Adverse Effects
Flufenoxuron
CAS No.
101463-69-8

 
 

Return to Flufenoxuron Index Page

Activity: Acaricide, Insecticide (Benzoylurea)
Structure:


Adverse Effects:
Blood
Bone
Endocrine: Adrenal
Endocrine: Ovary
Endocrine: Testicular
Endocrine: Thyroid
Kidney

Liver

Spleen
Environmental

Registered use in: Australia, Hungary, India, Japan, Philippines, Portugal, Tanzania, South Africa, US, Vietnam

In US: Apple, Cattle, Goat, Grape, Horse, Milk, Orange, Pear, Raisin, Sheep (imported commodities only: Acute toxicity studies are not required for import tolerance.)

In Japan this pesticide is used on the following food commodities:
Apple, Brussel Sprouts, Cabbage, Celery, Cherry, Cotton seeds, Cucumber, Eggplant, Grape, Grapefruit, Multiplying onion (inc Shallot), Lemon, Lime, Melons, Mushrooms (other than Shitake or Button), Natsudaidai (whole), Other Citrus fruits, Orange, Peach, Pear, Radish (Japanese), Strawberry, Sugar beet, Tea, Tomato, Unshu orange, Welsh (inc Leek)

METABOLITES & DEGRADATES:
2,6,-difluorobenzoic acid
2,6,-difluorobenzamide
4-(2-chloro,á, á, á trifluoro-p-tolyoxy)-2-fluorophenyl urea (WL129183)
4-(2-chloro,á, á, á rifluoro-p-tolyoxy)-2-fluoroaniline (WL15096)
Ref: August 15, 2006. US EPA Human Health Risk Assessment

• The database is adequate for establishment of tolerances on the requested commodities, except for a developmental toxicity study in rat which was classified as unacceptable/guideline....
Ref: August 15, 2006. US EPA Human Health Risk Assessment


Blood (click on for all fluorinated pesticides)

The critical toxicological effects of flufenoxuron in mammals are on the hemopoeitic [sic hematopoietic] system. These effects include shifts in red blood cell parameters (decreased in hemoglobin, hematocrit, red blood cells and erythroid: myloid ratio) resulting in mild anemia and enhanced levels of methemoglobin and sulfhemoglobin in dogs and rats. Dogs appears to be more susceptible to the hematopoetic effects described above. It is likely that a metabolite (aniline metabolite (4-[2chloro, á, á, á-trifluoro-p-tolyoxy]-2-fluoroaniline) is responsible for the formation of methemoglobin and sulfhemoglobin. Two oncogenicity studies in mice and one in rat; were conducted at doses exceeding 4 - 7.5x limit dose.
Reference: August 15, 2006. US EPA Human Health Risk Assessment for proposed tolerances on apples, pears, grapes, organges and livestock commodities imported into US. http://www.fluorideaction.org/pesticides/flufenoxuran.hra.epa.2006.pdf

-- Repeat dose mammalian studies. Studies submitted were 28 d rat, 90 d rat/mouse/dog, 12 and 24 month rat, and 12 month dog. In both the rat and dog there was evidence of regenerative anaemia and increased methaemoglobin levels with NELs of 5 mg.kg-1 (rat 28- and 90- day) and 2.5 mg.kg-1.d-1 (dog 12 month). In mice the NEL was 7.5 mg.kg-1.d-1 based on increased plasma bilirubin. Plasma bilirubin was also increased in rats (24 month). Evidence of regenerative anaemia (increased methaemoglobin, decreased erythrocyte parameters, increased reticulocytes, increased marrow cellularity and increased spleen weight) was seen in most studies. In addition at higher doses triglycerides were decreased and heart weight increased in the rat.
-- Repeat dose studies. Sub-Acute Toxicity. In an adequately conducted study 7/sex/dose Fischer 344 rats were administered 0, 50, 500, 5000, 10000 or 50000 ppm flufenoxuron [in] the diet for 28 days... Haematology parameters were measured at necropsy. Methaemoglobin concentrations were increased 100% at and above 500 ppm in males and 5000 ppm in females...
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

Bone (click on for all fluorinated pesticides)

