite were conducted in yeast cells containing human estrogen and androgen receptors. No receptor activity was found with any of the test materials over a sufficiently wide concentration range (page 18-19).
Ref: December 10, 2004. US EPA> Fluazifop-P-butyl: Revised HED Chapter of the Tolerance Reassessment Eligibility Decision (TRED) Document. EPA Docket number: OPP-2004-0347-0003
http://www.fluorideaction.org/pesticides/f-p-b.opp-2004-0347-0003.pdf

ONCOGENICITY, MOUSE [OR HAMSTER] 411-125 180756 Rattray, N. J., "Fluazifop-p-butyl: 80 week carcinogenicity study in hamsters," Central Toxicology Laboratory (CTL), Alderley Park Macclesfield, 2/1/01. Lab Study ID: Syngenta No.1606-01. Golden Syrian hamsters, 51/sex/group, were dosed in diet with 0, 0, 200, 750, or 3000 ppm fluazifop-p-butyl (91.6%) for 81-83 weeks. The dual control groups were treated identically. An additional 12/sex/group (same doses) were allocated for 1-yr sacrifice (for hematology only). Estimated achieved doses were 12.5, 47, and 194 mg/kg/day (M) and 12.1, 46, and 181 mg/kg/day (F). No NOEL was established... Findings at the higher two dose levels only included decreased testes weights, reduced spermatozoa counts in epididymides and increased cataract development in males. Stromal cell/sex cord hyperplasia was elevated in high dose females... Aldous, 5/20/02.
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf

-- Reproductive Effects: In a 3-generation reproductive study in rats, effects included reductions in weight gain, fetal weight, ossification, testicular weight, spleen weight, increased prostate weight and gestational length. No Effect Level (NEL) was 1 mg/kg/day.
Target Organs: Liver, skin, kidney, eye, bone marrow, blood, reproductive system.
Ref: Material Safety Data Sheet for Fusilade DX (active indredient Fluazifop-P-Butyl). Syngenta. January 21, 2002.

http://www.fluoridealert.org/pesticides/Fluazifop-P-Butyl.MSDS.pdf

The chronic dietary (all populations), intermediate-term dermal and inhalation, and intermediateterm incidental oral endpoints were selected from the 2-generation reproduction study in rats based on decreased spleen, testes and epididymal weights in males, and decreased uterine and pituitary weights in females (page 5).
Ref: December 10, 2004. US EPA> Fluazifop-P-butyl: Revised HED Chapter of the Tolerance Reassessment Eligibility Decision (TRED) Document. EPA Docket number: OPP-2004-0347-0003
http://www.fluorideaction.org/pesticides/f-p-b.opp-2004-0347-0003.pdf

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

-- In subchronic and chronic toxicity studies, fluazinam targeted the following organs: liver, lung, uterus, testes, pancreas, thymus, thyroid, stomach, eyes and brain. Generalized toxicity was observed in rats, mice and dogs as decreases in body weight, body-weight gain, food consumption and/or food efficiency. Liver toxicity was evident in most studies including increased size and weight, fatty changes, pallor, as well as hepatocyte hypertrophy, necrosis and apoptosis. 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.
-- Recommended ADI. 0.0011 mg/kg bw/d based on 2 year carcinogenicity in mice (1.1 mg/kg/d with 100- fold UF, three-fold SF for endocrine-related effects (testicular atrophy, pancreatic exocrine atrophy), and three-fold for lack of DNT). MOS for other critical endpoint(s) White matter vacuolation/Neurotox NOEL for white matter vacuolation was 10 mg/kg/d in chronic dog study (equivalent to 0.02 mg/kg/d Impurity-5). MOS = 9100. Tumours NOEL for tumours was 3.8 mg/kg bw/d in 2-year rat study. MOS = 3450. Developmental effects NOAEL for developmental effects was 7 mg/kg bw/d in developmental rabbit study. MOS = 6350
[ MOS = Margin of Safety ]

