See some background information and definitions on liver
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.
Fipronil
- Acaricide, Insecticide, Wood Preservative - CAS No. 120068-37-3
•
Reproductive and developmental toxicity. In
a two-generation rat study, the NOEL for
parental (systemic) toxicity was 3 ppm (0.26 mg/kg/day for both
sexes combined), based on increased
weight of the thyroid glands and liver
in males and females, decreased weight
of the pituitary gland in females, and
an increased incidence of follicular epithelial hypertrophy in
females at 30 ppm.
• Subchronic
toxicity. The
NOAEL for systemic toxicity in
rat was 5 ppm (0.35 mg/kg/day for
both sexes combined), based on alterations
in serum protein values and increased weight of the liver
and thyroid at 30 ppm (1.93 and 2.28 mg/kg/day
for males and females, respectively).
•
Chronic toxicity.
The NOAEL for systemic toxicity in mice
was 0.5 ppm (0.06 mg/kg/day) based on decreased
body weight gain, decreased food conversion efficiency in males,
increased liver weights, and liver histopathology at 10 ppm (1.3
mg/kg/day).
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
Short-term toxicity.
-- 28 day dietary administration to rats.
Technical-grade fipronil (batch number IGB 464, purity, 93%) was
administered in the diet for four weeks to groups of five Cr1:CD
(SD) BR rats of each sex at concentrations of 25, 50, 100, 200,
or 400 ppm, equal to 3.4, 6.9, 13, 24, or 45 mg/kg bw per day
for males and 3.5, 6.7, 13, 25, or 55 mg/kg bw per day for females
... The target organs were the liver and
thyroid. Liver weights were significantly increased in females
at all doses and in males at 200 and 400 ppm. At necropsy,
liver enlargement was observed in one or both sexes starting at
50 ppm, and five males and three females at 400 pm had enlarged
livers. Generalised hepatocyte enlargement was observed microscopically
in one male at 100 ppm, with increasing incidence in animals of
each sex at 200 and 400 ppm. Thyroid follicular-cell hypertropy,
generally of minimal severity but of moderate severity in several
males at 200 and 400 ppm, was found in almost all treated animals
but not in the controls. (page 77)
-- 90-day dietary administration to rats. In a 13-week
study, rats (CD strain 10/sex/group) received dietary administration
of either 1, 5, 30 or 300 ppm fipronil (batch number PGS 963,
95.4% purity). This was equivalent to 0.07, 0.3, 2.1 or 22 mg/kg/d.
Doses were selected after a preliminary 14-d study showed deaths
(3/10 animals by 5 d) and muscular spasms at 30 mg/kg/d ...
In males, the absolute liver weight was significantly increased
at the top dose only (42%). In females liver weights were elevated
in all treatment groups (4.6-35%) at 1-300 ppm), achieving statistical
significance at ≥5 ppm. Absolute thyroid weights
were elevated (4.2-100% at 5-300 ppm) achieving statistical significance
at ≥30 ppm in females and at 300 ppm in males ... Histopathological
examination found treatment-related effects at the top dose in
the thyroids and livers of both sexes. Oil red O staining revealed
a high incidence of fat deposits in all liver samples, including
controls. A statistically significant
increase in panacinar hepatic fatty vacuolation (controls
0/10 and 7/10 at 300 ppm) was reported in males only. (page 78-79)
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety
Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
Flazasulfuron
- Herbicide - CAS No. 104040-78-0
• Short term toxicity Target / critical effect: Liver (centrolobulillar
hepatocyte hypertrophy). Lowest relevant oral NOAEL / NOEL:
2 mg/kg bw/day, 13-week dogs and 1-year dogs.
• Long term toxicity and carcinogenicity . Target / critical
effect: Liver (centrolobulillar hypertrophy)
in mice and kidney (chronic nephropathy) in rats. Lowest
relevant NOAEL: 1.3mg/kg bw/day: 2-years rats. No evidence for
carcinogenic potential.
Flocoumafen
- Rodenticide - CAS No. 90035-08-8
Sub-acute Toxicity.
... Male and female Fischer 344 rats received 0, 0.01, 0.05, 0.1
or 0.2 ppm flocoumafen (cis:trans ration - 55:44) in the diet
for 28 days. (3 ppm vitamin K3 was also incorporated into the
diet.) There were no deaths and no clinical signs of toxicity
were reported. small increases were observed in the prothrombin
and activated partial thromboplastin times in both sexes receiving
0.2 ppm and total protein was decreased in females receiving 0.1
and 0.2 ppm and in males receiving 0.2 ppm.
The majority of males receiving 0.2 ppm had treatment-related
histopathological changes in the liver (reduced periportal glycogenic
vacuolation and increased histiocytic foci). 0.05 ppm (equivalent
to 0.0025 mg/kg bw per day) was the no-effect level.
Ref:
Evaluation
on Flocoumafen. April 1987. UK Department
for Environment, Food and Rural Affairs, Pesticides Safety Directorate,
Mallard House, Kings Pool 3 Peasholme Green, York YO1 7PX. Also
available at
http://www.pesticides.gov.uk/citizen/evaluations/evallist.htm
Flonicamid
- Insecticide - CAS No. 158062-67-0
-- Reproductive and
developmental toxicity. A developmental toxicity study in rats
resulted in the maternal and developmental no observed adverse
effect levels (NOAELs) of 100 mg/kg/day. The maternal lowest observed
adverse effect level (LOAEL) was 500 mg/kg/day based on the treatment-related
effects observed on the liver and
kidney of the dams in the
highest dose group. The developmental LOAEL was 500 mg/kg/ day
based on the increases in placental weights and incidences of
fetal skeletal variations seen only at maternally toxic doses
of 500 mg/kg/ day.
-- In the multi-generation rat reproduction study, the
NOAEL was 300 ppm for both parental animals (13.5-32.8 and 16.3-67.0
mg/kg/day, respectively, for males and females) and their offspring.
The effects at the highest dose of 1,800 ppm included the following:
increased kidney weights
and gross and histopathological alterations in the kidney.
Findings noted in the top dose females included
delayed vaginal opening and increased liver,
kidney and spleen weights
in the F1 generation...
-- In a 90-day rat feeding study the NOAEL was established
at 200 ppm (12.11 mg/kg/day) for males and 1,000 ppm (72.3 mg/kg/day)
for females. The NOAELs were based on effects on hematology,
triglycerides, and pathology in the
liver and kidney.
-- In a 13-week mouse study, the NOAEL was 100 ppm (15.25 mg/kg/day
in males and 20.1 mg/kg/day in females). The LOAEL is 1,000 ppm
(153.9 mg/kg/day in males and 191.5 mg/kg/day in females) based
on hematology effects and changes
in glucose, creatinine, bilirubin, sodium, chloride and potassium
levels, increased liver and
spleen weights and histopathology
findings in the bone marrow, spleen and kidney.
-- In a rat 24-month combined chronic and oncogenicity
study, flonicamid technical was not carcinogenic in rats. The
NOAEL was 200 ppm (7.32 mg/kg/day) for males and 1,000 ppm (44.1
mg/kg/day) for females. The LOAEL was 1,000 ppm for males and
5,000 ppm for females based on histopathology in the kidney,
hematology effects, hepatic effects
including changes in biochemical parameters, increased organ weights,
and histopathological changes. Atrophy of
striated muscle fibers, cataract and retinal atrophy observed
in the high dose females were considered to be due to acceleration
of spontaneous age-related lesions.
-- In the 18-month mouse study, effects were observed in
the lung, liver,
spleen and bone marrow at
250 ppm or higher. Findings included, centrilobular
hepatocellular hypertrophy...
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
-- 90-Day
oral toxicity rodents (rats). 28-day range-finding. NOAEL
is 100 ppm (7.47 mg/kg/day) for males and 1,000 ppm (81.9 mg/kg/day)
for females.
LOAELs were 500 ppm (36.45 mg/kg/day) for males based on changes
in the kidney (hyaline deposition) and 5,000
ppm for females (372.6mg/kg/day) based on kidney (hyaline deposition),
liver changes (centrilobularhypertrophy),
hematological effects (anemia) and clinical chemistry (increased
cholesterol)
--
Prenatal
developmental toxicity (rats).
Maternal.
NOAEL is 100 mg/kg bw/day. LOAEL is 500 mg/kg bw/day, based on
increased liver weight,
and liver
and kidney pathological
changes (hypertrophy of centrilobular hepatocytes in liver
and vacuolation of proximal tubular cell in kidneys).
--
Carcinogenicity
(mice). NOAEL
was not established. LOAEL is 250 ppm (equivalent to 29/38mg/kg/
day [M/F]), based on minimal to moderate
centrilobular hepatocellular hypertrophy,
minimal to severe extramedullary hematopoiesis,
minimal to moderate pigment
deposition in the sternal bone marrow, and
increased incidence of tissue masses/nodules in the lungs in the
males, and minimal to moderate decreased
cellularity in the femoral bone marrow and hyperplasia/hypertrophy
of the epithelial cells of the terminal bronchioles of the females.
At the doses tested, the carcinogenic potential of IKI-220 (flonicamid)
is positive at 250 ppm in males and females based on the increased
incidence of alveolar/bronchiolar adenomas, carcinomas, and combined
adenomas/carcinomas. Dosing was considered adequate based on increased
incidence of tissue masses/nodules in the lungs and microscopic
findings in the liver, spleen, bone
marrow, and lungs. However, data were provided suggesting this
effect is specific to sensitive strains of mice. Carcinogenic
in mice.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Floransulam
- Herbicide - CAS No. 145701-23-1
Short
term toxicity. Target / critical effect:
Anemia, hepatotoxicity , renal hypertrophy
epithelial cells, collecting ducts, adrenal
vacuolation(dog ) Lowest relevant oral NOAEL / NOEL: 1
y & 90 d dog (oral feed) ; 5 mg/kg bw/d;...
Ref: September 18, 2002 - Review report
for the active substance florasulam. European Commission Health
& Consumer Protection Directorate-General.
http://www.fluoridealert.org/pesticides/Florasulam.EU.Sept.2002.pdf
-- The subchronic and
chronic toxicity of florasulam was investigated in the mouse,
rat and dog. A 28-d repeat dose dermal toxicity study was also
carried out in rats. In the subchronic and chronic studies, treatment-related
findings were observed in the kidney in
all species and in the liver and
adrenal glands in dogs.
In the kidney, hypertrophy of the epithelial cells of the collecting
ducts occurred in all species tested.
-- In subchronic and chronic dietary studies, treatment-related
findings were observed in the kidneys in mice, rats and dogs and
in the liver and adrenal glands in the dog. In the kidney, hypertrophy
of the epithelial cells of the collecting duct was observed in
all species tested. In rats, hypertrophy of the epithelial cells
correlated with elevated serum bicarbonate levels, urinary acidification,
decreased urinary specific gravity and increased kidney weights.
In dogs, treatment-related
findings associated with the liver
included increased ALP activity, decreased
serum albumin and protein levels, increased liver weights and
increased incidence or severity of hepatic vacuolation. Dogs also
exhibited slight vacuolization of the zona reticularis and zona
fasciculata in the adrenal glands; however, in the absence of
any associated inflammation, necrosis or other changes,
the toxicological significance was uncertain. The most appropriate
NOAEL for subchronic and chronic toxicity end points is 5.0 mg/kg
bw/d in the 90-d and 1-year dietary studies in dogs. At the LOAEL,
50 mg/kg bw/d, treatment-related findings were observed in the
kidneys and
liver in the
90-d and 1-year dietary studies and in the
adrenal glands in the 1-year dietary study.
-- In the dog, an increased incidence and severity of
hypertrophy of the epithelial cells was observed in both sexes
at 50 mg/kg bw/d and above in both the 90-d and 1-year dietary
study. There were no treatment-related urinalysis findings
in either the 90-d or 1-year dietary study. The severity (slight)
of the hypertrophy did not appear to increase with prolonged exposure.
In the 90-d dietary study treatment-related findings associated
with the liver included
increased alkaline phosphatase (ALP) activity
in both sexes at 50 and 100 mg/kg bw/d, increased
liver weights in both sexes at 100
mg/kg bw/d and a slight increased
incidence or severity of hepatic vacuolation in
both sexes at 50 and 100 mg/kg bw/d.
Increased liver weights and hepatic vacuolation were not observed
in the 1-year dietary study. In the 1-year dietary study, treatment-related
findings associated with the liver,
included increased alanine aminotransferase
(ALAT) and ALP activity and decreased serum albumin and
protein levels in both sexes at 100 mg/kg bw/d. After the high
dose was reduced to 50 mg/kg bw/d (week 15), ALP activity remained
elevated and serum albumin and protein levels remained lower in
both sexes. In the 1-year dietary study, no histopathological
findings were evident in the liver. In the 1-year dietary study,
slight vacuolization of the zona reticularis
and zona fasciculata in the adrenal glands was observed in the
high-dose males and females; however, in the absence of any associated
inflamation, necrosis or other changes, the toxicological significance
of this finding was uncertain. The vacuolization was consistent
with fatty changes. Body weight, body-weight gain and food consumption
were significantly lower in both sexes at 100 mg/kg bw/d
and remained lower in the high-dose females after the high dose
was reduced in the 1-year dietary study. Body weight, body-weight
gain and food consumption were unaffected by treatment in the
90-d dietary study.
-- Ref: Florasulam EF-1343 Suspension Concentrate
Herbicide. REF2001-12. September 21, 2001. Canadian Pest Management
Regulatory Agency. Health Canada.
http://www.hc-sc.gc.ca/pmra-arla/english/pdf/reg/reg2001-12-e.pdf
Fluazifop-butyl
- Herbicide - CAS No. 69806-50-4
A 3-month rat feeding
study demonstrated hepatocyte hypertrophy in males (the LOEL was
5 mg/kg/day; the NOEL was 0.5 mg/kg/ day). In a 1-year feeding
study, dogs had changes in serum alkaline phosphatase and alanine
aminotransferase and/or alanine sulfatransferase (the LOEL was
25 mg/kg/day; the NOEL was 5 mg/kg/day). Similar changes were
also reported in dogs following 3 months exposure in their diet
(the LOEL was 125 mg/kg/day). In a carcinogenicity study, male
mice fed 20 ppm (2.6 mg/kg/day, the LOEL) had an increased incidence
of hepatocyte hypertrophy. The NOEL
was 5 ppm or 0.65 mg/kg/ day. Male and female mice exposed to
a higher dose of 80 ppm (10.4 mg/ kg/day) had increased
liver weight (relative and absolute) and hypertrophy of
periacinal hepatocytes. Males in this dose group also had increased
pigmentation in hepatocytes and Kupffer cells. In a teratogenicity
study in Sprague-Dawley rats exposed via oral gavage, delayed
ossification and an increased incidence of hydroureter were observed
in fetuses (the fetotoxic LOEL was 5 mg/kg/day; the NOEL 1 mg/kg/day)
and a teratogenic LOEL of 200 mg/kg/day (the NOEL was 10 mg/kg/day)
was determined based on the incidence of diaphragmatic hernia.
