Adverse Effects
Fluoxastrobin
CAS Nos. 361377-29-9 and 193740-76-0
 
 

Return to Fluoxastrobin Index Page

Activity: Fungicide (strobin)
Structure:



Adverse Effects:
Body Weight
Bone
Decrease

Endocrine: Adrenal
Endocrine: Testicular
Endocrine: Thyroid
Endocrine: Uterus
Kidney
Liver
Reproductive
Spleen
Urinary tract

Environmental:
• Moderately to highly persistent in soil.
Moderately toxic to estuarine/marine fish.
• Highly toxic to freshwater fish and invertebrates.
• Very highly toxic to estuarine/marine invertebrates.

• Risks to endangered
/threatened freshwater fish species.

Body Weight Decrease (click on for all fluorinated pesticides)

-- Subchronic toxicity. A subchronic toxicity feeding study with rats over 90 days demonstrated a NOAEL of 7.3 and 18.3 mg/kg bwt/day for males and females, respectively, based on reduced body weights and alterations in several urinary tract-related clinical chemistry parameters, at the higher dose levels. In a subchronic feeding study in mice over 14 weeks, a NOAEL was not established based on decreased alanine aminotransferase (ALAT) and increased absolute and relative liver weights at the low dose level (21.7 and 35.3 mg/kg bwt/day for males and females respectively). A 14-week feeding study in dogs demonstrated a NOAEL of 3.0 mg/kg bwt/day based on decreased body weights and food consumption, and liver effects (enzyme induction, increased liver weights, cytoplasmic change), and thyroid effects (decreased T3)
-- Chronic toxicity... A 1-year feeding study with dogs demonstrated a NOAEL of 1.7 and 1.5 mg/kg bwt/day for males and females, respectively based on decreased body weights and slight liver effects (increased alkaline phosphatase (Aph) and liver weights).
Ref: Federal Register: April 23, 2003. Fluoxastrobin; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm

• Reproduction and fertility - rats. Offspring systemic: decreased body weights, delayed preputial separation, and incomplete ossification in the F1 and/or F2 males and females. Parental systemic: decreased premating body weight gain of the P-generation males and females and decreased premating absolute body weight of the F1 males and females.
• Chronic toxicity-dogs. LOAEL was 8.1 mg/kg/day for males and 7.7 mg/kg/day for females based on body weight reductions and hepatocytomegaly and cytoplasmic changes associated with increased serum liver alkaline phosphatase indicative of cholestasis.
• 90-Day oral toxicity-rats. reduced body weight gain and food intake, vacuolation in the zona fasciculate of the adrenal cortex, calculi in the urethra and kidney, and histological lesions in kidney, urinary bladder, and urethra;
• 90-Day oral toxicity-dogs.
dose-related reductions in net body weight gain and food efficiency in addition to toxicity findings in the liver in both sexes (cholestasis) and in kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).
• Combined chronic toxicity / carcinogenicity--rats. decreased body weight, decreased body weight gain, and decreased food efficiency in both sexes; decreased spleen weight in males; and microscopic lesions in the uterus of females. The apparent increase in tumors in the uterus and thyroid were addressed and resolved by an Agency committee, which concluded that no carcinogenic concern exists for fluoxastrobin.
90-Day Subchronic Oral Toxicology-Dog. dose-related reductions in net body weight gain and food efficiency; toxicity findings in the liver (cholestasis) in both sexes; and toxicity findings in the kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Bone (click on for all fluorinated pesticides)

Reproduction and fertility - rats. Offspring systemic: decreased body weights, delayed preputial separation, and incomplete ossification in the F1 and/or F2 males and females.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Endocrine: Adrenal (click on for all fluorinated pesticides)

• 90-Day oral toxicity-rats. reduced body weight gain and food intake, vacuolation in the zona fasciculate of the adrenal cortex, calculi in the urethra and kidney, and histological lesions in kidney, urinary bladder, and urethra;
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Definitions:
• the outer portion of the adrenal gland that secretes hormones that are vital to the body. adrenal gland - the pair of adrenal glands are located on top of both kidneys. Adrenal glands work hand-in-hand with the hypothalamus and pituitary gland.