Ref:
Canada: Regulatory Note REG2003-12. Fluazinam. Pest Management Regulatory Agency. Health Canada. Ottawa. October 27, 2003.
http://www.fluorideaction.org/pesticides/fluazinam.canada.report2003.pdf

Chronic toxicity. Fluazinam was not carcinogenic in rats. A NOAEL of 10 ppm (0.43 mg/kg/day) of fluazinam was established based on the following effects at 1,000 and/or 100 ppm: lower food consumption and efficiency of food utilization, slight anemia, elevated cholesterol, increased liver weights, an increased number of macroscopic liver and testes lesions and an increased incidence of microscopically observed lung, liver, pancreas, lymph node and testes lesions. An additional study was conducted to further define the NOAEL for long-term effects in the rat. In the second study, a NOAEL of 50 ppm (2.2 mg/kg/day) was established based on liver and testes effects.
Ref: Federal Register. December 6, 2000. [PF-983; FRL-6573-7]

http://www.fluoridealert.org/pesticides/Fluazinam.FR.December.2000.htm

-- 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.
-- 7-Day inhalation toxicity rats. Test Material: Frowncide WP (51.9% a.i.). NOAEL = Males: 1.38 mg/kg/day; Females: 1.49 mg/ kg/day LOAEL = Males: 3.97 mg/kg/day; Females: 4.25 mg/ kg/day based on increased testes weight (males) and increased liver weight (females)
.
Ref: Federal Register: April 18, 2002. Fluazinam; Pesticide Tolerance. Final Rule.

http://www.fluoridealert.org/pesticides/Fluazinam.FR.Apr.18.2002.htm

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

PubMed Abstract: Basalin, a herbicide, was administered orally to male rats at doses ranging from 60 mg to 1.92 g/kg for 13 weeks. Oral LD50 of the compound was 1.65 g/kg. Toxic effects included hyperexcitability and tremors. The cumulative lethal dose (CLD50) at the end of week 13 was 135 mg/kg with a cumulative toxicity factor (CTF) of 12.22. At 1.92 g/kg, no animals survived to 13 weeks. At 60 and 120 mg/kg, there were no significant changes in body weight gain compared with the controls and a significant decrease in total leukocyte count (TLC), erythrocyte sedimentation rate (ESR) and Hb was observed. There was a decrease in spermatogenesis and infiltration of mononucleated cells in the liver.
Ref: Toxicol Lett 1983 Aug;18(1-2):13-8. Subacute toxicity of Basalin in rats. Gupta PK, Singh YP, Parihar NS.

http://www.fluoridealert.org/pesticides/Fluchloralin.PubMebAbstract.htm

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

-- Groups of 6 male and 6 female Beagle dogs received technical flucythrinate (87.3% pure) in the diet at 0, 30, 100, or 300 ppm daily for 24 months... At sacrifice, the relative liver, kidney, and pituitary weights were increased in both high-dose males and females, while increases in relative spleen, testis and lung weights were noted for high-dose males only... (Spicer et al., 1984).
Ref: 1985 World Health Organization Review for Flucythrinate.

