ACTIVITY: Fungicide (Carbamate)

Name: [[isopropyl[(S)-1-[(R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]carbamoyl-2-methylpropyl]carbamate]

Structure for Benthiavalicarb-isopropyl

Adverse Effects
Anemia
Bone
Cancer: Uterine, Liver, Thyroid
Endocrine: Uterus
Kidney
Liver
Reproductive/Developmental
Thyroid

Anemia (click on for all fluorindated pesticides)

• In the 13-week feeding study with mice, the dose levels were 0, 50, 200, 7,000, or 20,000 ppm. The NOAEL was 200 ppm (equivalent to 33.0 mg/kg/day and 45.2 mg/kg/day in males and females, respectively, based on systemic toxicity of decreased body weights, anemias, and generalized liver toxicity at 7,000 ppm.
Ref: March 9, 2005. Petition for the establishment of Tolerances on Imported Grapes and Tomatoes. Federal Register: March 9, 2005.

Bone (click on for all fluorindated pesticides)

• In a developmental toxicity study in New Zealand White rabbits receiving 0, 10, 20 or 40 mg/kg/day benthiavalicarb-isopropyl from day 6 to 28 of gestation, the maternal NOAEL was 20 mg/kg/day based on abortion and increased liver weights at the 40 mg/kg/day dose. The developmental NOAEL was 20 mg/kg/day based on increased incidence of small fetus and delayed ossification of the hindlimb talus at 40 mg/kg/day.
Ref: March 9, 2005. Petition for the establishment of Tolerances on Imported Grapes and Tomatoes. Federal Register: March 9, 2005.

Cancer (click on for all fluorinated pesticides)

Likely to be Carcinogenic to Humans. Malignant uterine tumors in female Fisher 344 rats; Liver tumors in both sexes of B6C3F1 mice with some supporting evidence of liver tumors in male rats; Thyroid follicular cell tumors in male B6C3F1 mice.
Ref: April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs.
From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

Endocrine: Uterus (click on for all fluorindated pesticides)

.• In a chronic/oncogenicity study Fisher rats received 0, 50, 200, 5,000, or 10,000 ppm of benthiavalicarb- isopropyl for up to 104 weeks. The NOAEL was 200 ppm (9.9 mg/kg/day and 12.5 mg/kg/day in males and females respectively), based on a variety
of toxic effects, primarily in the liver and kidney, and adenocarcinomas of the uterus at 5,000 ppm.
Ref: March 9, 2005. Petition for the establishment of Tolerances on Imported Grapes and Tomatoes. Federal Register: March 9, 2005.

Kidney (click on for all fluorindated pesticides)

• In a chronic/oncogenicity study Fisher rats received 0, 50, 200, 5,000, or 10,000 ppm of benthiavalicarb- isopropyl for up to 104 weeks. The NOAEL was 200 ppm (9.9 mg/kg/day and 12.5 mg/kg/day in males and females respectively), based on a variety
of toxic effects, primarily in the liver and kidney, and adenocarcinomas of the uterus at 5,000 ppm.
• In an oncogenicity study in mice, the dietary doses were 0, 20, 100, 2,500 or 5,000 ppm. The NOAEL was 100 ppm (13.7 mg/kg/day and 18.6 mg/kg/day in males and females, respectively) based on a variety of toxic effects, primarily in the liver and kidney, and hepatocellular blastoma and carcinoma at 2,500 ppm.
Ref: March 9, 2005. Petition for the establishment of Tolerances on Imported Grapes and Tomatoes. Federal Register: March 9, 2005.

Liver (click on for all fluorindated pesticides)

Likely to be Carcinogenic to Humans. Malignant uterine tumors in female Fisher 344 rats; Liver tumors in both sexes of B6C3F1 mice with some supporting evidence of liver tumors in male rats; Thyroid follicular cell tumors in male B6C3F1 mice.
Ref: April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs.
From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

