EPA Registration Division contact: Andrew Ertman, 703-308-9367 

Interregional Research Project Number 4 (IR-4)

PP No. 1E7959 

 EPA has received a pesticide petition (PP No. 1E7959) from IR-4, 500 College 

Road East, Suite 201W, Princeton, New Jersey, 08540, proposing, pursuant to section 

408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to 

amend 40 CFR part 180 by establishing a tolerance for residues of fluazinam in or on 

the raw agricultural commodity fruiting vegetables group, pepper/eggplant subgroup 

8-10B at 0.10 parts per million (ppm) and cucurbit vegetables, melon subgroup 9A at 

0.08 ppm. EPA has determined that the petition contains data or information regarding 

the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully 

evaluated the sufficiency of the submitted data at this time or whether the data supports 

granting of the petition. Additional data may be needed before EPA rules on the petition. 

This notice includes information from a separate petition submitted by ISK 

Biosciences Corporation, 7470 Auburn Road, Suite A, Concord, OH 44057.

A. Residue Chemistry

Plant metabolism. The residue of concern is best defined as the parent, fluazinam in 

most crops and as the parent, fluazinam and its metabolite, AMGT, in fruit crops 

(grape and blueberry). The metabolism of fluazinam in plants (potatoes, peanuts, 

apples and wine grapes) is adequately understood for the purposes of these 

tolerances. The metabolism of fluazinam in peanut and potato involves initial 

reduction of the nitro groups, hydrolysis of the trifluoromethyl group as well as 

replacement of chlorine by glutathione with subsequent reactions along the 

glutathione pathway. Following replacement of the deactivating NO2 and Cl groups 

with activating groups such as OH, NH2 and sulfhydryl, ring cleavage occurs. 

Parent fluazinam is then rapidly degraded to form CO2 and carbon fragments 

which are incorporated into natural products such as glucose, fructose, sucrose, oils 

and protein. Thus, parent fluazinam is either not found or barely detectable in 

peanuts and potatoes. Fluazinam parent was the major identifiable residue in both 

the grape and apple metabolism studies. However, minor levels of AMGT (less than 

5% of the total radioactive residue) were also formed in grapes and apples. In 

grape and apple metabolism studies, following reduction of the nitro groups and 

replacement of chlorine with a sulfur containing side-chain such as glutathione (as 

occurred in peanuts and potatoes), glucose is attached to the thiolactic acid 

conjugate of AMPA to form the metabolite known as AMGT. This metabolite was 

not found in the peanut or potatoes metabolism studies. It is analogous to the 

cysteine conjugate of AMPA found in rats. Identifiable residues in plant 

metabolism studies either closely resemble fluazinam in structure or are the result 

of re-incorporation of the fluazinam carbon pool into natural products. 

 Ruminant and poultry metabolism studies demonstrated that the transmittal of 

residues from the feed of goats and hens through to meat, milk, and eggs was low. 

Total 14C residues were below 1 ppm in all tissues, milk and eggs. Identifiable 
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residues were less than 2% of the administered dose in all matrices, except for 

chicken fat and liver. The major metabolite found in animal tissues and milk were 

DAPA, AMPA, and their sulfamate conjugates. Parent Fluazinam was only 

detected in very small amounts.

 2. Analytical method. An analytical method using LC-MS/MS for the 

determination of fluazinam and AMGT residues on cantaloupe and pepper has been 

developed and validated. The method involves solvent extraction followed by 

liquid-liquid partitioning and concentration prior to a final purification. The 

method has been successfully validated by an independent laboratory using peanut 

nutmeat as the matrix. The limit of quantitation (LOQ) of the method is 0.01 ppm 

for both fluazinam and AMGT in both crops.

 3. Magnitude of residues. Cantaloupe. A total of 11 field trials were conducted 

on cantaloupe. Treatment 2 of each field site consisted of six (6) foliar applications 

at the target rate of approximately 0.78 lb a.i./A, applied at 7 (+1) day intervals. 

Cantaloupes were harvested approximately 30 days after the last application. One 

decline trial was included with sampling at 6, 12, 19, 28 and 34 days after the last 

application. The results show that the maximum Fluazinam residue in cantaloupes 

following a total application of approximately 4.68 lb a.i./A/season with an average 

PHI of 30 days, was 0.077 ppm. The mean fluazinam residue was 0.014 ppm. 

Residues declined over time. No residues of AMGT above the LOQ of 0.01 ppm 

were observed in any sample. 

