Document ID: EPA-HQ-OPP-2011-0357-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-06-29T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION 

EPA Registration Division contact: [Gene Benbow, 703-347-0235]   

Valent U.S.A. Company 

EPA has received a pesticide petition ([1F7841]) from Valent U.S.A.
Company, 1600 Riviera Ave., Walnut Creek, CA 94596-8025 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. 

1. by establishing a tolerance for residues of 

Fenpyrazamine in or on the raw agricultural commodity: Almond at 0.02
ppm; Almond hulls at 1.5 ppm; Small fruit vine climbing (except fuzzy
kiwifruit) subgroup 13-07F at 3.5 parts per million (ppm); Raisin at 4.5
ppm; grape juice at 7.0 ppm; lettuce, head at 2.5 ppm; lettuce, leaf
lettuce at 2.5 ppm; and Low growing berry subgroup 13-07G at 3.0 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 supports 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 S2188-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 S2188-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 V10135 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.   

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. 

 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 tenfold, 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.