-- Mammalian Toxicokinetics. Oral Administration in the rat. Single high dose. In an adequately conducted study groups of 5/sec Fischer 344 rats received a single dose of 350 mg.kg-1 bw of either unlabelled or [14 C-aniline]-flufenoxuron by gavage... There was a significant sex difference in the concentration of radioactivity found in the gonads (7.9 ppm in the males, 52 ppm in the females) and bone marrow (21.6 ppm in the males and 52.6 ppm in the females) (approximately 13 ppm).
-- Mammalian Toxicokinetics. Oral Administration in the rat. Single low dose. In a preliminary study, 1/sex Fischer 344 rats received a single dose of 3.5 mg.kg-1 bw [14 C-aniline]-flufenoxuron by gavage... Radioactivity was found to be extensively distributed throughout the carcass. Substantial concentrations of radioactivity were associated with the fat, GI tract, bone marrow and skin.
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 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

90-Day oral toxicity in dog: LOAEL = 38 mg/kg/day (M/F), based on decreased hemoglobin, hematocrit levels, and erythrocyte counts in males and increased absolute liver weights, bone marrow hyperplasia and methemoglobinemia in males and females.
Reference: August 15, 2006. US EPA Human Health Risk Assessment for proposed tolerances on apples, pears, grapes, organges and livestock commodities imported into US. http://www.fluorideaction.org/pesticides/flufenoxuran.hra.epa.2006.pdf

Endocrine: Adrenal (click on for all fluorinated pesticides)

Carcinogenicity. Rat. Groups of 50/sex/group Fischer 344 rats were administered 0, 500, 5000 or 50000 ppm flllufenoxuron in the diet for 24 months... In males relative spleen weight was reduced in all treatment groups (respectively 14, 29 and 32 %)...In the females there was a significant increase in adrenal weight in all treatment groups (respectively 9, 7 and 15%).
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

Endocrine: Ovary (click on for all fluorinated pesticides)

-- Abstract: Flufenoxuron (Benzoylphenylurea derivative)-an environmental antimoulting insecticide-is recently used for controlling insect production in cultivated areas. In the present work, the insecticide was administered intragastrically by stomach tube at a dose of 20 mg/kg b.wt. to the Juvenile female and male albino rats (Rattus norvegicus) every other day for three weeks. Histological examination of ovaries revealed that the flufenoxuron induced massive degeneration of ovarian follicles with much cellular debris in the antrum and pyknotic granulosa cells. On the other hand, the testis of flufenoxuron-treated animals exhibited marked decrease of the thickness of tunica albuginea and atrophy of the seminiferous tubules. There was a marked increase of desquamated spermatogenic cells within the lumina of seminiferous tubules. Multinucleated giant cells and vanishing of sperms were observed in the majority of tubules of flufenoxuron-treated animals in comparison with control. Epididymides sperm of experimental group exhibited the presence of increased number of spermatic precursors as well as varieties of sperm anomalies. The hepatic tissues toxicated with the insecticide showed nuclear disintegration, massive breakdown of hepatocytes and internal haemorrhage. The observed gonadal dysfunction may be attributed to hepatic damage or decline of gonadal hormone involved in either processes.
Ref: J. Egypt. Ger. Soc. Zool., Vol. 25(B), 45-64, 1998.
EFFECTS OF FLUFENOXURON-AN ENVIRONMENTAL ANTIMOULTING INSECTICIDE ON GONAD FUNCTION OF ALBINO RATS; by EL-Sayyad, H.I. and Karim, S.A. http://www.egsz.org/BiologicalCurrentContent/Zoology/Comparative%20Physiology/TOXICOLOGY.htm

Endocrine: Testicular (click on for all fluorinated pesticides)

-- Abstract: Flufenoxuron (Benzoylphenylurea derivative)-an environmental antimoulting insecticide-is recently used for controlling insect production in cultivated areas. In the present work, the insecticide was administered intragastrically by stomach tube at a dose of 20 mg/kg b.wt. to the Juvenile female and male albino rats (Rattus norvegicus) every other day for three weeks. Histological examination of ovaries revealed that the flufenoxuron induced massive degeneration of ovarian follicles with much cellular debris in the antrum and pyknotic granulosa cells. On the other hand, the testis of flufenoxuron-treated animals exhibited marked decrease of the thickness of tunica albuginea and atrophy of the seminiferous tubules. There was a marked increase of desquamated spermatogenic cells within the lumina of seminiferous tubules. Multinucleated giant cells and vanishing of sperms were observed in the majority of tubules of flufenoxuron-treated animals in comparison with control. Epididymides sperm of experimental group exhibited the presence of increased number of spermatic precursors as well as varieties of sperm anomalies. The hepatic tissues toxicated with the insecticide showed nuclear disintegration, massive breakdown of hepatocytes and internal haemorrhage. The observed gonadal dysfunction may be attributed to hepatic damage or decline of gonadal hormone involved in either processes.
Ref: J. Egypt. Ger. Soc. Zool., Vol. 25(B), 45-64, 1998.
EFFECTS OF FLUFENOXURON-AN ENVIRONMENTAL ANTIMOULTING INSECTICIDE ON GONAD FUNCTION OF ALBINO RATS; by EL-Sayyad, H.I. and Karim, S.A. http://www.egsz.org/BiologicalCurrentContent/Zoology/Comparative%20Physiology/TOXICOLOGY.htm