• In a 2-generation reproduction study in Sprague Dawley rats receiving 0, 100, 1,000 or 10,000 ppm benthiavalicarb-isopropyl in the diet, the parental noobserved adverse effect level (NOAEL) was 100 ppm based on hepatocyte hypertrophy at the next higher dose level. The reproductive NOAEL was 10,000 ppm.
• In a developmental toxicity study in New Zealand White rabbits receiving 0, 10, 20 or 40 mg/kg/day benthiavalicarb-isopropyl from day 6 to 28 of gestation, the maternal NOAEL was 20 mg/kg/day based on abortion and increased liver weights at the 40 mg/kg/day dose.
• In a developmental toxicity study in Sprague Dawley rats receiving 0, 10, 100 or 1,000 mg/kg/day from day 7 to day 19 of
gestation, the maternal NOAEL was 10 mg/kg/day based on elevated liver and adrenal weights at 100 mg/kg/day. The NOAEL for developmental toxicity was 1,000 mg/kg/day.
• In the 13-week feeding study with mice, the dose levels were 0, 50, 200, 7,000, or 20,000 ppm. The NOAEL was 200 ppm (equivalent to 33.0 mg/kg/day and 45.2 mg/kg/day in males and females, respectively, based on systemic toxicity of decreased body weights, anemias, and generalized liver toxicity at 7,000 ppm.
• In the 3 month dog feeding study the dose levels were 0, 40, 200, or 1,000 mg/kg/day. The NOAEL was 40 mg/kg/day based on hematological and clinical chemistry changes, organ weight changes and the findings of hepatocyte hypertrophy and pigmentation in the spleen at 200 mg/kg/day.
.• In a chronic/oncogenicity study Fisher rats received 0, 50, 200, 5,000, or 10,000 ppm of benthiavalicarb- isopropyl for up to 104 weeks. The NOAEL was 200 ppm (9.9 mg/kg/day and 12.5 mg/kg/day in males and females respectively), based on a variety
of toxic effects, primarily in the liver and kidney, and adenocarcinomas of the uterus at 5,000 ppm.
• In an oncogenicity study in mice, the dietary doses were 0, 20, 100, 2,500 or 5,000 ppm. The NOAEL was 100 ppm (13.7 mg/kg/day and 18.6 mg/kg/day in males and females, respectively) based on a variety of toxic effects, primarily in the liver and kidney, and hepatocellular blastoma and carcinoma at 2,500 ppm.
• In a 52-week study with Beagle dogs, the dietary dose levels were 0, 4, 40, or 400 mg/kg/day. The NOAEL was 40 mg/kg/day based on increased liver weights in males and females at 400 mg/kg/day.
• Numerous supplemental mechanistic studies in the rodent were carried out to further elucidate the mechanisms involved in tumor formation in the lifetime rodent studies. These studies indicated that benthiavalicarb-isopropyl behaves like a promotor following initiation with diethylnitrosamine (DEN), and does not have initiating activity. The compound did not cause oxidative damage in studies on rat or mouse liver, was a slight enzyme inducer, and did not cause hepatocyte proliferation.
Ref: March 9, 2005. Petition for the establishment of Tolerances on Imported Grapes and Tomatoes. Federal Register: March 9, 2005.

Reproductive / Developmental (click on for all fluorindated pesticides)

• In a 2-generation reproduction study in Sprague Dawley rats receiving 0, 100, 1,000 or 10,000 ppm benthiavalicarb-isopropyl in the diet, the parental noobserved adverse effect level (NOAEL) was 100 ppm based on hepatocyte hypertrophy at the next higher dose level. The reproductive NOAEL was 10,000 ppm.
• In a developmental toxicity study in New Zealand White rabbits receiving 0, 10, 20 or 40 mg/kg/day benthiavalicarb-isopropyl from day 6 to 28 of gestation, the maternal NOAEL was 20 mg/kg/day based on abortion and increased liver weights at the 40 mg/kg/day dose. The developmental NOAEL was 20 mg/kg/day based on increased incidence of small fetus and delayed ossification of the hindlimb talus at 40 mg/kg/day.
• In a developmental toxicity study in Sprague Dawley rats receiving 0, 10, 100 or 1,000 mg/kg/day from day 7 to day 19 of
gestation, the maternal NOAEL was 10 mg/kg/day based on elevated liver and adrenal weights at 100 mg/kg/day. The NOAEL for developmental toxicity was 1,000 mg/kg/day.
Ref: March 9, 2005. Petition for the establishment of Tolerances on Imported Grapes and Tomatoes. Federal Register: March 9, 2005.

Thyroid (click on for all fluorindated pesticides)

Likely to be Carcinogenic to Humans. Malignant uterine tumors in female Fisher 344 rats; Liver tumors in both sexes of B6C3F1 mice with some supporting evidence of liver tumors in male rats; Thyroid follicular cell tumors in male B6C3F1 mice.
Ref: April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs.
From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf