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.

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

-- 2) 13-Week Feeding - dog: Dietary levels tested: 0, 2, 5, and 20 mg/kg/day; Beagle dogs (4/sex/dose level) were administered haloxyfop-methyl in the diet for 13 weeks. A statistically significant decrease in serum cholesterol values was reported for males fed 2 mg/kg/day. A statistically significant decrease in serum cholesterol values was reported for males and females fed 5 mg/kg/day. A significant decrease in male and female triiodothyronine and free thyroxine values was accompanied by a significant decrease in male and female relative thyroid/parathyroid weights. Hepatic peroxisomal fatty acid beta-oxidation was increased in males and females fed 5 mg/kg/day. Histological changes reported at this level were hepatocellular enlargement with increased glycogen content, decrease in follicular size and hypertrophy of the follicular epithelial cells of the thyroid, and decrease size of the testicular tubules. The LEL for systemic toxicity is 2 mg/kg/day, the lowest dose tested, based on decreases in serum cholesterol values in males. A NOEL for systemic toxicity was not established; core grade minimum (Dow Chemical Co., 1987a)
-- 4) 16-Week Feeding - rat: Dietary levels tested: 0, 0.002, 0.02, 0.2, and 2 mg/kg/day; CDF Fischer 344 rats (15/sex/group) were administered haloxyfop- methyl in the diet for 16 weeks. A significant dose-related increase in relative liver weight was reported for male rats of the 0.002, 0.02, 0.2, and 2.0 mg/kg/day levels by 4, 5, 11, and 44%, respectively. Female relative liver weights were increased significantly (4%) at the 2.0 mg/kg/day levels. Males fed the 0.2 and 2.0 mg/kg/day levels showed enlarged hepatocytes and increased cytoplasmic homogeneity. An increase in hepatocellular cytoplasmic homogeneity was reported for females at 2.0 mg/kg/day. A significant decrease in relative testes weight (5%) accompanied by atrophy of the seminiferous tubules were reported for males fed the 2.0 mg/kg/day level. The LEL for systemic toxicity is 0.002 mg/kg/day, the lowest dose tested, based on a dose related increase in relative liver weight in males. A NOEL for systemic toxicity was not established.; core grade minimum (Dow Chemical U.S.A., 1982a)
-- Critical Effect: Reduced relative kidney weights in F0, F1, and F2b adults; Reduced fertility in the F1/F2b generation. 3-Generation Rat Reproduction Study. Dow Chemical U.S.A.,1985a. NOEL: 0.005 mg/kg/day; LEL: 0.05 mg/kg/day....

Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

Hydramethylnon - Insecticide - CAS No. 67485-29-4

- Mutagenicity There are five acceptable mutagenicity (84-2) studies of hydramethylnon. The findings of adverse effects on spermatocyte and/or spermatogonia in the dominant lethal assay are consistent with the results of the 2-generation reproduction study in rats showing that hydramethylnon is a reproductive toxicant which appears to specifically target the germinal cells and/or tissues in the testes.
- On May 28, 1998, the Agency’s Cancer Peer Review Committee concluded that the dose levels of 100 ppm in males, and 50 ppm in females were adequate to assess the carcinogenic potential of hydramethylnon in rats.... The statistically significant increases in tumors observed in the uterus (adenomatous polyps) and adrenals (medullary adenomas) were not considered to be biologically significant since they were seen at excessive doses (i.e., at 200 ppm). Under the conditions of this study, the NOAEL was 50 ppm (2.4 mg/kg/day in males, 3.0 mg/kg/day in females), and the LOAEL was 100 ppm (4.9 mg/kg/day in males, 6.2 mg/kg/day in females) based on small, soft testes, decreased testicular weights, and testicular atrophy in males; and decreased body weight gain in females. This study is classified as acceptable and satisfies guideline requirement 83-5 for a chronic feeding/carcinogenicity study in rodents.
- In a carcinogenicity study, MRID 00101563, groups of 50 male and 50 female Charles River CD-1 mice received diets containing hydramethylnon at dose levels of 0, 25, 50, 100, or 200 ppm (0, 3.57, 6.93, 14.2, or 28.6 mg/kg/day in males, and 0, 4.45, 6.87, 17.3, or 33.1 mg/kg/day in females, based on food consumption) for 18 months. The 200 ppm males and females were sacrificed after 55 weeks because of high mortality. Survival after 18 months at the 50 and 100 ppm doses was 72% and 46% in males, and 66% and 46% in females (compared to control survival of 86% in males and 76% in females)... Histopathologic findings of testicular degeneration in the 50, 100, and 200 ppm males displayed a dose-related pattern of incidence and severity, and included hypospermia, interstitial cell hyperplasia of Leydig cells, and germinal cell degeneration...
- Mutagenicity There are five acceptable mutagenicity (84-2) studies of hydramethylnon. The findings of adverse effects on spermatocyte and/or spermatogonia in the dominant lethal assay are consistent with the results of the 2-generation reproduction study in rats showing that hydramethylnon is a reproductive toxicant which appears to specifically target the germinal cells and/or tissues in the testes.
Ref: US EPA. Reregistration Eligibility Decision (RED) Hydramethylnon. EPA 738-R-98-023. December 1998.

http://www.fluoridealert.org/pesticides/Hydramethylnon.RED.1998.pdf

Hydramethylnon is a male reproductive toxicant which appears to specifically target the germinal cells and/or tissues in the testes... The reproductive NOEL was 25 ppm (1.66 mg/kg/day for males) and the lowest observed effect level (LOEL) was 50 ppm (3.32 mg/kg/day for males), based upon histopathological findings in the testes and the epididymides. Also, at 75 ppm (5.05 mg/kg/day in males), reproductive performance of the males was decreased with longer precoital intervals, lower pregnancy rates, reduced gestation weight gain for females and smaller litters... The evidence of male infertility and testicular atrophy at 90 mg/kg/day in the dominant lethal assay is consistent with similar findings observed in the chronic rat study, the 18-month mouse feeding study, the 2-generation reproduction study, and the 91-day oral gavage study in dogs.
Ref: Federal Register. August 14, 1998. [PF-824; FRL-6023-2]

http://www.fluoridealert.org/pesticides/Hydramethylnon.FR.Aug.14.98.htm

In a 90-day dog feeding study, testicular atrophy was observed at 6 mg/ kg/day (LOEL). The NOEL was 3 mg/kg/day. In a 90-day rat study, dietary administration of 5 mg/kg/day (LOEL) produced testicular atrophy. The NOEL was 2.5 mg/kg/day. Dietary administration of 6.5 mg/kg/day for 18 months produced testicular lesions in mice. The NOEL was 2.75 mg/kg/ day. In a 2-year rat study, dietary administration of 5 mg/kg/day produced decreased testicular weight and testicular atrophy. The NOEL was 2.5 mg/kg/day. In a 3-generation rat reproduction study, oral administration of 5 mg/kg/day produced male infertility. The NOEL was 2.5 mg/kg/day... EPA believes that there is sufficient evidence for listing hydramethylnon on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available reproductive, developmental, and hepatic toxicity data for this chemical.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

