Document ID: EPA-HQ-OPP-2010-0349-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-10-27T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division Contact: Tony Kish (703) 308-9443

 

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.

TEMPLATE:

[MITSUI CHEMICALS AGRO, INC.]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from
MITSUI CHEMICALS AGRO, INC. c/o Landis International, Inc., P. O. Box
5126 Valdosta, GA  31603-5126 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  tolerances for residues of
Penthiopyrad,
(RS)-N-[2-(1,3-dimethylbutyl)-3-thienyl]-1-methyl-3-(trifluoromethyl)-py
razole-4-carboxamide in or on the raw agricultural commodities fruit,
pome, group 11 at 0.4 parts per million (ppm); apple, wet pomace at 1.0
ppm; fruit, stone, group 12 at 3.0 ppm; low growing berry, subgroup
13-07G at 3.0 ppm; vegetable, bulb, group 3 at 4.0 ppm; vegetable,
brassica leafy, group 5 TBD; vegetable, fruiting, group 8 at 2.5 ppm;
tomato, paste at 5.0 ppm; vegetable, cucurbit, group 9 at 1.0 ppm;
vegetable, leafy, except brassica, group 4 at 20 ppm; vegetable, root
and tuber, group 1 TBD; potato at 0.06 ppm; vegetable, legume, group 6
TBD; pea and bean, dried shelled, except soybean, subgroup 6C at 0.2
ppm; peanut at 0.04 ppm; grain, cereal, group 15 TBD; barley at 0.2 ppm
(for import); wheat at 0.1 ppm (for import); nut, tree, group 14 at 0.05
ppm; almond, hulls at 6.0 ppm; canola at 0.6 ppm; sunflower at 0.03 ppm
(for import); cotton TBD; pea, field, hay at 45 ppm; pea, field, vines
at 30 ppm; peanut, hay at 30 ppm; grain, cereal, forage, fodder and
straw, group 16 TBD, alfalfa TBD,  and establishing tolerances for
residues of Penthiopyrad,
(RS)-N-[2-(1,3-dimethylbutyl)-3-thienyl]-1-methyl-3-(trifluoromethyl)-py
razole-4-carboxamide and its major metabolite PAM
(1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide) in animal
commodities  hog, meat at 0.01 ppm; hog, fat at 0.01 ppm; hog, liver at
0.01 ppm; hog, kidney at 0.01 ppm; hog, meat byproducts at 0.01 ppm;
cattle, meat at 0.01; cattle, fat at 0.02 ppm; cattle, liver at 0.05
ppm; cattle, kidney at 0.02 ppm; cattle, meat byproducts at 0.05 ppm;
sheep, meat at 0.01 ppm; sheep, fat at 0.02 ppm; sheep, liver at 0.05
ppm; sheep, kidney at 0.02 ppm; sheep, meat byproducts at 0.05 ppm; milk
at 0.01 ppm; milk, fat at 0.01 ppm; poultry, meat at 0.01 ppm; poultry,
fat at 0.01 ppm; poultry, liver at 0.01 ppm; poultry, meat byproducts at
0.01 ppm; poultry, eggs at 0.01 ppm. [TBD: to be determined in June 2010
submission]. 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.

Residue Chemistry

1. Plant Metabolism. The metabolic fate of penthiopyrad in plants is
adequately understood.  The metabolism of penthiopyrad was studied in
five crops using penthiopyrad labeled with carbon 14 in both rings.  The
following metabolic processes were observed in all studies: 

1.	Hydroxylation of the alkyl side chain leading to 753-A-OH and its
isomers. Conjugates of these metabolites were observed in all crops at
higher amounts than the free metabolites.

2.	Oxidation of the thienyl ring leading to 753-T-DO, which is further
oxidized to the lactone 753-F-DO.  Neither 753-T-DO nor 753-F-DO
persists in plant matrices.  

3.	Oxidative degradation of 753-F-DO leading to the cleavage of the
two-ring structure and the formation of PAM; PAM is then hydrolyzed to
form PCA.  

The major metabolism pathways are consistent in all five crops studied,
which represent fruiting vegetables, fruits, leafy crops, cereals and
oil seeds as well as the various commodity types: watery, acidic, dry
and oily.  In grape, tomato, cabbage and wheat the major residue in all
crop parts used for human food or animal fodder was penthiopyrad.  In
canola forage, while penthiopyrad was a major component of the residue,
the various conjugated metabolites were present at higher levels. In
canola seed, penthiopyrad was observed only at very low level. The main
cleavage products identified in all crops were PAM and PCA. 

