Return to Diflubenzuron
Index Page
ACTIVITY: Insecticide,
Acaricide, Chemosterilant (Benzoylurea)
Structure::
Adverse Effects:
Cancer:
Co-mutagenic
potential
Endocrine: Suspected Disruptor
Endocrine: Testicular
Environmental
Effects
attributed to diflubenzuron metabolites, particularly PCA (4-Chloroaniline)
:
Bone
Blood
Cancer:
Spleen, Liver due to metabolite 4-chloroaniline
Endocrine: Adrenal
Liver
Spleen
Rationale
for US EPA to add Diflubenzuron to the Toxic Release Inventory
In
a 2-year study in which beagle dogs received diflubenzuron
daily in gelatin capsules, the LOAEL for increases in sulfhemoglobin
and methemoglobin was 10 mg/kg/day and the NOAEL was 2 mg/kg/day.
EPA has derived an oral RfD of 0.02 mg/kg/day for this chemical
from this study. Similar effects were noted in two separate
2-year rat feeding studies (the LOAEL was 7.8 to 8 mg/kg/day;
the NOAEL was 2 mg/kg/day), and in a lifetime oral study
in mice (the LOAEL was 12 mg/kg/day; the NOAEL was 2.4 mg/kg/day).
EPA believes that there is sufficient evidence for listing
diflubenzuron on EPCRA section 313 pursuant to EPCRA section
313(d)(2)(B) based on the available hematological toxicity
data. Measured aquatic acute toxicity data for diflubenzuron
include a 48-hour LC 50 of 4.55 ppb for daphnids. EPA
believes that there is sufficient evidence for listing diflubenzuron
on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(C)
based on the environmental toxicity data for this chemical.
Ref:
USEPA/OPPT. Support Document for the Health and Ecological
Toxicity Review of TRI Expansion Chemicals. U. S. Environmental
Protection Agency, Washington, DC (1993). As cited by US
EPA in: Federal
Register: January 12, 1994. Part IV. 40 CFR Part 372.
Addition of Certain Chemicals; Toxic Chemical Release Reporting;
Community Right-to-Know; Proposed Rule.
|
As
of February 14, 2005, this herbicide is permitted in
or on over 400 food commodities
in the United States - see list at http://www.fluorideaction.org/pesticides/diflubenzuron.epa.tolerance.htm
Diflubenzuron
was first registered in the United States in 1979 for use
as an insecticide. The Agency issued a Registration Standard
for diflubenzuron in September, 1985, (NTIS #PB86-176500).
In July 1995 the patent and all other interests in diflubenzuron
were acquired by Uniroyal Chemical
Company.
One
of the metabolites of diflubenzuron, PCA (4-chloroaniline),
is associated with the majority of the severe health effects
found in animal studies, particularly cancer of the spleen
and liver and osteosarcomas in male rats.
One
of the effects not attributed to the diflubenzuron metabolite
PCA is an effect on the testes - see 2003 report by WHO
titled 4-Chloroaniline at
http://www.who.int/pcs/cicad/full_text/cicad48.pdf
Note:
PCA [4-chloroaniline] is used
as an intermediate in the production of several urea herbicides
and insecticides (e.g., monuron, diflubenzuron, monolinuron),
azo dyes and pigments (e.g., Acid Red 119:1, Pigment Red
184, Pigment Orange 44), and pharmaceutical and cosmetic
products (e.g., chlorohexidine, triclocarban [3,4,4'-trichloro-
carbanilid], 4-chlorophenol) (Srour, 1989; BUA, 1995; Herbst
& Hunger, 1995; Hunger et al., 2000; IFOP, 2001). In 1988,
about 65% of the global annual produc- tion was processed
to pesticides (Srour, 1989). In Germany, in 1990, about
7.5% was used as dye precur- sors, 20% as intermediates
in the cosmetics industry, and 60% as pesticide intermediates.
The use for the remaining 12.5% of the production quantity
was not specified (BUA, 1995). More recent data on the use
pattern of PCA are not available.
Ref: Concise International
Chemical Assessment Document 48. 4-CHLOROANILINE. World
Health Organization Geneva, 2003.
http://www.who.int/pcs/cicad/full_text/cicad48.pdf
|
Blood
•••
Effects attributed to diflubenzuron metabolite: PCA
•••
(click on for all fluorinated pesticides)
-- 90-Day oral toxicity
rodents. NOAEL < 8 mg/kg/day LOAEL = 8 mg/kg/day based on increased
methemoglobinemia, and signs of hemolytic
anemia, erythrocyte destruction in the spleen and liver
and regeneration of erythrocytes in the bone marrow.
-- 90-Day oral toxicity in nonrodents. NOAEL = 2 mg/kg/day LOAEL
= 6.24 mg/kg/day based on methemoglobinemia.
-- 21/28-Day dermal toxicity NOAEL = 500 mg/kg/day LOAEL = 1,000
mg/kg/day based on methemoglobinemia
(limit dose).
-- Reproduction and fertility effects. Parental/Systemic NOAEL
< 36 mg/kg/day (LDT) LOAEL = 36 mg/kg/day based on dose-related
decreased hematocrit, hemoglobin concentration,
red blood cell count and an increase in percent methemoglobin,
changes in cell morphology and brown pigment in Kupffer
cells. Reproductive NOAEL> 4254 mg/kg/day (HDT) LOAEL was not
established. Offspring NOAEL = 427 mg/kg/day LOAEL = 4254 mg/kg/day
based on Significant decrease in F-1 pup
weights on day 4, 8 and 21 of lactation.
-- Chronic toxicity dogs NOAEL = 2 mg/kg/day LOAEL = 10 mg/kg/day
based on methemoglobinemia and sulfhemoglobinemia.