Pepper. A total of 13 field trials were conducted on pepper (9 on bell and 4 on nonbell). Treatment 2 of each field site consisted of six (6) applications at the target rate 

of approximately 0.78 lb a.i./A, applied in general at 7 day intervals but was 

extended between the third and fourth application at some sites to achieve the target 

PHI. Peppers were harvested approximately 30 days after the last application. 

One decline trial was included with sampling at 7, 13, 20 and 35 days after the last 

application. The results show that the maximum Fluazinam residue following a 

total application of approximately 4.68 lb a.i./A/season with an average PHI of 30 

days, was 0.038 ppm in bell peppers and 0.053 ppm in non-bell peppers. The mean 

fluazinam residue was 0.011 ppm in bell peppers and 0.017 ppm in non-bell 

peppers. Residues declined over time. No residues of AMGT above the LOQ of 

0.01 ppm were observed in any sample. 

B. Toxicological Profile

 1. Acute toxicity. A battery of acute toxicity studies was conducted which 

placed technical fluazinam in Toxicity Category IV for acute oral LD50 and dermal 

irritation, and Category III for dermal LD50, inhalation LC50 and eye irritation. 

Technical fluazinam showed potential for dermal sensitization. In an acute 

neurotoxicity study, the NOAEL for neurotoxicity was 2000 mg/kg bw (the highest 

dose tested) and the NOAEL for systemic effects was 50 mg/kg bw.
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 2. Genotoxicty. A battery of tests has been conducted to assess the genotoxic 

potential of technical fluazinam. Assays conducted included two gene mutation tests 

in bacteria, a chromosomal aberration test in mammalian cells, a mouse 

micronucleus test and a DNA repair test in bacteria. Technical fluazinam did not 

elicit a genotoxic response in any of the studies conducted.

 3. Reproductive and developmental toxicity. In a two-generation reproductive 

toxicity study, the NOAEL for reproductive effects was 100 ppm (10.6 mg/kg 

bw/day). The NOAEL for parental toxicity was 20 ppm (1.9 mg/kg bw/day). 

 In a rat developmental study, there were no developmental effects observed at 

non-maternally toxic doses. The developmental NOAEL was 50 mg/kg bw/day and 

the LOAEL was 250 mg/kg bw/day, based upon decreased mean fetal body weight 

and other evidence suggestive of delayed fetal development related to maternal 

toxicity. The maternal NOAEL was shown to be 50 mg/kg bw/day. 

 In a rabbit developmental study, there were no developmental effects observed at 

non-maternally toxic doses. The developmental NOAEL was 7 mg/kg bw/day and 

the LOAEL was 12 mg/kg bw/day, based on increased incidence of total litter loss 

and possible slightly increased incidences of fetal findings at this dose. It was 

concluded that the maternal NOAEL was 4 mg/kg bw/day.

 4. Subchronic toxicity. The NOAEL for the 13-week feeding study in rats was 

50 ppm (3.8 mg/kg bw/day in males, 4.3 mg/kg bw/day in females). The LOAEL 

was 500 ppm (38 mg/kg bw/day in males, 44 mg/kg bw/day in females), based on 

periacinar hepatocellular hypertrophy and sinusoidal chronic inflammation in 

males, increased liver weights in males and increased lung weights in females. 

 In a 13-week dog study, the NOAEL was 10 mg/kg bw/day. The LOAEL was 100 

mg/kg bw/day, based on ocular change observed ophthalmoscopically and liver 

effects consisting of increased relative liver to body weight, bile duct hyperplasia 

with or without cholangiofibrosis and increased plasma phosphatase levels. 

 In a 21-day dermal study, the NOAEL for systemic effects was 10 mg/kg bw/day. 

The LOAEL was 100 mg/kg bw/day, based on hepatocelluar hypertrophy and 

increases in AST and cholesterol levels. 

 In a subchronic neurotoxicity study, no effects considered to be indicative of 

neurotoxicity were observed at the highest dose tested, 3000 ppm (233 mg/kg bw/day 

in males, 280 mg/kg bw/day in females). The NOAEL for systemic toxicity (body 

weight differences) was 1000 ppm (74 mg/kg bw/day). 

