EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR 

PUBLICATION IN THE FEDERAL REGISTER 

EPA Registration Division contact: Sidney Jackson (703) 305-7610

The Interregional Research Project Number 4 

PP# 1E7850

EPA has received a pesticide petition (PP) 1E7850 from Interregional

Research Project Number 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State

University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08450 

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 fenpyrazamine in or on the raw agricultural commodity: Caneberry subgroup 

(13-07A) at 7.0 parts per million (ppm), Bushberry subgroup (13-07B) at 7.0 ppm, 

pistachio at 0.02 ppm and ginseng at 0.8 ppm. EPA has determined that the petition 

contains data or information regarding the elements set forth in section 408(d)(2) of the 

FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at 

this time or whether the data support granting of the petition. Additional data may be 

needed before EPA rules on the petition.

A. Residue Chemistry 

1. Plant metabolism. The fate of fenpyrazamine in plants is clearly understood. 

The metabolism of fenpyrazamine in plants has been studied in grape vine (berries and 

leaves), rapeseed (forage, haulm and seed), and lettuce (leaves). These studies show 

comparable metabolism in three diverse crops, covering fruit crops, pulses/oilseeds and 

leafy crops. The metabolism of fenpyrazamine in crops proceeds via cleavage of the 

carbamate linkage on the pyrazolyl ring to give S-2188-DC, followed by hydroxylation 

of the pyrazolyl ring to form S-2188-OH. In addition, in rapeseed (seed,) a significant 

proportion of the residue had been incorporated into naturally occurring compounds 

(protein, starch and lignin). Parent fenpyrazamine was the major residue found in all 

crops. The metabolites S-2188-DC and S-2188-OH were found in all crops at low levels.

2. Analytical method. A practical analytical method utilizing liquid 

chromatography and mass spectrometry detection is available and has been validated for 

detecting and measuring residues of fenpyrazamine (fenpyrazamine and S-2188-DC) in 

and on crops. The validated limit of quantitation for both fenpyrazamine and S-2188-DC 

is 0.02 ppm.

3. Magnitude of residues. Residue data for the use of fenpyrazamine on the 

commodities listed within this notice have been submitted.

B. Toxicological Profile
1. Acute toxicity. The acute toxicity of fenpyrazamine and the formulated 

product V-10135 4 SC has been evaluated in rats, rabbits and guinea pigs following 

different routes of exposure. Fenpyrazamine and the formulated product have a low oral 

and inhalation toxicity and no dermal toxicity to rats. Both are considered sensitizers in 

the guinea pig. Fenpyrazamine is non-irritating to rabbit skin and minimally irritating to 

rabbit eye. The formulated product is a slight irritant to rabbit skin and a non-irritant to 

rabbit eye

2. Genotoxicty. Fenpyrazamine is not genotoxic as demonstrated by results of a 

bacterial reverse mutation assay, a chromosome aberration assay, a V79/HPRT 

mammalian cell gene mutation test, and an in-vivo mouse micronucleus assay.

3. Reproductive and developmental toxicity. In a 2-generation study of 

fenpyrazamine in rats, there was no evidence of a specific effect on fertility, mating 

behavior, or the ability to rear young. The key findings were of retarded weight gain in 

parents, then in pups. In litters born to F1 females of the top dose, a slight increase in 

post-implantation loss and in postnatal mortality was detected. These findings were 

considered secondary to maternal toxicity, and the dams of this group had been smaller 

than controls since birth. Among animals sacrificed as adults (both F0 and F1) there was 

again hepatic hypertrophy and occasional evidence of corresponding thyroid hypertrophy, 

findings in close correlation to subchronic and chronic testing. 

Findings in a teratogenicity study in rats were considered secondary to clear maternal 

toxicity. At the top dose level, which caused suppression of maternal weight gain, fetal 

weight was smaller than controls and a slightly increased incidence of visceral and 

skeletal variations was noted. The NOAEL for fetal findings was in excess of the 

maternal NOAEL indicating no evidence for increased susceptibility of the fetus.

In rabbits, findings were once again secondary to maternal toxicity, but of a highly 

individual nature. Affected does showed marked impairment of food consumption, 

resulting in secondary impairment of weight gain then abortion or premature 

delivery. Unaffected does at any dose level were found to be closely comparable to 

controls at necropsy, with no impairment of gestation or development of pups. 

There was no evidence of specific effects on development of the fetus.