Maternal toxicity was observed in this study at doses higher than
those causing fetotoxicity and included reduced body weight gain
and decreased gravid uterus (the maternal LOEL was 200 mg/kg/day;
the NOEL was 10 mg/kg/day). In a 2-generation reproductive toxicity
dietary study in Wistar rats, the reproductive LOEL of 250 ppm
(12.5 mg/kg/day; the NOEL was 80 ppm or 4 mg/kg/day) was based
on reduced litter sizes, reduced viability, reduced testis and
epididymis weights and tubular atrophy in offspring. Fetotoxicity
(delayed ossification and eye opacities) was also demonstrated
in New Zealand White rabbits (the LOEL was 30 mg/kg/day; the NOEL
was 10 mg/kg/day). EPA believes that there
is sufficient evidence for listing fluazifop butyl on EPCRA section
313 pursuant to EPCRA section 313(d)(2)(B) based on the available
hepatic and developmental 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.
http://www.epa.gov/tri/frnotices/59fr1788.htm
-- 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... Distended gall bladders, large
friable livers and congested caecum and colon from engorgement
of the blood vessels were noted upon necropsy. Histopathological
evaluation confirmed treatment-related lesions of the eyes, liver,
testes and gastrointestinal tract. [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 (CAS # 69806-50-4) was evaluated for subchronic
dietary toxicity in Wistar rats (20/sex/group) receiving 0, 10,
100 and 2000 ppm by dietary inclusion for 13 weeks. Mean achieved
dosages during 13-week treatment were 0, 0.7, 7.1 and 144.5 mg/kg/day
in males of the respective treatment groups and 0, 0.8, 8.0 and
161.9 mg/kg/day in females... Upon terminal necropsy, only high-dose
males had evidence of hepatic enlargement or swelling (7/20),
although higher absolute and relative liver weights were significant
(p < 0.01, Student's t-test) in both males and females of the
2000 ppm group... Histopathology confirmed a specific liver
toxicity in male rats, marked by significant dose-related hepatocytic
hypertrophy with isolated instances of vesicular nuclei and or
periacinal hepatocytic necrosis... [ICI AMERICAS INC; 13 Week
Dietary Toxicity Study with PP009 in Rats (Final Report); 05/29/80;
EPA Doc No. 88-920006943; Fiche No. OTS0545346]
-- -- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subacute
oral toxicity in Wistar albino rats (10/sex/group) administered
10 ml/kg doses in corn oil of 0, 4, 20, 100 and 500 mg/kg/day
by oral gavage, 5 days/week for 2 weeks. Five-day weekly treatment
periods were each followed by 2-day recovery... Male rats of 100
and 500 mg/kg/day dosages had higher absolute and relative liver
weights that was not seen in their female counterparts. Microscopic
examination confirmed a particular liver
pathology of treated males, characterized by dosage-related hepatocytic
hypertrophy and necrosis (study lethalities), and dosage-related
slight to moderate periacinal hepatocytic hypertrophy... [ICI
AMERS INC; 14 Day Subacute Oral Toxicity Study with PP009 in Rats;
07/11/80; EPA Doc No. 88-920007017; Fiche No. OTS0545392]
-- Fluazifop butyl (CAS # 69806-50-4) was evaluated for developmental
toxicity in the progeny of Sprague-Dawley CD rats administered
oral doses of 0 (corn oil vehicle control), 10, 50 and 200 mg/kg/day
by gavage on gestation days 6-20... Relative
liver weights were also significantly (p < 0.05) greater
in high-dose dams... [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy)
propionate butyl: Effects of Oral Administration Upon Pregnancy
in Rats; 05/23/80; EPA Doc No. 88-920006839; Fiche No. OTS0543844]
-- 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...
Liver and kidney weights were
significantly high (250 ppm) relative to controls, while spleen
weights were low in both sexes (80, 250 ppm)... [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]
-- 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. Prior to sacrifice... Histopathological
evaluation confirmed treatment-related lesions of the
eyes, liver,
testes and gastrointestinal tract. [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]
Ref: Fluazifop-butyl. TOXNET profile from
Hazardous Substances Data Bank.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm
**411-083 069476 Virgo,
D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle
dogs," Life Science Research, Stock, Essex, England, 10/15/82.
LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for
55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules
at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study.
Test article within capsules was dissolved in 0.4 ml/kg corn oil
vehicle. NOEL = 5 mg/kg/day... All
other noteworthy findings were limited to the high dose group,
as follows. Seven 125 mg/kg/day dogs (5 M, 2 F) were killed in
extremis prior to term, generally after at least 29 weeks on study...
Liver dysfunction was indicated by periacinar hepatocytic degeneration
and thinning of hepatic cords in some dogs, other hepatocytic
changes such as vacuolation and/or granular cytoplasm, and occasional
bile plugs in the canaliculi •.
Most clinical chemistry changes were plausibly related to liver
toxicity, including elevated alkaline phosphatase, ALT, and occasionally
AST. Substantially increased BSP retention was consistent
with biliary disturbance. Urine was typically bright yellow or
orange due to high bile pigment concentrations. Cholesterol
was consistently reduced. 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
• Canaliculi
- In liver, small channels between hepatocytes
through which bile flows to the bile duct and thence to the intestinal
lumen.
Abstract:
The
aim of this study was to determine the effect of herbicide fluazifop,
on the early occurring changes in rat liver regarded as hepatic
markers of peroxisome proliferators (PPs). Fluazifop was administered
orally to male Wistar rats at increasing doses from 5.6 to 891
mg/kg body weight per day for 1, 2, 4, 7 and 14 consecutive days
and peroxisome proliferation, induction of some peroxisome-associated
enzymes and mitogenesis (S-phase, M-phase and percentage of binucleated
hepatocytes) were studied. Short-term treatment
of rats with fluazifop resulted in hepatomegaly due to time dependent
proliferation of smooth endoplasmic reticulum (SER) and peroxisomes.
The increase in the number of peroxisomes in the hepatocytes
was supported by an increase in peroxisomal palmitoyl-CoA oxidation
and catalase activity. In contrast to other PPs fluazifop induced
low rate of rcplicative DNA synthesis and did not affect mitoses
(M-phase). DNA synthesis was accompanied by the appearance of
binucleated hepatocytes. Thus, we can conclude
that fluazifop produces in male Wistar rats hepatomegaly due to
cellular hypertrophy. The threshold dose for palmitoyl-CoA
oxidation and DNA synthesis was 112 and 223 mg/kg body weight
per day, respectively. The value for hepatomegaly and catalase
activity was 56 mg/kg body weight per day. The
results presented in this paper demonstrated that fluazifop can
be classified as a weak rodent PPs.
Ref:
Hepatocellular peroxisome proliferation and DNA synthesis in Wistar
rats treated with herbicide fluazifop; by Kostka G, Palut D, Ludwicki
JK, Kopec-Szlezak J, Wiadrowska B, Lembowicz K. Toxicology. 2002
Sep 16;178(3):221-8.
Fluazifop-P-butyl
- Herbicide - CAS No. 79241-46-6
Chronic/Subcrhonic
Toxicity Studies: Chronic toxicity studies in rodents have shown
liver changes (cellular hypertrophy). The No Effect Level
(LEL) in rats is 10 ppm (0.5 mg/kg/day). Long term feeding studies
in dogs produced a range of potentially serious effects at high
dose rates (red cell, bone marrow and lymphadenopathy changes
and liver and spleen damage) with
a No Effect Level of 25 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
Fluazinam
-
Fungicide
- CAS
No. 79622-59-6
Suggestive
Evidence of Carcinogenicity to Humans.
An increase in thyroid gland follicular
cell tumors in male rats, and an increased incidence of hepatocellular
tumors observed in the male mice was treatment-related.
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
In subchronic and chronic
toxicity studies, fluazinam targeted the following organs:
liver, lung, uterus, testes, pancreas, thymus, thyroid,
stomach, eyes and brain... Liver toxicity
was evident in most studies including increased size and weight,
fatty changes, pallor, as well as hepatocyte hypertrophy, necrosis
and apoptosis...
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
-- Carcinogenicity
mice NOAEL = Males:1.1 mg/kg/day; Females: 1.2 mg/kg/day [[Page
46732]] LOAEL = Males: 10.7 mg/kg/day; Females: 11.7 mg/kg/day
based on increased incidences of brown macrophages in the liver
of both sexes, eosinophilic vacuolated hepatocytes in males, and
increased liver weight in females.
Clear evidence of carcinogenicity (hepatocellular tumors) in male
mice, but not in females.
-- 90-Day oral toxicity rats NOAEL: Males = 3.8 mg/kg/day; Females
= 4.3 mg/kg/day [[Page 46731]] LOAEL Males = 38 mg/kg/day; Females
= 44 mg/kg/day based on increased liver
weights and liver histopathology
in males, and increased lung and uterus weights in females.
-- 90-Day oral toxicity dogs NOAEL = 10 mg/kg/day LOAEL = 100
mg/kg/day based on retinal effects, increased relative liver
weight, liver histopathology and
possible increased serum alkaline phosphatase in females and possible
marginal vacuolation of the cerebral white matter (equivocal).
-- Prenatal developmental toxicity Maternal NOAEL = 4 mg/kg/day
rabbits LOAEL = 7 mg/kg/day based on decreased food consumption
and increased liver histopathology...
-- Reproduction and fertility effects Parental/Systemic NOAEL
= 1.9 mg/ rats kg/day LOAEL = 9.7 mg/kg/day based on liver
pathology in F1 males...
-- Combined chronictoxicity/ NOAEL = Males: 0.38 mg/kg/day; carcinogenicity
rats 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.
-- Carcinogenicity mice NOAEL = Males:<126 mg/kg/day, Females:
<162 mg/kg/day LOAEL = Males: 126 mg/kg/day; Females: 162 mg/kg/day
based on increased liver weights
and liver and brain histopathology
in both sexes Equivocal/some evidence of carcinogenicity (hepatocellular
tumors) in male mice, but not in females,
-- Special studies:
4-Week dietary (Range-finding) rats NOAEL = Males: 5.1 mg/kg/day;
Females: 5.3 mg/kg/day LOAEL = Males: 26.4 mg/kg/day; Females:
25.9 mg/kg/day based on decreased body weight gain and food consumption,
increased serum phospholipids, increased total cholesterol, increased
relative liver weights, and liver
histopathology.
-- 4-Week dietary (Range-finding) mice NOAEL = not identified
(Males; <555 mg/kg/day; Females: <658 mg/ kg/day) LOAEL = Males:
555 mg/kg/day; Females: 658 mg/kg/day based on vacuolation of
white matter in brain, increased liver
weights, histopathology in liver.
-- 90-Day dietary (Special liver
study) rats NOAEL = not determined (Males: <37.6 mg/kg/day, Females:
<44.7 mg/kg/day) LOAEL = Males: 37.6 mg/kg/day, Females: 44.7
mg/kg/day based on increased relative liver
weights and liver histopathology...
Ref: Federal Register. September 7, 2001.
Fluazinam; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fluazinam.FR.Sept.7.2001.htm
-- Metabolism and pharmacokinetics
rats. Only 33-40% of the administered dose was absorbed. Most
of the administered dose was recovered in the feces (>89%). Excretion
via the urine was minor (<4%). Total biliary radioactivity, however,
represented 25- 34% of the administered dose, indicating
considerable enterohepatic circulation [Recycling
of certain compounds between the small intestine and the liver].
-- Cancer (oral, dermal, inhalation). `Suggestive evidence of
carcinogenicity, but not sufficient to assess human carcinogenic
potential'' 2 . Quantification of human cancer risk not required.
2 Increases in thyroid gland follicular
cell tumors in male rats; increases in hepatocellular (liver)
tumors in male mice.2 (Ref 2: 2Cancer Assessment Document
- Evaluation of the Carcinogenic Potential of Fluazinam, March
29, 2001, HED Doc. No. 014512.)
-- Cancer. Since fluazinam has been classified as ``Suggestive
evidence of carcinogenicity, but not sufficient to assess human
carcinogenic potential,'' an exposure assessment was not performed.
Ref: Federal Register: April 18, 2002. Fluazinam;
Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fluazinam.FR.Apr.18.2002.htm
Flubendiamide
- Insecticide - CAS No. 272451-65-7
Results
of a reproductive toxicity study in rats (exposure route not stated):
• Increased incidence of eyeball enlargement and dark-colored
liver in 2000 and 20000 ppm F1 and F2 pups.
•
Thyroid, liver, uterine, thymus,
and spleen weight changes in 2000
and 20000 ppm F1 and F2 pups.
Ref: TSCA Health & Safety Study
Cover Sheet "Public Display Copy"
http://www.epa.gov/opptintr/tsca8e/doc/8ehq/2004/november04/8ehq-1004-15768a.pdf
••
This
document was cited at EPA's
site: "TSCA 8(e) and FYI Submissions Received from 11-15-04-11-26-04".
It is important to note this as the document itself does not identify
flubendiamide or its CAS No.
•• This
study was conducted in the laboratory of The Institute of Environmental
Toxicology - Japan
•• Source of Data/Study
Sponsor: Bayer Material Science Corporation, 100 Bayer Road, Pittsburg
PA 15205
Flucarbazone-sodium
- Herbicide
- CAS No. 181274-17-9
SUBCHRONIC/CHRONIC
TOXICITY
-- Study # 870.3150. 90-Day oral toxicity in nonrodents (dogs)
NOAEL = 33.8 mg/kg/day in males and 35.2 mg/kg/day in females
with the occurrence of slight, adaptive induction of hepatic microsomal
enzymes. LOAEL = 162 mg/kg/day in males and 170 mg/kg/day in females
based on decreased T4 levels, increased thyroxine-binding capacity,
induction of microsomal enzymes, gross pathology and histopathology
in the stomach, and histopathology
in the liver in both sexes.
-- Study # 870.3800. Reproduction and fertility effects in rats
Parental/Systemic NOAEL = 287 mg/kg/day for males and 340 mg/kg/day
for females with a slight, increased incidence of moderate cecal
enlargement occurring as an adaptive response to treatment. LOAEL
= 800 mg/kg/day for males based decreased
liver weight and 991 mg/kg/day for females based on decreased
uterine weight and increased incidence of severe
cecal enlargement. Reproductive/Offspring NOAEL = 287 mg/kg/day
for males and 340 mg/kg/day for females LOAEL = 800 mg/kg/day
for males and 991 mg/kg/day for females based on reduced pup weights,
decreased liver weight in male pups,
marbled liver, air filled stomach
-- Study # 870.4100b. Chronic toxicity in dogs NOAEL = 35.9 mg/kg/day
in males and 37.1 mg/kg/day in females. LOAEL = 183 mg/kg/day
in males and 187 mg/kg/day in females based upon body
weight gain depression and increased N-demethylase levels
in both sexes, decreased T4 levels and marginally increased
liver weight in females.