Lactofen - Herbicide - CAS No. 77501-63-4

-- Subchronic feeding-- Mice-- 3-month. Groups of Male and female mice were fed diets containing Lactofen Technical at concentrations of 0, 40, 200, 1,000, 5,000, and 10,000 for 13-weeks. At week 5, the dosage of the 40 ppm groups was increased to 2,000 ppm. Treatment related mortality occurred at dosages above 1,000 ppm. The LOEL was 200 ppm based on: increased WBC; decreased hematocrit, hemoglobin and RBC; increased alkaline phosphatase, SGOT, SGPT, cholesterol and total serum protein levels; increased weights or enlargement of the spleen, liver, adrenals, heart and kidney; histopathological changes of the liver, kidney, thymus, spleen, ovaries and testes. In general, effects were slight in the 200 ppm groups, and moderate to severe in the 1,000 ppm groups.
-- Reproduction-- Rats. Groups of male and female rats were fed 0, 50, 500 or 2,000 ppm of Lactofen Technical continuously in their diets for 2-generations. Adult systemic toxicity (mortality, reduced body weight, increased liver and spleen weight, decreased kidney weight and histological changes in the liver and testes) was observed at levels of 500 ppm and greater.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.

http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

90-Day Feeding - mouse: LEL=200 ppm (increased leucocytes, decreased Hct, Hgb, WBC); increased alkaline phosphatase, SGOT, SGPT, cholesterol; increased liver weight and enlarged spleen, liver and heart; liver vacuolation necrosis of individual hepatocytes, biliary hyperplasia, extramedullary hematopoiesis, kidney nephrosis and fibrosis; follicular atreria, abnormal sperm forms); core grade minimum (PPG Industries, 1983b)
Ref: US EPA IRIS. (Online October 11, 2003). Available at
Toxnet.

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

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

Abstract. The actue toxicity of N-methyl-N- ( 1-napthyl ) fluoroacetamide ( MNFA, Nissol ) was determined in detail in different species of animals and its subacute toxicity was determined in the rat. The LD50 of Nissol and its active ingredient MNFA were determined in male and female mice by oral, subcutaneous, dermal, intraperitoneal and intravenous administration; in male rats and guinea pigs by oral, dermal and subcutaneous administration; in male rats and guinea pigs by oral, dermal and subcutaneous administration; in male cats and dogs by oral and dermal routes; in adult monkeys by oral, dermal, subcutaneous, intraperitoneal and intravenous administration and orally in hens. Fish toxicity was investigaged in carp and inhalation toxicity tests were made in mice, rats and guinea pigs. The tabulated results show that the toxicity varied markedly with species. The toxicity of MNFA in mice, rats or monkeys was 1/100 to 1/200 of that in rabbits, guinea pigs, cats or dogs. In mice the oral LD50 ranged from 250-370 mg/kg, while by subcutaneous and intraperitoneal administration, the LD50 values were about 250 mg/kg or less. The approximate toxicity of MNFA for monkeys was less than for other species, the oral minimum lethal dose ( MLD ) being 300 mg/kg, subcutaneous MLD 150 mg/kg, intraperitoneal MLD 100 mg/kg and dermal MLD 800 mg/kg. The toxic symptoms produced by MNFA were charcteristic or organic fluorine poisoning in mammals. In the subacute toxicity tests, five groups of rats, 12 male and 12 female in each group were given oral daily doses of 0.625, 1.25, 2.50, 5 and 10 mg/kg MNFA for 6 months. Blood and urine tests were taken at 40-day intervals and pathological examination during autopsy revealed aspermatogenesis in some tubules of the testis from the rats of the two high dose groups. Destruction of the germinal epithelium was more striking in mature cell series than in immature cells. Does below 2.5 mg/kg did not produce significant changes in the testis. A dose dependent decline in the systolic arterial blood pressure was noticed. The reduction ranged from 5 to 20% of the normal blood pressure. The blood pressure reduction was not accompanied by gross or microscopic changes of morphology of the cardiovascular system or kidney. The serum level of SGOT also was reduced in the treated rats.
Ref. Acute an/ subchronic toxicity of a new fluorine pesticide, N-methyl- N-( 1-naphthyl ) fluoracetamide; by Hashimoto Y, Makita T, Miyata H, Noguchi T, Ohta G. Toxicol, App. Pharmacol.; 12(3), 536-47, 1968.

Novaluron - Insecticide - CAS No. 116714-46-6

Excerpt from Table 1.--Subchronic, Chronic, and Other Toxicity
-- Reproduction and fertility- rat. NOAEL (M/F)= 74.2>=1009.8 mg/kg/day; LOAEL= 297.5 mg/kg/ day based on decreased epididymal sperm counts and increased age of preputial separation in the F1 generation, reproductive LOAEL for females was not established.
Re: June 2, 2004. Novaluron; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/novaluron.fr.june.2.2004.htm