Penthiopyrad was the major residue in most matrices, followed by PAM and
PCA. Lower amounts of 753-F-DO were found in leaves. Conjugates of
753-A-OH were significant residues in many crop matrices especially in
canola forage. 

2. Analytical method. Adequate enforcement methods are available to
enforce the proposed tolerances.  Samples of plant matrices from field
residue trials were analyzed for penthiopyrad and its metabolites using
a validated residue method, which involves the extraction of analytes
from crops, hydrolysis of conjugates, partition of analytes, followed by
LC-MS/MS detection.  The limit of quantification (LOQ) is 0.01 mg/kg
for most matrices except for very dry matrices, e.g., pea hay, for which
the LOQ is 0.05 mg/kg.  

An LC-MS/MS residue method has been used in the animal feeding studies
and is proposed for enforcement purposes.  The method involves the
extraction of analytes from animal matrices and LC-MS/MS detection. 
This method has been validated for the determination of penthiopyrad and
its metabolites in chicken tissues, eggs, ruminant tissues and milk. 
The limit of quantification is 0.01 mg/kg for all animal matrix groups.
 

3. Magnitude of residues. Penthiopyrad and its plant metabolites PCA,
PAM, 753-A-OH, and 753-F-DO, were quantified in the field residue trials
along with DM-PCA, the major soil metabolite.  Penthiopyrad (parent) was
found to be the major component of the residue in raw agricultural crop
matrices following post-emergence applications of penthiopyrad.
High-temperature hydrolysis data showed that penthiopyrad is stable
under various processing conditions.

The field trials data for representative processed food commodities of
apples, tomatoes, potatoes, plums, cereals, and oilseeds indicate that
metabolite residues were detected in only a few end-processed
commodities and were always significantly lower than the parent.
Therefore exposure to the metabolites relative to exposure to parent
penthiopyrad from raw and processed commodities will be low.  

DM-PCA, the major soil metabolite, is the predominant component of the
residue in raw agricultural crop matrices in succeeding crops; however,
DM-PCA has been shown to be not toxicologically significant and minimal
exposure is expected through the diet. 

The main residue in the crops with significance for human dietary
exposure is penthiopyrad (parent).  For commodities where there are
higher relative metabolite residues, the total magnitude of residues is
quite low and does not significantly contribute to human exposure.  

A harmonized residue definition for food of crop origin for
monitoring/enforcement and risk assessment is therefore proposed as
penthiopyrad.

Crop Rotation Study

Penthiopyrad residues in succeeding crops grown under realistic field
conditions are very low with less than 0.010 mg/kg in leafy vegetables,
cereal grains and wheat forages/grains for all plant back intervals and
less than 0.10 mg/kg in vegetable root crops. No residues greater than
0.01 mg/kg are anticipated in any edible tissues, milk, or egg products
following consumption by livestock of rotational crop commodities. 

Cow and Hen Feeding Studies

The metabolic fate of penthiopyrad in livestock is adequately
understood.  Penthiopyrad is extensively metabolized in and excreted
from livestock and residues do not accumulate in milk, egg or tissues.
PAM was the major component of the residue in meat, milk and eggs. 
Total radioactive residues were very low in fat, where penthiopyrad was
present at higher levels than PAM or the other identified metabolites. 
Along with low levels of penthiopyrad, PAM, PCA, and 753-A-OH, numerous
low level metabolites were observed in hen and goat liver and goat
kidney. These were identified mainly as cysteine conjugates of 753-F-DO
and 753-T-DO and their hydroxylated analogues. 

Residues of penthiopyrad and its metabolites PAM, PCA and 753-A-OH were
measured in the cow and hen feeding studies. Residues were very low and
were generally less than LOQ (0.01 mg/kg). Penthiopyrad was the
predominant component in fat and PAM was predominant in liver, kidney,
meat, milk and eggs.   

Therefore, the proposed definition of the residue for risk assessment
and monitoring for food of animal origin is penthiopyrad plus PAM.   