-- Carcinogenicity mice NOAEL = 2.4 mg/kg/day LOAEL = 12 mg/kg/day
based on increased methemoglobin and sulfhemoglobin
levels. No evidence of carcinogenicity
-- Special studies. In acute oral toxicity study in rats CPA at
62 mg/kg caused significant increase in
methemoglobinemia while CPU at 200 mg/kg did not cause
methemoglobinemia.
Ref: Federal Register: September 19, 2002.
Diflubenzuron; Pesticide Tolerances. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/Diflubenzuron.FR.Sept19.02.htm
In a 2-year study in
which beagle dogs received diflubenzuron daily in gelatin capsules,
the LOAEL for increases in sulfhemoglobin
and methemoglobin was 10 mg/kg/day and the NOAEL was 2
mg/kg/day. EPA has derived an oral RfD of 0.02 mg/kg/day for this
chemical from this study. Similar effects were noted in two separate
2-year rat feeding studies (the LOAEL was 7.8 to 8 mg/kg/day;
the NOAEL was 2 mg/kg/day), and in a lifetime oral study in mice
(the LOAEL was 12 mg/kg/day; the NOAEL was 2.4 mg/kg/day). EPA
believes that there is sufficient evidence for listing diflubenzuron
on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based
on the available hematological toxicity
data. Measured aquatic acute toxicity data for diflubenzuron include
a 48-hour LC 50 of 4.55 ppb for daphnids. EPA believes that
there is sufficient evidence for listing diflubenzuron on EPCRA
section 313 pursuant to EPCRA section 313(d)(2)(C) based on the
environmental toxicity data for this chemical.
Ref:
USEPA/OPPT. Support Document for the Health and Ecological Toxicity
Review of TRI Expansion Chemicals. U. S. Environmental Protection
Agency, Washington, DC (1993). As cited by US EPA in: Federal
Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition
of Certain Chemicals; Toxic Chemical Release Reporting; Community
Right-to-Know; Proposed Rule.
Chronic dietary (all
populations) - Chronic toxicity study (dog): LOAEL = 10 mg/kg/day
based on methemoglobinemia and
sulfhemoglobinemia
Ref: Federal Register. February 15,
2002. Diflubenzuron; Pesticide Tolerance in or on Pear at 0.50
ppm. Final Rule.
http://www.fluoridealert.org/pesticides/Diflubenzron.FR.Feb.15.2002.htm
-- To assess subacute
dermal toxicity, diflubenzuron was applied to the backs of male
and female CD rats for 3 weeks at dose levels of 20, 500, and
1,000 mg/kg/day. Hematology evaluation showed reductions in
red blood cell (RBC), hemoglobin (Hgb) and hematocrit values
at 500 and 1,000 mg/kg/day. An increased incidence of
polychromasia, hypochromasia, and anisocytosis was
seen at 500 and 1,000 mg/kg/day. An increase in methemoglobin
and sulfhemoglobin values was seen at 1,000 mg/kg/day.
The NOAEL for systemic toxicity was 20 mg/kg/day. Also, a dermal
absorption factor of 0.5%, for systemic absorption, was derived
from a study where rats were dosed with either 0.005 or 0.05 mg/cm\2\
of (\14\C) diflubenzuron technical. This value can be used for
converting dermal exposure to oral equivalents.
-- Chronic toxicity. Diflubenzuron was given by capsule to male
and female Beagle dogs for 1 year at dose levels of 0, 2, 10,
50, and 250 mg/kg/day. Body weight (bwt) gain was slightly reduced
in females at 250 mg/kg/day. Absolute liver and spleen weights
were increased in males given 50 and 250 mg/kg/day. A
reduction in hemoglobin and mean corpuscular hemoglobin concentration,
with an elevation in reticulocyte count, was seen at 50 and 250
mg/kg/day. Methemoglobin and sulfhemoglobin values were increased
at doses of 10 mg/kg/day and greater. Histopathological
findings were limited to pigmented macrophages and Kupffer cells
in the liver at doses of 50 and 250
mg/ kg/day. The NOAEL for chronic toxicity in dogs was 2 mg/kg/day.
-- Diflubenzuron was fed to male and female Sprague Dawley rats
for 2 years at dose levels of 0, 156, 625, 2,500, and 10,000 ppm.
Methemoglobin values were elevated in female
rats at all dose levels and in male rats at the two highest dose
levels. Sulfhemoglobin was elevated in females, only, at dose
levels of 2,500 and 10,000 ppm. Mean corpuscular volume (MCV)
and reticulocyte counts were increased in high dose females...
In another study diflubenzuron was administered to male and female
CD rats for 2 years at dose levels of 0, 10, 20, 40, and 160 ppm.
Elevated methemoglobin levels were seen
in high dose males and females. No additional effects,
including carcinogenic findings, were observed. The NOAEL for
chronic toxicity in rats was 40 ppm (2 mg/kg/ day).
-- A 91-week carcinogenicity study in CFLP mice was conducted
at doses of 0, 16, 80, 400, 2,000, and 10,000 ppm. There was no
increase in tumor incidence as a result of diflubenzuron administration.
Target organ effects included: Increased
methemoglobin and sulfhemoglobin values, Heinz
bodies, increased liver and spleen weight, hepatocyte
enlargement, and vacuolation, extramedullary hemopoiesis in the
liver and spleen, siderocytosis in the spleen and pigmented
Kupffer cells. A NOAEL for these effects was 16 ppm (2 mg/kg/day).
-- Diflubenzuron was fed to male and female Sprague Dawley rats
for 2 years at dose levels of 0, 156, 625, 2,500, and 10,000 ppm.