 In a developmental neurotoxicity study in rats, fluazinam was administered by 

gavage to female rats from Day 6 after mating to Day 20 of lactation and 

additionally to their offspring from Day 7 of age to Day 20 or 21 of age. The author 

concluded that the maternal NOAEL was 2 mg/kg bw/day based on reduced body 

weights and lower food intake. No effects were seen on the microscopic structure of 

the nervous system of the dams at any dose level (maximum dose of 50 mg/kg 

bw/day). The NOAEL for behavior and nervous system of the dams was >50 mg/kg 

bw/day, the highest dose tested. No adverse effect of treatment at any dose level was 

seen on number of implantations, litter size or offspring survival. Signs of general 

toxicity in the offspring were evident based on lower Day 1 body weights and lower 

weight gains at 10 and 50 mg/kg bw/day through weaning. The NOAEL for general 
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toxicity to offspring was 2 mg/kg bw/day. There was no evidence of developmental 

neurotoxicity in the offspring. The NOAEL for the functional and morphological 

development of the nervous system in the offspring was >50 mg/kg bw/day, the 

highest dose tested. There was no increased sensitivity of the fetus or young rat 

pups to fluazinam as compared to the dams.

 5. Chronic toxicity. Fluazinam was not carcinogenic in rats. A NOAEL of 10 

ppm (Males: 0.38 mg/kg bw/day; Females: 0.47 mg/kg bw/day) of fluazinam was 

established based on the following effects at 1000 and/or 100 ppm: lower food 

consumption and efficiency of food utilization, slight anemia, elevated cholesterol, 

increased liver weights, an increased number of macroscopic liver and testes lesions 

and an increased incidence of microscopically observed lung, liver, pancreas, lymph 

node and testes lesions. 

 An additional study was conducted to further define the NOAEL for long-term 

effects in the rat. In the second study, a NOAEL of 50 ppm (2.2 mg/kg bw/day) was 

established based on liver and testes effects. 

 Two long-term feeding studies were conducted in mice. In the first, the NOAEL 

for all effects was 10 ppm (Males: 1.1 mg/kg bw/day; Females: 1.2 mg/kg bw/day) 

and the LOAEL was 100 ppm (Males: 10.7 mg/kg bw/day; Females: 11.7 mg/kg 

bw/day) based on the treatment-related effects observed in the liver. 

 A second oncogenicity study in mice was conducted at 1000, 3000 and 7000 ppm 

to ensure that an MTD dose was studied. Findings included increased female 

mortality, reduced body weight gains, increased brain weights and/or liver weights. 

An impurity in the test material used in this study resulted in vacuolation of the 

white matter of the brain and cervical spinal cord in treated animals. A statistically 

significant higher incidence of hepatocellular adenomas was observed in the 3000 

ppm dose males. Hepatocellular adenomas are common tumors in male mice. 

There was no dose relationship in the induction of the adenoma and no increase in 

hepatocellular carcinomas. It was concluded that fluazinam is not carcinogenic in 

the mouse. 

 In a chronic dog study, the NOAEL was determined to be 1 mg/kg bw/day. The 

LOAEL was 10 mg/kg bw/day based on generalized, nonspecific toxicity. No ocular 

effects were observed ophthalmoscopally at any dose in this study.

 6. Animal metabolism. After an oral dose of fluazinam the median peak time 

for blood concentration of radiolabel activity for both sexes was 6 hours. The major 

route of excretion was the feces with urine contributing as a minor route. Less than 

1% of the administered dose was found in the terminated animals. The highest 

concentration in tissues was found in the liver. There were no major differences 

related to sex or dose level in the findings. It was concluded that fluazinam is 

metabolized by both reduction and glutathione and glucuronide conjugation and 

further metabolism.

 7. Metabolite toxicology. The same metabolic processes occur in plants and 

animals but metabolism in plants is more extensive than in animals. All of the major 

identified metabolites in both plants and animals retain the phenylpyridinylamine 

structure. Many of the metabolites resulting from fluazinam are similar in plants 
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and animals and, therefore, have already been evaluated toxicologically. 

 Because of the rapid and complete elimination (in animals) and re-incorporation 

(in plants) of fluazinam, the toxicity of metabolites is expected to be similar to but 

lower than the toxicity of the parent compound. The residue of concern is parent 

fluazinam only in most crops and parent fluazinam plus its minor metabolite 

AMGT on/in fruit crops such as grape and blueberry.

 8. Endocrine disruption. The toxicological profile of fluazinam shows no 

evidence of physiological effects characteristic of the disruption of the hormone 

estrogen in mammalian chronic studies or in mammalian or avian reproduction 

studies. It is therefore considered that there is an adequate level of safety over the 

reference dose for possible endocrine effects and that an additional safety factor for 

possible endocrine effects is not warranted.