Noviflumuron - Insecticide - CAS No. 121451-02-3

-- REPRODUCTION, RAT. “XDE-007: Two-Generation Dietary Reproduction Toxicity Study in CD Rats,” (Carney, E.W., Zablotny, C.L., Liberacki, A.B., Yano, B.L.;Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI; 3/22/04). XDE -007 (97.9% pure) was fed in diet to Crl:CD (SD) IGS BR rats (30/sex/dose/generation) at 0, 0.5, 5 or 25 mg/kg/day continuously from pre-mating of parental generation 1 (P1) through weaning of offspring through 2 generations (2 matings for P2 generation) to F2b weaning.. ... Reproduction and Fertility NOEL = 5.0 mg/kg/day (There was an increased proportion of abnormal P2 sperm at 25 mg/kg. Although not statistically significant, there were decreased mating and fertility indices in both sexes of P2a and P2b adults at > 5.0 mg/kg.)... F2a male weanlings had statistically significantly decreased body weights, relative brain and absolute spleen weights at 25 mg/kg. Neonates at 25 mg/kg in both F1 and F2 generations showed tonoclonic convulsions, as well as in 1 litter of F2a at 5.0 mg/kg. P2 females (1, 1, 5 and 7 at 0, 0.5, 5.0 and 25 mg/kg, respectively) failed to litter, so the female is considered to be an affected sex.) Possible adverse effects on reproduction, fertility and pup survival, along with numerous other toxicologically relevant effects. M. Silva, 6/18/04
-- “XDE-007: Two-year Dietary Chronic Toxicity/Oncogenicity and Chronic Neurotoxicity Study in Fischer 344 Rats,” (Yano, B.L., Dryzga, M.D., Thomas, J.; Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI; Laboratory Project Study ID: 011168; 4.22.05). Noviflumuron ((N-[3,5-dichloro-2-fluoro-4(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-N’-(2,6-difluorobenzoyl)urea; XDE-007, 97.9% pure) was fed in diet to Fischer 344 rats (75/sex/dose) for 90 days, 1 or 2 years at 0, 0.1, 1.0, 75 or 300 mg/kg/day. Subchronic toxicity was assessed after 90 days of treatment on 10/sex/dose at 0 and 1.0 mg/kg/day doses only. At 1 year,10/sex/dose (chronic toxicity group), and 5/sex/dose (chronic neurotoxicity group) were necropsied. The remaining 50/sex/dose were necropsied after 2 years (oncogenicity group). Chronic NOEL = 1.0 mg/kg/day (At > 75 mg/kg/day there were decreased body weights and body weight gains along with increases or decreases in absolute and/or relative organ weights (liver, kidney, brain, heart, adrenal, testes, spleen, epididymides were affected) at 12 and/or 24 months. Skin/tail papules and pustules were observed in males (300 mg/kg/day) and females (> 75 mg/kg/day) in the second year. Females showed an increase in phthisis bulbi at 300 mg/kg/day. Prothrombin time in males and cholesterol levels in females were increased at > 75 mg/kg/day at 24 months. ALP activities were increased in both sexes at > 75 mg/kg/day at 24 months. Urine specific gravity was decreased (both sexes at > 75 mg/kg/day) and urine volume was increased (M 300 mg/kg/day and F > 75 mg/kg/day) at 24 months. Lung inflammation, hepatocytic hypertrophy (both sexes > 75 mg/kg/day), mineralization of renal pelvic epithelium (M > 75 mg/kg/day), epididymal aspermia* (M > 75 mg/kg/day), atrophy of seminiferous tubules (300 mg/kg/day), tail hyperkeratosis +/- inflammation (both sexes 300 mg/kg/day), tail tip necrosis (M 300 mg/kg/day) and hyperplasia of renal pelvic epithelium (M 300 mg/kg/day) were observed at 24 months. Leukemia was decreased in both sexes at > 75 mg/kg/day at 24 months.) Possible adverse effect: Hepatocellular adenomas (benign, M 300 mg/kg/day), uterine stromal polyps (F > 75 mg/kg/day), and liver foci (M > 75 mg/kg/day) were increased at 24 months. Acceptable. Silva, 8/19/05
Ref: August 2005 - Summary of toxicological data. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/noviflumuron.ca.epa.2005.pdf

* Definition: Aspermia = the complete absence of semen.

Penoxsulam - Herbicide - CAS No. 219714-96-2

-- Significant dose-related effects in the two-generation reproduction study were limited to the delay in preputial separation.
-- 2-Generation Reproduction and fertility effects in rats - Reproductive/Offspring LOAEL = 100 mg/kg/day based on delayed preputial separation
Ref: September 24, 2004. Penoxsulam Pesticide tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/penoxsulam.fr.sept.24.04.htm

-- Preputial separation, an indicator of sexual maturation, was significantly (p#0.05) delayed in mid and high dose F1 males. The mean age at which preputial separation was attained for the control, low, mid, and high dose groups was 43.6, 44.0, 45.5, and 46.0 days, respectively. In addition, at the mid dose, 1 animal did not separate and at the high dose, 3 animals did not separate whereas all animals at the control and low doses did separate. The delay in preputial separation at the mid and high doses was considered to be a treatment-related effect.
-- Endocrine Disruption. For penoxsulam, effects which indicate potential endocrine disruption include kidney lesions (crystals) in female rats and delay in preputial separation in male rats. When the appropriate screening and/or testing protocols being considered under the Agency‘s EDSP have been developed, penoxsulam may be subjected to additional screening and/or testing to better characterize effects related to endocrine disruption.
Reference: September 2004. US EPA Fact Sheet on Penoxsulam. Page 4.
http://www.fluorideaction.org/pesticides/penoxsulam.epa.fact.sheet.2004.pdf

PFOS - PFOS - Insecticide, US EPA List 3 Inert

Due to length, click here for effects page


Picoxystrobin - Fungicide -
CAS No. 117428-22-5

-- Other toxicological studies. o-phthalic acid (Metabolite 15, grain): Survey of published literature (November 2000) Acute oral LD50, rat: 7500-8400 mg/kg bw In-vitro genotoxicity (Ames test & cytogenetic assay in CHO cells): negative. Dominant lethal test: questionable positive test result involving reduced male fertility and abnormal sperm morphology. Non-carcinogenic in rats and mice according to NTP carcinogenicity programme. Reduced foetal body weight and retarded ossification in rats at maternal toxic doses
Ref: July 2003 - Review report for the active substance picoxystrobin. Picoxystrobin SANCO/10196/2003-Final. 3 June 2003. Finalised in the [European Commission] Standing Committee on the Food Chain and Animal Health at its meeting on 4 July 2003 in view of the inclusion of picoxystrobin in Annex I of Directive 91/414/EEC/.
http://www.fluorideaction.org/pesticides/picoxystrobin.eu.june.2003.pdf
Note: This report identified o-phthalic acid (Metabolite 15, grain) as a "Toxicologically significant compound"

Primisulfuron-methyl - Fungicide, Herbicide- CAS No. 86209-51-0

-- Chronic toxicity: Doses of 125 mg/kg/day administered in the diet to dogs over a 1-year period produced decreased body weight gain, anemia, increased liver weight, and thyroid hyperplasia (abnormal growth) [15]. Rats fed dietary doses of about 180 mg/kg/day over 90 days showed effects similar to those noted in dogs, as well as spleen weight increases [24]. In another study, doses of 480 mg/kg/day in rats over 18 months produced increased incidence of tooth disorders, chronic nephritis (kidney damage), and testicular atrophy [4]. In two 18-month studies in mice, testicular atrophy, chronic nephritis, and increased tooth and bone disorders were seen at doses of 180 mg/kg/day and 360 mg/kg/day, respectively [4].
-- Reproductive effects: Changes in the function of the testes were noted in rats fed high doses (250 mg/kg/day) of primisulfuron-methyl over two generations. There was also a decrease in the body weight of the offspring. No compound-related effects on reproduction were noted at doses below 50 mg/kg/day [15]. Testicular atrophy was seen in rats in chronic studies (see above), which could result in reproductive effects. The available data suggest that reproductive effects in humans due to primisulfuron are not likely under normal circumstances.
-- Organ toxicity: Target organs identified in animal studies include the liver, kidneys, spleen, and
testes, as well as the skeleton.
Ref: E X T O X N E T Extension Toxicology Network Pesticide Information Profiles. Revised June 1996.

