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Activity: Herbicide
Structure:

Adverse Effects:
Blood
Body Weight Decrease
Bone
Brain
Cholesterol
Endocrine: Adrenal
Endocrine: Ovary
Endocrine: Pituitary
Endocrine: Suspected Endocrine Disruptor
Endocrine: Testicular
Endocrine: Thymus
Endocrine: Uterus
Eye
Fetotoxic
Gastrointestinal Tract
Kidney
Liver
Mesenteric Lymph Nodes
Reproductive
Spleen
Teratogenic
Environmental

**411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... All other noteworthy findings were limited to the high dose group, as follows. Seven 125 mg/kg/day dogs (5 M, 2 F) were killed in extremis prior to term, generally after at least 29 weeks on study. Fluazifop-butyl caused ulcerations in the g.i. tract, specifically in the tongue, lip, mouth lining, stomach pylorus, or cecum. Ulcerations may have contributed to low RBC parameters in both sexes (reduced HCT, Hb levels, and RBC counts, particularly in males). Platelet counts were reduced by about half in both sexes. Bone marrow samples taken at weeks 10 and 52 for smear analyses showed "reduced numbers of megakaryocytes," suggesting reduced production as a reason for low platelet counts. Other hematology-related findings included increased incidence/degree of thymic involution, decreased lymphocyte counts, increased degree of hemosiderin-laden Kupffer cells, hypercellular sternal marrow, and severe extramedullary hematopoiesis in 4 male and 1 female decedent. Four of the latter 5 dogs also had substantially increased splenic weights, "pallor" in clinical signs as part of moribund condition, and their final hematology red cell values (RBC count, Hb, HCT) were very low. Eyes of eight high dose dogs had cataracts, usually accompanied by miliary ("seed-like" appearance) vacuolation of the lens. Liver dysfunction was indicated by periacinar hepatocytic degeneration and thinning of hepatic cords in some dogs, other hepatocytic changes such as vacuolation and/or granular cytoplasm, and occasional bile plugs in the canaliculi. Most clinical chemistry changes were plausibly related to liver toxicity, including elevated alkaline phosphatase, ALT, and occasionally AST. Substantially increased BSP retention was consistent with biliary disturbance. Urine was typically bright yellow or orange due to high bile pigment concentrations. Cholesterol was consistently reduced. Male reproductive toxicity included testicular tubular degeneration and reduced/absent spermatozoa in epididymides. Possible adverse effects (many-faceted toxicity, including mortalities, at 125 mg/kg/day). Acceptable. Aldous, 5/20/02.
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf

Body Weight Decrease (click on for all fluorinated pesticides)

-- Fluazifop butyl (CAS # 69806-50-4) was evaluated for developmental toxicity in the progeny of Sprague-Dawley CD rats administered oral doses of 0 (corn oil vehicle control), 10, 50 and 200 mg/kg/day by gavage on gestation days 6-20... Delayed fetal ossification and reduced fetal weight were dose-related and evident at all treatment levels, although fetal weights in association with dosages of 10 and 50 mg/kg/day were within the threshold of historical controls... [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate butyl: Effects of Oral Administration Upon Pregnancy in Rats; 05/23/80; EPA Doc No. 88-920006839; Fiche No. OTS0543844]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

In a teratogenicity study in Sprague-Dawley rats exposed via oral gavage, delayed ossification and an increased incidence of hydroureter were observed in fetuses (the fetotoxic LOEL was 5 mg/kg/day; the NOEL 1 mg/kg/day) and a teratogenic LOEL of 200 mg/kg/day (the NOEL was 10 mg/kg/day) was determined based on the incidence of diaphragmatic hernia. Maternal toxicity was observed in this study at doses higher than those causing fetotoxicity and included reduced body weight gain and decreased gravid uterus (the maternal LOEL was 200 mg/kg/day; the NOEL was 10 mg/kg/day). In a 2-generation reproductive toxicity dietary study in Wistar rats, the reproductive LOEL of 250 ppm (12.5 mg/kg/day; the NOEL was 80 ppm or 4 mg/kg/day) was based on reduced litter sizes, reduced viability, reduced testis and epididymis weights and tubular atrophy in offspring. Fetotoxicity (delayed ossification and eye opacities) was also demonstrated in New Zealand White rabbits (the LOEL was 30 mg/kg/day; the NOEL was 10 mg/kg/day). EPA believes that there is sufficient evidence for listing fluazifop butyl on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and developmental toxicity data for this chemical.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

Fluazifop butyl was evaluated for developmental toxicity in adult virgin Sprague-Dawley CD rats (160/treatment group) administered oral doses of 0, 1, 5, 10 and 200 mg/kg/day during gestation days 6-20. No increased maternal mortality or overt toxicity was attributed to treatment. At gestation Day 21 sacrifice of the dams, a slight but significantly depressed mean bodyweight gain among those of a 200 mg/kg/day dosage was indicative of dose- related and significant (p < 0.05; Student's t-test) reduction in gravid uterus weights. Significant (p < 0.01; Student's t-tests) dosage-related reductions in fetal weights in association with treatment from 5 mg/kg/day were found to correlate with increased incidence of small fetuses; Placental weights were also significantly low in association with treatment at 200 mg/kg/day relative to controols. Gross pathological changes included increased incidence of diaphragmatic hernia (4.4% in association with 200 mg/kg/day) noted at all treatment levels relative to controls (0%), and slight dosage-related increased occurrence of hydroureter, partnered with a marginal increase in hydronephrosis in 200 mg/kg/day fetuses. Micropathological investigation validated dosage-related incidence of hydroureter, hydronephrosis in association with a 200 mg/kg/day regimen, and subcutaneous edema among 200 mg/kg/day fetuses. Skeletal examinations further revealed retarded ossification that was dosage-related in fetuses of gestational treatment levels at 5 mg/kg/day and above. Treatment levels of 1 mg/kg/day were associated with no toxic, reproductive or developmental consequences relative to controls under the conditions of this study.
Ref: 1992 - INITIAL SUBMISSION: TERATOLOGY STUDY WITH FLUAZIFOP BUTYL IN RATS WITH COVER LETTER DATED 08-28-92. LIFE SCI RESEARCH. NTIS/OTS0545395 and EPA/OTS; Doc #88-920007020. [Abstract from Toxline at Toxnet.]