C. Aggregate Exposure

 1. Dietary exposure. Potential dietary exposures from food were estimated 

using the proposed tolerances for all crops (except apples as noted below), using the 

Dietary Exposure Evaluation Model-Food Consumption Intake Database (DEEMFCIDTM) and percent crop treated of 100% (with the exception of imported wine 

grapes as discussed below). The following raw agricultural commodities were 

included: apple, carrot, brassica (cole) leafy vegetables (Group 5) including turnip 

greens, bean (Groups 6A, 6B and 6C), bushberry (Group 13-07B), ginseng, head 

lettuce, leaf lettuce, bulb onion (Crop 3-07A), peanut, potato, pepper/eggplant 

subgroup 8-10B, melon subgroup 9A, soybeans, imported wine grapes and sherry 

and resulting secondary residues in meat and milk. For acute dietary exposure, the 

acute population adjusted dose (aPAD) was based on the NOAEL of 50 mg/kg 

bw/day from an acute rat neurotoxicity study. For females 13-49 years of age, the 

NOAEL of 7 mg/kg bw/day from the rabbit developmental toxicity study was used 

for acute dietary exposure. For chronic dietary exposure, the chronic population 

adjusted dose (cPAD) was based on the NOAEL from the mouse carcinogenicity 

study (1.1 mg/kg bw/day). An uncertainty factor of 100 was used in both cases since 

the results of a DNT study confirmed there was no increased sensitivity of the fetus 

or young rat pups to fluazinam as compared to the dams and the FQPA uncertainty 

factor could be reduced to one (1).

 i. Food. Acute Risk Tier 1 acute dietary exposure analyses were conducted 

for fluazinam to determine the exposure contribution of the above mentioned 

commodities to the diet and to ascertain the acute risk potential. The estimates were 

based on: proposed tolerance level residues for all the crops; apple, peanut and 

potato processing studies; market share assumptions of 100% crop treated (except 

wine grapes where it was assumed that 100% of the imported wine grapes would be 

treated and 39% of wine consumed in the US is imported); screening-level acute 

EDWC of 218 ppb for water; and consumption data from USDA’s CSFII (1994 

through 1998) continuing survey of food intake. 

 Even using all of the worst-case exposure scenarios listed above, the Tier 1 95th 

percentile acute dietary exposure (per capita) from food and drinking water for the 
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U.S. population was estimated to be 0.024402 mg/kg bw/day or 4.9% of the aPAD. 

The highest acute exposure estimate (95th percentile) was observed in the females 

13-49 yrs. subpopulation: 0.018334 mg/kg bw/day. This corresponds to 26.1% of 

the aPAD. 

 Chronic Risk Tier 1 dietary exposure analyses were conducted for fluazinam to 

determine the exposure contribution of the above mentioned commodities to the diet 

and to ascertain the chronic risk potential. The estimates were based on: proposed 

tolerance level residues for all the crops, accept apples where average field residues 

were used; apple, peanut and potato processing studies; market share assumptions 

of 100% crop treated (except wine grapes where it was assumed that 100% of the 

imported wine grapes would be treated and 39% of wine consumed in the US is 

imported); screening-level chronic EDWC of 37 ppb; and consumption data from 

USDA’s CSFII (1994 through 1998) continuing survey of food intake. 

 Even using all of the worst-case exposure scenarios listed above, the Tier 1 

chronic dietary exposure estimates resulted in an estimated exposure for the U.S. 

population of 0.001924 mg/kg bw/day. This exposure corresponds to 17.5% of the 

cPAD of 0.011mg/kg bw/day. The highest exposure estimate was calculated for the 

all infants (<1 year) population subgroup. This exposure was determined to be 

0.005609 mg/kg bw/day (51.0% of the cPAD) most of which was due to the water 

contribution. 

 It can be concluded that acute or long-term dietary exposure to fluazinam 

through residues on treated apple, carrot, brassica (cole) leafy vegetables (Group 5) 

including turnip greens, bean (Groups 6A, 6B and 6C), bushberry (Group 13-07B), 

ginseng, head lettuce, leaf lettuce, bulb onion (Crop 3-07A), peanut, potato, 

pepper/eggplant subgroup 8-10B, melon subgroup 9A, soybeans, imported wine 

grapes and sherry should not be of cause for concern.

 ii. Drinking water. Since fluazinam is intended for application outdoors to 

field grown crops, the potential exists for parent and/or metabolites to reach ground 

or surface water that may be used for drinking water. The potential estimated 

drinking water concentrations (EDWCs) associated with the application of 

fluazinam to pepper/eggplant subgroup 8-10B, melon subgroup 9A, or soybeans, is 

less than the maximum values estimated for turf. Thus, the more conservative 

screening-level acute EDWC (218 ppb) and chronic EDWC (37 ppb) for turf were 

incorporated into the DEEM-FCID model to estimate dietary exposure.