http://www.fluoridealert.org/pesticides/Flucythrinate.1985.WHO.htm

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

-- Abstract: Flufenoxuron (Benzoylphenylurea derivative)-an environmental antimoulting insecticide-is recently used for controlling insect production in cultivated areas. In the present work, the insecticide was administered intragastrically by stomach tube at a dose of 20 mg/kg b.wt. to the Juvenile female and male albino rats (Rattus norvegicus) every other day for three weeks. Histological examination of ovaries revealed that the flufenoxuron induced massive degeneration of ovarian follicles with much cellular debris in the antrum and pyknotic granulosa cells. On the other hand, the testis of flufenoxuron-treated animals exhibited marked decrease of the thickness of tunica albuginea and atrophy of the seminiferous tubules. There was a marked increase of desquamated spermatogenic cells within the lumina of seminiferous tubules. Multinucleated giant cells and vanishing of sperms were observed in the majority of tubules of flufenoxuron-treated animals in comparison with control. Epididymides sperm of experimental group exhibited the presence of increased number of spermatic precursors as well as varieties of sperm anomalies. The hepatic tissues toxicated with the insecticide showed nuclear disintegration, massive breakdown of hepatocytes and internal haemorrhage. The observed gonadal dysfunction may be attributed to hepatic damage or decline of gonadal hormone involved in either processes.
Ref: J. Egypt. Ger. Soc. Zool., Vol. 25(B), 45-64, 1998.
EFFECTS OF FLUFENOXURON-AN ENVIRONMENTAL ANTIMOULTING INSECTICIDE ON GONAD FUNCTION OF ALBINO RATS; by EL-Sayyad, H.I. and Karim, S.A. http://www.egsz.org/BiologicalCurrentContent/Zoology/Comparative%20Physiology/TOXICOLOGY.htm

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

-- Reproduction. Two pilot range-finding rat reproduction studies were conducted with flumioxazin technical at dosages from 100 to 5,000 ppm in the diet. In the definitive 2-generation reproduction study in the rat dietary levels of 0, 50, 100, 200, and 300 ppm established a systemic NOAEL of 200 ppm based on increased clinical signs (both sexes and generations); mortality, gross, and histopathology findings in the liver (F1 females); decreased body weight/weight w/w gain (F0 and F1 females during gestation, F1 males during premating) and decreased food consumption (F0 and F1 females during lactation). The reproductive NOAEL of 100 ppm was mainly based on developmental toxicity at 200 ppm. Observed at 200 ppm were a decreased number of liveborn pups and reduced pup bwts. At 300 ppm the following effects were observed: decreased pup bwt (both generations); decreased number of live pups/litter and viability index (both generations); increased incidence of abnormalities of the reproductive organs (predominately atrophied or hypoplastic testes and/or epididymides in F1 males); decreased gestation index (F0 females); decreased mating and fertility indices (F1 males) and increased clinical signs (F1 pups).
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

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

-- Mutagenic Effects. In two separate assays, one on yeast and the other on bacterial cell cultures, fluometuron failed to cause mutations. Fluometuron interfered with DNA synthesis in the testes of mice given a single oral dose of 2,000 mg/kg (20).
Ref: Flumeturon. EXTOXNET. Pesticide Information Profile. March 1994.

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

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

Abstract: Orally administered FAA produces severe general toxic effects and massive testicular degeneration. The present study was designed to determine whether low doses of parenterally administered FAA will produce testicular lesions in absence of general toxic effect; and if so, what specific cell types will be affected. Adult rats were used. FAA was administered sc in daily injections in doses varying from 50 to 1000 mcg/rat. Animals were sacrificed at periods varying from 4 to 56 days after institution of treatment. At the dose of 250 mcg daily no general toxic effects were observed, but testes diminished in size by 50%. Microscopic studies revealed a specific effect of the drug, primarily centered on the division process of secondary spermatocytes and on spermiogenesis. The spermatogonia and primary spermatocytes were not affected. At the dose of 50 mcg the testes weight was not affected, but microscopic study revealed changes in the same cell types mentioned above. This is the 1st demonstration of a specific morphologically demonstrable effect of a compound on postmeiotic stages of the spermatogenic process.
Ref: Specificity of the effect of fluoroacetamide (FAA) on spermatogenesis. Authors: Sud BN; Steinberger E. Source: Anatomical Record 163: 271-272. 1969.
http://www.popline.org/docs/691972.html