androgen hormone - a hormone secreted by the adrenal cortex which affects the development of male characteristics. aldosterone - a hormone secreted by the adrenal cortex which affects blood pressure and saline balance. ...
www.chw.org/display/PPF/DocID/2687/router.asp
• The outer part of the adrenal gland, which secretes a group of hormones involved in mineral metabolism and glucose metabolism.
www.enzy.com/glossary/searchresults.asp
• An endocrine organ that secretes corticosteroids for metabolic functions: aldosterone for sodium retention in the kidneys, androgens for male sexual development, and oestrogens for female sexual development.
www.mindsci-clinic.com/neuro_jargon.htm
• the cortex of the adrenal gland; secretes corticosterone and sex hormones
wordnet.princeton.edu/perl/webwn
• In mammals, the adrenal glands (also known as suprarenal glands) are the triangle-shaped endocrine glands that sit atop the kidneys. They are chiefly responsible for regulating the stress response through the synthesis of corticosteroids and catecholamines, including cortisol and adrenalin.
en.wikipedia.org/wiki/Adrenal_cor

Endocrine: Testicular (click on for all fluorinated pesticides)

Offspring systemic (rat): decreased body weights, delayed preputial separation*, and incomplete ossification in the F1 and/or F2 males and females. Parental systemic: decreased premating body weight gain of the P-generation males and females and decreased premating absolute body weight of the F1 males and females.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

* Note: Preputial separation is an indicator of sexual maturation

Endocrine: Thyroid (click on for all fluorinated pesticides)

-- Subchronic toxicity... A 14-week feeding study in dogs demonstrated a NOAEL of 3.0 mg/kg bwt/day based on decreased body weights and food consumption, and liver effects (enzyme induction, increased liver weights, cytoplasmic change), and thyroid effects (decreased T3)
Ref: Federal Register: April 23, 2003. Fluoxastrobin; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm

-- In response to a comment submitted to EPA by FAN Pesticide Project, EPA stated:
FAN suggested that a 14-week feeding study using dogs showed an effect on the thyroid, which seems to conflict with the statement that ``...There is no evidence to suggest that fluoxastrobin has any primary endocrine disruptive potential.'' FAN stated that a ``discussion or rationale'' addressing this should have been provided. EPA does believe that the thyroid effects seen in the dog study indicated that fluoxastrobin is an endocrine disruptor. An effect on the thyroid gland, even though this gland is part of the endocrine system, does not necessarily mean that endocrine disruption has or will occur. In this case, the effects observed in the thyroid gland were induced by effects fluoxastrobin had on liver enzymes and are therefore considered secondary.
-- Combined chronic toxicity / carcinogenicity--rats. decreased body weight, decreased body weight gain, and decreased food efficiency in both sexes; decreased spleen weight in males; and microscopic lesions in the uterus of females. The apparent increase in tumors in the uterus and thyroid were addressed and resolved by an Agency committee, which concluded that no carcinogenic concern exists for fluoxastrobin.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Endocrine: Uterus (click on for all fluorinated pesticides)

Combined chronic toxicity / carcinogenicity--rats. decreased body weight, decreased body weight gain, and decreased food efficiency in both sexes; decreased spleen weight in males; and microscopic lesions in the uterus of females. The apparent increase in tumors in the uterus and thyroid were addressed and resolved by an Agency committee, which concluded that no carcinogenic concern exists for fluoxastrobin.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

The incidence of uterus adenocarcinomas was statistically significantly increased. The RMS concluded that this was not a substance-related carcinogenic effect. However, the range of the historical control is not the only criterion for the biological relevance of an increased tumor incidence. The incidence of the adenocarcinomas in the uterus is significantly increased from 3/50 animals in the control group to 10/49 animals in the highest dose and furthermore, the incidence of uterine glandular hyperplasia is also clearly increased from 1/50 to 6/49. A common (e.g. endocrine) mechanism of both findings can not be excluded (page 2).
Ref: PEER REVIEW REPORT ON FLUOXASTROBIN. August 15, 2005.
European Food Safety Authority.
http://www.fluorideaction.org/pesticides/fluoxastrobin.eu.comments.2005.pdf

Kidney (click on for all fluorinated pesticides)