B. Toxicological Profile

1.  Acute Toxicity. Penthiopyrad was found to be of a low order of acute
toxicity following exposure via oral (gavage), dermal and inhalation
routes of administration, non-irritating to the skin and to the eye and
not sensitizing. 

Acute Toxicology Study Results - Penthiopyrad, Proposed EPA Tox
Categories

Acute Oral - III

Acute Dermal - III

Acute Inhalation - IV

Acute Eye Irritation - IV

Acute Dermal Irritation - IV

Dermal Sensitization - Not a sensitizer (MKMM)

Overall Category - III

2.  Genotoxicity. Penthiopyrad has been evaluated in a comprehensive
battery of 6 genotoxicity assays comprising in vitro bacterial and
mammalian gene mutation, in vitro mammalian cytogenetics, DNA repair and
UDS assays and in vivo clastogenicity.  The in vitro assays were
performed with and without exogenous metabolic activation.  All assays
were OPPTS and/or OECD and Japan MAFF guideline studies and all were
considered to be valid assays based on sensitivity to known positive
control substances.  The results of these studies indicate that
penthiopyrad has no genotoxic potential at relevant doses in these
assays at the DNA, gene and chromosome levels of genetic organization.

3.  Reproductive and developmental toxicity. Guideline pre-natal
developmental oral (gavage) toxicity studies in rats and rabbits and a
dietary 2-generation reproductive toxicity study have been performed on
penthiopyrad. 

Penthiopyrad did not produce any effects in the rat on prenatal fetal
growth and development at maternal dose levels up to 1000 mg/kg/day.  At
that dose level there was a minimal and transient reduction in maternal
weight gain.  Litter effects at this dose level were confined to an
increase in the number of early resorptions, leading to slightly reduced
gravid uterus weight, litter weight and litter number.  There were no
adverse maternal or embryo-fetal effects at the 250 mg/kg/day dose
level.  Therefore, maternal and embryo-fetal NOAEL values were
established as 250 mg/kg/day.

In the rabbit developmental toxicity study, a maternal high dose level
of 225 mg/kg/day produced one abortion, which was considered to be
treatment-related.  At 225 mg/kg/day fetal weight was slightly reduced
but there were no effects on fetal growth and development.  Therefore,
maternal and embryo-fetal NOAEL values were established as 75 mg/kg/day.
 This NOAEL, with an adjustment factor of 100, is proposed as the basis
for an Acute Reference Dose (aRfD) of 0.75 mg/kg.

Penthiopyrad is not a reproductive toxin in the rat 2-generation study
at any parental dose level, the highest of which elicited slightly
reduced weight gain prior to mating in the F1 parental animals, and in
intermediate dose F1 males.  No functional reproductive and fertility
effects or histopathological alterations in the reproductive organs
occurred at the highest dose level employed.  Therefore, the NOAEL for
reproductive effects was established as > 278 mg/kg/day (highest dose
tested - HDT) for both sexes.  In the parental and F1 generation,
increased liver, thyroid and adrenal weights were evident at the HDT. 
Increased relative liver weight also occurred in females of both
generations at 54.0 - 95.6 mg/kg/day.  These effects and the effect on
F1 male pre-mating weight gain resulted in a parental NOAEL value of
11.0 mg/kg/day.  Reduced pre-weaning weight gain occurred only at the
HDT in both sexes and in both the F1 and F2 generations.  The NOAEL for
offspring effects was established as 54.0 mg/kg/day.

These data indicate that penthiopyrad is not a morphological
developmental toxin in rats and rabbits, is not a reproductive toxin in
rats, and does not produce enhanced sensitivity to penthiopyrad on
embryo-fetal and/or neonatal exposure.

4.  Subchronic toxicity. 28-day dietary dose range finding studies were
conducted in the rat, mouse and dog to establish appropriate dose levels
to be used in the 90-day studies. 90-day dietary studies were conducted
in the same 3 species, as well as a 52-week feeding study in dog and a
28-day dermal study in rat.

The liver was a common target organ in all 3 species in the 28-day and
13-week studies.  The thyroid gland in mice and dogs, and the adrenal
gland in dogs, were also target organs after 13 weeks treatment. 
Hematological perturbations also occurred at high dose levels in all
three species after 28 and/or 90 days treatment and in the dog after 52
weeks.  However, the changes
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Male rats treated at dose levels ≥100 mg/kg/day showed significantly
reduced motor activity during a quantitative assessment.  However, there
were no effects at dose levels up to 625 mg/kg/day on a battery of
functional observations performed towards the end of the 13-week
treatment period.