-- REPRODUCTIVE HAZARDS... In mice, oral administration of fluoroacetamide resulted in a prolonged pregnancy and the young suffered from cyanosis, respiratory distress, reduced growth, and decreased survival. Fluoroacetamide has caused testicular degeneration in rats.
.. MALE RATS THAT RECEIVED A DIETARY LEVEL OF 50 PPM (USUALLY CALCULATED AS ABOUT 2.5 MG/KG/DAY BUT SAID TO BE ABOUT 3.4 MG/KG/DAY IN THESE RATS) SHOWED MARKED MORPHOLOGICAL CHANGES IN THE NUCLEUS OF STEP-13 SPERMATIDS WITHIN 24 HR, & EFFECTS BECAME MORE PRONOUNCED & THE ENTIRE CELL BECAME DISTORTED IN 5 DAYS. AFTER 10 DAYS OF TREATMENT, EARLIER STEP SPERMATIDS SHOWED DEGENERATIVE CHANGES & GIANT CELL FORMATION. EVENTUALLY, EVEN SPERMATOCYTES WERE AFFECTED. DIETARY LEVELS OF 20, 10, & 5 PPM, PRODUCED CHARACTERISTIC CHANGES IN LATE STAGE SPERMATIDS BUT NO EFFECT ON SPERMATOCYTES. ... SC ADMIN ... AT A RATE OF ABOUT 1.0 MG/KG/DAY PRODUCED THE CHARACTERISTIC CHANGES IN STAGE-13 SPERMATIDS WITHIN 4 DAYS & A 50% REDUCTION IN THE WT OF THE TESTES IN 28 DAYS. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 3. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. 1279]
-- SELECTIVE DESTRUCTION OF THE GERMINAL EPITHELIUM OF THE TESTES OF MALE RATS WAS REPORTED ... SINGLE DOSAGE LEVEL RESULTING FROM A DIETARY LEVEL OF 50 PPM. ON THIS DIET, THE BODY WT OF 150 TO 160 G RATS INCR BY 88% IN 90 DAYS, BUT THE TESTES WERE REDUCED TO SLIGHTLY LESS THAN 1/3 THE WT OF CONTROLS. AFTER 64 DAYS, THE TUBULES WERE ALMOST COMPLETELY LACKING IN SEMINAL CELLS ... PECULIAR GIANT CELLS WERE OBSERVED. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 3. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. 1278]
Ref: FLUOROACETAMIDE CASRN: 640-19-7. Hazardous Substances Data Bank.
http://www.fluorideaction.org/pesticides/fluoroacetamide.hsdb.htm

Fluorouracil - Former insect chemosterilant; now used as a chemotherapeutic drug - CAS No. 51-21-8

Fluorouracil has not been adequately studied in animals to determine its effects on fertility and general reproductive performance. Following intraperitoneal administration of 125 or 250 mg/kg in rats, chromosomal aberrations and changes in chromosomal organization of spermatogonia were induced; spermatogonial differentiation was also inhibited, resulting in transient infertility. In a strain of mouse that is sensitive to the induction of sperm head abnormalities after exposure to a number of chemical mutagens and carcinogens, no abnormalities were produced at oral dosages of up to 80 mg/kg daily. Following intraperitoneal administration at weekly doses of 25 or 50 mg/kg weekly for 3 weeks during the preovulatory phases of oogenesis in female rat, the incidence of fertile matings was substantially reduced, development of preimplantation and postimplantation embryos was delayed, and the incidence of preimplantation lethality and chromosomal anomalies in the embryos was increased. In a limited study in rabbits, a single 25 mg/kg dose or daily doses of 5 mg/kg for 5 days had no effect on ovulation, appeared not to affect implantation, and had only a limited effect in producing zygote destruction. Drugs that inhibit DNA, RNA, and protein synthesis like fluorouracil might be expected to have adverse effects on gametogenesis. [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]
Ref: TOXNET profile from Hazardous Substances Data Base for FLUOROURACIL.

http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm
Definition
Gametogenesis: The meiotic process by which mature gametes (ova and sperm) are formed.
Oogenesis refers specifically to the production of ova and spermatogenesis to the production of sperm. [ Definition from: GeneTests from the University of Washington and Children's Health System, Seattle]