 2. Non-dietary exposure. A registration for the use of fluazinam on golf 

courses is pending. Applications are to be made by golf course workers only, thus 

no residential handler exposure is expected. However, post-application dermal 

exposure from contact with the treated turf on golf courses may occur. Thus, postapplication dermal exposure was calculated for adults and for youth playing golf, 

using the general US population subgroup and youth, 13-19 years subgroup. The 

Margins of Exposure (MOE) for both the adults (21,800) and the youth (14,300) 

were well above the acceptable MOE of 100. 

D. Cumulative Effects
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 Fluazinam is a phenylpyridinylamine fungicide. Since there are no other 

members of this class of fungicides, it is considered unlikely that fluazinam would 

have a common mechanism of toxicity with any other pesticide in use at this time.

E. Safety Determination

 1. U.S. population. Dietary and post-application dermal exposure from 

recreational contact with treated turf on golf courses will be the routes of exposure 

to the U.S. population. Ample margins of safety have been demonstrated for both 

situations. For the general U.S. population, the chronic aggregate risk assessment is 

based on exposure from food and drinking water only, since no residential uses 

exist. As noted above, the chronic dietary exposure to fluazinam represents 17.5% 

of the cPAD for the overall U.S. population, using the conservative Tier I 

assumptions. A cancer dietary assessment was not conducted because this product 

has been classified as “suggestive evidence of carcinogenicity, but not sufficient to 

assess human carcinogenic potential.” 

An acute aggregate risk assessment is required for the general population and for 

the subgroup of females 13-49 years old. For both of these populations, the acute 

dietary (food and drinking water) risk assessment represents acute aggregate risk 

since the dietary route alone is relevant for acute exposure and risk assessment. As 

noted above, the acute dietary exposure to fluazinam is estimated to be 4.9% of the 

aPAD for the overall U.S. population, and 26.1% of the aPAD for the subgroup of 

females 13-49 years old. These values were presented above and are below the 

Agency’ level of concern. 

Short-term and intermediate-term aggregate risks include chronic dietary and 

short-term residential sources of exposure. Since Fluazinam is proposed for use on 

golf courses there is potential for post-application exposure to adults and youths 

from playing golf. The US general population was chosen as the representative 

short-term population for adults, while the dietary subpopulation youths aged 13 to 

19 was chosen to match with the youth golfer residential exposure. The dietary 

(food and drinking water) exposure was based on the Tier I chronic exposure 

assessment as noted above but converted to an MOE. This was aggregated with the 

appropriate post-application residential golfer MOE to yield the following aggregate 

short/intermediate-term MOEs: US general population MOE = 1811; youths, 13-19 

= 2779. These aggregate risks are well above 100 for all populations, indicating 

acceptable risks for both adults and youth. 

Based on this information, it can be concluded that there is reasonable certainty that 

no harm will result from acute, short/intermediate term or chronic exposure to 

fluazinam. 

 2. Infants and children. Data from developmental toxicity studies in the rat 

and rabbit, a 2-generation reproduction study and a developmental neurotoxicity 
8

study were considered. These studies, that were described earlier, demonstrated no 

increased sensitivity of rats or rabbits to in utero or gavage exposure of pups to 

fluazinam. In addition, the multigeneration reproductive toxicity study did not 

identify any increased sensitivity of rats to in utero or postnatal exposure. For all 

four studies, parental NOAELs were lower than or equivalent to the developmental 

or offspring NOAELs. It is concluded that the standard margin of safety will 

protect the safety of infants and children and that an additional FQPA safety factor 

is not warranted. 

 The dietary exposure of fluazinam to infants and children is estimated to be less 

than any level of concern. The proposed tolerances plus drinking water input will 

utilize 20.5% of the aPAD for the “Children (1-2 years)” subgroup, and 51.0% of 

the cPAD for the “All Infants (<1 year) “subgroup. (These were the most sensitive 

infant/child subgroups.) Thus, it can be concluded that there is reasonable certainty 

that no harm will result to infants and children from acute or chronic exposure to 

fluazinam.

F. International Tolerances

 There are presently no Codex maximum residue levels (MRLs) established 

for residues of fluazinam on any crop. The Canadian and Mexican MRLs for beans 

and potatoes are similar to the tolerances established for these crops in the USA.