The lowest relevant NOAEL determined in the short-term toxicity
evaluation was 40 mg/kg/day, established in the male rat and based on
histomorphological alterations in the liver and reduced motor activity
at 100 mg/kg/day.  

Although there were other, lower NOEL values in the 28-day studies in
the rat and mouse because these effects were not adverse, were
transient, or occurred in only one animal of each sex, none of these
were considered an appropriate basis for short-term risk assessment.  

In the 28-day dermal study, a no observed adverse effect level (NOAEL)
was established as 1000 mg/kg/day, based on the absence of adverse
findings at the highest dose level evaluated. 

5.  Chronic toxicity.  Three guideline long-term toxicity studies have
been performed on penthiopyrad: a rat 52-week dietary toxicity study,
and 104-week and 78-week oncogenicity studies in the rat and the mouse,
respectively.  In addition, three non-guideline studies were performed
to investigate the thyroid follicular cell proliferation potential of
penthiopyrad in rats and hepatic enzyme induction potential in rats and
mice.  The investigative studies were designed to provide evidence to
support the contention that excess incidences of thyroid adenoma in male
rats and hepatic adenomas in male mice had non-genotoxic etiologies
based on threshold mechanisms of action. 

In the rat 52-week study, the liver, adrenal, thyroid gland and ovary
were identified as target organs.  Increased prothrombin time at 400
mg/kg/day and increased plasma enzyme activities and lipid
concentrations at 100 or 400 mg/kg/day were suggestive of hepatic
dysfunction.  These effects occurred in the presence of increased liver
weight and hepatocyte hypertrophy in both sexes, and periportal fat
vacuolation, cell swelling and single cell necrosis in male rats only. 
Adrenal cortical lipid vacuolation and hypertrophy of the zona
glomerulosa, diffuse follicular hypertrophy in the thyroid and ovarian
interstitial cell hypertrophy were also apparent.  

In addition to liver, adrenal, thyroid and ovary effects identified in
13- and/or 52-week studies, further non-neoplastic effects seen in the
rat 104-week study comprised increased incidences of alveolar
macrophages and interstitial inflammation in the lungs of females and
chronic progressive nephropathy in males.

The numbers of rats with neoplasms, the multiplicity of tumors and the
latency period for tumor formation did not distinguish treated animals
from the controls.  There were no excess incidences of neoplasia in any
tissue, with the exception of the male thyroid in which the incidence of
follicular adenoma was slightly, but significantly, increased in males
at the highest dose level, 250 mg/kg/day, surviving to termination.  The
incidence of follicular carcinoma was unaffected by treatment.  The
increased incidence of follicular adenoma is considered to be an effect
of treatment, but a secondary effect to prolonged metabolic adaptation
et seq.  Therefore, penthiopyrad is considered not to be a primary
carcinogen in the rat at dose levels up to 250 mg/kg/day.

In the 78-week mouse carcinogenicity study, lung was identified as a
target organ for non-neoplastic alterations in which an increased
incidence of alveolar foamy cells occurred at the highest dose level
only (600 mg/kg/day).  The thyroid follicular epithelial hypertrophy
noted after 13 weeks of treatment was accompanied by further changes
comprising altered colloid and lipofuscin deposits.  Marked hepatomegaly
at dose levels of 200 or 600 mg/kg/day was accompanied by increased
incidences of hepatocellular adenoma, and adenoma plus carcinoma in male
mice surviving to termination.  Although the incidences remained within
the laboratory historical control ranges, the changes are considered,
conservatively, to be treatment-related but secondary to marked and
prolonged hepatomegaly.

Two mechanistic studies were performed in the rat to investigate the
effects of penthiopyrad on hepatic drug metabolizing enzymes and cell
proliferation.  Based on the results of the first study, it was
concluded that penthiopyrad is likely to be a phenobarbital-type enzyme
inducer.  At 1000 ppm, penthiopyrad produced effects similar to, but
milder than, those seen with phenobarbital, including enhanced hepatic
cell proliferation during the early stages of treatment and increased
hepatic microsomal cytochrome P450 isozymes, POD and UDPGT activities. 
There were no effects of treatment on any parameter at 100 ppm. 
Therefore, an NOEL for enzyme induction was established as 100 ppm
(equivalent to a dose level of 6.47 mg/kg/day penthiopyrad).