-- Study # 870.3150. 28-Day oral toxicity in nonrodents (dogs)
NOAEL = 164 mg/kg/day in males and 171 mg/kg/day in females. LOAEL
= 1,614 mg/kg/day in males and 1,319 mg/kg/day in females based
on decreased body weight gain, decreased
food consumption, decreased T4 levels and increased thyroxine-binding
capacity, induction of microsomal enzymes, increased
liver weight and liver histopathology in both sexes.
Ref: US EPA Pesticide Fact Sheet for Flucarbazone-sodium.
September 29, 2000. http://www.epa.gov/opprd001/factsheets/flucarbazone.pdf
Fluchloralin
- Herbicide
- CAS No. 33245-39-5
PubMed Abstract: Basalin
[Fluchloralin], 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 by Gupta PK, Singh YP, and
Parihar NS.
http://www.fluoridealert.org/pesticides/Fluchloralin.PubMebAbstract.htm
Flucythrinate
-
Acaricide, Insecticide - CAS No. 70124-77-5
Groups
of 50 male and 50 female CD-1 mice received technical flucythrinate
(80% pure) in the diet at 0, 30, 60, or 120 ppm daily for 18 months.
Skin lesions (abrasions, ulceration and scabs) were observed in
high-dose males and females. No treatment-related symptoms or
treatment-related changes in survival were found. No haematology,
clinical chemistry or urinalysis were undertaken. At necropsy,
hepatocellular adenomas were found
in all control and treated groups. The incidence
was variable and statistically- significant only in high-dose
males. Hepatocellular adenocarcinoma and hepatocellular carcinoma
were found in low incidence in all male groups, but only
in control and low-dose female mice. The incidences of these neoplasms
were similar to those previously found in mice and were apparently
unrelated to treatment.
Ref: 1985 World Health Organization
Review for Flucythrinate.
http://www.fluoridealert.org/pesticides/Flucythrinate.1985.WHO.htm
Abstract: Male Sprague-Dawley
rats dosed with N-nitrosodiethylamine (NDEA) 24 h after two-thirds
partial hepatectomy were treated with the pyrethroid insecticides
fenvalerate, flucythrinate or cypermethrin
in the diet for 20 weeks. Altered hepatic foci were analyzed by
quantitative stereology from paraffin-embedded sections stained
for gamma-glutamyltranspeptidase (GGT) or glutathione S-transferase
P (GST-P). The present results demonstrate that the pyrethroids
tested all enhance the development of NDEA-initiated,
GGT-positive foci in rat liver at non-hepatotoxic doses.
On the contrary, the volume fractions of GST-P-positive foci were
not elevated as compared to the control group. The
three pyrethroids tested all inhibited the transfer of Lucifer
Yellow CH between WB-F344 rat liver epithelial cells in culture,
supporting the increase of GGT-positive foci and suggesting that
these substances can act as tumour promoters. The
discrepancy between the results from analyses using GGT or GST-P
as markers emphasizes the importance of understanding the mechanism
underlying the expression of different markers for preneoplastic
lesions and the importance of such effects in tumour promotion.
Ref: Carcinogenesis 1993 Dec;14(12):2531-5.
Enhancement of altered hepatic foci in rat liver and inhibition
of intercellular communication in vitro by the pyrethroid insecticides
fenvalerate, flucythrinate and cypermethrin. Hemming H, Flodstrom
S, Warngard L.
Fludioxonil
- Fungicide - CAS No. 131341-86-1
-- Combined Chronic
Toxicity/ Carcinogenicity in rats: NOAEL = 37 mg/kg/day (M) and
44 mg/kg/day (F) LOAEL = 113 mg/kg/day (M) and 141 mg/kg/day (F)
based on decreased mean body weight gain, slight anemia (F), and
increased incidence and severity of liver
lesions (degeneration) in both sexes. There was no evidence of
carcinogenicity in male rats, but there was a statistically significant
increase, both trend and pairwise, of combined hepatocellular
tumors in female rats. Classified as ``Group D'' by OPP
Cancer Peer Review Committee. Carcinogenicity mice: increased
incidence of mice convulsing when handled (M) and increased absolute
liver weight and grossly enlarged
livers (F). Statistically significant
trend for malignant lymphomas in females...
-- 90-Day oral toxicity in NOAEL = 64 mg/kg/day (M) and 70 mg/kg/day
rats (F) LOAEL = 428 mg/kg/day (M) and 462 mg/kg/day (F) based
on decreased weight gain (both sexes), chronic nephropathy (M)
and centrilobular hepatocyte hypertrophy
(F).
-- In vivo Rat hepatocyte Male rats were orally dosed 1250, 2500
and micronucleus assay 5,000 mg/kg and hepatocytes were harvested.
Micronucleated hepatocytes were found in Phase II at the low and
mid dose levels but not at the high dose level and not in Phase
I. Positive for mutagenicity in hepatocytes exposed in vivo.
Ref: Federal Register: December 29, 2000.
Fludioxonil; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Dec.2000.htm
The kidney and liver
have been identified as target organs in subchronic and chronic
toxicity studies... In a 90-day subchronic dietary toxicity study
in rats, the NOEL was 10 ppm based on liver
toxicity.
Ref: Federal Register. Februry 5, 1997.
[PF-695; FRL-5584-1]
http://www.epa.gov/docs/fedrgstr/EPA-PEST/1997/February/Day-05/p2711.htm
-- 13
Week Oral Feeding Study - rat. Systemic. NOAEL= 64 mg/kg/day.
LOAEL = 428 mg/kg/day based on decreased
body weight gain in both sexes, chronic nephropathy in males,
and centrilobular
hepatocyte hypertrophy in females.
-- The EPA classified Fludioxonil as a Group D - not classifiable
as to human carcinogenicity. The evidence is inadequate and cannot
be interpreted as showing either the presence or absence of a
carcinogenic effect. In one mouse study, there was a significant
trend for malignant lymphomas in female mice up to 3,000 ppm.
However, in a second study up to 7,000 ppm, the limit dose, there
was no evidence of carcinogenicity for either sex. In rats, fludioxonil
produced a significant trend and pair- wise
increase in hepatocellular tumors, combined, in female rats at
doses adequate to assess carcinogenicity. The EPA determined
that based on the increase in liver tumors
in female rats that was statistically
significant for combined adenoma/carcinoma only, the lack
of tumorogenic response in male rats or in either sex of mice,
and the need for additional mutagenicity studies, a Group D classification
was appropriate. However, the Agency has since received the additional
mutagenicity studies and based on the negative preliminary findings
of the studies, the fact that the statistical increase in liver
tumors in female rats occurred only at the highest dose, the lack
of tumorigenic response in male rats and mice, the Agency has
concluded that fludioxonil does not pose a significant cancer
risk.
Ref: Federal Register: September 12, 2001.
Fludioxonil; Pesticide Tolerances for Emergency Exemptions. Final
Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Sept.12.2001.htm
Flufenacet
- Herbicide - CAS No. 142459-58-3
Chronic feeding studies
in dog and rat showed structural or functional alterations in
liver, kidney, haematology, spleen,
and thyroid. Flufenacet induces neuropathogical changes in the
brain and spinal cord (axonal swelling) in rat and dog. The overall
evaluation of the observed changes demonstrates that these effects
occur only after repeated and prolonged exposure to high dose
levels of flufenacet, which saturate metabolic pathways, and exceed
the animal capacity to rapidly metabolise and excrete it. The
liver was considered
the primary target organ, with increases in organ weight,
cell size and number, and/or associated changes in
liver function tests.
Ref: European Commission, Health & Consumer
Protection Directorate-General, Scientific Committee on Plants,
October 17, 2001. SCP/FLUFEN/002-Final.
http://europa.eu.int/comm/food/fs/sc/scp/out112_ppp_en.pdf
-- 21-day dermal (rats): Dermal Irritation NOEL = 1000
mg/kg/day (males and females) Systemic NOEL = 20 mg/kg/day (males)
Systemic NOEL = 150 mg/kg/day (females) Systemic LOEL = 150 mg/kg/day
for males and 1000 mg/kg/day for females based on clinical chemistry
data (decreased T4 and FT4 levels in both
sexes) and centrilobular hepatocytomegaly
in females.
-- Two Generation Reproduction (rat): Parental Systemic NOEL =
20 ppm [1.4 mg/kg/day in males and 1.5 mg/kg/day in females] Parental
Systemic LOEL = 100 ppm [7.4 mg/kg/day in males and 8.2 mg/kg/day
in females] based on increased liver weight
in F1 females and hepatocytomegaly
in F1 males. Reproductive NOEL = 20 ppm [1.3 mg/kg/day] Reproductive
LOEL = 100 ppm [6.9 mg/kg/day] based on increased pup death in
early lactation (including cannibalism) for F1 litters and the
same effects in both F1 and F2 pups at the high dose level of
500 ppm [37.2 mg/kg/day in F1 males and 41.5 mg/kg/day in F1 females,
respectively].
Ref: US EPA. Pesticide Fact Sheet. Flufenacet
Reason for Issuance: Conditional Registration Date Issued: April
1998.
http://www.epa.gov/opprd001/factsheets/flufenacet.pdf
- Reproductive and developmental toxicity--
---- A 2-generation rat reproduction study with a parental systemic
no observed adverse effect level (NOAEL) of 20 ppm (1.4 mg/kg/day
in males and 1.5 mg/kg/day in females) and a reproductive NOAEL
of 20 ppm (1.3 mg/kg/day) and a parental systemic lowest observed
adverse effect level (LOAEL) of 100 ppm (7.4 mg/kg/day in males
and 8.2 mg/kg/day in females), based on increased
liver weight in F1 females and hepatocytomegaly in F1 males,
and a reproductive LOAEL of 100 ppm (6.9 mg/kg/ day) based on
increased pup death in early lactation (including cannibalism)
for F1 litters and the same effects in both F1 and F2 pups at
the high dose level of 500 ppm (37.2 mg/kg/day in males and 41.5
mg/kg/day in females), respectively.
---- A rabbit developmental study with a maternal NOAEL of 5 mg/kg/
day and a maternal LOAEL of 25 mg/kg/day based on histopathological
finds in the liver and a developmental
NOAEL of 25 mg/kg/day and a developmental LOAEL of 125 mg/kg/day
based on increased skeletal variations.
Subchronic toxicity:
----- A 13-week mouse feeding study with a NOAEL of 100 ppm (18.2
mg/ kg/day for males and 24.5 mg/kg/day for females), and a LOAEL
of 400 ppm (64.2 mg/kg/day for males and 91.3 mg/kg/day for females)
based on histopathology of the liver,
spleen and thyroid.
---- A 13-week dog dietary study with a NOAEL of 50 ppm (1.70
mg/ kg/day for males and 1.67 mg/kg/day for females), and a LOAEL
of 200 ppm (6.90 mg/kg/day for males and 7.20 mg/kg/day for females),
based on evidence that the bio-transformation capacity of the
liver has been exceeded (as indicated by increase in LDH,
liver weight, ALK and hepatomegaly),
globulin and spleen pigment in females, decreased T4 and ALT values
in both sexes, decreased albumin in males, and decreased serum
glucose in females.
- Chronic toxicity
---- A 1-year dog chronic feeding study with a NOAEL was 40 ppm
(1.29 mg/kg/day in males and 1.14 mg/kg/day in females), and a
LOAEL of 800 ppm (27.75 mg/kg/day in males and 26.82 mg/kg/day
in females) based on increased alkaline phosphatase, kidney, and
liver weight in both sexes, increased
cholesterol in males, decreased T2, T4 and ALT values in both
sexes, and increased incidences of microscopic lesions in the
brain, eye, kidney, spinal cord, sciatic nerve, and
liver.
Ref:
Federal Register. March 29, 2000. Notice of Filing a Pesticide
Petition to Establish a Tolerance for Certain Pesticide Chemicals
in or on Food.
http://www.fluoridealert.org/pesticides/Flufenacet.FR.Mar.29.2000.htm
Flufenoxuron
- Acaracide, Insecticide, Herbicide - CAS No. 101463-69-8
Carcinogenicity data.
Adequately conducted carcinogenicity studies in the rat and mouse
have been reported. Flufenoxuron was not carcinogenic in the rat.
The NOEL for non-neoplastic effects (body weight and relative
spleen weight changes) was 25 mg-1.kg-1.d-1. In the mouse there
was an increased incidence of haemangiosarcoma
in the liver (males) and spleen (females) at 50000
ppm, and an apparent increase in hepatocellular
carcinoma in males at all dose levels. The apparent increase
in liver tumors was due to an abnormally low control incidence,
and therefore flufenoxuron had no significant carcinogenic activity
in the mouse. No NEL was established in this study.
Ref:
December
1995. Evaluation of Flufenoxuron use as a public hygiene insecticide.
UK: Health and Safety Executive, Biocides & Pesticides Assessment
Unit. Available at http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm
Abstract: Flufenoxuron
(Benzoylphenyl urea derivative) - antimoulting insecticide Ð is
recently used for controlling insect reproduction in cultivated
areas. The study determined the hazardous effects of the applied
dose-treatment during the critical period of rat embryonic development
and the induction of growth retardation. In the present work,
flufenoxuron was intragastrically administered by stomach intubation
to pregnant rats at concentration levels 0 & 20 mg/kg b.wt.
in saline solution every other day on gestation day 7 till parturition.
Experimental and control pregnant rats were sacrificed on days
13 & 16 of gestation and the foetuses were fixed in 10 percent
formol saline. Histological abnormalities
of thyroid, liver and
kidneys of mothers as well as of skeletal axial and appendicular
regions of foetuses were investigated.
Foetuses
maternally treated
with flufenoxuron exhibited delayed differentiation
of chondrification and ossification of axial and appendicular
regions. The observed defects in foetuses
may be attributed to the histological abnormalities of thyroid,
liver and kidneys
of maternal tissues as well as to the direct effect of
the parents as a result of the insecticide or its metabolites
on the affected structures during early morphogenesis and differentiation.
