Adverse Effects
Diflubenzuron
CAS No. 35367-38-5
 
 

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 an
d 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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