Methemoglobin values were elevated in female
rats at all dose levels and in male rats at the two highest dose
levels. Blood sulfhemoglobin was elevated in females, only, at
dose levels of 2,500, and 10,000 ppm. MCV and reticulocyte counts
were increased in high dose females. Spleen and liver weights
were elevated at the two highest doses. Histopathological examination
demonstrated an increase in hemosiderosis
of the liver and spleen, bone marrow and erythroid hyperplasia,
and areas of cellular alteration in the liver. There was no increase
in tumor formation. In another study, diflubenzuron was administered
to male and female CD rats for 2 years at dose levels of 0, 10,
20, 40, and 160 ppm. Elevated methemoglobin
levels were seen in high dose males and females. No additional
effects, including carcinogenic findings, were observed.
-- In single dose treatments, after 7 days, 20% and 3% of the
applied dose 5 and 100 mg/kg, respectively, were excreted in urine,
while 79% and 98% of the applied dose 5 and 100 mg/ kg, respectively,
were eliminated in the feces. Very little bioaccumulation in the
tissues was observed. In the feces, only unchanged parent compound
was detected. Several metabolites were observed
in the urine which are, among others, 2,6-diflurobenzoic acid
(DFBA), 2,6-difluorophippuric acid, 2,6-difluorobenzamide (DFBAM),
and 2-hydroxydiflubenzuron (2-HDFB).
-- PCA [p-chloroaniline; a metabolite of Diflubenzuron] was administered
5 days/week by oral gavage, as a hydrochloride salt in water,
to male and female F344/N rats at doses of 0, 2, 6, or 18 mg/kg/day.
Mean body weights of dosed rats were generally within 5% of those
of controls throughout the study. High dose animals generally
showed mild hemolytic anemia and dose-related
methemoglobinemia. Non- neoplastic lesions seen were bone
marrow hyperplasia, hepatic hemosiderosis, and splenic fibrosis,
suggesting treatment-related effects on the hematopoietic system.
Adrenal medullary hyperplasia was observed in high dose female
rats...
-- In addition to PCA, 4-chlorophenylurea (CPU) is also a potential
minor metabolite of diflubenzuron. By association with PCA, EPA
has concluded that CPU has carcinogenic potential and the same
carcinogenic potency (q\1\*) as PCA. In the NTP report of the
PCA bioassay, it is proposed that PCA undergoes N-hydroxylation
to form the corresponding N-hydroxylamine [[Page 64827]] metabolites;
N-hydroxylation of aromatic amines is a well know mechanism of
aromatic amine carcinogenicity. This metabolite, or proximate
carcinogen, is then conjugated to form the ultimate carcinogen
capable of ionizing and reacting with DNA to form adducts which
result in splenic tumor formation. An alternate mechanism involving
toxicity resulting in erythrocyte damage,
splenic scavenging, hemorrhage, hyperplasia and fibrosis and ultimately
splenic tumor formation is also proposed, but
both mechanisms are based on the formation of N-hydroxy PCA.
Ref: Federal Register: December 14, 2001.
(Volume 66, Number 241)] [Notices] [Page 64823-64828]. Notice
of Filing Pesticide Petitions to Establish a Tolerance for a Certain
Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Diflubenzuron.FR.Dec14.2001.htm
Abstract: Five benzoylphenylurea
insecticides were administered to male Wistar rats for 28 days
at oral doses of 100 mg kg-1 each. Elevation
of methaemoglobin was found only in the diflubenzuron- and triflumuron
treated groups. The number of reticulocytes was increased
in all of the treated groups.
Ref: J Appl Toxicol. 1993 Jan-Feb;13(1):67-8.
Comparative
study on the effects of five benzoylphenylurea insecticides on
haematological parameters in rats. Tasheva M, Hristeva V.
"Diflubenzuron
causes methaemoglobinaemia and sulfhaemo-
globinaemia. Dose-related methaemoglobinaemia has been
demonstrated after oral, dermal or inhalatory exposure to diflubenzuron
in various species. This effect is the most sensitive toxicological
end-point in experimental animals. The NOEL based on methaemoglobin
formation is 2 mg/kg body weight per day in rats and dogs and
2.4 mg/kg body weight per day in mice. In long-term toxicity studies
with mice and rats, treatment-related changes were principally
associated with oxidation of haemoglobin or with hepatocyte changes...
It is attributable to the metabolite, 4-chloroaniline,
which is known to induce methaemoglobin formation in several animal
species and in humans."
Ref: ENVIRONMENTAL HEALTH CRITERIA 184:
International Programme on Chemical Safety http://www.inchem.org/documents/ehc/ehc/ehc184.htm
Bone
•••
Effects attributed to diflubenzuron metabolite: PCA
•••
(click on for all fluorinated pesticides)
At all dose levels,
histopathological examinations indicated dose related increases
of hemosiderosis and congestion of the spleen, hemosiderosis and
chronic hepatitis of the liver, and mild erythroid hyperplasia
of the bone marrow...
Male rats at 6 and 18 mg/kg/day and female rats at 18 mg/kg/day
had blue extremities indicative of cyanosis. Histopathological
examinations indicated non-neoplastic treatment-related effects
in the spleen, liver, bone
marrow
and adrenal gland...
Ref: US EPA RED. August 1997.
http://www.fluoridealert.org/pesticides/Diflubenzuron.RED.pdf
Groups of 49 or 50 rats and mice of each sex (7 to 8 weeks old)
were administered PCA at dose levels of 2, 6 or 18 mg/kg (rats)
or 3, 10, or 30 mg/kg (mice) on 5 days per week for 103 weeks.