Bone (click on for all fluorinated pesticides)

-- Fluazifop butyl (CAS # 69806-50-4) was evaluated for developmental toxicity in the progeny of Sprague-Dawley CD rats administered oral doses of 0 (corn oil vehicle control), 10, 50 and 200 mg/kg/day by gavage on gestation days 6-20... Delayed fetal ossification and reduced fetal weight were dose-related and evident at all treatment levels, although fetal weights in association with dosages of 10 and 50 mg/kg/day were within the threshold of historical controls... [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate butyl: Effects of Oral Administration Upon Pregnancy in Rats; 05/23/80; EPA Doc No. 88-920006839; Fiche No. OTS0543844]
-- Fluazifop butyl was evaluated for developmental toxicity in adult virgin Sprague-Dawley CD rats (160/group) administered oral doses of 0, 1, 5, 10 and 200 mg/kg/day during gestation days 6-20... Skeletal examinations further revealed retarded ossification that was dosage-related in fetuses of gestational treatment levels of 5 mg/kg/day and above... [ICI AMERS INC; Teratology Study with Fluazifop Butyl in Rats; 06/03/81; EPA Doc No. 88-920007020; Fiche No. OTS0545395]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

**411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... All other noteworthy findings were limited to the high dose group, as follows. Seven 125 mg/kg/day dogs (5 M, 2 F) were killed in extremis prior to term, generally after at least 29 weeks on study... Bone marrow samples taken at weeks 10 and 52 for smear analyses showed "reduced numbers of megakaryocytes •," suggesting reduced production as a reason for low platelet counts. Other hematology-related findings included increased incidence/degree of thymic involution, decreased lymphocyte counts, increased degree of hemosiderin-laden Kupffer cells, hypercellular sternal marrow, and severe extramedullary hematopoiesis •• in 4 male and 1 female decedent....
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf
• Megakaryocytes - Very large bone marrow cells which release mature blood platelets.
••  Hematopoiesis - The formation and development of blood cells, usually takes place in the bone marrow.

4.2.3.2 Fluazifop-butyl - Sprague Dawley Rats In a developmental toxicity study (MRID# 00088857, 92067047 and 92067019), fluazifop-butyl, [PP009 (94.8% a.i., batch/lot # P14)] was administered to 22 female CD Sprague Dawley strain rats/group in a corn oil (2 ml/kg) gavage at dose levels of 0, 10, 50 or 200 mg/kg bw/day from days 6 through 20 of gestation. Animals were sacrificed on day 21 ... Various parameters significant to development were affected relative to concurrent and/or historical controls. Post implantation loss was increased (125%) at 200 mg/kg/day. Examination of the heads of fetuses showed increased large fontanelles at 200 and 50 mg/kg/day (45.9% and 11.9%, respectively, versus 3.4% in concurrent controls. Increased incomplete and/or irregular ossification of cranial sutures at 200 and 50 mg/kg/day (58.9% and 43.7%, respectively, versus 14.3% in concurrent controls. The incidence of fissures into the interparietal bone was increased at 200 mg/kg/day (2.2% versus 0% in concurrent and historical controls. Only the percentages of fetal anomalies were presented with no litter incidence. No statistical analysis was presented for the fetal anomalies. Increased incidence of incomplete ossification of thoracic vertebral centra at 200, 50 and 10 mg/kg/day (75.`5%, 58.7, 48.4, respectively, versus 38.5% in concurrent controls, with a historical control range of 0-70.3%) appeared to be test material related. An increased incidence of absent hyoid bone at 200 and 50 mg/kg/day (23.0% and 17.2% versus 10.8% in concurrent controls) was observed. Increased incidence of incomplete ossification of one or more pelvic bones at 200 and 50 mg/kg/day (7.4% and 2.3%, respectively, versus 1.4% in concurrent control) was also observed. Absent hyoid bone and incomplete and/or irregular ossification of the cranial bones, and incomplete ossification of one or more pelvic bones may have been increased at 50 mg/kg/day, but since concurrent controls were higher than the mean historical control, these effects may have been incidental. The incidence of bilateral hydronephrosis at 200 mg/kg/day exceeded the historical control mean but not the range. The incidence of bilateral hydroureter at 200 mg/kg/day exceeded the historical control range and mean. No hydronephrosis nor hydroureter were seen in concurrent controls. In addition, subcutaneous edema (17.7% at 200 mg/kg/day versus 3.4% in concurrent controls) exceeded the mean of 8.9% in historical controls (the upper range was unreadable). The concurrent controls also were less than the mean of historical controls. Diaphragmatic hernia was seen in 1 fetus at 10 mg/kg/day, none at 50 mg/kg/day, and in 3 fetuses at 200 mg/kg/day, with no incidences in 2970 historical control fetuses. However a subsequent much larger study (MRID# 00088858) with 160 litter/group, showed an incidence of diaphragmatic hernias of 3/1113 in control fetuses, 1/1081 fetuses at 1 mg/kg/day, 3/1073 fetuses at 5 mg/kg/day, 2/1064 fetuses at 10 mg/kg/day, and a statistically significantly increased incidence in 59/1064 fetuses and 45/159 litters at 200 mg/kg/day. Since this anomaly was seen at a higher incidence (3 fetuses) in the controls in this study and was not replicated at the same dose in the second study, the single incidence of diaphragmatic hernia at 10 mg/kg/day was considered to be an aberration and not attributable to treatment. For developmental toxicity, the LOAEL is 10 mg/kg/day based on incomplete and/or irregular ossification of the cranial bones and incomplete ossification of thoracic vertebral centra; a NOAEL was not established.
Ref: December 10, 2004. US EPA> Fluazifop-P-butyl: Revised HED Chapter of the Tolerance Reassessment Eligibility Decision (TRED) Document. EPA Docket number: OPP-2004-0347-0003
http://www.fluorideaction.org/pesticides/f-p-b.opp-2004-0347-0003.pdf