Ref: J. Egypt. Ger. Soc. Zool., Vol. 25(B),
65-81, 1998. PATTERNS OF DEVELOPMENTAL DEFECTS OF RAT FOETUSES
MATERNALLY TREATED WITH AN ENVIRONMENTAL ANTIMOULTING INSECTICIDE
FLUFENOXURON; by Karim,
S.A.
http://www.egsz.org/BiologicalCurrentContent/Zoology/Comparative%20Physiology/TOXICOLOGY.htm
Flufenpyr-ethyl
- Herbicide - CAS No. 188489-07-8
Carcinogenicity
rodents (mouse) - [870.4200]. NOAEL = 39.9 - 43.7 mg/kg/day M/F
LOAEL = 401.8 - 447.9 mg/kg/day M/F, based on liver
toxicity in both sexes and mild anemia in males. No evidence
of carcinogenicity.
Ref: Federal Register: September 19, 2003.
Flufenpyr-Ethyl; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/flufenpyr-ethyl.fr.sept2003.htm
-- The kidney
and liver appear to be the target organs of flufenpyr-ethyl.
EPA has not had the opportunity to review
the toxicity studies on flufenpyr-ethyl and has not established
toxic endpoints.
-- Reproduction. In the rat reproduction study, flufenpyr-ethyl
technical was administered in the diet at levels of 0, 200, 2,000,
and 20,000 ppm for 2-generations. Parental toxicity was observed
at all dose levels, although the effects at the low dose were
minimal. Parental toxicity was exhibited by dose-related
microscopic changes in the kidney in high dose F0 animals,
in all treated F1 males, and in high dose F1 females. There were
also 2 high dose F1 males that died possibly as a result of treatment.
Midzonal cytoplasmic vacuolation of the
hepatocytes was also observed in the liver of all groups of treated
animals in both generations. Based on the results of this
study, the NOAEL for parental toxicity was considered to be less
than 200 ppm. The NOAEL for reproductive and neonatal toxicity
was considered to be 20,000 ppm.
-- Subchronic toxicity. Subchronic oral toxicity studies conducted
with flufenpyr-ethyl in the rat, mouse and dog indicate a low
level of toxicity. i. Rats. Pure (99.4%) flufenpyr-ethyl was tested
in rats at dose levels of 0, 600, 2,000, 6,000, and 20,000 ppm
in the diet for 13 weeks. Effects observed included urinary incontinence,
increased food and water consumption, slight hematological and
blood biochemistry changes, decreased spleen weights, an
increase in the incidence and severity of basophilic tubules of
the kidneys and slight to mild diffusely distributed vacuolation
in the liver. Based on these results,
the NOAEL was 2,000 ppm (134.2 mg/kg/day) for the males and 20,000
ppm (1,509.6 mg/kg/day) for the females.
-- In an additional study, flufenpyr-ethyl technical was tested
in rats at dose levels of 0, 1,000, 10,000, and 20,000 ppm in
the diet for 13 weeks. Effects observed included urinary incontinence,
increased food and water consumption, and mild urinalysis, hematological
and blood biochemistry changes. Thymus weights were slightly increased.
Diffusely distributed hepatic vacuolation
was seen in the high dose males. Based on these findings, the
NOAEL was 10,000 ppm (595.2 mg/kg/ day) in the males and 20,000
ppm (1,377.5 mg/kg/day) in the females.
-- Mice. In a 4-week study, CD-1 mice were fed pure flufenpyr-
ethyl at dose levels of 0, 300, 1,000, 3,000, and 7,000 ppm. Effects
were slight anemia, changes in blood biochemistry, increased liver
and thymus weights, and enlarged
liver. Centrilobular hepatocellular
hypertrophy and vacuolation and increases in the severity
and incidence of hepatic focal and single
cell necrosis were observed. Based on these findings, the
NOAEL was 300 ppm (44.9 mg/kg/day) for males
and 1,000 (210.5 mg/kg/day) for females.
-- In a 13-week study, flufenpyr-ethyl technical was administered
to mice at dose levels of 0, 300, 1,000, 3,000, and 7,000 ppm.
Slight anemia and blood biochemistry changes were noted. Liver
weights were increased and ovary weights were decreased.
Histopathological findings included: Hepatocellular
fatty vacuolation. The NOAEL for this study in both sexes
was [[Page 37818]] 1,000 ppm (128.4 mg/kg/day for males and 155.7
mg/kg/day for females).
-- Mice. In a 78-week oncogenicity study with mice, flufenpyr-
ethyl technical was administered at dose levels of 0, 350, 3,500,
and 7,000 ppm. Male animals exhibited slight anemia. Females had
increased liver and kidney weights
(week 53 only). Slight to moderate hepatocellular
fatty vacuolation and necrosis were observed. There were
no increases in incidence of pre-neoplastic or neoplastic lesions.
Based on these results, the NOAEL was 350 ppm for both sexes (39.9
mg/ kg/day for males and 43.7 mg/kg/day for females).
Ref:
Federal Register: June 25, 2003 (Volume 68, Number 122)] [Notices]
[Page 37813-37820]. Flufenpyr-ethyl; Notice of Filing a Pesticide
Petition to Establish a Tolerance for a Certain Pesticide Chemical
in or on Food.
http://www.fluorideaction.org/pesticides/flufenpyr-ethyl.fr.june.03.htm
Flumequine
- Microbiocide - CAS No. 42835-25-6
BIOLOGICAL DATA 2.1. Hepatotoxicity and carcinogenicity. In short-term
and long-term studies of toxicity that were evaluated by the Committee
at its forty-second and forty-eighth meetings, oral administration
of flumequine caused dose-related hepatotoxic
effects in rats and CD-1 mice. The liver damage was most pronounced
in male mice, and included degenerative changes with hypertrophy,
fatty vacuolation, focal necrosis and increased mitotic activity.
After cessation of treatment with flumequine, the liver damage
was reversed. Treatment with flumequine had little or no effect
on P450-dependent hepatic drugmetabolizing enzymes or on glucuronyl
transferase. Flumequine increased the plasma activities of alanine
and aspartate aminotransferases, alkaline phosphatase and lactate
dehydrogenase. The overall no-observed-effect level (NOEL) for
hepatotoxic effects in mice was 25mg/kg bw per day. The results
of long-term studies of toxicity that were evaluated by the Committee
at its forty-second meeting showed that flumequine had no carcinogenic
effects in rats, whereas in CD-1 mice an
increase in the incidence of liver tumours was observed at oral
doses of flumequine of ≥400mg/kg bw per day (the lowest
dose tested) in an 18-month study. The incidence of tumours in
male mice was significantly higher than that in female mice. In
male mice, the incidence of liver tumours increased in a dose-related
and time-dependent manner, and was paralleled by an increase in
the incidence of hepatotoxic changes. The present Committee
re-evaluated the three short-term studies in mice, which used
a two-stage hepatocarcinogenesis protocol, that were presented
to the Committee at its sixtieth meeting. In these studies, treatment
with flumequine caused the development of basophilic liver foci,
which could suggest that flumequine has tumour initiating potential.
However, the Committee also noted that concurrent hepatotoxicity
(evidenced by pale, vacuolated hepatocytes with fatty droplets,
inflammatory cell infiltration, increased mitotic figures and/or
necrosis) was observed, as well as a regenerative response to
these toxic changes and indications of oxidative stress.
Ref: 2004
- Flumequine (addendum). First draft prepared by Mrs. M.E.J. Pronk,
Centre for Substances and Integrated Risk Assessment, National
Institute for Public Health and the Environment. Bilthoven, The
Netherlands.
http://www.fluorideaction.org/pesticides/flumequine.netherlands.2005pdf
-- PubMed Abstract:
In order to elucidate the tumor-initiating potential of flumequine
(FL) in the liver, male C3H mice were given dietary administration
of 4000 ppm FL throughout the study or for 2 weeks at the initiation
stage, and then received 2 intraperitoneal injections of D-galactosamine
(Gal) at weeks 2 and 5, with or without 500 ppm phenobarbital
(PB) in their drinking water for 13 weeks to provide tumor-promoting
effects. Hepatocellular foci were observed in 2 out of 8 and 6
out of 7 animals in the FL/PB + Gal and FL/FL + Gal groups, respectively.
In addition, in an alkaline single-cell gel electrophoresis (comet)
assay that was performed using adult, infant, or partial hepatectomized
male ddY mice to evaluate the potential of FL at 500 mg/kg or
less, to act as a DNA damaging agent. FL
induced dose-dependent DNA damage in the stomach, colon, and urinary
bladder of adult mice at 3 h but not at 24 h after its administration.
Similarly, DNA damage was noted in
the regenerating liver and the livers of infant mice at the 3
h time point. Furthermore, in in vitro assays that were
conducted to investigate the potential of FL to inhibit eukaryotic
topoisomerase II, which is responsible for the double-strand DNA
breakage reaction as well as bacterial gyrase, inhibitory effects
of FL on topoisomerase II were high relative to the influence
on bacterial gyrase. The results of our
studies thus strongly suggest that FL has initiating potential
in the livers of mice that is attributable to its induction of
DNA strand breaks.
Ref:
Toxicol Sci 2002 Oct;69(2):317-21;
Mechanistic study on flumequine hepatocarcinogenicity focusing
on DNA damage in mice; Y Kashida et al.
-- 1999 PubMed Abstract:
It has been reported that flumequine
(FLU) induces
hepatic tumors in mice when given orally for 18 months.
We investigated possible underlying mechanisms using a two-stage
mouse hepatocarcinogenesis model. After initiation with a single
intraperitoneal injection of 100 mg/kg body weight diethylnitrosamine
(DEN) or saline, male CD-1 mice were given 4000 ppm FLU
in the diet or 500 ppm phenobarbital (PB) in drinking water for
9, 19, 24 or 30 weeks. Toxicity, evidenced
by centrilobular swollen and polar hepatocytes with fatty droplets,
infiltration of inflammatory cells and increased numbers of mitosis
in hepatocytes, was apparent in the livers of mice treated with
FLU at all time points, but its severity declined towards the
termination. FLU did not induce
cytochrome P-450 enzymes such as 1A1, 2B1 and 3A2 as assessed
immunohistochemically, while positive expression of 8-hydroxy-2'-deoxyguanosine
(8-OHdG) was increased in hepatocytes of both DEN + FLU
and FLU groups compared with the relevant controls. In
animals given PB, eosinophilic swelling of hepatocytes was prominent,
and the hepatocytes showed strongly positive reactions for CYP
1A1 and 3A2. Altered cell foci were induced in the livers of FLU-treated
animals both with and without DEN initiation, especially the former,
and their development paralleled the degree of hepatic toxicity.
These results suggest that FLU hepatocarcinogenicity
in mice is dependent on hepatotoxic damage and consequently increased
cell proliferation. Oxidative damage to DNA may also be
a crucial factor.
Ref: Cancer Lett 1999 Jul 1;141(1-2):99-107. Hepatotoxicity
and consequently increased cell proliferation are associated with
flumequine hepatocarcinogenesis in mice. Yoshida M et al.
-- Maximum Residue
Limits. In calculating MRL values for flumequine, the following
factors were considered: á An ADI of 0-30 m g/kg, based on a toxicological
end-point, was established by JECFA. This will yield a daily intake
of 0-1800 m g/kg for a 60-kg person. á The parent drug was selected
as the marker residue. á Muscle
and kidney were proposed as target tissues. For
practical reasons, however, liver is
the proposed target tissue for chickens in place of kidney.
Ref: Flumequine.
http://www.fao.org/docrep/W8338E/w8338e0a.htm#TopOfPage
-- In the 90-day subchronic
toxicity carried out on CD-1 mice, flumequine was administered
to at level doses of 0, 25, 50, 100, 400 and 800 mg/kg bw/day
for males and dosages of 1, 100, 400 and 800 mg/kg bw/day for
females. In the two high doses groups, the histopathological examination
of the livers revealed, in both males
and females, periacinar single cell necrosis
and inflammation, periacinar pigment laden
macrophages, increased ploidy of hepatocytes, hepatocytic intranuclear
inclusions, increased periacinar hepatocytic fatty vacuolation.
However, a periacinar hepatocytic hypertrophy was only observed
in males : in 7 of 12 animals of the 800 and 400 mg/kg bw dose
group, in 5 of 12 animals in the 100 mg/kg bw dose group and in
1 animal in the 50 mg/kg bw dose group and these lesions were
dosage-related. In addition, an inhibition of the activity of
NADPH-cytochrome P450 for females of the two highest dose grop
and of UDP-glucuronosyltranferase for males at 50 mg/kg bw was
also reported... 25 mg/kg bw/day was considered
as the NOEL for hepatotoxicity in mice.
-- In an 18-month carcinogeniciy study in mice, flumequine was
administered in the feed at 0, 400 or 800 mg/kg bw. The combined
incidence of benign and malignant liver
tumours was dose related : 37 % in the 400 mg/kg bw dose
group, 88 % in the high dose group vs. 9 % in the control group
for males and 13 % in the high dose females vs. 0 % for the contrl
and the low dose groups. Dose related changes in the hepatocytes
which paralleled the liver tumour incidence occurred in the low
dose males and in the high dose males and females.
-- There is evidence of compound-related tumorigenic
efffects in the liver of mice. In order to explain the
mechanism of liver tmour induction, the dosage of a preneoplastic
markter yGT and of a detoxification enzymes, GSH S-transferase,
were performed on liver samples collected in the 90-toxicity study
carried out in mice. No variations of yGT were noted whatever
the dosage used. However, an increase of the GSH S-transferase
activity in females dosed at 400 and 800 mg/kg bw and in males
dosed at 800 mg/kg bw showed that flllumequine induced detoxification
phenomena, showing cells hepatotoxicity. However, this phenomena
was not correlated with the number of tumours incidence. As the
tumorigenicity is considered to be a consequence of hepatotoxiciity,
it was concluded that the NOEL of 25 mg/kg bw/day covered both
end-points.
Ref: Committee for Veterinary Medicinal
Products. Flumequine. Summary Report. EMEA/MRL/104/96-FINAL. June
1996. Study performed by EMEA, London UK for the European Agency
for the Evaluation of Medicinal Products. Veterinary Medicines
Evaluation Unit.
http://www.fluoridealert.org/pesticides/Flumequine.Report.1996.pdf
Flumethrin
-
Acaricide - CAS No. 69770-45-2
Abstract: The effects
of repeated exposure to the pyrethroid insecticide flumethrin
(40 mg/kg intraperitoneally once a day for 6 days) on the activity
of cytochrome P450-dependent monooxygenases and UDP-glucuronosyltransferase
as well as on antipyrine disposition were investigated in male
Wistar rats. Pretreatment with flumethrin decreased the activities
of NADPH-cytochrome c reductase (38%), aniline hydroxylase (53%),
aminopyrine N-demethylase (54%), and UDP-glucuronosyltransferase
(34%), and the content of cytochrome P450 (36%) in hepatic microsomes.