• 90-Day oral toxicity-rats. reduced body weight gain and food intake, vacuolation in the zona fasciculate of the adrenal cortex, calculi in the urethra and kidney, and histological lesions in kidney, urinary bladder, and urethra;
• 90-Day oral toxicity-dogs.
dose-related reductions in net body weight gain and food efficiency in addition to toxicity findings in the liver in both sexes (cholestasis) and in kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).
• 90-Day oral toxicity-mice. There was a dose related increase in liver weight in both sexes and in kidney weight in females, in addition to other effects whose toxicological relevance was considered uncertain. Among these effects were increased hepatocellular hypertrophy with cytoplasmic changes in the high-dose males and minimal to moderate kidney tubular hypertrophy in mid- and high-dose females.
90-Day Subchronic Oral Toxicology-Dog. dose-related reductions in net body weight gain and food efficiency; toxicity findings in the liver (cholestasis) in both sexes; and toxicity findings in the kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Liver (click on for all fluorinated pesticides)

2.3 SHORT TERM TOXICITY. The short-term toxicity of fluoxastrobin has been investigated in dietary studies in rats (28-day and 90-day studies), mice (2-week and 90-day studies) and dogs (90-day and 1-year studies). A 28-day dermal toxicity study in rats has also been conducted. The liver is the main target organ in all tested species (rats, mice and dogs). Histological changes were seen in the urinary system of rats (high doses) and dogs. Male rats were more sensitive than females to the effects of fluoxastrobin/HEC 5725 on the liver and urinary tract. Other target organs were adrenals, erythrocytes and thyroid. Reduced body weight gain was a key finding in dog studies. (page 12).
Ref: Conclusion regarding the peer review of the pesticide risk assessment of the active substance fluoxastrobin finalised: August 10, 2005. European Food Safety Authority.
http://www.fluorideaction.org/pesticides/fluoxastrobin.eu.review.2005.pdf

-- Subchronic toxicity. A subchronic toxicity feeding study with rats over 90 days demonstrated a NOAEL of 7.3 and 18.3 mg/kg bwt/day for males and females, respectively, based on reduced body weights and alterations in several urinary tract-related clinical chemistry parameters, at the higher dose levels. In a subchronic feeding study in mice over 14 weeks, a NOAEL was not established based on decreased alanine aminotransferase (ALAT) and increased absolute and relative liver weights at the low dose level (21.7 and 35.3 mg/kg bwt/day for males and females respectively). A 14-week feeding study in dogs demonstrated a NOAEL of 3.0 mg/kg bwt/day based on decreased body weights and food consumption, and liver effects (enzyme induction, increased liver weights, cytoplasmic change), and thyroid effects (decreased T3)
-- Chronic toxicity. A 24-month chronic/oncogenicity feeding study in rats demonstrated a NOAEL of 53.0 and 35.2 mg/kg bwt/day for males and females, respectively. An oncogenicity study in the mouse revealed a NOAEL of 18.5 and 29.5 mg/kg bwt/day for males and females, respectively based on liver effects. There was no indication in the rat or mouse for an oncogenic effect of fluoxastrobin. A 1-year feeding study with dogs demonstrated a NOAEL of 1.7 and 1.5 mg/kg bwt/day for males and females, respectively based on decreased body weights and slight liver effects (increased alkaline phosphatase (Aph) and liver weights).
Ref: Federal Register: April 23, 2003. Fluoxastrobin; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm

• Chronic toxicity-dogs. LOAEL was 8.1 mg/kg/day for males and 7.7 mg/kg/day for females based on body weight reductions and hepatocytomegaly [see definition below] and cytoplasmic changes associated with increased serum liver alkaline phosphatase indicative of cholestasis.
• 90-Day oral toxicity-dogs.
dose-related reductions in net body weight gain and food efficiency in addition to toxicity findings in the liver in both sexes (cholestasis) and in kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).
• 90-Day oral toxicity-mice. There was a dose related increase in liver weight in both sexes and in kidney weight in females, in addition to other effects whose toxicological relevance was considered uncertain. Among these effects were increased hepatocellular hypertrophy [see definition below] with cytoplasmic changes in the high-dose males and minimal to moderate kidney tubular hypertrophy in mid- and high-dose females.
90-Day Subchronic Oral Toxicology-Dog. dose-related reductions in net body weight gain and food efficiency; toxicity findings in the liver (cholestasis) in both sexes; and toxicity findings in the kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Definitions:
Hepatocytomegaly is an enlargement of the hepatocytes and is generally classified into three types: hepatocellular hypertrophy, megalocytosis, and hepatocellular vacuolation. Hepatocellular hypertrophy is an enlargement of cellular diameter without accompanying nuclear changes, leading to a net gain in the dry mass of the liver. A common cause of hepatocellular hypertrophy is proliferation of endoplasmic reticulum, indicating induction of cytochrome P450, that is, exposure to cytochrome P450-inducing compounds. Megalocytosis is characterized by enlargement of both the cell and the nucleus, and hepatocellular vacuolation is characterized by vacuolation, or formation of pockets of fluid within the hepatocytes. Little is known about the mechanism of the latter two types of hepatocytomegaly, but all three types are associated with exposure to genotoxic contaminants.
Ref: Environmental Effects of Dredging Technical Notes. Methods for the Assessment of the Genotoxic Effects of Environmental Contaminants; Cellular and Organ/Organism Effects. US Army Engineer Waterways Experiment Station. EEDP-04-25. July 1995.
http://www.fluorideaction.org/pesticides/genotoxic.army.1995.report.pdf

Reproduction and fertility (click on for all fluorinated pesticides)

- Rats. Offspring systemic: decreased body weights, delayed preputial separation*, and incomplete ossification in the F1 and/or F2 males and females. Parental systemic: decreased premating body weight gain of the P-generation males and females and decreased premating absolute body weight of the F1 males and females.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

*Note: Preputial separation is an indicator of sexual maturation

Spleen (click on for all fluorinated pesticides)

• Combined chronic toxicity / carcinogenicity--rats. decreased body weight, decreased body weight gain, and decreased food efficiency in both sexes; decreased spleen weight in males; and microscopic lesions in the uterus of females. The apparent increase in tumors in the uterus and thyroid were addressed and resolved by an Agency committee, which concluded that no carcinogenic concern exists for fluoxastrobin.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Urinary tract (click on for all fluorinated pesticides)

-- Subchronic toxicity. A subchronic toxicity feeding study with rats over 90 days demonstrated a NOAEL of 7.3 and 18.3 mg/kg bwt/day for males and females, respectively, based on reduced body weights and alterations in several urinary tract-related clinical chemistry parameters, at the higher dose levels...
Ref: Federal Register: April 23, 2003. Fluoxastrobin; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm

-- 90-Day oral toxicity-rats. reduced body weight gain and food intake, vacuolation in the zona fasciculate of the adrenal cortex, calculi in the urethra and kidney, and histological lesions in kidney, urinary bladder, and urethra.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Environmental (click on for all fluorinated pesticides)

Soil: Depending on the soil, fluoxastrobin was shown to be highly persistent in soil and hence it was present in rotational crops at plant back intervals up to 328 days as the major residue. Decline of fluoxastrobin residues under processing conditions does not occur (page 2)... Persistence of fluoxastrobin in soil may be very variable. Fluoxastrobin may behave as a moderate to high persistent compound. Metabolite M48-E is moderate to medium persistent in soil. Anaerobic metabolite M40 is moderately persistent in soil under aerobic conditions (page 3).
A high risk is identified to aquatic organisms. A bufferzone of 15 metres is needed to respect the Annex VI trigger value for the long term risk for the use of fluoxastrobin as a spray application in cereals (page 5). A high risk to aquatic organisms is identified which requires consideration of appropriate risk mitigation measures. A bufferzone of 15 metres is needed to respect the Annex VI trigger value for the long term risk (page 41).
Ref: Conclusion regarding the peer review of the pesticide risk assessment of the active substance fluoxastrobin finalised: August 10, 2005. European Food Safety Authority.
http://www.fluorideaction.org/pesticides/fluoxastrobin.eu.review.2005.pdf