4.2.3.4 Fluazifop-P-butyl - Wistar Rats In a developmental toxicity study (MRID 46028903) [Fluazifop-p-butyl, calculated as 90.9% a.i.; batch/lot# BX 247T A10209)] was administered to [(24 females) Alderly Park strain of Wistar rats] rats/dose by gavage at dose levels of 0, 2, 5 or 100 mg a.i./kg bw/day from days 7 through 21 of gestation ... Delayed ossification was seen in skull bones. The incidence of the partially ossified occipital (3.3% to 7.1% versus 0% in control), interparietals (9.5% to 29.5% versus 0.4% in control, historical controls), and in parietal bones (14.2% to 38.2% versus 0.4% in control) were dose related and statistically significant in fetuses and litters at 5.0 mg/kg/day and above. [In this study, historical control data are useful but limited because it was collected on studies with dosing gestational day 7 - 16.] The mean manus [10% to 30% of control] and pes scores [4% to 14% of control] showed a statistically significant dose related increase delayed ossification, starting at 5 mg/kg/day. [Manus and pes scores (1-6) were a subjective index of delayed ossification (1-6) in the fore paws and hind paws of each fetus.] Other indications of delayed ossification were seen at the highest dose tested for cervical vertebral arches and centrum (not ossified) and sternebrae 5 and 6. In addition, the odontoid [tooth related] and calcaneum [heel bone] were not ossified at 100 mg/kg/day. Fetal weight was significantly decreased 7% at 100 mg/kg/day only. Increased incidence of dilated ureter was seen only in litters at 100 mg/kg/day and kinked ureter in was dose related and statistically significant at all doses in fetuses, but not in litters at any dose level. There were no incidences of diaphragmatic hernias seen in this study. For developmental toxicity, the NOAEL is 2.0 mg/kg/day and the LOAEL is 5.0 mg/kg/day based on dose related delayed ossification in skull bones [occipital and parietal] in fetuses and litters (page 34-35).
Ref: December 10, 2004. US EPA> Fluazifop-P-butyl: Revised HED Chapter of the Tolerance Reassessment Eligibility Decision (TRED) Document. EPA Docket number: OPP-2004-0347-0003
http://www.fluorideaction.org/pesticides/f-p-b.opp-2004-0347-0003.pdf

Brain (click on for all fluorinated pesticides)

Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically... . Testis and epididymis weights in the males (80, 250 ppm), and pituitary gland (80, 250 ppm), uterus (80, 250 ppm), brain (250 ppm) and lung weights (250 ppm) in females were significantly reduced... [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

Cholesterol (click on for all fluorinated pesticides)

-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic dietary toxicity in Wistar rats (20/sex/group) receiving 0, 10, 100 and 2000 ppm by dietary inclusion for 13 weeks. Mean achieved dosages during 13-week treatment were 0, 0.7, 7.1 and 144.5 mg/kg/day in males of the respective treatment groups and 0, 0.8, 8.0 and 161.9 mg/kg/day in females... cholesterol and total protein concentrations were low as compared to controls. [ICI AMERICAS INC; 13 Week Dietary Toxicity Study with PP009 in Rats (Final Report); 05/29/80; EPA Doc No. 88-920006943; Fiche No. OTS0545346]
-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subacute oral toxicity in Wistar albino rats (10/sex/group) administered 10 ml/kg doses in corn oil of 0, 4, 20, 100 and 500 mg/kg/day by oral gavage, 5 days/week for 2 weeks. Five-day weekly treatment periods were each followed by 2-day recovery... Blood chemistry indicated a dose-related elevation of alkaline phosphatase activity in 100 and 500 mg/kg/day males, elevated aspartate amino-transferase activity in 500 mg/kg/day males, and elevated cholesterol concentrations in 500 mg/kg/day males and females. Conversely, enzyme activity was depressed in rats of lower dosages... [ICI AMERS INC; 14 Day Subacute Oral Toxicity Study with PP009 in Rats; 07/11/80; EPA Doc No. 88-920007017; Fiche No. OTS0545392]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

**411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... All other noteworthy findings were limited to the high dose group, as follows. Seven 125 mg/kg/day dogs (5 M, 2 F) were killed in extremis prior to term, generally after at least 29 weeks on study ... Cholesterol was consistently reduced. Male reproductive toxicity included testicular tubular degeneration and reduced/absent spermatozoa in epididymides. Possible adverse effects (many-faceted toxicity, including mortalities, at 125 mg/kg/day). Acceptable. Aldous, 5/20/02.
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf

Endocrine: Adrenal (click on for all fluorinated pesticides)

**411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day. The degree of adrenal gland cortical fatty degeneration evident in one mid-dose female was sufficiently greater than that of any of the control dogs that investigators attributed this finding to treatment. Cortical fatty degeneration of moderate to severe degree was observed in one high dose male and in all high dose females. All other noteworthy findings were limited to the high dose group, as follows... Male reproductive toxicity included testicular tubular degeneration and reduced/absent spermatozoa in epididymides. Possible adverse effects (many-faceted toxicity, including mortalities, at 125 mg/kg/day). Acceptable. Aldous, 5/20/02.
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf

Endocrine: Ovary (click on for all fluorinated pesticides)

-- Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically... Necropsy of F0 parents revealed no gross pathology and, although testes and epididymis of F0 males of a 250 ppm exposure were reduced, histological review identified no treatment-related changes. Conversely, F1 parents were found with gross indications of toxicity.. . Testis and epididymis weights in the males (80, 250 ppm), and pituitary gland (80, 250 ppm), uterus (80, 250 ppm), brain (250 ppm) and lung weights (250 ppm) in females were significantly reduced. Female F1 ovarian weights were increased relative to controls in association with a 250 ppm dietary exposure. Upon histological investigation, increased incidence geriatric nephropathy [kidney](both sexes, 80 and 250 ppm), distension of mesenteric and/or cervical lymph nodes (250 ppm) and increased severity of nephrocalcinosis (females, 80 and 250 ppm), and an increased slight testicular tubular atrophy in males (250 ppm) were noted... [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

Endocrine: Pituitary (click on for all fluorinated pesticides)

-- Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically... Necropsy of F0 parents revealed no gross pathology and, although testes and epididymis of F0 males of a 250 ppm exposure were reduced, histological review identified no treatment-related changes. Conversely, F1 parents were found with gross indications of toxicity.. . Testis and epididymis weights in the males (80, 250 ppm), and pituitary gland (80, 250 ppm), uterus (80, 250 ppm), brain (250 ppm) and lung weights (250 ppm) in females were significantly reduced. Female F1 ovarian weights were increased relative to controls in association with a 250 ppm dietary exposure. Upon histological investigation, increased incidence geriatric nephropathy [kidney](both sexes, 80 and 250 ppm), distension of mesenteric and/or cervical lymph nodes (250 ppm) and increased severity of nephrocalcinosis (females, 80 and 250 ppm), and an increased slight testicular tubular atrophy in males (250 ppm) were noted... [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

Endocrine: Suspected Endocrine 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)

-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic oral toxicity in beagle dogs (4/sex/group) administered doses of 0 (vehicle control, corn oil), 5, 25 and 250 mg/kg/day in gelatin capsules for 13 weeks. Severe corneal ulceration, requiring humane sacrifice of 2 males and 1 female of a 250 mg/kg/day dosage during Week 4, prompted adjustment of this regimen to 125 mg/kg/day for the remainder of study... Histopathological evaluation confirmed treatment-related lesions of the eyes, liver, testes and gastrointestinal tract... Conversely, all dogs surviving 13-week treatment showed no clinical signs of toxicity, and no treatment-related changes on physical and ophthalmic examinations at Weeks 4, 8 and 12. .. Upon terminal necropsy, organ weights and gross pathology of dogs surviving 13-week study were unremarkable and histopathological analysis identified a solitary incidence of arrested maturation in the testicular germinal epithelium of one high-dose male. [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate: 13-Week Oral Toxicity Study in Beagle Dogs; 04/24/80; EPA Doc No. 88-920006846; Fiche No. OTS0543851]
-- Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically... Necropsy of F0 parents revealed no gross pathology and, although testes and epididymis of F0 males of a 250 ppm exposure were reduced, histological review identified no treatment-related changes. Conversely, F1 parents were found with gross indications of toxicity.. . Testis and epididymis weights in the males (80, 250 ppm), and pituitary gland (80, 250 ppm), uterus (80, 250 ppm), brain (250 ppm) and lung weights (250 ppm) in females were significantly reduced. Female F1 ovarian weights were increased relative to controls in association with a 250 ppm dietary exposure. Upon histological investigation, increased incidence geriatric nephropathy [kidney](both sexes, 80 and 250 ppm), distension of mesenteric and/or cervical lymph nodes (250 ppm) and increased severity of nephrocalcinosis (females, 80 and 250 ppm), and an increased slight testicular tubular atrophy in males (250 ppm) were noted... [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

-- 411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... Male reproductive toxicity included testicular tubular degeneration and reduced/absent spermatozoa in epididymides. Possible adverse effects (many-faceted toxicity, including mortalities, at 125 mg/kg/day). Acceptable. Aldous, 5/20/02.
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf

Endocrine: Thymus

**411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... All other noteworthy findings were limited to the high dose group, as follows. Seven 125 mg/kg/day dogs (5 M, 2 F) were killed in extremis prior to term, generally after at least 29 weeks on study... Platelet counts were reduced by about half in both sexes. Bone marrow samples taken at weeks 10 and 52 for smear analyses showed "reduced numbers of megakaryocytes," suggesting reduced production as a reason for low platelet counts. Other hematology-related findings included increased incidence/degree of thymic involution, decreased lymphocyte counts, increased degree of hemosiderin-laden Kupffer cells, hypercellular sternal marrow, and severe extramedullary hematopoiesis in 4 male and 1 female decedent. Four of the latter 5 dogs also had substantially increased splenic weights, "pallor" in clinical signs as part of moribund condition, and their final hematology red cell values (RBC count, Hb, HCT) were very low....
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf
• Thymic involution:
-- One major change that occurs as the body ages is a process termed "thymic involution." ... As humans age, the thymus naturally atrophies... Once the immune system fully develops and can protect the host against a myriad of antigens, the thymus may be too costly to maintain, so it is evolutionarily advantageous to decrease the amount of thymic tissue and use the energy that would have supported the thymus for other purposes. However, because T cells play such a prominent role in immunity, longer-lived individuals still need a continuous supply of "fresh" T cells to protect against newly-encountered antigens, and this slow but progressive loss of thymic tissue has profound effects on the entire immune system of the aged.
Ref: The Immunology of Aging
Also see: Thymic involution tied to progression of pediatric HIV infection

Endocrine: Uterus (click on for all fluorinated pesticides)