Vehicle control groups of 50 males and 50 females received deionized
water by gavage. ... The combined incidences of uncommon splenic
sarcomas (fibrosarcomas, osteosarcomas or
haemangiosarcomas) were increased in male rats but not in females
(males: 0/49, 1/50, 3/50, 38/50; females: 0/50, 0/50, 1/50, 1/50)...
Bone-marrow hyperplasia was also observed.
Ref: Diflubenzuron. Environmental Health
Criteria Report 184. WHO International Programme on Chemical Safety.
1996.
http://www.fluorideaction.org/pesticides/diflubenzuron.who.review.htm
One
of the metabolites of Diflubenzuron is 4-chloroaniline (PCA).
-- ... PCA is carcinogenic in male rats,
with the induction of unusual and rare tumours of the spleen (fibrosarcomas
and osteosarcomas), which is typical
for aniline (EU, 2002) and related substances. In the NTP (1989)
study, PCA was found to be carcinogenic in male rats, based on
the increased incidence of splenic sarcoma, osteosarcoma,
and haemangiosarcoma in high-dose (18 mg/kg body weight) rats.
The dose-response was non-linear, the incidence of sarcomas at
2 and 6 mg/kg body weight being marginal.
-- Uses
of PCA: PCA
is used as an intermediate in the production of several urea herbicides
and insecticides (e.g., monuron, diflubenzuron, monolinuron),
azo dyes and pigments (e.g., Acid Red 119:1, Pigment Red 184,
Pigment Orange 44), and pharmaceutical and cosmetic products (e.g.,
chlorohexidine, triclocarban [3,4,4'-trichloro- carbanilid], 4-chlorophenol)
(Srour, 1989; BUA, 1995; Herbst & Hunger, 1995; Hunger et al.,
2000; IFOP, 2001). In 1988, about 65% of the global annual produc-
tion was processed to pesticides (Srour, 1989). In Germany, in
1990, about 7.5% was used as dye precur- sors, 20% as intermediates
in the cosmetics industry, and 60% as pesticide intermediates.
The use for the remain- ing 12.5% of the production quantity was
not specified (BUA, 1995). More recent data on the use pattern
of PCA are not available.
Ref: Concise International Chemical Assessment
Document 48. 4-CHLOROANILINE. World Health Organization Geneva,
2003.
http://www.who.int/pcs/cicad/full_text/cicad48.pdf
Cancer:
Co-mutagenic potential
(click
on for all fluorinated pesticides)
EXCERPTS: ... Diflubenzuron was found to induce murine CYP3A1/2
(activating, for example, aflatoxins and nitropyrenes) in lung
(both sexes) and kidney (for females only), as exemplified by
the increase 6B and 2B hydroxylations of testosterone. Inductions
were also recorded for CYP2B1/2 (activating olefins and halogenated
hydrocarbons) in lung (both sexes) and kidney (for female mice
only), as shown by the enhancement of testosterone 6a, 16a, 16B
and 2B hydroxylases. In the lung, induction in the 7a position
(linked to CYP2A, responsible for metabolizing nitrosamines, and
specific compounds such as esamethyl phospamide and butadiene)
was registered for both sexes. A generalized induction was seen
in the lung. Simultaneously, a marked reduction of testosterone
metabolism in the liver (both sexes), kidney (6? and 16? hydroxylations,
females) and lung (6a, 16a, 16B and 2B positions, males) was observed.
... In summary, our results demonstrated the induction and suppression
properties of diflubenzuron and acephate. With the increased bioactivating
potential toward ubiquitous environmental pollutants the induction
generates large amounts of oxygen free radicals acting at all
levels of multistep carcinogenesis (Paolini et al., 1999). Our
observations are in line with previous data on diflubenzuron or
acephate’s abilities to induce positive foci in Balb/c3T3
cells in an in vitro cell transformation model (medium-term test,
6–8 weeks) (Perocco et al., 1993 and Perocco et al.,
1996) as well as with the co-carcinogenicity potential of acephate
found in the rat (Paolini et al., 1997).
Notwithstanding diflubenzuron is negative in in vivo long-term
carcinogenicity studies, its co-mutagenic potential may be of
concern in the presence of ubiquitous premutagens (e.g. diet,
environmental pollutants). Furthermore, the ability of these insecticides
to act as homeostatic disruptors should not be underestimated.
Ref: CYP superfamily perturbation by diflubenzuron
or acephate in different tissues of CD1 mice. By A Sapone et al.
Food Chem Toxicol. 2005 Jan;43(1):173-83.
Cancer:
Spleen, Liver, Adrenal
•••
Effects attributed to diflubenzuron metabolite: PCA •••
(click on for all fluorinated
pesticides)
Chloroaniline,
p (or 4-chloraniline) is a metabolite of Diflubenzuron.
In 2006, USEPA classified chloroaniline, p as
a "Group B2 -- Probable Human Carcinogen." "Spleen
(fibrosarcomas,
hemangiosarcomas & osteosarcomas) (M); Adrenal
(pheochromocytomas (M & F); F344/N rats. Hepatocellular
adenomas/carcinomas (M); Hemangiosarcomas
in spleen and/or liver (M) in B6C3F1 mice."
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
--
The minor metabolite,
4-chloroaniline, was shown to be
positive in several in vitro mutagenicity assays using various
endpoints. It is carcinogenic in rats and
mice. The neoplastic lesions related to administration
of 4-chloroaniline were benign and malignant
mesenchymal tumours in the spleens of male rats and haemangiomas
and haemangiosarcomas, primarily in the spleen and liver of
male mice.
-- Effects on humans. The diflubenzuron metabolite, 4-chloroaniline,
has been reported to cause methaemoglobinaemia
in exposed workers and in neonates inadvertently exposed.