4. Subchronic toxicity. General toxicity was assessed in ninety-day feeding 

studies with dogs, mice and rats. Subchronic dermal toxicity, neurotoxicity and 

immunotoxicity studies were also conducted in rats.

i. In a 90-day dog study with dietary levels of 25, 50 and 150 mg/kg/day, the NOAEL in 

dogs is 25 mg/kg/day for males and 50 mg/kg/day for females primarily based upon liver 

findings that are considered to be adaptive changes related to induction of drug 

metabolizing enzymes and not to be toxic effects.

ii. In 90-day feeding studies with the CD-1 mouse, liver was the only target organ 

identified with decreased hematocrit seen at dietary levels of 4,000 ppm and higher in 

males and 6,000 in females. The NOAEL in CD-1 mice was 296 mg/kg/day. 
iii. In a 90-day rat study with dietary levels of 300, 600, 1,000, and 3,000 ppm, the 

NOAEL was determined to be 1,000 ppm for both genders (64 mg/kg/day for males and 

69 mg/kg/day for females) based upon reduced mean body weight and body weight gain. 

iv. In a subchronic neurotoxicity study, rats were treated with 0, 500, 1200 or 3,000 ppm 

in the diet for at least 90 days. The NOAEL for general toxicity is 1200 ppm (87.6 

mg/kg/day in males and 100.2 mg/kg/day in females) based on reductions in body weight 

gain. There were no neurotoxicity findings. The NOAEL for neurotoxicity is 3,000 ppm.

v. In a subchronic dermal toxicity study, male and female rats were treated with 

fenpyrazamine at dose levels of 0, 100, 300, and 1000 mg/kg/day. There were no effects 

at any dose level. The NOAEL of the study is 1000 mg/kg/day.

vi. In a 28-day dietary study in rats, there ware no immunotoxic effects noted following 

doses of 500, 1500 and 4000 ppm fenpyrazamine. The NOAEL for immunotoxicity is 

4000 ppm (>392 mg/kg/day), the highest dose tested.

5. Chronic toxicity. 

i. In a 52-week dog study performed at 5, 25, and 100 mg/kg/day, the NOAEL in dogs 

was established at 25 mg/kg/day for males and 100 mg/kg/day for females based upon 

impaired body weight gain and increased serum ALP. 

ii. Chronic toxicity/carcinogenicity was assessed in rats at dietary levels of 100, 300, 

1,200 and 2,400 ppm. The NOAEL was 300 ppm (12.7 mg/kg/day in males and 15.6 

mg/kg/day in females) based on hepatocellular changes and mild RBC effects. No 

evidence of carcinogencity was observed in rats up to 2400 ppm. 

iii. The oncogenic potential of fenpyrazamine was investigated in CD-1 mice at dietary 

levels of 0, 100, 1,500, or 3,000 ppm in males and 0, 100, 2,000, and 4,000 in females. 

There was no indication for an oncogenic potential. Under the conditions of this study, 

and based on retarded body weights in males in the highest treatment group in the first 

year of the treatment period, the findings of anemia in both sexes of the highest treatment 

group after 78 weeks of treatment, increased liver weights and the occurrence of 

hepatocellular hypertrophy in males and females in the highest treatment groups after 78 

weeks of treatment, a no-observed-adverse effect-level (NOAEL) for fenpyrazamine has 

been determined at 1500 ppm for males and 2000 ppm for females, corresponding to 

176.2 mg/kg/day for males and 282.8 mg/kg/day for females.

6. Animal metabolism. The animal metabolism of fenpyrazamine is well 

understood. Fenpyrazamine is extensively and rapidly absorbed, metabolized and 

excreted when administered to rats and the resulting tissue residues are very low. The 

metabolic pathway for fenpyrazamine is similar in rodents, goats and hens. Metabolism 

proceeded primarily via hydrolysis and hydroxylation followed by sulfation or 

glucuronidation

7. Metabolite toxicology. The metabolite S-2188-DC is common to all crop 

metabolism studies and was found in lettuce leaves and rapeseed haulm at levels >10% 

TRR. S-2188-DC is a major rat metabolite, and its toxicity is considered to have been 

adequately covered by the toxicology studies. It is not mutagenic or acutely toxic and is 

therefore not of toxicological concern. However, as S-2188-DC was found at levels 
exceeding 10% TRR in crops, it is therefore proposed that this metabolite be included in 

the residue definition for risk assessment.