-- Fluazifop butyl was evaluated for developmental toxicity in adult virgin Sprague-Dawley CD rats (160/group) administered oral doses of 0, 1, 5, 10 and 200 mg/kg/day during gestation days 6-20. No increased maternal mortality or overt toxicity was attributed to treatment. At gestation Day 21 sacrifice of the dams, a slight but significantly depressed mean bodyweight gain among those of a 200 mg/kg/day dosage was indicative of dose-related and significant (p < 0.05; Student's t-test) reduction in gravid uterus weights... [ICI AMERS INC; Teratology Study with Fluazifop Butyl in Rats; 06/03/81; EPA Doc No. 88-920007020; Fiche No. OTS0545395]
-- Fluazifop butyl (CAS # 69806-50-4) was evaluated for developmental toxicity in the progeny of Sprague-Dawley CD rats administered oral doses of 0 (corn oil vehicle control), 10, 50 and 200 mg/kg/day by gavage on gestation days 6-20. The general condition of treated rats was comparable to controls. Treatment did not alter food consumption and usage efficiency, although terminal mean bodyweights were significantly (p < 0.05; multiple t-test) depressed in the high-dose (200 mg/kg/day) group. Gravid uterus weights were also significantly (p < 0.01) elevated in association with the high dosage... [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate butyl: Effects of Oral Administration Upon Pregnancy in Rats; 05/23/80; EPA Doc No. 88-920006839; Fiche No. OTS0543844]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

Eye (click on for all fluorinated pesticides)

-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic oral toxicity in beagle dogs (4/sex/group) administered doses of 0 (vehicle control, corn oil), 5, 25 and 250 mg/kg/day in gelatin capsules for 13 weeks. Severe corneal ulceration, requiring humane sacrifice of 2 males and 1 female of a 250 mg/kg/day dosage during Week 4, prompted adjustment of this regimen to 125 mg/kg/day for the remainder of study. Prior to sacrifice, these dogs also exhibited progressive conjunctivitis and photophobia, and all lost weight... Histopathological evaluation confirmed treatment-related lesions of the eyes, liver, testes and gastrointestinal tract. [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate: 13-Week Oral Toxicity Study in Beagle Dogs; 04/24/80; EPA Doc No. 88-920006846; Fiche No. OTS0543851]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

**411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... All other noteworthy findings were limited to the high dose group, as follows... Eyes of eight high dose dogs had cataracts, usually accompanied by miliary ("seed-like" appearance) vacuolation of the lens... Possible adverse effects (many-faceted toxicity, including mortalities, at 125 mg/kg/day). Acceptable. Aldous, 5/20/02.
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf

Fetotoxic (click on for all fluorinated pesticides)

-- Fetotoxicity (delayed ossification and eye opacities) was also demonstrated in New Zealand White rabbits (the LOEL was 30 mg/kg/day; the NOEL was 10 mg/kg/day). EPA believes that there is sufficient evidence for listing fluazifop butyl on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and developmental toxicity data for this chemical.
-- In a teratogenicity study in Sprague-Dawley rats exposed via oral gavage, delayed ossification and an increased incidence of hydroureter were observed in fetuses (the fetotoxic LOEL was 5 mg/kg/day; the NOEL 1 mg/kg/day) and a teratogenic LOEL of 200 mg/kg/day (the NOEL was 10 mg/kg/day) was determined based on the incidence of diaphragmatic hernia.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

-- Reproductive Effects: In a 3-generation reproductive study in rats, effects included reductions in weight gain, fetal weight, ossification, testicular weight, spleen weight, increased prostate weight and gestational length. No Effect Level (NEL) was 1 mg/kg/day. Fetotoxic effects seen in the rabbit, including reduced fetal weight and reduced ossification at higher doses. No Effect Level (NEL) was 30 mg/kg/day in rabbits. The NEL for teratogenic effects is at least 10/mg/day in the rat, with diaphragmatic hernia at higher doses. Not teratogenic at highest dose tested in rabbits (90 mg/kg/day). While fluazifop-p-butyl is fetotoxic when fed to pregnant rats, human exposure data has concluded that female formulation workers are not at increased risk of fetotoxic effects when skin protection measures are applied.
Ref: Material Safety Data Sheet for Fusilade DX (active indredient Fluazifop-P-Butyl). Syngenta. January 21, 2002.
http://www.fluoridealert.org/pesticides/Fluazifop-P-Butyl.MSDS.pdf

Gastrointestinal Tract (click on for all fluorinated pesticides)

**411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... All other noteworthy findings were limited to the high dose group, as follows. Seven 125 mg/kg/day dogs (5 M, 2 F) were killed in extremis prior to term, generally after at least 29 weeks on study. Fluazifop-butyl caused ulcerations in the g.i. tract, specifically in the tongue, lip, mouth lining, stomach pylorus, or cecum. Ulcerations may have contributed to low RBC parameters in both sexes (reduced HCT, Hb levels, and RBC counts, particularly in males)...
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf

Hydroureter

4.2.3.2 Fluazifop-butyl - Sprague Dawley Rats In a developmental toxicity study (MRID# 00088857, 92067047 and 92067019), fluazifop-butyl, [PP009 (94.8% a.i., batch/lot # P14)] was administered to 22 female CD Sprague Dawley strain rats/group in a corn oil (2 ml/kg) gavage at dose levels of 0, 10, 50 or 200 mg/kg bw/day from days 6 through 20 of gestation. Animals were sacrificed on day 21 ... The incidence of bilateral hydronephrosis at 200 mg/kg/day exceeded the historical control mean but not the range. The incidence of bilateral hydroureter at 200 mg/kg/day exceeded the historical control range and mean. No hydronephrosis nor hydroureter were seen in concurrent controls. In addition, subcutaneous edema (17.7% at 200 mg/kg/day versus 3.4% in concurrent controls) exceeded the mean of 8.9% in historical controls (the upper range was unreadable). The concurrent controls also were less than the mean of historical controls. Diaphragmatic hernia was seen in 1 fetus at 10 mg/kg/day, none at 50 mg/kg/day, and in 3 fetuses at 200 mg/kg/day, with no incidences in 2970 historical control fetuses. However a subsequent much larger study (MRID# 00088858) with 160 litter/group, showed an incidence of diaphragmatic hernias of 3/1113 in control fetuses, 1/1081 fetuses at 1 mg/kg/day, 3/1073 fetuses at 5 mg/kg/day, 2/1064 fetuses at 10 mg/kg/day, and a statistically significantly increased incidence in 59/1064 fetuses and 45/159 litters at 200 mg/kg/day. Since this anomaly was seen at a higher incidence (3 fetuses) in the controls in this study and was not replicated at the same dose in the second study, the single incidence of diaphragmatic hernia at 10 mg/kg/day was considered to be an aberration and not attributable to treatment. For developmental toxicity, the LOAEL is 10 mg/kg/day based on incomplete and/or irregular ossification of the cranial bones and incomplete ossification of thoracic vertebral centra; a NOAEL was not established.
Ref: December 10, 2004. US EPA> Fluazifop-P-butyl: Revised HED Chapter of the Tolerance Reassessment Eligibility Decision (TRED) Document. EPA Docket number: OPP-2004-0347-0003
http://www.fluorideaction.org/pesticides/f-p-b.opp-2004-0347-0003.pdf

Kidney (click on for all fluorinated pesticides)

-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic dietary toxicity in Wistar rats (20/sex/group) receiving 0, 10, 100 and 2000 ppm by dietary inclusion for 13 weeks. Mean achieved dosages during 13-week treatment were 0, 0.7, 7.1 and 144.5 mg/kg/day in males of the respective treatment groups and 0, 0.8, 8.0 and 161.9 mg/kg/day in females... Upon terminal necropsy, only high-dose males had evidence of hepatic enlargement or swelling (7/20), although higher absolute and relative liver weights were significant (p < 0.01, Student's t-test) in both males and females of the 2000 ppm group. Also, relative kidney weights were also significantly elevated in the high-dose males. Histopathology confirmed a specific liver toxicity in male rats, marked by significant dose-related hepatocytic hypertrophy with isolated instances of vesicular nuclei and or periacinal hepatocytic necrosis. Renal tubular degeneration, 70% and 20% in 2000 and 100 ppm males respectively, correlated with elevated kidney weights in these groups. [ICI AMERICAS INC; 13 Week Dietary Toxicity Study with PP009 in Rats (Final Report); 05/29/80; EPA Doc No. 88-920006943; Fiche No. OTS0545346]
-- Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically... F1 parents were found with gross indications of toxicity. Liver and kidney weights were significantly high (250 ppm) relative to controls, while spleen weights were low in both sexes (80, 250 ppm).Upon necropsy, these F1 progeny were found with dose-related increased hydronephrosis [kidney]... Upon histological investigation, increased incidence geriatric nephropathy [kidney] (both sexes, 80 and 250 ppm), distension of mesenteric and/or cervical lymph nodes (250 ppm) and increased severity of nephrocalcinosis (females, 80 and 250 ppm), .. [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
--- Definition for nephrocalcinosis: A form of renal stone disease where the kidney tissue is characterised by foci of calcification in addition to numerous deposits of calcium phosphate and calcium oxalate.
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

4.2.3.2 Fluazifop-butyl - Sprague Dawley Rats In a developmental toxicity study (MRID# 00088857, 92067047 and 92067019), fluazifop-butyl, [PP009 (94.8% a.i., batch/lot # P14)] was administered to 22 female CD Sprague Dawley strain rats/group in a corn oil (2 ml/kg) gavage at dose levels of 0, 10, 50 or 200 mg/kg bw/day from days 6 through 20 of gestation. Animals were sacrificed on day 21 ... The incidence of bilateral hydronephrosis at 200 mg/kg/day exceeded the historical control mean but not the range. The incidence of bilateral hydroureter at 200 mg/kg/day exceeded the historical control range and mean. No hydronephrosis nor hydroureter were seen in concurrent controls. In addition, subcutaneous edema (17.7% at 200 mg/kg/day versus 3.4% in concurrent controls) exceeded the mean of 8.9% in historical controls (the upper range was unreadable). The concurrent controls also were less than the mean of historical controls. Diaphragmatic hernia was seen in 1 fetus at 10 mg/kg/day, none at 50 mg/kg/day, and in 3 fetuses at 200 mg/kg/day, with no incidences in 2970 historical control fetuses. However a subsequent much larger study (MRID# 00088858) with 160 litter/group, showed an incidence of diaphragmatic hernias of 3/1113 in control fetuses, 1/1081 fetuses at 1 mg/kg/day, 3/1073 fetuses at 5 mg/kg/day, 2/1064 fetuses at 10 mg/kg/day, and a statistically significantly increased incidence in 59/1064 fetuses and 45/159 litters at 200 mg/kg/day. Since this anomaly was seen at a higher incidence (3 fetuses) in the controls in this study and was not replicated at the same dose in the second study, the single incidence of diaphragmatic hernia at 10 mg/kg/day was considered to be an aberration and not attributable to treatment. For developmental toxicity, the LOAEL is 10 mg/kg/day based on incomplete and/or irregular ossification of the cranial bones and incomplete ossification of thoracic vertebral centra; a NOAEL was not established.
Ref: December 10, 2004. US EPA> Fluazifop-P-butyl: Revised HED Chapter of the Tolerance Reassessment Eligibility Decision (TRED) Document. EPA Docket number: OPP-2004-0347-0003
http://www.fluorideaction.org/pesticides/f-p-b.opp-2004-0347-0003.pdf

Liver (click on for all fluorinated pesticides)