Aquatic Animals. Toxicity: On an acute basis, Fluoxastrobin is moderately toxic to estuarine/marine fish; highly toxic to freshwater fish and invertebrates; and very highly toxic to estuarine/marine invertebrates. Chronic LOCs are also exceeded for estuarine/marine invertebrates and mollusks. Chronic effects for estuarine/marine invertebrates include reduced survival and reductions in wet weight of surviving adults following a 28-day exposure duration. No data were available to assess the chronic toxicity of fluoxastrobin to estuarine/marine mollusks. Therefore, the NOAEC value was estimated based on the acute-to-chronic ratio for mysid shrimp. .. The ecological risks to fish and invertebrates are considered conservative estimates because they are based on worst case exposure and use scenarios. Nonetheless, because of the potential for exposure and possible adverse effects of fluoxastrobin to endangered and nonendangered fish and invertebrates, the registrant is required to provide information on the proximity of Federally listed freshwater fish and invertebrates to the fluoxastrobin use sites...

Risk to Endangered Species The preliminary risk assessment for endangered species indicates that fluoxastrobin exceeds the endangered species LOCs for the following combinations of analyzed uses and species:

• Use of fluoxastrobin on the following crop scenarios indicate an exceedance of the endangered species LOC for freshwater fish: Maine potatoes (ground and aerial application), Florida tomatoes, peanuts, and turf (at the maximum application rate of 4 times per year).

• Use of fluoxastrobin on Idaho potatoes (aerial application only), Maine potatoes (ground and aerial application), tomatoes, peppers, cabbage, peanuts, and turf (at maximum [4x/year] and reduced [2x/year] application rates) indicate endangered LOC exceedances for endangered freshwater invertebrates.

• Use of fluoxastrobin on Idaho and Maine potatoes (aerial and ground application), tomatoes, peppers, cabbage, peanuts, and turf (at maximum [4x/year] and reduced [2x/year] application rates) indicate endangered acute and chronic LOC exceedances for estuarine/marine invertebrates.

• Use of fluoxastrobin on Maine potatoes (ground and aerial application), Florida tomatoes, peppers, cabbage, peanuts, and turf in Florida (at maximum [4x/year] application rates only) and Pennsylvania (for applications of both 4 and 2x/year) indicate chronic LOC exceedances for estuarine/marine mollusks.

The list of endangered/threatened freshwater fish species where potatoes, tomatoes, peppers, and peanuts are grown is comprised of 84 different species representing 36 States. The three States with the largest number of endangered/threatened freshwater fish species include California, Washington, and Oregon. Within these States, the majority of endangered/threatened fish species are salmon and steel head (Orcorhynchus sp.). The predominant endangered fish species in Florida and North Carolina, where tomatoes, peppers, and peanuts are grown, is the sturgeon (Acipenser sp.).

The list is of freshwater invertebrates is primarily comprised of bivalves (70% of all listed invertebrates; present in 20 States), crustaceans (i.e., amphipods, crayfish, and shrimp) (~19 of all listed invertebrates; present in 6 States), and snails (~11% of all listed invertebrates; present in 2 States). While the majority of listed freshwater invertebrates are bivalves, the amphipod (Gammarus acherondytes) was listed as endangered in Illinois. The identification of an endangered amphipod is a factor because this species was identified as the most sensitive freshwater invertebrate from the available effects data. It appears, however, that the endangered amphipods in Illinois are present only in caves, where pesticides are not likely to be present in water at concentrations that would cause adverse effects.

The Agency’s levels of concern for endangered and threatened freshwater fish and invertebrates and estuarine/marine invertebrates and mollusks are exceeded for the use of fluoxastrobin. However, the Agency recognizes that there are no Federally listed estuarine/marine invertebrates/mollusks.

The registrant must provide information on the proximity of Federally listed freshwater fish and invertebrates to the fluoxastrobin use sites. This requirement may be satisfied in one of three ways:

1) having membership in the FIFRA Endangered Species Task Force (Pesticide Registration [PR] Notice 2000-2);

2) citing FIFRA Endangered Species Task Force data; or

3) independently producing these data, provided the information is of sufficient quality to meet FIFRA requirements.

The information will be used by the OPP Endangered Species Protection Program to develop recommendations to avoid adverse effects to listed species. The registrant has satisfied this requirement using option #1 above.
Reference:
November 2005 - US EPA Pesticide Fact Sheet: Fluoxastrobin.
http://www.fluorideaction.org/pesticides/fluoxastrobin.epa.fact.sheet.2005.pdf

 
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