http://ace.ace.orst.edu/info/extoxnet/pips/primisul.htm

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

-- A 2-year chronic feeding/carcinogenicity study in rats fed dosages of 0, 0.4, 7.9, 79.9 or 160.9 (males), and 0, 0.5, 9.2, 95.7 or 205.8 mg/kg/day (females) was conducted. There was uncertain evidence of carcinogenicity with slight increases in the incidence of mammary gland adenocarcinomas in females at 95.7 and 205.8 mg/kg/day, slight increase in incidence of benign testicular interstitial cell tumors at 79.9 and 160.9 mg/kg/day (significant trend only). A systemic NOAEL of 7.9 mg/kg/day was based on decreased body weight and body weight gain, hematopoietic effects (males), and possibly increased serum GGT and decreased liver, kidney and adrenal weights (females) at 79.9 mg/kg/ day.
-- Carcinogenicity. The HED RfD/Peer Review Committee (PRC) classified this chemical as a Class D oncogen based on the conclusion that there was uncertain evidence of carcinogenicity. No relevant treatment-related oncogenic potential was observed in rats and mice. The slightly increased incidence of testicular interstitial cell tumors in male rats at 79.9 mg/kg/day and the slightly increased incidence of mammary gland adenocarcinoma in females at 95.7 mg/kg/day was not significant when the increased survival in these groups was considered. Furthermore, the overall incidence of mammary tumors was essentially identical in all groups including the control. There was no evidence of carcinogenicity in mice and dosages in both studies were sufficient for identifying a cancer risk. In the absence of carcinogenicity, it is appropriate that a RfD approach be used for quantitation of human risks.
Ref: Federal Register: August 25, 1999. [PF-882; FRL-6093-7]. Notice of Filing a Pesticide Petition to Establish a Tolerance for Certain Pesticide Chemicals in or on Food.

http://www.fluorideaction.org/pesticides/prosulfuron.fr.aug.25.1999.htm

Pyridalyl - Insecticide - CAS No. 179101-81-6

Possible effect of pyridalyl on the steroid synthesis pathway was surveyed in rats. It was revealed that pyridalyl affected the sex hormone synthetic pathway in the testis at the concentration of 3 µM and higher, and this effect was caused by an inhibition of testosterone synthesis, via weak but significant inhibition of 17a-HSD activity. (Ref. 44. Effect of pyridalyl on the sexual hormonal synthetic pathway in rats: Sumitomo Chemical Co., Ltd., 2002, unpublished.)
Ref: Evaluation Report. PYRIDALYL. January 14, 2004. Japan Food Safety Commission. Pesticides Expert Committee.

Quinoxyfen - Fungicide - CAS No. 124495-18-7

-- ** 039 – 181139 "XDE-795: Two-Generation Dietary Reproduction Study in Sprague-Dawley Rats,"(Liberacki, A.B., Breslin, W.J., Zwinker, G.M., Johnson, K.A., Freshour, N.L.; The Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical, Midland, MI; Laboratory ID#’s: DR-0325- 7474-013 [P1, F0, W1, FB, WB, P2, F2 & W4]; 5/23/95). XDE-795 (97.4% pure) was fed in diet to Sprague-Dawley rats (30/sex/dose) at 0, 5, 20 and 100 mg/kg/day, 7 days/week for 2 generations. Systemic NOEL = 20 mg/kg (Kidney pathology was observed in P1 and P2 females at 100 mg/kg. Males showed liver, kidney and epididymal histopathology at 100 mg/kg in P1 and P2 adults.) Reproductive NOEL = 100 mg/kg/day (There were no treatment-related reproductive effects in either sex.) Pup NOEL = 20 mg/kg/ (F1a & F1b pups showed decreased bodyweights at 21 days of lactation and this was considered to be due to excessive dose and decreased food consumption.) No adverse effect. Acceptable. M. Silva, 8/9/01
-- 030; 181170; "XR-795: Four Week Dietary Toxicity Study in Fischer 344 Rats" (Szabo, J.R. and Davis, N.L., Health and Environmental Sciences-Texas Lake Jackson Research Center, The Dow Chemical Company, Freeport, Texas, Laboratory Project Study ID TXT: DR-0325-7474-002, 10/12/92). XR-795 (TSN100003, DECO-36-106, purity = 97.6%) was admixed to the diet at dose levels of 0 (untreated diet only), 250, 500, or 1000 mg/kg/day and fed continuously to 5 Fischer 344 rats per sex per dose for 4 weeks. No clinical signs were observed. A treatment-related decrease in mean body weight at all dose levels in both sexes was observed. Treatment-related increases in mean relative liver (in both sexes at all dose levels) and in mean relative kidney (in males at all dose levels and in females at 500 and 1000 mg/kg/day) weights and a treatment-related decrease in mean relative testes weight at 1000 mg/kg/day were observed. Macroscopic examination revealed bilateral testicular atrophy in 3/5 animals at 1000 mg/kg/day. Microscopic examination revealed a moderate to severe decrease in spermatogenesis in 4/5 animals at 1000 mg/kg/day. Possible adverse effect indicated: testicular atrophy with a decrease in spermatogenesis. NOEL (M/F) < 250 mg/kg/day (based on body weight and mean relative organ weight data). Supplemental (only 5 animals per sex per dose were used and the animals were only dosed for 4 weeks). (Corlett, 8/27/01)
-- (Corlett, 8/27/01) 030; 181171; "XR-795: Palatability and Toxicity Probe Study in Beagle Dogs" (Szabo, J.R. and Rachunek, B.L., Health and Environmental Sciences-Texas Lake Jackson Research Center, The Dow Chemical Company, Freeport, Texas, Laboratory Project Study ID: DR-0325-7474-001, 2/28/92). XR-795 (TSN100008, Lot # DECO-36-111, purity = 98.8%) was admixed to the diet at dose levels of 0 (untreated diet only), 100, 500, or 1000 mg/kg/day and fed continuously to 1 beagle dog per sex per dose for 30 days. No clinical signs were observed. A treatment-related decrease in body weight gain or outright body weight loss at all dose levels in males and at 500 and 1000 mg/kg/day in females was observed. A treatment-related decrease in feed consumption in males at all dose levels and in females at 500 and 1000 mg/kg/day was observed. Macroscopic examination revealed a small/atrophic thymus in both the male and the female at 1000 mg/kg/day and small/atrophic testes in the male at 1000 mg/kg/day. Microscopic examination revealed vacuolation of midzonal and centrilobular hepatocytes at 500 and 1000 mg/kg/day in both sexes and thymic lymphoid depletion in the male and female at 1000 mg/kg/day. No adverse effects. NOEL (M) < 100 mg/kg/day, NOEL (F) = 100 mg/kg/day (based on body weight and feed consumption data). Supplemental (only 1 animal per sex per dose was used and the animals were only dosed for 30 days). (Corlett, 8/28/01)
Ref: October 4, 2001. SUMMARY OF TOXICOLOGY DATA QUINOXYFEN (XDE-795 & XR-795). California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

http://www.fluoridealert.org/pesticides/quinoxyfen.ca.epa.2001.pdf

 

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

Due to length, see special section on Testes for Sodium fluoride

 

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

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

Subchronic Toxicity:
-- Technical sodium fluoroacetate was administered by gavage for 13 weeks to Crl:CD(SD)Br rats. The doses were 0, 0.05, 0.20, or 0.50 mg/kg/day. The NOEL was 0.05 mg/kg/day. The LOEL was 0.20 mg/kg/day, based on dose-related findings in histopathology (hypospermatogenesis, fusion bodies, and immature or abnormal sperm) and decreased size and weight of testes and epididymides in males. Females had dose-related increases in absolute and relative heart weights at the mid and high doses (Wolfe, 1988).
-- In a study with male Sprague Dawley rats, the animals were dosed with 0, 0.07, 0.19, or 0.71 mg/kg/day of sodium fluoroacetate in their drinking water for seven days. This was followed by 21 days without the test compound. A group of rats from each dose level was killed each day of treatment and on days 3, 7, 14, and 21 after dosing. The testes, kidneys and liver were examined. Testicular atrophy and nonreversible tubular degeneration were found at the mid and high dose. Testicular atrophy with reversible tubular degeneration was found at the low dose. No effects on liver or kidney were seen. The lowest dose was the LOEL (MRID 40016990).
Ref: US EPA Reregistration Eligibility Decision (RED) for Sodium fluoroacetate. September 1995.

http://www.fluoridealert.org/PESTICIDES/Sodium_fluoroacetate.RED.95.pdf

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

-- PubMed Abstract: Rats recieving 20, 6.6 or 2.2 p.p.m. sodium fluoroacetate in the drinking water were killed daily during the 7 days of treatment and at more widely spaced intervals in the succeeding 21 days. Testicular weight and ATP concentrations decreased in rats receiving 20 or 6 p.p.m. fluoroacetate, while citrate concentrations were elevated and morphological damage was seen in the testes of all the treated rats. Initial cellular changes common to the three treatment groups included altered appearance and decreased numbers of spermatids, and formation of spermatid and spermatocyte giant cells. At the two higher concentrations damage progressed to marked seminiferous tubule atrophy. Regeneration of the seminiferous tubules was complete by 7 days after treatment, in the rats given 2 p.p.m. but regeneration was not complete by Day 21 after treatment in those receiving the higher doses. Spermatogenesis was abnormal in some instances during the regneration period in these groups. The findings are consistent with impaired energy production via blockage of the Krebs cycle, and subsequent impairment of carbohydrate metabolism through the Embden-Meyerhof pathway.
Ref:
J Reprod Fertil 1979 May;56(1):201-7; Effects of fluoroacetate on the testis of the rat; Sullivan JL, Smith FA, Garman RH. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=469843&dopt=Abstract

Abstract
1. 1. Administration of multiple or single doses of sodium fluoroacetate (1080) to male Tiliqua rugosa caused a decrease in plasma testosterone concentration.
2. 2. A single dose of 100 or 250 mg 1080 kg-1 body weight decreased plasma testosterone by 52%. However, 25 mg kg-1 had little apparent effect on testosterone levels. When lizards were given the multiple dose equivalent of these doses over 12 days at 3 day intervals, the effect was much less dramatic with plasma testosterone concentration steadily declining over 15 days for the two higher doses.
3. 3. There was a suggestion of degeneration of seminiferous tubules in some individuals.
Ref: The effect of sodium monofluoroacetate on plasma testosterone concentration in Tiliqua rugosa (gray); by L. E. Twigg, D. R. King, and A. J. Bradley. Comparative Biochemistry and Physiology Part C: Comparative Pharmacology; Volume 91, Issue 2 , 1988, Pages 343-347

Sulfentrazone - Herbicide - CAS No. 122836-35-5

-- Toxicological Profile... A two-generation reproduction study in the rat at dietary levels of 14, 33, or 46 mg/kg/day in males and 16, 40, or 56 mg/kg/day in females established a NOEL for systemic and reproductive/ developmental parameters of 14 mg/kg/day for males and 16 mg/kg/day for females. The LOEL for systemic and reproductive/development parameters was 33 mg/kg/day for males and 40 mg/kg/day for females. Systemic effects were comprised of decreased body weight gains, while reproductive/developmental effect at the LOEL included degeneration and/or atrophy in the testes, with epididymal sperm deficits, in the second (F1) generation males. Male fertility in the F1 generation was reduced at higher doses; litter size, pup survival, and pup body weight for both generations were also effected at higher doses.
Ref: Federal Register: March 10, 1997. Sulfentrazone; Establishment of Tolerances. Final Rule. Federal Register.

http://www.fluoridealert.org/pesticides/Sulfentrazone.FR.Mar10.1997.htm


-- Chronic dietary (all populations) NOAEL= 14.0 mg/kg/day. 2-Generation Reproduction in Rats. LOAEL = 33/44 mg/kg/day in males and females, respectively, based on: (1) Decreased maternal body weight and/or body weight gain during gestation in both P and F1 generations, (2) reduced premating body weight gains in the second generation (F1 adults), (3) increased duration of gestation in both F1 and F2 dams, (4) reduced prenatal viability (fetal and litter), (5) reduced litter size, (6) increased number of stillborn pups, (7) reduced pup and litter postnatal survival, and (8) decreased pup body weights throughout gestation. In males, effects included decreased fertility in F1 generation and/or atrophy of the germinal epithelium of the testes, oligospermia and intratubular degeneration of the seminal product in the epididymis.
Ref: Federal Register. August 1, 2001. Sulfentrazone; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Sulfentrazone.FR.Aug1.2001.htm

-- Reproduction and fertility effects (rat) Nonguideline - [870.3800] Parental/Systemic NOAEL = 20 mg/kg/day LOAEL = 51 mg/kg/ day (F1 females) based on decrease in pre-mating body weight gain (10%) Offspring and Reproductive NOAEL = 16 mg/kg/ day LOAEL = 40 mg/kg/ day based on reduced gestation day 20 fetal weights; decreased postnatal day 0, 4 and 7 pup weights; decreased pup survival; delayed vaginal patency; reduced epididymal, prostate, and testicular weights. Additional information supports the conclusions reached in the 2- generation reproduction study in rats
-- 2-Generation reproduction and fertility effects (rats) - [870.3800] Parental/Systemic... Reproductive NOAEL = 14 mg/kg/ day for males and 16 mg/kg/day for females LOAEL = 33 mg/kg/ day for males and 40 mg/kg/day for females based on increased duration of gestation in females and degeneration and/ or atrophy of the germinal epithelium of the testes and oligospermia and intratubular degenerated seminal material in the epididymis of F1 males...
Ref: Federal Register: September 24, 2003. Sulfentrazone; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/sulfentrazone.fr.sept24.03.htm

Sulfluramid - Acaricide, Insecticide - CAS No. 4151-50-2

-- CHRONIC EFFECTS FROM OVEREXPOSURE: ... Sulfluramid was shown to be non-teratogenic in developmental toxicity studies with laboratory animals. Preliminary studies in dogs suggest that the ingestion of high doses for prolonged periods may arrest spermatogenesis.
Ref: FMC CORPORATION. MATERIAL SAFETY DATA SHEET FIRSTLINE™ GT plus TERMITE BAIT STATION.