Endocrine: Thyroid (click on for all fluorinated pesticides)

-- Abstract: Flufenoxuron (Benzoylphenyl urea derivative) - antimoulting insecticide 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

Kidney (click on for all fluorinated pesticides)

Abstract: Flufenoxuron (Benzoylphenyl urea derivative) - antimoulting insecticide 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

Liver (click on for all fluorinated pesticides)

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

One of the mouse studies conducted at 7.5x limit dose had an increased incidence of vascular tumors in males and females. Total incidence of vascular tumors (combined hemangiosarcomas of the liver and spleen) among high-dose females (16%) was significantly increased over controls (0%) and was slightly outside the published data for historical controls (mean: 3.7%; range: 0%-14%). The overall increase in splenic hemangiosarcomas in high-dose females (14%, p<0.01) and the increase in total vascular tumors in the liver of high-dose males (20% vs 12% in controls) occurred at doses that exceeded the limit dose. The mouse oncogenicity study was repeated with the high dose exceeding 1.5x limit dose; and there was no increased incidence of any tumors. Therefore, the increased incidences of vascular tumors are considered high dose effects only.
Reference: August 15, 2006. US EPA Human Health Risk Assessment for proposed tolerances on apples, pears, grapes, organges and livestock commodities imported into US. http://www.fluorideaction.org/pesticides/flufenoxuran.hra.epa.2006.pdf

Abstract: Flufenoxuron (Benzoylphenyl urea derivative) - antimoulting insecticide 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

Spleen (click on for all fluorinated pesticides)

-- Repeat dose mammalian studies. Studies submitted were 28 d rat, 90 d rat/mouse/dog, 12 and 24 month rat, and 12 month dog. In both the rat and dog there was evidence of regenerative anaemia and increased methaemoglobin levels with NELs of 5 mg.kg-1 (rat 28- and 90- day) and 2.5 mg.kg-1.d-1 (dog 12 month). In mice the NEL was 7.5 mg.kg-1.d-1 based on increased plasma bilirubin. Plasma bilirubin was also increased in rats (24 month). Evidence of regenerative anaemia (increased methaemoglobin, decreased erythrocyte parameters, increased reticulocytes, increased marrow cellularity and increased spleen weight) was seen in most studies. In addition at higher doses triglycerides were decreased and heart weight increased in the rat.
-- Carcinogenicity. Rat. Groups of 50/sex/group Fischer 344 rats were administered 0, 500, 5000 or 50000 ppm flllufenoxuron in the diet for 24 months...
In males relative spleen weight was reduced in all treatment groups (respectively 14, 29 and 32 %)...In the females there was a significant increase in adrenal weight in all treatment groups (respectively 9, 7 and 15%).
--
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

Environmental (click on for all fluorinated pesticides)

Environmental fate, behaviour and toxicology. Flufenoxuron does not readily break down in the environment. The most rapid form of degradation reported was aqueous photolysis, with a half-life (T 1/2) of 11 days. However the solubility of flufenoxuron, in water is extremely low (0.0040 mg.1-1 at pH7 and 25C). Flufenoxuron readily adsorbs to organic matter. Consequently it is immobile and also persists in soil (T 1/2 42 days for clay loam and >6 months for sandy loam)...

Flufenoxuron is extremely toxic to Daphnia (48 hour EC50 0.065 ug.1-1). This is consistent with the compound's mode of action against target pests, inhibiting chitin synthesis/deposition. No fish toxicity could be established due to flufenoxuron's low water solubility and the failure to use an appropriate solvent vehicle. Similarly, no accurate toxicity to freshwater algae was establishsed...Pond overspray studies indicated that flufenoxuron could have adverse efects on aquatic invertebrate populations, especially crustacea zooplankton. Flufenoxuron may also have the potential to bioaccumulate in fish and aquatic gastropods although this has not been confirmed in a laboratory bioaccumulation study. ... due to the acute toxicity of flufenoxuron to Daphnia and the lack of any suitable fish toxicity data, products containing the compound are to be classified 'EXTREMELY DANGEROUS TO FISH AND OTHER AQUATIC LIFE."
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

 
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