In the second study in the rat, penthiopyrad at dietary concentrations
of 4000 and/or 16000 ppm elicited a similar pattern of effects that were
fully reversible on withdrawal of treatment for 28 days.  Based on these
results it was postulated that penthiopyrad is a phenoparbital-type
enzyme inducer which results in an increase in circulating TSH through
negative feedback leading to thyroid follicular cell hypertrophy. 
Furthermore, prolonged follicular cell hypertrophy under the influence
of increased TSH is considered to be a rational, non-genotoxic basis for
the development of a slightly increased number of thyroid adenomas in
the 104-week study.  In addition, it is concluded that the effects of
penthiopyrad on thyroid function, and thus on neoplasia in the long-term
study, have a threshold below which thyroid neoplasia will not occur.  A
clear NOAEL for the postulated mechanism was established as 400 ppm,
equivalent to a dose level of 37.5 mg/kg/day penthiopyrad.

A mechanistic study was performed in the mouse to investigate the
effects of penthiopyrad on hepatic drug metabolizing enzymes and cell
proliferation in order to support a putative mechanism for the low
incidence of hepatocellular adenoma in this species.  The effects of
penthiopyrad were compared with the effects of an established hepatic
enzyme-inducer, phenobarbital.  Phenobarbital administration produced a
pattern of effects comprising increases in liver weight, microsomal
protein and P450 content, microsomal ECOD and PROD activities, hepatic
P450 Cyp1A, 2B and 3A isozyme content and hepatic BrdU labeling index,
associated with histological evidence of centrilobular hepatic
hypertrophy.  A similar pattern of effects occurred in response to 600
mg/kg/day penthiopyrad and at 200 mg/kg/day penthiopyrad, but to a
lesser extent. Long-term administration of penthiopyrad to mice produced
a very marked increase in liver weight (> 150%) at dose levels of 200 or
600 mg/kg/day, but had no effect on liver weight at dose levels
≤ 60 mg/kg/day.

The lowest NOAEL in these long-term toxicity and carcinogenicity studies
was 25 mg/kg/day (LOEL 100 mg/kg/day) established in the 52-week rat
study.  However, the NOAEL of 27 mg/kg/day, established in the 104-week
rat study, based on a LOAEL of 83 mg/kg/day, is proposed for use in
long-term risk assessments since dose spacing in this study provided a
more accurate NOAEL. This NOAEL, with an adjustment factor of 100, is
proposed as the basis for a chronic RfD of 0.27 mg/kg bw/day.

6.  Animal metabolism.  The pathways of metabolism in the rat, ruminant
and hen are consistent. Primary metabolism of penthiopyrad proceeds in
rat, ruminant and hen by three major pathways which proceed in parallel.

N-demethylation of the pyrazole ring to form DM-penthiopyrad which can
enter pathways 2 and or 3.   N-demethylation may also occur after
hydroxylation. 

Hydroxylation on one or more of several positions on the alkyl moiety to
form 753-A-OH analogs and dihydroxy compounds which can be further
oxidized to carboxylic acids or conjugated.  

Sequential oxidation of the thienyl ring of penthiopyrad to yield
753-T-DO and 753-F-DO and their hydroxy and desmethyl forms which are
degraded to PAM and DM-PAM either before or after conjugation with
glutathione. 

753-T-DO and 753-F-DO (and their hydroxylated and demethylated
derivatives) are conjugated with glutathione in rat, ruminant and hen. 
Subsequent catabolism to yield a complex range of cysteine conjugates
was observed in the rat, ruminant and hen.  In a supplementary study in
rat, additional intermediate metabolites were identified in bile (0-6
hours after administration).   These were notably the
cysteine-glutamate conjugates of 753-F-DO and to a lesser extent the
glycine-cysteine conjugates which are intermediates in the pathway
between the glutathione conjugates and the cysteine conjugates.
Acetylation of some of the cysteine conjugates was also observed in this
study.