A 3-month rat feeding study demonstrated hepatocyte hypertrophy in males (the LOEL was 5 mg/kg/day; the NOEL was 0.5 mg/kg/ day). In a 1-year feeding study, dogs had changes in serum alkaline phosphatase and alanine aminotransferase and/or alanine sulfatransferase (the LOEL was 25 mg/kg/day; the NOEL was 5 mg/kg/day). Similar changes were also reported in dogs following 3 months exposure in their diet (the LOEL was 125 mg/kg/day). In a carcinogenicity study, male mice fed 20 ppm (2.6 mg/kg/day, the LOEL) had an increased incidence of hepatocyte hypertrophy. The NOEL was 5 ppm or 0.65 mg/kg/ day. Male and female mice exposed to a higher dose of 80 ppm (10.4 mg/ kg/day) had increased liver weight (relative and absolute) and hypertrophy of periacinal hepatocytes. Males in this dose group also had increased pigmentation in hepatocytes and Kupffer cells. In a teratogenicity study in Sprague-Dawley rats exposed via oral gavage, delayed ossification and an increased incidence of hydroureter were observed in fetuses (the fetotoxic LOEL was 5 mg/kg/day; the NOEL 1 mg/kg/day) and a teratogenic LOEL of 200 mg/kg/day (the NOEL was 10 mg/kg/day) was determined based on the incidence of diaphragmatic hernia. Maternal toxicity was observed in this study at doses higher than those causing fetotoxicity and included reduced body weight gain and decreased gravid uterus (the maternal LOEL was 200 mg/kg/day; the NOEL was 10 mg/kg/day). In a 2-generation reproductive toxicity dietary study in Wistar rats, the reproductive LOEL of 250 ppm (12.5 mg/kg/day; the NOEL was 80 ppm or 4 mg/kg/day) was based on reduced litter sizes, reduced viability, reduced testis and epididymis weights and tubular atrophy in offspring. Fetotoxicity (delayed ossification and eye opacities) was also demonstrated in New Zealand White rabbits (the LOEL was 30 mg/kg/day; the NOEL was 10 mg/kg/day). EPA believes that there is sufficient evidence for listing fluazifop butyl on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and developmental toxicity data for this chemical.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.
http://www.epa.gov/tri/frnotices/59fr1788.htm

-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic oral toxicity in beagle dogs (4/sex/group) administered doses of 0 (vehicle control, corn oil), 5, 25 and 250 mg/kg/day in gelatin capsules for 13 weeks. Severe corneal ulceration, requiring humane sacrifice of 2 males and 1 female of a 250 mg/kg/day dosage during Week 4, prompted adjustment of this regimen to 125 mg/kg/day for the remainder of study... Distended gall bladders, large friable livers and congested caecum and colon from engorgement of the blood vessels were noted upon necropsy. Histopathological evaluation confirmed treatment-related lesions of the eyes, liver, testes and gastrointestinal tract. [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate: 13-Week Oral Toxicity Study in Beagle Dogs; 04/24/80; EPA Doc No. 88-920006846; Fiche No. OTS0543851]
-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic dietary toxicity in Wistar rats (20/sex/group) receiving 0, 10, 100 and 2000 ppm by dietary inclusion for 13 weeks. Mean achieved dosages during 13-week treatment were 0, 0.7, 7.1 and 144.5 mg/kg/day in males of the respective treatment groups and 0, 0.8, 8.0 and 161.9 mg/kg/day in females... Upon terminal necropsy, only high-dose males had evidence of hepatic enlargement or swelling (7/20), although higher absolute and relative liver weights were significant (p < 0.01, Student's t-test) in both males and females of the 2000 ppm group... Histopathology confirmed a specific liver toxicity in male rats, marked by significant dose-related hepatocytic hypertrophy with isolated instances of vesicular nuclei and or periacinal hepatocytic necrosis... [ICI AMERICAS INC; 13 Week Dietary Toxicity Study with PP009 in Rats (Final Report); 05/29/80; EPA Doc No. 88-920006943; Fiche No. OTS0545346]
-- -- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subacute oral toxicity in Wistar albino rats (10/sex/group) administered 10 ml/kg doses in corn oil of 0, 4, 20, 100 and 500 mg/kg/day by oral gavage, 5 days/week for 2 weeks. Five-day weekly treatment periods were each followed by 2-day recovery... Male rats of 100 and 500 mg/kg/day dosages had higher absolute and relative liver weights that was not seen in their female counterparts. Microscopic examination confirmed a particular liver pathology of treated males, characterized by dosage-related hepatocytic hypertrophy and necrosis (study lethalities), and dosage-related slight to moderate periacinal hepatocytic hypertrophy... [ICI AMERS INC; 14 Day Subacute Oral Toxicity Study with PP009 in Rats; 07/11/80; EPA Doc No. 88-920007017; Fiche No. OTS0545392]
-- Fluazifop butyl (CAS # 69806-50-4) was evaluated for developmental toxicity in the progeny of Sprague-Dawley CD rats administered oral doses of 0 (corn oil vehicle control), 10, 50 and 200 mg/kg/day by gavage on gestation days 6-20... Relative liver weights were also significantly (p < 0.05) greater in high-dose dams... [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate butyl: Effects of Oral Administration Upon Pregnancy in Rats; 05/23/80; EPA Doc No. 88-920006839; Fiche No. OTS0543844]
-- Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically... Liver and kidney weights were significantly high (250 ppm) relative to controls, while spleen weights were low in both sexes (80, 250 ppm)... [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic oral toxicity in beagle dogs (4/sex/group) administered doses of 0 (vehicle control, corn oil), 5, 25 and 250 mg/kg/day in gelatin capsules for 13 weeks. Severe corneal ulceration, requiring humane sacrifice of 2 males and 1 female of a 250 mg/kg/day dosage during Week 4, prompted adjustment of this regimen to 125 mg/kg/day for the remainder of study. Prior to sacrifice... Histopathological evaluation confirmed treatment-related lesions of the eyes, liver, testes and gastrointestinal tract. [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate: 13-Week Oral Toxicity Study in Beagle Dogs; 04/24/80; EPA Doc No. 88-920006846; Fiche No. OTS0543851]
Ref: Fluazifop-butyl. TOXNET profile from Hazardous Substances Data Bank.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

