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. OÕByrne, 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 DogsÓ; (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 sexual
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., ÒFluazifop-butyl: 55 week oral toxicity study in beagle
dogs,Ó 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
-- Continue to more pesticides beginning with
the letters
•
H-Z
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