Hydroxy-penthiopyrad and/or it’s demethyl analogs can be sequentially
oxidized on the thienyl ring or be transformed by glucuronidation of the
side chain hydroxyl group. Alternatively these hydroxyl groups can be
further oxidized to yield the carboxylic acids 753-A-COOH and
DM-753-A-COOH respectively.  These acids were major metabolites in rat
urine and feces. 

Following cleavage of the two ring structure, PAM is the most abundant
metabolite in rat, goat and hen together with DM-PAM and PCA (mainly in
rat and goat urine). Metabolites containing the thienyl moiety after
cleavage were not observed in any significant amounts.

7.  Metabolite toxicology. The metabolites DM-PCA, PCA, PAM, 753-A-OH
and 753-T-DO were evaluated for toxicity.

All acute oral LD50 estimates were > 2000 mg/kg, except for PAM which
was 300 - 2000 mg/kg. In a 13-week oral rat study, the NOAEL for DM-PCA
was 258 mg/kg/day based on reduced weight gain in males. In a 4-week
oral rat study the NOAEL for the metabolite PCA was 1000 mg/kg/day based
on no effects.

In Ames studies, in vitro chromosome aberrations and mouse lymphoma
assays on DM-PCA, 753-A-OH and 753-T-DO were all clearly negative.
Mammalian cell gene mutation assay (mouse lymphoma) for PCA was an
equivocal positive, but an in vivo mouse micronucleus test was clearly
negative. The in vitro chromosome aberration test and mouse lymphoma
assays for PAM were positive, but the in vivo mouse micronucleus test
was clearly negative.

On the basis of the toxicity studies and genotoxicity tests performed
with DM-PCA, PCA, PAM, 753-A-OH and 753-T-DO, it is concluded that these
metabolites are not of toxicological concern. 

8.  Endocrine disruption. Penthiopyrad does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system. There is no evidence that penthiopyrad has any effect on
endocrine function in developmental, reproduction or developmental
neurotoxicity studies.  Furthermore, histological investigation of
endocrine organs in chronic dog, rat and mouse studies did not indicate
that the endocrine system is targeted by penthiopyrad.

C. Aggregate Exposure

The following exposure analysis was completed for the US.

	1. Dietary exposure. It can be concluded with reasonable certainty that
residues of penthiopyrad in food will not result in unacceptable human
health risk since both the acute and chronic dietary exposure
assessments result in exposures that are well below the EPA level of
concern.

	i. Food. 

The chronic dietary exposure assessment was determined with the Dietary
Exposure Evaluation Model software with Food Commodity Intake Database
(DEEM-FCID(TM)), version 2.14, from Exponent, Inc.  This model
incorporates nationwide food consumption data as reported by respondents
in the U.S. Department of Agriculture (USDA) 1994-1996, 1998 Continuing
Surveys of Food Intake by Individuals (CSFII).  The chronic exposure
assessment used conservative residue values as generated from supervised
residue trials and adjustments for processing; no adjustment for percent
crop treated was made (100% crop treated was assumed).  Thus, the actual
chronic dietary exposure will be much less than that determined here.  

The chronic exposure to penthiopyrad for the overall U.S. population in
this very conservative analysis is less than 1% of the Chronic Reference
Dose (cRfD = ADI = 0.27 mg/kg bw/day).  The chronic exposure of the most
highly exposed subgroup, Children 1-2 years, is 1% of the cRfD.  There
are large margins of safety for all population groups.  

The acute dietary exposure assessment was determined with the Dietary
Exposure Evaluation Model software with Food Commodity Intake Database
(DEEM-FCID(TM)), version 2.14, from Exponent, Inc.  This model
incorporates nationwide food consumption data as reported by respondents
in the U.S. Department of Agriculture (USDA) 1994-1996, 1998 Continuing
Surveys of Food Intake by Individuals (CSFII).  The acute exposure
assessment used conservative residue values as generated from supervised
residue trials and adjustments for processing. No adjustment for percent
crop treated was made (100% crop treated was assumed).  Thus, the actual
acute dietary exposure will be much less than that determined here.  

The acute exposure to penthiopyrad at the 95th percentile, calculated in
a conservative deterministic assessment, for the overall
U.S. population is 2% of the aRfD (0.75 mg/kg bw/day).  The acute
exposure of the most highly exposed subgroup, Children 1-2 years, is 3%
of the aRfD.  There are large margins of safety for all population
groups.

	ii. Drinking water. 