Abstract: Introduction: Anticancer drugs have variable effects on male gonadal function. There were many reports regarding gonadotoxicity induced by drugs like vinblastine, procarbazine and methotrexate. However, literature of 5-fluorouracil induced gonadotoxicity appears to be lacking. The present study investigates the sperm shape anomalies induced by 5-fluorouracil at various doses on Swiss albino mice. Methods: Mice were treated with therapeutic (12 mg/kg body weight) and high dose (24 mg/kg body weight) of 5-fluorouracil for 5 consecutive days. Mice were sacrificed on 35th day after the first injection. Epididymis were minced with normal saline and stained with eosin. One thousand sperms/animal were counted including the control groups. Normal and abnormal sperms were recorded. Results: A mean abnormality of 13.26% at therapeutic dose and 8.76% at high dose was observed. Conclusion: 5-fluorouracil was found to be gonadotoxic to mice which is directly proportional to the dosage. Hence care must be taken before commencing 5-fluorouracil therapy.
Ref: D'Souza AS (2001). 5-Fluorouracil induced sperm shape anomalies in Swiss albino mice. Indian J Pharmacol Aug;33(4):308. As cited on
Toxnet.

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

Offspring systemic (rat): decreased body weights, delayed preputial separation*, and incomplete ossification in the F1 and/or F2 males and females. Parental systemic: decreased premating body weight gain of the P-generation males and females and decreased premating absolute body weight of the F1 males and females.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

* Note: Preputial separation is an indicator of sexual maturation

Fluridone - Herbicide - CAS No. 59756-60-4

In the combined chronic toxicity/carcinogenicity study in rats, chronic toxicity consisted of
decreased body weights, decreased eosinophil counts and decreased absolute and relative liver and kidney weights at 81 mg/kg/day In addition, fluridone at 81 mg/kg/day also caused an increased incidence of small testes, ocular keratitis and pale or granular kidneys. In a chronic toxicity study in dogs, significant increases in absolute liver weights and increases in alkaline phosphatase activity in female dogs were seen at the highest dose-tested (400 mg/kg/day).
Ref: US EPA. August 17, 2004. Human Health Risk Assessment for Fluridone TRED.

-- Three studies were conducted concurrently, using Fischer rats fed the same dietary levels of Fluridone [0, 200, 650, 2000 ppm (0, 8, 25, 81 mg/kg/day)]. The first study was a 1-year feeding study (R-1126) in which 120 animals were divided into four groups of 15 animals/sex/dietary level. The other two studies were reported to be replicate 2-year oncogenic assays (Nos. R-1136 and R-1146), in which 240 animals per assay were divided into four groups of 30 animals/sex/dietary level. These three studies constitute a 2-year study with 75 animals/sex/dietary level of which 15 animals/sex/dietary level were sacrificed at 12 months. Effects observed at 650 ppm included glomerulonephritis, atrophic testes, eye keratitis, decreased body weight and organ weights. [Elanco Products Company, Division of Eli Lilly and Company. 1980a. MRID No. 00103251, 00103305. Available from EPA. Write to FOI, EPA, Washington, DC 20460.]
Ref: US EPA IRIS for Fluridone. 1990
.
http://www.fluoridealert.org/pesticides/Fluridone.EPA.IRIS.1990.htm