**411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... All other noteworthy findings were limited to the high dose group, as follows. Seven 125 mg/kg/day dogs (5 M, 2 F) were killed in extremis prior to term, generally after at least 29 weeks on study... Liver dysfunction was indicated by periacinar hepatocytic degeneration and thinning of hepatic cords in some dogs, other hepatocytic changes such as vacuolation and/or granular cytoplasm, and occasional bile plugs in the canaliculi •. Most clinical chemistry changes were plausibly related to liver toxicity, including elevated alkaline phosphatase, ALT, and occasionally AST. Substantially increased BSP retention was consistent with biliary disturbance. Urine was typically bright yellow or orange due to high bile pigment concentrations. Cholesterol was consistently reduced. Male reproductive toxicity included testicular tubular degeneration and reduced/absent spermatozoa in epididymides. Possible adverse effects (many-faceted toxicity, including mortalities, at 125 mg/kg/day). Acceptable. Aldous, 5/20/02.
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Fluazifop-P-butyl.CAepa.02.pdf
• Canaliculi - In liver, small channels between hepatocytes through which bile flows to the bile duct and thence to the intestinal lumen.

Abstract: The aim of this study was to determine the effect of herbicide fluazifop, on the early occurring changes in rat liver regarded as hepatic markers of peroxisome proliferators (PPs). Fluazifop was administered orally to male Wistar rats at increasing doses from 5.6 to 891 mg/kg body weight per day for 1, 2, 4, 7 and 14 consecutive days and peroxisome proliferation, induction of some peroxisome-associated enzymes and mitogenesis (S-phase, M-phase and percentage of binucleated hepatocytes) were studied. Short-term treatment of rats with fluazifop resulted in hepatomegaly due to time dependent proliferation of smooth endoplasmic reticulum (SER) and peroxisomes. The increase in the number of peroxisomes in the hepatocytes was supported by an increase in peroxisomal palmitoyl-CoA oxidation and catalase activity. In contrast to other PPs fluazifop induced low rate of rcplicative DNA synthesis and did not affect mitoses (M-phase). DNA synthesis was accompanied by the appearance of binucleated hepatocytes. Thus, we can conclude that fluazifop produces in male Wistar rats hepatomegaly due to cellular hypertrophy. The threshold dose for palmitoyl-CoA oxidation and DNA synthesis was 112 and 223 mg/kg body weight per day, respectively. The value for hepatomegaly and catalase activity was 56 mg/kg body weight per day. The results presented in this paper demonstrated that fluazifop can be classified as a weak rodent PPs.
Ref: Hepatocellular peroxisome proliferation and DNA synthesis in Wistar rats treated with herbicide fluazifop; by Kostka G, Palut D, Ludwicki JK, Kopec-Szlezak J, Wiadrowska B, Lembowicz K. Toxicology. 2002 Sep 16;178(3):221-8.

Mesenteric Lymph Nodes (click on for all fluorinated pesticides)

Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subacute oral toxicity in Wistar albino rats (10/sex/group) administered 10 ml/kg doses in corn oil of 0, 4, 20, 100 and 500 mg/kg/day by oral gavage, 5 days/week for 2 weeks. Five-day weekly treatment periods were each followed by 2-day recovery. High-dose males only displayed overt toxicity and comprised the 2 study lethalities. These two 500 mg/kg/day males were sacrificed in extremis on Days 11 and 14 with severe pharmacotoxic signs including piloerection, reduced motor activity, retinal pallor, and a prone or hunched posture. One rat was bleeding from the penis ... The decedent animals were found with abnormal upper gastrointestinal contents, and one rat exhibited congestion of mesenteric lymph nodes with pallor of kidneys, liver and spleen... [ICI AMERS INC; 14 Day Subacute Oral Toxicity Study with PP009 in Rats; 07/11/80; EPA Doc No. 88-920007017; Fiche No. OTS0545392].
-- Fuazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2)... Upon histological investigation, increased incidence geriatric nephropathy (both sexes, 80 and 250 ppm), distension of mesenteric and/or cervical lymph nodes (250 ppm) and increased severity of nephrocalcinosis (females, 80 and 250 ppm), and an increased slight testicular tubular atrophy in males (250 ppm) were noted. F2 female progeny of 250 ppm exposed parents were found with significantly increased absolute and relative spleen weights. Histological changes were limited to marginal increases in hydronephrosis. [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
Ref: TOXNET profile from Hazardous Substances Data Bank. FLUAZIFOP-BUTYL. CASRN: 69806-50-4.
http://www.fluoridealert.org/pesticides/fluazifop-butyl.toxnet.hsdb.htm

Spleen (click on for all fluorinated pesticides)

Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically.... F2 female progeny of 250 ppm exposed parents were found with significantly increased absolute and relative spleen weights... [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
Ref: TOXNET profile from Hazardous Substances Data Bank for FLUAZIFOP-BUTYL.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

Teratogenic (click on for all fluorinated pesticides)

In a teratogenicity study in Sprague-Dawley rats exposed via oral gavage, delayed ossification and an increased incidence of hydroureter were observed in fetuses (the fetotoxic LOEL was 5 mg/kg/day; the NOEL 1 mg/kg/day) and a teratogenic LOEL of 200 mg/kg/day (the NOEL was 10 mg/kg/day) was determined based on the incidence of diaphragmatic hernia.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993).
As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.