Total plasma clearance of antipyrine was decreased by flumethrin
pretreatment (54%), while the elimination half-life at beta phase
and the mean residence time of antipyrine were increased (96 and
88%, respectively). Urinary excretion of norantipyrine, 4-hydroxyantipyrine,
and 3-hydroxymethylantipyrine was decreased by 60, 38, and 33%,
respectively, in the 96 hr after flumethrin treatment. In addition,
the rate constants for formation of each of these metabolites
were decreased by an average of approximately 74%. These
findings provide evidence that flumethrin exposure diminishes
hepatic enzyme levels and catalytic activities of monooxygenase
systems as well as oxidative metabolism of antipyrine.
Ref: Effects
of flumethrin on hepatic drug-metabolizing enzymes and antipyrine
disposition in rats; by A Anadon et al. Toxicol Appl Pharmacol
1995 May;132(1):14-8.
Flumiclorac-pentyl
- Herbicide - CAS No. 87546-18-7
-- Chronic Toxicity
(Including Cancer): Studies with Flumiclorac Pentyl Technical
indicate that repeated high exposures produced changes in
liver, kidney, and red blood cells
but did not produce cancer in test animals.
-- Potentially Aggravated Condition: Individuals with preexisting
diseases of the liver, kidney,
or red blood cells may have
increased susceptibility to the toxicity of excessive exposures.
-- SUBCHRONIC:
Compound-related effects noted at very high dose levels of Flumiclorac
Pentyl Technical in rodents and/or dogs included: increased liver
and kidney weights; histological changes
in the kidney and liver; slight changes
in blood biochemistry parameters; decreased red blood cell count,
hemoglobin, and hematocrit;
and slight decreases in body weight. The NOEL in rats and mice
was 1000 ppm.
-- CHRONIC/CARCINOGENICITY: Effects of long-term high dose exposures
to Flumiclorac Pentyl Technical in rodents and/or dogs consisted
primarily of increases in kidney and liver
weights, slight changes in blood
biochemistry, and histological changes
in the liver. The lowest NOEL was 300 ppm in the mouse
study. Flumiclorac Pentyl Technical was not carcinogenic in either
rats or mice.
Ref: Material
Safety Data Sheet for RESOURCE TM Herbicide.
http://www.fluoridealert.org/pesticides/Flumiclorac-pentyl.MSDS.htm
Flumioxazin
- Herbicide - CAS No. 103361-09-7
Subchronic, Chronic,
and Other Toxicity
-- 870.3100 90-Day oral toxicity -mouse NOAEL = mg/kg/day: 429
(M & F) LOAEL = mg/kg/day: 1429 (M & F) based on increased
liver weight in males
-- 870. 3100 4-Week oral toxicity -mouse NOAEL = mg/kg/day: 151.5
(M), 164.5 (F) LOAEL = mg/kg/day: 419.9 (M), 481.6 (F) based on
increased absolute &/or relative liver weights
in M & F
-- 870.4100 12-Month capsule -dog NOAEL = 100 mg/kg/day (M & F)
LOAEL = 1000 mg/kg/day (M &F), (LIMIT DOSE) based on the following
for males and females: increased absolute and relative liver
weights; 300% increase in alkaline
phosphatase values
Ref: US EPA Pesticide Fact Sheet. April
12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf
Fluometuron
- Herbicide - CAS No. 2164-17-2
The spleen, kidney, and
liver appear to be the organs consistently
affected following exposure to moderate doses of fluometuron
in rats and dogs in subchronic, chronic, developmental, and reproductive
studies. (page 8)
Ref.
February 1, 2005. US EPA: Fluometuron: Revised HED Risk Assessment
for Phase III of the Reregistration Eligibility Decision. Docket
Identification Number: OPP-2004-0372-0008.
http://www.fluorideaction.org/pesticides/fluometuron.opp-2004-0372-0008.pdf
Groups of 50 /B6C3F1/
mice of each sex were fed diets containing 500 or 1,000 ppm of
fluometuron for 103 weeks. Matched controls consisted of groups
of 25 untreated mice of each sex. All surviving animals were killed
at 103 to 105 weeks. Mean body weights of the dosed groups of
male and female mice were essentially the same as those of the
corresponding control groups. Survival of dosed groups of mice
were similar to that of the corresponding control groups. Similarities
between mean body weights and survival between dosed and control
animals in the chronic study suggest that these animals could
have tolerated higher doses. The only possible carcinogenic effects
from compound administration were in male
mice. Incidences of hepatocellular
carcinomas or adenomas in male mice were dose
related, and the incidence in the
high-dose group was marginally higher than that in the corresponding
matched controls or pooled controls from concurrent studies.
Under the conditions of this bioassay, fluometuron was
not carcinogenic for F344 rats or for female B6C3F1 mice.
Equivocal results were obtained for male B6C3F1 mice which may
have had an increased incidence of hepatocellular tumors.
Because of the equivocal findings and because both rats and mice
may have been able to tolerate higher doses,
it is concluded that additional testing of fluometuron for carcinogenicity
is warranted. (Summary page v)
Reference: 1980. Bioassay of fluometuron
for possible carcinogenicty. NCI-CG-TR-195. NTPO-80-11. National
Cancer Institute. Carcinogenesis. Technical Report Series No.
195. NTP No. 80-11.
http://www.fluorideaction.org/pesticides/fluometuron.ntp.1980.pdf
Groups of 50 /B6C3F1/
mice of each sex were fed diets containing 500 or 1,000 ppm of
fluometuron for 103 weeks. Matched controls consisted of groups
of 25 untreated mice of each sex. All surviving animals were killed
at 103 to 105 weeks. Mean body weights of the dosed groups of
male and female mice were essentially the same as those of the
corresponding control groups. Survival of dosed groups of mice
were similar to that of the corresponding control groups. Similarities
between mean body weights and survival between dosed and control
animals in the chronic study suggest that these animals could
have tolerated higher doses. ... The only possible carcinogenic
effects from compound administration were in
male mice. Incidences of hepatocellular
carcinomas or adenomas in male mice were dose related,
and the incidence in the high-dose group was marginally higher
than that in the corresponding matched controls or pooled controls
from concurrent studies. ... Under the conditions of this bioassay,
fluometuron was not carcinogenic for female B6C3F1 mice. Equivocal
results were obtained for male B6C3F1 mice which may have had
an increased incidence of hepatocellular tumors. [DHEW/NCI; Bioassay
of Fluometuron for Possible Carcinogenicity p.V (1980) Technical
Rpt Series No. 195 DHEW Pub No. (NIH) 80-1751]
Ref: TOXNET profile from Hazardous Substances
Data Base for FLUOMETURON.
http://www.fluoridealert.org/pesticides/FLUOMETURON.TOXNET.HSDB.htm
PubMed abstract: The
experiments on the investigation of pesticide fluometuron (cotoran)
influence on nuclease sensitivity and template activity of rat
liver chromatin were carried out. Cotoran was found to
bind specifically with non-histone proteins of chromatin. It was
shown that this pesticide considerably decreases template activity
of chromatin and its sensitivity to the action of nucleases. It
suggests, that certain conformation changes occur in chromatin
upon the action of cotoran.
Ref: Biull Eksp Biol Med 1992 Mar;113(3):261-3.
[Effects of pesticide fluometuron (cotoran) on template synthesis
of RNA] [Article in Russian] Khamidov DKh, Mirakhmedov AK, Sagatova
GA, Azimova ShS. PMID: 1384777 [PubMed - indexed for MEDLINE]
-- Organ Toxicity.
Toxic injury to the liver, kidneys,
gut and brain is induced when
lethal doses of fluometuron are administered experimentally (10).
An increase in spleen weight and in the incidence of abnormalities
in red-blood cells, and decreased weight gain in females were
observed in a 90-day study of rats (18).
-- Carcinogenic Effects. EPA has determined that there is not
enough evidence that fluometuron causes cancer in animals to justify
its classification as a carcinogen. Fluometuron is not classified
as a carcinogen by the EPA (20). An increased incidence of
liver-cell tumors in male mice was noted in a study of
rats and mice. In the same study, no carcinogenic effects were
observed in female mice or in rats of either sex (18). Mice that
were given oral doses of 87 mg/kg for two years had evidence of
liver tumors and leukemia,
a condition characterized by uncontrolled growth in the number
of white blood cells in the blood stream (7).
-- CHRONIC TOXICITY. Rats were fed 7.5, 75, or 750 mg/kg/day for
90 days. At the 750 mg/kg dose, decreased
body weight and congestion in the
spleen, adrenals, liver,
and kidneys
were evident.
The NOAEL for this study was 7.5 mg/kg/day (100 ppm). When doses
of 1.5, 15 or 150 mg/kg/day were fed to puppies for 90 days, congestion
of the liver, kidneys
and spleen
occurred at the
150 mg/kg dose. No effects were seen at 15 mg/kg/day (400 ppm)
(20).
Ref: Fluometuron. EXTOXNET. Pesticide Information
Profile. March 1994. http://pmep.cce.cornell.edu/profiles/extoxnet/dienochlor-glyphosate/fluometuron-ext.html
-- PubMed abstract:
Twelve of fifteen 6-9-mo-old clinically healthy Desert sheep were
given single or repeated daily doses of 25 to 4000 mg cotoran/kg
by drench. Cotoran poisoning was characterized
by grinding of the teeth, ruminal tympany, mydriasis, dyspnea,
staggering, paresis of the hind and forelimbs, and recumbency.
Lesions were widespread congestion and hemorrhage, hepatic
fatty change, catarrhal enteritis and degeneration
of the epithelial cells of the renal proximal convoluted tubules.
These were accompanied by significant increases in the activities
of GOT, LDH and GGT and decreases in serum total protein and calcium.
Ref: Vet Hum Toxicol 1995 Jun;37(3):214-6. Toxicity
of cotoran (fluometuron) in Desert sheep; by Mohamed OS, Ahmed
KE, Adam SE, Idris OF.
-- PubMed abstract:
The experiments on the investigation of pesticide cotoran-effect
on RNA synthesis and transport were carried out. Cotoran was shown
to destroy considerably the processes of
RNA biosynthesis in rat liver, that results in the decrease
of RNA transport from nuclei into cytoplasm. By special experiments
it was established that functional activity and the integrity
of nuclear membrane (according to the alteration in the activity
of nuclear membrane enzyme Mg2-dependent ATP-ase) was not destroyed.
Ref: Biull Eksp Biol Med 1992 Jan;113(1):40-2.
[RNA
synthesis and transport in the rat liver under the effects of
pesticide cotoran (fluometuron)].
[Article in Russian]; by Khamidov DKh, Marakhmedov AK, Sagatova
GA, Azimova ShS.
Fluopicolide
- Fungicide - CAS
No. 239110-15-7
Chronic
toxicity (page 4)
ii. Chronic toxicity/carcinogenicity was assessed in rats
at dietary levels of 50, 200, 750 and 2500 ppm. The NOAEL was
200 ppm (8.4 mg/kg/day in males and 10.8 mg/kg/day in females)
based on microscopic changes in the liver
and kidneys similar to those observed in the 90-day rat study.
No evidence of carcinogenicity was observed in rats up to 2500
ppm.
iii. The oncogenic potential of fluopicolide was investigated
in C57BL/6 mice at dietary levels of 0, 50, 400,
or 3200 ppm. Significantly lower body weight
gain was seen at 3200 ppm in conjunction with a slight
decrease in food consumption. Increased
liver weight and centrilobular hepatocellular hypertrophy
were observed at 400 and 3200 ppm in both sexes. In addition at
3200 ppm, an increased incidence of hepatocellular
adenomas was noted in both sexes, but the incidence of
hepatocellular carcinomas was not affected. The NOAEL was 50 ppm
(equivalent to 7.9 and 11.5 mg/kg/day in males and females, respectively).
Subsequent mechanistic work demonstrated a marked transient hepatocellular
profileration, whch returned to control levels after 28 days of
treatment. This was accompanied by a clear induction of total
cytochrome P-450 and related enzymes. These results parallel findings
with Phenobarbital, which has a well understood threshold-based
mechanism of roden tumor formation commonly known to be of no
relevance to humans.
Subchronic toxicity (pages 3-4)
Ninety-day feeding studies were conducted in dogs, mice and rats.
ii. In 90-day feeding studies in both CD-1 and C57BL/6 mice,
liver was the only target organ identified
with hepatocellular hypertrophy seen at dietary levels
of 320 ppm and higher. The NOAEL in C57BL/6 mice was 200 ppm (equivalent
to 37.8 and 52.8 mg/kg/day in males and females, respectively.)
iii. In a 90-day rat study with dietary levels of 100, 1400 and
20,000 ppm, the maximum tolerated dose (MTD) was exceeded at 20,000
ppm based on body weight gain of 30 to 40% below control. The
target organs identified in rats were the liver (centrilobular
hypertrophy) in both sexes and the kidneys
in males (accumulation of hyaline droplets, single cell death
at the proximal tubule epithelium, slight foci of basophilic tubules
and granular casts) at 1400
ppm and 20,000 ppm. The NOAEL was 100 ppm, equivalent to
7.4 and 8.4 mg/kg/day, in males and females, respectively.
Reference: January
1, 2005, submission to US EPA from Valent U.S.A. Company. Federal
Register Docket EPA-HQ-OPP-2006-0481-0002.
http://www.fluorideaction.org/pesticides/fluocopicolide.valent.june.2005.pdf
Fluoroglycofen-ethyl
- Herbicide
-
CAS No.
77501-90-7
-- The pertinent study
proposed for consumer risk assessment was the rat chronic study.
However, 2 mouse chronic/oncongenicity studies were performed.
The first showed liver neoplasia
at <> 50 ppm, whilst histopatholical and organ weight effects
were seen at all doses (10-250 ppm). Hence a NOEL could not be
determined. The second sudy failed to find effects at up to 10
ppm. The mouse NOEL was therefore cncluded to be 10 ppm based
on the second study, which allowed for the NOEL for neoplasia
as seen in the first study. It should be noted that the
second study employed technical material with lower levels of
impurities. The technical fluoroglycofen-ethyl used in the initial
mouse study was used in the rat chronic study without any treatment-related
carcinogenicity. Peroxisome proliferation
has been implicated by the applicant as the cause of hepatic neoplasia
in mice. Subchronic studies in mice have shown peroxisome
proliferation, along with biochemical
and morphological changes in liver attributable to peroxisome
proliferation, at similar doses to those which have caused
hepatic neoplasia in the chronic
study. It is important to note that this assessment is based only
on fluoroglycofen-ethyl and its mammalian metabolites in which
the diphenyl ether bond remains intact.