Fluroxypyr - Herbicide - CAS No. 69377-81-7

-- Chronic toxicity. EPA has established the RfD for fluroxypyr at 0.5 mg/kg/day. This RfD is based on histopathological lesions in the kidneys, decreased testes weights, and increased adrenal weights in both sexes observed in a 4-week range-finding feeding study in the dog with a NOAEL of 50 mg/kg/day. An uncertainty factor of 100 was used in calculating the RfD to account for both inter- and intra-species variations.
-- A 28-day feeding study in Beagle dogs administered Fluroxypyr 98.0% a.i. in the diet at levels of 0, 50, 150 or 450 mg/kg/day for 28 days. Dogs at 500 mg/kg/day exhibited ataxia and hind limb weakness as well as decreases in body weight and food consumption and were sacrificed on days 16/17 of the study. Histopathology showed moderate acute tubular nephrosis and a slight to moderate acute gastroenteritis. Some early signs of acute tubular nephrosis were also seen in both sexes of dogs at 150 mg/kg/day. The NOAEL for the study was 50 mg/kg/ day, the LOEL was 150 mg/kg/day based on histopathological lesions in the kidneys, decreased testes weights, and increased adrenal weights in both sexes.
Ref: Federal Register: September 30, 1998. Fluroxypyr; Pesticide Tolerance. Final Rule.

http://www.fluoridealert.org/pesticides/Fluroxypyr.FR.Sept.30.1998.htm

Fluroxypyr 1-methylheptyl ester - Herbicide - CAS No. 81406-37-3

Reproductive toxicity study. In the 2-generation reproductive toxicity study in rats, the maternal (systemic) NOAEL was 100 mg/kg/ day, based on increased kidney weights and kidney histopathology at the LOAEL of 500 mg/kg/day. The developmental (pup) NOAEL was 500 mg/kg/ day, based on decreased body weight at the LOAEL of 1,000 mg/kg/day. The reproductive NOAEL was 1,000 mg/kg/day (HDT).... Chronic dietary all populations: 28-day dog range- finding feeding study LOAEL = 150 mg/kg/day based on histopathological lesions in the kidneys, decreased testes weights, and increased adrenal weights in both sexes...
Ref: Federal Register. September 17, 2001. Fluroxypyr 1-Methylheptyl Ester; Pesticide Tolerances for Emergency Exemptions. Final Rule.