Some individuals who are deficient in NADH-methaemoglobin reductase
may be particularly sensitive to 4-chloroaniline and hence to
diflubenzuron exposure.
-- Evaluation of human health risks. The primary manifestation
of diflubenzuron toxicity is methaemoglobin induction. This toxicity
occurs in a range of test animal species. It is attributable to
the metabolite, 4-chloroaniline,
which is known to induce methaemoglobin formation in several animal
species and in humans. Diflubenzuron does not cause other toxicities
on chronic dietary administration. It is not mutagenic or carcinogenic
in mice or rats. However, its metabolite,
4-chloroaniline, is mutagenic in vitro and is carcinogenic in
mice and male rats. Although 4-chloroaniline is a minor
urinary metabolite of diflubenzuron in rats, the extent to which
it is formed in vivo in various animal species remains unknown.
Similarly, the comparative degree of absorption of its parent
compound in various species is unknown. The sensitivity of human
haemoglobin to methaemoglobin formation by 4-chloroaniline in
vivo is not known. However, since induction of methaemoglobinaemia
is consistently the most sensitive measure of diflubenzuron toxicity
in the various animal species tested, it may be used as the basis
to estimate the levels causing no toxicological effect. Evaluation
of effects on the environment.
Ref: Diflubenzuron.
TA:Environmental Health Criteria PG:153 p; 1996
IP: VI:184.
Endocrine:
Adrenal •••
Effects attributed to diflubenzuron metabolite: PCA
•••
(click on for all fluorinated pesticides)
Chloroaniline,
p (or 4-chloraniline) is a metabolite of Diflubenzuron.
In 2006, USEPA classified chloroaniline, p as
a "Group B2 -- Probable Human Carcinogen." "Spleen
(fibrosarcomas,
hemangiosarcomas & osteosarcomas) (M); Adrenal
(pheochromocytomas (M & F); F344/N rats. Hepatocellular
adenomas/carcinomas (M); Hemangiosarcomas
in spleen and/or liver (M) in B6C3F1 mice."
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
--
PCA [p-chloroaniline;
a metabolite of Diflubenzuron] was administered 5 days/week
by oral gavage, as a hydrochloride salt in water, to male and
female F344/N rats at doses of 0, 2, 6, or 18 mg/kg/day. Mean
body weights of dosed rats were generally within 5% of those of
controls throughout the study. High dose animals generally showed
mild hemolytic anemia and dose-related methemoglobinemia. Non-
neoplastic lesions seen were bone marrow hyperplasia, hepatic
hemosiderosis, and splenic fibrosis, suggesting treatment-related
effects on the hematopoietic system. Adrenal
medullary hyperplasia was
observed in high dose female rats.
The incidence of uncommon sarcomas of the spleen was significantly
increased in high dose male rats. A marginal
increase in pheochromocytomas of the adrenal gland was
seen in high dose male and female rats. It was concluded that,
under the conditions of this 2-year gavage study, there was clear
evidence of carcinogenic activity of PCA hydrochloride for male
F344/N rats and equivocal evidence of carcinogenic activity of
PCA hydrochloride for female F344/N rats.
Ref: Federal Register: December 14, 2001.
(Volume 66, Number 241)] [Notices] [Page 64823-64828]. Notice
of Filing Pesticide Petitions to Establish a Tolerance for a Certain
Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Diflubenzuron.FR.Dec14.2001.htm
Endocrine:
Suspected Disruptor (click
on for all fluorinated pesticides)
Suspected
Endocrine Disruptor
Ref: June 14, 2001 - Implementation of the
Community Strategy for Endocrine Disruptors - a range of substances
suspected of interfering with the hormone systems of humans and
wildlife. Communication from the Commission to the Council and
the European Parliament. Commission of the European Communities,
Brussels COM (2001) 262 final.
http://www.fluoridealert.org/pesticides/Endocrine.Disruptors.EC2001.pdf
(More information available at:
http://europa.eu.int/eur-lex/en/com/cnc/2001/com2001_0262en01.pdf)
Endocrine:
Testicular (click
on for all fluorinated pesticides)
-- In another 21-day
dermal study, technical diflubenzuron (96.7% a.i.) was administered
in 0.25% gum tragacanth in distilled deionized water to the dorsal
skin on the backs of 10 rats/sex/dose at 0, 20, 500, or 1000 mg/kg
bwt/day for 6 hour periods each day. At 1000 mg/kg/day, dermal
irritation was seen in the males as a trace of acanthosis and
hyperkeratosis. Females also exhibited the same type and degree
of dermal irritation at 1000 mg/kg/day. Kidney and liver changes
of trace levels of mineralization and chronic inflammation of
the liver were similar to that seen in the controls of both male
and female test animals. Only increased
absolute organ weight changes of testes were reported in the mid-
and high-dose males... (MRID 43954101)
-- In a 14-week feeding study technical grade diflubenzuron was
administered in the diet to mice at dose levels of 0 (control),
80, 400, 2000, 10000 or 50000 ppm (equivalent to 0, 12, 60, 300,
1500 or 7500 mg/kg/day). Methemoglobinemia and sulfhemoglobinemia
(accompanied by Heinz bodies) were observed in male and female
mice at all dose levels. The study noted decreased erythrocyte
counts, decreased packed cell volume, and increased reticulocytes
at dose levels of 60 mg/kg/day and higher. The terminal sacrifice
showed the following effects: increased spleen weights at 60/mg/kg/day
dose levels and above; increased liver weights and decreased
seminal vesicle weights at dose levels of 300 mg/kg/day and above;
and decreased kidney weights at dose levels of 1500 mg/kg/day
and above... (MRIDs 00074534 and 00114330)
Ref: August 1997. US EPA Reregistration
Eligibility Decision (RED) for Diflubenzuron. EPA 738-R-97-008.
http://www.fluorideaction.org/pesticides/diflubenzuron.red.pdf
Liver
•••
Effects attributed to diflubenzuron metabolite: PCA
•••
(click on for all fluorinated pesticides)
Chloroaniline,
p (or 4-chloraniline) is a metabolite of Diflubenzuron.
