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Abstracts

Activity: Fungicide (azole)

ACTIVITY: Fungicide (azole)

Synonyms for Triflumizole [BSI:ISO] - CAS No. 68694-11-1
• (E)-4-Chloro-alpha,alpha,alpha-trifluoro-N-(1-imidazol-1-yl-2-propoxyethylidene)-o-toluidine
• 1-(1-((4-Chloro-2-(trifluoromethyl)phenyl)imino)-2-propoxyethyl)-1H-imidazole
• 4-Chloro-alpha,alpha,alpha-trifluoro-N-(1-imidazol-1-yl-2-propoxyethylidene)-o-toluidine

Structure for CAS No. 99387-89-0	Structure for CAS No. 68694-11-1

Adverse Effects:
Anemia
Body Weight Decrease
Bone
Endocrine: Ovary
Endocrine: Vaginal
Kidney
Liver
Reproductive Toxicant
Environmental

Anemia (click on for all fluorinated pesticides)

-- Chronic toxicity nonrodents (dog): LOAEL = Males: 34.10 mg/kg/day; Females: 35.17 mg/ kg/daybased on increased alkaline phosphatase activity and a mild, macrocytic anemia in males, increased absolute and relative liver weights in both sexes, and on macroscopic findings in the liver of both sexes.
Ref: Federal Register: June 12, 2002. Triflumizole; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Triflumizole.FR.June12.2002.htm

Body Weight Decrease (click on for all fluorinated pesticides)

-- Reproduction and fertility effects (rat): ... Parental/Systemic: LOAEL = 21 mg/kg/ day based on decreased body weight and overall body weight gain, increased relative liver weights, and increased mortality in females.
Ref: Federal Register: June 12, 2002. Triflumizole; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Triflumizole.FR.June12.2002.htm

Bone (click on for all fluorinated pesticides)

-- Prenatal Maternal developmental in rodents (rat): Developmental NOAEL = 10 mg/kg/ day LOAEL = 35 mg/kg/ day based on decreased numbers of viable fetuses, increased dead or resorbed fetuses, increased numbers of late resorptions, decreased fetal body weight, and increased incidences of cervical ribs.
-- Prenatal Maternal developmental in nonrodents (rabbit): Developmental NOAEL = 50 mg/kg/ day LOAEL = 100 mg/kg/ day based on decreased 24-hour survival, decreased placental weights, and increased fetal and litter incidences of lumbar ribs.
Ref: Federal Register: June 12, 2002. Triflumizole; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Triflumizole.FR.June12.2002.htm

-- The teratology studies were conducted in the rabbit and rat. In the rat studies, incidences of dilatation of the renal pelvis and increased 14th rudimentary ribs were seen. In the rabbit, an increase in postimplantation losses was noted.
Ref: Ref: EPA Pesticide Fact Sheet September 1991. Triflumizole (Terraguard, Procure).
http://pmep.cce.cornell.edu/profiles/fung-nemat/tcmtb-ziram/triflumizole/fung-prof-triflumizole.html

Endocrine: Ovary (click on for all fluorinated pesticides)

-- Chronic feeding/oncogenicity studies were conducted in both the rat and mouse. The chronic feeding study in the rat suggests that the liver is the main target organ with the ovary and kidney as secondary target organs. Although there was an accompanying increase in organ weights, no carcinogenic effects were seen...
-- A 2-year feeding/oncogenicity study with Sprague-Dawley rats was conducted. Rats were fed 0, 5, 20 or 80 mg/kg/day doses of triflumizole equivalent to 0, 100, 400 and 1600 ppm triflumizole for 104 weeks with an interim sacrifice at 52 weeks. Numerous organ weights, clinical chemistry and hematology parameters and microscopic changes indicate the main target organ is the liver, with fatty vacuolization and periacinar hepatic hypertrophy seen at all dose levels tested. Ovarian organ weights as well as well-developed follicles indicate the ovary as a target...
-- In a 3-generation rat reproduction study, dose levels of 0, 70, 170 and 420 ppm in feed resulted in a NOEL greater than 70 ppm (LDT) based on increased gestation length. At 170 ppm there was pup mortality. At 420 ppm, there was reduced body weight gain, increased length of estrous cycles, reduced vaginal cornification, extended gestation length and high pup mortality.
Ref: EPA Pesticide Fact Sheet September 1991. Triflumizole (Terraguard, Procure).
http://pmep.cce.cornell.edu/profiles/fung-nemat/tcmtb-ziram/triflumizole/fung-prof-triflumizole.html