http://www.fluoridealert.org/pesticides/Fluroxypyr.FR.Sept.17.2001.htm

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

-- A second, two-year chronic toxicity and carcinogenicity flusilazole feeding study was carried out in the rat to achieve an MTD (MRID 42613202). Rats were fed diets containing 0, 125, 375, and 750 pprn flusilazole for two years. Toxicologically significant effects of treatment with flusilazole were seen at every dose level in this study. The following were also observed: mortality (5) and induced hepatocellular hypertrophy, fatty change and mixed cell foci, testicular interstitial cell hyperplasia and interstitial cell adenomas in males; decreased mean final body weight and hepatocellular centrilobular hypertrophy in females; and increased mean absolute and relative liver weights, hepatocellular lamellar bodies, urinary bladder mucosal hyperplasia, and --. transitional cell neoplasms in both sexes. There was no NOEL for non-neoplastic lesions in either sex. The NOEL for neoplasms was 375 pprn (14.8 and 20.5 mgikglday in males and females, respectively). - (Page 18)
-- In the rat, target organs were consistent with the subchronic administration studies, i.e., liver and bladder. Flusilazole was oncogenic at the higher doses, causing bladder transitional cell neoplasia in both sexes and testicular Leydig cell adenomas in males... Based on subsequent mechanistic work (see mechanistic section that follows) interference of flusilazole with hypothalmic-pituitary-gonadal (HPG) axis is a possible mechanism of testicular tumor induction. Therefore, it is reasonable to conclude that a threshold exists for the induction by flusilazole of testicular adenomas. The NOEL for neoplasms was 375 pprn (14.8 and 20.5 mglkglday in males and females, respectively). (Page 19)
SUPPLEMENTARY MECHANISTIC STUDIES
---- A 90-day study (MRID 42613204) was conducted to investigate mechanisms of toxicity (hepatotoxicity) and oncogenicity (urinary bladder transitional cell tumors and testicular Leydig cell adenomas) of flusilazole in the rat. Since genotoxicity tests were negative, a non-genotoxic mechanisms of tumor induction were investigated i.e., increased cellular proliferation rates due to irritation or chronic toxicity, and peroxisome proliferation-mediated events. Flusilazole was administered to rats in the diet at concentrations of 0, 10, 125, 375 and 750 ppm. Rats were sacrificed after 1 or 2 weeks or 1.5 or 3 months. Liver weight increases correlated well with the observed cytochrome P-450 induction. It was concluded from these results that the liver toxicity seen in this study and therefore the long-term studies also was due to the observed induction of cytochrome P-450 causing proliferation of the SER and hepatocellular hypertrophy. In the urinary bladder, there was a clear proliferative response following treatment with flusilazole. Serum hormone levels were not significantly altered in this study. It was suggested that the mechanism may lie in the ability to inhibit cytochrome P-450 activity thereby inhibiting steroidogenesis. An additional study was carried out to further investigate the possible mechanism of testicular adenoma induction. The results of this study support the proposal that the toxicity of flusilazole results from effects on cytochrome P-450, and direct toxic effects on the bladder. (Page 28)
---- In the final two-year feeding study in the rat, flusilazole was found to induce testicular adenomas in males. A possible non-genotoxic mechanism for such tumor induction was investigated (HLR 410-93). Flusilazole has been shown to inhibit cytochrome P-450 by the same mechanism as ketoconazole (an anti-tumor agent used in the treatment of human testicular carcinoma). In an in vivo experiment, rats were treated twice daily with either 0, 10,25, 75 or 125 mg/kg/day of flusilazole or 0, 10, 25,50 or 100 mg/kg/day of ketoconazole for 14 days. In an in vitro experiment, Leydig cells were isolated from rats and cultured with ketoconazole or flusilazole and the concentrations of steroids were measured. In the in vivo study, relative accessory sex gland weights were reduced with ketoconazole, but not flusilazole. It was concluded that either the flusilazole was less potent than ketoconazole or operated by another mechanism. Ketoconazole produced a decrease in serum testosterone and related steroids. Flusilazole caused reduction in both serum and testicular testosterone and estradiol, but was far less potent than ketoconazole. It was proposed that this data supported the theory that flusilazole could induce Leydig cell tumors by decreasing testosterone and estradiol synthesis thus disrupting the HPT axis. (Page 28)
-- The chronic toxicity/carcinogenicity studies in the rat, the target organs identified were consistent with the sub-chronic administration studies, i.e., liver and bladder. Flusilazole was found to be oncogenic at the higher doses, causing bladder transitional cell neoplasia in both sexes and testicular Leydig cell adenoma in males. There is evidence of a proliferative effect of flusilazole in the bladder transitional epithelium, which is likely the mechanism of tumorigenesis. Therefore, the urinary bladder tumors are considered to be caused by an epigenetic, threshold-associated mechanism. Interference of flusilazole with hypothalmic- pituitary-gonadal (HPG) axis is suggested as a possible mechanism of testicular tumor induction. Evidence in support of this theory was provided by a comparative study with the aromatase inhibitor, ketoconazole. Flusilazole did cause a slight reduction in both serum and testicular - testosterone and a dose-dependent decrease in serum estradiol, but was far less potent than ketoconazole. It would appear reasonable to conclude that a threshold exists for the induction by flusilazole of testicular aienomas. The NOEL for neoplasms was 375 ppm (14.8 and 20.5 mglkgiday in males and females, respectively). (Page 29)
Ref: DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma (Active ingredients: Flusilazole and Famoxadone): Summary of data compiled in support of a Section 18 Emergency Exemption request for control of Asian soybean rust on soybeans. By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.
http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf

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

-- In a 2-generation rat study with racemic fluvalinate reproduction was subnormal in all groups, including controls... Beginning with the low dose (20 ppm), a dose dependent impairment of spermatogenesis was observed in males of the F0 generation.
Ref:
Revised Summary Report. Committee for Veterinary Medicinal Products. The European Agency for the Evaluation of Medicinal Products. Also available at: http://www.emea.eu.int/pdfs/vet/mrls/002195r1.pdf


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