The metabolite S-2188-OH is common to all crop metabolism studies and was a minor rat 

metabolite. As this metabolite was found in the rat, the toxicity is considered to have 

been adequately covered by the toxicology studies. S-2188-OH was not detected at 

levels above 10% TRR, and therefore it has not been included in the residue definition for 

risk assessment or monitoring. It is therefore recommended that the residue definition for 

risk assessment is the sum of fenpyrazamine and S-2188-DC (expressed as parent 

equivalents), and that the residue definition for monitoring includes both fenpyrazamine 

and S-2188-DC.

8. Endocrine disruption. The toxicology database for fenyprazamine is current 

and complete. No special studies to evaluate the potential endocrine effects have been 

conducted. However, the studies in this database include evaluation of the potential 

effects on reproduction and development, and an evaluation of the pathology of the 

endocrine organs following short- or long-term exposure. These studies revealed no 

endocrine-related effects.

C. Aggregate Exposure

1. Dietary exposure. A Tier 1 dietary (food and water) exposure assessment was 

conducted to evaluate the potential risk due to chronic dietary exposure of the U.S. 

population and various subpopulations to residues of fenpyrazamine. The analysis 

included all the proposed tolerance values in addition to IR-4 proposed uses on 

caneberries, bushberries and ginseng. No acute assessment was conducted because there 

are no applicable acute toxicity endpoints and the evaluation was not warranted. 

The resulting exposure estimates were compared against the fenpyrazamine chronic 

Population Adjusted Dose (cPAD) of 0.13 mg/kg/day. This endpoint is based on the 

NOAEL from a chronic toxicity study in the rat.

i. Food. 

Chronic assessments were conducted to evaluate potential risks due to chronic dietary 

exposure to the U.S. population and selected population subgroups to residues of 

fenpyrazamine. This analysis was conducted using DEEM-FCID version 2.16 with 

tolerance-level residues on all commodities, 100% crop treated and default processing 

factors for processed commodities without processing data. These Tier 1 assumptions 

introduce considerable conservatism. Therefore, one can confidently conclude that actual 

dietary exposures will be much lower than those estimated here. 

ii. Drinking water. 
The EPA Tier 1 surface water model FIRST and ground water model SCIGROW were 

used to estimate concentrations of Fenpyrazamine in drinking water associated with the 

proposed uses. Estimated drinking water concentrations (EDWCs) were calculated for 

surface water to be 17.4 ppb (maximum annual mean) based on the nursery ornamental 

use pattern.

Total chronic aggregate dietary exposures (including food and water) are estimated to be 

3.8% of the cPAD for the total U.S. population, 5.9% for all infants, 16.3% for children 

aged 1-2 years old (the most highly exposed subpopulation), and 10.5% for children aged 

3-5 years old. Chronic dietary exposures below 100% of the cPAD are reasonably 

anticipated to result in no harm to exposed populations.

2. Non-dietary exposure. No residential uses are proposed for fenpyrazamine, 

therefore, residential exposure to residues will be through dietary exposure only. 

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information” concerning 

the cumulative effects of a particular pesticide’s residues and “other substances that have 

a common mechanism of toxicity”. EPA does not have, at this time, available data to 

determine whether fenpyrazamine has a common mechanism of toxicity with other 

substances or how to include this pesticide in a cumulative risk assessment. For the 

purposes of this tolerance action, EPA has not assumed that fenpyrazamine has a 

common mechanism of toxicity with other substances.

E. Safety Determination. 

FFDCA section 408 provides that EPA shall apply an additional margin of safety, up to 

ten-fold, for added protection for infants and children in the case of threshold effects, 

unless EPA determines that a different margin of safety will be safe for infants and 

children. The toxicological database for evaluating prenatal and postnatal toxicity for 

fenpyrazamine is complete with respect to current data requirements, and there are no 

special prenatal or postnatal toxicity concerns for infants and children. This therefore, 

warrants reducing the FQPA Safety Factor for protection of infants and children to 1X.

1. U.S. population. Based on a highly conservative risk assessment, Valent USA 

Corporation concludes that there is a reasonable certainty that no harm will result to the 

general population from the aggregate exposure to Fenpyrazamine from the proposed 

uses. 

2. Infants and children. Based on a highly conservative risk assessment, Valent 

USA Corporation concludes that there is a reasonable certainty that no harm will result to 

infants and children from the aggregate exposure to Fenpyrazamine from the proposed 

uses.
F. International Tolerances

There are no CODEX tolerances for residues of fenpyrazamine.