-- Endocrine disruption. In the rat reproduction study there was an increase in placental weight in females at the high dose level of 170 ppm. There was also a biologically significant increase in gestation length in high dose F0 and F2 females (F1a and F3a intervals). The NOAEL for endocrine effects is 70 ppm (3.5 mg/kg/day).
Ref: [Federal Register: July 6, 2001 [Notices] [Page 35623-35628]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food. http://www.fluoridealert.org/pesticides/Triflumizole.FR.July6.2001.htm

-- Two three-generation reproduction studies in rats (when considered together) with a reproductive toxicity NOEL of 30 ppm (1.5 mg/kg/day) and a reproductive toxicity LEL of 70 ppm (3.5 mg/kg/day). Triflumizole is considered a reproductive toxicant.
Ref: Federal Register: November 16, 1994. Pesticide Tolerances and Feed Additive Regulations for Triflumizole. Final Rule.
http://www.fluoridealert.org/pesticides/Triflumizole.FR.Nov.16.1994.htm

Endocrine: Vaginal (click on for all fluorinated pesticides)

-- In a 3-generation rat reproduction study, dose levels of 0, 70, 170 and 420 ppm in feed resulted in a NOEL greater than 70 ppm (LDT) based on increased gestation length. At 170 ppm there was pup mortality. At 420 ppm, there was reduced body weight gain, increased length of estrous cycles, reduced vaginal cornification, extended gestation length and high pup mortality.
Ref: EPA Pesticide Fact Sheet September 1991. Triflumizole (Terraguard, Procure).
http://pmep.cce.cornell.edu/profiles/fung-nemat/tcmtb-ziram/triflumizole/fung-prof-triflumizole.html

Kidney (click on for all fluorinated pesticides)

-- Reproduction and fertility effects (rat): Reproductive NOAEL = not identified LOAEL = 3.5 mg/kg/ day based on increased gestation length in P. Offspring NOAEL = 8.5 mg/kg/ day LOAEL = 21 mg/kg/ day based on decreased pup body weight, survival indices, and litter sizes and a slight increased incidence of hydronephrosis in F1a pups.
Ref: Federal Register: June 12, 2002. Triflumizole; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Triflumizole.FR.June12.2002.htm

-- Chronic feeding/oncogenicity studies were conducted in both the rat and mouse. The chronic feeding study in the rat suggests that the liver is the main target organ with the ovary and kidney as secondary target organs...
-- A 2-year feeding/oncogenicity study with Sprague-Dawley rats was conducted. Rats were fed 0, 5, 20 or 80 mg/kg/day doses of triflumizole equivalent to 0, 100, 400 and 1600 ppm triflumizole for 104 weeks with an interim sacrifice at 52 weeks. Numerous organ weights, clinical chemistry and hematology parameters and microscopic changes indicate the main target organ is the liver, with fatty vacuolization and periacinar hepatic hypertrophy seen at all dose levels tested. Ovarian organ weights as well as well-developed follicles indicate the ovary as a target. Kidney weights were affected as well with increased cortical cysts seen in the kidneys of mid and high dose animals. The NOEL is greater than 100 ppm, based on fatty vacuolization and periacinar hepatic hypertrophy seen at all dose levels tested. An increase in tumor incidence was not noted in any treatment groups.
Ref: Ref: EPA Pesticide Fact Sheet September 1991. Triflumizole (Terraguard, Procure).
http://pmep.cce.cornell.edu/profiles/fung-nemat/tcmtb-ziram/triflumizole/fung-prof-triflumizole.html

Liver (click on for all fluorinated pesticides)

-- Reproduction and fertility effects (rat): ... Parental/Systemic: LOAEL = 21 mg/kg/ day based on decreased body weight and overall body weight gain, increased relative liver weights, and increased mortality in females.
-- Chronic toxicity nonrodents (dog): LOAEL = Males: 34.10 mg/kg/day; Females: 35.17 mg/ kg/daybased on increased alkaline phosphatase activity and a mild, macrocytic anemia in males, increased absolute and relative liver weights in both sexes, and on macroscopic findings in the liver of both sexes.
-- Carcinogenicity (mouse): LOAEL = Males: 67.4 mg/kg/day; Females: 86.1 mg/ kg/day based on microscopic lesions of the liver. No evidence of carcinogenicity.
-- 90-Day oral toxicity rodents (rats): LOAEL = Males: 176.5 mg/kg/day; Females: 217.9 mg/ kg/daybased on increased kidney and liver weights and the accumulation of fat droplets in the liver.
Ref: Federal Register: June 12, 2002. Triflumizole; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Triflumizole.FR.June12.2002.htm