http://www.fluoridealert.org/pesticides/Sulfluramid.MSDS.Firstline.htm


-- According to an EPA assessment, if a child ingested the bait, he or she could suffer irreversible reproductive damage, and boys could be rendered infertile.
Ref: August 22, 2001 Press Release. Office of the New York State Attorney General Eliot Spitzer. LARGEST PESTICIDE PENALTY IN STATE HISTORY SECURED S.C. Johnson Fined for Illegally Distributing Unsafe Roach Baits.
http://www.fluoridealert.org/pesticides/Sulfluramid.Largest.Fine.01.htm

--Study: 90-day dogs. NOEL 35 ppm (0.825 mg/kg). LEL 100 ppm (2.5 mg/kg). LEL based on: 1 epididymal & testicular lesions affecting seminiferous tubules in testes.
-- Study: 1-week dermal. NOEL 100 mg/kg/day. LEL 300 mg/kg/day. 1 testicular & epididymal atrophy, aspermia (epididymides), seminal vesicle distension.
Ref: August 10, 1994. US EPA memorandum, "Sulfluramid - Amount of A.I. in Raid Max Roach Bait." To Mike Mendelsohn, PM Team Reviewer, Registration Division (7505C). From Linda L. Talor, Ph.D., Toxicology Branch II, Health Effects Division (7509C) and Marcia van Gemert, Ph.D., Chief, Toxicology Branch II/HED (7509C). Action Requested: Please define what constitutes human exposure to an amount of Sulfluramid via this product that may produce serious personal injury or illness to a 25 lb. child. (Copy of this memorandum was
requested and received by Ellen Connett in October 2002 from Michael H. Surgan, Ph.D., Chief Scientist, Environmental Protection Bureau, State of New York, Office of Attorney General Eliot Spitzer to Ellen Connett..)

tau-Fluvalinate - Acaricide, Insecticide - CAS No. 102851-06-9

-- 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.
-- A 2-generation reproduction toxicity study in rats with tau fluvalinate showed parental and developmental effects in the mid and high dose group. 2 of 4 males of the F1-generation from the median dose group failing to mate had strophic seminiferous tubles in both testes and spermatozoa were partly absent from the epididymides. Litter and mean pup weights of the F2 generation of the median dose group were lower between days 8 and 21. Incidence of fur loss and scabbing was a marginally increased among adults. F1 and F2 pups of the highest groups had tremors, mainly around lactation day 14, indicating toxic effects of tau fluvalinate excreted in rat milk.
As toenails of all animals were clipped prior to treatment and later at weekly intervals a final NOEL can not be derived. No adverse substance related effects were observed at 0.5 mg/kg bw/day.
Ref:
Revised Summary Report. EMEA/MRL/021-REV1/95. Committee for Veterinary Medicinal Products. The European Agency for the Evaluation of Medicinal Products.
http://www.fluorideaction.org/pesticides/tau.fluvalinate.1995.review.pdf

Tembotrione - Herbicide - CAS No. 335104-84-2

• Certain changes in multiple organs seen in the subchronic, chronic, dermal, and reproduction studies (e.g., microscopic changes in the thyroid gland, adrenal gland, and pancreas; increased number of corpora lutea in the ovary, and delayed preputial separation) may be due to various mechanisms including possible liver-pituitary-thyroid homeostatic disruption or inhibition of steroid synthesis (Page 6)... When additional appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed, tembotrione may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption (page 29).
In the 2-generation reproduction study in rats, offspring effects. Treatment-related decreases (p≤0.05) in pup body weights were observed: in the F1 pups at 200 and 1500 ppm beginning on PND 7 and continuing throughout the reminder of the post-natal period; and in the F2 pups at 200 ppm beginning on PND 21 and at 1500 ppm beginning on PND 14. Body-weight gains in these groups were dose-dependently decreased. Compared to controls, the time until preputial separation was dose-dependently delayed in all treated groups in the F1 and F2 offspring. This effect was considered treatment related. Also, the time to vaginal opening was longer in the 1500 ppm F1 offspring (page 68).
In the 2-generation reproduction study in rats, offspring effects. The LOAEL for offspring toxicity is 20 ppm (equivalent to 1.4/1.6 mg/kg/day in males/females) based on effects on the eyes, including corneal opacity, acute inflammation, and neovascularization; increased incidences of minimal extramedullary hematopoeisis in the spleen, delayed preputial separation, and decreased absolute brain weight. The NOAEL was not observed (page 68).
In a carcinogenicity study with mice (MRID 46695706), AE 0172747 (95% w/w a.i.; Batch No. PFI 0195) was administered in the diet to C57BL/6 J@ Ico mice (50/sex/dose) at doses of 0, 30, 300, 1000, or 3000 ppm (equivalent to 0/0, 4/5, 43/54, 146/179, and 440/552 mg/kg/day in males/females) for up to 78 weeks. Additionally, 10 mice/sex/dose were treatedsimilarly for up to 52 weeks. At 1000 ppm and above at 18 months, the incidences of the following lesions were increased in males:
(i) minimal to marked epithelial hyperplasia (multifocal/diffuse) in the gallbladder;
(ii) minimal to marked focal tubular degeneration (bilateral) in the testes; and
(iii) minimal to slight interstitial cell hyperplasia (focal/multifocal) in testes. Increased incidences of dilatation of uterine horns were noted grossly at ≥1000 ppm.
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.
In the 2-generation reproduction study in rats, offspring effects. Treatment-related decreases (p≤0.05) in pup body weights were observed: in the F1 pups at 200 and 1500 ppm beginning on PND 7 and continuing throughout the reminder of the post-natal period; and in the F2 pups at 200 ppm beginning on PND 21 and at 1500 ppm beginning on PND 14. Body-weight gains in these groups were dose-dependently decreased. Compared to controls, the time until preputial separation was dose-dependently delayed in all treated groups in the F1 and F2 offspring. This effect was considered treatment related. Also, the time to vaginal opening was longer in the 1500 ppm F1 offspring (page 68).
In the 2-generation reproduction study in rats, offspring effects. The LOAEL for offspring toxicity is 20 ppm (equivalent to 1.4/1.6 mg/kg/day in males/females) based on effects on the eyes, including corneal opacity, acute inflammation, and neovascularization; increased incidences of minimal extramedullary hematopoeisis in the spleen, delayed preputial separation, and decreased absolute brain weight. The NOAEL was not observed (page 68).
In a carcinogenicity study with mice (MRID 46695706), AE 0172747 (95% w/w a.i.; Batch No. PFI 0195) was administered in the diet to C57BL/6 J@ Ico mice (50/sex/dose) at doses of 0, 30, 300, 1000, or 3000 ppm (equivalent to 0/0, 4/5, 43/54, 146/179, and 440/552 mg/kg/day in males/females) for up to 78 weeks. Additionally, 10 mice/sex/dose were treatedsimilarly for up to 52 weeks. At 1000 ppm and above at 18 months, the incidences of the following lesions were increased in males:
(i) minimal to marked epithelial hyperplasia (multifocal/diffuse) in the gallbladder;
(ii) minimal to marked focal tubular degeneration (bilateral) in the testes; and
(iii) minimal to slight interstitial cell hyperplasia (focal/multifocal) in testes. Increased incidences of dilatation of uterine horns were noted grossly at ≥1000 ppm.
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.