In 2006, USEPA classified chloroaniline, p as
a "Group B2 -- Probable Human Carcinogen." "Spleen
(fibrosarcomas,
hemangiosarcomas & osteosarcomas) (M); Adrenal
(pheochromocytomas (M & F); F344/N rats. Hepatocellular
adenomas/carcinomas (M); Hemangiosarcomas
in spleen and/or liver (M) in B6C3F1 mice."
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
At all dose levels,
histopathological examinations indicated dose related increases
of hemosiderosis and congestion of the spleen, hemosiderosis and
chronic hepatitis of the liver, and mild erythroid hyperplasia
of the bone marrow... Male rats at 6 and 18 mg/kg/day and female
rats at 18 mg/kg/day had blue extremities indicative of cyanosis.
Histopathological examinations indicated non-neoplastic treatment-related
effects in the spleen, liver, bone
marrow and adrenal gland... (National Toxicology Program (NTP)
Report No. 351; July, 1989)..."
Ref: US EPA RED. August 1997.
http://www.fluoridealert.org/pesticides/Diflubenzuron.RED.pdf
-- Chronic toxicity.
Diflubenzuron was given by capsule to male and female Beagle dogs
for 1 year at dose levels of 0, 2, 10, 50, and 250 mg/kg/day.
Body weight (bwt) gain was slightly reduced in females at 250
mg/kg/day. Absolute liver and spleen weights were increased in
males given 50 and 250 mg/kg/day. A reduction
in hemoglobin and mean corpuscular hemoglobin concentration, with
an elevation in reticulocyte count, was seen at 50 and 250 mg/kg/day.
Methemoglobin and sulfhemoglobin values were increased at doses
of 10 mg/kg/day and greater. Histopathological findings
were limited to pigmented macrophages and
Kupffer cells in the liver at doses of 50 and 250 mg/ kg/day.
The NOAEL for chronic toxicity in dogs was 2 mg/kg/day.
-- A 91-week carcinogenicity study in CFLP mice was conducted
at doses of 0, 16, 80, 400, 2,000, and 10,000 ppm. There was no
increase in tumor incidence as a result of diflubenzuron administration.
Target organ effects included: Increased
methemoglobin and sulfhemoglobin values, Heinz bodies,
increased liver and spleen weight,
hepatocyte enlargement, and vacuolation,
extramedullary hemopoiesis in the liver and
spleen, siderocytosis in the spleen and
pigmented Kupffer cells. A NOAEL
for these effects was 16 ppm (2 mg/kg/day).
-- Diflubenzuron was fed to male and female Sprague Dawley rats
for 2 years at dose levels of 0, 156, 625, 2,500, and 10,000 ppm.
Methemoglobin values were elevated in female
rats at all dose levels and in male rats at the two highest dose
levels. Blood sulfhemoglobin was elevated in females, only, at
dose levels of 2,500, and 10,000 ppm. MCV and reticulocyte counts
were increased in high dose females. Spleen and liver
weights were elevated at the two highest doses. Histopathological
examination demonstrated an increase in hemosiderosis
of the liver and spleen, bone marrow
and erythroid hyperplasia, and areas of cellular alteration
in the liver. There was no increase
in tumor formation...
-- PCA [p-chloroaniline; a metabolite of
Diflubenzuron] hydrochloride was administered 5 days/week
by oral gavage to male and female B6C3F1 mice at doses of 0, 3,
10, or 30 mg/kg/day. Mean body weights of high dose male and female
mice were generally within 5% of those of controls throughout
the study. The incidence of hepatocellular
adenomas or carcinomas (combined) was increased in a non-dose-dependent
manner in treated male mice. Metastasis
of carcinoma to the lung was seen in the high dose group. An
increased incidence of hemangiosarcomas of the liver or spleen
was seen in high dose male mice. It
was concluded that, under the conditions of this 2-year gavage
study, there was some evidence of carcinogenic activity of PCA
hydrochloride for male B6C3F1 mice and no evidence of carcinogenic
activity of PCA hydrochloride for female B6C3F1 mice.
Ref: Federal Register: December 14, 2001.
(Volume 66, Number 241)] [Notices] [Page 64823-64828]. Notice
of Filing Pesticide Petitions to Establish a Tolerance for a Certain
Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Diflubenzuron.FR.Dec14.2001.htm
Abstract: Diflubenzuron (DFB), a potent inhibitor of insect chitin
synthesis, was administered to Swiss Webster mice in a 30-day
oral intubation study. Animal groups received either no treatment,
vehicle control (Polyethylene glycol 400), or DFB suspensions
at doses of 125, 500, and 2,000 mg/kg body weight. Hepatic glutathione
S-transferase activity as well as morphological characteristics
were studied. DFB was shown to elicit hepatocellular
changes at all dose levels. The activities
of three glutathione S-transferases (S-aryl, S-aralkyl, and S-epoxide)
were all altered after DFB administration. Light microscopy
revealed radial arrays of hepatocellular
vacuolization between the portal and central vein areas.
Electron-microscopic examination, verified by morphometric analysis,
revealed degenerative changes as well as
an increased volume density of the endoplasmic reticulum.
Ref: J Appl Toxicol. 1986 Oct;6(5):343-8.