-- Chronic feeding/oncogenicity studies were conducted in both the rat and mouse. The chronic feeding study in the rat suggests that the liver is the main target organ with the ovary and kidney as secondary target organs. Although there was an accompanying increase in organ weights, no carcinogenic effects were seen. In the chronic feeding study in mice, the results of blood chemistry, organ weights and gross and histological examinations also indicate the liver as the target organ...
-- A 2-year feeding/oncogenicity study with Sprague-Dawley rats was conducted. Rats were fed 0, 5, 20 or 80 mg/kg/day doses of triflumizole equivalent to 0, 100, 400 and 1600 ppm triflumizole for 104 weeks with an interim sacrifice at 52 weeks. Numerous organ weights, clinical chemistry and hematology parameters and microscopic changes indicate the main target organ is the liver, with fatty vacuolization and periacinar hepatic hypertrophy seen at all dose levels tested...
-- A 2-year feeding/oncogenicity study with male and female mice using dietary concentrations of 0, 100, 400 and 1600 ppm equivalent to 0, 15, 60 and 240 mg/kg/day was conducted. There were interim sacrifices at 26, 54, 78 and 104 weeks. Major effects were seen in the liver at all doses tested. Clinical chemistry changes reflecting liver toxicity included changes in alkaline phosphatase, BUN, SGOT, SGPT and cholesterol. Absolute and relative liver weights were increased at all time periods in the high dose males and females and in some animals of the mid dose groups. At sacrifice, liver changes in all dose groups included hepatic nodules and cytoplasmic alterations. The systemic NOEL was less than 100 ppm. Although there was a slight increase the incidence of lymphoma in both treated males and females, it was judged not be compound-related.
-- A 30-day feeding study with rats was conducted using dietary concentrations of 20, 200 and 2000 ppm equivalent to 0, 2, 20 and 200 mg/kg/day. The NOEL was 200 ppm and the LEL was 2000 ppm based on liver changes, necrosis and fatty metamorphosis.
Ref: EPA Pesticide Fact Sheet September 1991. Triflumizole (Terraguard, Procure).
http://pmep.cce.cornell.edu/profiles/fung-nemat/tcmtb-ziram/triflumizole/fung-prof-triflumizole.html

Abstract: The hepatotoxic effects of 22 pesticides were studied. Hepatocytes, mitochondria, and microsomes were prepared from Sprague-Dawley-rats and incubated with the test substances in-vitro ... Hepatic mitochondrial respiration was affected by ... triflumizole (68694-11-1).
Ref: Effects of pesticides on isolated rat hepatocytes, mitochondria, and microsomes II; by YAMANO T, MORITA S. ARCHIVES OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY; 28 (1). 1995. 1-7.

Reproductive Toxicant (click on for all fluorinated pesticides)

-- Two three-generation reproduction studies in rats (when considered together) with a reproductive toxicity NOEL of 30 ppm (1.5 mg/kg/day) and a reproductive toxicity LEL of 70 ppm (3.5 mg/kg/day). Triflumizole is considered a reproductive toxicant.
Ref: Federal Register: November 16, 1994. Pesticide Tolerances and Feed Additive Regulations for Triflumizole. Final Rule. http://www.fluoridealert.org/pesticides/Triflumizole.FR.Nov.16.1994.htm

-- In a 3-generation rat reproduction study, dose levels of 0, 70, 170 and 420 ppm in feed resulted in a NOEL greater than 70 ppm (LDT) based on increased gestation length. At 170 ppm there was pup mortality. At 420 ppm, there was reduced body weight gain, increased length of estrous cycles, reduced vaginal cornification, extended gestation length and high pup mortality.
Ref: EPA Pesticide Fact Sheet September 1991. Triflumizole (Terraguard, Procure).
http://pmep.cce.cornell.edu/profiles/fung-nemat/tcmtb-ziram/triflumizole/fung-prof-triflumizole.html

-- Endocrine disruption. In the rat reproduction study there was an increase in placental weight in females at the high dose level of 170 ppm. There was also a biologically significant increase in gestation length in high dose F0 and F2 females (F1a and F3a intervals). The NOAEL for endocrine effects is 70 ppm (3.5 mg/kg/day).
Ref: [Federal Register: July 6, 2001 [Notices] [Page 35623-35628]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food. http://www.fluoridealert.org/pesticides/Triflumizole.FR.July6.2001.htm