To assess the aggregate dietary exposure to food and drinking water,
water residue values were included in the acute and chronic dietary
assessment described above for food only.  Worst-case concentrations of
penthiopyrad in groundwater were modeled using Screening Concentration
in Ground Water (SCI-GROW, v2), and worst-case surface water
concentrations were modeled using The Pesticide Root Zone Model (PRZM
v3.12.2) and Exposure Analysis Modeling System (EXAMS v2.98.04.06)
coupled with the input shell PE Version 5.0. The groundwater
concentrations for penthiopyrad are less than those in surface water.
The highest 1 in 10 year peak penthiopyrad concentration was 19.1 ppb in
surface water; the 1 in 10 year annual mean penthiopyrad value for
surface water was 1.15 ppb. When the higher surface water concentrations
were included in the acute and chronic dietary risk assessments, there
was little change from the food-only dietary risk assessments.  For the
acute assessment which included drinking water as a point estimate the
predicted exposure at the 95th percentile for the general U.S.
population was 0.013044 mg/kg/day which corresponds to 2% of the aRfD;
the most sensitive subpopulation, children 1-2 years, had an estimated
exposure of 0.026236 mg/kg/day, 4% of the aRfD.  For the chronic
assessment which included drinking water the predicted exposure for the
general population was 0.001340 mg/kg/day, <1% of the cRfD; the most
sensitive subpopulation, children 1-2 years, had an estimated exposure
of 0.003140 mg/kg/day, 1% of the cRfD.  Thus, the aggregate acute and
chronic dietary exposure of penthiopyrad, including the contribution of
drinking water, clearly meets the standard of reasonable certainty of no
harm.  

2. Non-dietary exposure.  Penthiopyrad product registrations for
residential turf uses have been submitted.  Residential exposure
(non-occupational, non-dietary exposure to consumers) was conservatively
assessed for dermal post-application exposure (children and adults), and
for children the oral exposures via hand-to-mouth, object-to-mouth, and
incidental ingestion of soil were also assessed.  The margins of
exposure (MOE) greatly exceed the 100-fold MOE required for these routes
and from the combined children’s incidental oral ingestion. 
Therefore, residential non-dietary exposure is not a concern.

D. Cumulative Effects

Penthiopyrad is classified as a succinate dehydrogenase inhibitor (SDHI)
fungicide (FRAC Group #7).  The mode of action of penthiopyrad is
different from that of most other fungicides presently on the market. 
There is no cross resistance to other non-carboxamide fungicides.  

E. Safety Determination

	1. U.S. population. The toxicity database for penthiopyrad is complete.
The chronic exposure to penthiopyrad for the overall U.S. population in
this very conservative analysis is less than 1% of the Chronic Reference
Dose (cRfD = ADI = 0.27 mg/kg bw/day).  The acute exposure to
penthiopyrad at the 95th percentile, calculated in a conservative
deterministic assessment, for the overall U.S. population is 2% of the
aRfD (0.75 mg/kg bw/day).  There are large margins of safety for all
population groups, thus there is reasonable certainty that no harm to
the U.S. population will result from the proposed uses of penthiopyrad.

	2. Infants and children. The toxicity database for penthiopyrad is
complete.  The database includes acute, subchronic, chronic,
mutagenicity, genotoxicity, developmental, reproduction, neurotoxicity
and immunotoxicity studies on penthiopyrad and acute mutagenicity and
genotoxicity studies on main metabolites.  The chronic exposure of the
most highly exposed subgroup, children 1-2 years, is 1% of the cRfD. 
The acute exposure of the most highly exposed subgroup, children 1-2
years, is 3% of the aRfD.  There are large margins of safety for all
population groups.

F. International Tolerances.

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=; tops of root and tuber vegetables at 0.01 ppm; legume vegetables at
0.01 ppm; roots of root and tuber vegetables at 0.01 ppm; legume
oilseeds at 0.01 ppm; cereal grains at 0.01 ppm; tree nuts at 0.01 ppm;
oilseed at 0.01 ppm; legume animal feeds at 0.01 ppm; straws, fodder and
forage of cereal grains and grasses at 0.01 ppm.  Global tolerances are
simultaneously being sought in the United States of America, Canada and
the European Union.  Codex tolerances have not yet been established but
penthiopyrad is in the process of being scheduled for review by JMPR.  

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