Effects
of diflubenzuron on the mouse liver. Young MF, Trombetta LD,
Carson S.
Spleen
•••
Effects attributed to diflubenzuron metabolite: PCA and CPU •••
(click on for all fluorinated pesticides)
Chloroaniline,
p (or 4-chloraniline) is a metabolite of Diflubenzuron.
In 2006, USEPA classified chloroaniline, p as
a "Group B2 -- Probable Human Carcinogen." "Spleen
(fibrosarcomas,
hemangiosarcomas & osteosarcomas) (M); Adrenal
(pheochromocytomas (M & F); F344/N rats. Hepatocellular
adenomas/carcinomas (M); Hemangiosarcomas
in spleen and/or liver (M) in B6C3F1 mice."
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
--
In a 28-day feeding study technical grade diflubenzuron was administered
in the diet to rats at dose levels of 0 (control), 800, 4000,
20000 or 100000 ppm (equivalent to 0, 40, 200, 1000 or 5000 mg/kg/day).
Methemoglobin was increased in males at all dose levels and in
females at dose levels of 200 mg/kg/day and higher. Sulfhemoglobin
was increased in all treated males and females. At 5000 mg/kg/day
males and females experienced decreased erythrocyte counts, packed
cell volumes and hemoglobin. Dose-related
increases in spleen weights at all dose levels and in liver
weights at dose levels of 200 mg/kg/day and higher were also observed.
No NOEL was established in this study since treatment-related
effects were observed at 40 mg/kg/day, the lowest dose level tested.
The LEL is 40 mg/kg/day, based on increased methemoglobin in males,
increased sulfhemoglobin in males and females and increased spleen
weights in males and females. (MRID 00070018)
-- At all dose levels, histopathological examinations indicated
dose related increases of hemosiderosis
and congestion of the spleen, hemosiderosis and chronic
hepatitis of the liver, and mild erythroid hyperplasia of the
bone marrow... Male rats at 6 and 18 mg/kg/day and female rats
at 18 mg/kg/day had blue extremities indicative of cyanosis. Histopathological
examinations indicated non-neoplastic treatment-related effects
in the spleen, liver, bone marrow
and adrenal gland... (National Toxicology Program (NTP) Report
No. 351; July, 1989)..."
Ref: US EPA RED. August 1997.
http://www.fluoridealert.org/pesticides/Diflubenzuron.RED.pdf
-- A 91-week carcinogenicity
study in CFLP mice was conducted at doses of 0, 16, 80, 400, 2,000,
and 10,000 ppm. There was no increase in
tumor incidence as a result of diflubenzuron administration. Target
organ effects included: Increased methemoglobin and sulfhemoglobin
values, Heinz bodies, increased liver and spleen weight,
hepatocyte enlargement, and vacuolation,
extramedullary hemopoiesis in the liver and spleen, siderocytosis
in the spleen and
pigmented Kupffer
cells. A NOAEL for these effects was 16 ppm (2 mg/kg/day).
- PCA [p-chloroaniline; a metabolite of
Diflubenzuron] was administered 5 days/week by oral gavage,
as a hydrochloride salt in water, to male and female F344/N rats
at doses of 0, 2, 6, or 18 mg/kg/day. Mean body weights of dosed
rats were generally within 5% of those of controls throughout
the study. High dose animals generally showed mild hemolytic anemia
and dose-related methemoglobinemia. Non- neoplastic lesions seen
were bone marrow hyperplasia, hepatic hemosiderosis, and splenic
fibrosis, suggesting treatment-related effects on the hematopoietic
system. Adrenal medullary hyperplasia was observed in high dose
female rats. The incidence of uncommon sarcomas
of the spleen was significantly increased in high dose male rats.
A marginal increase in pheochromocytomas of the adrenal gland
was seen in high dose male and female rats. It was concluded that,
under the conditions of this 2-year gavage study, there was clear
evidence of carcinogenic activity of PCA hydrochloride for male
F344/N rats and equivocal evidence of carcinogenic activity of
PCA hydrochloride for female F344/N rats.
-- PCA [p-chloroaniline;
a metabolite of Diflubenzuron] hydrochloride was administered
5 days/week by oral gavage to male and female B6C3F1 mice at doses
of 0, 3, 10, or 30 mg/kg/day. Mean body weights of high dose male
and female mice were generally within 5% of those of controls
throughout the study. The incidence of hepatocellular adenomas
or carcinomas (combined) was increased in a non-dose-dependent
manner in treated male mice. Metastasis of carcinoma to the lung
was seen in the high dose group. An increased incidence of hemangiosarcomas
of the liver or spleen was seen in high dose male mice.
It was concluded that, under the conditions of this 2-year gavage
study, there was some evidence of carcinogenic activity of PCA
hydrochloride for male B6C3F1 mice and no evidence of carcinogenic
activity of PCA hydrochloride for female B6C3F1 mice.
-- In addition to PCA,
4-chlorophenylurea (CPU) is also
a potential minor metabolite of diflubenzuron. By association
with PCA, EPA has concluded that CPU has carcinogenic potential
and the same carcinogenic potency (q\1\*) as PCA. In the
NTP report of the PCA bioassay, it is proposed that PCA undergoes
N-hydroxylation to form the corresponding N-hydroxylamine metabolites;
N-hydroxylation of aromatic amines is a well know mechanism of
aromatic amine carcinogenicity. This metabolite, or proximate
carcinogen, is then conjugated to form the ultimate carcinogen
capable of ionizing and reacting with DNA to form adducts which
result in splenic tumor formation. An alternate mechanism
involving toxicity resulting in erythrocyte damage,
splenic scavenging, hemorrhage, hyperplasia and fibrosis and ultimately
splenic tumor formation is also proposed,
but both mechanisms are based on the formation
of N-hydroxy PCA.
