EPA REGISTRATION DIVISION

- COMPANY N OTICE 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 petit ion (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 f

enpyrazamine in or on the raw agricultural commodity : C aneberry subgroup (13

- 07A) at 7.0 parts per million ( ppm )

, B ushberry subgroup ( 13

- 07B) at 7.0 ppm

, p istachio at 0.02 ppm and g inseng 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 fenpyraz amine 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. I n 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 be en submitted

.

B. Toxicological Profile1. 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 f ormulated 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 fin dings 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 slight ly 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 mate rnal 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 wit h 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

, t he 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 id entified 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 det ermined 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 s ubchronic 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 r ats, 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 10 0, 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 potent ial 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 reta rded 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 hepatocellul ar 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/d ay 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 tissu e 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

- 2 188

- 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 no t mutagenic or acutely toxic and is therefore not of toxicological concern . However, as S

- 2188

- DC was found at levelsexceeding 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 le vels 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 par ent 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 endocri ne 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 st udies 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 vari ous 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 to xicity 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 v ersion 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 foo d 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 belo w 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 “ot her 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 ass essment. 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 safet y, 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 postna tal 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 inf ants 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 Fenpyra zamine 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 t o Fenpyrazamine from the proposed

uses.F. International Tolerances

There are no CODEX tolerances for residues of fenpyrazamine.