-- The pertinent no effect level from subacute/subchronic studies
was 9 mg/kg bw/day (80 ppm) taken from the 14 day rat study, based
primarily on enlarged livers and altered
liver enzyme function at 800 ppm. This figure is above
the no observed effect levels for the 3 month dietary mouse study
and the 14 days perosxome prolifertion study. However, these figures
were based on slight increases in hepatocellular
hypertrophy at the next dose, which in the 3 month mouse
study were shown to be reversible, especially at the lower dose.
Hence the no adverse effect level for mice was concluded to be
9.6 mg/kg bw/day. The rat 8 mg/kg bw/day NEL is also lower than
the dog 52 week study NEL (9.9-9.9 mg/kg bw/day) which was based
on increased liver and kidney weights at higher doses.
-- The chronic toxicity and oncongenicity of fluoroglycofen-ethyl
was investigated in mice (2 studies) and rats. In both species,
the systemic toxicity was much the same as had been seen in the
sub-acute studies, the main effects being on the liver
and kidneys. In the first mouse study, carcinogenicity,
as seen by primary liver neoplasms,
was increased at 50 and 250 pm but not at 10 ppm...
-- A satellite group which was treated for 14 weeks and then given
a 13 week recovery period showed that the compound related effects
were at least partially reversible. The NOEL for chronic oral
exposure to fluoroglycofen-ethyl was 0.95 mg/kg bw/da (20 ppm)
based on the hepatic and renal effects
at 100 ppm.
Ref:
Evaluation on: Fluoroglycofen-ethyl. May 1992. Issue No. 50. Department
for Environment, Food and Rural Affairs, Pesticides Safety Directorate,
UK.
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm
Fluoxastrobin
- Fungicide - CAS No. 193740-76-0
2.3 SHORT TERM TOXICITY. The short-term toxicity of fluoxastrobin
has been investigated in dietary studies in rats (28-day and 90-day
studies), mice (2-week and 90-day studies) and dogs (90-day and
1-year studies). A 28-day dermal toxicity study in rats has also
been conducted. The liver is the main target
organ in all tested species (rats, mice and dogs). Histological
changes were seen in the urinary system of rats (high doses) and
dogs. Male rats were more sensitive than
females to the effects of fluoxastrobin/HEC 5725 on the liver
and urinary tract. Other target organs were adrenals, erythrocytes
and thyroid. Reduced body weight gain was a key finding in dog
studies. (page 12).
Ref: Conclusion regarding the peer review
of the pesticide risk assessment of the active substance fluoxastrobin
finalised: August 10, 2005. European Food Safety Authority.
http://www.fluorideaction.org/pesticides/fluoxastrobin.eu.review.2005.pdf
-- Subchronic toxicity.
A subchronic toxicity feeding study with rats over 90 days demonstrated
a NOAEL of 7.3 and 18.3 mg/kg bwt/day for males and females, respectively,
based on reduced body weights and alterations
in several urinary tract-related clinical chemistry parameters,
at the higher dose levels. In a subchronic feeding study in mice
over 14 weeks, a NOAEL was not established based on decreased
alanine aminotransferase (ALAT) and increased absolute and relative
liver weights at the low dose level
(21.7 and 35.3 mg/kg bwt/day for males and females respectively).
A 14-week feeding study in dogs demonstrated a NOAEL of 3.0 mg/kg
bwt/day based on decreased body weights
and food consumption, and liver effects
(enzyme induction, increased liver weights, cytoplasmic change),
and thyroid effects (decreased T3)
-- Chronic toxicity. A 24-month chronic/oncogenicity feeding study
in rats demonstrated a NOAEL of 53.0 and 35.2 mg/kg bwt/day for
males and females, respectively. An oncogenicity study in the
mouse revealed a NOAEL of 18.5 and 29.5 mg/kg bwt/day for males
and females, respectively based on liver
effects. There was no indication in the rat or mouse for
an oncogenic effect of fluoxastrobin. A 1-year feeding study with
dogs demonstrated a NOAEL of 1.7 and 1.5 mg/kg bwt/day for males
and females, respectively based on decreased
body weights and slight liver effects
(increased alkaline phosphatase (Aph) and liver weights).
Ref: Federal Register: April 23, 2003. Fluoxastrobin;
Notice of Filing a Pesticide Petition to Establish a Tolerance
for a Certain Pesticide Chemical in or on Food. http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm
• Chronic
toxicity-dogs. LOAEL was
8.1 mg/kg/day for males and 7.7 mg/kg/day for females based on
body weight reductions and hepatocytomegaly
[see definition below] and cytoplasmic
changes associated with increased serum liver
alkaline phosphatase indicative of cholestasis.
• 90-Day oral toxicity-dogs.
dose-related
reductions in net body weight gain and food efficiency in addition
to toxicity findings in the liver
in both sexes (cholestasis) and in
kidneys (increased relative weights in females and degeneration
of the proximal tubular epithelium in males).
•
90-Day oral toxicity-mice. There was a dose
related increase in liver weight
in both sexes and in kidney weight in females, in addition to
other effects whose toxicological relevance was considered uncertain.
Among these effects were increased hepatocellular
hypertrophy [see
definition below] with
cytoplasmic changes in the high-dose males and minimal to moderate
kidney tubular hypertrophy in mid- and high-dose females.
•
90-Day Subchronic Oral Toxicology-Dog.
dose-related reductions in net body weight
gain and food efficiency; toxicity findings in the liver
(cholestasis) in both sexes; and
toxicity findings in the kidneys (increased relative weights in
females and degeneration of the proximal tubular epithelium in
males).
Ref: Federal Register. September 16, 2005.
Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html
Definitions:
Hepatocytomegaly is an enlargement
of the hepatocytes and is generally classified into three types:
hepatocellular hypertrophy, megalocytosis, and hepatocellular
vacuolation. Hepatocellular hypertrophy
is an enlargement of cellular diameter without accompanying
nuclear changes, leading to a net gain in the dry mass of the
liver. A common cause of hepatocellular hypertrophy is proliferation
of endoplasmic reticulum, indicating induction of cytochrome
P450, that is, exposure to cytochrome P450-inducing compounds.
Megalocytosis is characterized by enlargement of both the cell
and the nucleus, and hepatocellular vacuolation is characterized
by vacuolation, or formation of pockets of fluid within the
hepatocytes. Little is known about the
mechanism of the latter two types of hepatocytomegaly, but all
three types are associated with exposure to genotoxic contaminants.
Ref: Environmental Effects of Dredging
Technical Notes. Methods for the Assessment of the Genotoxic
Effects of Environmental Contaminants; Cellular and Organ/Organism
Effects. US Army Engineer Waterways Experiment Station. EEDP-04-25.
July 1995.
http://www.fluorideaction.org/pesticides/genotoxic.army.1995.report.pdf
Flupyrsulfuron-methyl
- Herbicide
- CAS No. 144740-54-5
-- Long term toxicity
and carcinogenicity. Target / critical effect: Indications of
liver toxicity. 18-month oral mouse : 25 ppm ( 3.51 mg/kg
bw/day). Carcinogenicity: (Liver
tumours in mice).
Ref: FINAL
European Commission Review report for the active substance flupyrsulfuron-methyl.
Finalised in the Standing Committee on Plant Health at its meeting
on 27 April 2001 in view of the inclusion of flupyrsulfuron-methyl
in Annex I of Directive 91/414/EEC.
http://europa.eu.int/comm/food/fs/ph_ps/pro/eva/newactive/list2_flupyrsulfi_en.pdf
Fluquinconazole
- Fungicide
- CAS No. 136426-54-5
-- Oral long-term toxicity
and carcinogenicity. 2-year dietary study in rats. groups of 50
male and 50 female outbred albino Sprague-Dawley CRL :COBS CD(SD)BR
rats were administered fluquinconazole (93.2% purity) in the diet
at concentrations of 0 (control), 1, 20 or 100 ppm. Additionally
20 animals/sex/dose designated for the interim-kill received the
test compound at concentrations of 0, 1, 5, 10 or 100 ppm for
12 months... Mortalities over the 24-month period were 24/50,
28/50, 28/50 and 31/50 in males and in females 33/50, 36/50 and
39/50 at dose levels of 0, 1, 20 and 100 ppm... Post-mortem examinations
showed the most probable cause of deaths in males to be pituitary
tumors followed by chronic progressive
nephropathy and urinary tract infections.
In females mammmary tumors followed by pituitary tumors were considered
the most probable cause of morbidity... At the interim-kill,
organ weights showed moderate significant treatment-related increase
in the absolute liver and kidney
weights in males and females at the 100 ppm dose level compared
with controls. The relative liver
and kidney weights were significantly increased
in males at the 100 ppm dose level and in females at ³ 10 ppm.
A significant increase in the incidence of hyaline droplet deposition
in the proximal tubular epithelium occurred in the kidneys of
males (15/20 compared with 6/20 controls) at the 100 ppm dose
level. Minimal to moderate hypertrophy of
centrilobular hepatocytes was observed in the liver
of all top dose animals and at the 10 ppm dose level (10/20
males and 3/20 females). In the thyroid, an increase int he follicular
epithelial height in both sexes was noted at the 100 ppm dose
level. At the terminal-kill, the absoloute and relative liver
and kidney weights of males and females were slightly to
moderately increased at 100 ppm dose level. Necropsy revealed
slightly increased incidence of liver masses
in top dose females (0/50, 0/50 and 6/50 at dose levels of 0.
1, 10 and 100 ppm respectively). Microscopic findings at 24 months
were slight increases in the incidence and severity of chronic
progressive nephropathy in males and females at the 100
ppm dose level. Slight to severe centrilobular
cellular hypertrophy, bile duct hyperplasia (51/100 compared
with 21/100 for controls in both sexes) and significant
increase in the incidence of malignant liver tumors (8/50
compared with 0/50 in males) in females occurred at the top dose
level...
-- For liver tumours, no clearcut
identifiable preneoplastic lesions were identified (No data requirement
for this to be demonstrated has previously been requested). Liver
tumors in both sexes at 100 ppm were associated with increased
liver weight, increased incidence and severity of hepatocyte hypertrophy
(both of which were observed in shorter term studies and responded
to changes in dose), and bile duct hyperplasia and a slight increase
in eosinophilic foci in females seen in the chronic study of the
rat at 24 months only. Clear NOELs for liver tumors and the induction
of associated liver effects were determined in rats and mice.
-- Short Term Toxicity. Oral route. Rat. (b)... Groups of 5 male
and 5 female outbred albino Sprague-Dawley Crl:COBS CD(SD)BR rats
were each administered fluquinconazole (100% purity) either in
the diet at concentrations of 0 (control), 5, 20, 100 and 400
ppm or by gavage dissolved in 1 % aqueous methlcellulose at a
dose level of 10 mg/kg bw/day for 28 days. Due to mortalities
at the 400 ppm dose level, a supplementary gorups of 5 male and
5 female animals were administered fluquinconazole at a dose level
of 200 ppm...Organ weights showed a dose-related increase in the
relative liver weight at dose levels
of ³ 20 ppm in males (15-44%) and at 100 ppm and 10 mg/kg bw/day
dose levels (25-27%). The relative kidney weight was increased
in males only (11-21%) compared with controls at dose levels of
³ 20 ppm. Gross examination at necropsy revealed accentuation
of the lobular pattern of the liver
at dose levels of ³ 5 ppm in females and at ³ 20 ppm in males.
Pale kidneys were observed in males at dose levels of ² 5 ppm...
Histopathology showed significant treatment-related
centrilobular hepatocyte hypertrophy in males and females
at dose levels of ³ 100 ppm. In the kidney, slight to moderate
hyaline droplet mephropathy was observed in males at ³ 20 ppm.
In the thyroid, the incidence and severity of thyroid effects
including colloid depletion, follicular cell hyperplasia and hypertrophy
did not show a clear treatment-relationship (statistically significant
compared with controls at 100 and 200 ppm but not at 400 ppm and
10 mg/kg bw/day dose levels). The NOEl was 5 ppm (0.45 mg/kg bw/day)
based on increased liver and kidney
weights and histopathological
changes in the liver, kidney and thyroid at the higher
dose level of 20 ppm... The liver, thyroid
and kidneys were noted to be the target organs of the test compound
and significant changes in these organs indicative of significant
hepatic enzyme induction were considered to be relevant for risk
assessment.
-- Haematology, clinical chemistry and urinalysis parameters showed
incidences of statistically significant changes which were considred
to be of limited toxicological significance because they were
eithe not dose-related or were reported to be withing the range
of historical data. There was an increase in the absolute
liver (35%) and adrenal (36.4%) weights in females at the
100 ppm dose level. The relative kidney (14%) and
liver (21%) weights in males and the relative kidney (6.9%)
and adrenal (30%) weights in females were significantly increased
at the 100 ppm dose level. In females, the relative liver
weight was increased at dose levels of 15 ppm (14%) and 100 ppm
(32%). At the end of the withdrawal period, the relative
kidney weight in males and the relative liver
weight in females were still siginficantly elevated compared with
controls. Gross examination of organs revealed accentuated
lobular pattern of the liver in males and females at the
15 ppm (on male only) and 100 ppm (3 males and 6 females) dose
levels but a significant reduction in the
incidence of lobulation of the liver (1 male only) was
observed at the end of the withdrawal period.
Ref: Evaluation on: Fluquinconazole. May
1999. No. 184. Evaluation of Fully Approved or Provisionally Approved
Products. Department for Environment, Food and Rural Affairs,
Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme
Green, York YO1 7 PX, UK. Available online:
http://www.pesticides.gov.uk/citizen/evaluations/evallist.htm
Fluridone
- Herbicide - CAS No. 59756-60-4
CHRONIC EXPOSURE (Fluridone
Technical). The following effects were reported in chronic, teratogenic,
and reproductive toxicity studies in laboratory animals where
experimental dosage levels and durations of exposure were far
in excess of those likely to occur in humans.
-- Chronic Toxicity - Decreased survival in lifetime feeding study.
Increased liver enzyme activity,
liver weight, liver
cell size, and microscopic liver
cell changes. Increased kidney weights, and microscopic kidney
cell changes. Increased serum enzyme levels...