Tetraconazole - Fungicide - CAS No. 112281-77-3

-- A chronic feeding/carcinogenicity study was conducted with tetraconazole in Crl:CD-l (ICR)BR mice at dietary levels of 10, 90, 800, and 1,250 ppm for 80 weeks. Treatment-related non-neoplastic changes were also seen at 1,250 ppm in the lungs, kidneys, testes, epididymides, ovaries and bone, particularly the cranium; a compression of the brain was noted in a number of mice reflecting the extent of cranial bone changes and an increased thymic involution was seen in male mice that died on test. The 1,250 ppm dietary level for tetraconazole, because of the substantial bwt gain changes and increased mortality (more in males), appeared to be above the maximum tolerated dose (MTD). At 800 ppm, there were increases in non neoplastic changes in lungs, kidneys, testes, epididymides, ovaries and bone. In addition, there was substantial reduction in weight gain as compared with zero-dose control animals, but the mortality rate was unaffected. Eight hundred ppm appeared to be a reasonable estimate of the MTD for mouse.
-- At 90 ppm, non-neoplastic changes were detected in bone and the
epididymides in addition to liver changes. No treatment-related findings were seen in mice treated at 10 ppm (approximately 1.5 mg/kg/ day), and this dose level was defined as the NOAEL.
Ref: Federal Register: October 14, 1999. Notice of Filing Pesticide Petitions to Establish a Tolerance for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023, and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm

-- Reproductive toxicity study-- Rats. In the 2-generation reproductive toxicity study in rats, the maternal (systemic) NOAEL was 0.7 mg/kg/day, based on dystocia, delayed vaginal opening, and increased liver weight at the LOAEL of 5.9 mg/kg/day. The developmental (pup) NOAEL was 0.7 mg/kg/day, based on increased time to observation of balanopreputial skin fold [foreskin] and liver weight at the LOAEL of 5.9 mg/ kg/day. At the high dose of 35.5 mg/kg/day, there was a decrease in the mean number of live pups per litter on lactation days 0 and 4 (precull) in the presence of significant maternal toxicity.
- Balanopreputial skin fold- see: http://www.cirp.org/library/history/hodges1/
Ref: Federal Register: December 6, 1999. Tetraconazole; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Dec.1999.htm

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

-- groups of 16 male and 16 female rats were exposed at concentrations of 9, 1000, 10,000, or 50,000 ppm 6 h/d for 20 d of a 28-d period (Riley et al. 1979). No treatment-related effects were observed with regard to body weight, clinical signs, hematology, blood chemistry, urine composition, or ophthalmoscopy. Changes in liver, kidney, and gonad weights of male rats in the group exposed to 50,000 ppm were noted with a significant increase in liver weight in the 10,000-ppm group also. In the absence of pathological changes in these organs, Riley et al. (1979) considered these changes physiological adaptations to treatment.
-- 3.4 Developmental and Reproductive Toxicity (pages 134 - 136)
-- In a 28-d study conducted by Riley et al. (1979), 16 male rats were exposed to HFC-134a at 0, 1,000, 10,000, or 50,000 ppm 6 h/d, 5 d/wk. Rats exposed at 50,000 ppm exhibited decreased testicular weights. However, in a 13-wk study, no effects on testicular weight were evident (see Section 3.7) (Hext 1989; Collins et al. 1995). In the chronic study (see Section 3.7) (Collins et al. 1995), Leydig (interstitial) cell hyperplasia and benign Leydig cell tumors were reported following exposure at 50,000 ppm for 104 wk; no such effects were reported following exposure for 104 wk at 10,000 ppm. However, it should be noted that these findings are not relevant for humans because the rat is prone to developing these types of tumors spontaneously.
--
3.7 Subchronic and Chronic Toxicity and Carcinogenicity (pages 138 - 139)
-- groups of 85 male and 85 female rats were exposed to concentrations at 0, 2,500, 10,000, or 50,000 ppm for 6 h/d, 5 d/wk for 104 wk (Collins et al. 1995). Exposure conditions and analytical measurements were identical to procedures followed in the 13 week study. Ten animals from each group were sacrificed at 52 wk. At 52 and 104 wk there were no effects on clinical condition, food consumption, growth, survival, hematology, clinical chemistry, or urinary parameters. Absolute liver weights of females were increased in the groups exposed at 2,500 and 50,000 ppm but not in the group exposed at 10,000 ppm. Males in groups that received 10,000 or 50,000 ppm for 104 wk had an increased incidence of enlarges testes (not statistically significant), and males in the group that received 50,000 ppm for 104 wk had a statistically significant increase in incidence of Leydig cell hyperplasia (40 vs. 27 in the concurrent control group) and Leydig cell adenomas (23 vs. 9 in the concurrent control group). There was no evidence of progression to malignancy. As discussed earlier, these tumors are not relevant to humans.
-- Although there was an increased incidence of testicular Leydig cell adenomas in male rats administered 50,000 ppm for 104 wk (Collins et al. 1995), these tumors do not progress to malignancy (Boorman et al. 1990) and have little significance in humans (Cook et al. 1999)...
-- Boorman GA, Eustis SL, Elwell MR. 1990. Pathology of the Fischer Rat: Reference and Atlas. New York Academic Press, Inc.
-- Riley RA, Bennett IP, Chart IS, Gore CW, Robinson M, Weight TM. 1979. Arcton-134a: Subacute toxicity to the rat by inhalation. ICI Report No. CTL/P/463. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, UK.
-- Collins MA, Rusch GM, Sato F, Hext PM, Millischer RJ. 1995. 1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo. Fundam Appl Toxicol 25:271-280.
-- Cook JC, Klinefelter GR, Hardisty JF, Sharpe RM, Foster PMD. 1999. Rodent Leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms, and relevance to humans. Crit Rev Toxicol 29:169-261.
-- Hext PM. 1989. 90-day inhalation toxicity study in the rat. ICI Report No. CTL/P/2466. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. (Cited in NRC 1996).
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels. Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. National Academy Press, Washington DC. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X . Online at:
http://books.nap.edu/books/030908511X/html/index.html

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

Group C -- Possible Human Carcinogen. Testicular interstitial cell adenomas; CD-1 rat (M).
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