Ref: Federal Register: December 14, 2001.
(Volume 66, Number 241)] [Notices] [Page 64823-64828]. Notice
of Filing Pesticide Petitions to Establish a Tolerance for a Certain
Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Diflubenzuron.FR.Dec14.2001.htm
Environmental
(click
on for all fluorinated pesticides) |
Measured
aquatic acute toxicity data for diflubenzuron include
a 48-hour LC 50 of 4.55 ppb for
daphnids. EPA believes that there is sufficient evidence
for listing diflubenzuron on EPCRA section 313 pursuant
to EPCRA section 313(d)(2)(C) based on the environmental
toxicity data for this chemical.
Ref: USEPA/OPPT. Support Document
for the Health and Ecological Toxicity Review of TRI Expansion
Chemicals. U. S. Environmental Protection Agency, Washington,
DC (1993). As
cited by US EPA in: Federal
Register: January 12, 1994. Part IV. 40 CFR Part 372.
Addition of Certain Chemicals; Toxic Chemical Release Reporting;
Community Right-to-Know; Proposed Rule.
|
...
extremely toxic to aquatic invertebrates.
Ref: US EPA. CHEMICAL FACT SHEET FOR:
DIFLUBENZURON (DIMILIN). FACT SHEET NUMBER: 68. SEPTEMBER
30, 1985
http://pmep.cce.cornell.edu/profiles/insect-mite/ddt-famphur/diflubenzuron/insect-prof-diflubenzuron.html
|
Marine
Environmental Research 1998
Dec;46(1-5):479-82
Effects
of selected pesticides, metals and organometallics on development
of blue crab (Callinectes sapidus) embryos. Lee
R, Oshima Y
...
Pesticides, including chlorpyrifos, cypermethrin, fenvalerate
and diflubenzuron, inhibited hatching
at concentrations ranging from 1.8 to 5.9 ug/L (EC50S).
|
Environ
Toxicol Chem 1995;14(8):1345-55
Effects
of diflubenzuron on the reproductive success of the bluegill
sunfish, Lepomis macrochirus. Tanner
DK, Moffett MF
Author
Address: U.S. Environmental Protection Agency, Environmental
Research Laboratory, Duluth, MN.
Abstract:
Exposure to diflubenzuron concentrations of 2.5 ug/L reduced
growth of young-of- the-year (Y-O-Y) bluegill by 56 and
86% in replicate enclosures and by 88 and 97% at
30 ug/L. An adult bluegill reproduction study was conducted
in six littoral enclosures located in a 2-ha pond near Duluth,
Minnesota. Decreased growth of Y-O-Y bluegill resulted from
the reduction or elimination of preferred invertebrate prey
items by diflubenzuron that led to different and/or less
Y-O-Y food consumption. Adult bluegill behavior and spawning,
embryo hatching, larval survival until swim-up, and Y-O-Y
biomass were also studied. Before the first two diflubenzuron
applications, spawning occurred in all enclosures; following
the first application, spawning occurred in both control
enclosures and one 30-ug/L enclosure. Successful embryo
hatching and larval swim-up occurred in all enclosures prior
to the first application, and in one control and one 30-ug/L
enclosure following application. The Y-O-Y growth was the
most sensitive end point, and Y-O-Y biomass was among the
least sensitive end points for bluegill reproductive success.
The Y-O-Y bluegills (and potentially other fish species)
that are exposed to diflubenzuron concentrations of greater
than or equal to 2.5 ug/L may experience reduced
growth, which can result in greater starvation, increased
predation, reductions in over-winter survival, and diminished
to poor recruitment.
|
Environmental
Toxicology and Risk Assessment: Modeling and Risk Assessment
(ASTM STP 1317) 1997;6:533-50
Age-specific
sensitivity of grass shrimp (Palaemonetes pugio) embryos
to sublethal concentrations of diflubenzuron. Wilson
JE
Author
Address: Department of Biology, Morgan State University,
Baltimore, MD.
Abstract:
Ovigerous grass shrimp (Palaemonetes pugio) carrying 0.5-,
1-, 3-, 6-, and 8-day-old embryos (i.e., stages 1, 2, 3,
4 and 5, respectively) were exposed continuously for 4 days
to a single dose of diflubenzuron (DFB) at sublethal concentrations
(0.3 to 5.0 ug/L) in a static system. After the 4-day exposure,
the shrimp were transferred to DFB-free seawater for the
rest of the embryonic development. When the eggs hatched,
the following toxicity-endpoints were measured: Hatchability
(% hatch), larval viability (% of larvae surviving to the
postlarval stage), duration of larval development from hatching
to the postlarval stage, and severity of morphological abnormality
in the larvae after hatching. There was no correlation between
the age of the embryos at exposure and either hatchability
or duration of larval development. Also, severity of abnormality
did not vary with age of embryos except at an exposure concentration
of 2.5 ug/L. However, within each
age group of the embryos, the severity of larval abnormality
was and duration of larval development was concentration
dependent. Larval viability was significantly (P less than
0.05) affected by the age of the embryos at the time of
exposure to DFB. For all the test concentrations,
exposure of 0.5- and 1-day-old embryos resulted in larval
viability that was similar to the control group (viability
greater than 80%). However, when 6-
and 8-day-old embryos were exposed to DFB concentrations
greater than 0.5 ug/L, larval viability was significantly
(P less than 0.05) less than the controls. These
results indicate that older embryos (at more advanced stages
of development) of the grass shrimp are more sensitive to
sublethal DFB concentrations.
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