Ref: Material Safety Data Sheet for Sonar
SRP Herbicide. SePro Corporation.
http://www.fluoridealert.org/pesticides/Fluridone.MSDS.Sepro.1994.PDF
REPRODUCTION, RAT **
018, 042; 44095, 138394; "One-Generation Reproduction Bridging
Study of Fluridone (EL-171, compound 112371) Administered in the
Diet to Fischer 344 Rats (Studies R04090 and R21890)" submitted
to support "A Multigeneration Reproduction Study with EL-171 in
Rat (Studies R-338, R-888 and R-19)" (J. A. Hoyt, Toxicology Research
Lab., Lilly Research Laboratories, Greenfield, IN, Study #s R04090
and R21890, 5/24/95); Dietary concentrations of fluridone (Lot#
117AS8, 99.5% purity): 0, 0.02, 0.065 or 0.2% administered daily
to 30 rats/sex/dose in the F7 generation for 10 weeks during premating,
mating, gestation and lactation and in the F7 generation throughout
a 10 week postweaning growth period; two deaths in the F7 generation
(one male from the 0.065% group and one female from the 0.2% group)
attributing to failure to adjust to ventilated caging were reported;
no treatment-related effects on reproduction parameters; however,
the live birth index was slightly depressed (92.74% of control,
p < 0.05) in the 0.2% group as compared to control group; at 0.2%,
8/23 litters contained one or more offspring which were considered
stillborn; in the F7 and F7 generations, males and females treated
at the 0.2% level exhibited increased absolute kidney weight;
minimal to slight bilateral chronic multifocal nephrosis detected
in F7 males of the 0.065% and 0.2% dose groups and in F7 males
and females of the 0.2% dose group; although dose related increases
in absolute liver weight occurred in F7 and F7 generations in
both sexes in the 0.065% and 0.2% dose groups, the liver weight
increases were not accompanied by histopathological changes; no
adverse effects; parental NOEL = 0.02% (based
on bilateral chronic multifocal nephrosis and increased liver
weight), developmental NOEL = 0.065% (depressed
liver birth index); originally unacceptable and not upgradeable
(Van Way and Parker, 7/18/86) and subsequently upgraded to acceptable
(Leung, 8/3/95).
Ref: Summary of Toxicology Data. Fluridone.
California EPA, Department of Pesticide Regulation, Medical Toxicology
Branch, Revised: 2/9/00.
http://www.fluoridealert.org/pesticides/Fluridone.CA.EPA.Tox.Data.pdf
Flurprimidol
- Plant Growth Regulator - CAS No. 56425-91-3
Summary Science Statement:
-- Chronic feeding/oncogenicity studies were conducted in both
the rat and mouse. Hepatocellular changes
in the males including enzyme induction, fatty change, hepatocellular
eosinophilic change and focal atypia were observed in the
rat study. A core- supplementary mouse study showed increased
absolute and relative liver weight
in females. Although both the rat and mouse study are core-supplementary
for oncogenicity due to inadequate dose selection, they both satisfy
the requirement for oncogenicity testing in one species for the
requested non-food uses. No oncogenic potential was observed at
any dose level in either of these two studies. New rat and mouse
studies (which achieve the Maximum Tolerated Dose - MTD) will
be required for any food use registrations.
-- The requirements for a 90-day feeding study have been satisfied.
A subchronic oral rat study showed an increased hepatic enzyme
induction in males (significant and dose increases in p-nitroanisol
o-demethylase activity). The subchronic oral mouse study indicated
an increased incidence of hepatocellular
hypertrophy in the males.
-- The requirements for a 2 generation reproductive study have
been satisfied. The Parental Systemic Toxicity in a 2 generation
reproduction study showed increased incidence of non-neoplastic
hepatocellular alteration including
fatty change and vacuolation (males) and increased susceptibility
to stress factors. Decreased mating, fertility, fetal survival
(stillbirths), neonatal survival and neonatal body weight in both
sexes and in both generations were observed at the Reproductive
NOEL. other parental signs of toxicity included increased susceptibility
to stress (pregnant females) resulting in death, increased relative
liver weight (males and females), depressed body weight,
weight gain and food consumption (males and females).
-- Subchronic Studies. A 90-day feeding study in rats treated
to 0, 1.68, 6.04, 20.39, 68.34 mg/kg/day (males) and 0, 1.98,
7.13, 24.37, 78.47 mg/kg/day (females) of flurprimidol. The systemic
No-Observable- Effect-Level (NOEL) was 1.68 mg/kg/day and the
Lowest-Effect- Level (LEL) was 6.04 mg/kg/day based on increased
hepatic enzyme induction in males
(significant and dose increases in p- nitroanisol O-demthylase
activity). At 24.37 mg/kg/day there was increased relative and
absolute ovarian (female) and relative
liver (male) weight. At 68.34 mg/kg/day,
there was increased absolute liver weight
(males).
-- A 90-day feeding study in the mouse, treated with 0, 15, 67.5
and 300 mg/kg/day of technical flurprimidol. The NOEL was 15 mg/kg/day
and the LEL was 67.5 mg/kg/day based on increased incidence of
hepatocellular hypertrophy in the males.
At 300 mg/kg/day, there was evidence of enzyme induction, increased
liver weight and
hepatocellular hypertrophy in females.
-- Chronic Studies - Rodent Feeding Studies.
A 2-year study in rats treated with either 0, 1.0, 3.6, 12.1 and
41.2 mg/kg/day of flurprimidol technical for males and 0, 1.2,
4.4, 14.5, and 49.3 mg/kg/day for females the NOEL was 3.6 mg/kg/day
and the LEL was 12.1 mg/kg/day based upon hepatocellular
changes in males including enzyme induction, fatty change,
hepatocellular eosinophilic change
and focal atypia. At 41.2 mg/kg/day there was also a transient
body weight and weight gain decrease (males), increased cholesterol
and triglycerides (males and females) increased hepatic enzyme
induction and liver weight, fatty
change and hepatocellular eosinophilic change
(females). No oncogenic potential was observed at any dose
level.
-- A 2-year core-supplementary study in mice treated with either
0, 1.4, 10.5 or 79.9 mg/kg/day of flurprimidol, the systemic NOEl
was 1.4 mg/kg/day. The LEL was 10.5 mg/kg/day based on increased
absolute and relative liver weight in the
males. No oncogenic potential was observed at any dose
level.
-- Reproduction Study, A 2 generation reproduction study in the
rat treated with (time weighted average) 0, 1.8, 7.3, and 74 mg/kg/day
of flurprimidol had a Parental Systemic Toxicity NOEL of 1.8 mg/kg/day
and a LEL of 7.3 mg/kg/day based on increased incidence of non-neoplastic
hepatocellular alterations including
fatty change and vacuolation (males) and increased susceptibility
to stress factors. The Reproductive NOEL was 7.3 mg/kg/ and the
LEL was 74 mg/kg/day based on decreased mating, fertility, fetal
survival (stillbirths), neonatal survival and neonatal body weight
in both sexes and in both generations. There was an increased
incidence of persistent vaginal estrous
and no corpora lutea. Additional parental signs of toxicity
at 74 mg/kg/day included increased susceptibility to stress (pregnant
females) resulting in death, increased relative liver
weight (males and females), depressed body weight, weight
gain and food consumption (males and females).
Ref: EPA Pesticide Fact Sheet for Flurprimidol.
Reason for Issuance: New Chemical Registration. Date Issued: FEB
22 1989. Fact Sheet Number: 202.
http://www.fluoridealert.org/pesticides/Flurprimidol.EPA.Facts.1989.htm
Flurtamone
- Herbicide - CAS No. 96525-23-4
Flurtamone:
Table 5.31 Incidence of centrilobular hypertrophy of the liver
Ref:
December
2000 . Evaluation
on: Flurtamone. No. 196. Department for Environment, Food
and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm
|
Dose |
FO
adults |
F1
adults |
ppm |
Male |
Female |
Male |
Female |
0 |
2/30 |
0/30 |
6/30 |
0/30 |
75 |
6/30 |
1/30 |
10/30 |
0/30 |
500 |
18/30 |
5/30 |
26/30 |
0/30 |
2000 |
28/30 |
17/30 |
29/30 |
22/30 |
5000 |
28/30 |
27/30 |
28/30 |
27/30 |
-- Short
term toxicity. Target / critical effect: Liver:
Hepatomegaly, centrilobular hypertrophy. Lowest relevant
oral NOAEL / NOEL: 5 mg/kg bw (1 year dog study). Lowest relevant
dermal NOAEL / NOEL: 1000 mg/kg bw (21 day study in rat)
-- Long term toxicity and carcinogenicity.
Target / critical effect: Liver: hypertrophy,
centrilobular hypertrophy. Kidney:
increased amyloidosis in mice. Lowest relevant
NOAEL: 2.8 mg/kg bw (2 year rat study) Carcinogenicity: No carcinogenic
potential
Ref:
July3, 2003. Flurtamone. Sanco/10162/2003-Final. Review report
for the active substance flurtamone. Finalised in the [EU] Standing
Committee on the Food Chain and Animal Health at its meeting on
4 July 2003 in view of the inclusion of flurtamone in Annex I
of Directive 91/414/EEC.
http://www.fluorideaction.org/pesticides/flurtamone.eu.july.2003.pdf
-- Two-year dietary
study in mice. In a carcinogenicity study, groups CD-1 mice (60/sex/dose)
were fed diets containing 0, 30, 300, 3500 and 7000 ppm flurtamone
(91.9% purity) for at least 78 weeks... The mean intake of flurtamone
for males and females was estimated to be 4.5, 45, 525 and 1050
mg/kg bwday at 30, 300, 3500 and 7000 ppm, respectively. After
78 weeks of treatment, the mortality rate for the 7000 ppm female
mice was significantly higher than controls and a significant
negative survival trend was found in both sexes. The test laboratory
pathologist considered systemic amyloidosis to be the major cause
of death (Table 5.34) [page 102]. Gross necropsy revealed an increased
incidence of enlarged livers and liver masses at dose levels
³3500 and of irregular shaped kidneys at 7000 ppm. Significant
increases in mean liver weight (absolute and relative)
were observed in 3500 and 7000 ppm animals (not statistically
significant in 3500 ppm males) at both the interim and terminal
sacrifices (Table 5.26). Significant decreases in mean absolute
kidney weights were observed in males at 7000 ppm at the interim
and terminal sacrifices [page 103]. Microscopic examinations revealed
an increased incidence of systemic amyloidosis (most severe in
the kidneys) in the 3500 and 7000 ppm animals and the 300 ppm
females that died or were sacrificed in extremis. The incidence
and severity of renal amyloidosis is given in Table 5.27. An increase
in the incidence of centrilobular hypertrophy
was observed in both sexes at dose levels ³ 3500 ppm. The incidence
of hepatic pigment (primarily in
the reticuloendothelial cells) was increased in males at dose
levels ³3500 ppm and in females at 7000 ppm... [page 105]. Significant
increases in mean relative liver weight were observed in
males and females in both generations at dose-levels ³2000 ppm.
Mean absolute liver weights were significantly
increased in F0 males, F0 females and F1 mates at 5000
ppm, and in F0 males and F1 females at 2000 ppm... The only microscopic
finding which could be attributed to compound administration was
centrilobular hypertrophy of the liver.
Dose-related increases in the incidence of centrilobular
hypertrophy were observed in F0 and F1 animals at dose
levels ³500 ppm (Table 5.31). This centrilobular
hypertrophy was considered to be an adaptive biological
response [page 108]
Ref: December
2000 . Evaluation on: Flurtamone.
No. 196. Department for Environment, Food and Rural Affairs, Pesticides
Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green,
York YO1 7PX, UK. Available
online at:
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm
Flusilazol
/ Flusilazole - Fungicide - CAS No. 85509-19-9
-- Oral RfD Summary:
Critical Effect Experimental Doses. Liver
cell enlargement. 1-Year Dog Feeding Study. du Pont, 1985.
NOEL: 5 ppm (0.2 mg/kg/day) LEL: 20 ppm (0.7 mg/kg/day).
-- Nustar was administered in the diet at 0, 5, 20, or 75 ppm
(0, 0.2, 0.7, or 2.5 mg/kg bw/day) to 5 dogs/sex/dose for 1 year.
Hypertrophy of the centrilobular hepatocytes
was noted in both sexes at the mid- and high-dose levels. Changes
observed only at the high dose were consistent with hepatotoxicity
and inflammation. In males these included: increased WBC counts
due to increased neutrophils, monocytes and eosinophils; increased
alkaline phosphatase and decreased cholesterol and total protein;
and hepatocytic vacuolation. Increased liver weight and centrilobular
inflammation of the liver occurred in both males and females.
Thus, the NOEL and LEL for systemic toxicity are 5 ppm (0.2 mg/kg/day)
and 20 ppm (0.7 mg/kg/day), respectively. [E.I. du Pont de Nemours
and Company. 1985. MRID No. 40042113. Available from EPA. Write
to FOI, EPA, Washington, DC 20460.]
-- 2-Year Feeding (oncogenic) - rat: No increase in neoplastic
lesions at any dose; Systemic NOEL=0.46 mg/kg/day; Systemic LEL=2.3
mg/kg/day (hepatic changes in females at
1 year, including increased relative liver weight and hepatocellular
hypertrophy); core grade minimum (E.I. du Pont de Nemours
& Co., Inc., 1986a)
-- Teratology - rat: Maternal NOEL=10
mg/kg/day; Maternal LEL=100 mg/kg/day (increased mortality after
day 23 of gestation, prolonged gestation, decreased
food consumption and weight gain, increased relative and absolute
liver weight); Developmental NOEL (pre and post natal)=2
mg/kg/day; Developmental LEL=10 mg/kg/day (increased incidence
of small renal papilla, distended ureter, dilated renal pelvis,
decreased pup survival); core grade minimum (E.I. du Pont
de Nemours & Co., Inc., 1985b)
-- 2-Year Feeding (oncogenic) - mouse: Systemic NOEL=3.4 mg/kg/day;
Systemic LEL=27 mg/kg/day (increased absolute and relative liver
weight and increased hepatocellular fatty change in male
and females); core grade supplementary (E.I. du Pont de Nemours
& Co., Inc., 1985d)
-- 90-Day Feeding - dog: NOEL=25
ppm (0.625 mg/kg/day); LEL=125 ppm (3.13 mg/kg/day) (bladder
hyperplasia, elevated alanine aminotransferase/serum glutamate
pyruvate transaminase, uric acid, decreased total protein Ca albumen,
cholesterol, increased liver weight);
core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1983b)
Ref: US EPA IRIS. NuStar CASRN: 85509-19-9.
Available October 6, 2003, at Toxnet.
-- Short-term exposure toxicity of flusilazole was investigated
in rats (gavage and dietary), mice (dietary), dogs (dietary) and
in rabbits (dermal application). The targets identified were the
blood system, liver and urinary bladder. The dog was found to
be the most sensitive species to the hepatotoxicity and bladder
toxicity of flusilazole. Degenerative liver
disorder and evidence of cellular proliferation (hyperplasia)
in the urinary bladder were seen at 125 ppm (4.3 mgikglday) in
the dog. The NOAEL was 0.9 mgkgiday. (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
Fluthiacet-methyl
- Herbicide
- CAS No. 117337-19-6
Likely to
be Carcinogenic to Humans. Pancreatic
cell tumors (exocrine
adenomas, islet cell adenomas, and combined islet cell tumors);
Sprague-Dawley rats (M). Hepatocellular
tumors (adenomas and combined adenoma/carcinoma); CD-1
mice (M & F). CD-1 mice (M & F).