-- 90-Day oral toxicity in nonrodents. NOAEL = 3.9/3.7 (m/f) mg/kg/day LOAEL = 146.9/159.9 (m/f) mg/kg/day based on decreased mean body weight and body weight gain, decreased hematocrit, hemoglobin, RBC`s, SGOT, SGPT, ALP, absolute and relative liver and testes weight; microscopic abnormalities of the liver and testes.
-- Chronic toxicity rodents NOAEL = 2.44 mg/kg/day LOAEL = 30.6 mg/kg/day based on decreased body weight and body weight gain, alteration in hematology (mainly males) and increased incidences of interstitial cell hyperplasia in testes.
-- Carcinogenicity rats NOAEL = 2.44 mg/kg/day LOAEL = 30.6 mg/kg/day based on decreased body weight and body weight gain, alteration in hematology (mainly males) and increased incidences of interstitial cell hyperplasia in the testes. (Possible) evidence of carcinogenicity
-- Special studies: In vivo and in vitro mechanic studies. The purpose of these studies was to investigate the mechanism of Leydig cell tumor induction in the testes of male rats. A dose-dependent decrease in aromatase enzyme activity was seen in vitro, but was inconclusive in vivo.
Ref: Federal Register: June 12, 2002 (Volume 67, Number 113). Triflusulfuron Methyl; Pesticide Tolerance. Final Rule.

http://www.fluorideaction.org/pesticides/triflusulfuron.m.fr.june.02.htm

-- Groups of 62 rats/sex were fed diets containing 0, 10, 100, 750 or 1500 ppm DPX-66037- 24 (95.6% purity) (equal to 0.406, 4.06, 30.6 or 64.5 mg/kg bw/d for males and 0.546, 5.47, 41.5 and 87.7 mg/kg bw/d for females) for 22 months. The NOEL for this study was 100 ppm (4.06 mg/kg bw/d). At 750 ppm, body weights and body-weight gains were lower than controls in both sexes and males had lower erythrocyte counts than controls at most time points and an increased incidence of Leydig cell hyperplasia compared to controls. The incidence of myelin/axonal degeneration of the sciatic nerve was increased compared to controls in the 1500-ppm group of females (25/48 versus [vs] 42/49). Triflusulfuron-methyl was oncogenic in male rats under the conditions of this study, with an increased incidence of Leydig cell adenomas in the 750- and 1500-ppm groups compared to controls.
-- Possible mechanisms of Leydig cell tumour development induced by triflusulfuron-methyl were studied. Ten Crl:CD ® BR male rats/group were treated by gavage for 15 days with 0, 1000, 1500 or 2000 mg/kg bw DPX-66037-24 (95.6% purity) in corn oil. An additional group of 10 control rats were pair-fed to the 2000 mg/kg bw group. Satellite groups of 10 rats treated with 0 or 2000 mg/kg bw DPX-66037 were given human chorionic gonadotropin (hCG) one hour before sacrifice. All treated groups had lower body weights and food consumption than controls. Absolute and relative weights of the prostate, seminal vesicles and coagulating glands were lower than controls. Serum estradiol was statistically significantly lower than controls. There were slight, but not statistically significant, increases in luteinizing hormone (LH), follicule-stimulating hormone (FSH) and prolactin in the treated groups compared to controls. In the rats treated with hCG, the 2000 mg/kg bw/d group had increased testosterone and lower estradiol than the controls.
-- Isolated Leydig cells from 11-week old male rats were exposed to 0, 0.1, 0.5, 1.0, 10, 100 or 1000 FM DPX-66037-24 for two hours. Three cultures from each dose were then exposed to two international units of hCG. No effect on hormone levels was observed in the hCG-treated cultures. In the triflusulfuron-methyl-only cultures, testosterone was significantly increased (198%) compared to controls, and estradiol was decreased. Triflusulfuron-methyl appears to inhibit the conversion of testosterone to estradiol by aromatase in vitro; the in vivo results are inconclusive.
-- In long-term rodent dietary studies, the NOEL for chronic (18-mo) systemic toxicity in mice was 20.9 mg/kg bw/d, based on increased absolute and relative liver weights along with histopathological changes in the liver at the LOEL of 349 mg/kg bw/d. Triflusulfuron was not oncogenic in the mouse. The NOEL for chronic (2-yr) systemic toxicity and oncogenicity in rats was 4.06 mg/kg bw/d, based on lower body weight and erythrocyte counts, and an increased incidence of Leydig cell tumours (adenomas) in males at 30.6 mg/kg bw/d. A study was performed that attempted to determine the mechanism of tumour formation. The results indicated that triflusulfuron-methyl appears to inhibit the conversion of testosterone to estradiol by aromatase in vitro, the in vivo results are inconclusive. Disruption of the hypothalmic-pituitary- testicular (HPT) axis is a well-recognized mechanism of Leydig cell adenoma formation in the rat by non-genotoxic compounds. Aromatase inhibition is one of the established mechanisms of disruption. A threshold for this effect exists; doses that do not disrupt the HPT axis should not cause tumours. The relevance of these tumours to humans is questionable, as they are extremely rare in humans.

Ref: Dec 3, 1999 - Report on Triflusulfuron methyl. Regulatory Note REG99-03. Pest Management Regulatory Agency, Health Canada, Ottawa.

http://www.fluorideaction.org/pesticides/triflusulfuron.methy.canada.pdf

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

Long term toxicity and carcinogenicity (Annex IIA, point 5.5). Carcinogenicity. Evidence of carcinogenic potential in Fischer 344 rat, (tumour formation in various tissues, i.e. kidney, urinary bladder, thyroid, Leydig cell). The mechanism of tumour formation is not identified. R40. (page 46)
Ref: March 14, 2005. European Food Safety Authority: Conclusion regarding the peer review of the pesticide risk assessment of the active substance trifluralin. EFSA Scientific Report (2005) 28, 1-77.
http://www.fluoridealert.org/pesticides/trifluralin.eu.long.2005.pdf

Triflusulfuron-methyl - Herbicide - CAS No. 126535-15-7

In another 90-day subchronic study, dogs were fed dosages of 3.87, 146.1, or 267.6 mg/kg/day (males) or 3.72, 159.9, or 250.7 mg/kg/day (females). Triflusulfuron methyl was found to be hepatotoxic at 4,000 ppm (146.1 mg/kg/day males and 159.9 mg/kg/day females), and greater elevated hepatic enzyme levels and postmortem evidence, including elevation in liver weights and microscopic evidence of bile stasis. Other microscopic findings considered to be treatment related were testicular atrophy and decreased testicular weights and hypercellularity of the sternal and femoral bone marrow, with a corresponding increase in reticulocyte and leukocyte counts seen in the high-dose males and females. Based on the microscopic findings in the liver and testes of the 4,000 ppm and greater treated animals, the NOAEL was 3.87 mg/kg/day (males) and 3.72 mg/kg/day (females).
Ref: Federal Register: August 8, 2001 [Page 41593-41597]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/triflusulfuron.m.fr.aug8.01.htm

 
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