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
A chronic reference
dose (RfD) (0.001 mg/kg/day) was identified for fluthiacet-methyl,
based on non-neoplastic liver findings
(increase in absolute and relative liver
weights, fatty changes, chronic inflammation, karyomegaly, single
cell necrosis and ceroid/lipofuscin pigmentation).
Ref. Federal Register. December 21, 2001.
Fluthiacet-methyl; Pesticide Tolerance. Final Rule.
http://www.epa.gov/fedrgstr/EPA-PEST/2001/December/Day-21/p31497.htm
-- Carcinogenicity rats.
NOAEL in males = 2.1 mg/kg/day LOAEL in males = 130 mg/kg/day
NOAEL in females = 2.5 mg/kg/day LOAEL in females = 154 mg/kg/dayIn
males there were decreased body weight,
liver
toxicity, pancreatic
toxicity and microcytic anemia. In
females there were liver toxicity, uterine
toxicity and slight microcytic anemia. In males only at
130 and 219 mg/kg/day there was respectively, an increase in the
trend toward pancreatic exocrine adenomas
and pancreatic islet cell adenomas.
-- Carcinogenicity mice. NOAEL in males and females = 0.1 mg/
kg/day LOAEL in males and females = 0.1 and 1.2 mg/kg/day, respectively,
based on non- neoplastic liver findings.
In males, and possibly females, at 10 mg/kg/day for males and
12 mg/kg/day for females; and at 32 gm/kg/day for males and 37
mg/ kg/day for females, there was an increase in the number of
mice with hepatocellular adenomas, carcinomos
and or adenomas/ carcinomas.
-- Chronic Dietary General population. 18-month carcinogenicity
in the mouse. NOAEL = 0.1 mg/kg/day Non-neoplastic liver findings
(increase in absolute and relative liver
weights,
fatty changes, chronic inflammation, karyomegaly, single cell
necrosis and ceroid/lipofuscin pigmentation).
-- Cancer. Fluthiacet-methyl has been classified as ``likely
to be a human carcinogen'' by EPA. The Office of Pesticide
Programs, Heath Effects Division, Cancer Assessment Review Committee
recommended a linear low-dose approach (Q1*) for human risk assessment.
The Q1* is 0.207 (mg/kg/day)-1 in human equivalents and is based
upon the combined hepatocellular tumors (adenomas and carcinomas)
in male mice. EPA conducted a cancer assessment analysis
(food) using DEEM software and Tier 2 chronic dietary exposure
assumptions. The assumptions of this Tier 2 chronic dietary analysis
are as specified above. The cancer risk estimate (food only) for
the U.S. population (total) is 3.93 x 10-8. This risk estimate
translates to a dietary exposure of 1.90 x 10-7 mg/kg/day. This
dietary exposure value was back-calculated based upon the cancer
risk estimate and the Q1*. As cancer risk = Exposure x Q1 * Thus,
Exposure = cancer risk estimate/ Q1 * or Exposure = 3.93 x 10-8/0.207.
Ref: Federal Register: December 21, 2001.
Fluthiacet-methyl; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Fluthiacet.M.FR.Dec.21.2001.htm
Flutolanil
- Fungicide - CAS No.
66332-96-5
A rabbit developmental
study with a maternal NOEL of 5 mg/kg/day and a maternal LOEL
of 25 mg/kg/day based on histopathological finds in the liver
and a developmental NOEL of 25 mg/kg/day and a developmental LOEL
of 125 mg/kg/day based on increased skeletal variations.
Ref: Federal Register. June 23, 1998. [PF-813;
FRL-5795-1]
http://www.fluoridealert.org/pesticides/Flutolanil.FR.June.23.1998.htm
Subchronic
toxicity. A 84-day rat feeding study with a No Observed Effect
Level ( NOEL) less than 100 ppm [6.0 mg/kg/day] for males and
a NOEL of 100 ppm [7.2 mg/kg/day] for females and with a Lowest
Observed Effect Level (LOEL) of 100 ppm [6.8 mg/kg/day] for males
based on suppression of thyroxine (T4) level and a LOEL of 400
ppm [28.8 mg/kg/day] for females based on hematology and clinical
chemistry findings. A 13-week mouse feeding study with a NOEL
of 100 ppm [18.2 mg/kg/day for males and 24.5 mg/kg/day for females]
and a LOEL of 400 ppm [64.2 mg/kg/day for males and 91.3 mg/kg/day
for females] based on histopathology of the liver, spleen
and thyroid. A 13-week dog dietary study with a NOEL of 50 ppm
[1.70 mg/kg/day for males and 1.67 mg/kg/day for females] and
a LOEL of 200 ppm [6.90 mg/ kg/day for males and 7.20 mg/kg/day
for females] based on evidence that the bio-transformation capacity
of the liver has been exceeded, (as indicated by increase in LDH,
liver weight, ALK and hepatomegaly), globulin and
spleen pigment in females, decreased T4 and [[Page 34180]]
ALT values in both sexes, decreased albumin in males, and decreased
serum glucose in females. A 21-day rabbit dermal study with the
dermal irritation NOEL of 1,000 mg/kg/day for males and females
and a systemic NOEL of 20 mg/kg/day for males and 150 mg/kg/day
for females and a systemic LOEL of 150 mg/kg/day
for males and 1,000 mg/kg/day for females based on clinical
chemistry data (decreased T4 and FT4 levels in both sexes) and
centrilobular
hepatocytomegaly
in females.
Ref:
Federal Register: June 23, 1998 [Page 34176-34184]. Notice of
Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/Flutolanil.FR.June.23.1998.htm
Flutriafol
- Fungicide
-
CAS No. 76674-21-0
-- 7.2 Subacute toxicity.
a) In a 90-day feeding study, rats were fed diet containing 0,
20, 200 or 2,000 ppm flutriafol. At the highest does,
reduced body weight and food intake, haemotological and
biochemical changes, increased liver weight,
centrilobular hypertrophy, proliferation of SER, elevated
hepatic aminopyrine-N-demethylase (APDM) activity were noted.
In females fed 200 ppm, only adaptive responses (liver
enlargement and elevated APDM) were seen, whereas minimal
fatty change was evident in some males. A NEL of 20 ppm (approx.
1 mg/kg bw/day) was established by the SSC (April 1983).
--b) In a 90-day study, dogs were administered oral doses (capsules)
of 0, 1, 5 or 15 mg flutriafol/kg bw/day. Reduced
body weight gain, increased liver
weight, elevated hepatic APDM and plasma ALP activity,
were observed in the 15 mg/kg bw/ dosage group. At the 5 mg/kg
dosage level, APDM activity was elevated in both sexes. Slight
increases in liver weight were seen
in females at the low and intermediate dosage levels. A NEL of
5 mg/kg bw/day was established by the SSC [Scientific Subcommittee
on Pesticides] (April 1983).
-- 7.7 Assessment a)... Although the incidence of hepatocellular
tumours was higher than the historical control data predicted,
the increased incidence of individual tumours was not significant,
only the combined incidence of hepatocellular
carcinoma and adenoma achieved statistical significance.
The available evidence suggested that the increase in hepatocellular
tumors involved an epigenetic mechanism, all in vitro and
in vivo mutagenicity assays were negative and changes in clinical
chemistry suggested altered liver metabolism
and liver injury. In addition, adaptive responses (increased
liver weight, centrilobular hypertrophy, proliferatin of SER and
enzyme induction) were evident at low doses in the subacutre rat
and dog studies. This evidence suggested
that flutriafol was possibly a weak tumour promoter at high dose
levels and this effect was possibly secondary to the liver
injury. The NOEL for the study was determined to be 20 ppm flutriafol
(about 1 mg/kg bw/day). (b) In the multigeneration study, dietary
administration of 1,000 ppm flutriafol during the premating period
induced a reduction in bodyweight gain and
food consumption in F0 parents, and reduced bodyweight gain in
F1 females. Increased liver weight, centrilobular
hypertrophy (males only) and fatty change were found in
F0 and F1 parents fed 1,000 ppm flutriafol. Fatty
change in the liver was also evident in F1 males fed 240
ppm flutriafol.... In the high dosage group, the proportion of
pups born alive in the second generation litters was significantly
reduced. Mean litter size was significantly
reduced in F1B and F2A litters. In the high dosage groups,
fatty change of the liver was evident
in F1B, F2A and F2B pups.. The NEL for reproductive performance
in rats was 240 ppm flutriafol (equivalent to approx 12 mg/kg
bw/day).
Evaluation
on: Flutriafol. October 1996. Issue No. 158, UK Department for
Environment, Food and Rural Affairs, Pesticides Safety Directorate,
Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX.
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm
Fluxofenim
- Herbicide safener - CAS No. 88485-37-4
Chronic/Subchronic
Toxicity Studies. Fluxofenim: Liver
and kidney effects; Thyroid effects
at high doses (dogs).
Target Organs Active Ingredients Fluxofenim: Liver,
kidney, and thyroid.
Ref: Ciba-Geigy Material Safety Data Sheet
for Concep-III.
http://www.fluoridealert.org/pesticides/Fluxofenim.MSDS.Ciba.1996.htm
Fomesafen
- Herbicide - CAS No. 72178-02-0
-- 4. Carcinogenicity.
Fomesafen is classified as a Group C carcinogen
with a Q* of 1.9 x 10-1 (mg/kg/ day)-1.
This classification was based on: (i) Increases in both adenomas
and carcinomas at several dose levels in both sexes of mice; (ii)
some evidence of reduced latency for the time of tumor appearance;
(iii) limited evidence of mutagenic effects; and, (iv) the structural
similarity of fomesafen to other biphenyl ether herbicides which
have been shown to be carcinogenic.
-- When considering structural similarities with other chemicals,
fomesafen falls into the class of ``biphenyl ether'' chemical
compounds; this means that this group of chemicals have structural
similarities, including a biphenyl ether group, in common. This
is used as a piece of supporting evidence for the classification
of fomesafen as a Group C carcinogen, since other chemicals of
this group (with similar structure) have been found to be carcinogens.
However, other indications of the carcinogenicity of fomesafen
(i.e., increases of adenomas and carcinomas in a mouse study,
limited evidence of mutagenic effects) were also used in deciding
this cancer classification. At this time, the Agency does
not have sufficient understanding of the structural relationship
to the mechanism of toxicity of these chemicals to conclude that
they may be combined for the purposes of conducting a risk assessment.
Although fomesafen contains some chemical structures in common
with other chemicals that have been found to be carcinogens, EPA
does not yet fully understand the implications of such a relationship,
nor how, or if, these structures relate to the toxicological activity
of the chemical. For the purposes of this tolerance action, therefore,
EPA has not assumed that fomesafen has a common mechanism of toxicity
with other substances.
Ref: Federal Register. November 19,
1997. Fomesafen; Pesticide Tolerances for Emergency Exemptions.
Final Rule.
http://www.fluoridealert.org/pesticides/Fomesafen.FR.Nov.19.1997.htm
-- Decreased plasma
cholesterol and triglycerides and increased
liver weights (reversible at 7 days post-treatment) were
observed at 50 mg/kg/day (only dose tested) when administered
in the diet of rats for 4 weeks. In a 90-day rat study, dietary
administration of 5 mg/kg/day (LOEL) produced alterations in lipid
metabolism and increases in liver weight. The NOEL was 0.25 mg/kg/day.
In a 26-week dog study, dietary administration of 25 mg/kg/day
(LOEL) produced alterations in lipid metabolism and liver
changes (changes not defined). The NOEL was 1 mg/ kg/day.
Liver toxicity (increased liver masses,
discolored hepatocytes, and pigmented Kupffer cells) was
observed in a 2-year rat feeding study at 50 mg/kg/day (LOEL).
The NOEL was 5 mg/kg/day. Metabolism studies have shown that fomesafen
accumulates in the liver. EPA believes that there is sufficient
evidence for listing fomesafen on EPCRA section 313 pursuant to
EPCRA section 313(d)(2)(B) based on the available 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.
-- Classification -- C; possible human carcinogen.
-- Animal Carcinogenicity Data. Limited. Sixty-four Charles River
CD-1 mice/sex/dose group were dosed for 2 years with fomesafen
at 0, 1, 5, 100 and 1000 ppm by dietary incorporation. A double-size
control group was used. At 12 months, 24 mice/sex from the controls
and 12 mice/sex from the treated groups were killed. In
male mice at termination, the incidence of liver adenomas was
significantly increased at 1, 100 and 1000 ppm when compared with
controls. The incidences of liver carcinomas and a combination
of liver adenomas and carcinomas were significantly increased
at 1000 ppm. In the females, the incidence of adenomas was increased
at 100 and 1000 ppm and carcinomas were increased at 1000 ppm
when compared with controls. The incidence
of adenomas and carcinomas combined was significantly increased
at 100 and 1000 ppm. Both sexes, therefore, showed a progression
from benign to malignant tumors with increased dose. Some liver
tumors (adenomas and carcinomas) were apparent at the 52-week
interval kill. There was increased mortality
in the males at 100 and 1000 ppm and in the females at 1000 ppm,
due to liver toxicity forcing termination of the study. The
1000 ppm animals were killed at 79 weeks (males) or 89 weeks (females).
The MTD appeared to be exceeded at 100 ppm in the males and 1000
ppm in the females. The tumor increases occurred at dose levels
of fomesafen that were both below and above the MTD (Huntingdon,
1985).
Ref: US EPA. Fomesafen
(CASRN 72178-02-0). IRIS (Integrated Risk Information System).
-- PubMed Abstract:
Administration of herbicide fomesafen and of fomesafen combined
with one dose of iron to 44 mice during 3 to 14 months caused
hyperplastic and preneoplastic changes in the liver
tissue which had been described in experimental carcinogenesis*
small groups of altered hepatocytes storing glycogen or lipids
and foci of small basophilic liver
cells occurred as early as after 3 months. Altered hepatocytes
were found more frequently in mice getting fomesafen and iron.
Later nodular hyperplasia of liver
cells developed with nodes 3-20 mm in diameter which mostly consisted
of altered hepatocytes with plenty of glycogen. After 12 and 14
month-lasting administration of fomesafen and fomesafen with iron,
the hepatocellular carcinoma was proved in 5 mice. In 4 mice,
the preneoplastic changes in liver
tissue were accompanied by micronodular hyperplasia of liver
cells which did not participate on the development of big nodes
and hepatocellular carcinoma.
Ref: Cesk Patol 1998. Apr;34(2):67-71. [Morphologic
findings in liver tissue in mice after long-term administration
of the herbicide fomesafan] by Chlumska A, Fakan F, Krijt J.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=9624829&form=6&db=m&Dopt=b
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